Proline derived guanidine catalysts forge extensive H-bonded architectures: A solution and solid state study

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Proline derived guanidine catalysts forge extensive

H-bonded architectures: a solution and solid state

study†

Cite this: RSC Adv., 2020, 10, 22397

ab

b

cd

d

Zahraa S. Al-Taie, Simon R. Anetts, Jeppe Christensen, Simon J. Coles,

d

b

e

b

Peter N. Horton, Daniel M. Evans, Leigh F. Jones, Frank F. J. de Kleijne,

b

Shaun M. Ledbetter, Yassin T. H. Mehdar, Patrick J. Murphy * and Jack A. Wilson

Received 17th September 2019

Accepted 25th February 2020

The preparation of a range of amino acid derived guanidine organocatalysts is reported together with their

application to the Michael addition of 2-hydroxy-1,4-napthoquinone to b-nitrostyrene, achieving

a maximum ee of 56%. Some insight into the mechanism was sought by using X-ray crystallography and

a detailed study of the intra- and intermolecular hydrogen bonding is reported.

DOI: 10.1039/c9ra07508a

rsc.li/rsc-advances

Michael reaction of b-ketoesters to 2-nitrostyrene 2 with ee's of

up to 95%. Terada et al. reported a series of novel axially chiral

Introduction

1

We recently reported the Michael addition of 2-hydroxy-1,4- guanidines 8 as highly eﬃcient Brønsted base catalysts to

5

napthoquinone 1 to b-nitrostyrene 2 catalyzed by the tetracy- promote Michael reactions in high ee's. Similarly, Najera et al.

clic guanidinium salts 3 in combination with L-proline 4. It was reported the benzimidazole catalyst 9 gave enantioselectivities

observed that the two substrates which were unreactive on in the Michael additions of malonates to nitrostyrene 2 with

combination in THF were slowly converted to the product 5 with selectivity of up to 96% ee, in the presence of TFA as a co-

6

a T1/2 of 465 h. The reaction was also catalyzed slowly in the catalyst. These authors also reported the use of the 2-

presence of L-proline 4 with a T1/2 of 579 h in THF. However if aminobenzimidazole-derived organocatalyst 10 for the eﬃcient

the two catalysts 3 and L-proline were used in combination the room temperature asymmetric conjugate addition of 1,3-dike-

reaction proceeded with a T1/2 of 80 h. Unfortunately no tones, b-ketoesters, and malonates to maleimides in up to 97%

7

appreciable enantioselectivity was observed in any of the cata- ee. An interesting catalyst containing both guanidine and

8

lysed reactions which might be attributed to the site of reaction thiourea moieties 11 was reported by Shubina et al. who re-

being too far removed from the point of asymmetric induction ported the Michael additions of acetylacetone to b-nitrostyrene

within the proposed intermediate 6 (Scheme 1).

2 in a low 25% ee. They reported that this poor selectivity was

The catalysis of the process by the guanidinium salt 3 in thought to arise from a high conformational activity of the

conjunction with L-proline 4 was of interest, as proline and guanidine–thiourea complex formed with the enolised acetyla-

proline derivatives have a long history of use in organo- cetone, leading to several diﬀerent transition states which are

2

8

catalysis. It is also known that several guanidine and guanidi- all of very similar energy (Fig. 1).

nium derivatives have proved eﬀective as organocatalysts. We

We were interested in preparing a series of guanidines in an

have reported the use of 3 and related in phase transfer alkyl- attempt to improve and extending the range of guanidines in

ations and epoxidations with high ee's and its free base as organocatalysis. We initially decided to focus on the prepara-

3

a catalyst for Michael additions albeit in low ee. Similarly Yu tion of N-alkylated proline derived catalysts and were inspired

4

et al. reported that guanidine 7 was an eﬃcient catalyst for the

a

Department of Chemistry, College of Science, Al-Nahrain University, Baghdad, Iraq

b

School of Natural Sciences (Chemistry), Bangor University, Bangor, Gwynedd, LL57

2

UW, UK. E-mail: paddy@bangor.ac.uk; Tel: +44 (0)1248 382392

c

Diamond Light Source, Didcot, OX12 0DE, UK

d

EPSRC National Crystallography Service, School of Chemistry, University of

Southampton, Higheld, Southampton, SO17 1BJ, UK

e

School of Biological, Physical and Forensic Sciences, University of Wolverhampton,

WV1 1LY, UK

†

Electronic supplementary information (ESI) available. CCDC 1952629–1952649.

For ESI and crystallographic data in CIF or other electronic format see DOI:

0.1039/c9ra07508a

Scheme 1 Condition (a) b-nitrostyrene 2, 3 (0.05 equiv.), L-proline 4

(0.05 equiv.), CH Cl , rt, 6 days 85%.

2

1

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1

Fig. 2 Generic catalyst structure 22. R ¼ alkyl, R ¼ alkyl, aryl, acyl.

Fig. 1 Guanidine organocatalysts. Dipp ¼ 2,6-diisopropylphenyl.

some electronic control of its hydrogen bonding ability and

basicity (Fig. 2). Our initial aim was thus to prepare a range of

guanidine catalysts.

9

by the work of Altenbach et al. who reported that the

benzimidazole-proline derivative 12 was an eﬀective catalyst in

the Hajose–Parrishe–Edere–Sauere–Wiechert aldol reaction of

Preparation of the studied catalysts

1

,3-ketone 13, leading to 14 in high yields and ee. Similarly, The catalysts initially investigated were prepared by the

10

a report by Bhowmick et al. detailed the structurally very coupling of the N-alkylated-L-proline 23a–d derivatives with

simple hydrazine derivative of L-proline 15 which was a viable alkyl, acyl or aryl substituted guanidines (see ESI†) using CDI as

organocatalyst for the aldol reaction of ketones 16 with alde- a coupling reagent in DMF (Scheme 3). This reagent was

hydes 17, leading to the aldol products 18 in 32–99% ee. Sim- employed, as several other reagent combinations that were

ilalrly the low molecular weight cyclohexanediamine derived tested (DCC/NHS, DCC/HOBT, HBTU, MeOCOCl/NEt ), were

3

11

thiourea catalyst 19, prepared by Dixon et al., was employed in found to be ineﬀective and gave considerable problems on

intramolecular Michael additions of a,b-unsaturated esters. For attempted purication. We initially attempted the preparation

example they reported the transformation of 20 into 21 in 86% of the benzoyl substituted catalyst 24 and the crude compound

yield and 94% ee using 19 as the catalyst (Scheme 2).

was obtained, however on attempted purication it underwent

We envisaged the preparation of a range of guanidines 22, hydrolysis on contact with moisture to give the parent benzoyl

based on a proline scaﬀold, which are both N-substituted and guanidine. This was somewhat worrying as if the other guani-

covalently bonded to a guanidine moiety via an amide bond. dines are prone to hydrolysis this might limit the use of these

This concept was to allow ease of exibility at these two sites compounds. We next attempted the coupling of N-Cbz-

and we hoped the catalysts might be “tunable” by modifying the guanidine and were pleased to obtain the compounds 25a–

proline nitrogen to inuence steric interactions. Similarly, d in good yields aer chromatography. We similarly prepared

modication of the groups on the guanidine could also oﬀer the diphenyl substituted catalysts 26a–d and found that the

yields were good for the isopropyl- and cyclohexyl-substituted

compounds whilst the methyl and benzyl were poor. The

observation that coupling of N-methyl-L-proline 23a under

mixed-anhydride and other peptide coupling methods is prob-

12

lematic has been made by Lygo and Moore who did not oﬀer

a clear insight as to why this was so, however our work might

oﬀer a possible explanation. The phenyl-substituted catalysts

27a-b were also prepared in reasonable yield using method B in

which the guanidine is generated in situ from a guanidinium

salt and sodium hydride. We next attempted the preparation of

the potentially more basic guanidines 28a–d, from 1,1-dimethyl

guanidine, using method B. On analysis of the crude reaction

mixture of this reaction by proton NMR, the reactions appeared

to be successful as the products were present. However, on work

up we found that the products were highly polar and diﬃcult to

separate from the by-products of the reaction. In particular, the

N-methyl substituted catalyst 28a had a high water solubility/

instability and was not isolatable if an aqueous work up was

employed. In the case of the N-benzyl substituted 28b, a low

yield of the desired product was obtained as was a low yield of

the dimeric compound 28e. For reasons to be discussed later,

the focus of catalyst preparation switched to the N-methyl

substituted prolines and we next prepared the substituted

Scheme 2 Recent organocatalytic reactions. Conditions: (a) 12 (0.05

mmol), TFA (0.05 mmol), THF, DMSO, MeOH or H O, rt. 24 h. (b) 15 (0.1

2

1

2

equiv.), PTSA, (0.05 equiv.) in H

9 (0.05 equiv.), PhCO

2

O; R ¼ alkyl, R ¼ H, alkyl, R ¼ aryl. (c)

ꢀ

1

2

H (0.025 equiv.), CH

2

Cl

2

, 50 C, 48 h.

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the low nucleophilicity of 2-aminobenzoxazole. Similarly the N-

methyl 38a and the N-benzyl-imidazole catalyst 38b were

prepared using the standard method in 97% and 68% yield

respectively. We also attempted to prepare other heterocyclic

derived catalysts with limited success. The pyridine derived

catalyst 39a was prepared using the CDI coupling method but

the yield obtained (18%) was poor. Unfortunately, the pyrimi-

dine 39b and pyrazine 39c derivatives could not be prepared

using these conditions. We next attempted the preparation of

the bis-L-proline substituted guanidines 40a–d (method C) and

found that the catalyst 40b–d were formed in good to excellent

yields. It was also observed that catalyst 40a appeared to be

formed under the conditions of the reaction as evidenced by

proton and carbon NMR, however the product was lost on

aqueous work up or on chromatography. This appeared to be

due to a combination of factors including high water solubility

and decomposition on silica gel and in water. The hydrazine

derived N-methyl-L-proline catalysts 41c-d were also prepared in

good yields by esterication of N-methyl-L-proline 23a with

methanolic HCl followed by reaction with the corresponding

hydrazine.

