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General asymmetric synthesis of 2,2,2-trifluoro-1-(1H-indol-3- and -2-yl)ethanamines
Accepted Manuscript Title: General asymmetric synthesis of 2,2,2-trifluoro-1-(1H-indol-3- and -2-yl)ethanamines Author: Lingmin Wu Chen Xie Jie Zhou Haibo Mei Vadim A. Soloshonok Jianlin Han Yi Pan PII: DOI: Reference:
S0022-1139(15)00003-2 http://dx.doi.org/doi:10.1016/j.jfluchem.2015.01.001 FLUOR 8487
To appear in:
FLUOR
Received date: Revised date: Accepted date:
17-11-2014 28-12-2014 2-1-2015
Please cite this article as: L. Wu, C. Xie, J. Zhou, H. Mei, V.A. Soloshonok, J. Han, Y. Pan, General asymmetric synthesis of 2,2,2-trifluoro-1-(1Hindol-3- and -2-yl)ethanamines, Journal of Fluorine Chemistry (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
General asymmetric synthesis of 2,2,2-trifluoro-1-(1H-indol-3- and -2-yl)ethanamines
ip t
Lingmin Wua, Chen Xiea, Jie Zhoua, Haibo Meia, Vadim A. Soloshonokc,d, Jianlin
School of Chemistry and Chemical Engineering, State Key laboratory of Coordination
us
a
cr
Hana,b,*, Yi Pana
Chemistry, Nanjing University, Nanjing, 210093, China. Fax: 86-25-83686133; Tel:
an
86-25-83686133; E-mail: [email protected].
Institute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing, 210093, China.
c
Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country
UPV/EHU, 20018 San Sebastian, Spain.
IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
d
d
M
b
Ac ce p
compounds; indole
te
Key words: CF3-imine; Friedel-Crafts reaction; Mannich reaction; trifluoromethyl-amino
ABSTRACT
This work describes an asymmetric functionalization of the pyrrole ring of an indole structure with (2,2,2-trifluoro)ethylamine moiety allowing for general access to two novel classes of trifluoromethyl-containing indoles. We found that under the Friedel-Crafts reaction conditions (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine (1) easily reacts with indole derivatives
affording the target 3-substituted products, while LDA-promoted reactions proceed exclusively at the 2-position. We demonstrate that both approaches feature wide substrate scope, high chemical yields and diastereoselectivities, which render these reactions readily applicable for straightforward preparation of biologically interesting compounds containing chiral CF3–CH(NH2)- and indole
groups. The mechanistic rationales accounting for the observed mode of stereochemical preferences are proposed. 1
Page 1 of 27
1. Introduction Heterocyclic structure of naturally occurring indole molecules is one of the most prolific motifs found in pharmaceutical products [1]. On the other hand, fluorine-containing organic
ip t
compounds are almost manmade as only a handful of highly toxic fluoroacetic acid and several ω-monofluoro-fatty acids have been isolated from natural sources [2]. Remarkably, the modern
cr
drug discovery relies heavily on the functionalization of bioactive compounds with various fluorine containing substituents [3]. In particular, incorporation of trifluoromethyl (CF3) group
us
into drug candidates leads to several beneficial properties, such as enhanced efficacy, increased metabolic stability and improved cellular membrane permeability [4]. Accordingly, synthesis of
an
fluorine-containing indole derivatives has been attracting much attention in medicinal chemistry research [4,5]. The established pharmacophores possess various types of aromatic as well as
M
aliphatic CF3-substitution [6]. 2,2,2-Trifluoro-1-(amino)ethyl [CF3–CH(NH2)-] moiety [7] is well recognized group of pharmaceutical potential featuring prominently in the new drug Odanacatib
d
[8], which has beendeveloped for treatment for osteoporosis and bone metastasis. Consistent with our interest in preparation of fluorine-containing derivatives of natural [9],
we
have
te
compounds
been
studying
(R)-
and
Ac ce p
(S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines 1 (Figure 1) as general reagents for convenient installation of 2,2,2-trifluoro-1-(amino)ethyl [CF3–CH(NH2)-] group into biologically
relevant organic compounds [10-13]. Considering biological potential of indole structure, we were motivated to explore preparation of CF3–CH(NH2)-containing derivatives using chemistry of sulfinyl-imines 1. Recently, we reported the first example of Friedel–Crafts reactions of imine (S)-1 with N-protected indole, resulting in the formation of derivatives bearing the fluorinated
substituents in the position 3 [14]. However, the Friedel-Crafts reaction of imine (S)-1 with N-unprotected indole has never been reported. Furthermore, the reactions between indoles and imine (S)-1, taking place in the position-2 of indole ring, also still remains unexplored. Therefore, we were quite exciting to explore the direct approaches to the selective formation of 2- and 3-substituted fluorinated derivatives of types 3 and 2 through the addition reactions with the chiral
imine 1. Herein we report the functionalization of indole skeleton with imines 1 allowing general 2
Page 2 of 27
access to derivatives 2 and 3 (Figure 1) bearing substituents on both six- and five-membered rings. Compounds of types 2 and 3 are novel and both of them can be prepared in enantiomerically pure
R1
N
F3C
N
O S
R1
NH2 N
(S)-1
CF3
(R)-1
R2
R
CF3
N R
NH2
3-(S) or (R)
us
2-(S) or (R)
R2
cr
F3C
O S
ip t
form in relatively large scale for comprehensive biological studies.
an
Fig. 1. Chiral reagents 1 and target structural types of indole derivatives 2 and 3.
2. Results and discussion
M
We began the present study with the reactions of unprotected indole 4 and imine 1 (Table 1), expecting this case to be the most interesting due to the potential reactivity of the NH function in molecule 4. Indeed, Friedel–Crafts reactions of imine (S)-1 with indole 4 turned out to be intricate
d
resulting in rather complex mixtures. After an extensive experimental investigation using various
te
Lewis acid catalysts, we have successfully found the most favorable conditions. First of all, relatively high reactivity of imine (S)-1 should be noted since most of the Lewis
Ac ce p
acids used in this study were found to catalyze the reactions and CH2Cl2 was identified as an
optimal solvent. Furthermore, application of 20 mol % of AlCl3, In(OTf)3 and La(OTf)3 (entries 1-3) gave excellent diastereoselectivity. However, the reactions were accompanied by formation of various by-products resulting in low isolated yields of target product 5. In sharp contrast, the
use of Cu(OTf)2 as a catalyst (entry 4), gave markedly improved yield but relatively low stereoselectivity. Among other interesting results, we should mention the application of AgBF4 (entry 5) which gave low yield and the lowest diastereoselectivity in this study. Eventually, we found that the use of BF3·Et2O provides reliable and reproducible results containing synthetically useful level of the stereochemical outcome. In this case optimal reaction rates were obtained using stoichiometric amount (100 mol %) of BF3·Et2O. At ambient temperature (entry 6) and 0 oC (entry 7) the reactions showed low diastereoselectivity along with a sizable formation of by-products. In contrast, the additions conducted at -78 oC gave the product 5 with good chemical yield and 3
Page 3 of 27
excellent stereoselectivity (entry 8).
N H 4
N
CF3 O S N H
Catalyst CH2Cl2
N H (S)(S)-5 + (S)(R)-5
(S)-1
Catalyst (mol%)
Temp. (oC)
Time (h)
Yield (%)b
1
AlCl3 (20)
rt
10
10
2
In(OTf)3 (20)
rt
10
3
La(OTf)3 (20)
rt
10
4
Cu(OTf)2 (20)
rt
5
AgBF4 (20)
rt
6
BF3·Et2O (100)
rt
7
BF3·Et2O (100)
8
BF3·Et2O (100)
Dr c
us
cr
Entry
99:1
99:1
20
99:1
10
85
80:20
10
17
55:45
10
29
77:23
0
18
36
77:23
-78-rt
10
78
99:1
d
M
an
55
Reaction conditions: sulfinylimine 1 (1 mmol), indole 4 (1.2 mmol), catalyst, 5 mL CH2Cl2.
b
te
a
+ F3C
O S
ip t
Table 1 Optimization of the reaction conditions for the reaction of indole 4 with imine (S)-1.a
Isolated yields of major diastereomers. c The diastereomeric ratio was determined by 19F-NMR of
Ac ce p
the crude reaction mixtures.
As the next step of this study, we decided to investigate the generality of this reaction for
preparation of various indoles bearing substituents on both aromatic rings of the parent indole structure. Results of Friedel–Crafts reactions of imine (S)-1 with indoles 6 are presented in Table 2. Reaction of 2-methyl substituted derivative 6a (entry 1) with imine (S)-1 occurred at normal
reaction rate affording the target product 7a with excellent diastereoselectivity and in high chemical yield. Substitution in the position-4 on the indole phenyl ring, compound 6b (entry 2), did not affect on the stereoselectivity (99:1), albeit the product 7b was isolated in a little bit lower yield. In contrast, the presence of the Br atom in the position-5 (entry 3) had a negative effect on the observed diastereoselectivity resulting in a 85:15 mixture of the diastereomeric products. Nevertheless, the major diastereomerically pure product 7 was isolated in 62% yield. In a series of 4
Page 4 of 27
other 5-substitued indoles reactions (entries 4-6) excellent level of stereocontrol was obtained for derivatives 6d,f, bearing in the position-5 nitro (entry 4) and methoxy-carbonyl groups (entry 6). All these reactions gave essentially single diastereomeric products 7d,f. On the other hand, 5-methoxy (entry 5) containing indole 6e gave the diastereoselectivity similar to that of
ip t
5-bromo-derivative 6c. Most likely, such a noticeable difference in diastereoselecitivity can be
explained by the steric properties of the substituents. Thus, while the steric bulk of each nitro and
cr
methoxy-carbonyl groups is larger than that of a bromine atom or a methoxy group, they can
minimize steric interactions due to their flat, planar structure, generating less destabilizing effect
us
on the corresponding transition states. Interestingly, the position-6 on the indole phenyl ring was also found to be sensitive to the substitution. As shown in entry 7, 6-Cl substituted indole 6g
an
reacted with imine (S)-1 in a less stereoselective manner affording a 90:10 mixture of the diastereomeric products. By this reaction, the major diastereomer 7g was prepared in pure form in
M
65% yield. Finally, we studied an example of di-substituted substrate 6h, which reacted smoothly with imine (S)-1 affording the target product 7h as a single diastereomer isolated in 65% yield
d
(entry 8).
R
te
Table 2 Substrate generality of the reactions of indoles 6 with imine (S)-1.a O S
Ac ce p
R
N H
6
+ F3C
N
BF3EtO2 (100 mol %)
R
CH2Cl2, 10 h -78 oC-rt
(S)-1
R
CF3 O S N H
N H (S)(S)-7 + (S)(R)-7
Entry
R
Product
Yield (%)b
Dr c
1
2-CH3
7a
87
99:1
2
4-Cl
7b
60
99:1
3
5-Br
7c
62
85:15
4
5-NO2
7d
90
99:1
5
5-MeO
7e
68
87:13
6
5-COOMe
7f
78
99:1
7
6-Cl
7g
65
90:10
5
Page 5 of 27
8 a
2-Me-5-MeO
65
7h
99:1
Reaction conditions: sulfinylimine 1 (1 mmol), indole 6 (1.2 mmol), BF3·Et2O (100 mol %), 5
mL CH2Cl2, reaction time 10 hrs.
b
Isolated yields of major diastereomers. c The diastereomeric
ip t
ratio was determined by 19F-NMR of the crude reaction mixtures.
The next goal of this Friedel–Crafts reactions was focused on determining the absolute
cr
configuration of the corresponding products and elucidating the mechanism. Taking advantage of high crystallinity of 2-methyl substituted derivative 7a (Table 2), we conducted its
us
crystallographic study to determine the absolute stereochemistry of the newly created stereogenic centre. As presented in Figures 2, compound 7a has (Ss)(S) stereochemistry suggesting common
an
mechanism of the asymmetric induction. Absolute configuration of other products 5 (Table 1) and 7a-h (Table 2) was assigned accordingly as (Ss)(S) based on close similarity between their spectral
Ac ce p
te
d
M
and chiroptical properties.
Fig. 2. Crystallographic structure of compound (S)(S)-7a.
Based on these results, a plausible mechanistic rationale for the observed stereochemical outcome was proposed. As presented in Figure 3, three possible transition states (TSs) A, B and C can be considered to account for the formation of the (S)(S)-configured Friedel–Crafts products. Careful examination of TSs A-C might lead to a conclusion that only TS A can fully account for all observed effects between the reactivity and substitution on the starting indoles. First of all, in 6
Page 6 of 27
the TS A the Lewis acid catalyst is in position to coordinate both the indole and imine nitrogens via sterically favourable six-membered arrangement (A’). TS A can easily account for the unexpected effect of the substitution in positions 5 and 6 of the indole phenyl ring. As it follows from the results obtained(Table 2, entries 3 and 7), the presence of a bulky substituent in these
CF3 H BF3
N
BF3
CF3
CF3
N
S
N
H
O
BF3
A'
B
BF3
S O
H
an
O A
S
N
H N
us
N
CF3 H N
cr
H
N
H
ip t
positions resulted in noticeable worsening of the normally excellent diastereoselectivity.
