Synthesis of hydantoins and dihydrouracils via thermally-promoted cyclization of ureidoacetamides

Accepted Manuscript Synthesis of hydantoins and dihydrouracils via thermally-promoted cyclization of ureidoacetamides Michael C. Hillier, Hai-Hua Gong, Dean S. Clyne, Martin J. Babcock PII:

S0040-4020(14)01472-0

DOI:

10.1016/j.tet.2014.10.033

Reference:

TET 26103

To appear in:

Tetrahedron

Received Date: 10 September 2014 Revised Date:

13 October 2014

Accepted Date: 14 October 2014

Please cite this article as: Hillier MC, Gong H-H, Clyne DS, Babcock MJ, Synthesis of hydantoins and dihydrouracils via thermally-promoted cyclization of ureidoacetamides, Tetrahedron (2014), doi: 10.1016/ j.tet.2014.10.033. 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.

ACCEPTED MANUSCRIPT Graphical Abstract

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Synthesis of Hydantoins and Dihydrouracils via Thermally-Promoted Cyclization of Ureidoacetamides

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Michael C. Hillier,* Hai-Hua Gong, Dean S. Clyne, Martin J. Babcock Manufacturing Science and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Il 60064 USA

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Tetrahedron journal homepage: www.elsevier.com

Michael C. Hillier,∗ Hai-Hua Gong, Dean S. Clyne, Martin J. Babcock

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Synthesis of hydantoins and dihydrouracils via thermally-promoted cyclization of ureidoacetamides Manufacturing Science and Technology, AbbVie Inc., 1 North Waukegan Road, North Chicago, Il 60064, USA

ABSTRACT

Article history: Received Received in revised form Accepted Available online

The synthesis of hydantoins and dihydrouracils from ureidoacetamides has been carried out at high temperature in glycol solvents. A series of substrates were prepared and examined to determine the effect of substrate structure, N-acyl substitution (X), and solvent on the course of the reaction. A dramatic effect was observed when using ureidoacetamides (e.g. X = N-methylN-phenyl), which led to higher yields, faster reaction times, and lower racemization of chiral substrates. The rate of racemization of a chiral hydantoin in the presence of dibenzylamine and N-methyl aniline has also been determined. The thermal cyclization methodology has been applied to the preparation of a complex hydantoin.

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ARTICLE INFO

2009 Elsevier Ltd. All rights reserved.

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Keywords: Hydantoin Dihydrouracil Ureidoacid Ureidoacetamide Thermal cyclization

——— ∗ Corresponding author. Tel.: +001-847-935-5724; fax: +001-847-938-5932; e-mail: [email protected]

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Scheme 1. Synthesis of 5 via Thermal Cyclization of 4.

2. Results and Discussion 2.1. Substrate Preparation

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Substrates for this work were prepared by a two-step process (Table 1). The first step involved chemistry originally developed by Rivette and Wilshire for the acylation of amino acids with a carbamoyl chloride to give the corresponding ureidoacid.11 This chemistry was attractive since a variety of amino acids are commercially available and carbamoyl chlorides can be purchased or are easily synthesized.12 In our hands, two separate conditions were found to be effective for this reaction: 1) Procedure A - carbamoyl chloride (1.1 eq.), DIEA (2.0 eq.), THF:water (3:1), 50 ºC; or 2) Procedure B - carbamoyl chloride (1.1 eq.), K2CO3 (2.0 eq.), acetone:water (1:1), 70 ºC. In one case, the ureidoacid 7e13 (entry 5) was obtained in very low yield (ca. <5%) due to the relative instability of the acylating reagent (N,N-dibenzylcarbamic chloride), which decomposed over the longer reaction time required with this substrate. Two chiral ureidoacids were also prepared using this methodology starting from L-valine to give 7l and 7m (entries 12 and 13) with no racemization.14 Subsequent activation of the ureidoacids with 1,1’-carbonyldiimidazole (CDI) followed by coupling with benzylamine afforded the ureidoacetamides 8a-m in good yield. This methodology was also used for the preparation of more complex chiral substrates 4 (X = N,N-dibenzyl) and 11 (X = Nmethyl-N-phenyl) from the ureidoacids 7l and 7m and an amine 10 (Scheme 2).

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Hydantoins1 and dihydrouracils2,3 are common heterocyclic structures that can be found in a wide array of biologically active materials. Many methods have been developed for the preparation of these compounds, which often rely on the intramolecular cyclization of α- or β-amino acid derivatives to form the heterocyclic five or six membered ring (Figure 1). For example, treatment of ureidoacetates 1 (R = alkyl) with acid or base results in cyclization of the urea moiety onto the pendant ester thus providing a hydantoin1d,4,5 or dihydrouracil3,6 product 2. Alternatively, ureidoacids 1 (R = H) undergo cyclization in the presence of a strong acid1d,7 or with an activator2 to give the desired heterocycle. Carbonylation of amino amides 3 is another effective method for the preparation of hydantoin1d or dihydrouracil compounds.8 Cuny and co-workers have demonstrated that treatment of chiral amino amides with triphosgene provides the desired product 2 with no racemization.9 However, in many cases the chemistry required to prepare hydantoins or dihydrouracils is not compatible with chiral centers or sensitive functional groups, resulting in racemization and byproduct formation. In addition, substrate preparation can be lengthy and difficult.

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1. Introduction

Figure 1. General Approaches to Hydantoins and Dihydrouracils.

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We became interested in hydantoins, in particular, as part of a general program to prepare and evaluate a series of cytochrome P-450 oxidase inhibitors similar to 5 (Scheme 1).10 During this investigation it was serendipitously discovered that heating the ureidoacetamide 4 in a high-boiling alcohol solvent such as 1,2propanediol gave 5 in good yield (80%) along with a small amount of the over-reaction compound 6 (7%). Significant racemization was also observed at the valine stereocenter (d.r. = 2.5:1.0) of the desired product (5), which was improved only slightly (d.r. = 3.6:1.0) by recrystallization. Longer reaction times led to increasing amounts of the bis-cyclization product 6 and complete racemization of the valine stereocenter. Despite these results, we were intrigued by the unique hydantoin formation and sought to better understand the scope and limitations of this chemistry.

Scheme 2. Preparation of Complex Chiral Ureidoacetamides.

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Table 1. Preparation of Ureidoacetamide Substrates.

Starting Material Entry n

R1

R2

R3

1

0

H

H

H

2

0

H

H

3

0

H

4

0

H

Acylation Procedure

Carbamoyl Chloride (X)

Ureidoacid

Ureidoacetamide

7

Yield, %

8

Yield, %

A

a

67

a

77

CH3

A

b

70

b

71

H

H

B

c

92

c

91

H

H

B

d

71

d

73

CH3

CH3

H

A

e

<5

e

71

6

0

CH3

CH3

H

B

f

76

f

75

7

1

H

H

H

B

g

85

g

78

8

1

CH3

CH3

H

B

h

59

h

59

9

2

H

H

H

B

i

60

i

78

10

3

H

H

H

B

j

11

4

H

H

H

B

12

0

H

iPr

H

13

0

H

iPr

H

85

j

73

k

84

k

64

A

l

90

l

B

m

86

m

2.2. Thermocyclization

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Entry

2

5 6 7 8

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3 4

Yield (12a), %b

toluenea

NR

DMF

NR

diglyme

NR

1-hexanol

NR

2-heptanol

NR

cyclohexanol

NR

2-methoxyethanol

NR

ethylene glycol

87

1,3-propanediol

79

10

1,4-butanediol

72

11

1,2-propanediol

80

12

1,2-propanediol/water (1:1)

75 (27h)

13

2,3-butanediol

23

14

pinacol

54

glycerol

56 (14h)

9

15 a

Solvent

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1

b

63 (>99% e.e.) 93 (>99% e.e.)

yield) when diol solvents were employed (entries 8-11). Exceptions to this trend were 2,3-butanediol and pinacol (entries 13-14), which gave 12a in a moderate 34% and 54% yield, respectively. The use of 1,2-propane diol and water (1:1) resulted in a much slower reaction wherein the hydantoin was obtained in 75% yield after 27h. A similar result was observed with a triol solvent, glycerol (entry 15), in that 12a was formed in 56% yield after 14h. During the course of these investigations, the main by-products were found to be the solvent adduct carbamate derivatives similar to 13,15 and dibenzylamine 14.

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Initial laboratory experiments focused on the use of a simplified substrate 8a to evaluate the effect of solvent on the course of the thermal cyclization reaction (Table 2) over 9h. In the event, when 8a was heated in a non-protic medium (entries 13), very little or no reaction was observed and starting material was recovered. Utilization of mono-ol solvents (entries 4-7) gave low to moderate yields of the hydantoin 12a (5%-31%). A dramatic increase in product formation was observed (72-87% Table 2. Conversion of Ureidoacetamide 8a to Hydantoin 12a.

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Carried out in sealed vessel. Yield determined by quantitative HPLC assay. NR = no reaction.

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Replacing the dibenzylamine group (X) with diphenylamine 8c The next series of experiments (Table 3) were carried out to MANUSCRIPT ACCEPTED provided 12a in 79% yield, but the reaction took 7 days to go to determine the effect of the urea or carbamate substituent (X), and completion at 140 ºC. A dramatic improvement was observed nitrogen substitution (R) on the course of the reaction. Heating when the N-methyl-N-phenylamine containing substrate 8d was of 8a was repeated at a slightly elevated temperature (140 ºC) in evaluated, and product 12a was obtained in 98% yield after 2 hrs. 1,2-propanediol to give the hydantoin product 12a in 69% yield. Reaction of the monobenzyl ureidoacetamide 15 (X = NA lower yield was obtained compared to the previous run (Table benzyl)16 gave product in 56% yield and the reaction rate was 2, entry 1) due to decomposition of product in favor of the solvent adduct impurity 13. Interestingly, reaction of the Nslower compared to the initial dibenzyl substrate 8a (ca. 16h methyl compound 8b (R = CH3) under the same conditions versus 5h). The carbamate derivatives 1617 and 1718 did not react provided none of the corresponding N-methyl hydantoin 12b. under these conditions and starting materials were recovered.

R

1

8a

H

2

8b

CH3

3

8c

H

4

8d

H

5

15

H

6

16

H

7

17

H

a

X

Reaction Time

Product

Yield, %a

5h

12a

69

5h

12b

NR

7 days

12a

79

2h

12a

98

16 h

12a

56

5h

12a

NR

5h

12a

NR

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Yield determined by quantitative HPLC assay. NR = no reaction.

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Table 3. Effect of Nitrogen Substitution and N-Acyl Group (X).

Conversely, the use of N-methyl aniline provided 12l in 85% e.e. over the same time period. Clearly, the higher basicity of dibenzylamine (pKa = 8.76) compared to N-methyl aniline (pKa = 4.70) results in greater scrambling of the hydantoin chiral center after product is formed. Figure 2. Racemization of the Chiral Hydantoin 12l.

In order to understand the cause of racemization during the cyclization of 8l and 8m, the chiral hydantoin product 12l was subjected to the reaction conditions in the presence of dibenzylamine and N-methyl aniline, respectively (1 equiv.) The extent of racemization of the chiral center was plotted versus time (Figure 2) and dibenzylamine was found to cause nearly complete racemization (ca. 10% e.e.) after one hour at 140 ºC.

100 90 80 70 60 % e.e.

