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DMAP catalyzed addition-cyclization reaction of 2-hydroxyphenyl-para-quinone methide with nitroalkenes: Facile entry into highly substituted chromane derivatives
Journal Pre-proofs DMAP catalyzed addition–cyclization reaction of 2-hydroxyphenyl-para-quinone methide with nitroalkenes: facile entry into highly substituted chromane derivatives Narsimulu Maripally, Venkatram R. Reddy, Ravikiran Donthi, Raghupathi Mutyala, Rajesh Chandra PII: DOI: Reference:
S0040-4039(19)31353-X https://doi.org/10.1016/j.tetlet.2019.151554 TETL 151554
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
2 October 2019 6 December 2019 17 December 2019
Please cite this article as: Maripally, N., Reddy, V.R., Donthi, R., Mutyala, R., Chandra, R., DMAP catalyzed addition–cyclization reaction of 2-hydroxyphenyl-para-quinone methide with nitroalkenes: facile entry into highly substituted chromane derivatives, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151554
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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.
© 2019 Published by Elsevier Ltd.
Tetrahedron Letters journal homepage: www.elsevier.com
DMAP catalyzed addition–cyclization reaction of 2-hydroxyphenyl-para-quinone methide with nitroalkenes: facile entry into highly substituted chromane derivatives Narsimulu Maripallya, Venkatram R. Reddya, Ravikiran Donthia, Raghupathi Mutyalaa, Rajesh Chandraa,b* Fluoro-Agro Chemicals Department, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India AcSIR, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India *Corresponding author: email: [email protected]; phone+91-4027191471 a b
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
The base catalyzed reaction of 2-hydroxyphenyl-para-quinone methide (p-QM) with nitroalkenes is reported. The DMAP catalyzed reaction afforded substituted chromane derivatives in excellent yields with moderate diastereoselectivity. The conversion of the initial products to other useful structures has also been achieved. 2009 Elsevier Ltd. All rights reserved.
Keywords: 2-Hydroxyphenyl-p-quinone methide Nitroalkene Michael addition – cyclization reaction Chromane derivatives
Quinone methides (QM), in their para- and ortho- iterations, have become valuable reactants in organic synthesis.1 The inherent electrophilic character of p-QM has found great utility, especially during the past decade, with several research groups reporting a plethora of reactivity patterns with a host of different nucleophilic counterparts.2 1,6-Addition, affording substituted phenol derivatives, and 1,6-addition followed by cyclization, giving spiro compounds, are archetypical reactivity patterns exhibited by p-QM (Scheme 1).3 para-Quinone methide with hydroxyphenyl substitution on the exocyclic double bond, introduced and studied by Ender’s group, is a versatile subclass of p-QMs.4 The structure includes a nucleophilic moiety in the form of a phenolic hydroxyl group in addition to the electrophilic p-QM architecture.5
Thus in reactions involving Ender’s p-QM, the reaction sequence can be triggered by either phenoxide (in base catalyzed nucleophilic
N R2
O
O
N
NC
tBu
O
O Centchroman Antiestrogen
O OH HO
O
OH OH
OH Catechin Antitumor agent
Ph
O
R R2 R
1
OH
O R1 OH
NO2
R1 NO2
OMe
OMe Dopamine D2 partial agonist Podophyllotoxin analogue Antimitotic agent
Figure 1. Representative biologically active chromane motifs.
Ac R2
OMe
O
Ar
G
H N
O
G = 9-Anthracenyl X = OH, SH
R3
OH tBu
tBu
O
MeO
O O OP X
1
R2
OH tBu
O
G tBu
R R
HN
Catanolide A Anti HIV O
catalyst
tBu
Feng and co-workers 6b
Ar
O
Me OTBS
uncatalyzed
N H
OH
HN HN
O
DMAP
Cromakalim Antihypertensive
R2
CO2R3
N H
tBu
Pengfei and co-workers 6a
3
N H
OH
O
B O
O
R1
A
OH O
F3C
R
N
S
R1
tBu
tBu
CF3
R1 N
O
O
O
catalyst
tBu
Enders and co-workers 4a
R
O
N
tBu O
R
O
OH
R3O2C
catalyst
R2
X
Yuan and co-workers6c
tBu
TsOH.H2O
X R
O NH Ac
R1
(racemic)
Scheme 1. Formal cycloaddition reactions of Ender’s p-QM:A) Prior art; B) Present study.