We also prepared

a range of N,N-dimethyl alanine

substituted guanidines (43a–47a) and also N,N-dimethyl

phenylalanine substituted guanidines (43b–47b) using the

previously employed CDI coupling method (Scheme 3). The

Cbz-substituted 43a-b and Boc-substituted guanidines 44a-

b were easily prepared in generally high yields. In the case of

44a, the slightly lower yield might be due to problems associ-

ated with the aqueous work up as signicant losses were

observed. The phenyl-substituted guanidines 45a-b were also

prepared using the CDI coupling method with phenyl-

guanidinium nitrate and hydrochloride, however compound

45a was a very polar material and proved impossible to purify

from polar organic and inorganic by products. Compound 45b

was less problematic and was puried by chromatography to

Scheme 3 Synthesis of the studied catalysts; conditions (A) 23a-d or

42a-b, CDI, DMF, rt, 24h. (B) (i) 23a-d or 42a-b, CDI, DMF, rt, 24h, (ii)

guanidine. HX (X ¼ Cl, HCO

3

, NO

3

), NEt

3

. (C) (i) 23a-d, CDI, DMF, rt, give a moderate yield (46%). The benzimidazole substituted

2

4h, (ii) guanidine hydrochloride (0.5 equiv.), NaH (0.6 equiv.) DMF, rt, guanidines 46a and 46b were similarly prepared using this

ꢀ

1

4h. (D) (i) 23a, AcCl, MeOH, 0 C 1h, (ii) reﬂux, 12h, (iii) NH

2

NHR , rt,

method in 92% and 42% yields respectively. The preparation of

the symmetric disubstituted catalysts 47a and 47b was also

attempted and again the L-alanine derived 47a could not be

obtained in a pure form which again appeared to be due to high

aqueous solubility/instability. Pleasingly the phenylalanine

derived compound 47b was obtained in 77% yield under iden-

tical conditions aer chromatography.

1

4h. R ¼ Me, Bn, iPr, Cy; R ¼ H, Ph, Boc, Cbz.

0

guanidines 29 (N-Boc), 30 (N-Me, N -Boc) and 31 (N-Me, N -Cbz)

by method A in good to excellent yields. We also attempted the

preparation of the 1,1-dimethyl substituted Cbz 32 and Boc 33

guanidines and found that there was no indication of the

formation of these compound, as on work up only recovered

guanidine starting material was observed. This would suggest Michael addition reaction of 2-hydroxy-1,4-napthoquinone 1

that either the guanidines were not reactive enough to displace with b-nitrostyrene 2

the imidazole in the coupling intermediate or that the products

With these catalysts in hand we investigated the Michael addi-

32 and 33 were hydrolysed during work up. We also prepared

tion reaction of 2-hydroxy-1,4-napthoquinone 1 with b-nitro-

styrene 2 which in our hands had proven to be a robust reaction

with little evidence of competing side reactions (Scheme 4a–c).

The catalysts 25a–d, were initially investigated (Scheme 4a)

and were pleased to see that all of these guanidines were

eﬀective catalysts leading to good conversions over 1–5 d as

evidenced by NMR sampling of the reaction mixtures. We were

pleased to observe some level of asymmetric induction (18–44%

the benzimidazole derived prolines 34a–d in good yields using

coupling method A with again the lowest yield being observed

for the N-methyl substituted 34a. Similarly we prepared the

methyl substituted benzimidazoles 35 and 36 in 41% and 45%

yield respectively. We also prepared the benzothiazole 37a

catalyst in 74% yield using method A, however the benzoxazole

37b was not accessible by this method which might be due to

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increased from Bn to iPr to Cy. The diphenyl-substituted cata-

lysts 26a–d were investigated next (Scheme 4a) and whilst these

compounds were found to catalyze the reaction at a similar rate

to 25a–d, the ee's of the product were consistently very low (1 to

5% ee) and at this point in the investigation we had no clear

explanation for this. We next investigated the N-alkylated-

benzimidazole prolines 34a–d (Scheme 4b) and the results ob-

tained with these catalysts were similar to those reported for

25a–d. It was found that the N-methyl catalyst 34a gave the

highest levels of asymmetric induction with a 32% ee in toluene

and a 27% ee in dichloromethane, however again there was

a steady decrease in ee as the size of the proline N-substituent

increased from Bn to iPr to Cy. We concluded from these studies

that the size of the N-substituent on the proline is critical and

that larger substituents appeared to detrimental to the ee of the

reaction. We next investigated the mono-phenyl substituted

catalysts 27a and 27b (Scheme 4a) and again the N-methyl

substituted catalyst 27a gave the best asymmetric induction.

Interestingly and in contrast to the previous catalysts, the

reaction time using 27a in dichloromethane was shorter,

leading to a 91% yield of 5 over 4 h with an ee of 21%. We

repeated this reaction at ꢁ20 ^ꢀC and obtained a slightly

improved 25% ee over 54 h. This result was in stark contrast to

the previous catalysts and we had no clear explanation for this

at this point in the investigation. Again increasing the size of the

N-substituent to a Bn group was detrimental to the ee as catalyst

27b gave no appreciable levels of asymmetric induction in any

of the solvents studied. We also investigated the Boc-

substituted guanidine 29 (Scheme 4a) which gave a 19% ee in

dichloromethane over 28 h and on the addition of benzoic acid

as a co-catalyst the ee improved to 28%. Interestingly the reac-

ꢀ

tion with 29 in toluene at 0 C was rapid when compared to

previous catalysts leading to an 89% yield of the product in 22%

ꢀ

ee over 2 h. Repeating this experiment at ꢁ20 C for 24 h gave an

improved 37% ee but a lower yield (37%). Repeating the reac-

tion in the presence of benzoic acid in toluene over 24 h gave

a diminished ee of 18% and a much lower yield (38%).

In an attempt to increase the basicity of the guanidine and to

modify the intramolecular hydrogen-bonding (vide infra) in the

Scheme 4 (a–c): Catalyzed Michael reaction between 1 and 2:

conditions (i) catalyst (0.1–0.04 equiv.), solvent (0.03–0.08 M), ꢁ78 to

0

catalysts, the N-methylated-N -Boc catalyst 30 and the N-meth-

ꢀ

0

C 7–8 h, then 0 C-rt. Results are given as ee (solvent, time); D ¼ ylated-N -Cbz catalyst 31 (Scheme 4a) were investigated. These

dichloromethane, T ¼ toluene.

catalysts both gave poor ee's and slower reaction times and

yields in both toluene and dichloromethane when compared to

catalysts 25a and 29. These results might indicate that

ee) with all the catalyst with 25a being the most eﬀective. The increasing the basicity of the guanidine does not help the

highest ee was obtained using toluene as solvent, giving the reaction process or that interfering with the hydrogen-bonding

product in 44% ee over 5 days and in a 75% isolated yield. pattern at this position is detrimental. These results were

2 2

Various solvent systems (CH Cl , MeCN, PhMe, THF, EtOAc and mirrored in the reactions of the N-methylated benzimidazole

benzene) were studied, with the best results being obtained in catalysts 35 and 36 (Scheme 4b) when compared to 34a. These

dichloromethane and toluene. Using toluene presented some compounds were found to catalyze the reaction but again yields

solubility problems associated with the starting material 1, and ee's were lower (6–14% ee) and reaction times generally

which was overcome by performing the reaction at higher slower. Two catalysts were prepared in which the guanidine was

dilution. It was also apparent that the catalytic reactions using replaced by a benzothiazole 37a and a pyridine 39a and again

25a–d were generally slow with 88–100 h being required for these catalyzed the reaction but gave poor ee's and slow reaction

a reasonable conversion. It was also apparent that whilst all times. The imidazole catalysts 38a and 38b (Scheme 4b) were

these compounds catalyzed the reaction, there was a steady both eﬀective catalysts with 38a leading to a 5 in 16% ee in

decrease in ee as the size of the L-proline N-substituent

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dichloromethane or toluene, whilst 39a gave lower ee's of 13% substituted variants of the Cbz-, Boc- and benzimidazole cata-

and 5% ee in the respective solvents. lysts led to lower ee's. Throughout this work the best solvent for

We next investigated the C -catalysts 40b–d (Scheme 4c) and this reaction appears to be toluene (and other aromatic

2

were disappointed to nd that whilst catalyzing the reactions solvents; see ESI†) with dichloromethane also being eﬀective,

eﬀectively the ee's of the products were very low (1–7%) in either however acetonitrile and other solvents were not successful.

toluene or dichloromethane. Interestingly adding benzoic acid Cooling of the more rapid reactions appears to increase the ee

to the reaction decreased the conversion time but no increase in of the product however, yields are lower and reaction times are

ee was apparent (see ESI†). The hydrazine derived catalysts 41a– prolonged. Throughout this work several catalysts seemed to

d (Scheme 4c) were investigated next and it was found that increase the rate of reaction leading to completion or near

unsubstituted hydrazine 41a gave slow reaction times and poor completion in 1–4 h instead of the more typical 2–7 days,

ee's. By contrast phenyl-substituted hydrazine 41b gave a more particularly catalysts 27a, 29 + BA, 40c + BA, 40d + BA, 41b, 43b +

rapid reaction in toluene whilst the reaction was again slow in BA, 44b and 47b. The exact reason for this was unclear and we

dichloromethane. Unfortunately, the ee's of these reactions thus decided to investigate the catalysts further.

were again very low (3% ee), however repeating the reaction of

ꢀ

4

1b in toluene at ꢁ20 C gave an improved ee of 17% but over

Crystallographic and racemization studies

a longer time (1 d). The Boc-substituted hydrazine 41c gave

much slower reaction times but an improved 13% ee with From the beginnings of this project we were interested in the

toluene as reaction solvent. This slower reaction time might be crystallographic nature of our catalysts as it was felt that this

due to an electronic eﬀect as reactions of the Cbz-substituted information might lead to an insight into the eﬃciency (or not)

hydrazine 41d were more rapid (10 h) but ee's were slightly of the systems employed. The initial crystallographic work of

lower (10% ee).