C
M
Fig. 3. Plausible transition states in the Friedel–Crafts reactions under study.
d
Finally, we decided to perform the deprotection of the obtained products, to prepare free
te
CF3-containing amines. Deprotection of a sulfinyl group is well established procedure [15]. However, considering that compound 5 contains free N-H function , we felt that preparing the
Ac ce p
corresponding free amino derivatives would be highly desirable. To this end, we conducted the deprotection (Scheme 1) of unsubstituted NH sulfinyl-amine 5 using standard acidic hydrolytic conditions. The procedure was accomplished without any complications and the free amino compound (S)-8 was isolated in 90% yield.
N H
CF3 O S N H
(S)(S)-5
CF3 NH2
1) ag HCl, MeOH, rt, 4h 2) Et3N, CH2Cl2, rt, 1h
N H (S)-8 90% yield
Scheme 1. Deprotection procedure for preparation of free amine (S)-8.
The second major objective of this study was the development of approach for preparing 7
Page 7 of 27
functionalized indoles of type 3 (Figure 1) bearing pharmacophoric (2,2,2-trifluoro)ethylamine moiety in the position-2 of the pyrrole ring. This structural type 3 can be assembled by the corresponding addition reactions between 2-lithiated indoles and (S)-N-sulfinyl imine 1. From our own experience in the reactions of lithiated aromatics and hetero-aromatics with imines (S)- and
ip t
(R)-1 [12] we have learned that proper protection of additional functional groups in the starting compounds is of paramount importance. Therefore, based on our own practice and drawing from
cr
the results reported by Chen group [16] we selected N-phenylsulfonylindoles 9 (Table 3) as the starting substrates to study the addition reactions with imine (S)-1.
us
Our first choice of a base, LiHMDS (entry 1), gave rather disappointing result as a complex mixture of products was formed, including decomposition of the staring imine (S)-1. On the other
an
hand, application of less bulker n-BuLi as a base, furnished the desired product 10 in good chemical yield and excellent diastereoselectivity (entry 2). Further experimentations allowed us to
M
identify LDA as the lithiating reagent providing noticeably improved yield and the diastereoselectivity. As shown in entry 3, the reaction of indole 9 with imine (S)-1 gave rise to
d
product 10 which was isolated in 85% yield as virtually pure diastereomer. Further optimization by changing the reaction solvent (entries 4 and 5) or temperature (entries 6 and 7) did not give the
Ac ce p
te
desired improvement.
Table 3 Optimization of the reaction conditions of indole 9 with imine (S)-1.a
+ F3C N SO2Ph
9
N
O S
Base, 2 h
N
CF3 O S N H SO2Ph
Solvent
(S)-1
(S)(S)-10 + (S)(R)-10
Entry
Base
Solvent
Temp. (oC)
Yield (%)b
Dr c
1
LiHMDS
THF
-78
mixture
---
2
n-BuLi
THF
-78
70
98:2
3
LDA
THF
-78
85
99:1
4
LDA
Toluene
-78
57
98:2
5
LDA
CH2Cl2
-78
0
---
8
Page 8 of 27
a
6
LDA
THF
-40
42
99:1
7
LDA
THF
rt
40
90:10
Reaction conditions: sulfinylimine 1 (1 mmol), indole 9 (1.25 mmol), base (1.5 mmol). b Isolated
yields of major diastereomers. c The diastereomeric ratio was determined by 19F-NMR using crude
ip t
reaction mixtures.
cr
Under the standard reaction conditions, we investigated series of substituted indoles 11 (Table 4) bearing various groups in all possible positions of an indole frame. First, we tried
us
substrate 11a bearing a methyl group on the pyrrole ring. The reaction of imine (S)-1 with lithiated indole 11a (entry 1) proceeded quite smoothly to give 12a with a bit lower diastereoselectivity, as
an
compared with that observed in the reaction of unsubstituted indole 9 (Table 3, entry 3 vs. Table 4, entry 1). Moving a substituent to the position-4 on the indole phenyl ring, compounds 11b,c
M
(entries 2 and 3), resulted in noticeable increase of both chemical yield and diastereoselectivity. For example, the reaction of 4-Cl indole 11b furnished product 12b (entry 2) in rather good 90%
d
yield and 98:2 ratio of diastereomers. Even better results were observed in the reaction of 4-CN derivative 11c affording 12c as virtually single product in 93% yield (entry 3). The same excellent
te
diastereoselectivity was recorded in the reactions of 5-substitued indoles 11d-f (entries 4-6). Thus,
Ac ce p
electron-donating (MeO, entry 4) and electron-withdrawing (NO2, entry 6) groups had no any apparent effect on the preparation of the corresponding products 12d-f in good yield and virtually
diastereomerically pure form. Introduction of a methyl group in the position-7 on the indole also did not influence the excellent diastereoselectivity. The reaction of derivative 11g gave pure diastereomer 12g (entry 7) albeit in moderate chemical yield. Comparing the results between the reactions of 3- and 7-methyl substituted derivatives 11a and 11g (entry 1 vs. 7) one might
conclude that the position-3, in some way, can influence integrity of the corresponding transition state and therefore very important for mechanistic considerations.
Table 4 Substrate generality of the reactions of indoles 11 with imine (S)-1.a
9
Page 9 of 27
O S
R
+ N SO2Ph
F3C
N
11
THF -78oC 2 h R
(S)-1
N
SO2Ph (S)(S)-12 + (S)(R)-12
Entry
R
Product
Yield (%)b
1
3-CH3
12a
74
2
4-Cl
12b
90
3
4-CN
12c
93
4
5-MeO
12d
87
5
5-Br
12e
6
5-NO2
12f
7
7-CH3
12g
Dr c
96:4
us
cr
98:2 99:1 99:1 99:1
89
99:1
55
99:1
an
70
Reaction conditions: sulfinylimine 1 (1 mmol), indole 10 (1.25 mmol), base (1.5 mmol).
M
a
LDA
CF3 O S N H
R
ip t
R
Isolated yields of major diastereomers. c The diastereomeric ratio was determined by
F-NMR
d
using crude reaction mixtures
19
b
te
With this in mind, and taking advantage of good crystallinity of 3-methyl substituted
Ac ce p
derivative 12a (Table 4, entry 1), we conducted crystallographic analysis of this compound. As shown in Figure 4, 12a has (S) absolute configuration of the newly generated stereogenic carbon.
Stereochemical (Ss)(S) assignment of other products 10 (Table 3) and 12b-g (Table 4) was made
accordingly, based on similarity of their spectral and chiroptical properties with the compound 12a.
10
Page 10 of 27
ip t cr
an
us
Figure 4. Crystallographic structure of compound (S)(S)-12a.
Having determined the (S)(S) absolute configuration of products 10 and 12a-g, we can discuss a plausible mechanistic rationale for the reactions of 2-lithiated indoles with imine (S)-1.
M
Figure 5 presents three possible transition states (TSs) A, B and C which can be proposed for the
N F3C N H
O
S
H N
Fig. 5.
Li N
O S O S O Ph
O
B
H
N
O
Ph
A
O S
CF3
S
Ac ce p
Li
te
d
formation of the (Ss)(S) configured compounds 10 and 12a-g.
O
N CF 3 O S
Li
Ph C
Plausible transition states in the reactions of 2-lithiated indoles with imine (S)-1.
Considering TSs A-C one might agree that only TSs A and B can account for the observed effect of a substituent in the position-3 on the stereochemical outcome of these reactions. Thus, in TS C the stereocontrolling CF3-group [17] is pointing away from the position-2 avoiding any steric interactions. On the other hand, in TSs A and B the trifluoromethyl group is in close proximity to the positin-2 and therefore, could be sterically interacting with the substituent. Now, comparing TSs A and B it is easy to notice that TS B seems rather sterically crowded as the 11
Page 11 of 27
N-sulfinyl and N-phenyl sulfonyl groups are overlapped suggesting multiple electrostatic repulsive interactions between the sulphur and the oxygen atoms. On the other hand, in the TS A, the position of N-sulfinyl and N-phenyl sulfonyl groups allows for additional coordination to lithium atom via sterically favourable six-membered ring. Consequently, we propose that the addition
ip t
reactions under study occur through TS A providing for excellent diastereoselectivity in the case
of substituent in any position on the phenyl ring and a bit reduced stereocontrol in the reactions of
cr
2-substituted substrates.
Finally, we decided to carry out the N-sulfinyl deprotection procedure. To this end we subjected
us
indole (S)(S)-10 to standard acidic hydrolytic conditions. As presented in Scheme 2, the process
CF3
1) aq HCl, MeOH, rt, 4h 2) Et3N, CH2Cl2, rt, 1h
M
CF3 O S N N H SO2Ph
an
proceeded quite smoothly and the target free amino compound (S)-13 was isolated in 87% yield.
87% yield
NH2
SO2Ph (S)-13
d
(S)(S)-10
N
Ac ce p
3. Conclusions
te
Scheme 2. Deprotection procedure for preparation of compound (S)-13.
The study described here demonstrates that asymmetric functionalization of the pyrrole ring
of indoles with (2,2,2-trifluoro)ethylamine moiety can be accomplished chemo-selectively in the positions-2 or -3 using CF3-imine (S)-1 as a common reagent. In particular, the target 2-substitued
derivatives can be synthesised by the reactions of N-protected (Ts group) 2-lithiated indoles with
imine (S)-1 leading to the target products of (S)(S) absolute configuration. On the other hand, preparation of the (S)(S)-3-substituted isomers can be achieved using BF3·Et2O-promoted
Friedel-Crafts reactions of free NH indoles. Both approaches show wide substrate scope, resulting in excellent diastereoselectivities and chemical yields. The described data render this methodology as a reliable synthetic access to two novel classes of trifluoromethyl-containing indoles of high pharmaceutical potential.
12
Page 12 of 27
4. Experimental 4.1 General information All reagents were obtained from commercial suppliers and used without further purification.
ip t
Indoles with different protecting groups were synthesized according to literatures [18]. The reactions were conducted in a closed system under an atmosphere of N2 and were monitored by
cr
TLC. Solvents were dried and distilled prior to use. Flash chromatography was performed using
silica gel 60 (200-300 mesh). Thin layer chromatography was carried out on silica gel 60 F-254 13
C and
19
F NMR spectra were recorded on a Bruker
us
TLC plates of 20 cm × 20 cm. 1H,
AVANCE400M spectrometer. Melting points are uncorrected. Values of optical rotation were
an
measured on Rudolph Automatic Polarimeter A21101. Infrared spectra were obtained on Bruker Vector 22 in KBr pellets. HRMS were recorded on a LTQ-Orbitrap XL (Thermofisher, U. S. A.).
M
4.2 Typical procedure for the Friedel-Crafts reaction of unprotected indoles and CF3-sulfinylimine
d
To a solution of indole 6 (1.2 mmol) in anhydrous CH2Cl2 (5 mL) at -78 oC was added BF3·Et2O (130 μL, 1.0 mmol) dropwise. Then the solution of CF3-sulfinylimine 1 (201 mg, 1.0
te
mmol) in CH2Cl2 (2 mL) was added in one portion. Stirring was continued with the reaction
Ac ce p
temperature rose to room temperature slowly. Then the reaction was run for 10 h and quenched with H2O (10 mL). The organic layer was taken and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (2× 30 mL) and brine solution (1 × 30 mL) and dried over anhydrous Na2SO4. The solvent was evaporated, and the crude
mixture was charged onto silica gel and purified through flash chromatography (elute: PE/EtOAc = 1:1) to furnish the corresponding product 7. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethyl)propane-2-sulfinamide (5). Pale
yellow solid, mp: 154–155 oC. Yield: 248 mg (78%). [α]D25 = +109.17 (c = 0.70, CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.38 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.26-7.18 (m, 1H), 7.16-7.12 (m, 2H), 5.16 (qd, J = 8.0, 4.0 Hz, 1H), 4.12 (d, J = 4.0 Hz, 1H), 1.24 (s, 9H).
13
C NMR (101 MHz, CDCl3): δ 136.7, 126.7, 125.9, 125.3 (q, JFC = 282.8 Hz),
122.5, 120.1, 119.9, 112.0, 104.9, 56.1, 54.9 (q, 3JFC = 32.3 Hz), 22.6.
19
F NMR (376 MHz,
13
Page 13 of 27
CDCl3): δ -73.90. IR (cm-1): 2957, 2923, 2852, 1462, 1266, 1254, 1174, 1118, 1068, 1032, 750. HRMS (TOF MS ESI): calcd for C14H17F3N2OSNa [M+Na]+ 341.0911, found 341.0911. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(2-methyl-1H-indol-3-yl)ethyl)propane-2-sulfinamide (7a). White solid, mp: 175-176 oC. Yield: 289 mg (87%). [α]D25 = +172.91 (c = 0.79, CHCl3). 1H
ip t
NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.16-7.06 (m, 2H), 5.09 (qd, J = 7.8, 2.9 Hz, 1H), 4.00 (d, J = 2.3 Hz, 1H), 2.35 (s, 3H), 1.23 (s,
119.9, 111.0, 100.1, 55.6, 54.0 (q, 3JFC = 32.3 Hz), 22.6, 11.7.