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Since urea moieties appeared to be critical for the thermocyclization reaction, the next series of compounds were intended to evaluate the effect of ureidoacetamide carbon chain substitution, length, and chirality (Table 4). For example, the dimethyl substituted compound 8e underwent cyclization to give the hydantoin 12e in 94% yield after 1h at 140 ºC. This increase in reaction rate compared to the unsubstituted derivative 8a (Table 4, entry 1) may result from a Thorpe-Ingold type acceleration due to the dimethyl substituents.17 Similar reactivity was observed with 8f (X = N-methyl-N-phenyl) wherein the hydantoin product 12e was obtained in 97% yield after only 30 min. Longer alkyl chain substrates 8g and 8h provided the corresponding dihydrouracil products 12g and 12h in 74% and 89% yield, respectively. However, attempts to prepare larger ring derivatives 12i-k (Table 4, entries 5-7) were not successful and the main products were solvent adduct carbamates similar to 13 (Table 2). Two chiral ureidoacetamides derived from L-valine were also examined (Table 4, entries 8-9). The N,N-dibenzyl substituted compound 8l was heated for 1h at 140 ºC to give the hydantoin 12l in 81% yield with complete racemization. Under the same conditions, the N-methyl-N-phenyl containing derivative 8m gave 12l in 61% yield with minimal erosion (97:3) of the valine chiral center. In all cases a major by-product of the cyclization was the corresponding amine (e.g. dibenzylamine, Nmethyl aniline).

Dibenzylamine

50 N-Methyl Aniline

40 30 20 10 0 0

10

20

30

40

Minutes

50

60

R1

R2

1

8e

0

CH3

2

8f

0

3

8g

4

X

Reaction Time, h

Product

Yield, %

CH3

1

12e

94

CH3

CH3

0.5

12e

97

1

H

H

3

12g

74

8h

1

CH3

CH3

1

12h

89

5

8i

2

H

H

24

12i

NDa

6

8j

3

H

H

24

12j

NDa

7

8k

4

H

H

24

12k

NDa

8

8l

0

H

iPr

1

12l

81 (e.r. = 1:1)

9

8m

0

H

iPr

1

12l

61 (e.r. = 97:3)

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Table 4. Effect of substrate structure.

Solvent adducts similar to 14 (Table 2) are the major products of this reaction.

ND = not detected, e.r. = enantiomer ratio.

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Having identified N-methyl-N-phenyl substituted ureidoacetamides as ideal cyclization substrates, the synthesis of the hydantoin 5 was re-examined. In the event, the appropriately substituted derivative 11 underwent cyclization in 1,2propanediol at 140 ºC for 2h to give 5 in 95% yield with minimal racemization at the valine stereocenter (98:2) (Scheme 3). In addition, only a small amount (ca. >0.5%) of the bis-cyclization product 6 (Scheme 1) was observed. These results are much improved compared to the initial N,N-dibenzyl substituted substrate 4 (Scheme 1), which suffered significant scrambling at the same chiral center and increased by-product formation. A single recrystallization of product isolated from this reaction gave 5 as essentially one diastereomer (>99%) in 70% isolated yield.

Scheme 3. Improved Preparation of 5.

3. Conclusion

A new method for the preparation of hydantoins and dihydrouracils via the thermal cyclization of ureidoacetamides in diol solvents has been demonstrated. Diol solvents appear to be important for this chemistry to occur, though the specific role of the reaction medium is not clear. It may be possible, however, that the slightly more acidic nature of diols (pka ≈ 14) versus mono-ol solvents (pKa ≈ 15) plays a role. Substrate structure and the nature of the urea moiety substitution have been shown to be important. In particular, ureidoacetamides containing N-methylN-phenyl ureas provide for relatively clean reactions with minimal racemization when using chiral substrates. This is likely due to the lower basicity of the N-methyl aniline by-product produced in this reaction, which causes less product racemization. The starting materials evaluated in this work were

prepared via an efficient two-step synthesis, which allows for access to both ureidoacid and ureidoacetamide compounds. Finally, the synthesis of a potential cytochrome P-450 inhibitor 5 was demonstrated using the thermal cyclization chemistry, wherein by-product formation and racemization were minimized using an optimized substrate. 4. Experimental section 4.1. General

Unless otherwise stated, solvents and reagents were reagent grade and used without further purification. Melting points ranges were determined on a Mel-Temp melting point apparatus and are uncorrected. 1H (400 MHz, 600 MHz, or 700 MHz) and 13 C (101 MHz, 151 MHz, or 176 MHz) NMR spectra were obtained using 400 MHz, 600 MHz or 700 MHz instruments as indicated in deuterated solvents, and chemical shifts are reported in parts per million (ppm). Coupling constants are reported in hertz (Hz). Spectral splitting patterns are designated as: ap, apparent; s, singlet; br, broad; d, doublet; t, triplet; q, quartet; m, multiplet; and comp, complex multiplet. Hi-resolution mass spectra (HRMS) were obtained using an electrospray ionization (ESI+) mass spectrometer. Determination of enantiomeric ratios for chiral products was carried out using a supercritical fluid chromatography (SFC) apparatus under the conditions and using the columns indicated. 4.2. Ureidoacid Formation General Procedures Procedure A: To the amino acid (1.0 mmol) in THF (2.7 mL) and water (0.9 mL) was added N,N-diisopropylethylamine (3.0 mmol) and the carbamoyl chloride (1.1 mmol). The resulting mixture was heated to reflux until judged complete by TLC or HPLC, cooled to rt and concentrated under reduced pressure. Conc. HCl (4.0 mmol) was added to neutralize base and the mixture was extracted with EtOAc. The combined organics were

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mmol) and the solution was extracted with EtOAc. The dried (MgSO4), filtered, and concentrated to give the crude MANUSCRIPT ACCEPTED combined organics were dried (MgSO4), filtered, and product as a solid mass. The material was purified by concentrated to crude product that was recrystallized from recrystallization from EtOAc/hexanes to give final product as a crystalline solid. Procedure B: A mixture of the amino acid EtOAc/hexanes to afford 1.77 g (74%) of 7e as a white solid: (1.0 mmol) in acetone (0.7 mL) and water (0.7 mL) was treated m.p. 101-102 ºC; 1H NMR (400 MHz, CDCl3) δ 8.02 – 6.60 (m, 10H), 4.69 (s, 1H), 4.53 (s, 4H), 1.41 (s, 6H); 13C NMR (101 with K2CO3 (3.4 mmol) and carbamoyl chloride (1.1 mmol), and was heated to reflux until reaction completion by TLC or HPLC. MHz, CDCl3) δ 175.8, 159.4, 136.4, 129.0, 128.0, 127.3, 57.8, The reaction was cooled to rt, neutralized by addition of conc. 51.0, 25.6; mass spectrum (ESI+) calcd. C19H22N2O3+H: M+H HCl (6.8 mmol), and extracted with EtOAc. The combined (theory), 327.1703; M+H (found), 327.1700. organics were dried (MgSO4), filtered, and concentrated to give 4.2.6. 2-Methyl-2-(3-methyl-3-phenylureido)propanoic acid (7f) crude product as a solid mass. The material was purified by 7f was prepared in 76% yield from aminobutyric acid and Nrecrystallization from EtOAc/hexanes to give final product as a methyl-N-phenylcarbamoyl chloride according to the general crystalline solid. uriedoacid formation procedure B as a white solid: m.p. 123-126 4.2.1. 2-(3,3-Dibenzylureido)acetic acid (7a) ºC; 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.32 (m, 5H), 4.67 (s, 7a was prepared in 67% yield from glycine and N,N1H), 3.31 (s, 3H), 1.46 (s, 6H); 13C NMR (101 MHz, CDCl3) δ dibenzylcarbamoyl chloride according to the general ureidoacid 176.4, 158.0, 142.5, 130.3, 127.9, 127.1, 57.1, 37.3, 25.7; mass formation procedure A as a white solid: m.p. 168-170 ºC; 1H spectrum (ESI+) calcd. C12H16N2O3+H: M+H (theory), NMR (400 MHz, DMSO-d6) δ 7.52 – 7.06 (m, 10H), 6.99 (t, J = 237.1234; M+H (found), 237.1235. 5.8 Hz, 1H), 4.35 (s, 4H), 3.70 (d, J = 5.7 Hz, 2H); 13C NMR 4.2.7. 3-(3-Methyl-3-phenylureido)propanoic acid (7g) (101 MHz, DMSO-d6) δ 172.5, 158.1, 138.2, 128.4, 127.3, 127.0, 7g was prepared in 85% yield from 3-aminopropanoic acid 48.5, 42.5; mass spectrum (ESI+) calcd. C17H18N2O3+H: M+H and N-methyl-N-phenylcarbamoyl chloride according to the (theory), 299.1390; M+H (found) 299.1388. general ureidoacid formation procedure B as a white solid: m.p. 4.2.2. 2-(3,3-Dibenzyl-1-methylureido)acetic acid (7b) 102-104 ºC; 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.15 (m, 5H), 7b was prepared in 70% yield from sarcosine and N,N4.94 (t, J = 6.1 Hz, 1H), 3.44 (q, J = 6.0 Hz, 2H), 3.27 (s, 3H), 2.56 (t, J = 6.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 176.3, dibenzylcarbamoyl chloride according to the general ureidoacid 1 formation procedure A as a white solid: m.p. 104-107 ºC; H 157.5, 142.9, 130.0, 127.5, 127.2, 37.2, 36.3, 34.7; mass spectrum (ESI+) calcd. C11H14N2O3+H: NMR (400 MHz, CDCl3) δ 7.47 – 7.25 (m, 6H), 7.23 – 7.14 (m, M+H (theory), 4H), 4.39 (s, 4H), 3.96 (s, 2H), 3.04 (s, 3H); 13C NMR (101 223.1077; M+H (found), 223.1082. MHz, CDCl3) δ 172.3, 166.1, 136.4, 128.7, 127.8, 127.6, 53.5, 4.2.8. 3-Methyl-3-(3-methyl-3-phenylureido)butanoic acid (7h) 50.8, 38.5; mass spectrum (ESI+) calcd. C18H20N2O3+H: M+H 7h was prepared in 59% yield from 3-amino-3-methylbutanoic (theory), 313.1547; M+H (found), 313.1541. acid and N-methyl-N-phenylcarbamoyl chloride according to the 4.2.3. 2-(3,3-Diphenylureido)acetic acid (7c) general ureidoacid formation procedure B as a white solid: m.p. 7c was prepared in 92% yield from glycine and N,N118-120 ºC; 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.20 (m, 5H), diphenylcarbamoyl chloride according to the general ureidoacid 4.72 (s, 1H), 3.24 (s, 3H), 2.81 (s, 2H), 1.36 (s, 6H); 13C NMR formation procedure B and the spectral data matched that (101 MHz, CDCl3) δ 175.6, 157.0, 143.1, 130.0, 127.4, 127.5, previously described.11 1H NMR (400 MHz, DMSO-d6) δ 7.79 – 51.7, 44.8, 37.0, 28.1; mass spectrum (ESI+) calcd. C13H18N2O3+H: M+H (theory), 251.1390; M+H (found), 6.78 (m, 10H), 6.23 (t, J = 5.8 Hz, 1H), 3.68 (d, J = 5.8 Hz, 2H). 251.1388. 4.2.4. 2-(3-Methyl-3-phenylureido)acetic acid (7d) 4.2.9. 4-(3-Methyl-3-phenylureido)butanoic acid (7i) 7d was prepared in 71% yield from glycine and N-methyl-N7i was prepared in 60% yield from 4-aminobutanoic acid and phenylcarbamoyl chloride according to the general ureidoacid formation procedure B as a white solid: m.p. 131-133 ºC; 1H N-methyl-N-phenylcarbamoyl chloride according to the general ureidoacid formation procedure B as a white solid: m.p. 115-117 NMR (400 MHz, CDCl3) δ 7.47 – 7.23 (m, 5H), 4.93 (t, J = 5.6 ºC; 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.00 (m, 5H), 4.50 (t, J Hz, 1H), 3.97 (d, J = 5.5 Hz, 2H), 3.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 173.1, 157.8, 142.4, 130.2, 127.9, 127.3, 43.1, = 5.9 Hz, 1H), 3.26 (m, 5H), 2.36 (t, J = 7.1 Hz, 2H), 1.78 (q, J = 6.9 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 177.0, 157.8, 37.5; mass spectrum (ESI+) calcd. C10H13N2O3+H: M+H (theory), 209.0921; M+H (found), 209.0918. 143.0, 130.1, 127.6, 127.4, 39.9, 37.3, 31.4, 25.7; mass spectrum (ESI+) calcd. C12H16N2O3+H: M+H (theory), 237.1234; M+H 4.2.5. 2-(3,3-Dibenzylureido)-2-methylpropanoic acid (7e) (found), 237.1233. A slurry of aminobutyric acid methyl ester, hydrochloride salt 4.2.10. 5-(3-Methyl-3-phenylureido)pentanoic acid (7j) i13 (10.2 g, 66.7 mmol) in CH2Cl2 (100 mL) was added to triphosgene (7.3 g, 24.6 mmol) in CH2Cl2 (50 mL) and stirred for 7j was prepared in 85% yield from 5-aminopentanoic acid and 10 min. The resulting crude solution was treated with N-methyl-N-phenylcarbamoyl chloride according to the general dibenzylamine (13.1 mL, 66.5 mmol) in CH2Cl2 (100 mL) ureidoacid formation procedure B as a white solid: m.p. 76-78 containing diisopropylethylamine (14 mL, 79.8 mmol) and the ºC; 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.21 (m, 5H), 4.42 (t, J mixture was stirred for 20 min. The resulting solid mass was = 5.8 Hz, 1H), 3.27 (s, 3H), 3.20 (q, J = 6.8 Hz, 2H), 2.35 (t, J = filtered and washed with CH2Cl2 to give 8.86g (39%) of ii as a 7.3 Hz, 2H), 1.67 – 1.54 (m, 2H), 1.55 – 1.36 (m, 2H); 13C NMR 1 white solid: m.p. 130-132 ºC; H NMR (400 MHz, CDCl3) δ (101 MHz, CDCl3) δ 177.9, 157.5, 143.2, 130.0, 127.4, 127.3, 7.66 – 7.03 (m, 10H), 4.86 (s, 1H), 4.48 (s, 4H), 3.75 (s, 3H), 40.3, 37.2, 33.5, 29.6, 21.8; mass spectrum (ESI+) calcd. 1.46 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 157.5, 137.4, 128.7, C13H19N2O3+H: M+H (theory), 251.1390; M+H (found), 127.5, 127.4, 127.3, 110.5, 56.6, 52.4, 50.1, 25.6; mass spectrum 251.1392. (ESI+) calcd. C20H24N2O3+H: M+H (theory), 341.1860; M+H 4.2.11. 6-(3-Methyl-3-phenylureido)hexanoic acid (7k) (found), 341.1856. To a mixture of ii in THF:H2O (20 mL:3 mL) 7k was prepared in 84% yield from 6-aminohexanoic acid Nwas added LiOH•H2O (0.5 g, 22.0 mmol) and the reaction was methyl-N-phenylcarbamoyl chloride according to the general heated at reflux for 1h. Solvent was removed in vacuo, and the ureidoacid formation procedure B as a white solid: m.p. 62-64 aqueous mixture was neutralized with conc. HCl (2.4 mL, 23.5