the previous student on this project gave some insight into the

Moving on from the L-proline derived catalysts we examined H-bonding patterns observed in the N-methyl-L-proline catalysts

those derived from L-alanine and L-phenylalanine. The N-Cbz- 25a, 26a, 27a and 34a catalysts. Three of these catalysts 25a, 26a

protected guanidines 43a and 43b (Scheme 4c) were investi- and 34a, had a distinctive H-bonding pattern (Fig. 3), which

gated initially and these were found to be eﬀective catalysts. consisted of a strong intramolecular H-bond between the amide

Compound 43a gave an ee of 7% in dichloromethane over 4 protons (NH) and the pyrrolidine nitrogen (bond a) and

d and 13% in toluene over 20 h, whilst 43b gave 4% ee in a complementary NH-bond between the guanidine NH and the

dichloromethane over 28 h and 15% ee in toluene over 3 d. The amide carbonyl (bond b). This pattern holds the amide at

latter result was repeated using benzoic acid as a co-catalyst and a trans-conguration (E-) and in compound 25a we refer to this

this led to a faster conversion and an improvement in ee to 25%. as E-abd as the carbamate has an H-bond to the guanidine NH₂.

Following this the N-Boc-protected guanidines 44a and 44b In the case of 26a and 34a where no carbamate is present the E-

(Scheme 4c) were investigated initially and again were found to ab pattern is found. We reasoned that the H-bonds found in

be eﬀective catalysts. Compound 44a gave an ee of 10% in these structures might still be present whilst they are in solution

dichloromethane over 2 d and 11% in toluene over 20 h, whilst and this explain why these bases are slow to catalyze the

4

4b gave 9% in dichloromethane over 2 d and an 18% ee in Michael reaction. Some NMR evidence is also available which

ꢀ

13

toluene over 1 h. The latter result was repeated at 0 C over 10 h demonstrated that the C NMR data for compound 26a shows

and gave product 5 in 31% ee. These results seem to suggest the distinctive individual signals for each phenyl suggesting that

bulkier benzyl group found in the L-phenylalanine catalysts rapid interconversion between these two phenyls is not occur-

gives a more eﬀective catalyst. Moving to the phenyl-substituted ring on the NMR timescale. Some further evidence for this is

catalyst 45b (Scheme 4c), similar results were found with an ee found in the structure of the guanidine 27a (Fig. 3), which

of 18% in dichloromethane over 8 h and 21% in toluene over diﬀers in its H-bonding pattern in that the pyrrolidine amine

1

0 h. The benzimidazole catalysts 46a and 46b (Scheme 4c) were (N1) is not intramolecularly H-bonded and only the carbonyl–

ꢀ

similarly investigated and overall were found to be slower that NH bond (bond b; N3(H1)/O1 ¼ 2.02 A) is present as the amide

the previously investigated cases. Thus 46a gave an ee of 10% in is in the form of a N-methyleneamide; this is termed a Free-

dichloromethane over 4 d and 16% in toluene over 7 d, whilst b type system. Whilst this evidence is tenuous, this diﬀerence in

46b gave 10% ee in dichloromethane over 5 d and 20% ee in H-bonding might explain the increased reaction rate observed

toluene over 5 d. Finally the C -catalyst 47b gave similar results in the Michael addition reaction for compound 27a (proceeded

2

with an ee of 21% in dichloromethane over 2 h and 24% ee in in a 91% yield over 4 h), which was rapid when compared to the

ꢀ

toluene over 2 h. These reactions were repeated at ꢁ20 C and ee timescale of the other catalysts (typically took 4–5 days to reach

of 25% in dichloromethane was obtained over 3 d and a 25% ee completion). Another interesting feature is that the N4-phenyl

in toluene over 1 d.

group found in catalyst 26a appears to eclipse the nitrogen

Our overall conclusions from this work appear to be that the N1. Catalysts 26a–d gave very poor ee's in their reactions to form

N-methyl-L-proline derived catalysts give better ee's in the 5 and this eclipsing of the N might be a contributing factor

reactions and increasing the substituent in general has a detri- (Fig. 3).

mental eﬀect on the ee. The best groups on the guanidine of

However, the most surprising and somewhat troubling result

these catalysts appears to be those with Cbz-, Boc-, phenyl and from our crystallographic studies was observed when exam-

benzimidazole substituents, whilst diphenyl and methyl ining the structure of 26a which was found to crystallize as

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Fig. 4 (a) Crystal structure highlighting the two organic moieties (S-

left and R-right) comprising the asymmetric unit in 26a. The chiral

protons are labelled H24 and H5. The dashed lines represent the

ꢀ

intramolecular H-bonding interactions: N8(H8)/O2

¼

2.03 A;

ꢀ

N6(H6)/N5 ¼ 2.07 A; N3(H3)/O1 ¼ 2.01 A and N2(H2)/N1 ¼ 2.15 A.

Note: the disorder observed at both proline moieties is not shown.

Catalyst 26a crystallises as an 2 : 1 S : R epimeric mixture. (b) The

asymmetric unit in 41c (crystal 1). Dashed lines represent the inter-

ꢀ

molecular H-bonding (O1/(H6)N6 ¼ 2.25 A, N3(H5)/O4 ¼ 2.18 A)

ꢀ

and intramolecular H-bonding (N2(H2)/N1A ¼ 2.37 A and N5(H3)/

ꢀ

N4 ¼ 2.20 A).

This was a surprising observation, as the L-proline used in

the synthesis was of the reported optical rotation, as was the N-

Fig. 3 ChemDraw representations (left) of catalysts 25a, 26a, 27a and

34a along with their corresponding crystal structures (right). Colour

code as used throughout this work: C (grey), N (blue), O (red) and H methylproline 23a, which was prepared using a literature

(

black). Dashed lines represent all intramolecular H-bonding interac-

13

procedure. The epimerization of several of the catalysts was

ꢀ

tions (N2(H52)/N1 ¼ 2.26 A, N3(H51)/O1 ¼ 1.87 A and N3(H50)/O2

investigated by NMR in deuterated methanol under neutral,

weakly basic (NEt ) and acidic (PhCO H) conditions and whilst

3 2

ꢀ

¼

2.00 A in 25a; N2(H2)/N1 ¼ 2.15 A and N3(H3)/O1 ¼ 2.01 A in 26a;

ꢀ ꢀ

N3(H1)/O1 ¼ 2.02 A in 27a; N2(H4)/N1 ¼ 2.21 A and N3(H1)/O1 ¼

ꢀ

.35 A in 34a.

decomposition (hydrolysis) was observed over prolonged time-

periods (>5 days), no evidence of deuterium incorporation at

the proline chiral center was observed. We thus investigated the

nature of the most successful catalyst 25a by HPLC and found it

to also be a 3 : 1 mixture of epimers by HPLC (by comparison

with a separately prepared racemic sample). For compound 25a,

the PXRD patterns show observable diﬀerences. Realistically the

only diﬀerences between the 86% ee and 100% ee patterns, is

the sharpness of the peaks in the 100% ee (Fig. S28†). However

they are both totally diﬀerent from the racemic mixture, sug-

gesting that the racemate has a completely diﬀerent type of

packing to the pure chiral form.

We concluded from this that the epimerisation must be

occurring at the CDI coupling stage. We thus repeated the

preparation of 25a by coupling 23a with N-Cbz-guanidine which

was activated using CDI in DMF over diﬀerent times. Analysis of

the products by HPLC and optical rotation data was performed

and the traces compared with an independently prepared

racemic and enantiomerically pure sample of 25a (obtained by

repeated recrystallization) (Scheme 5, Table 1).

2

a 2 : 1 (S : R) mixture of epimers within the unit cell (Fig. 4).

Upon comparison with a simulated spectrum, the pXRD

collection on 26a was consistent with this observation

(

Fig. S25†). Similar racemization was observed in the crystal

structures of compounds 41c and 43a. More specically, the

species 41c was found to produce two types of crystal (crystals 1

and 2) within the same batch having crystallized in the Pna2₁

(

41c-crystal 1) and P2 (41c-crystal 2) space groups. Crystal 1 is

1

racemic in nature (Fig. 4), while all 41c units in crystal 2 exhibit

the S conguration (Fig. S22†). Interestingly, the simulated

powder patterns obtained from crystal 1 and crystal 2 are

virtually identical. Although they have almost identical unit cell

dimensions (Table S5† and Fig. S26†), this also means there is

signicant correlation in how the species pack within a unit

cell. Likewise, the bulk powder sample of 41c also corresponds

well to both simulated patterns. Unfortunately, the near iden-

tical nature of their simulated patterns severely hampers any

attempts at obtaining a crystal 1/crystal 2 ratio in 41c. The

catalyst 43a also crystallized as a racemate (Fig. S23†).

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S24†), intramolecular hydrogen bonding is commonplace

within each catalyst. More specically, the majority of interac-

tions occur between guanidine protons, neighboring carbonyl

oxygen and proline nitrogen acceptor atoms (e.g. N7(H54)/O5

ꢀ

¼

1.83 A and (N6(H55)/N5 ¼ 2.26 A, respectively; Fig. 5).

We hoped to use the X-ray structures obtained to give some

insight into the possible H-bonding patterns found in these

catalysts in solution. We initially compared the X-ray structures

of the compounds 25a, 29, 30 and 31. Compounds 25a and 29

Scheme 5 (a) (i) 23a, CDI, DMF, 5 min, 1 h or/24 h, rt; (ii) N-Cbz- have no methyl substituent on the guanidine and 25a gave two

guanidine, rt 24h; 47–53% yield.