19
cr
9H). 13C NMR (101 MHz, CDCl3): δ 137.2, 135.6, 126.8, 125.7 (q, JFC = 282.8 Hz), 121.5, 120.1, F NMR (376 MHz, CDCl3): δ
us
-73.50. IR (cm-1): 3410, 3285, 3217, 3197, 1459, 1367, 1284, 1270, 1165, 1152, 1128, 1076, 1052, 755, 731. HRMS (TOF MS ESI): calcd for C15H19F3N2OSNa [M+Na]+ 355.1068, found
an
355.1065.
(S)-N-((S)-1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide
M
(7b). White solid, mp: 174-175 oC. Yield: 212 mg (60%). [α]D25 = -40.82 (c = 0.59, CHCl3). 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 7.26 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.99-6.93 (m, 1H), 6.11 (s, 1H), 4.18-4.10 (m, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.4, 125.9,
19
F NMR (376 MHz, CDCl3): δ -73.38. IR (cm-1): 3256, 1368, 1341, 1271, 1249, 1181,
te
22.5.
d
125.2 (q, JFC = 282.8 Hz), 124.8, 122.8, 122.7, 121.3, 111.0, 106.3, 56.7, 53.4(q, 3JFC = 32.3 Hz),
Ac ce p
1167, 1123, 1065, 1009, 733. HRMS (TOF MS ESI): calcd for C14H16ClF3N2OSNa [M+Na]+ 375.0522, found 375.0518.
(S)-N-((S)-1-(5-bromo-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide
(7c). White solid, mp: 70-71oC. Yield: 246 mg (62%). [α]D25 = +129.43 (c = 0.67, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 7.81 (s, 1H), 7.29-7.25 (m, 1H), 7.19-7.15 (m, 2H), 5.16-5.07 (m, 1H), 4.26 (d, J = 4.0 Hz, 1H), 1.27 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 135.3,
127.8, 127.5, 125.4, 125.0 (q, JFC = 282.8 Hz), 122.5, 113.4, 113.4, 104.4, 56.3, 54.7 (q, 3JFC = 32.3 Hz), 22.6. 19F NMR (376 MHz, CDCl3): δ -73.90. IR (cm-1): 3421, 3245, 2962, 2924, 1458, 1367, 1269, 1174, 1125, 1055, 1012, 886, 798. HRMS (TOF MS ESI): calcd for C14H16BrF3N2OSNa [M+Na]+ 419.0017, found 419.0009. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-nitro-1H-indol-3-yl)ethyl)propane-2-sulfinamide (7d). Yellow solid, mp: 165-166 oC. Yield: 327 mg (90%). [α]D25 = +128.15 (c = 0.68, CHCl3). 1H 14
Page 14 of 27
NMR (400 MHz, CDCl3): δ 9.93 (s, 1H), 8.65 (s, 1H), 8.09 (dd, J = 9.0, 2.2 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 5.23-5.14 (m, 1H), 4.24 (d, J = 4.0 Hz, 1H), 1.29 (s, 9H). 13
C NMR (101 MHz, CDCl3): δ 142.3, 139.6, 129.7, 125.2, 124.8 (q, JFC = 282.8 Hz), 118.4,
117.7, 111.9, 107.6, 56.4, 54.5 (q, 3JFC = 32.3 Hz), 22.6. 19F NMR (376 MHz, CDCl3): δ -74.03.
ip t
IR (cm-1): 3345, 2924, 1523, 1474, 1336, 1265, 1174, 1128, 1031, 739, 675. HRMS (TOF MS ESI): calcd for C14H16F3N3O3SNa [M+Na]+ 386.0762, found 386.0759.
cr
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-yl)ethyl)propane-2-sulfinami
de (7e). Brown solid, mp: 84-85 oC. Yield: 237 mg (68%). [α]D25 = +83.92 (c = 0.80, CHCl3). 1H
us
NMR (400 MHz, CDCl3): δ 9.19 (s, 1H), 7.21 (d, J= 8.8 Hz, 1H), 7.15 (d, J= 2.6 Hz, 1H), 7.10 (d, J= 1.8 Hz, 1H), 6.86 (dd, J= 8.0, 2.0 Hz, 1H), 5.11 (qd, J= 8.0, 4.0 Hz, 1H), 4.09 (d, J= 4.0 Hz,
an
1H), 3.80 (s, 3H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 154.3, 131.7, 127.2, 126.3, 125.3 (q, JFC = 282.8 Hz), 112.9, 112.6, 104.6, 101.6, 55.9, 55.7, 54.8 (q, 3JFC = 32.3 Hz), 22.6. 19F NMR
M
(376 MHz, CDCl3): δ -73.80. IR (cm-1): 3243, 2959, 2925, 1489, 1461, 1442, 1367, 1269, 1215, 1171, 1121, 1040, 802, 696. HRMS (TOF MS ESI): calcd for C15H19F3N2O2SNa [M+Na]+
d
371.1017, found 371.1015.
Methyl-3-((S)-1-((S)-1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-1H-indole-5-carb
te
oxylate (7f). White solid, mp: 92-93 oC. Yield: 293 mg (78%). [α]D25 = +126.91 (c = 0.65,
Ac ce p
CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.44 (s, 1H), 7.92 (dd, J = 8.6, 1.5 Hz, 1H), 7.38-7.29 (m, 2H), 5.18 (qd, J = 8.0, 4.0 Hz, 1H), 4.11 (d, J = 4.0 Hz, 1H), 3.91 (s, 3H), 1.25 (s,
9H). 13C NMR (101 MHz, CDCl3): δ 168.2, 139.2, 127.9, 125.5, 125.0 (q, JFC = 281.8 Hz), 123.7, 122.9, 122.1, 111.7, 106.4, 56.3, 54.5 (q, 3JFC = 32.3 Hz), 51.9, 22.6.
19
F NMR (376 MHz,
CDCl3): δ -74.02. IR (cm-1): 3274, 3214, 3184, 1697, 1438, 1355, 1301, 1279, 1243, 1170, 1130, 1046, 772, 750. HRMS (TOF MS ESI): calcd for C16H19F3N2O3SNa [M+Na]+ 399.0966, found
399.0964.
(S)-N-((S)-1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (7g). White solid, mp: 137-138 oC. Yield: 229 mg (65%). [α]D25 = +119.68 (c = 0.86, CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.80 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 8.6, 1.8 Hz, 1H), 5.16-5.07 (m, 1H), 4.25 (d, J = 4.0 Hz, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.1, 128.3, 127.4, 125.1 (q, JFC = 282.8 Hz), 124.4, 15
Page 15 of 27
120.9, 120.8, 111.9, 105.0, 56.2, 54.8 (q, 3JFC = 32.3 Hz), 22.6.
19
F NMR (376 MHz, CDCl3): δ
-73.95. IR (cm-1): 3368, 3307, 3226, 1367, 1263, 1173, 1126, 1068, 1040, 1029, 908, 812. HRMS (TOF MS ESI): calcd for C14H16 ClF3N2OSNa [M+Na]+ 375.0522, found 375.0519. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-methoxy-2-methyl-1H-indol-3-yl)ethyl)propane-2-
ip t
sulfinamide (7h). Yellow solid, mp: 164-165 oC. Yield: 235 mg (65%). [α]D25+ = + 195.11 (c =
0.61, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 7.10-7.05 (m, 2H), 6.78 (dd, J = 8.7,
cr
2.0 Hz, 1H), 5.05 (d, J = 6.6 Hz, 1H), 3.99 (s, 1H), 3.80 (s, 3H), 2.29 (s, 3H), 1.24 (s, 9H). 13C
NMR (101 MHz, CDCl3): δ 154.1, 137.8, 130.6, 127.3, 125.7 (q, JFC = 282.8 Hz), 111.5, 111.3, 19
F NMR (376 MHz, CDCl3): δ
us
102.5, 99.9, 55.7, 55.4, 53.9 (q, 3JFC = 32.3 Hz), 22.6, 11.8.
-73.42. IR (cm-1): 3259, 1489, 1456, 1272, 1216, 1166, 1137, 1126, 1098, 1063, 1037, 1029, 739,
an
607. HRMS (TOF MS ESI): calcd for C16H21 F3N2O2SNa [M+Na]+ 385.1174, found 385.1172. 4.3Procedure for deprotection of 5
M
Cleavage of the chiral tert-butylsulfinyl group was carried out in a 25 mL round-bottom flask where 0.5 mmol 5 and 5 mL MeOH were added. Then 1mL aqueous HCl (36%) was added
d
dropwise with stirring at room temperature. After 4 h when the reaction was completed by
te
monitoring of the TLC, volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and Et3N (15.0 mmol) was added. The mixture was stirred at rt for 1 h, then
Ac ce p
H2O (10 mL) was added. The organic layer was taken, washed with water and brine and dried with anhydrous Na2SO4. The mixture was filtered and concentrated. The crude product was
purified by layer chromatography to give product 8 in 90% yield. (S)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethanamine (8). White solid, mp: 114-115 oC. Yield: 96
mg (90%). [α]D25 = -1.52 (c =0.66, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.28-7.22 (m, 1H), 7.21-7.15 (m,
1H), 4.78 (q, J = 8.0 Hz, 1H), 1.81 (s, 2H). 13C NMR (101 MHz, CDCl3): δ 136.1, 126.3 (q, JFC = 282.8 Hz), 126.1, 123.0, 122.7, 120.3, 119.2, 111.4, 110.9, 51.4 (q, 3JFC = 32.3 Hz).
19
F NMR
(376 MHz, CDCl3): δ -76.86. IR (cm-1): 3386, 3316, 3177, 1451, 1276, 1195, 1157, 1109, 957, 944, 815, 750, 618. HRMS (TOF MS EI+) m/z calcd for C10 H9F3N2 214.0718, found 214.0716. 4.4 Typical procedure for the Mannich reaction of N-phenylsulfonylindoles to CF3-sulfinylimine 16
Page 16 of 27
Into an oven-dried reaction vial flushed with N2 was taken N-phenylsulfonylindole 11 (1.25 mmol) and anhydrous THF (5 mL). The reaction vial was cooled to -78 oC and LDA (1 M in THF, 1.5 mL) was added dropwise with stirring. After the reaction was stirred for 1 h at -78oC, the solution of CF3-sulfinylimine 1 (201 mg, 1 mmol) in THF (2 mL) was added in one portion and
ip t
the mixture stirred at -78oC for 2 h. The reaction mixture was quenched by a saturated aqueous solution of NH4Cl (5 mL), followed by extraction with EtOAc (2 × 20 mL). The combined
cr
organic layers were washed with water (1 × 30 mL) and brine solution (1 × 30 mL) and dried
overanhydrous Na2SO4. Most of the solvent was removed under reduced pressure. The residue
us
was purified by flash chromatographyon silica gel (elute: PE/EtOAc = 1:1) to afford product 12. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)propane-2-su
an
lfinamide (10). White solid, mp: 77-78 oC. Yield: 390 mg (85%). [α]D25 = +43.24 (c = 0.44, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.49 (t,
M
J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.36-7.30 (m, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.18-6.09 (m, 1H), 4.27 (s, 1H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.8, 137.1, 134.2, 132.7, 129.4, 128.8, 126.6, 126.0, 124.3, 124.2 (q, JFC = 282.8 Hz), 121.7, 115.2, 113.9, 57.2, 54.3
d
(q, 3JFC = 32.3 Hz), 22.4. 19F NMR (376 MHz, CDCl3): δ -72.43. IR (cm-1): 2961, 1449, 1366,
te
1178, 1154, 1119, 1090, 1073, 751, 590, 573. HRMS (TOF MS ESI): calcd for
Ac ce p
C20H21F3N2O3S2Na [M+Na]+ 481.0843, found 481.0843. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(3-methyl-1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)pro
pane-2-sulfinamide (12a). White solid, mp: 159-160 oC. Yield: 350 mg (74%). [α]D25 = -62.94 (c
= 0.80, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H),
7.55-7.47 (m, 2H), 7.44-7.36 (m, 3H), 7.30 (t, J = 8.0 Hz, 1H), 6.55-6.46 (m, 1H), 4.00 (s, 1H), 2.37 (s, 3H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 138.3, 136.7, 134.0, 130.7, 129.2,
126.8, 126.5, 126.2, 124.7 (q, JFC = 282.8 Hz), 124.0, 123.0, 119.4, 115.5, 56.8, 54.2 (q, 3JFC =
32.3 Hz), 22.4, 10.4. 19F NMR (376 MHz, CDCl3): δ -71.88. IR (cm-1): 2955, 1449, 1369, 1252, 1228, 1187, 1172, 1152, 1089, 1078, 755, 743, 725, 592, 574. HRMS (TOF MS ESI): calcd for C21H23F3N2O3S2Na [M+Na]+ 495.10000, found 495.0998. (S)-N-((S)-1-(4-chloro-1-(phenylsulfonyl)-1H-indol-2-yl)-2,2,2-trifluoroethyl)-2-methylpro pane-2-sulfinamide (12b). White solid, mp: 70-71 oC. Yield: 443 mg (90%). [α]D25 = +89.37 (c = 17
Page 17 of 27
0.92, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.29-7.22 (m, 2H), 7.09 (s, 1H), 6.20-6.11 (m, 1H), 4.40 (d, J = 8.0 Hz, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.6, 137.6, 134.5, 133.5, 129.5, 127.7, 126.8, 126.7, 126.6, 124.0, 124.0 (q, JFC = 283.8 Hz), 113.6, 111.4, 57.2, 54.0
ip t
(q, 3JFC = 32.3 Hz), 22.4. 19F NMR (376 MHz, CDCl3): δ -72.39. IR (cm-1): 3225, 1370, 1254, 1223, 1178, 1155, 1119, 1091, 1069, 1050, 726, 591, 563. HRMS (TOF MS ESI): calcd for
cr
C20H21ClF3N2O3S2 [M+H]+ 493.0634, found 493.0630.