Tetrahedron Letters
2
addition to electrophiles) or by the addition of nucleophiles to the electrophilic p-QM moiety. Several electron deficient alkenes6 and alkynes7 have been reported to take part in the base catalyzed addition-cyclization reaction affording chromane and chromene derivatives. It is worth noting that chromanes/chromenes are important structural entities appearing in a variety of important natural and non-natural compounds (Fig. 1).8 In spite of the highly useful base catalyzed additioncyclization reaction of Ender’s p-QM with various electron deficient carbon-carbon multiple bonds (Scheme 1),9 there has not been any report on the reaction involving simple, acyclic electron deficient alkenes. This is quite surprising as there are reports involving the addition to simple electron deficient alkynes and even benzynes.10 This literature backdrop coupled with our own interest in p-QM chemistry prompted us to investigate the addition of Ender’s p-QM to simple electron deficient alkenes. Our choice of simple, acyclic alkenes was nitro alkenes, which in their own right, are a versatile class of reagents.11 Incidentally, the formation of tetrahydroquinolines via the formal [4+2] cycloaddition reaction of aza analogs of Ender’s p-QM (generated in situ) with nitroalkenes has been reported.11c The initial results of our studies are reported herein. OH
O tBu
tBu
tBu
NO2
tBu
Et3N (20 mol%) CHCl3, 25 °C
4
4
3 NO2
O 1 2 (±)-3aa
OH 1a
OH tBu
tBu
2a
3 NO2
1O 2 (±)-4aa 60:40
Scheme 2. Model reaction of 1a and 2a.
We initiated our studies by treating para-quinone methide (1a) with nitrostyrene (2a) in the presence of 20 mol% of triethylamine at 25 C in chloroform. The reaction was extremely slow; the conversion was less than 25% even after 24 h. The reaction mixture was maintained for 3 days, at which time no further conversion occurred. Further processing and analysis of crude mixture indicated that the product, resulting from the
tandem oxa-Michael – 1,6-addition, was formed in 75% yield as a 60:40 mixture of two diastereomers (Scheme 2). These diastereomers were separable by column chromatography and the major diastereomer (60%) was the all cis derivative 3aa as determined from the coupling constant values. In 3aa, where H2, H3 and H4 are all cis to one another, the H2 – H3 coupling and H3 – H4 coupling constants were 2.5 Hz and 1.8 Hz respectively. The corresponding coupling constants in 4aa, where H2, H3 and H4 are trans to each other, were 9.7 Hz and 10.9 Hz. The prolonged reaction time, generally observed in the reactions involving Ender’s p-QM,4a may presumably be due to the stability of the initially formed phenoxide ion. The oxa-Michael addition of the highly delocalized phenoxide anion to the nitroalkene may dictate the rate of the reaction. We then proceeded to optimize the reaction conditions and the results are summarised in Table 1. The first variable studied was the base employed (Entries 2-7, Table 1). Similar results were obtained when other alkyl amines, such as diethylamine and diisopropylethylamine, were employed (Entries 2 and 3, Table 1). However, the use of cyclic amines such as DMAP, DBU and DABCO resulted in an appreciable difference in the yield and diastereoselectivity (Entries 4-6, Table 1). In particular, DMAP afforded the product in 92% yield with a diastereomeric ratio of 70:30. Furthermore, we observed that the reaction did not proceed in the presence of Na2CO3. Having identified DMAP as the ideal catalyst for the conversion, we then went on to optimize the other reaction parameters. The reaction of (1a) and (2a) catalyzed by DMAP was conducted in various solvents at 25 C (Entries 8-12, Table 1). It became apparent that dichloromethane was ideal for this reaction as the yield of the product was near quantitative (95%, Entry 8, Table 1). However, the diastereoselectivity of the reaction could not be improved, and the product was still formed as a mixture of diastereomers in a 70:30 ratio. The long duration required for the conversion prompted us to study the effect of temperature. Thus, the reaction was carried out at 60 C in chloroform and at 90 C in toluene (Entries 14 and 15). However, elevation of the reaction temperature did not increase the rate of product formation, instead an intractable mixture of products resulted.