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43.0, 37.9; mass spectrum (ESI+) calcd. C25H27N3O2+H: M+H ºC; 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.20 (m, 5H), 4.39 – MANUSCRIPT ACCEPTED 4.32 (m, 1H), 3.27 (d, J = 0.7 Hz, 3H), 3.18 (dt, J = 7.2, 5.8 Hz, (theory), 402.2176; M+H (found), 402.2162. 2H), 2.34 (t, J = 7.4 Hz, 2H), 1.63 (ddd, J = 7.5, 7.5, 7.5 Hz, 4.4.3. N-Benzyl-2-(3,3-diphenylureido)acetamide (8c) 2H), 1.45 (ddd, J = 6.5, 8.0, 14.8 Hz, 2H), 1.37 – 1.21 (m, 2H); 13 8c as prepared from 7c and benzylamine according to the C NMR (101 MHz, CDCl3) δ 178.1, 157.5, 143.3, 130.0, 127.3, general ureidoacetamide formation procedure in 91% yield as a 40.6, 37.2, 33.8, 29.9, 26.2, 24.4; mass spectrum (ESI+) calcd. white solid: m.p. 147-149 ºC; 1H NMR (400 MHz, CDCl3) δ C14H20N2O3+H: M+H (theory), 265.1547; M+H (found), 7.50 – 7.13 (m, 16H), 5.42 (t, J = 5.3 Hz, 1H), 4.33 (d, J = 6.0 265.1553. Hz, 2H), 4.00 (d, J = 5.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 4.2.12. (S)-2-(3,3-Dibenzylureido)-3-methylbutanoic acid (7l) 169.4, 156.3, 142.2, 138.3, 129.4, 128.4, 127.4, 127.3, 127.1, 7l was prepared in 90% yield from L-valine and N,N126.5, 44.4, 43.1; mass spectrum (ESI+) calcd. C22H21N3O2+H: dibenzylcarbamoyl chloride according to the general ureidoacid M+H (theory), 360.1707; M+H (found), 360.1715. formation procedure A as an oil; [α]23D -2.2 (c 5.1, CH2Cl2); 4.4.4. N-Benzyl-2-(3-methyl-3-phenylureido)acetamide (8d) chiral SFC: >99.5% e.e.; Chiralpak ID column (4.6mm x 8d was prepared from 7d and benzylamine according to the 250mm), 3 mL/min., 10% MeOH in CO2 for 10 min., tR = 4.9 1 general ureidoacetamide formation procedure in 73% yield as a min. (R - minor), 5.4 min. (S - major); H NMR (400 MHz, white solid: m.p. 97-99 ºC; 1H NMR (400 MHz, CDCl3) δ 7.55 – CDCl3) δ 9.12 (bs, 1H), 7.50 – 7.20 (m, 10H), 5.14 – 4.84 (m, 7.18 (m, 12H), 5.15 (t, J = 5.3 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 1H), 4.65 – 4.49 (m, 4H), 4.43 (dd, J = 4.7, 8.1 Hz, 1H), 2.15 3.92 (d, J = 5.4 Hz, 2H), 3.16 (s, 3H); 13C NMR (101 MHz, (dd, J = 4.9, 6.9 Hz, 1H), 0.86 (d, J = 6.8 Hz, 3H), 0.71 (d, J = 13 CDCl3) δ 169.8, 157.2, 142.7, 138.1, 130.0, 128.5, 127.5, 127.5, 6.8 Hz, 3H); C NMR (101 MHz, CDCl3) δ 172.0, 158.0, 138.2, 127.2, 127.0, 44.5, 43.2, 37.1; mass spectrum (ESI+) calcd. 137.4, 128.9, 128.6, 127.6, 127.3, 127.2, 60.2, 50.7, 43.4, 30.5, C17H19N3O2+H: M+H (theory), 298.1550; M+H (found), 19.4, 17.7; mass spectrum (ESI+) calcd. C20H24N2O3+H: M+H 298.1558. (theory), 341.1860; M+H (found), 341.1869. 4.4.5. N-Benzyl-2-(3,3-dibenzylureido)-2-methylpropanamide 4.3. (S)-3-Methyl-2-(3-methyl-3-phenylureido)butanoic acid (7m) (8e) 7m was prepared in 86% yield from L-valine and N-methyl-N8e was prepared from 7e and benzylamine according to the phenylcarbamoyl chloride according to the general ureidoacid general ureidoacetamide formation procedure in 71% yield as a formation procedure B as a solid: m.p. 118-120 ºC; [α]23D +32.2 white solid: m.p. 178-182 ºC; 1H NMR (400 MHz, CDCl3) δ (c 1.61, CH2Cl2); chiral SFC: >99.5% e.e.; Chiralpak IC column 7.48 – 7.18 (m, 15H), 7.14 (t, J = 5.9 Hz, 1H), 4.75 (s, 1H), 4.51 (4.6mm x 250mm), 3 mL/min., 5% MeOH in CO2 to 10% MeOH (s, 4H), 4.46 (d, J = 5.7 Hz, 2H), 1.48 (s, 6H); 13C NMR (101 in CO2 over 10 min., tR = 7.8 min. (S - major), 8.1 min. (R MHz, CDCl3) δ 175.0, 157.4, 138.6, 137.3, 128.9, 128.6, 127.7, minor); 1H NMR (400 MHz, CDCl3) δ 8.81 (bs, 1H), 7.59 – 7.39 127.6, 127.2, 57.4, 50.7, 43.6, 26.0; mass spectrum (ESI+) calcd. (m, 5H), 4.81 (d, J = 8.4 Hz, 1H), 4.34 (dd, J = 5.1, 8.4 Hz, 1H), C26H29N3O2+H: M+H (theory), 416.2333; M+H (found), 3.30 (s, 3H), 2.15 (dd, J = 5.2, 6.9 Hz, 1H), 0.94 (d, J = 6.8 Hz, 416.2326. 3H), 0.77 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 4.4.6. N-Benzyl-2-methyl-2-(3-methyl-3-phenylureido) 175.7, 157.6, 142.6, 130.1, 127.7, 127.2, 58.9, 37.4, 30.4, 19.2, propanamide (8f) 17.6; mass spectrum (ESI+) calcd. C13H18N2O3+H: M+H 8f was prepared from 7f and benzylamine according to the (theory), 251.1390; M+H (found), 251.1397. general ureidoacetamide formation procedure in 75% yield as a 4.4. Ureidoacetamide Formation General Procedure white solid: m.p. 103-105 ºC; 1H NMR (700 MHz, CDCl3) δ 7.49 (t, J = 7.7 Hz, 2H), 7.43 – 7.19 (m, 9H), 4.79 (s, 1H), 4.52 To a slurry of the ureidoacid (1.0 mmol) in EtOAc (5 mL) at rt (d, J = 5.8 Hz, 2H), 3.30 (s, 3H), 1.53 (s, 6H); 13C NMR (176 was added 1,1’-carbonyldiimidazole (1.1 mmol). The resulting MHz, CDCl3) δ 175.1, 156.7, 143.2, 138.8, 130.2, 128.6, 127.6, mixture was stirred for 1h, heated to reflux, and treated with 127.5, 127.3, 127.1, 57.4, 43.6, 37.1, 26.1; mass spectrum (ESI+) benzylamine (1.1 mmol). This mixture was stirred for 1h at calcd. C19H23N3O2+H: M+H (theory), 326.1863; M+H (found), reflux, cooled to rt, washed with 10% citric acid, 5% NaHCO3, 326.1861. and brine followed by drying (MgSO4), filtration, and concentration in vacuo. The resulting crude material was 4.4.7. N-Benzyl-3-(3-methyl-3-phenylureido)propanamide (8g) purified by silica chromatography or recrystallized from 8g was prepared from 7g and benzylamine according to the EtOAc/hexanes to give purified product. general ureidoacetamide formation procedure in 78% yield as a white solid: m.p. 100-102 ºC; 1H NMR (700 MHz, CDCl3) δ 4.4.1. N-Benzyl-2-(3,3-dibenzylureido)acetamide (8a) 7.55 – 7.16 (m, 10H), 6.77 – 6.62 (m, 1H), 4.97 (t, J = 5.9 Hz, 8a was prepared from 7a and benzylamine according to the 1H), 4.43 (d, J = 5.9 Hz, 2H), 3.49 (q, J = 6.1 Hz, 2H), 3.25 (s, general ureidoacetamide formation procedure in 77% yield as a 3H), 2.47 (t, J = 6.0 Hz, 2H); 13C NMR (176 MHz, CDCl3) δ 1 white solid: m.p. 110-112 ºC; H NMR (400 MHz, CDCl3) δ 171.4, 157.5, 143.1, 138.5, 130.1, 128.7, 127.8, 127.4, 127.2, 7.41 – 7.17 (m, 15H), 7.13 (t, J = 5.9 Hz, 1H), 5.46 (t, J = 5.3 43.5, 37.2, 37.0, 36.8; mass spectrum (ESI+) calcd. Hz, 1H), 4.47 (s, 4H), 4.37 (d, J = 5.8 Hz, 2H), 3.96 (d, J = 5.2 C18H21N3O2+H: M+H (theory), 312.1707; M+H (found), 13 Hz, 2H); C NMR (101 MHz, CDCl3) δ 170.0, 158.4, 138.0, 312.1704. 137.0, 128.8, 128.5, 127.5, 127.3, 127.1, 50.1, 44.9, 43.3; mass spectrum (ESI+) calcd. C24H25N3O2+H: M+H (theory) 388.2020; 4.4.8. N-Benzyl-3-methyl-3-(3-methyl-3phenylureido)butanamide (8h) M+H (found) 388.2022. 8h was prepared from 7h and benzylamine according to the 4.4.2. N-Benzyl-2-(3,3-dibenzyl-1-methylureido)acetamide (8b) general ureidoacetamide formation procedure in 59% yield as a 8b was prepared from 7b and benzylamine according to the white solid: m.p. 122-123 ºC; 1H NMR (700 MHz, CDCl3) δ general ureidoacetamide formation procedure in 71% yield as an 7.72 – 7.22 (m, 8H), 7.10 (d, J = 7.9 Hz, 2H), 6.83 – 6.49 (m, oil; 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 5.6 Hz, 1H), 7.27 1H), 4.61 (s, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.16 (s, 3H), 2.76 (s, – 6.98 (m, 15H), 4.30 (d, J = 6.0 Hz, 2H), 4.24 (s, 4H), 3.78 (s, 2H), 1.35 (s, 6H); 13C NMR (176 MHz, CDCl3) δ 170.9, 157.0, 13 2H), 2.86 (s, 3H); C NMR (101 MHz, CDCl3) δ 167.0, 165.0, 143.3, 138.6, 130.0, 128.7, 127.9, 127.4, 127.2, 127.0, 52.5, 46.8, 138.2, 136.9, 128.6, 128.4, 127.5, 127.3, 127.2, 127.1, 54.7, 51.1,