(S)-N-((S)-1-(4-cyano-1-(phenylsulfonyl)-1H-indol-2-yl)-2,2,2-trifluoroethyl)-2-methylprop
us
ane-2-sulfinamide (12c). White solid, mp: 81-82 oC. Yield: 450 mg (93%). [α]D25 = +123.12 (c = 0.80, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H),
an
7.60 (t, J = 8.0 Hz, 2H), 7.51-7.40 (m, 3H), 7.15 (s, 1H), 6.15-6.06 (m, 1H), 4.12 (d, J = 8.0 Hz, 1H), 1.25 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.5, 136.7, 135.9, 134.8, 130.5, 129.7, 128.8,
22.4.
19
M
126.7, 125.8, 123.8 (q, JFC = 283.8 Hz), 119.6, 117.1, 111.2, 104.7, 57.3, 54.0 (q, 3JFC = 32.3 Hz), F NMR (376 MHz, CDCl3): δ -72.25. IR (cm-1): 3261, 1379, 1249, 1185, 1161, 1122,
506.0796, found 506.0795.
d
1094, 1067, 726, 685, 587, 570. HRMS (TOF MS ESI): calcd for C21H20F3N3O3S2Na [M+Na]+
te
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-methoxy-1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)pr
Ac ce p
opane-2-sulfinamide (12d). Pale yellow solid, mp: 67-70 oC. Yield: 425 mg (87%). [α]D25 = +68.09 (c = 0.56, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.0
Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 2H), 6.99-6.93 (m, 2H), 6.87 (s, 1H), 6.11-6.02 (m, 1H), 4.04-3.97 (m, 1H), 3.80 (s, 3H), 1.23 (s, 9H). 13C NMR (101 MHz, CDCl3): δ
157.0, 137.7, 134.1, 133.2, 131.7, 129.9, 129.3, 126.5, 124.1 (q, JFC = 283.8 Hz), 116.3, 115.3,
114.0, 103.6, 57.1, 55.6, 54.4 (q, 3JFC = 32.3 Hz), 22.4. 19F NMR (376 MHz, CDCl3): δ -72.35. IR (cm-1): 3215, 2960, 2926, 1475, 1449, 1367, 1255, 1219, 1202, 1164, 1116, 1090, 1072, 1048, 724, 686, 598, 575. HRMS (TOF MS ESI): calcd for C21H23F3N2O4S2Na [M+Na]+ 511.0949,
found 511.0948. (S)-N-((S)-1-(5-bromo-1-(phenylsulfonyl)-1H-indol-2-yl)-2,2,2-trifluoroethyl)-2-methylpro pane-2-sulfinamide (12e). Yellow oil. Yield: 376 mg (70%). [α]D25 = +95.57 (c = 0.86, CHCl3). 1
H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 1.8 18
Page 18 of 27
Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.45-7.39 (m, 3H), 6.90 (s, 1H), 6.13-6.04 (m, 1H), 4.26 (d, J = 7.0 Hz, 1H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.6, 135.8, 134.5, 134.0, 130.5, 129.5, 128.8, 126.6, 124.3, 124.0 (q, JFC = 283.8 Hz), 117.7, 116.6, 112.8, 57.2, 54.1 (q, 3JFC = 32.3 Hz), 22.4. 19F NMR (376 MHz, CDCl3): δ -72.34. IR (cm-1): 3213, 2924, 1447, 1367, 1325,
ip t
1254, 1226, 1172, 1118, 1090, 1062, 1045, 727, 685, 596, 580. HRMS (TOF MS ESI): calcd for C20H20BrF3N2O3S2Na [M+Na]+ 558.9949, found 558.9947.
cr
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-nitro-1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)propa
ne-2-sulfinamide (12f). Pale yellow solid, mp: 108-109 oC. Yield: 448 mg (89%). [α]D25 = +81.16
us
(c = 0.80, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 1.6 Hz, 1H), 8.25-8.16 (m, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.10 (s, 1H), 6.12-6.03
an
(m, 1H), 4.12 (d, J = 8.0 Hz, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 144.6, 139.7, 137.5, 136.0, 134.9, 129.8, 128.6, 126.8, 123.9 (q, JFC = 283.8 Hz), 120.8, 117.9, 115.4, 113.6,
M
57.3, 53.8 (q, 3JFC = 32.3 Hz), 22.3. 19F NMR (376 MHz, CDCl3): δ -72.16. IR (cm-1): 3209, 2963, 2926, 1524, 1449, 1380, 1346, 1252, 1233, 1181, 1162, 1120, 1089, 1076, 1044, 752, 726, 685,
526.0692.
d
595, 574. HRMS (TOF MS ESI): calcd for C20H20F3N3O5SNa [M+Na]+ 526.0694, found
te
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(7-methyl-1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)pro
Ac ce p
pane-2-sulfinamide (12g). Pale yellow solid, mp: 59-60 oC. Yield: 260 mg (55%). [α]D25 = +37.34 (c = 0.48, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.44 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0
Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H), 7.21-7.12 (m, 3H), 6.84 (s, 1H), 6.01-5.91 (m, 1H), 4.07 (d, J = 8.0 Hz, 1H), 2.70 (s, 3H), 1.26 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 140.4, 136.5, 135.5, 133.8,
132.6, 130.1, 129.7, 128.5, 126.6, 125.8, 124.1 (q, JFC = 283.8 Hz), 119.5, 119.4, 57.4, 56.7 (q, 3
JFC = 32.3 Hz), 22.5, 21.7. 19F NMR (376 MHz, CDCl3): δ -72.21. IR (cm-1): 2958, 2923, 2852,
1450, 1367, 1255, 1182, 1147, 1117, 1083, 755, 722, 687, 619, 588. HRMS (TOF MS ESI): calcd for C21H23F3N2O3S2Na [M+Na]+ 495.1000, found 495.0998. 4.5 Procedure for deprotection of 10 Cleavage of the chiral tert-butylsulfinyl group was carried out in a 25 mL round-bottom flask
where 0.5 mmol 10 and 5 mL MeOH were added. Then 1 mL aqueous HCl (36%) was added dropwise with stirring at room temperature. After 6 h when the reaction was completed by 19
Page 19 of 27
monitoring of the TLC, volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and Et3N (15.0 mmol) was added. The mixture was stirred at rt for 1 h, then H2O (10 mL) was added. The organic layer was taken, washed with water and brine and dried with anhydrous Na2SO4. The mixture was filtered and concentrated. The crude product was
ip t
purified by layer chromatography to give product 13 in 87% yield.
(S)-2,2,2-trifluoro-1-(1-(phenylsulfonyl)-1H-indol-3-yl)ethanamine (13). Yellow oil. Yield:
cr
154 mg (87%). [α]D25 = +6.21 (c = 0.87, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.85-7.81 (m, 2H), 7.56-7.47 (m, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.37-7.31 (m, 1H), 13
C NMR (101 MHz,
us
7.28-7.22 (m, 1H), 6.86 (s, 1H), 5.46 (q, J = 8.0 Hz, 1H), 1.96 (s, 2H).
CDCl3): δ 138.0, 136.9, 136.5, 134.1, 129.3, 129.1, 126.5, 125.7, 124.3, 125.5 (q, JFC = 283.8 Hz), 19
F NMR (376 MHz, CDCl3): δ
an
121.5, 115.2, 111.2 (d, J = 2.0 Hz), 51.2 (q, 3JFC = 32.3 Hz).
-74.87. IR (cm-1): 1449, 1368, 1268, 1236, 1178, 1159, 1115, 1090, 1044, 750, 725, 685, 591,
M
575, 559. HRMS (TOF MS ESI): calcd for [M+Na]+ C16H13F3N2O2SNa 377.0548, found
Acknowledgment
d
377.0545.
te
We gratefully acknowledge the financial support from the National Natural Science
Ac ce p
Foundation of China (No. 21102071). The Jiangsu 333 program (for Pan) is also acknowledged.
References
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(c) J. P. Begue, D. Bonnet-Delpon, J. Fluorine Chem. 127 (2006) 992–1012; (d) K. L. Kirk, J. Fluorine Chem. 127 (2006) 1013–1029; (e) X. Yang, A. Guan, J. Fluorine Chem. 161 (2014) 1–10.
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ip t
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cr
(d) J. P. Bégué, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, Wiley: New York, 2008;
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(b) V. A. Soloshonok, T. Hayashi, K. Ishikawa, N. Nagashima, Tetrahedron Lett. 35 (1994) 1055–1058; (c) V. A. Soloshonok, A. G. Kirilenko, V. P. Kukhar, G. Resnati, Tetrahedron Lett. 34 (1993) 3621–3624;
ip t
(d) V. A. Soloshonok, H. Ohkura, A. Sorochinsky, N. Voloshin, A. Markovsky, M. Belik, T. Yamazaki, Tetrahedron Lett. 43 (2002) 5445–5448;
cr
(e) P. Bravo, A. Farina, M. Frigerio, S. Valdo Meille, F. Viani, V. A. Soloshonok, Tetrahedron: Asymmetry 5 (1994) 987–1004.
For the reactions with ketone-derived enolates, see: (a) H. Mei, Y. Xiong, J. L. Han, Y. Pan, Org. Biomol. Chem. 9 (2011) 1402–1406;
us
[10]
an
(b) C. Xie, H. B. Mei, L. M. Wu, V. A. Soloshonok, J. L. Han, Y. Pan, RSC Adv. 4 (2014) 4763–4768;
M
(c) L. Wu, C. Xie, H. Mei, V. A. Soloshonok, J. L. Han, Y. Pan, Org. Biomol. Chem. 12 (2014) 4620–4627.
For the reactions with ester-derived enolates, see: (a) N. Shibata, T. Nishimine, E.
d
[11]
Tokunaga, K. Kawada, T. Kagawa, A. E. Sorochinsky, V. A. Soloshonok, Chem.
te
Comm. 48 (2012) 4124–4126;
Ac ce p
(b) M. V. Shevchuk, V. P. Kukhar, G. V. Roeschenthaler, B. S. Bassil, K. Kawada, V. A. Soloshonok, A. E. Sorochinsky, RSC Adv. 3 (2013) 6479–6484; (c) N. Shibata, T. Nishimine, N. Shibata, E. Tokunaga, K. Kawada, T. Kagawa, J. L. Aceña, A. E. Sorochinsky, V. A. Soloshonok, Org. Biomol. Chem. 12 (2014) 1454–1462;
(d) C. Xie, H. Mei, L. Wu, V. A. Soloshonok, J. L. Han, Y. Pan, Eur. J. Org. Chem. (2014) 1445–1451.
[12]
For the reactions with lithiated aromatic/heterocyclic compounds, see: (a) H. Mei, C. Xie, L. Wu, V. A. Soloshonok, J. L. Han, Y. Pan, Org. Biomol. Chem. 11 (2013) 8018–8021; (b) H. B. Mei, Y. W. Xiong, C. Xie, V. A. Soloshonok, J. L. Han, Y. Pan, Org. Biomol. Chem. 12 (2014) 2108–2113; 22
Page 22 of 27
(c) H. B. Mei, Y. L. Dai, L. M. Wu, V. A. Soloshonok, J. L. Han, Y. Pan, Eur. J. Org. Chem. 12 (2014) 2429–2433; (d) C. Xie, H. B. Mei, L. M. Wu, J. L. Han, V. A. Soloshonok, Y. Pan, J. Fluorine Chem. 165 (2014) 67–75;
ip t
(e) P. Qian, C. Xie, L. M. Wu, H. B. Mei, V. A. Solochonok, J. L. Han, Y. Pan, Org. Biomol. Chem. 12 (2014) 7909–7913.
For other types of nucleophiles, see: (a) G. V. Röschenthaler, V. P. Kukhar, I. B. Kulik,
cr
[13]
M. Y. Belik, A. E. Sorochinsky, E. B. Rusanov, V. A. Soloshonok, Tetrahedron Lett. 53
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(2012) 539–542;
(b) K. V. Turcheniuk, K. O. Poliashko, V. P. Kukhar, A. B. Rozhenko, V. A.
an
Soloshonok, A. E. Sorochinsky, Chem. Commun. 48 (2012) 11519–11521; (c) T. Milcent, J. Hao, K. Kawada, V. A. Soloshonok, S. Ongeri, B. Crousse, Eur. J.
M
Org. Chem. (2014) 3072–3075;
(d) C. Xie, L. Wu, H. Mei, V. A. Soloshonok, J. L. Han, Y. Pan, Org. Biomol. Chem. 12
d
(2014) 7836–7843;
(e) Y. Liu, J. Liu, Y. Huang, F. L. Qing, Chem. Commun. 49 (2013) 7492–7494;
te
(f) W. Jiang, C. Chen, D. Marinkovic, J. A. Tran, C. W. Chen, L. M. Arellano, N. S.