Table 1. Optimization of the reaction conditions OH
O tBu
tBu
tBu
NO2
OH
Entrya 1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e
Cat. TEA DEA DIPEA DMAP DBU DABCO Na2CO3 DMAP DMAP DMAP DMAP DMAP DMAP DMAP
2a
Solvent CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CH2Cl2 Toluene Xylene Acetonitrile Ethyl acetate CH2Cl2 CHCl3 Toluene
tBu
tBu
Cat. (20 mol%) NO2
solvent, 25 °C, T(days)
1a
OH tBu
T (d) 3 3 3 3 3 3 5 3 3 3 3 5 5 3 3
NO2
O
O
(±)-3aa
(±)-4aa
Yield (%)b 75 70 78 92 90 90 trace 95 90 88 90 trace nr 88 85
dr (3/4)f 60:40 58:42 65:35 70:30 67:33 68:32 70:30 68:32 64:36 65:35 70:30 70:30
Reactions were performed using cat (20 mol%), 1 (0.10 mmol), 2 (0.11 mmol) in 1.0 ml solvent. b Isolated yield. Control reaction without any catalyst. d Reaction at 60 °C. e Reaction at 90 °C, f Diastereomeric ratio determined by 1H-NMR spectroscopy of the crude reaction mixture. a c
Once the optimized reaction conditions were identified, we studied the scope and limitations of the reaction. Different nitroalkenes (2a-g) were reacted with quinonemethide 1a possessing an unsubstituted phenol ring (Entries 1-7, Table 2). It can be seen from Table 2 that the effect of a substituent is minimal. The electron rich ring substituted nitroalkene 2c and the electron deficient phenyl ring substituted nitroalkene 2e reacted similarly with 1a (Entries 3 and 5, Table 2). The thienyl substituted nitroalkene 2f also reacted effectively, however with lower yield and better diastereoselectivity (Entry 6), although in
this case, the product was formed as an inseparable mixture of the diastereomers 3af and 4af. In the case of alkyl substituted nitroalkene 2h, the product was formed in lower yield with a diasteromeric ratio of 60:40 (Entry 8). We then turned our attention to examining the substituent on the phenol ring of the quinonemethide 1, and found substituent effects to be minimal (Entries 9-13, Table 2). Interestingly, when the methyl group was present at position 5, we observed that the reaction became more selective with a diastereomeric ratio of 90:10 (Entry 13, Table 2).