H-bonds between the amide carbonyls and two of the N–H's of

ꢀ

the guanidine (bond b; N3(H51)/O1 ¼ 1.87 A and bond d;

ꢀ

N3(H50)/O2 ¼ 2.00 A). Additionally a H-bond between the

proline nitrogen atoms (N1) and the amide NH (bond a;

ꢀ

N2(H52)/N1 ¼ 2.26 A) was present and this compound was

thus an E-abd type (Fig. 5).

The analogous Boc-protected compound 29 was prepared in

order to study changes in steric factors near the guanidine and

surprisingly it had a diﬀerent H-bonding pattern (E-abc) to that

of 25a. Catalyst 29 had two H-bonds between the amide and the

carbamate carbonyls and two of the N–H's of the guanidine

ꢀ

(

ꢀ

bond b; N3(H3)/O1 ¼ 1.94 A and bond c; N2(H1)/O2 ¼ 2.09

A). The H-bond between the proline nitrogen atom (N1) and the

Scheme 6 Proposed mechanism for the racemization of the proline

catalyst 25a. (a) (i) CDI, DMF, (ii) N-Cbz-guanidine.

ꢀ

amide NH (bond a; N2(H1)/N1 ¼ 2.10 A) was also present

(Fig. 6).

It was apparent from these experiments that even under

short activation times racemization was occurring very rapidly.

The only possible explanation of this is that the intermediate

imidazole amide 48 was undergoing base catalyzed epimeriza-

tion, via enolate 49. The likely base for this process is the amide

48 itself and in the cases where relatively strong guanidine

bases are used in the coupling, their presence might exacerbate

this process (Scheme 6).

We thus repeated the preparation of the Michael adduct 5

using enantiomerically pure 25a and were able to increase the

ee of 5 to 56% ee over 48 h reaction in toluene. Similarly catalyst

29 was prepared using a short coupling time and repeated

recrystallized to constant optical rotation and this again gave an

increases ee for 5 to 41% (from 22%) over 10 h in toluene. These

two compounds represent the best catalysts studied to date

within this work.

Comparison of crystal H-bonding patterns and solution

chemistry

We still wished to rationalize the reactions from the standpoint

of the crystal structures and to this end, investigated the

structures of several of the catalysts and were able to obtain

crystallographic data on compounds 25a, 26a, 26c, 26d, 27a, 29,

30, 31, 34a, 34b, 34c, 38b, 39, 40b, 40d, 41b, 41c, 43a, 43b and

4

4b. As expected prior to their crystallization (and shown in Fig. 5 ChemDraw (top) and crystal structure (middle) representations

of 25a. (Bottom): The two asymmetric units in 25a. The dashes lines

Tables S1–S5†), the majority of our catalysts crystallized in

represent the intramolecular interactions within each moiety. These

Sohncke type space groups which include: P1 (30), P2 (25a, 26c,

6d, 29, 34a, 38, 40d, 41c (crystal 2) and 43b), P2 2 2 (27a and

1 1 1

1

ꢀ

distances are: N2(H52)/N1 ¼ 2.26 A; N3(H50)/O2 ¼ 2.00 A;

2

4

ꢀ

N3(H51)/O1 ¼ 1.87 A; N6(H55)/N5 ¼ 2.26 A; N7(H53)/O4 ¼ 2.03 A;

ꢀ

0b), C222

1

(39) and P6

5

(34b). On close inspection and as

ꢀ

N7(H54)/O5 ¼ 1.83 A. The longer contacts O2/H9A(C9) ¼ 2.36 A

ꢀ

highlighted in Fig. 3–12 as well as throughout the ESI (Fig. S1– and O5/H24B(C24) ¼ 2.33 A are not shown.

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It was observed that both catalyst 30 and 31 gave very slow

reaction times and very low ee's in all the solvents studied and

might indicate that substituting the hydrogens on the guani-

dine leads to a lowering of ee, possibly because we are blocking

a site for H-bonding interactions. Contrasting these results to

catalyst 29, which gave very rapid reaction times in toluene, the

lack of a methyl group might enable the guanidine N3–H2 and

N4 positions to form a bidentate interaction with the quinone 1

or the nitro-group of b-nitrostyrene 2 and promote the reaction.

We were unable to obtain any X-ray data on the methyl-

substituted benzimidazoles 35 and 36, however we were able

to obtain a structure on the imidazole compound 38b (Fig. 7b).

Compound 38b had an E-ab hydrogen bonding pattern and

possessed a H-bond between the proline nitrogen and the

ꢀ

amide HN bond (bond a; N2(HN2)/N1 ¼ 2.36 A) and a H-bond

between the imidazole NH and the amide carbonyl (bond b;

ꢀ

N4(HN4)/01 ¼ 2.24 A). The ee's for the reaction of this catalyst

were low, which might be due to the eﬀect of the N-benzyl group

as the corresponding N-methyl catalyst 38a gave slightly better

ee's. The lower ee's might indicate that the benzimidazole ring

plays a role in the better ee's achieved with the catalyst 34a.

The pyridine catalyst 39 had a single H-bond (E-a) between

the proline nitrogen and the amide HN bond (bond a;

ꢀ

N2(HN2)/N1 ¼ 2.29 A). Reaction times were reasonable for this

catalyst (48 h) which might reect the basicity of the pyridine,

however no appreciable ee's were observed in the reactions

(

Fig. 7c). The two C -symmetric catalysts 40b and 40d and were

2

Fig. 6 (a) ChemDraw, H-bonding and crystal structure representa-

tions of 29. The intramolecular H-bonding distances (dashed lines) are:

N2(H1)/N1 ¼ 2.10 A, N2(H1)/O2 ¼ 2.09 A and N3(H3)/O1 ¼ 1.94 A.

found to possess similar hydrogen bonding patterns (see Fig. 7d

and e). In compound 40b, one amide NH was H-bonding to the

ꢀ

The chiral proton is labelled H7. Note: there are two units of 29 in the proline nitrogen (bond a; N4(H14)/N5 ¼ 2.44 A) and this

asymmetric unit and therefore only one is shown here. (b) ChemDraw,

H-bonding and crystal structure of 30. The intramolecular H-bonding

hydrogen was also H-bonding to the other amide carbonyl

0

ꢀ

(

bond c/b : N4(H14)/O2 ¼ 1.99 A). The amide carbonyl is also

ꢀ

distances (dashed lines) are 2.37 A (N2(H2)/N1), 1.92 A (N3(H3)/O1)

H-bonding to the guanidine NH

2

(bond b; N3(H12)/O3 ¼ 1.99

ꢀ

and 1.92 A (N2(H2)/O2). Note: there are two complete molecules in

ꢀ

A). The other proline nitrogen is free of intramolecular H-bonds

so this H-bonding interaction overall is an E-abc/Free-

b arrangement (Fig. 7d). Similarly an identical H-bonding

patterns was observed for 40d in that one amide NH was H-

bonding to the proline nitrogen (bond a; N4(H4)/N5 ¼ 2.28

the asymmetric unit and so only one is shown here.

Compounds 30 and 31 were prepared in order to disrupt the

intramolecular hydrogen bonding patterns in the catalysts.

Catalyst 30 gave a structure with an identical H-bonding pattern

ꢀ

A) and this hydrogen was also H-bonding to the other amide

(E-abc) to catalyst 29 as it had two H-bonds between the amide

0

ꢀ

carbonyl (bond c/b : N4(H4)/O1 ¼ 1.93 A). The amide carbonyl

carbonyls and two of the N–H's of the guanidine (bond b;

2

is also H-bonding to the guanidine NH (bond b; N3(H3B)/O2

ꢀ

N3(H3)/O1 ¼ 1.92 A and bond c; N2(H2)/O2 ¼ 1.92 A). The H-

ꢀ

¼

2.06 A). Again the other proline nitrogen is free of intra-

bond between the proline nitrogen atom (N1) and the amide NH

molecular H-bonds so this H-bonding interaction is also an E-

abc/Free-b arrangement (Fig. 7e).

ꢀ

(

bond a; N2(H2)/N1 ¼ 2.37 A) was also present (Fig. 6).

On close inspection of the X-ray crystal structure of

In both 40b and 40d it is apparent that the proline nitrogen

compound 31, more evidence of the proposed racemization

process was observed as the unit-cell was shown to comprise

a 2 : 1 mixture of S : R enantiomers. The powder X-ray diﬀrac-

tion spectrum obtained from 31 was found to compare favour-

ably with the corresponding simulated spectrum generated by

single crystal data (ESI, Fig. S29†). Despite this the S-enan-

tiomer had an identical E-abc arrangement to 29 with two H-

bonds between the amide carbonyls and two of the N–H's of

(

labelled N5 in both cases) is not involved in intramolecular

hydrogen-bonding and this might leave it free for base catalysed

reactions. This observation might explain why several of the

reactions of these catalysts took relatively short times to

complete (24–48 h, Scheme 4c and appendix IV). Unfortunately

it seems apparent that the relatively strong intramolecular H-

bonds of the guanidine NH's and the carbonyls might

preclude the formation of the bidentate H-bonding pattern we

had hoped for. This, together with the known problems asso-

ciated with bulky nitrogen substituent groups may have led to

the poor ee's.

ꢀ

the guanidine (bond b; N7(H34)/O4 ¼ 1.90 A and bond c;

ꢀ

N6(H33)/O5 ¼ 1.95 A). The H-bond between the proline

nitrogen atom (N5) and the amide NH (bond a; N6(H33)/N5 ¼

ꢀ

2

.44 A) was also still present (Fig. 7a).