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White, Tucci, F. C. J. Org. Chem. 70 (2005) 8924–8931; (g) H. Zhang, Y. Li, W. Xu, W. Zheng, P. Zhou, Z. Sun, Org. Biomol. Chem. 9 (2011) 6502–6505;
(h) C. Xie, L. M. Wu, H. B. Mei, V. A. Soloshonok, J. L. Han, Y. Pan, Tetrahedron Lett. 55 (2014) 5908–5910.
[14]
L. Wu, C. Xie, H. Mei, V. A. Soloshonok, J. L. Han, Y. Pan, J. Org. Chem. 79 (2014) 7677–7681.
[15]
M. T. Robak, M. A. Herbage, J. A. Ellman, Chem. Rev. 110 (2010) 3600–3740.
[16]
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[17]
(a) V. A. Soloshonok, T. Ono, Tetrahedron 52 (1996) 14701–14712;
23
Page 23 of 27
(b) P. Bravo, A. Farina, V. P. Kukhar, A. L. Markovsky, S. V. Meille, V. A. Soloshonok, A. E. Sorochinsky, F. Viani, M. Zanda, C. Zappala, J. Org. Chem. 62 (1997) 3424–3425; (c) V. A. Soloshonok, A. G. Kirilenko, N. A. Fokina, I. P. Shishkina, S. V. Galushko,
ip t
V. P. Kukhar, V. K. Svedas, E. V. Kozlova, Tetrahedron: Asymmetry 5 (1994) 1119–1126;
cr
(d) V. A. Soloshonok, A. G. Kirilenko, N. A. Fokina, S. V. Galushko, V. P. Kukhar, V. K. Svedas, G. Resnati, Tetrahedron: Asymmetry 5 (1994) 1225–1228.
(a) X. H. Xu, G. K. Liu, A. Azuma, E. Tokunaga, N. Shibata, Org. Lett. 13 (2011)
us
[18]
4854–4857;
an
(b) Q. Liu, Q. Y. Zhao, J. Liu, P. Wu, H. Yi, A. Lei, Chem. Commun. 48 (2012)
Ac ce p
te
d
M
3239–3241.
24
Page 24 of 27
2
R
N R1
CF3 O N S H (S)(S)
F3C
N
O S 2
R
(S)
F3C
N
O S
R2
(S)
BF3 Et2O N 1 up to 90% yield R up to 99:1 dr
N R1
(S)(S)
ip t
LDA up to 93% yield up to 99:1 dr Mannich reaction on position-2
CF3 O S N H
Ac ce p
te
d
M
an
us
cr
Friedel-Crafts reaction on position-3
25
Page 25 of 27
We described asymmetric functionalization of indoles with (2,2,2-trifluoro)ethylamine moiety by using chiral CF3-imine as a common reagent with chemo-selectivity in the positions-2 or -3, which proceeded through Mannich
Ac ce p
te
d
M
an
us
cr
ip t
reaction and Friedel-Crafts reaction respectively.
26
Page 26 of 27
Asymmetric functionalization of indoles with CF3–CH(NH2)- was accomplished. 2-Substitued product was obtained by reaction of 2-lithiated indoles and CF3-imine. Preparation of the 3-substituted isomers was achieved by Friedel-Crafts reactions.
Ac ce p
te
d
M
an
us
cr
ip t
These methods provide a way to fluorinated indoles of pharmaceutical potential.
27
Page 27 of 27
S0022-1139(15)00003-2 http://dx.doi.org/doi:10.1016/j.jfluchem.2015.01.001 FLUOR 8487
To appear in:
FLUOR
Received date: Revised date: Accepted date:
17-11-2014 28-12-2014 2-1-2015
Please cite this article as: L. Wu, C. Xie, J. Zhou, H. Mei, V.A. Soloshonok, J. Han, Y. Pan, General asymmetric synthesis of 2,2,2-trifluoro-1-(1Hindol-3- and -2-yl)ethanamines, Journal of Fluorine Chemistry (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
General asymmetric synthesis of 2,2,2-trifluoro-1-(1H-indol-3- and -2-yl)ethanamines
ip t
Lingmin Wua, Chen Xiea, Jie Zhoua, Haibo Meia, Vadim A. Soloshonokc,d, Jianlin
School of Chemistry and Chemical Engineering, State Key laboratory of Coordination
us
a
cr
Hana,b,*, Yi Pana
Chemistry, Nanjing University, Nanjing, 210093, China. Fax: 86-25-83686133; Tel:
an
86-25-83686133; E-mail: [email protected].
Institute for Chemistry & BioMedical Sciences, Nanjing University, Nanjing, 210093, China.
c
Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country
UPV/EHU, 20018 San Sebastian, Spain.
IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
d
d
M
b
Ac ce p
compounds; indole
te
Key words: CF3-imine; Friedel-Crafts reaction; Mannich reaction; trifluoromethyl-amino
ABSTRACT
This work describes an asymmetric functionalization of the pyrrole ring of an indole structure with (2,2,2-trifluoro)ethylamine moiety allowing for general access to two novel classes of trifluoromethyl-containing indoles. We found that under the Friedel-Crafts reaction conditions (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine (1) easily reacts with indole derivatives
affording the target 3-substituted products, while LDA-promoted reactions proceed exclusively at the 2-position. We demonstrate that both approaches feature wide substrate scope, high chemical yields and diastereoselectivities, which render these reactions readily applicable for straightforward preparation of biologically interesting compounds containing chiral CF3–CH(NH2)- and indole
groups. The mechanistic rationales accounting for the observed mode of stereochemical preferences are proposed. 1
Page 1 of 27
1. Introduction Heterocyclic structure of naturally occurring indole molecules is one of the most prolific motifs found in pharmaceutical products [1]. On the other hand, fluorine-containing organic
ip t
compounds are almost manmade as only a handful of highly toxic fluoroacetic acid and several ω-monofluoro-fatty acids have been isolated from natural sources [2]. Remarkably, the modern
cr
drug discovery relies heavily on the functionalization of bioactive compounds with various fluorine containing substituents [3]. In particular, incorporation of trifluoromethyl (CF3) group
us
into drug candidates leads to several beneficial properties, such as enhanced efficacy, increased metabolic stability and improved cellular membrane permeability [4]. Accordingly, synthesis of
an
fluorine-containing indole derivatives has been attracting much attention in medicinal chemistry research [4,5]. The established pharmacophores possess various types of aromatic as well as
M
aliphatic CF3-substitution [6]. 2,2,2-Trifluoro-1-(amino)ethyl [CF3–CH(NH2)-] moiety [7] is well recognized group of pharmaceutical potential featuring prominently in the new drug Odanacatib
d
[8], which has beendeveloped for treatment for osteoporosis and bone metastasis. Consistent with our interest in preparation of fluorine-containing derivatives of natural [9],
we
have
te
compounds
been
studying
(R)-
and
Ac ce p
(S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines 1 (Figure 1) as general reagents for convenient installation of 2,2,2-trifluoro-1-(amino)ethyl [CF3–CH(NH2)-] group into biologically
relevant organic compounds [10-13]. Considering biological potential of indole structure, we were motivated to explore preparation of CF3–CH(NH2)-containing derivatives using chemistry of sulfinyl-imines 1. Recently, we reported the first example of Friedel–Crafts reactions of imine (S)-1 with N-protected indole, resulting in the formation of derivatives bearing the fluorinated
substituents in the position 3 [14]. However, the Friedel-Crafts reaction of imine (S)-1 with N-unprotected indole has never been reported. Furthermore, the reactions between indoles and imine (S)-1, taking place in the position-2 of indole ring, also still remains unexplored. Therefore, we were quite exciting to explore the direct approaches to the selective formation of 2- and 3-substituted fluorinated derivatives of types 3 and 2 through the addition reactions with the chiral
imine 1. Herein we report the functionalization of indole skeleton with imines 1 allowing general 2
Page 2 of 27
access to derivatives 2 and 3 (Figure 1) bearing substituents on both six- and five-membered rings. Compounds of types 2 and 3 are novel and both of them can be prepared in enantiomerically pure
R1
N
F3C
N
O S
R1
NH2 N
(S)-1
CF3
(R)-1
R2
R
CF3
N R
NH2
3-(S) or (R)
us
2-(S) or (R)
R2
cr
F3C
O S
ip t
form in relatively large scale for comprehensive biological studies.
an
Fig. 1. Chiral reagents 1 and target structural types of indole derivatives 2 and 3.
2. Results and discussion
M
We began the present study with the reactions of unprotected indole 4 and imine 1 (Table 1), expecting this case to be the most interesting due to the potential reactivity of the NH function in molecule 4. Indeed, Friedel–Crafts reactions of imine (S)-1 with indole 4 turned out to be intricate
d
resulting in rather complex mixtures. After an extensive experimental investigation using various
te
Lewis acid catalysts, we have successfully found the most favorable conditions. First of all, relatively high reactivity of imine (S)-1 should be noted since most of the Lewis
Ac ce p
acids used in this study were found to catalyze the reactions and CH2Cl2 was identified as an
optimal solvent. Furthermore, application of 20 mol % of AlCl3, In(OTf)3 and La(OTf)3 (entries 1-3) gave excellent diastereoselectivity. However, the reactions were accompanied by formation of various by-products resulting in low isolated yields of target product 5. In sharp contrast, the
use of Cu(OTf)2 as a catalyst (entry 4), gave markedly improved yield but relatively low stereoselectivity. Among other interesting results, we should mention the application of AgBF4 (entry 5) which gave low yield and the lowest diastereoselectivity in this study. Eventually, we found that the use of BF3·Et2O provides reliable and reproducible results containing synthetically useful level of the stereochemical outcome. In this case optimal reaction rates were obtained using stoichiometric amount (100 mol %) of BF3·Et2O. At ambient temperature (entry 6) and 0 oC (entry 7) the reactions showed low diastereoselectivity along with a sizable formation of by-products. In contrast, the additions conducted at -78 oC gave the product 5 with good chemical yield and 3
Page 3 of 27
excellent stereoselectivity (entry 8).
N H 4
N
CF3 O S N H
Catalyst CH2Cl2
N H (S)(S)-5 + (S)(R)-5
(S)-1
Catalyst (mol%)
Temp. (oC)
Time (h)
Yield (%)b
1
AlCl3 (20)
rt
10
10
2
In(OTf)3 (20)
rt
10
3
La(OTf)3 (20)
rt
10
4
Cu(OTf)2 (20)
rt
5
AgBF4 (20)
rt
6
BF3·Et2O (100)
rt
7
BF3·Et2O (100)
8
BF3·Et2O (100)
Dr c
us
cr
Entry
99:1
99:1
20
99:1
10
85
80:20
10
17
55:45
10
29
77:23
0
18
36
77:23
-78-rt
10
78
99:1
d
M
an
55
Reaction conditions: sulfinylimine 1 (1 mmol), indole 4 (1.2 mmol), catalyst, 5 mL CH2Cl2.
b
te
a
+ F3C
O S
ip t
Table 1 Optimization of the reaction conditions for the reaction of indole 4 with imine (S)-1.a
Isolated yields of major diastereomers. c The diastereomeric ratio was determined by 19F-NMR of
Ac ce p
the crude reaction mixtures.
As the next step of this study, we decided to investigate the generality of this reaction for
preparation of various indoles bearing substituents on both aromatic rings of the parent indole structure. Results of Friedel–Crafts reactions of imine (S)-1 with indoles 6 are presented in Table 2. Reaction of 2-methyl substituted derivative 6a (entry 1) with imine (S)-1 occurred at normal
reaction rate affording the target product 7a with excellent diastereoselectivity and in high chemical yield. Substitution in the position-4 on the indole phenyl ring, compound 6b (entry 2), did not affect on the stereoselectivity (99:1), albeit the product 7b was isolated in a little bit lower yield. In contrast, the presence of the Br atom in the position-5 (entry 3) had a negative effect on the observed diastereoselectivity resulting in a 85:15 mixture of the diastereomeric products. Nevertheless, the major diastereomerically pure product 7 was isolated in 62% yield. In a series of 4
Page 4 of 27
other 5-substitued indoles reactions (entries 4-6) excellent level of stereocontrol was obtained for derivatives 6d,f, bearing in the position-5 nitro (entry 4) and methoxy-carbonyl groups (entry 6). All these reactions gave essentially single diastereomeric products 7d,f. On the other hand, 5-methoxy (entry 5) containing indole 6e gave the diastereoselectivity similar to that of
ip t
5-bromo-derivative 6c. Most likely, such a noticeable difference in diastereoselecitivity can be
explained by the steric properties of the substituents. Thus, while the steric bulk of each nitro and
cr
methoxy-carbonyl groups is larger than that of a bromine atom or a methoxy group, they can
minimize steric interactions due to their flat, planar structure, generating less destabilizing effect
us
on the corresponding transition states. Interestingly, the position-6 on the indole phenyl ring was also found to be sensitive to the substitution. As shown in entry 7, 6-Cl substituted indole 6g
an
reacted with imine (S)-1 in a less stereoselective manner affording a 90:10 mixture of the diastereomeric products. By this reaction, the major diastereomer 7g was prepared in pure form in
M
65% yield. Finally, we studied an example of di-substituted substrate 6h, which reacted smoothly with imine (S)-1 affording the target product 7h as a single diastereomer isolated in 65% yield
d
(entry 8).