Table 2. Substrate scope studies. O tBu
4
3
OH
tBu
2
NO2 R1
1 5 OH R 6 1a-f
tBu
OH tBu
tBu
tBu
DMAP (20 mol%)
CH2Cl2, 25 °C, T(days)
NO2 R
2a-h
O ±)-3
NO2
R1
R
O (±)-4
R1
Entrya
R
R1
T (d)
Products(3/4)
Yield(%)b
dr (3/4)c
1
H
Ph
2
3aa/4aa
95
70:30
2
H
4-BrC6H4
3
3ab/4ab
85
65:35
3
H
4-OMeC6H4
2
3ac/4ac
90
70:30
4
H
4-MeC6H4
2
3ad/4ad
87
66:34
5
H
4-CNC6H4
3
3ae/4ae
92
68:32
6d
H
Thienyl
3
3af/4af
80
80:20
7d
H
2,4-ClC6H3
3
3ag/4ag
75
70:30
8d
H
isobutyl
2
3ah/4ah
50
60:40
9
4F-
Ph
3
3ba/4ba
88
62:38
10
4Cl-
Ph
3
3ca/4ca
90
68:32
11
4Br-
Ph
3
3da/4da
85
65:35
12
4OMe
Ph
3
3ea/4ea
80
60:40
13d
5Me-
Ph
3
3fa/4fa
90
90:10
Reactions were performed using DMAP (20 mol%), 1 (0.1 mmol), 2 (0.11 mmol) in 1.0 ml solvent. Isolated yield, Diastereomeric ratio determined by 1H-NMR spectroscopy of the crude reaction mixture, d Inseparable diastereomers. a
b
c
OH
With a view to rendering the reaction enantioselective, chiral bases belonging to cinchona alkaloid family were employed in the reaction.12 To our dismay, none of the quinine, cinchonine, (DHQD)2Pyr or β-isocupridine did not impart much selectivity. Not only that, in those cases the reaction was inordinately long (Table 3).
OH tBu
tBu
c
d
The initial adduct can be converted to other useful structures through functional group transformations as depicted in Scheme 3. Reduction of the nitro group using Zn/AcOH13 afforded the corresponding primary amine 5 in excellent yield. In addition, the tert-butyl group, originally present in the starting p-QM for its stability, could be removed by treating the product with triflic anhydride (Scheme 3).14 Thus product 6 can be considered as resulting from the addition – cyclization reaction of unsubstituted p-QM with nitrostyrene.
4aa
tBu
NH2 O 5 yield 95% OH
NO2
3aa/ 4aa
Entry Cat. T (d) Yield (%) dr ee (%) 1 Quinine 7 60 70:30 11 2 Cinchonine 7 58 70:30 10 3 (DHQD)2Pyr 7 60 70:30 0 4 β-ICD 7 50 70:30 8 a Reactions were performed using cat. (20 mol%), 1a (0.10 mmol), 2a (0.11 mmol) in 1.0 ml solvent. b Isolated yield. c Diastereomeric ratio determined by 1H-NMR spectroscopy of the crude reaction mixture, d Enantiomeric excess determined by chiral HPLC of compound 3aa. b
Zn-AcOH 0 - 20 °C,3h
O
Table 3. Attempted asymmetric catalysis a
tBu
TfOH/Tf2O (1/10 v/v) toluene, 60 °C, 12h 3aa
NO2 O 6 yield 85%
Scheme 3. Functional group conversion of the initial adducts
In conclusion, we have identified an optimal catalyst system and condition for the reaction of 2-hydroxyphenyl-p-quinone methide (Ender’s p-QM) with nitroalkenes. To the best of our knowledge this is the first instance of an acyclic, electron deficient alkene reacting with 2-hydroxyphenyl-p-quinone methide. The products, substituted chromane derivatives, are formed in excellent yields with moderate diastereoselectivity. The functionally rich initial adduct could be converted to other useful compounds through functional group transformations. Our initial efforts to make the reaction enantioselective by using cinchona alkaloid based chiral bases were not successful. Further efforts in this direction are currently being carried out.
Acknowledgments
Tetrahedron
4
The financial support from Department of Biotechnology, New Delhi (6242-P85/RGCB/PMD/DBT/RJCH/2015) is gratefully acknowledged. MN, RM, RVR and RD thank CSIR, New Delhi for doctoral fellowships. We gratefully acknowledge the help received from Centre for NMR & Structural Chemistry and Analytical Chemistry & Mass Spectrometry, CSIR–IICT. Manuscript number IICT/Pubs./2019/312.
9. 10. 11.
References and notes 12. 1.
2.