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Fig. 7 ChemDraw and crystal structure representations of 31 (a), 38b (b), 39 (c), 40b (d), 40d (e) and 41c (f). All intramolecular H-bonding

ꢀ

distances are represented as dashes lines. These distances are: (a) N6(H33)/N5 ¼ 2.44 A, N6(H33)/O5 ¼ 1.95 A, N7(H34)/O4 ¼ 1.90 A. (b)

ꢀ

N2(HN2)/N1 ¼ 2.36 A, N4(HN4)/O1 ¼ 2.24 A. (c) N2(HN2)/N1 ¼ 2.29 A. (d) N4(H14)/N5 ¼ 2.44 A, N4(H14)/O2 ¼ 1.99 A, N3(H12)/O3 ¼

ꢀ

1

.99 A. (e) N4(H4)/N5 ¼ 2.28 A, N3(H3B)/O2 ¼ 2.06 A, N4(H4)/O1 ¼ 1.93 A. (f) N2(H1)/N1B ¼ 2.32 A. Note: 31 crystallises as an 2 : 1 S : R

epimer mixture. The S-enantiomer is shown here. There are two types of crystals in the bulk material of 41c (labelled crystal 1 and crystal 2).

Crystal 1 is racemic in nature and all 41c units in crystal 2 exhibit the S conﬁguration. The S-enantiomer extracted from crystal 1 is shown in (f).

As previously stated the co-crystallisation of two polymorphs of the S- and R-enantiomers again indicating partial racemiza-

of 41c (crystal 1: 1 : 1 racemic mixture and crystal 2: S-congu- tion or preferential crystallization. The powder XRD data ob-

ration only) indicated that the reaction has proceeded with tained from a polycrystalline sample of 41b suggests that its

partial racemization and that the 1 : 1 mixture has crystallized single crystal data is representative of the bulk sample

from a partially racemic mixture together with the S-enan- (Fig. S30†). The H-bond pattern is similar to the majority of the

0

tiomer. Despite this a similar H-bond between the proline guanidine catalysts in that it is an E-amide-ab type arrange-

nitrogen and the amide HN bond (bond a; N2(H2)/N1 ¼ 2.23 ment. As such, there is a H-bond between the nitrogen and the

ꢀ

A) was observed (E-a type) on examination of the S-enantiomer. amide NH bond (bond a; N2(H2)/N3 ¼ 2.29 A) and a long H-

This was shorter than that found in other catalysts, which might bond between the amide carbonyl and the other NH of the

0

ꢀ

explain the slow reaction times for this compound compared to hydrazine (bond b ; N1(H1)/O1 ¼ 2.68 A). This catalyst gave

the other hydrazine catalyst (Fig. 7f). a very short Michael reaction time (1 h in toluene, xylene and

The X-ray structure was also obtained for the phenyl hydra- benzene) and may be explained by the presence of the hydrazine

zine catalyst 41b and was found to crystallize as a 2 : 1 mixture PhNH, which will be more basic than the examples where this

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Fig. 8 ChemDraw (inset) and crystal structure representations of 41b.

The dashed lines represent intra- and intermolecular H-bonding

ꢀ

interactions with distances: N2(H2)/N3 ¼ 2.29 A, N5(H5)/N6A ¼

ꢀ

2

.30 A, N2(H2)/N4 ¼ 2.26 A and N5(H5)/N1 ¼ 2.18 A. Note: the A

label denotes a disordered (R : S) proline unit (only A is shown here).

For clarity the N1(H1)/O1 intramolecular interaction is not shown

here.

NH is a carbamate. Low ee's (2–3%) were obtained using this

catalyst, however, on cooling the ee in toluene was improved to

17% (Fig. 8).

X-Ray structures of the dimethyl-L-alanine catalyst 43a and

the dimethyl-L-phenylalanine catalysts 44a and 44b were also

obtained. Again, unfortunately, the dimethyl-L-alanine catalyst

43a crystallized as a racemic mixture (single crystal and pXRD

corroborate batch uniformity; ESI, Fig. S31†), however the S-

enantiomer gave an E-abc type with H-bonds between the N–H

of the amide and the dimethylamine together with an H-bond

between a guanidine NH and the amide carbonyl (bond a;

ꢀ

N3B(HN3)/N4 ¼ 2.30 A and bond b; N2(HN2A)/O3B ¼ 2.05

ꢀ

A). A third H-bond between the amide NH and the carbonyl of

the Cbz groups was also observed (bond c; N3B(HN3)/O2 ¼

ꢀ

1

.96 A), which was the shortest H-bond of the three (Fig. 9).

The structure of the dimethyl-L-phenylalanine-phenyl

guanidine catalyst 43b was obtained and this had a signi-

cantly diﬀerent Free-b type H-bonding pattern. In this structure

the amide was present as an N-methyleneformamide which

Fig. 9 (a) The ChemDraw representation and crystal structures of the

R- and S-enantiomers observed in the racemic compound 43a.

lacks an N–H bond. The only intramolecular H-bond was Intramolecular H-bonding shown using dashed lines at distances:

ꢀ

between the guanidine NH and the amide carbonyl (bond b; N2(NH2A)/O3A ¼ 2.06 A, N3A(HN3)/N4 ¼ 2.30 A and N3A(HN3)/

2

ꢀ

O2 ¼ 1.96 A (in R) and N2(HN2A)/O3B ¼ 2.05 A, N3B(HN3)/2.30 A

ꢀ

N7(H7A)/O2 ¼ 1.98 A) (Fig. 12).

ꢀ

and N3B(HN3)/O2 ¼ 1.96 A (in S). (b) ChemDraw and crystal of

The dimethyl-L-phenylalanine catalyst 44b gave no signs of

racemization in the crystal. This compound displayed an E-abd

catalyst 43b. The dashed lines represent intramolecular H-bonding

ꢀ

interactions (N7(H7A)/O2 ¼ 1.98 A). Note: there are four molecules of

H-bonding pattern with a hydrogen bond between the N–H of 43b in the asymmetric unit. A solitary unit is shown here. (c) Crystal

the amide and the dimethylamine together with a H-bond structure obtained from 44b. The dashed lines represent intra-

ꢀ

molecular H-bonding at distances: N2(HN2B)/O3

N2(HN2A)/O2 ¼ 1.98 A and N3(HN3)/N4 ¼ 2.48 A.

¼

2.03 A,

between a guanidine NH and the amide carbonyl (bond a;

ꢀ

N3(HN3)/N4 ¼ 2.48 A and bond b; N2(HN2B)/O3 ¼ 2.03 A). A

third H-bond was again observed, this time between the

guanidine NH

2

and the carbonyl of the Cbz group (bond c;

(

18–96 h). This might be a reection on the degree of race-

ꢀ

N2(HN2A)/O2 ¼ 1.98 A), which again was the shortest H-bond

misation or possibly the level of H bonding. The dimethyl-L-

phenylalanine catalyst 44b gave better ee's (4–25%) but again

generally relatively long reaction times. In contrast, the

of the three (Fig. 9).

The Michael reaction using the dimethyl-L-alanine catalyst

43a gave poor ee's (7–13%), over relatively long reaction times

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Fig. 10 (Top): Intermolecular H-bonding arrangement (dashed lines)

between two crystallographically equivalent 25a units. Selected

0

ꢀ

0

ꢀ

distances: O3/(H50 )N3 ¼ 2.20 A; N4/(H51 )N3 ¼ 2.63 A and Fig. 11 (Top): The crystal structure of 40b. The dashed lines represent

0

ꢀ

N2(H52)/O1 ¼ 2.58 A. Note: intramolecular H-bonding also shown the intramolecular hydrogen bonding interactions: N4(H14)/O2 ¼

ꢀ

(

dashed lines). (Bottom): Regular (a and c) and space-ﬁll (b and d) views 1.99 A; N3(H12)/O3 ¼ 1.99 A and N4(H14)/N5 ¼ 2.44 A. (Bottom): A

of the packing arrangement observed in 25a. Each unit (in b and d) is section of the H-bonded (dashed lines) chains in 40b as viewed oﬀ-set

represented by a diﬀerent colour to highlight the space eﬃcient (a) and parallel (c) to the plane of the H-bonded guanidine moieties

interdigitation of the U-shaped organic units in 25a.

along with their space-ﬁll representations (b and d respectively). The

individual guanidine units are colour coded. The intermolecular H-

0

ꢀ

bonded distances are: N1/(H13 )C13 ¼ 2.06 A (not shown); O2/

0

ꢀ

0

(

H12 )N3 ¼ 2.40 A and C17(H17A)/O3 ¼ 2.80 A.

dimethyl-L-phenylalanine phenyl guanidine catalyst 43b gave

rapid reaction times (8–10 h) in all solvents and the ee's (18–

2

1%) were high when compared to the other two catalysts. This

interactions as highlighted in Fig. 10 (25a), Fig. 11 (40b) and

Fig. 12 (44b). In all these examples, the H-bond connections are

forged through guanidine protons and neighboring carbonyl

oxygen, alcohol oxygen and/or guanidine nitrogen acceptor

might possibly be due to the more basic nature of the guani-

dine, which is substituted with only one electron withdrawing

carbonyl containing group. These observations might suggest

that the presence of the carbamate protecting groups is detri-

mental to the eﬃciency of the reaction and does not lead to

a high ee product (as previously postulated).

Whilst it is diﬃcult to draw conclusions from the X-ray data,

it is obvious the presence of racemization is a major concern in

the potential for these catalysts. Despite this there is some

evidence that the more substituted catalysts are less eﬃcient

and that a maximum of two substituents seems to be the most

promising. Some interesting observations were also made

regarding intermolecular H-bonding interactions and this is

discussed below.

0

ꢀ

0

ꢀ

atoms (i.e. N2(H52)/O1 ¼ 2.58 A and N4/(H51 )N3 ¼ 2.63 A

in Fig. 10). For example, the catalyst 25a comprises two organic

crystallographically unique moieties within its asymmetric unit

and partake in side-on C–H/p intermolecular interactions

between proline protons and juxtaposed benzoate aromatic

ꢀ

rings (e.g. C17(H17B)/[C10–C15] ¼ 3.01 A and C2(H2B)/[C25–

ꢀ

C30] ¼ 3.20 A) to form an interdigitated rectangular dimeric

assembly. Likewise, intermolecular complementary H-bonding

between the individual guanidine units connect these dimeric

units along the a unit cell direction to form tubular sheet-like

arrays throughout the crystal structure in 25a (Fig. 10).