R
te
Table 2 Substrate generality of the reactions of indoles 6 with imine (S)-1.a O S
Ac ce p
R
N H
6
+ F3C
N
BF3EtO2 (100 mol %)
R
CH2Cl2, 10 h -78 oC-rt
(S)-1
R
CF3 O S N H
N H (S)(S)-7 + (S)(R)-7
Entry
R
Product
Yield (%)b
Dr c
1
2-CH3
7a
87
99:1
2
4-Cl
7b
60
99:1
3
5-Br
7c
62
85:15
4
5-NO2
7d
90
99:1
5
5-MeO
7e
68
87:13
6
5-COOMe
7f
78
99:1
7
6-Cl
7g
65
90:10
5
Page 5 of 27
8 a
2-Me-5-MeO
65
7h
99:1
Reaction conditions: sulfinylimine 1 (1 mmol), indole 6 (1.2 mmol), BF3·Et2O (100 mol %), 5
mL CH2Cl2, reaction time 10 hrs.
b
Isolated yields of major diastereomers. c The diastereomeric
ip t
ratio was determined by 19F-NMR of the crude reaction mixtures.
The next goal of this Friedel–Crafts reactions was focused on determining the absolute
cr
configuration of the corresponding products and elucidating the mechanism. Taking advantage of high crystallinity of 2-methyl substituted derivative 7a (Table 2), we conducted its
us
crystallographic study to determine the absolute stereochemistry of the newly created stereogenic centre. As presented in Figures 2, compound 7a has (Ss)(S) stereochemistry suggesting common
an
mechanism of the asymmetric induction. Absolute configuration of other products 5 (Table 1) and 7a-h (Table 2) was assigned accordingly as (Ss)(S) based on close similarity between their spectral
Ac ce p
te
d
M
and chiroptical properties.
Fig. 2. Crystallographic structure of compound (S)(S)-7a.
Based on these results, a plausible mechanistic rationale for the observed stereochemical outcome was proposed. As presented in Figure 3, three possible transition states (TSs) A, B and C can be considered to account for the formation of the (S)(S)-configured Friedel–Crafts products. Careful examination of TSs A-C might lead to a conclusion that only TS A can fully account for all observed effects between the reactivity and substitution on the starting indoles. First of all, in 6
Page 6 of 27
the TS A the Lewis acid catalyst is in position to coordinate both the indole and imine nitrogens via sterically favourable six-membered arrangement (A’). TS A can easily account for the unexpected effect of the substitution in positions 5 and 6 of the indole phenyl ring. As it follows from the results obtained(Table 2, entries 3 and 7), the presence of a bulky substituent in these
CF3 H BF3
N
BF3
CF3
CF3
N
S
N
H
O
BF3
A'
B
BF3
S O
H
an
O A
S
N
H N
us
N
CF3 H N
cr
H
N
H
ip t
positions resulted in noticeable worsening of the normally excellent diastereoselectivity.
C
M
Fig. 3. Plausible transition states in the Friedel–Crafts reactions under study.
d
Finally, we decided to perform the deprotection of the obtained products, to prepare free
te
CF3-containing amines. Deprotection of a sulfinyl group is well established procedure [15]. However, considering that compound 5 contains free N-H function , we felt that preparing the
Ac ce p
corresponding free amino derivatives would be highly desirable. To this end, we conducted the deprotection (Scheme 1) of unsubstituted NH sulfinyl-amine 5 using standard acidic hydrolytic conditions. The procedure was accomplished without any complications and the free amino compound (S)-8 was isolated in 90% yield.
N H
CF3 O S N H
(S)(S)-5
CF3 NH2
1) ag HCl, MeOH, rt, 4h 2) Et3N, CH2Cl2, rt, 1h
N H (S)-8 90% yield
Scheme 1. Deprotection procedure for preparation of free amine (S)-8.
The second major objective of this study was the development of approach for preparing 7
Page 7 of 27
functionalized indoles of type 3 (Figure 1) bearing pharmacophoric (2,2,2-trifluoro)ethylamine moiety in the position-2 of the pyrrole ring. This structural type 3 can be assembled by the corresponding addition reactions between 2-lithiated indoles and (S)-N-sulfinyl imine 1. From our own experience in the reactions of lithiated aromatics and hetero-aromatics with imines (S)- and
ip t
(R)-1 [12] we have learned that proper protection of additional functional groups in the starting compounds is of paramount importance. Therefore, based on our own practice and drawing from
cr
the results reported by Chen group [16] we selected N-phenylsulfonylindoles 9 (Table 3) as the starting substrates to study the addition reactions with imine (S)-1.
us
Our first choice of a base, LiHMDS (entry 1), gave rather disappointing result as a complex mixture of products was formed, including decomposition of the staring imine (S)-1. On the other
an
hand, application of less bulker n-BuLi as a base, furnished the desired product 10 in good chemical yield and excellent diastereoselectivity (entry 2). Further experimentations allowed us to
M
identify LDA as the lithiating reagent providing noticeably improved yield and the diastereoselectivity. As shown in entry 3, the reaction of indole 9 with imine (S)-1 gave rise to
d
product 10 which was isolated in 85% yield as virtually pure diastereomer. Further optimization by changing the reaction solvent (entries 4 and 5) or temperature (entries 6 and 7) did not give the
Ac ce p
te
desired improvement.
Table 3 Optimization of the reaction conditions of indole 9 with imine (S)-1.a
+ F3C N SO2Ph
9
N
O S
Base, 2 h
N
CF3 O S N H SO2Ph
Solvent
(S)-1
(S)(S)-10 + (S)(R)-10
Entry
Base
Solvent
Temp. (oC)
Yield (%)b
Dr c
1
LiHMDS
THF
-78
mixture
---
2
n-BuLi
THF
-78
70
98:2
3
LDA
THF
-78
85
99:1
4
LDA
Toluene
-78
57
98:2
5
LDA
CH2Cl2
-78
0
---
8
Page 8 of 27
a
6
LDA
THF
-40
42
99:1
7
LDA
THF
rt
40
90:10
Reaction conditions: sulfinylimine 1 (1 mmol), indole 9 (1.25 mmol), base (1.5 mmol). b Isolated
yields of major diastereomers. c The diastereomeric ratio was determined by 19F-NMR using crude
ip t
reaction mixtures.
cr
Under the standard reaction conditions, we investigated series of substituted indoles 11 (Table 4) bearing various groups in all possible positions of an indole frame. First, we tried
us
substrate 11a bearing a methyl group on the pyrrole ring. The reaction of imine (S)-1 with lithiated indole 11a (entry 1) proceeded quite smoothly to give 12a with a bit lower diastereoselectivity, as
an
compared with that observed in the reaction of unsubstituted indole 9 (Table 3, entry 3 vs. Table 4, entry 1). Moving a substituent to the position-4 on the indole phenyl ring, compounds 11b,c
M
(entries 2 and 3), resulted in noticeable increase of both chemical yield and diastereoselectivity. For example, the reaction of 4-Cl indole 11b furnished product 12b (entry 2) in rather good 90%
d
yield and 98:2 ratio of diastereomers. Even better results were observed in the reaction of 4-CN derivative 11c affording 12c as virtually single product in 93% yield (entry 3). The same excellent
te
diastereoselectivity was recorded in the reactions of 5-substitued indoles 11d-f (entries 4-6). Thus,
Ac ce p
electron-donating (MeO, entry 4) and electron-withdrawing (NO2, entry 6) groups had no any apparent effect on the preparation of the corresponding products 12d-f in good yield and virtually
diastereomerically pure form. Introduction of a methyl group in the position-7 on the indole also did not influence the excellent diastereoselectivity. The reaction of derivative 11g gave pure diastereomer 12g (entry 7) albeit in moderate chemical yield. Comparing the results between the reactions of 3- and 7-methyl substituted derivatives 11a and 11g (entry 1 vs. 7) one might
conclude that the position-3, in some way, can influence integrity of the corresponding transition state and therefore very important for mechanistic considerations.
Table 4 Substrate generality of the reactions of indoles 11 with imine (S)-1.a
9
Page 9 of 27
O S
R
+ N SO2Ph
F3C
N
11
THF -78oC 2 h R
(S)-1
N
SO2Ph (S)(S)-12 + (S)(R)-12
Entry
R
Product
Yield (%)b
1
3-CH3
12a
74
2
4-Cl
12b
90
3
4-CN
12c
93
4
5-MeO
12d
87
5
5-Br
12e
6
5-NO2
12f
7
7-CH3
12g
Dr c
96:4
us
cr
98:2 99:1 99:1 99:1
89
99:1
55
99:1
an
70
Reaction conditions: sulfinylimine 1 (1 mmol), indole 10 (1.25 mmol), base (1.5 mmol).
M
a
LDA
CF3 O S N H
R
ip t
R
Isolated yields of major diastereomers. c The diastereomeric ratio was determined by
F-NMR
d
using crude reaction mixtures
19
b
te
With this in mind, and taking advantage of good crystallinity of 3-methyl substituted
Ac ce p
derivative 12a (Table 4, entry 1), we conducted crystallographic analysis of this compound. As shown in Figure 4, 12a has (S) absolute configuration of the newly generated stereogenic carbon.
Stereochemical (Ss)(S) assignment of other products 10 (Table 3) and 12b-g (Table 4) was made
accordingly, based on similarity of their spectral and chiroptical properties with the compound 12a.
10
Page 10 of 27
ip t cr
an
us
Figure 4. Crystallographic structure of compound (S)(S)-12a.
Having determined the (S)(S) absolute configuration of products 10 and 12a-g, we can discuss a plausible mechanistic rationale for the reactions of 2-lithiated indoles with imine (S)-1.
M
Figure 5 presents three possible transition states (TSs) A, B and C which can be proposed for the
N F3C N H
O
S
H N
Fig. 5.
Li N
O S O S O Ph
O
B
H
N
O
Ph
A
O S
CF3
S
Ac ce p
Li
te
d
formation of the (Ss)(S) configured compounds 10 and 12a-g.
O
N CF 3 O S
Li
Ph C
Plausible transition states in the reactions of 2-lithiated indoles with imine (S)-1.
Considering TSs A-C one might agree that only TSs A and B can account for the observed effect of a substituent in the position-3 on the stereochemical outcome of these reactions. Thus, in TS C the stereocontrolling CF3-group [17] is pointing away from the position-2 avoiding any steric interactions. On the other hand, in TSs A and B the trifluoromethyl group is in close proximity to the positin-2 and therefore, could be sterically interacting with the substituent. Now, comparing TSs A and B it is easy to notice that TS B seems rather sterically crowded as the 11
Page 11 of 27
N-sulfinyl and N-phenyl sulfonyl groups are overlapped suggesting multiple electrostatic repulsive interactions between the sulphur and the oxygen atoms. On the other hand, in the TS A, the position of N-sulfinyl and N-phenyl sulfonyl groups allows for additional coordination to lithium atom via sterically favourable six-membered ring. Consequently, we propose that the addition
ip t
reactions under study occur through TS A providing for excellent diastereoselectivity in the case
of substituent in any position on the phenyl ring and a bit reduced stereocontrol in the reactions of
cr
2-substituted substrates.
Finally, we decided to carry out the N-sulfinyl deprotection procedure. To this end we subjected
us
indole (S)(S)-10 to standard acidic hydrolytic conditions. As presented in Scheme 2, the process
CF3
1) aq HCl, MeOH, rt, 4h 2) Et3N, CH2Cl2, rt, 1h
M
CF3 O S N N H SO2Ph
an
proceeded quite smoothly and the target free amino compound (S)-13 was isolated in 87% yield.
87% yield
NH2
SO2Ph (S)-13
d
(S)(S)-10
N
Ac ce p
3. Conclusions
te
Scheme 2. Deprotection procedure for preparation of compound (S)-13.
The study described here demonstrates that asymmetric functionalization of the pyrrole ring
of indoles with (2,2,2-trifluoro)ethylamine moiety can be accomplished chemo-selectively in the positions-2 or -3 using CF3-imine (S)-1 as a common reagent. In particular, the target 2-substitued
derivatives can be synthesised by the reactions of N-protected (Ts group) 2-lithiated indoles with
imine (S)-1 leading to the target products of (S)(S) absolute configuration. On the other hand, preparation of the (S)(S)-3-substituted isomers can be achieved using BF3·Et2O-promoted
Friedel-Crafts reactions of free NH indoles. Both approaches show wide substrate scope, resulting in excellent diastereoselectivities and chemical yields. The described data render this methodology as a reliable synthetic access to two novel classes of trifluoromethyl-containing indoles of high pharmaceutical potential.