3.
4.
5.
6.
7.
8.
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Highlights DMAP catalyzes the addition – cyclization reaction of Ender’s p-QM with nitroalkenes The products chroman derivatives are formed in excellent yields The products are formed with moderate to good diastereoselectivities The initial functionally rich adduct can be converted to useful structures in good yields
S0040-4039(19)31353-X https://doi.org/10.1016/j.tetlet.2019.151554 TETL 151554
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
2 October 2019 6 December 2019 17 December 2019
Please cite this article as: Maripally, N., Reddy, V.R., Donthi, R., Mutyala, R., Chandra, R., DMAP catalyzed addition–cyclization reaction of 2-hydroxyphenyl-para-quinone methide with nitroalkenes: facile entry into highly substituted chromane derivatives, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151554
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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.
© 2019 Published by Elsevier Ltd.
Tetrahedron Letters journal homepage: www.elsevier.com
DMAP catalyzed addition–cyclization reaction of 2-hydroxyphenyl-para-quinone methide with nitroalkenes: facile entry into highly substituted chromane derivatives Narsimulu Maripallya, Venkatram R. Reddya, Ravikiran Donthia, Raghupathi Mutyalaa, Rajesh Chandraa,b* Fluoro-Agro Chemicals Department, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India AcSIR, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India *Corresponding author: email: [email protected]; phone+91-4027191471 a b
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
The base catalyzed reaction of 2-hydroxyphenyl-para-quinone methide (p-QM) with nitroalkenes is reported. The DMAP catalyzed reaction afforded substituted chromane derivatives in excellent yields with moderate diastereoselectivity. The conversion of the initial products to other useful structures has also been achieved. 2009 Elsevier Ltd. All rights reserved.
Keywords: 2-Hydroxyphenyl-p-quinone methide Nitroalkene Michael addition – cyclization reaction Chromane derivatives
Quinone methides (QM), in their para- and ortho- iterations, have become valuable reactants in organic synthesis.1 The inherent electrophilic character of p-QM has found great utility, especially during the past decade, with several research groups reporting a plethora of reactivity patterns with a host of different nucleophilic counterparts.2 1,6-Addition, affording substituted phenol derivatives, and 1,6-addition followed by cyclization, giving spiro compounds, are archetypical reactivity patterns exhibited by p-QM (Scheme 1).3 para-Quinone methide with hydroxyphenyl substitution on the exocyclic double bond, introduced and studied by Ender’s group, is a versatile subclass of p-QMs.4 The structure includes a nucleophilic moiety in the form of a phenolic hydroxyl group in addition to the electrophilic p-QM architecture.5
Thus in reactions involving Ender’s p-QM, the reaction sequence can be triggered by either phenoxide (in base catalyzed nucleophilic
N R2
O
O
N
NC
tBu
O
O Centchroman Antiestrogen
O OH HO
O
OH OH
OH Catechin Antitumor agent
Ph
O
R R2 R
1
OH
O R1 OH
NO2
R1 NO2
OMe
OMe Dopamine D2 partial agonist Podophyllotoxin analogue Antimitotic agent
Figure 1. Representative biologically active chromane motifs.
Ac R2
OMe
O
Ar
G
H N
O
G = 9-Anthracenyl X = OH, SH
R3
OH tBu
tBu
O
MeO
O O OP X
1
R2
OH tBu
O
G tBu
R R
HN
Catanolide A Anti HIV O
catalyst
tBu
Feng and co-workers 6b
Ar
O
Me OTBS
uncatalyzed
N H
OH
HN HN
O
DMAP
Cromakalim Antihypertensive
R2
CO2R3
N H
tBu
Pengfei and co-workers 6a
3
N H
OH
O
B O
O
R1
A
OH O
F3C
R
N
S
R1
tBu
tBu
CF3
R1 N
O
O
O
catalyst
tBu
Enders and co-workers 4a
R
O
N
tBu O
R
O
OH
R3O2C
catalyst
R2
X
Yuan and co-workers6c
tBu
TsOH.H2O
X R
O NH Ac
R1
(racemic)
Scheme 1. Formal cycloaddition reactions of Ender’s p-QM:A) Prior art; B) Present study.