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4.4.14. (S)-N-((2S,4S,5R)-5-Benzyl-4-hydroxy-6-imino-7-oxo-1,743.5, 36.8, 28.7; mass spectrum (ESI+) calcd. C20H25N3O2+H: MANUSCRIPT ACCEPTED diphenylheptan-2-yl)-2-(3,3-dibenzylureido)-3-methylbutanamide M+H (theory), 340.2020; M+H (found), 340.2028. (4) 4.4.9. N-Benzyl-4-(3-methyl-3-phenylureido)butanamide (8i) To slurry of benzyl tert-butyl ((2S,3S,5S)-3-hydroxy-1,68i was prepared from 7i and benzylamine according to the diphenylhexane-2,5-diyl)dicarbamate 919 (6.7 g, 12.8 mmol) in general ureidoacetamide formation procedure in 78% yield as a EtOAc (50 ml) was added excess conc. HCl (5.6 ml, 64.1 mmol) waxy off-white solid; 1H NMR (700 MHz, CDCl3) δ 7.51 – 7.22 and the reaction was stirred until judged complete by HPLC (m, 10H), 7.12 (t, J = 6.1 Hz, 1H), 4.63 (t, J = 6.0 Hz, 1H), 4.43 analysis. The resulting slurry was slowly quenched into a rapidly (d, J = 6.1 Hz, 2H), 3.38 – 3.09 (m, 5H), 2.26 (t, J = 7.2 Hz, 2H), stirred solution of aq. K2CO3 (10% w/w) (106 g, 77 mmol) and 13 1.77 (p, J = 6.9 Hz, 2H); C NMR (176 MHz, CDCl3) δ 172.8, the phases were separated. The organics were washed with aq. 157.7, 143.3, 138.7, 130.1, 128.6, 127.7, 127.4, 127.3, 127.2, NaCl (5% w/w), dried (MgSO4), and concentrated in vacuo and 43.5, 40.1, 37.2, 33.6, 26.7; mass spectrum (ESI+) calcd. the resulting crude amine 10 was taken up in EtOAc:water (100 C19H23N3O2+H: M+H (theory), 326.1863; M+H (found), mL:3 mL) and heated to reflux. In a separate flask, a slurry of 326.1866. (S)-2-(3,3-dibenzylureido)-3-methylbutanoic acid (7l, 4.8 g, 14.1 mmol) in EtOAc (23 mL) was treated with 1,1’4.4.10. N-Benzyl-5-(3-methyl-3-phenylureido)pentanamide (8j) carbonyldiimidazole (2.4 g, 14.8 mmol) and this mixture was 8j was prepared from 7j and benzylamine according to the stirred at rt for 1h. This solution was added to the pre-heated general ureidoacetamide formation procedure in 73% yield as a 1 solution of the free-base in EtOAc, and the resulting mixture was waxy off-white solid; H NMR (700 MHz, CDCl3) δ 7.48 – 7.19 stirred for 1h at reflux then cooled to rt. Water (50 mL) was (m, 10H), 6.72 – 6.61 (m, 1H), 4.47 (t, J = 5.9 Hz, 1H), 4.43 (d, J added and the phases were separated. The organics were washed = 6.1 Hz, 2H), 3.37 – 3.00 (m, 5H), 2.26 (t, J = 7.6 Hz, 2H), with 10% citric acid, 5% NaHCO3, and brine then dried 1.63 (dddd, J = 7.5, 7.5, 7.6, 7.6 Hz, 2H), 1.46 (dddd, J = 7.1 Hz, 13 (MgSO 4), filtered, and purified using silica gel chromatography 2H); C NMR (176 MHz, CDCl3) δ 173.0, 157.5, 143.4, 138.7, eluting with EtOAc/hexanes. The resulting purified material was 130.1, 128.6, 127.8, 127.4, 127.3, 127.3, 43.4, 39.9, 37.1, 35.8, recrystallized from EtOAc/hexanes to give 5.5 g (60% yield) of 4 29.8, 22.9; mass spectrum (ESI+) calcd. C20H25N3O2+H: M+H as a white solid: m.p. 158-160 ºC; [α]23D -3.7 (c 1.28, DMSO); (theory), 340.2020; M+H (found), 340.2025. 1 H NMR (600 MHz, DMSO-d6, 60 ºC) δ 7.49 (d, J = 8.4 Hz, 4.4.11. N-Benzyl-6-(3-methyl-3-phenylureido)hexanamide (8k) 1H), 7.38 – 7.02 (m, 25H), 6.52 (s, 1H), 5.60 (d, J = 8.4 Hz, 1H), 8k was prepared from 7k and benzylamine according to the 4.91 (t, J = 14.8 Hz, 2H), 4.57 – 4.34 (m, 5H), 4.15 (q, J = 7.3 general ureidoacetamide formation procedure in 64% yield as a Hz, 1H), 4.03 (dd, J = 6.4, 8.4 Hz, 1H), 3.82 (dddd, J = 2.3, 5.6, waxy off-white solid; 1H NMR (700 MHz, CDCl3) δ 7.50 – 7.21 9.0, 9.0 Hz, 1H), 3.60 (dddd, J = 2.4, 6.6, 6.6, 6.7 Hz, 1H), 3.12 (m, 10H), 6.37 – 6.24 (m, 1H), 4.45 (d, J = 5.9 Hz, 2H), 4.39 (t, J (s, 2H), 2.81 – 2.58 (m, 4H), 2.49 (p, J = 1.9 Hz, 2H), 1.84 (h, J = 5.9 Hz, 1H), 3.26 (d, J = 1.9 Hz, 3H), 3.17 (q, J = 6.7 Hz, 2H), = 6.7 Hz, 1H), 1.52 (m, 2H), 0.70 (d, J = 6.7 Hz, 3H), 0.61 (d, J 2.24 (t, J = 7.6 Hz, 2H), 1.67 (dddd, J = 7.7 Hz, 2H), 1.45 (dddd, = 6.7 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 170.9, 157.2, J = 7.3 Hz, 2H), 1.31 (dddd, J = 7.8 Hz, 2H); 13C NMR (176 155.9, 139.4, 138.7, 138.3, 137.4, 129.2, 129.0, 128.4, 128.2, 127.9, 127.8, 127.5, 127.1, 127.1, 126.9, 126.5, 125.7, 125.7, MHz, CDCl3) δ 172.9, 157.4, 143.5, 138.6, 130.1, 128.7, 127.8, 69.0, 64.8, 59.4, 55.5, 49.4, 47.0, 38.2, 37.2, 30.5, 19.3, 17.9; 127.4, 127.3, 127.3, 43.5, 40.6, 37.2, 36.5, 30.0, 26.4, 25.3; mass spectrum (ESI+) calcd. C21H27N3O2+H: M+H (theory), mass spectrum (ESI+) calcd. C46H52N4O5+H: M+H (theory), 354.2176; M+H (found), 354.2172. 741.4010; M+H (found), 741.4028.

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4.4.12. (S)-N-Benzyl-2-(3,3-dibenzylureido)-3-methylbutanamide (8l) 8l was prepared from 7l and benzylamine according to the general ureidoacetamide formation procedure in 63% yield as a white solid: m.p. 92-95 ºC; [α]23D +29.0 (c 1.27, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.45 – 6.85 (m, 15H), 6.47 (t, J = 5.8 Hz, 1H), 4.85 (d, J = 8.0 Hz, 1H), 4.48 (d, J = 16.3 Hz, 2H), 4.41 – 4.21 (m, 4H), 4.12 (dd, J = 6.2, 8.1 Hz, 1H), 1.96 (dq, J = 6.7, 13.3 Hz, 1H), 0.72 (d, J = 6.7 Hz, 3H), 0.56 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 172.0, 158.0, 138.2, 137.4, 128.9, 128.6, 127.6, 127.3, 127.2, 60.0, 50.7, 43.4, 30.5, 19.4, 17.7; mass spectrum (ESI+) calcd. C27H33N3O2+H: M+H (theory), 430.2489; M+H (found), 430.2485. 4.4.13. (S)-N-Benzyl-3-methyl-2-(3-methyl-3-phenylureido) butanamide (8m) 8m was prepared from 7m and benzylamine according to the general ureidoacetamide formation procedure in 93% yield as an oil; [α]23D +22.7 (c 8.75, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.21 (m, 10H), 7.12 (dt, J = 3.1, 7.1 Hz, 1H), 4.90 (d, J = 8.6 Hz, 1H), 4.52 (dd, J = 6.0, 14.9 Hz, 1H), 4.37 (dd, J = 5.6, 14.9 Hz, 1H), 4.24 (ddd, J = 1.5, 6.9, 8.3 Hz, 1H), 3.17 (s, 3H), 2.03 (m, 1H), 0.94 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 172.0, 157.1, 142.8, 138.3, 130.0, 128.5, 127.6, 127.5, 127.2, 127.14, 59.9, 43.3, 37.1, 30.7, 19.5, 18.1; mass spectrum (ESI+) calcd. C20H25N3O2+H: M+H (theory), 340.2020; M+H (found), 340.2035.