12
Page 12 of 27
4. Experimental 4.1 General information All reagents were obtained from commercial suppliers and used without further purification.
ip t
Indoles with different protecting groups were synthesized according to literatures [18]. The reactions were conducted in a closed system under an atmosphere of N2 and were monitored by
cr
TLC. Solvents were dried and distilled prior to use. Flash chromatography was performed using
silica gel 60 (200-300 mesh). Thin layer chromatography was carried out on silica gel 60 F-254 13
C and
19
F NMR spectra were recorded on a Bruker
us
TLC plates of 20 cm × 20 cm. 1H,
AVANCE400M spectrometer. Melting points are uncorrected. Values of optical rotation were
an
measured on Rudolph Automatic Polarimeter A21101. Infrared spectra were obtained on Bruker Vector 22 in KBr pellets. HRMS were recorded on a LTQ-Orbitrap XL (Thermofisher, U. S. A.).
M
4.2 Typical procedure for the Friedel-Crafts reaction of unprotected indoles and CF3-sulfinylimine
d
To a solution of indole 6 (1.2 mmol) in anhydrous CH2Cl2 (5 mL) at -78 oC was added BF3·Et2O (130 μL, 1.0 mmol) dropwise. Then the solution of CF3-sulfinylimine 1 (201 mg, 1.0
te
mmol) in CH2Cl2 (2 mL) was added in one portion. Stirring was continued with the reaction
Ac ce p
temperature rose to room temperature slowly. Then the reaction was run for 10 h and quenched with H2O (10 mL). The organic layer was taken and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (2× 30 mL) and brine solution (1 × 30 mL) and dried over anhydrous Na2SO4. The solvent was evaporated, and the crude
mixture was charged onto silica gel and purified through flash chromatography (elute: PE/EtOAc = 1:1) to furnish the corresponding product 7. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethyl)propane-2-sulfinamide (5). Pale
yellow solid, mp: 154–155 oC. Yield: 248 mg (78%). [α]D25 = +109.17 (c = 0.70, CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.38 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.26-7.18 (m, 1H), 7.16-7.12 (m, 2H), 5.16 (qd, J = 8.0, 4.0 Hz, 1H), 4.12 (d, J = 4.0 Hz, 1H), 1.24 (s, 9H).
13
C NMR (101 MHz, CDCl3): δ 136.7, 126.7, 125.9, 125.3 (q, JFC = 282.8 Hz),
122.5, 120.1, 119.9, 112.0, 104.9, 56.1, 54.9 (q, 3JFC = 32.3 Hz), 22.6.
19
F NMR (376 MHz,
13
Page 13 of 27
CDCl3): δ -73.90. IR (cm-1): 2957, 2923, 2852, 1462, 1266, 1254, 1174, 1118, 1068, 1032, 750. HRMS (TOF MS ESI): calcd for C14H17F3N2OSNa [M+Na]+ 341.0911, found 341.0911. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(2-methyl-1H-indol-3-yl)ethyl)propane-2-sulfinamide (7a). White solid, mp: 175-176 oC. Yield: 289 mg (87%). [α]D25 = +172.91 (c = 0.79, CHCl3). 1H
ip t
NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.16-7.06 (m, 2H), 5.09 (qd, J = 7.8, 2.9 Hz, 1H), 4.00 (d, J = 2.3 Hz, 1H), 2.35 (s, 3H), 1.23 (s,
119.9, 111.0, 100.1, 55.6, 54.0 (q, 3JFC = 32.3 Hz), 22.6, 11.7.
19
cr
9H). 13C NMR (101 MHz, CDCl3): δ 137.2, 135.6, 126.8, 125.7 (q, JFC = 282.8 Hz), 121.5, 120.1, F NMR (376 MHz, CDCl3): δ
us
-73.50. IR (cm-1): 3410, 3285, 3217, 3197, 1459, 1367, 1284, 1270, 1165, 1152, 1128, 1076, 1052, 755, 731. HRMS (TOF MS ESI): calcd for C15H19F3N2OSNa [M+Na]+ 355.1068, found
an
355.1065.
(S)-N-((S)-1-(4-chloro-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide
M
(7b). White solid, mp: 174-175 oC. Yield: 212 mg (60%). [α]D25 = -40.82 (c = 0.59, CHCl3). 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 7.26 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.99-6.93 (m, 1H), 6.11 (s, 1H), 4.18-4.10 (m, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.4, 125.9,
19
F NMR (376 MHz, CDCl3): δ -73.38. IR (cm-1): 3256, 1368, 1341, 1271, 1249, 1181,
te
22.5.
d
125.2 (q, JFC = 282.8 Hz), 124.8, 122.8, 122.7, 121.3, 111.0, 106.3, 56.7, 53.4(q, 3JFC = 32.3 Hz),
Ac ce p
1167, 1123, 1065, 1009, 733. HRMS (TOF MS ESI): calcd for C14H16ClF3N2OSNa [M+Na]+ 375.0522, found 375.0518.
(S)-N-((S)-1-(5-bromo-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide
(7c). White solid, mp: 70-71oC. Yield: 246 mg (62%). [α]D25 = +129.43 (c = 0.67, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 7.81 (s, 1H), 7.29-7.25 (m, 1H), 7.19-7.15 (m, 2H), 5.16-5.07 (m, 1H), 4.26 (d, J = 4.0 Hz, 1H), 1.27 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 135.3,
127.8, 127.5, 125.4, 125.0 (q, JFC = 282.8 Hz), 122.5, 113.4, 113.4, 104.4, 56.3, 54.7 (q, 3JFC = 32.3 Hz), 22.6. 19F NMR (376 MHz, CDCl3): δ -73.90. IR (cm-1): 3421, 3245, 2962, 2924, 1458, 1367, 1269, 1174, 1125, 1055, 1012, 886, 798. HRMS (TOF MS ESI): calcd for C14H16BrF3N2OSNa [M+Na]+ 419.0017, found 419.0009. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-nitro-1H-indol-3-yl)ethyl)propane-2-sulfinamide (7d). Yellow solid, mp: 165-166 oC. Yield: 327 mg (90%). [α]D25 = +128.15 (c = 0.68, CHCl3). 1H 14
Page 14 of 27
NMR (400 MHz, CDCl3): δ 9.93 (s, 1H), 8.65 (s, 1H), 8.09 (dd, J = 9.0, 2.2 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 5.23-5.14 (m, 1H), 4.24 (d, J = 4.0 Hz, 1H), 1.29 (s, 9H). 13
C NMR (101 MHz, CDCl3): δ 142.3, 139.6, 129.7, 125.2, 124.8 (q, JFC = 282.8 Hz), 118.4,
117.7, 111.9, 107.6, 56.4, 54.5 (q, 3JFC = 32.3 Hz), 22.6. 19F NMR (376 MHz, CDCl3): δ -74.03.
ip t
IR (cm-1): 3345, 2924, 1523, 1474, 1336, 1265, 1174, 1128, 1031, 739, 675. HRMS (TOF MS ESI): calcd for C14H16F3N3O3SNa [M+Na]+ 386.0762, found 386.0759.
cr
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-methoxy-1H-indol-3-yl)ethyl)propane-2-sulfinami
de (7e). Brown solid, mp: 84-85 oC. Yield: 237 mg (68%). [α]D25 = +83.92 (c = 0.80, CHCl3). 1H
us
NMR (400 MHz, CDCl3): δ 9.19 (s, 1H), 7.21 (d, J= 8.8 Hz, 1H), 7.15 (d, J= 2.6 Hz, 1H), 7.10 (d, J= 1.8 Hz, 1H), 6.86 (dd, J= 8.0, 2.0 Hz, 1H), 5.11 (qd, J= 8.0, 4.0 Hz, 1H), 4.09 (d, J= 4.0 Hz,
an
1H), 3.80 (s, 3H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 154.3, 131.7, 127.2, 126.3, 125.3 (q, JFC = 282.8 Hz), 112.9, 112.6, 104.6, 101.6, 55.9, 55.7, 54.8 (q, 3JFC = 32.3 Hz), 22.6. 19F NMR
M
(376 MHz, CDCl3): δ -73.80. IR (cm-1): 3243, 2959, 2925, 1489, 1461, 1442, 1367, 1269, 1215, 1171, 1121, 1040, 802, 696. HRMS (TOF MS ESI): calcd for C15H19F3N2O2SNa [M+Na]+
d
371.1017, found 371.1015.
Methyl-3-((S)-1-((S)-1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-1H-indole-5-carb
te
oxylate (7f). White solid, mp: 92-93 oC. Yield: 293 mg (78%). [α]D25 = +126.91 (c = 0.65,
Ac ce p
CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.44 (s, 1H), 7.92 (dd, J = 8.6, 1.5 Hz, 1H), 7.38-7.29 (m, 2H), 5.18 (qd, J = 8.0, 4.0 Hz, 1H), 4.11 (d, J = 4.0 Hz, 1H), 3.91 (s, 3H), 1.25 (s,
9H). 13C NMR (101 MHz, CDCl3): δ 168.2, 139.2, 127.9, 125.5, 125.0 (q, JFC = 281.8 Hz), 123.7, 122.9, 122.1, 111.7, 106.4, 56.3, 54.5 (q, 3JFC = 32.3 Hz), 51.9, 22.6.
19
F NMR (376 MHz,
CDCl3): δ -74.02. IR (cm-1): 3274, 3214, 3184, 1697, 1438, 1355, 1301, 1279, 1243, 1170, 1130, 1046, 772, 750. HRMS (TOF MS ESI): calcd for C16H19F3N2O3SNa [M+Na]+ 399.0966, found
399.0964.
(S)-N-((S)-1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (7g). White solid, mp: 137-138 oC. Yield: 229 mg (65%). [α]D25 = +119.68 (c = 0.86, CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.80 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 8.6, 1.8 Hz, 1H), 5.16-5.07 (m, 1H), 4.25 (d, J = 4.0 Hz, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.1, 128.3, 127.4, 125.1 (q, JFC = 282.8 Hz), 124.4, 15
Page 15 of 27
120.9, 120.8, 111.9, 105.0, 56.2, 54.8 (q, 3JFC = 32.3 Hz), 22.6.
19
F NMR (376 MHz, CDCl3): δ
-73.95. IR (cm-1): 3368, 3307, 3226, 1367, 1263, 1173, 1126, 1068, 1040, 1029, 908, 812. HRMS (TOF MS ESI): calcd for C14H16 ClF3N2OSNa [M+Na]+ 375.0522, found 375.0519. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-methoxy-2-methyl-1H-indol-3-yl)ethyl)propane-2-
ip t
sulfinamide (7h). Yellow solid, mp: 164-165 oC. Yield: 235 mg (65%). [α]D25+ = + 195.11 (c =
0.61, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 7.10-7.05 (m, 2H), 6.78 (dd, J = 8.7,
cr
2.0 Hz, 1H), 5.05 (d, J = 6.6 Hz, 1H), 3.99 (s, 1H), 3.80 (s, 3H), 2.29 (s, 3H), 1.24 (s, 9H). 13C
NMR (101 MHz, CDCl3): δ 154.1, 137.8, 130.6, 127.3, 125.7 (q, JFC = 282.8 Hz), 111.5, 111.3, 19
F NMR (376 MHz, CDCl3): δ
us
102.5, 99.9, 55.7, 55.4, 53.9 (q, 3JFC = 32.3 Hz), 22.6, 11.8.
-73.42. IR (cm-1): 3259, 1489, 1456, 1272, 1216, 1166, 1137, 1126, 1098, 1063, 1037, 1029, 739,
an
607. HRMS (TOF MS ESI): calcd for C16H21 F3N2O2SNa [M+Na]+ 385.1174, found 385.1172. 4.3Procedure for deprotection of 5
M
Cleavage of the chiral tert-butylsulfinyl group was carried out in a 25 mL round-bottom flask where 0.5 mmol 5 and 5 mL MeOH were added. Then 1mL aqueous HCl (36%) was added
d
dropwise with stirring at room temperature. After 4 h when the reaction was completed by
te
monitoring of the TLC, volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and Et3N (15.0 mmol) was added. The mixture was stirred at rt for 1 h, then
Ac ce p
H2O (10 mL) was added. The organic layer was taken, washed with water and brine and dried with anhydrous Na2SO4. The mixture was filtered and concentrated. The crude product was
purified by layer chromatography to give product 8 in 90% yield. (S)-2,2,2-trifluoro-1-(1H-indol-3-yl)ethanamine (8). White solid, mp: 114-115 oC. Yield: 96
mg (90%). [α]D25 = -1.52 (c =0.66, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.28-7.22 (m, 1H), 7.21-7.15 (m,
1H), 4.78 (q, J = 8.0 Hz, 1H), 1.81 (s, 2H). 13C NMR (101 MHz, CDCl3): δ 136.1, 126.3 (q, JFC = 282.8 Hz), 126.1, 123.0, 122.7, 120.3, 119.2, 111.4, 110.9, 51.4 (q, 3JFC = 32.3 Hz).