Akin to the connectivity arrangements in 25a, the chair-

shaped organic units in 40b produce superimposable H-

bonded sheets along the a unit cell direction (Fig. 11). The

intermolecular hydrogen bonding interactions are forged

between guanidine protons and neighbouring carbonyl oxygen

Intermolecular interactions

In terms of intermolecular interactions and as exampled by the

species 25a, 40b and 43b, the individual organic moieties in

a number of our catalysts self-assemble in the solid-state as

planar sheet arrays through complementary H-bonding

0

ꢀ

acceptor atoms (e.g. N3(H12)/O2 ¼ 2.40 A). The individual H-

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Fig. 12 (Top left): Crystal structure of 44b highlighting (a) the intramolecular H-bonding interactions in 44b (dashed lines) (N3(HN3)/N4 ¼ 2.48

ꢀ

A; N2(HN2A)/O2 ¼ 1.98 A and N2(HN2B)/O3 ¼ 2.03 A) and (b and c) the superimposable U-shaped 1D H-bonded rows of 44b units prop-

0

ꢀ

0

ꢀ

agating along the a direction of the unit cell. Selected intermolecular H-bonding interactions: N3(HN3)/O3 ¼ 2.54 A; N1/(HN2B )N2 ¼ 2.49 A

0

ꢀ

and O1/(HN2A )N2 ¼ 2.22 A. (d) is a space-ﬁll representation of the 1D rows in 44b. Each colour represents a single organic unit. (Top right):

Crystal structure of the dimeric asymmetric unit 40d as viewed perpendicular (a) and parallel (c) to the plane of the H-bonded (dashed lines)

guanidine moieties along with their colour coded space-ﬁll representations (b and d, respectively). Intramolecular H-bonded distances:

ꢀ

N3(H3B)/O2 ¼ 2.06 A; N4(H4)/O1 ¼ 1.93 A; N8(H8D)/O3 ¼ 2.05 A; N7(H7)/O4 ¼ 1.95 A; N7(H7)/N6 ¼ 2.31 A and N4(H4)/N5 ¼ 2.28 A.

ꢀ

Intermolecular H-bonded distances: N8(H8C)/N2 ¼ 2.11 A; N3(H3A)/N9 ¼ 2.09 A; N3(H3B)/N10 ¼ 2.89 A and N8(H8D)/N1 ¼ 2.96 A.

(

Bottom left): (a) A H-bonded helical chain of individual units of 34b propagating along the c unit cell direction. The dashed lines represent the

0

ꢀ

0

ꢀ

intermolecular H-bonding interactions in 34b (N2(H20)/O1 ¼ 2.26 A and N4/H19 (N3 ) ¼ 2.02 A). (b) The asymmetric unit in 34b highlighting

ꢀ

(

dashed lines) the intramolecular H-bonding interactions (N2(H20)/N1 ¼ 2.33 A and N3(H19)/O1 ¼ 2.36 A). (c) A single H-bonded helical chain

in 34b as viewed along the c direction of the unit cell. (Bottom right): Crystallographic packing of 34b as viewed along the c direction of the unit

cell.

bonded rows in 40b connect along the bc plane of the unit cell guanidine moieties H-bond to one another via their guanidine

through C–H/p interactions between proline protons and protons (H3A and H8C) to form dimeric units that forge a U-

neighbouring aromatic rings at distances of (for instance): 3.83 shaped half-pipe motif as highlighted in Fig. 12.

ꢀ

A (C15(H15)/[C20–C25]), 3.46 A (C15(H16B)/[C20–C25]) and

Interestingly, the benzimidazole containing proline derived

space group whose

ꢀ

3.44 A (C17(H17B)/[C20–C25]). In a similar fashion, the indi- catalyst 34b crystallises in the hexagonal P6

5

vidual U-shaped organic units in 44b connect along the a cell translational symmetry is manifested through the formation of

direction via numerous intermolecular interactions to form a H- H-bonded helical chains propagating along the c direction of

bonded half pipe array as highlighted in Fig. 12.

the unit cell (Fig. 12-bottom le). These chains organise them-

In a similar vein, the catalysts 29, 30 and 40d arrange into H- selves into a space eﬃcient brickwork motif to give the packing

bonded dimers and are presumably too sterically hindered by arrangement shown in Fig. 12 (bottom right). Moreover, the

their tert-butyl (29 and 30) and cyclohexane (40d) groups to structurally related catalyst 34c is the only member to encap-

forge planar sheet topologies as previously described. For sulate a solvent molecule during crystallisation. More speci-

instance, the catalyst 40d crystallises in the monoclinic P2

1

cally, a crystallographically unique water of crystallisation lies at

space group (screw axis along b cell direction) and exhibits two H-bonding distance from the organic moiety in 34c. This

organic moieties in the asymmetric unit. Indeed these U-shaped molecule is held in position through H-bonding with

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ꢀ

a guanidine proton (H2N) at a distance of 2.15 A (N2(H2N)/O2) recorded on a Micromass Quattro II spectrometer and high

and a guanidine N acceptor atom of an adjacent organic moiety resolution mass spectra were recorded on either a Finnigan

ꢀ

at a distance of 2.09 A (N4/(H20)O2) (Fig. S14 and S15†). As MAT 900 XLT or a Finnigan MAT 95 XP. Infrared samples were

a result, these waters of crystallisation as molecular cement in prepared as thin lms or solutions using sodium chloride plates

connecting the individual brick units in 34c as they propagate or as KBr discs; spectra were recorded on a Bruker Tensor 37 FT-

along the a unit cell direction (Fig. S16†).

IR. Optical rotations were determines on an ADP400 polarim-

eter. The N-alkylated prolines were prepared by literature

methods and the guanidines and heterocycles used in the study

were prepared by literature methods or are commercially

Conclusions

The work presented here has illustrated that amino acid derived available, full details of these preparations are given in the ESI.†

guanidine have some potential as asymmetric organocatalysts All PXRD samples were collected on a Rigaku MiniFlex 600

ꢀ

however several problems have arisen. Crystallographic inves- (CuK radiation (40.0 kV, 15.0 mA), over a 2q range of 5 to 40 .

a

tigation of the catalysts has led to the discovery of quite preva-

lent racemization occurring during their formation under CDI

activated coupling. Obviously, this is a major drawback to their

use as catalysts and they are not competitive in terms of

producing the targeted asymmetric products. Our investigation

General methods for the preparation of the catalysts 21–41

and 43–47

in the solid state demonstrated extensive intra- and intermo-

Method A. The N-alkyl-L-proline (1.0–1.6 equiv.) was dis-

lecular H-bonding abilities of the proline, guanidine and/or solved in DMF (1–2.5 mL per mmol), CDI (1.2 equiv.) was added

ꢀ

amide functional groups within these organic moieties. These and the mixture stirred for 5 min to 24 h. Aer cooling (0 C) the

interactions lead to the production of elaborate and aestheti- mixture, the required guanidine (1.0 equiv.) was added as

cally pleasing hydrogen bonded extended network architec- a solid and the mixture stirred to rt over 16–168 h. Aer evap-

tures. Consideration of the intramolecular H-bonding gave oration under reduced pressure (freeze dryer) or dilution with

a loose correlation with catalytic eﬃciency and it inferred that water and extracting with ethyl acetate, drying (MgSO ) and

4

these interactions remain in place in solution. A consideration evaporation under reduced pressure, the product was obtained

of these structural interactions might lead the way to develop- and was puried by column chromatography (DE/PE or EA/PE),

ment of new catalysts. Indeed our current work addresses this recrystallization, trituration or

together with new methodology to produce related catalysts techniques.

a combination of these

without the problems associated with racemisation.

Method B. The N-alkyl-L-proline (1.0 equiv.) was dissolved in

dry DMF (1–2.5 mL per mmol), CDI (1.2 equiv.) was added and

the mixture stirred for 3–16 h. In a separate ask, sodium metal

Experimental

General procedures

(1.0 equiv.) was added to methanol (1–2 mL per mmol) and aer

complete reaction, the phenylguanidinium salt (1.0 equiv.) was

Unless otherwise noted, reactions were stirred and monitored added and the solution stirred for 30 min. This mixture was

by TLC. TLC plates were visualized using iodine, phosphomo- evaporated under high vacuum to dryness and the activated

lybdic acid or under UV light. All anhydrous reactions were proline solution was added to it via cannula. The resultant

conducted under a static argon atmosphere using oven dried mixture was stirred for 5 days, then water (100 mL) was added

glassware that had previously been cooled under a constant and the mixture extracted with EA (3ꢂ 100 mL). Once

stream of nitrogen. Reagents and starting materials were combined, the extracts were washed with water (3ꢂ 500 mL),

4

purchased from commercial suppliers and used without further dried (MgSO ) then evaporated under reduced pressure. Puri-

purication unless otherwise noted. All anhydrous solvents cation was by column chromatography (EA in PE), recrystalli-

used in reactions were distilled over either sodium wire and zation, tritutation or a combination of these techniques.

benzophenone (THF/DE) or calcium hydride (DCM), and used

2

Method C. (C -catalysts): the N-alkyl-L-amino acid (1 equiv.)

either immediately or stored over molecular sieves prior to use. and CDI (1.20 equiv.) were added sequentially to dry DMF (0.5–

Flash column chromatography was performed on Davisil® 2.5 mL per mmol) and the mixture stirred for 1–16 h. In

silica gel (35–70 microns) with the eluent specied in each case, a separate ask, NaH (0.60 equiv.) was suspended in dry DMF

TLC was conducted on precoated E. Merck silica gel 60 F₂₅₄(1.0–2.0 mL per mmol) and dried (over P O ) guanidinium

2

5

glass plates. Melting points were determined using a Gallen- chloride (0.50 equiv.) was added. Aer stirring for 1 h the acti-

1

13

kamp MF370 instrument and are uncorrected. H and C NMR vated amino acid solution was transferred into this ask via

spectra were recorded on a Bruker Avance 400 or 500 spec- cannula and the mixture stirred for 24–48 h. The mixture was

trometer with an internal deuterium lock at ambient tempera- diluted with water (100 mL) and EA (100 mL), separated and the

ture at 400 or 500 MHz with internal references of d

7.016 ppm for CDCl , d 3.31 and d 49.0 ppm for CD

d 2.54 ppm and d 39.52 ppm for DMSO. All mass spectra were (MgSO ) and evaporation under reduced pressure the residue

H

7.26 and d

C

aqueous layer extracted with further EA (2ꢂ 100 mL) and the

7

3

H

C

3

OD and combined extracts washed with water (2ꢂ 100 mL). Aer drying

H

4

performed at the EPSRC National Mass Spectrometry Service was co-evaporated with heptane to remove residual DMF and

Centre based in Swansea. Low resolution Chemical Ionisation puried by silica gel chromatography (EA in PE), recrystalliza-

(CI) and Electrospray Ionisation (ESI) mass spectra were tion, tritutation or a combination of these techniques.