4.4.15. Benzyl-((2S,3S,5S)-3-hydroxy-5-((S)-3-methyl-2-(3methyl-3-phenylureido)butanamido)-1,6-diphenylhexan-2yl)carbamate (11) To slurry of benzyl tert-butyl ((2S,3S,5S)-3-hydroxy-1,6diphenylhexane-2,5-diyl)dicarbamate 920 (3.3 g, 6.3 mmol) in EtOAc (50 mL) was added excess conc. HCl (2.5 ml, 28.4 mmol) and water (1 mL) and the reaction was stirred until judged complete by HPLC analysis. The resulting slurry was slowly quenched into a rapidly stirred solution of aq. K2CO3 (10% w/w) (22 g, 32 mmol) and the phases were separated. The organics were washed with aq. NaCl (5% w/w), dried (MgSO4), and concentrated in vacuo to give the crude amine 10 that was taken up in EtOAc:water (50 mL:2 mL) and heated to reflux. In a separate flask, a slurry of (S)-3-methyl-2-(3-methyl-3phenylureido)butanoic acid (7m, 1.7 g, 6.6 mmol) in EtOAc (20 mL) was treated with 1,1’-carbonyldiimidazole (1.1 g, 6.9 mmol) and this mixture was stirred at rt for 1h. This solution was added to the pre-heated solution of the free-base in EtOAc, and the resulting mixture was stirred for 1h at reflux then cooled to rt. Water (50 mL) was added and the phases were separated. The organics were washed with 10% citric acid, 5% NaHCO3, and brine then dried (MgSO4), filtered, and purified using silica gel chromatography eluting with EtOAc/hexanes. The resulting purified material was recrystallized from EtOAc/hexanes to give 2.48 g (60% yield) of 15 as a white solid: m.p. 116-119 ºC; [α]23D +9.9 (c 1.27, ACN); 1H NMR (600 MHz, DMSO-d6, 60 ºC) δ 7.60 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.19 (m, 18H), 6.53 (s, 1H), 5.05 (d, J = 8.6 Hz, 1H), 4.92 (q, J = 12.5 Hz, 2H),

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12g was prepared in 74% yield from N-benzyl-3-(3,34.39 (d, J = 6.6 Hz, 1H), 4.09 (dt, J = 6.7, 12.8 Hz, 1H), 4.00 MANUSCRIPT ACCEPTED dibenzylureido)propanamide 8g according to the general (dd, J = 5.8, 8.6 Hz, 1H), 3.80 (dddd, J = 2.3, 5.6, 9.0, 9.0 Hz, thermocyclization procedure and the spectral data matched that 1H), 3.57 (dddd, J = 2.3, 6.7, 6.7, 6.7 Hz, 1H), 3.16 (s, 3H), 3.11 previously described.22 1H NMR (400 MHz, CDCl3) δ 7.32 – 6.91 (s, 3H), 2.78 – 2.57 (m, 4H), 2.49 (p, J = 1.9 Hz, 1H), 1.79 (dq, J = 6.7, 13.3 Hz, 1H), 1.52 (m, 2H), 0.75 (d, J = 6.7 Hz, 3H), 0.59 (m, 5H), 6.12 (s, 1H), 4.73 (s, 2H), 3.14 (ddd, J = 2.7, 6.8, 6.8 (d, J = 6.8 Hz, 3H).; 13C NMR (151 MHz, DMSO-d6) δ 170.4, Hz, 2H), 2.50 (t, J = 6.8 Hz, 2H). 155.9, 155.9, 143.4, 139.4, 138.8, 137.4, 129.6, 129.1, 129.0, 4.5.4. 3-Benzyl-6,6-dimethyldihydropyrimidine-2,4(1H,3H)-dione 128.2, 127.9, 127.8, 127.5, 127.1, 126.6, 126.4, 125.7, 68.88, (12h) 64.8, 58.4, 55.4, 47.2, 38.5, 37.2, 36.8, 31.0, 19.3, 17.4; mass 12h was prepared in 89% yield from N-benzyl-3-(3,3spectrum (ESI+) calcd. C39H46N4O5+H: M+H (theory), dibenzylureido)-3-methylbutanamide 8h according to the general 651.3541; M+H (found), 651.3560. thermocyclization procedure as a white solid: m.p. 109-111 ºC; 1 4.4.16. N-Benzyl-2-(3-benzylureido)acetamide (15) H NMR (600 MHz, CDCl3) δ 7.58 – 6.91 (m, 5H), 5.18 (s, 1H), 4.89 (s, 2H), 2.55 (d, J = 0.9 Hz, 2H), 1.21 (s, 6H); 13C NMR To a mixture of tert-butyl 2-(benylamino)-2(151 MHz, CDCl3) δ 168.9, 153.5, 137.6, 128.6, 128.4, 127.3, oxoethylcarbamate 1718 (4.6 g, 17.5 mmol) in EtOAc (50 mL) 48.6, 44.8, 43.4, 28.6; mass spectrum (ESI+) calcd. was added conc. HCl (4.6 mL) and the reaction was stirred until M+H (theory), 233.1285; M+H (found), C13H16N2O2+H: judged to be complete by HPLC. Aqueous NaHCO3 (5% w/w, 233.1284. 50 mL) was added to quench the acid and the layers were separated. The aqueous phase was extracted with a mixture of 4.5.5. (S)-3-Benzyl-5-isopropylimidazolidine-2,4-dione (12l) EtOAc/2-butanol (1:1, 2 x 20 mL), and the organics were 12l was prepared from (S)-N-benzyl-2-(3,3-dibenzylureido)-3combined, dried (MgSO4), filtered and concentrated in vacuo. methylbutanamide (8l) as a mixture (1:1) of enantiomers in 81% The resulting crude product was taken up in CH2Cl2 (100 mL), yield or from (S)-N-benzyl-3-methyl-2-(3-methyl-3treated with benzyl isocyanate (2.2 mL, 17.5 mmol), stirred at rt. phenylureido)butanamide (8m) as a mixture (97:3) of After 3h the mixture was quenched with water (20 mL), the enantiomers in 61% yield according to the general layers were separated, and the organics were dried (MgSO4) thermocyclization procedure as a solid. This material was filtered, and concentrated in vacuo. Recrystallization of the recrystallized from EtOAc/heptanes to give 12l as a white solid: solids thus obtained, provided 1.0 g of 15 (20%) as a white solid: 1 m.p. 100-101 ºC; [α]23D -101.9 (c 0.04, ACN); chiral SFC: m.p. 195-198 ºC; H NMR (700 MHz, DMSO-d6) δ 8.36 (t, J = Chiralpak AD-H column (4.6mm x 250mm), 3 mL/min., 20% 6.1 Hz, 1H), 7.48 – 7.11 (m, 10H), 6.70 (t, J = 6.0 Hz, 1H), 6.28 iPrOH in CO2 for 30 min., tR = 14.3 min. (R - minor), 15.0 min. (t, J = 5.7 Hz, 1H), 4.32 (d, J = 6.1 Hz, 2H), 4.25 (d, J = 6.1 Hz, 13 (S - major); 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.25 (m, 5H), 2H), 3.75 (d, J = 5.8 Hz, 2H); C NMR (176 MHz, DMSO-d6) δ 6.06 (s, 1H), 4.74 – 4.61 (m, 2H), 3.95 (dd, J = 1.2, 3.7 Hz, 1H), 170.5, 158.5, 141.2, 139.9, 128.7, 128.7, 127.7, 127.5, 127.2, 2.24 (ddq, J = 3.4, 6.9, 10.6 Hz, 1H), 1.03 (d, J = 7.0 Hz, 3H), 127.0, 43.5, 43.4, 42.5; mass spectrum (ESI+) calcd. 0.86 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.1, C17H19N3O2+H: M+H (theory), 298.1550; M+H (found), 157.7, 128.6, 128.5, 127.8, 110.4, 62.3, 42.1, 30.3, 18.7, 15.9; 298.1552. mass spectrum (ESI+) calcd. C13H16N2O2+H: M+H (theory), 4.5. Thermocyclization General Procedure 233.1285; M+H (found), 233.1284.

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A mixture of the ureidoacetamide (1 mmol) in 1,2-propanediol (10 volumes) was heated to 125-140 ºC and the reaction monitored by TLC or HPLC for disappearance of starting material. The reaction mixture was cooled to rt and diluted with water (10 volumes) to crystallize the product. Subsequent filtration, washing with water, and drying provided the hydantoin or dihydrouracil products. These materials were recrystallized from EtOAc/hexanes to give analytically pure material for analysis.

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4.5.1. 3-Benzylimidazolidine-2,4-dione (12a) 12a was prepared in 23-87% yield from N-benzyl-2-(3,3dibenzylureido)acetamide 8a (Tables 2 & 3), 79% from Nbenzyl-2-(3,3-diphenylureido)acetamide 8c (Table 3), 98% yield from N-benzyl-2-(3-methyl-3-phenylureido)acetamide 8d (Table 3), and 56% yield from 15 (Table 3) according to the general thermocyclization procedure and the spectral data matched that previously described.20 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.05 (m, 5H), 5.78 (s, 1H), 4.61 (s, 2H), 3.91 (d, J = 1.1 Hz, 2H). 4.5.2. 3-Benzyl-5,5-dimethylimidazolidine-2,4-dione (12e) 12e was prepared in 94% yield from N-benzyl-2-(3,3dibenzylureido)-2-methylpropanamide 8e or 97% yield from Nbenzyl-2-methyl-2-(3-methyl-3-phenylureido)propanamide 8f (Table 4) according to the general thermocyclization procedure and the spectral data matched that previously described.21 1H NMR (400 MHz, CDCl3) δ 7.95 – 6.90 (m, 5H), 6.17 (s, 1H), 4.67 (s, 2H), 1.44 (s, 6H). 4.5.3. 3-Benzyldihydropyrimidine-2,4(1H,3H)-dione (12g)

4.5.6. (S)-3-((2S,4S,5R)-5-Benzyl-4-hydroxy-6-imino-7-oxo-1,7diphenylheptan-2-yl)-5-isopropylimidazolidine-2,4-dione (5) 5 was prepared from 11 as a mixture (98:2) of diastereomers in 95% yield according to the general thermocyclization procedure. This material was recrystallized to give diastereomerically pure 5 in 70% isolated yield as a white solid: m.p. 175-176 ºC ; [α]23D -63.3 (c 1.14, DMSO); chiral SFC: Chiralpak AD-H column (4.6mm x 250mm), 3 mL/min., 20% iPrOH in CO2 for 15 min., tR = 10 min. (S - major), 12.0 min. (R minor); 1H NMR (600 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.40 – 6.97 (m, 16H), 6.68 (s, 1H), 4.97 (s, 2H), 4.65 – 4.51 (m, 1H), 4.44 (s, 1H), 3.89 (q, J = 4.9, 6.3 Hz, 1H), 3.58 (d, J = 3.6 Hz, 1H), 3.52 (td, J = 5.3, 7.9 Hz, 1H), 3.18 (dd, J = 11.2, 13.7 Hz, 1H), 3.11 (s, 2H), 2.80-2.60 (m, 3H), 2.49 (s, 1H), 1.97 (dt, J = 8.2, 13.7 Hz, 1H), 1.92 – 1.67 (m, 2H), 0.74 (d, J = 7.0 Hz, 3H), 0.46 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 173.8, 157.2, 156.1, 139.5, 138.4, 137.5, 129.1, 128.8, 128.3, 128.2, 128.1, 127.6, 127.2, 126.7, 126.2, 125.9, 69.2, 64.9, 60.8, 55.7, 49.7, 36.7, 36.53, 35.8, 29.3, 18.4, 15.4; mass spectrum (ESI+) calcd. C32H37N3O5+H: M+H (theory), 544.2806; M+H (found), 544.2807.