19
F NMR
(376 MHz, CDCl3): δ -76.86. IR (cm-1): 3386, 3316, 3177, 1451, 1276, 1195, 1157, 1109, 957, 944, 815, 750, 618. HRMS (TOF MS EI+) m/z calcd for C10 H9F3N2 214.0718, found 214.0716. 4.4 Typical procedure for the Mannich reaction of N-phenylsulfonylindoles to CF3-sulfinylimine 16
Page 16 of 27
Into an oven-dried reaction vial flushed with N2 was taken N-phenylsulfonylindole 11 (1.25 mmol) and anhydrous THF (5 mL). The reaction vial was cooled to -78 oC and LDA (1 M in THF, 1.5 mL) was added dropwise with stirring. After the reaction was stirred for 1 h at -78oC, the solution of CF3-sulfinylimine 1 (201 mg, 1 mmol) in THF (2 mL) was added in one portion and
ip t
the mixture stirred at -78oC for 2 h. The reaction mixture was quenched by a saturated aqueous solution of NH4Cl (5 mL), followed by extraction with EtOAc (2 × 20 mL). The combined
cr
organic layers were washed with water (1 × 30 mL) and brine solution (1 × 30 mL) and dried
overanhydrous Na2SO4. Most of the solvent was removed under reduced pressure. The residue
us
was purified by flash chromatographyon silica gel (elute: PE/EtOAc = 1:1) to afford product 12. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)propane-2-su
an
lfinamide (10). White solid, mp: 77-78 oC. Yield: 390 mg (85%). [α]D25 = +43.24 (c = 0.44, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.49 (t,
M
J = 8.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.36-7.30 (m, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.18-6.09 (m, 1H), 4.27 (s, 1H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.8, 137.1, 134.2, 132.7, 129.4, 128.8, 126.6, 126.0, 124.3, 124.2 (q, JFC = 282.8 Hz), 121.7, 115.2, 113.9, 57.2, 54.3
d
(q, 3JFC = 32.3 Hz), 22.4. 19F NMR (376 MHz, CDCl3): δ -72.43. IR (cm-1): 2961, 1449, 1366,
te
1178, 1154, 1119, 1090, 1073, 751, 590, 573. HRMS (TOF MS ESI): calcd for
Ac ce p
C20H21F3N2O3S2Na [M+Na]+ 481.0843, found 481.0843. (S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(3-methyl-1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)pro
pane-2-sulfinamide (12a). White solid, mp: 159-160 oC. Yield: 350 mg (74%). [α]D25 = -62.94 (c
= 0.80, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H),
7.55-7.47 (m, 2H), 7.44-7.36 (m, 3H), 7.30 (t, J = 8.0 Hz, 1H), 6.55-6.46 (m, 1H), 4.00 (s, 1H), 2.37 (s, 3H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 138.3, 136.7, 134.0, 130.7, 129.2,
126.8, 126.5, 126.2, 124.7 (q, JFC = 282.8 Hz), 124.0, 123.0, 119.4, 115.5, 56.8, 54.2 (q, 3JFC =
32.3 Hz), 22.4, 10.4. 19F NMR (376 MHz, CDCl3): δ -71.88. IR (cm-1): 2955, 1449, 1369, 1252, 1228, 1187, 1172, 1152, 1089, 1078, 755, 743, 725, 592, 574. HRMS (TOF MS ESI): calcd for C21H23F3N2O3S2Na [M+Na]+ 495.10000, found 495.0998. (S)-N-((S)-1-(4-chloro-1-(phenylsulfonyl)-1H-indol-2-yl)-2,2,2-trifluoroethyl)-2-methylpro pane-2-sulfinamide (12b). White solid, mp: 70-71 oC. Yield: 443 mg (90%). [α]D25 = +89.37 (c = 17
Page 17 of 27
0.92, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.29-7.22 (m, 2H), 7.09 (s, 1H), 6.20-6.11 (m, 1H), 4.40 (d, J = 8.0 Hz, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.6, 137.6, 134.5, 133.5, 129.5, 127.7, 126.8, 126.7, 126.6, 124.0, 124.0 (q, JFC = 283.8 Hz), 113.6, 111.4, 57.2, 54.0
ip t
(q, 3JFC = 32.3 Hz), 22.4. 19F NMR (376 MHz, CDCl3): δ -72.39. IR (cm-1): 3225, 1370, 1254, 1223, 1178, 1155, 1119, 1091, 1069, 1050, 726, 591, 563. HRMS (TOF MS ESI): calcd for
cr
C20H21ClF3N2O3S2 [M+H]+ 493.0634, found 493.0630.
(S)-N-((S)-1-(4-cyano-1-(phenylsulfonyl)-1H-indol-2-yl)-2,2,2-trifluoroethyl)-2-methylprop
us
ane-2-sulfinamide (12c). White solid, mp: 81-82 oC. Yield: 450 mg (93%). [α]D25 = +123.12 (c = 0.80, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.32 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H),
an
7.60 (t, J = 8.0 Hz, 2H), 7.51-7.40 (m, 3H), 7.15 (s, 1H), 6.15-6.06 (m, 1H), 4.12 (d, J = 8.0 Hz, 1H), 1.25 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.5, 136.7, 135.9, 134.8, 130.5, 129.7, 128.8,
22.4.
19
M
126.7, 125.8, 123.8 (q, JFC = 283.8 Hz), 119.6, 117.1, 111.2, 104.7, 57.3, 54.0 (q, 3JFC = 32.3 Hz), F NMR (376 MHz, CDCl3): δ -72.25. IR (cm-1): 3261, 1379, 1249, 1185, 1161, 1122,
506.0796, found 506.0795.
d
1094, 1067, 726, 685, 587, 570. HRMS (TOF MS ESI): calcd for C21H20F3N3O3S2Na [M+Na]+
te
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-methoxy-1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)pr
Ac ce p
opane-2-sulfinamide (12d). Pale yellow solid, mp: 67-70 oC. Yield: 425 mg (87%). [α]D25 = +68.09 (c = 0.56, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.0
Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 2H), 6.99-6.93 (m, 2H), 6.87 (s, 1H), 6.11-6.02 (m, 1H), 4.04-3.97 (m, 1H), 3.80 (s, 3H), 1.23 (s, 9H). 13C NMR (101 MHz, CDCl3): δ
157.0, 137.7, 134.1, 133.2, 131.7, 129.9, 129.3, 126.5, 124.1 (q, JFC = 283.8 Hz), 116.3, 115.3,
114.0, 103.6, 57.1, 55.6, 54.4 (q, 3JFC = 32.3 Hz), 22.4. 19F NMR (376 MHz, CDCl3): δ -72.35. IR (cm-1): 3215, 2960, 2926, 1475, 1449, 1367, 1255, 1219, 1202, 1164, 1116, 1090, 1072, 1048, 724, 686, 598, 575. HRMS (TOF MS ESI): calcd for C21H23F3N2O4S2Na [M+Na]+ 511.0949,
found 511.0948. (S)-N-((S)-1-(5-bromo-1-(phenylsulfonyl)-1H-indol-2-yl)-2,2,2-trifluoroethyl)-2-methylpro pane-2-sulfinamide (12e). Yellow oil. Yield: 376 mg (70%). [α]D25 = +95.57 (c = 0.86, CHCl3). 1
H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 1.8 18
Page 18 of 27
Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.45-7.39 (m, 3H), 6.90 (s, 1H), 6.13-6.04 (m, 1H), 4.26 (d, J = 7.0 Hz, 1H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 137.6, 135.8, 134.5, 134.0, 130.5, 129.5, 128.8, 126.6, 124.3, 124.0 (q, JFC = 283.8 Hz), 117.7, 116.6, 112.8, 57.2, 54.1 (q, 3JFC = 32.3 Hz), 22.4. 19F NMR (376 MHz, CDCl3): δ -72.34. IR (cm-1): 3213, 2924, 1447, 1367, 1325,
ip t
1254, 1226, 1172, 1118, 1090, 1062, 1045, 727, 685, 596, 580. HRMS (TOF MS ESI): calcd for C20H20BrF3N2O3S2Na [M+Na]+ 558.9949, found 558.9947.
cr
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(5-nitro-1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)propa
ne-2-sulfinamide (12f). Pale yellow solid, mp: 108-109 oC. Yield: 448 mg (89%). [α]D25 = +81.16
us
(c = 0.80, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 1.6 Hz, 1H), 8.25-8.16 (m, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.10 (s, 1H), 6.12-6.03
an
(m, 1H), 4.12 (d, J = 8.0 Hz, 1H), 1.24 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 144.6, 139.7, 137.5, 136.0, 134.9, 129.8, 128.6, 126.8, 123.9 (q, JFC = 283.8 Hz), 120.8, 117.9, 115.4, 113.6,
M
57.3, 53.8 (q, 3JFC = 32.3 Hz), 22.3. 19F NMR (376 MHz, CDCl3): δ -72.16. IR (cm-1): 3209, 2963, 2926, 1524, 1449, 1380, 1346, 1252, 1233, 1181, 1162, 1120, 1089, 1076, 1044, 752, 726, 685,
526.0692.
d
595, 574. HRMS (TOF MS ESI): calcd for C20H20F3N3O5SNa [M+Na]+ 526.0694, found
te
(S)-2-methyl-N-((S)-2,2,2-trifluoro-1-(7-methyl-1-(phenylsulfonyl)-1H-indol-2-yl)ethyl)pro
Ac ce p
pane-2-sulfinamide (12g). Pale yellow solid, mp: 59-60 oC. Yield: 260 mg (55%). [α]D25 = +37.34 (c = 0.48, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.44 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0
Hz, 2H), 7.25 (t, J = 8.0 Hz, 2H), 7.21-7.12 (m, 3H), 6.84 (s, 1H), 6.01-5.91 (m, 1H), 4.07 (d, J = 8.0 Hz, 1H), 2.70 (s, 3H), 1.26 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 140.4, 136.5, 135.5, 133.8,
132.6, 130.1, 129.7, 128.5, 126.6, 125.8, 124.1 (q, JFC = 283.8 Hz), 119.5, 119.4, 57.4, 56.7 (q, 3
JFC = 32.3 Hz), 22.5, 21.7. 19F NMR (376 MHz, CDCl3): δ -72.21. IR (cm-1): 2958, 2923, 2852,
1450, 1367, 1255, 1182, 1147, 1117, 1083, 755, 722, 687, 619, 588. HRMS (TOF MS ESI): calcd for C21H23F3N2O3S2Na [M+Na]+ 495.1000, found 495.0998. 4.5 Procedure for deprotection of 10 Cleavage of the chiral tert-butylsulfinyl group was carried out in a 25 mL round-bottom flask
where 0.5 mmol 10 and 5 mL MeOH were added. Then 1 mL aqueous HCl (36%) was added dropwise with stirring at room temperature. After 6 h when the reaction was completed by 19
Page 19 of 27
monitoring of the TLC, volatiles were removed under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and Et3N (15.0 mmol) was added. The mixture was stirred at rt for 1 h, then H2O (10 mL) was added. The organic layer was taken, washed with water and brine and dried with anhydrous Na2SO4. The mixture was filtered and concentrated. The crude product was
ip t
purified by layer chromatography to give product 13 in 87% yield.
(S)-2,2,2-trifluoro-1-(1-(phenylsulfonyl)-1H-indol-3-yl)ethanamine (13). Yellow oil. Yield:
cr
154 mg (87%). [α]D25 = +6.21 (c = 0.87, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.85-7.81 (m, 2H), 7.56-7.47 (m, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.37-7.31 (m, 1H), 13
C NMR (101 MHz,
us
7.28-7.22 (m, 1H), 6.86 (s, 1H), 5.46 (q, J = 8.0 Hz, 1H), 1.96 (s, 2H).
CDCl3): δ 138.0, 136.9, 136.5, 134.1, 129.3, 129.1, 126.5, 125.7, 124.3, 125.5 (q, JFC = 283.8 Hz), 19
F NMR (376 MHz, CDCl3): δ
an
121.5, 115.2, 111.2 (d, J = 2.0 Hz), 51.2 (q, 3JFC = 32.3 Hz).
-74.87. IR (cm-1): 1449, 1368, 1268, 1236, 1178, 1159, 1115, 1090, 1044, 750, 725, 685, 591,
M
575, 559. HRMS (TOF MS ESI): calcd for [M+Na]+ C16H13F3N2O2SNa 377.0548, found
Acknowledgment
d
377.0545.
te
We gratefully acknowledge the financial support from the National Natural Science
Ac ce p
Foundation of China (No. 21102071). The Jiangsu 333 program (for Pan) is also acknowledged.
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cr
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cr
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te
d
M
3239–3241.
24
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2
R
N R1
CF3 O N S H (S)(S)
F3C
N
O S 2
R
(S)
F3C
N
O S
R2
(S)
BF3 Et2O N 1 up to 90% yield R up to 99:1 dr
N R1
(S)(S)
ip t
LDA up to 93% yield up to 99:1 dr Mannich reaction on position-2
CF3 O S N H
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te
d
M
an
us
cr
Friedel-Crafts reaction on position-3
25
Page 25 of 27
We described asymmetric functionalization of indoles with (2,2,2-trifluoro)ethylamine moiety by using chiral CF3-imine as a common reagent with chemo-selectivity in the positions-2 or -3, which proceeded through Mannich
Ac ce p
te
d
M
an
us
cr
ip t
reaction and Friedel-Crafts reaction respectively.
26
Page 26 of 27
Asymmetric functionalization of indoles with CF3–CH(NH2)- was accomplished. 2-Substitued product was obtained by reaction of 2-lithiated indoles and CF3-imine. Preparation of the 3-substituted isomers was achieved by Friedel-Crafts reactions.
Ac ce p
te
d
M
an
us
cr
ip t
These methods provide a way to fluorinated indoles of pharmaceutical potential.
27
Page 27 of 27