Tetrahedron Letters
2
addition to electrophiles) or by the addition of nucleophiles to the electrophilic p-QM moiety. Several electron deficient alkenes6 and alkynes7 have been reported to take part in the base catalyzed addition-cyclization reaction affording chromane and chromene derivatives. It is worth noting that chromanes/chromenes are important structural entities appearing in a variety of important natural and non-natural compounds (Fig. 1).8 In spite of the highly useful base catalyzed additioncyclization reaction of Ender’s p-QM with various electron deficient carbon-carbon multiple bonds (Scheme 1),9 there has not been any report on the reaction involving simple, acyclic electron deficient alkenes. This is quite surprising as there are reports involving the addition to simple electron deficient alkynes and even benzynes.10 This literature backdrop coupled with our own interest in p-QM chemistry prompted us to investigate the addition of Ender’s p-QM to simple electron deficient alkenes. Our choice of simple, acyclic alkenes was nitro alkenes, which in their own right, are a versatile class of reagents.11 Incidentally, the formation of tetrahydroquinolines via the formal [4+2] cycloaddition reaction of aza analogs of Ender’s p-QM (generated in situ) with nitroalkenes has been reported.11c The initial results of our studies are reported herein. OH
O tBu
tBu
tBu
NO2
tBu
Et3N (20 mol%) CHCl3, 25 °C
4
4
3 NO2
O 1 2 (±)-3aa
OH 1a
OH tBu
tBu
2a
3 NO2
1O 2 (±)-4aa 60:40
Scheme 2. Model reaction of 1a and 2a.
We initiated our studies by treating para-quinone methide (1a) with nitrostyrene (2a) in the presence of 20 mol% of triethylamine at 25 C in chloroform. The reaction was extremely slow; the conversion was less than 25% even after 24 h. The reaction mixture was maintained for 3 days, at which time no further conversion occurred. Further processing and analysis of crude mixture indicated that the product, resulting from the
tandem oxa-Michael – 1,6-addition, was formed in 75% yield as a 60:40 mixture of two diastereomers (Scheme 2). These diastereomers were separable by column chromatography and the major diastereomer (60%) was the all cis derivative 3aa as determined from the coupling constant values. In 3aa, where H2, H3 and H4 are all cis to one another, the H2 – H3 coupling and H3 – H4 coupling constants were 2.5 Hz and 1.8 Hz respectively. The corresponding coupling constants in 4aa, where H2, H3 and H4 are trans to each other, were 9.7 Hz and 10.9 Hz. The prolonged reaction time, generally observed in the reactions involving Ender’s p-QM,4a may presumably be due to the stability of the initially formed phenoxide ion. The oxa-Michael addition of the highly delocalized phenoxide anion to the nitroalkene may dictate the rate of the reaction. We then proceeded to optimize the reaction conditions and the results are summarised in Table 1. The first variable studied was the base employed (Entries 2-7, Table 1). Similar results were obtained when other alkyl amines, such as diethylamine and diisopropylethylamine, were employed (Entries 2 and 3, Table 1). However, the use of cyclic amines such as DMAP, DBU and DABCO resulted in an appreciable difference in the yield and diastereoselectivity (Entries 4-6, Table 1). In particular, DMAP afforded the product in 92% yield with a diastereomeric ratio of 70:30. Furthermore, we observed that the reaction did not proceed in the presence of Na2CO3. Having identified DMAP as the ideal catalyst for the conversion, we then went on to optimize the other reaction parameters. The reaction of (1a) and (2a) catalyzed by DMAP was conducted in various solvents at 25 C (Entries 8-12, Table 1). It became apparent that dichloromethane was ideal for this reaction as the yield of the product was near quantitative (95%, Entry 8, Table 1). However, the diastereoselectivity of the reaction could not be improved, and the product was still formed as a mixture of diastereomers in a 70:30 ratio. The long duration required for the conversion prompted us to study the effect of temperature. Thus, the reaction was carried out at 60 C in chloroform and at 90 C in toluene (Entries 14 and 15). However, elevation of the reaction temperature did not increase the rate of product formation, instead an intractable mixture of products resulted.