Acknowledgments

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The authors acknowledge Marquessa M.ACCEPTED Rowe for initial laboratory work on this project.

22. Beckwith, A. L. J.; Hickman, R. J.; J. Chem. Soc. (C), 1968, 2756MANUSCRIPT 2759.

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Copies of 1H NMR and 13C NMR spectra for compounds described in this article can be found in the supplemental material section.

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a) Hudkins, R. L.; DeHaven-Hudkins, D. L.; Doukas, P. Bioorg. Med. Chem. Lett. 1997, 7, 979-984; b) Scholl, S.; Koch, A.; Henning, D.; Kempter, G.; Kleinpeter, E. Struct. Chem. 1999, 10, 355-366; c) Stilz, H. U.; Guba, W.; Jablonka, B.; Just, M.; Klingler, O.; König, W.; Wehner, V.; Zoller, G. J. Med. Chem. 2001, 44, 1158-1176; d) Meusel, M.; Gütschow, M. Org. Prep. Proc. Int. 2004, 36, 391-443; e) Teng, X.; Degterev, A.; Jagtap, P.; Xing, X.; Choi, S.; Denu, R.; Yuan, J.; Cuny G. D. Bioorg. Med. Chem. Lett. 2005, 15, 5039-5044. a) Johnson, T. B.; Livak, J. E. J. Am. Chem. Soc. 1936, 58, 299303; b) Guillon, J.; Daoust, M.; Radulovic, D.; Boulouard, M.; Dallemagne, P.; Legrand, E.; Rault, S.; Quermonne, M. A.; Robba, M. Eur. J. Med. Chem. 1996, 31, 335-339. Nair, L.; Bogen, S.; Doll, R. J.; Shih, N. –Y.; Njoroge, G. Tetrahedron Lett. 2010, 51, 1276-1279. a) Boeijen, A.; Kruijtzer, A. W. J.; Liskamp, R. M. J.; Bioorg. Med. Chem. Lett. 1998, 8, 2375-2380; b) Lee, S-H.; Chung, S-H.; Lee, Y-S. Tetrahedron Lett. 1998, 39, 9469-9472.; c) Gong, Y-D.; Sohn, H-Y.; Kurth, M. J. J. Org. Chem. 1998, 63, 4854-4856; d) Charton, J.; Delarue, S.; Vendeville, S.; Debreu-Fontaine, M-A.; Girault-Mizzi, S.; Sergheraert, C. Tetrahedron Lett. 2001, 42, 7559-7561. Via in-situ generated ureidoacetates: a) León-Romo, J. L.; Virues, C. I.; Aviña, J.; Regla, I.; Jauaristi, E. Chirality 2002, 14, 144-150; b) Zhao, B.; Haifeng, D.; Shi, Y. J. Am. Chem. Soc. 2006, 130, 7220-7221 Patiño-Molina, R.; Cubero-Lajo, I.; Pérez de Vega, M. J.; GarcíaLópez, M. T.; Gonzolez-Muñiz, R. Tetrahedron Lett. 2007, 48, 3613-3616. a) Lickefett, H.; Krohn, K.; König, W. A.; Gehrcke, B.; Syldatk, C. Tetrahedron: Asymm. 1993, 4, 1129-1135; b) Kumar, V.; Kaushik, M. P.; Mazumdar, A. Eur. J. Org. Chem. 2008, 19101916. Stájer, G.; Szóke-Molnár, Z.; Bernáth, G. Tetrahedron 1990, 46, 1943-1950. Zhang, D.; Xing, X.; Cuny, G. D. J. Org. Chem. 2006, 71, 17501753. Klein, L. L.; Chen, H-J.; Yeung, M. C.; Flentge, C. A.; Randolph, J. T.; Huang, P. P.; Hutchinson, D. K.; Kempf, D. J. WO 2008/027932 A2. Rivett, D. E.; Wilshire, J. F. K. Aus. J. Chem. 1965, 18, 16671675. Yasui, Y.; Tsuchida, S.; Miyabe, H.; Takemoto, Y. J. Org. Chem. 2007, 72, 5898-5900. Alternatively, 7e was prepared from aminobutyric acid methyl ester, hydrochloride salt i as described in the experimental section:

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References and notes

14. Chiral purity was determined using super critical fluid chromatography (SFC) compared to authentic racemic materials. 15. For conversion of ureas to carbamates in the presence of alcohols see: a) Ulrich, H.; Tucker, B.; Richter, R. J. Org. Chem. 1978, 43, 1544-1546. a) Hennecke, U.; Clayden, J. Org. Lett. 2008, 10, 3567-3570. b) Hutchby, M.; Houlden, C. E.; Ford, J. G.; Tyler, S. N. G.; Gagné, M. R.; Lloyd-Jones, G. C.; Milburn-Booker, K. I. Angew. Chem. Int. Ed. 2009, 48, 8721-8724. c) Samuilov, A. Y.; Valeev, A. R.; Balabanova, F. B.; Samuilov, Y, D.; Konovalov, A. I. Russ. J. Org. Chem. 2013, 49, 1723-1727. 16. Grob, H.; Bilk, L. Liebigs Ann. Chem. 1969, 725, 212-221. 17. Gaeta, A.; Molina-Holgado, F.; Kong, X. L.; Salvage, S.; Fakih, S.; Francis, P. T.; Williams, R. J.; Hider, R. C. Bioorg. Med. Chem. 2011, 19, 1285-1297. 18. Li, N.; Lim, R. K. V.; Edwardraja, S.; Lin, Q. J. Am. Chem. Soc. 2011, 133, 15316-15319. 19. Cullen, A. J.; Hung Chiu, Y. R. WO 2013/116715 A1. 20. Fraile, J. M.; Lafuente, G.; Mayoral, J. A.; Pallarés, A. Tetrahedron 2011, 67, 8639-8647. 21. Schläpfer-Dähler, M.; Mukherjee-Müller, G.; Heimgertner, H. Helv. Chim. Acta, 1992, 75, 1251-1261.

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Synthesis of Hydantoins and Dihydrouracils via ThermallyPromoted Cyclization of Ureidoacetamides Michael C. Hillier,* Hai-Hua Gong, Dean S. Clyne, Martin J. Babcock

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0.0

240

260

280

300

320

340

360

-20

0

20

40

60

80

100

120

140

160

180

200

220

ACCEPTED MANUSCRIPT

6.39

380

10173190-176-1 in CDCL3 $05 BC5945 5mg Temp = 25 C C12H16N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HI

S13

210

200

190

176.44

180

170

160

142.49

150

140

EP

130.26 127.91 127.12

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

70

60

37.32

50

40

30

RI PT

57.09

SC

20

10

0

110

120

130

140

150

160

170

180

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

220

157.97

AC C

25.68

10173190-176-1 in CDCL3 $05 BC5945 5mg Temp = 25 C C12H16N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist:190 MICHAEL HI

S14

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

5.5

5.32

4.0

M AN U

5.0 4.5 f1 (ppm)

1.01

TE D

6.0

EP

3.5

2.12

AC C

3.0

SC 2.41

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

140

150

160

170

180

190

200

210

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

2.00

220

10173190-36-1 in CDCL3 $05 BC5946 5mg Temp = 25 C C11H14N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HIL 230

S15

210

200

190

180

170

160

142.86

150

140

EP

130.01 127.50 127.20

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

70

60

SC

50

40

30

RI PT 20

10

0

110

120

130

140

150

160

170

180

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

220

157.48

AC C

37.22 37.22 36.27 34.68

10173190-36-1 in CDCL3 $05 BC5946 5mg Temp = 25 C C11H14N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: 190 MICHAEL HIL

S16

176.26

10.0

9.5

9.0

8.5

8.0

4.72

7.5

7.0

6.5

5.5

4.0

3.5

M AN U

0.96

5.0 4.5 f1 (ppm)

TE D

6.0

EP

3.0

SC 2.87

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

220

240

260

280

300

320

-20

0

20

40

60

80

100

120

140

160

180

200

ACCEPTED MANUSCRIPT

2.03

AC C

6.07

10173190-85-1 in CDCL3 $05 BC5947 5mg Temp = 25 C C13H18N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HIL 340

S17

210

200

190

180

170

160

143.14

150

140

EP

129.97 127.39 127.25

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

70

60

SC

36.96

44.75

51.73

50

40

30

RI PT 20

10

0

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

ACCEPTED MANUSCRIPT

220

157.02

AC C

28.13

175.57

10173190-85-1 in CDCL3 $05 BC5947 5mg Temp = 25 C C13H18N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: 190 MICHAEL HIL

S18

10.0

9.5

9.0

8.5

8.0

5.01

7.5

7.0

6.5

5.5

4.0

3.5

M AN U

1.01

5.0 4.5 f1 (ppm)

TE D

6.0

EP

3.0

SC 5.21

AC C

2.5

2.0

1.5

RI PT 2.15

1.0

0.5

0.0

140

150

160

170

180

190

200

210

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

2.15

220

10173190-35-1 in CDCL3 $05 BC5948 5mg Temp = 25 C C12H16N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HIL 230

S19

210

200

190

176.95

180

170

160

142.96

150

140

EP

130.13 127.60 127.35

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

70

60

SC

31.42

39.87 37.31

50

40

30

RI PT 20

10

0

110

120

130

140

150

160

170

180

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

220

157.82

AC C

25.71

10173190-35-1 in CDCL3 $05 BC5948 5mg Temp = 25 C C12H16N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: 190 MICHAEL HIL

S20

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

5.5

4.82

4.0

3.5

M AN U

0.98

5.0 4.5 f1 (ppm)

TE D

6.0

EP

3.0

SC 3.00 2.13

AC C

2.5

2.0

RI PT 2.08

1.5

1.0

0.5

0.0

140

150

160

170

180

190

200

210

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

2.22 2.04

220

10173190-307-1 in CDCL3 $05 BC5949 5mg Temp = 25 C C13H18N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HI 230

S21

210

200

190

177.86

180

170

160

143.21

150

140

EP

130.04 127.39 127.33

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

70

60

SC

40.25 37.22 33.53 29.64

50

40

30

RI PT 20

10

0

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

ACCEPTED MANUSCRIPT

220

157.53

AC C

21.83

10173190-307-1 in CDCL3 $05 BC5949 5mg Temp = 25 C C13H18N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist:190 MICHAEL HI