This journal is © The Royal Society of Chemistry 2020

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0

(S)-N-Cbz-N -carbamimidoyl-1-isopropylpyrrolidine-2-carboxa-

Method D: (S)-1-methylpyrrolidine-2-carbohydrazide 41a. N-

Methyl-L-proline 23a (2.30 g, 17.8 mmol, 1.0 equiv.) was dis- mide 25c: method A. Isopropyl-L-proline 23c (1.0 g, 6.36 mmol,

ꢀ

solved in MeOH (10 mL), cooled (0 C) and acetyl chloride (2 1.0 equiv.); DMF (10 mL); CDI (1.24 g, 7.63 mmol, 1.2 equiv.); 4 h;

mL, 2.2 g, 28.0 mmol, 1.6 equiv.) was slowly added over 5 min. Cbz-guanidine (1.23 g, 6.36 mmol, 1.0 equiv.); 16 h. Extraction,

The mixture was heated at reux for 12 h, cooled to rt and co-evaporation with heptane (4ꢂ 50 mL) and column chroma-

concentrated under reduced pressure. The residue was tritu- tography (0–100% EA in PE) gave 25c (2.09 g, 6.29 mmol) in 99%

2

0

rated with DE (3ꢂ 50 mL) and dried under vacuum to give (2S)- yield as a pale yellow oil. R 0.30 (80% EA/PE); [a] ꢁ31.1 (CHCl ,

f

D

3

2

1

-(methoxycarbonyl)-1-methylpyrrolidin-1-ium chloride (2.51 g, c ¼ 1.0); d (CDCl ) 7.62–11.45 (3H, br s, 3ꢂ NH), 7.25–7.44 (5H,

H

3

4.0 mmol) as a brown gum in 79% yield. The crude ester m, Ph), 5.17 (1H, d, J 12.4 Hz, CH), 5.13 (1H, d, J 12.5 Hz, CH),

(1.57 g, 8.77 mmol) was dissolved in MeOH (9 mL) and hydra- 3.35 (1H, br d, J 10.5, CH), 3.12 (1H, t, J 7.5 Hz, CH), 2.73–2.81

zine hydrate (98%, 8.27 g, 0.165 mols, 8.1 mL, 9.3 equiv.) was (1H, m, CH), 2.49–2.57 (1H, m, CH), 2.07–2.17 (1H, m, CH), 1.89–

added drop wise over 5 min. Aer stirring for 24 h, a white 1.98 (1H, m, CH), 1.73–1.81 (1H, m, CH), 1.62–1.73 (1H, m, CH),

precipitate was removed by ltration and the ltrate concen- 1.07 (3H, d, J 7.4 Hz, Me), 1.06 (3H, d, J 7.0 Hz, Me); d (CDCl )

C 3

trated under reduced pressure to give a yellow oily residue. 179.7, 163.9, 158.7, 136.7, 128.5, 128.3, 128.0, 67.1, 64.5, 53.3,

Trituration of the residue with CHCl (2ꢂ 40 mL) followed by 50.9, 31.8, 24.7, 21.1, 20.1; n_m_a_x(KBr disc) 3388, 3080, 2968, 1706,

3

ꢁ

1

drying under vacuum gave the crude product as a yellow oil 1651, 1562, 1413, 1275, 1135 cm ; MS (ESI) m/z 333.2 (100%, [M

1.75 g) which was puried by column chromatography (5–10% + H] ); HRMS (ESI) m/z found 333.1920, C17H N O ([M + H] )

25 4 3

+

(

MeOH in CHCl

a pale yellow oil in 93% yield (73% over 2 steps).

3

with 1% NEt

3

) to give 41a (1.15 g, 8.03 mmol) as requires 333.1921.

0

(S)-N-Cbz-N -carbamimidoyl-1-cyclohexylpyrrolidine-2-car-

boxamide 25d: method A. N-Cyclohexyl-L-proline 23d (0.4 g,

2

1

.03 mmol, 1.0 equiv.); DMF (5 mL); CDI (0.39 g, 2.43 mmol,

.2 equiv.); 4 h; Cbz-guanidine (0.39 g, 2.03 mmol, 1.0 equiv.);

8 h. Extraction and recrystallization (ME/DE) gave 25d

Spectroscopic data

0

(

S)-N-Cbz-N -carbamimidoyl-1-methylpyrrolidine-2-carboxa-

(0.70 g, 1.88 mmol) in 93% yield as a pale yellow solid. R 0.19

f

ꢀ

16

D

mide 25a: method A. N-Methyl-L-proline 23a (0.50 g, 3.87 mmol, (80% EA/PE); mp 167–168 C; [a] ꢁ63.5 (CHCl , c ¼ 1.0); d

3

H

1

3

.0 equiv.); DMF (10 mL); CDI (0.75 g, 4.65 mmol, 1.2 equiv.); (CDCl ) 9.39–10.66 (1H, br s, NH), 8.26–9.39 (2H, br s, 2ꢂ NH),

3

h; N-Cbz-guanidine (0.74 g, 3.87 mmol, 1.0 equiv.); 27 h. 7.39 (2H, br d, J 7.2 Hz, 2ꢂ CH), 7.32 (2H, br t, J 7.2 Hz, 2ꢂ

Evaporation then column chromatography (0–60% DE in PE) CH), 7.27 (1H, br d, J 7.2 Hz, CH), 5.13 (1H, d, J 12.3 Hz, CH),

gave 25a (0.86 g, 2.82 mmol) as a white solid in 73% yield. R

f

5.09 (1H, d, J 12.3 Hz, CH), 3.34 (1H, dd, J 2.4, 10.7 Hz, CH),

3.10 (1H, br t, J 7.4 Hz, m, CH), 2.49–2.56 (1H, m, CH), 2.27–

ꢀ

21

0

.17 (10% DE/PE); mp 67–70 C; [a]_Dꢁ64.8 (CHCl , c ¼ 1.0); d

3

H

(CDCl ) 8.24–10.8 (3H, br. s, 2ꢂ NH), 7.38–7.44(2H, m, 2ꢂ CH), 2.36 (1H, m, CH), 2.00–2.15 (1H, m, CH), 1.81–1.94 (2H, m, 2ꢂ

3

7

1

.26–7.38 (3H, m, 3ꢂ CH), 5.16 (H, d, J 12.9 Hz, CH), 5.12 (H, d, J CH),1.54–1.79 (6H, m, 6ꢂ CH), 1.00–1.25 (5H, m, 5ꢂ CH); d

C

2.9 Hz, CH), 3.05–3.08 (1H, m, CH), 3.01 (1H, dd, J 4.8, 10.5 Hz, (CDCl ) 179.8, 163.8, 158.7, 136.6, 128.4, 128.3, 128.0, 67.0,

3

CH), 2.42 (1H, dd, J 6.5, 10.1 Hz, CH), 2.38 (3H, s, Me), 2.2–2.32 64.5, 62.4, 51.1, 31.6, 31.5, 30.8, 25.8, 25.4, 25.4, 24.6; n_m_a_x

1H, m, CH), 1.71–1.96 (3H, m, CH, CH ); d (CDCl ) 178.0, (KBr disk) 3407, 3273, 3058, 2932, 1702, 1650, 1604, 1450,

63.9, 158.8, 136.6, 128.4, 128.2, 128.0, 68.9, 67.0, 56.5, 41.7, 1374, 1090 cm ; MS (ESI) m/z 373.2 (100%, [M + H] ), HRMS

(

2

C

3

ꢁ

1

+

1

3

1

+

1.3, 24.6; nmax (KBr disk) 3395, 3279, 3086, 2945, 1704, 1656, (ESI) m/z found 373.2233, C H N O ([M + H] ) requires

611, 1375, 1090 cm ; MS (EI) m/z 305.2 (100%, M + H] ); 373.2234.

2

0

29

4 3

ꢁ

1

+

0

HRMS (ESI) m/z, found 305.1610, C H N O ([M + H] )

requires 305.1608.

S)-N-Cbz-1-benzyl-N -carbamimidoylpyrrolidine-2-carboxa-

(S)-N-(N,N -Diphenylcarbamimidoyl)-1-methylpyrrolidine-2-

carboxamide 26a: method A. N-Methyl-L-proline 23a (2.0 g,

15.5 mmol, 1.0 equiv.); dry DMF (8 mL); CDI (3.01 g, 18.6 mmol,

1

5

21 4 3

0

(

0

mide 25b: method A. N-Benzyl-L-proline 23b (1.0 g, 4.87 mmol, 1.2 equiv.); 24 h; N,N -diphenylguanidine (3.27 g, 15.5 mmol, 1.0

1

3

.0 equiv.); DMF (11 mL); CDI (0.95 g, 5.85 mmol, 1.2 equiv.); equiv.); 24 h. Extraction and column chromatography (0–80%

h; Cbz-guanidine (0.95 g, 4.87 mmol, 1.0 equiv.); 48 h. EA in PE) gave 26a (1.37 g, 4.25 mmol) in 28% as a yellow solid.