Table 1. Optimization of the reaction conditions OH
O tBu
tBu
tBu
NO2
OH
Entrya 1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e
Cat. TEA DEA DIPEA DMAP DBU DABCO Na2CO3 DMAP DMAP DMAP DMAP DMAP DMAP DMAP
2a
Solvent CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CH2Cl2 Toluene Xylene Acetonitrile Ethyl acetate CH2Cl2 CHCl3 Toluene
tBu
tBu
Cat. (20 mol%) NO2
solvent, 25 °C, T(days)
1a
OH tBu
T (d) 3 3 3 3 3 3 5 3 3 3 3 5 5 3 3
NO2
O
O
(±)-3aa
(±)-4aa
Yield (%)b 75 70 78 92 90 90 trace 95 90 88 90 trace nr 88 85
dr (3/4)f 60:40 58:42 65:35 70:30 67:33 68:32 70:30 68:32 64:36 65:35 70:30 70:30
Reactions were performed using cat (20 mol%), 1 (0.10 mmol), 2 (0.11 mmol) in 1.0 ml solvent. b Isolated yield. Control reaction without any catalyst. d Reaction at 60 °C. e Reaction at 90 °C, f Diastereomeric ratio determined by 1H-NMR spectroscopy of the crude reaction mixture. a c
Once the optimized reaction conditions were identified, we studied the scope and limitations of the reaction. Different nitroalkenes (2a-g) were reacted with quinonemethide 1a possessing an unsubstituted phenol ring (Entries 1-7, Table 2). It can be seen from Table 2 that the effect of a substituent is minimal. The electron rich ring substituted nitroalkene 2c and the electron deficient phenyl ring substituted nitroalkene 2e reacted similarly with 1a (Entries 3 and 5, Table 2). The thienyl substituted nitroalkene 2f also reacted effectively, however with lower yield and better diastereoselectivity (Entry 6), although in
this case, the product was formed as an inseparable mixture of the diastereomers 3af and 4af. In the case of alkyl substituted nitroalkene 2h, the product was formed in lower yield with a diasteromeric ratio of 60:40 (Entry 8). We then turned our attention to examining the substituent on the phenol ring of the quinonemethide 1, and found substituent effects to be minimal (Entries 9-13, Table 2). Interestingly, when the methyl group was present at position 5, we observed that the reaction became more selective with a diastereomeric ratio of 90:10 (Entry 13, Table 2).