S22

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

5.5

0.95

4.78

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

EP

3.0

SC 2.95 2.05

AC C

2.5

2.0

RI PT 2.03

1.5

1.0

0.5

0.0

140

150

160

170

180

190

200

210

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

2.16 2.16 2.00

220

10173190-37-1 in CDCL3 $05 BC5950 5mg Temp = 25 C C14H20N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HIL 230

S25

210

200

190

178.13

180

170

160

143.33

150

140

EP

130.02 127.34

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

70

60

SC

50

40

30

RI PT 20

10

0

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

ACCEPTED MANUSCRIPT

220

157.47

AC C

40.57 37.19 33.84 29.85 26.19 24.35

10173190-37-1 in CDCL3 $05 BC5950 5mg Temp = 25 C C14H20N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: 190 MICHAEL HIL

S26

10.0

9.5

1.21

9.0

8.5

8.0

7.5

7.0

6.5

5.5

10.00

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

0.94

TE D

6.0

EP

3.97 1.13

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

140

150

160

170

180

190

200

210

220

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

1.15

AC C

3.57 3.09

10173190-346-2 in CDCL3 $03 BC5971 5mg Temp = 25 C C20H24N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HI 230

S27

210

200

190

180

170

160

137.03

150

140

EP

128.82 127.60 127.28

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

58.88

70

60

SC

30.42

50.67

50

40

30

RI PT 20

10

0

110

120

130

140

150

160

170

180

-20

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

220

158.61

AC C

18.99 17.33

176.01

10173190-346-2 in CDCL3 $03 BC5971 5mg Temp = 25 C C20H24N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist:190 MICHAEL HI

S28

10.0

9.5

9.0

8.5

8.0

4.95

7.5

7.0

6.5

5.5

1.01

1.12

4.0

3.5

M AN U

1.01

5.0 4.5 f1 (ppm)

TE D

6.0

EP

3.0

SC 3.00

2.5

2.0

1.5

RI PT 1.0

3.23

0.5

0.0

140

150

160

170

180

190

200

210

220

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

1.06

AC C

3.06

10173190-61-1 in CDCL3 $05 BC5951 5mg Temp = 25 C C13H18N2O3 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HIL 230

S29

210

200

190

180

170

160

142.63

150

140

EP

130.10 127.73 127.20

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

58.91

70

60

SC

37.36

50

40

30

RI PT

30.37

175.67

20

10

0

110

120

130

140

150

160

170

180

190

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

220

157.60

AC C

19.21 17.58

10173190-61-1 in CDCL3 BC#5951 $5 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER

S30

10.0

9.5

9.0

8.5

8.0

7.5

15.04 1.06

7.0

6.5

5.5

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

EP

0.98

AC C

3.76 2.00

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

140

150

160

170

180

190

200

210

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

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130

ACCEPTED MANUSCRIPT

2.04

220

92604-42-5 in CDCL3 $20 BC5938 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER 230

S31

210

200

190

180

170.04

170

160

150

140

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

138.03 137.03 128.77 128.53 127.51 127.27 127.09

EP

70

60

SC

50

40

30

RI PT 20

10

0

110

120

130

140

150

160

170

180

-20

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

220

158.37

AC C

50.11 44.91 43.25

92604-42-5 in CDCL3 $20 BC5938 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER190

S32

10.0

9.5

9.0

8.5

8.0

7.5

14.93

7.0

6.5

5.5

1.97 3.85

1.00

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

EP

2.00

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

140

150

160

170

180

190

200

210

220

230

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

3.20

AC C

90645-75 in CDCL3 $19 BC5930 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER

S33

220

210

200

190

180

165.12

170.10

170

160

140

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

137.03 128.67 128.56 127.55 127.44 127.35 127.21

EP

150

AC C

70

60

SC

43.13

54.94 51.16

50

40

30

RI PT

38.01

20

10

0

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

10173190-437-1 in CDCL3 $13 BC5946 5mg Temp = 25 C C25H27N3O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/m300l Chemist: MICHAEL H 190

ACCEPTED MANUSCRIPT

10.0

9.5

9.0

8.5

8.0

1.05 15.73

7.5

7.0

6.5

5.5

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

EP

1.00

AC C

2.00

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

220

240

260

280

300

-20

0

20

40

60

80

100

120

140

160

180

200

ACCEPTED MANUSCRIPT

2.00

320

92604-41 in CDCL3 $19 BC5931 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/i500l Chemist: MICHAEL HILLIER 340

S35

210

200

190

180

169.39

170

160

150

140

EP

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

142.20 138.25 129.36 128.42 127.39 127.31 127.11 126.47

70

60

SC

50

40

30

RI PT 20

10

0

120

130

140

150

160

170

180

-10

0

10

20

30

40

50

60

70

80

90

100

110

ACCEPTED MANUSCRIPT

220

156.29

AC C

44.42 43.06

92604-41 in CDCL3 $19 BC5931 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/i500l Chemist: MICHAEL HILLIER 190

S36

10.0

9.5

9.0

8.5

8.0

12.02

7.5

7.0

6.5

5.5

5.0 4.5 f1 (ppm)

0.99

4.0

3.5

M AN U

2.00

TE D

6.0

EP

2.03

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

140

150

160

170

180

190

200

210

220

230

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

3.02

AC C

92604-45 in CDCL3 $19 BC5932 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER

S37

210

200

190

180

169.77

170

160

150

142.66

140

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

138.13 130.00 128.47 127.54 127.51 127.20 127.04

EP

70

60

SC

44.51 43.24

50

40

30

RI PT 20

10

0

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

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170

180

ACCEPTED MANUSCRIPT

220

157.17

AC C

37.11

92604-45 in CDCL3 $19 BC5932 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER 190

S38

10.0

9.5

9.0

8.5

8.0

7.5

1.09

7.0

6.5

5.5

14.69

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

EP

1.03 4.00 2.10

3.0

SC

2.5

2.0

RI PT 1.5

1.0

0.5

0.0

0

50

100

150

200

250

300

350

400

450

500

ACCEPTED MANUSCRIPT

6.16

AC C

92604-59 in CDCL3 $19 BC5933 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER

S39

210

200

190

180

170

160

150

140

130

120

110 100 f1 (ppm)

TE D

138.62 137.33 128.88 128.55 127.65 127.57 127.17

EP

90

80

70

60

43.59

50.70

50

40

30

RI PT

57.42

SC

20

10

0

110

120

130

140

150

160

170

180

190

-20

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

220

157.41

AC C M AN U

92604-59 in CDCL3 BC#5933 $19 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER

S40

25.98

174.98

10.0

9.5

9.0

8.5

8.0

1.96

7.5

7.0

6.5

5.5

1.02

9.03

4.0

3.5

M AN U

2.00

5.0 4.5 f1 (ppm)

TE D

6.0

EP

3.0

SC 2.79

2.5

2.0

RI PT 1.5

1.0

0.5

0.0

220

240

260

280

300

320

340

360

-20

0

20

40

60

80

100

120

140

160

180

200

ACCEPTED MANUSCRIPT

5.99

AC C

10173190-383-1 in CDCl3 5972 $6 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S41

220

210

200

190

180

170

160

150

143.23

140

130

100

90

80

M AN U

120 110 f1 (ppm)

TE D

138.75 130.21 128.63 127.61 127.52 127.25 127.14

EP

70

43.59

50

40

RI PT

57.41

60

SC

37.14

175.10

30

20

10

0

0

5

10

15

20

25

30

35

40

45

50

55

ACCEPTED MANUSCRIPT

230

156.68

AC C

26.08

10173190-383-1 in CDCl3 5972 $6 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S42

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

5.0 4.5 f1 (ppm)

1.02

1.00

10.07

4.0

M AN U

2.00

TE D

3.5

2.11

EP

3.0

SC 2.83

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

150

160

170

180

190

200

210

220

230

240

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

ACCEPTED MANUSCRIPT

2.11

AC C

10173190-38-2 in CDCL3 5938 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S43

220

210

200

190

180

171.37

170

160

150

140

EP

143.10

130

100

90

80

M AN U

120 110 f1 (ppm)

TE D

70

43.48 37.19 37.00 36.82

50

40

RI PT 60

SC

30

20

10

0

110

120

130

140

150

160

170

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

230

157.47

AC C

138.46 130.05 128.65 127.78 127.43 127.18

10173190-38-2 in CDCL3 5938 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/gucci

S44

10.0

9.5

9.0

8.5

8.0

8.08

7.5

1.77

7.0

6.5

6.0

5.5

1.05

4.0

3.5

M AN U

1.05

5.0 4.5 f1 (ppm)

TE D

2.00

EP

3.0

SC 2.72

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

200

220

240

260

280

300

320

-20

0

20

40

60

80

100

120

140

160

180

ACCEPTED MANUSCRIPT

2.00

AC C

5.79

10173190-86-2 in CDCL3 5937 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S45

220

210

200

190

180

170.89

170

160

143.33

150

140

EP

130

100

90

80

M AN U

120 110 f1 (ppm)

TE D

70

36.83

52.53 46.84 43.53

50

40

RI PT 60

SC

28.70

30

20

10

0

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

ACCEPTED MANUSCRIPT

230

157.03

AC C

138.59 130.02 128.68 127.90 127.39 127.24 126.98

10173190-86-2 in CDCL3 5937 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/gucci

S46

10.0

9.5

9.0

8.5

8.0

7.5

1.07

7.0

6.5

EP

6.0

4.5

2.00

1.07

10.23

4.0

M AN U

5.5 5.0 f1 (ppm)

TE D

3.5

2.5

2.0

RI PT 3.0

SC 5.20

1.5

1.0

0.5

150

160

170

180

190

200

210

220

230

240

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

ACCEPTED MANUSCRIPT

2.13

AC C

2.13

10173190-30-2 in CDCL3 5936 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S47

220

210

200

190

180

172.77

170

160

150

140

EP

143.25

130

100

90

80

M AN U

120 110 f1 (ppm)

TE D

70

43.45 40.07 37.24 33.61

50

40

RI PT 60

SC

30

20

10

0

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

ACCEPTED MANUSCRIPT

230

157.72

AC C

138.72 130.09 128.58 127.71 127.42 127.33 127.24

10173190-30-2 in CDCL3 5936 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/gucci

S48

26.72

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

1.00

10.20

4.0

3.5

M AN U

1.04 1.91

5.0 4.5 f1 (ppm)

TE D

3.0

SC 5.00

EP

2.5

2.0

RI PT 2.00

1.5

1.0

0.5

0.0

150

160

170

180

190

200

210

220

230

240

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

ACCEPTED MANUSCRIPT

1.97 2.04

AC C

10173190-31-2 in CDCL3 5935 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S49

220

210

200

190

180

173.04

170

160

150

140

EP

143.36

130

100

90

80

M AN U

120 110 f1 (ppm)

TE D

70

43.44 39.87 37.13 35.76

50

40

RI PT 60

SC

29.80

30

22.85

20

10

0

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

ACCEPTED MANUSCRIPT

230

157.47

AC C

138.71 130.08 128.59 127.75 127.36 127.32 127.30

10173190-31-2 in CDCL3 5935 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/gucci

S50

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

0.99

9.97

4.0

3.5

M AN U

1.96 1.03

5.0 4.5 f1 (ppm)