Table 2. Substrate scope studies. O tBu
4
3
OH
tBu
2
NO2 R1
1 5 OH R 6 1a-f
tBu
OH tBu
tBu
tBu
DMAP (20 mol%)
CH2Cl2, 25 °C, T(days)
NO2 R
2a-h
O ±)-3
NO2
R1
R
O (±)-4
R1
Entrya
R
R1
T (d)
Products(3/4)
Yield(%)b
dr (3/4)c
1
H
Ph
2
3aa/4aa
95
70:30
2
H
4-BrC6H4
3
3ab/4ab
85
65:35
3
H
4-OMeC6H4
2
3ac/4ac
90
70:30
4
H
4-MeC6H4
2
3ad/4ad
87
66:34
5
H
4-CNC6H4
3
3ae/4ae
92
68:32
6d
H
Thienyl
3
3af/4af
80
80:20
7d
H
2,4-ClC6H3
3
3ag/4ag
75
70:30
8d
H
isobutyl
2
3ah/4ah
50
60:40
9
4F-
Ph
3
3ba/4ba
88
62:38
10
4Cl-
Ph
3
3ca/4ca
90
68:32
11
4Br-
Ph
3
3da/4da
85
65:35
12
4OMe
Ph
3
3ea/4ea
80
60:40
13d
5Me-
Ph
3
3fa/4fa
90
90:10
Reactions were performed using DMAP (20 mol%), 1 (0.1 mmol), 2 (0.11 mmol) in 1.0 ml solvent. Isolated yield, Diastereomeric ratio determined by 1H-NMR spectroscopy of the crude reaction mixture, d Inseparable diastereomers. a
b
c
OH
With a view to rendering the reaction enantioselective, chiral bases belonging to cinchona alkaloid family were employed in the reaction.12 To our dismay, none of the quinine, cinchonine, (DHQD)2Pyr or β-isocupridine did not impart much selectivity. Not only that, in those cases the reaction was inordinately long (Table 3).
OH tBu
tBu
c
d
The initial adduct can be converted to other useful structures through functional group transformations as depicted in Scheme 3. Reduction of the nitro group using Zn/AcOH13 afforded the corresponding primary amine 5 in excellent yield. In addition, the tert-butyl group, originally present in the starting p-QM for its stability, could be removed by treating the product with triflic anhydride (Scheme 3).14 Thus product 6 can be considered as resulting from the addition – cyclization reaction of unsubstituted p-QM with nitrostyrene.
4aa
tBu
NH2 O 5 yield 95% OH
NO2
3aa/ 4aa
Entry Cat. T (d) Yield (%) dr ee (%) 1 Quinine 7 60 70:30 11 2 Cinchonine 7 58 70:30 10 3 (DHQD)2Pyr 7 60 70:30 0 4 β-ICD 7 50 70:30 8 a Reactions were performed using cat. (20 mol%), 1a (0.10 mmol), 2a (0.11 mmol) in 1.0 ml solvent. b Isolated yield. c Diastereomeric ratio determined by 1H-NMR spectroscopy of the crude reaction mixture, d Enantiomeric excess determined by chiral HPLC of compound 3aa. b
Zn-AcOH 0 - 20 °C,3h
O
Table 3. Attempted asymmetric catalysis a
tBu
TfOH/Tf2O (1/10 v/v) toluene, 60 °C, 12h 3aa
NO2 O 6 yield 85%
Scheme 3. Functional group conversion of the initial adducts
In conclusion, we have identified an optimal catalyst system and condition for the reaction of 2-hydroxyphenyl-p-quinone methide (Ender’s p-QM) with nitroalkenes. To the best of our knowledge this is the first instance of an acyclic, electron deficient alkene reacting with 2-hydroxyphenyl-p-quinone methide. The products, substituted chromane derivatives, are formed in excellent yields with moderate diastereoselectivity. The functionally rich initial adduct could be converted to other useful compounds through functional group transformations. Our initial efforts to make the reaction enantioselective by using cinchona alkaloid based chiral bases were not successful. Further efforts in this direction are currently being carried out.
Acknowledgments
Tetrahedron
4
The financial support from Department of Biotechnology, New Delhi (6242-P85/RGCB/PMD/DBT/RJCH/2015) is gratefully acknowledged. MN, RM, RVR and RD thank CSIR, New Delhi for doctoral fellowships. We gratefully acknowledge the help received from Centre for NMR & Structural Chemistry and Analytical Chemistry & Mass Spectrometry, CSIR–IICT. Manuscript number IICT/Pubs./2019/312.
9. 10. 11.
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Highlights DMAP catalyzes the addition – cyclization reaction of Ender’s p-QM with nitroalkenes The products chroman derivatives are formed in excellent yields The products are formed with moderate to good diastereoselectivities The initial functionally rich adduct can be converted to useful structures in good yields