TE D

3.0

SC 2.78 2.04

EP

2.5

2.0

RI PT 2.13

1.5

1.0

0.5

0.0

150

160

170

180

190

200

210

220

230

240

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

ACCEPTED MANUSCRIPT

2.00 2.02 2.17

AC C

10173190-39-2 in CDCL3 5934 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S51

220

210

200

190

180

172.86

170

160

150

140

EP

143.49

130

100

90

80

M AN U

120 110 f1 (ppm)

TE D

70

43.50 40.56 37.16 36.47

50

40

RI PT 60

SC

30.04 26.41 25.32

30

20

10

0

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

ACCEPTED MANUSCRIPT

230

157.37

AC C

138.60 130.06 128.66 127.76 127.38 127.33 127.30

10173190-39-2 in CDCL3 5934 $5 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/gucci

S52

10.0

9.5

9.0

8.5

8.0

7.5

7.0

1.00

6.5

6.0

5.5

15.00

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

0.97

EP

2.03 4.25 1.14

3.0

SC

1.56 H2O

2.5

2.0

1.5

RI PT 1.0

3.36

0.5

0.0

140

150

160

170

180

190

200

210

220

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

1.09

AC C

3.12

10173190-391-1 in CDCL3 $08 BC5921 5mg Temp = 25 C C27H31N3O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HI 230

S53

210

200

190

180

171.97

170

160

150

140

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

138.16 137.36 128.85 128.60 127.61 127.33 127.17

EP

60.02

70

60

SC

30.47

43.37

50.67

50

40

30

RI PT 20

10

0

120

130

140

150

160

170

180

190

200

210

-40

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

ACCEPTED MANUSCRIPT

220

158.04

AC C

19.36 17.65

10173190-391-1 in CDCL3 $08 BC5921 5mg Temp = 25 C C27H31N3O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist:220 MICHAEL HI

S54

10.0

9.5

9.0

8.5

8.0

7.5

0.91

7.0

6.5

5.5

9.74

4.0

3.5

M AN U

1.02 1.05 1.06

1.00

5.0 4.5 f1 (ppm)

TE D

6.0

EP

3.0

SC 3.07

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

140

150

160

170

180

190

200

210

220

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

1.15

AC C

3.64 3.17

10173190-387-2 in CDCL3 $08 BC5976 5mg Temp = 25 C C20H25N3O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/m300l Chemist: MICHAEL H 230

S55

210

200

190

180

172.03

170

160

150

142.80

140

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

138.33 130.03 128.52 127.57 127.52 127.21 127.14

EP

59.89

70

60

SC

37.14

43.29

50

40

30

RI PT

30.74

20

10

0

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

ACCEPTED MANUSCRIPT

220

157.10

AC C

19.48 18.09

10173190-387-2 in CDCL3 $08 BC5976 5mg Temp = 25 C C20H25N3O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/m300l Chemist: MICHAEL H 190

S56

10.0

9.5

9.0

8.5

8.0

1.01

7.5

7.0

0.93

6.5

6.0

1.00

5.5

5.10

1.98

5.0 4.5 f1 (ppm)

4.0

1.00 1.04 0.99 1.00

25.43

3.5

SC

3.0

1.60

M AN U

4.03

TE D

2.5

2.0

RI PT 1.74

EP

0.95

1.5

1.0

2.82 2.83

0.5

0.0

140

150

160

170

180

190

200

210

220

230

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

1.97

AC C

10173190-301-2 in DMSO BC#6582 $8 Temp=60C i600 Acq:VnmrJ VERSION 3.2 REVISION A Proc: VnmrJ VERSION 3.2 REVISION A/i500l

S57

220

210

200

190

180

170.90

170

160

150

140

EP

130

120

90

80

60

SC

70

M AN U

110 100 f1 (ppm)

TE D

139.44 138.65 138.33 137.38 129.20 129.01 128.36 128.16 127.90 127.79 127.45 127.14 127.10 126.92 126.52 125.71 125.68

30.53

38.19 37.22

49.36 47.00

50

40

30

RI PT

19.26 17.85

20

10

0

-10

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

ACCEPTED MANUSCRIPT

230

157.21 155.86

AC C

68.96 64.78 59.41 55.51

10173190-301-2 in DMSO BC#6582 $8 i600 Acq:VnmrJ VERSION 3.2 REVISION A Proc: VnmrJ VERSION 3.2 REVISION A/sasha

S58

10.0

9.5

9.0

8.5

8.0

0.88 1.79 18.00

7.5

7.0

0.84

6.5

6.0

5.5

0.98

0.91 1.93

5.0 4.5 f1 (ppm)

4.0

3.5

1.03 0.87 0.92 0.93

M AN U SC

3.0

2.64 2.52

TE D

2.5

2.0

RI PT 3.99 1.34

EP

0.87

1.5

1.0

2.55 2.46

0.5

0.0

140

150

160

170

180

190

200

210

220

230

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

1.80

AC C

10173190-411-3 in DMSO BC#6583 $8 Temp=60C i600 Acq:VnmrJ VERSION 3.2 REVISION A Proc: VnmrJ VERSION 3.2 REVISION A/i500l

S59

220

210

200

190

180

170.43

170

160

150

140

130

120

90

80

60

SC

70

M AN U

110 100 f1 (ppm)

TE D

143.44 139.40 138.80 137.39 129.56 129.14 129.01 128.16 127.89 127.78 127.45 127.12 126.56 126.42 125.70

EP

68.88 64.78

38.47 37.22 36.78 31.03

47.24

50

40

30

RI PT

19.31 17.39

20

10

0

-10

200

220

240

260

280

300

0

20

40

60

80

100

120

140

160

180

ACCEPTED MANUSCRIPT

230

155.94 155.87

AC C

58.41 55.44

10173190-411-3 in DMSO BC#6583 $8 i600 Acq:VnmrJ VERSION 3.2 REVISION A Proc: VnmrJ VERSION 3.2 REVISION A/sasha

S60

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

1.02

1.03

9.91

5.5

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

EP

2.00 2.00

AC C

1.97

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

150

160

170

180

190

200

210

220

230

240

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

ACCEPTED MANUSCRIPT

1.02

10173190-237-3 in DMSO 5940 $14 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S61

220

210

200

190

180

170.52

170

160

150

140

130

100

90

80

M AN U

120 110 f1 (ppm)

TE D

141.21 139.88 128.72 128.67 127.66 127.50 127.21 127.03

EP

70

50

40

RI PT 60

SC

30

20

10

0

0

5

10

15

20

25

30

35

40

45

ACCEPTED MANUSCRIPT

230

158.53

AC C

43.49 43.43 42.47

10173190-237-3 in DMSO 5940 $14 av700 Acq: Topspin Version 2.1 patchlevel 6 Proc: VnmrJ VERSION 3.2 REVISION A/coffee Chemist: MICHAEL HILLIER

S62

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

1.00

4.95

5.5

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

EP

2.16

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

140

150

160

170

180

190

200

210

220

230

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

2.17

AC C

92604-124 in CDCL3 $10 BC5240 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER

S63

10.0

9.5

9.0

8.5

8.0

7.5

4.70

7.0

6.5

EP

5.5

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

1.00

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

-20

0

20

40

60

80

100

120

140

160

180

200

220

240

260

280

ACCEPTED MANUSCRIPT

2.19

AC C

6.09

90645-104 in CDCL3 $08 BC5208 5mg Temp = 25 C m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/m300l Chemist: MICHAEL HILLIER300

S64

10.0

9.5

9.0

8.5

8.0

7.5

4.47

7.0

6.5

5.5

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

TE D

6.0

0.95

EP

2.00

AC C

3.0

SC

2.5

2.0

1.5

RI PT 2.03

1.0

0.5

0.0

140

150

160

170

180

190

200

210

220

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

2.04

1.56 H2O

10173190-420-2 in CDCL3 $09 BC5217 5mg Temp = 25 C C11H12N2O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/m300l Chemist: MICHAEL H 230

S65

10.0

9.5

9.0

8.5

8.0

4.72

7.5

7.0

6.5

0.96

5.5

TE D

6.0

EP

4.0

3.5

M AN U

5.0 4.5 f1 (ppm)

2.00

3.0

SC

2.5

2.0

1.5

RI PT 1.0

0.5

0.0

140

150

160

170

180

190

200

210

220

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

2.00

AC C

6.13

10173190-412-1 in CDCL3 $18 BC5904 5mg Temp = 25 C C13H16N2O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HI 230

S66

210

200

190

180

169.03

170

160

137.63

150

140

EP

128.50 128.31 127.28

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

70

60

SC

48.49 44.79 43.30

50

40

30

RI PT 20

10

0

110

120

130

140

150

160

170

180

-30

-20

-10

0

10

20

30

40

50

60

70

80

90

100

ACCEPTED MANUSCRIPT

220

153.81

AC C

28.42

10173190-412-1 in CDCL3 $18 BC5904 5mg Temp = 25 C C13H16N2O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist:190 MICHAEL HI

S67

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

1.10

6.0

5.5

5.27

4.0

3.5

M AN U

2.24

5.0 4.5 f1 (ppm)

TE D

1.00

EP

3.0

SC

2.5

2.0

RI PT 1.11

1.5

1.0

0.5

0.0

300

350

400

450

0

50

100

150

200

250

ACCEPTED MANUSCRIPT

0.34

AC C

3.40 3.33

10173190-392-1 in CDCL3 $15 BC5979 5mg Temp = 25 C C13H16N2O2 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HI

S68

210

200

190

180

173.11

170

160

150

140

110.43

128.56 128.46 127.82

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

62.32

70

60

SC

30.26

42.07

50

40

30

RI PT

18.72 15.90

20

10

0

200

220

240

260

280

300

320

-20

0

20

40

60

80

100

120

140

160

180

ACCEPTED MANUSCRIPT

220

157.73

AC C EP

10173190-392-1 in CDCL3 BC#5979 $15 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist: MICHAEL HILLIER

S69

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

1.03 1.11

2.04

5.0 4.5 f1 (ppm)

1.00

4.0

3.5

0.98 1.00

0.92

15.96

1.00

M AN U SC

3.0

1.04 1.94

TE D

3.10

EP

2.5

2.0

1.5

RI PT 1.28

1.0

2.69

0.5

0.0

140

150

160

170

180

190

200

210

220

230

-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

120

130

ACCEPTED MANUSCRIPT

1.04 2.03

AC C

10173190-414-2 in DMSO BC#6584 $8 Temp=60C i600 Acq:VnmrJ VERSION 3.2 REVISION A Proc: VnmrJ VERSION 3.2 REVISION A/sasha

S70

2.80

210

200

190

180

170

160

150

140

130

120

90

80

M AN U

110 100 f1 (ppm)

TE D

139.53 138.41 137.53 129.14 128.84 128.29 128.17 128.06 127.58 127.17 126.73 126.17 125.86

EP

69.21 64.93 60.77 55.72

70

60

SC

36.66 36.54 35.84 29.33

49.71

50

40

30

RI PT 20

10

0

0

20

40

60

80

100

120

140

160

180

200

220

240

ACCEPTED MANUSCRIPT

220

157.20 156.14

AC C

18.41 15.37

173.75

10173190-414-2 in DMSO $20 BC5909 5mg Temp = 25 C C32H37N3O5 m400 Acq: VnmrJ VERSION 3.2 REVISION A/m400l Proc: VnmrJ VERSION 3.2 REVISION A/sasha Chemist:260 MICHAEL HI

S71