ꢀ

20

Extraction and column chromatography (0–60% EA in PE) gave R 0.39 (80% EA in PE); mp 110 C; [a] +38.1 (CHCl , c ¼ 1.0);

f

D

3

25b (1.63 g, 4.29 mmol) in 89% yield as a white solid. R 0.10 d (D -DMSO) 9.92 (1H, br s, NH), 9.78 (1H, s, NH), 7.70 (2H, d, J

f

H 6

ꢀ

21

(

5

(

20% EA/PE); mp 101–103 C; [a]_Dꢁ67.1 (CHCl , c ¼ 1.0); d

7.8 Hz, 2ꢂ CH), 7.29–7.34 (4H, m, 4ꢂ CH), 6.99–7.07 (2H, m, 2ꢂ

) 7.93–11.30 (3H, br s, 3ꢂ NH), 7.21–7.29 (10H, m, 2ꢂ Ph) CH), 6.90 (2H, d, J 7.6 Hz, 2ꢂ CH), 2.93 (1H, dd, J 4.1, 10.5 Hz,

.20 (1H, d, J 12.4 Hz, CH), 5.15 (1H, d, J 12.4 Hz, CH), 3.74 CH), 2.65 (1H, br t, 7.6 Hz, CH), 2.20 (1H, ddd, J 6.1, 9.1, 10.5 Hz,

2H, s, CH ), 3.29 (1H, dd, J 3.9, 10.3 Hz, CH), 3.06–3.19 (1H, m, CH). 2.10 (3H, s, Me), 2.02–2.14 (1H, m, CH), 1.61–1.77 (2H, m,

CH), 2.45–2.56 (1H, m, CH), 2.18–2.33 (1H, m, CH), 1.69–1.97 2ꢂ CH), 1.36–1.51 (1H, m, CH); d (D -DMSO) 174.3, 147.4,

3

H

CDCl

3

2

C

6

(

3H, m, CH, CH

2

C 3

); d (CDCl ) 177.9, 163.5, 158.5, 136.7, 136.7, 140.8, 139.2, 129.2, 128.7, 122.7, 122.4, 122.2, 119.3, 68.1, 55.7,

1

3

1

29.5, 128.6, 128.4, 128.1, 128.0, 127.8, 67.0, 66.9, 59.7, 54.2, 40.8, 30.3, 24.2; n_m_a_x(KBr disc) 3550, 3057, 2944, 1701, 1604,

ꢁ

1

1.0, 24.2; n_m_a_x(KBr disc) 3381, 3059, 2938, 1703, 1652, 1607, 1420, 1321, 1208, 1157, 1080 cm ; MS (ESI) m/z 323.2 (100%,

ꢁ

1

+

553, 1404, 1118, 1028 cm ; MS (ESI) m/z 381.2 (100%, [M + [M + H] ); HRMS (ESI) m/z found 323.1865, C H N O ([M +

1

9

23 4

+

25 4 3

H] ); HRMS (ESI) m/z found 381.1914, C21H N O ([M + H] ) H] ) requires 323.1866.

requires 381.1921.

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S)-1-Benzyl-N-(N,N -diphenylcarbamimidoyl)pyrrolidine-2-

RSC Advances

0

(

119.7, 64.5, 61.6, 50.5, 31.9, 31.2, 30.1, 25.8, 25.2, 25.1, 24.6; nmax

ꢁ1

carboxamide 26b: method A. N-Benzyl-L-proline 23b (1.0 g, (KBr disk) 3058, 2927, 1691, 1650, 1589, 1316, 1028, 750 cm ; MS

+

4

.87 mmol, 1.0 equiv.); DMF (4 mL); CDI (0.95 g, 5.85 mmol, 1.2 (ESI) m/z 391.2 (%, [M + H] ); HRMS (ESI) m/z found 391.2482;

equiv.); 5 h; N,N -diphenylguanidine (1.03 g, 4.87 mmol, 1.0

0

+

C

24

H

N

O [M + H] requires 391.2492.

31

4

0

equiv.); 24 h. Extraction, co-evaporation with toluene and

(S)-1-Methyl-N-(N -phenylcarbamimidoyl)pyrrolidine-2-car-

column chromatography (0–60% EA in PE) gave 26b (0.64 g, 1.60 boxamide 27a: method B. N-Methyl-L-proline 23a (0.50 g,

mmol) in 33% yield as a pale yellow solid. R 0.32 (30% EA in 3.87 mmol, 1.0 equiv.); DMF (10 mL); CDI (0.75 g, 4.65 mmol,

f

ꢀ

21

PE); mp 135–136 C; [a]_D+22.3 (CHCl , c ¼ 1.0); d (D -DMSO) 1.2 equiv.); 3 h; Na (0.09 g, 3.87 mmol, 1.0 equiv.); methanol (4

3

H

6

9

7

.97 (1H, s, NH), 9.89 (1H, s, NH), 7.67 (2H, d, J 7.6 Hz, 2ꢂ CH), mL) 2-phenylguanidinium nitrate (0.84 g, 4.26 mmol, 1.1

.38 (2H, t, J 7.7 Hz, 2ꢂ CH), 7.30 (2H, t, J 7.8 Hz, 2ꢂ CH) 7.17– equiv.); 5 d. Extraction and column chromatography (0–50%

.23 (3H, m, 3ꢂ CH), 7.10 (1H, t, J 7.3 Hz, CH) 7.01 (1H, t, J EA in PE) gave 27a (0.38 g, 1.53 mmol) in 40% yield as a pale

ꢀ

16

.4 Hz, CH), 6.98 (2H, d, J 7.7 Hz, 2ꢂ CH), 6.69–6.75 (2H, m, 2ꢂ yellow solid. R

0.28 (50% EA in PE); mp 133 C; [a]

ꢁ80.1

f

D

CH), 3.66 (1H, d, J 13.0 Hz, CH), 3.37 (1H, d, J 13.0 Hz, CH), 3.27 (CHCl

3

, c ¼ 1.0); d (CDCl ) 7.32 (2H, t, J 7.8 Hz, 2ꢂ CH), 7.06

H

3

(

1

2

1H, dd, J 3.5, 10.2 Hz, CH), 2.59–2.66 (1H, m, CH), 2.09–2.28 (1H, t, J 7.4H, CH), 6.96–7.00, (2H, m, 2ꢂ CH), 5.03–6.85 (3H,

2H, m, 2ꢂ CH), 1.82–1.92 (1H, m, CH), 1.68–1.78 (1H, m, CH), br s, 3ꢂ NH), 3.12–3.22 (1H, m, CH), 3.02 (1H, dd, J 4.8,

.51–1.64 (1H, m, CH); d (D -DMSO) 174.8, 147.0, 140.3, 139.0, 10.4 Hz, CH), 2.44 (3H, s, Me), 2.36–2.46 (1H, m, CH), 2.21–

C 6

37.7, 129.4, 128.7, 128.3, 128.3, 127.0, 122.8, 122.4, 122.3, 2.32 (1H, m, CH), 1.91–2.02 (1H, m, CH), 1.76–1.86 (2H, m, 2ꢂ

19.3, 66.7, 58.7, 53.3, 30.2, 24.0; nmax (KBr disc) 3550, 3054, CH); d (CDCl ) 176.7, 148.2, 146.1, 129.7, 123.6, 122.9, 69.2,

924, 1698, 1651, 1588, 1321, 1205, 1077, 1028 cm ; MS (ESI) 56.5, 41.7, 31.1, 24.5; nmax (KBr disc) 3314, 3085, 2903, 1631,

C

3

ꢁ

1

+

ꢁ1

m/z 399.2 (100%, [M + H] ); HRMS (ESI) m/z found 399.2177, 1590, 1515, 1391, 1286, 1183, 1039 cm ; MS (ESI) m/z 247.2

+

C

25

H

(

27

N

4

O ([M + H] ) requires 399.2179.

(100%, [M + H] ); HRMS (ESI) m/z found 247.1556, C13

H

19

N

4

O

0

+

S)-N-(N,N -Diphenylcarbamimidoyl)-1-isopropylpyrrolidine- ([M + H] ) requires 247.1553.

-carboxamide 26c: method A. N-Isopropyl-L-proline 23c (1.0 g,

0

2

(S)-1-Benzyl-N-(N -phenylcarbamimidoyl)pyrrolidine-2-car-

6

.36 mmol, 1.0 equiv.); DMF (10 mL); (1.24 g, 7.63 mmol, 1.2 boxamide 27b: method B. N-Benzyl-L-proline 23b (2.0 g,

0

equiv.); 5 h; N,N -diphenylguanidine (1.30 g, 6.36 mmol, 1.0 9.74 mmol, 1.0 equiv.); DMF (10 mL); CDI (1.9 g, 11.69 mmol,

equiv.); 16 h. Extraction and column chromatography (0–80% 1.20 equiv.); 16 h; Na metal (0.224 g, 9.74 mmol 1.0 equiv.);

0

EA in PE) gave 26c (1.87 g, 5.34 mmol) in 84% yield as a pale methanol (8 mL) N,N -diphenylguanidine (1.93 g, 9.74 mmol,

ꢀ

16

yellow solid. R

c ¼ 1.0); d (CDCl

d, J 7.9 Hz, 2ꢂ CH), 7.27–7.37 (4H, m, 4ꢂ CH), 6.99–7.08 (2H, m, a yellow gum. R

ꢂ CH), 6.94 (2H, d, J 7.7 Hz, 2ꢂ CH), 3.25 (1H, dd, J 1.8, 9.6 Hz, 1.0); d (CDCl ) 7.24–7.37 (7H, m, 7ꢂ CH), 7.08 (1H, t, J 7.4 Hz,

CH), 2.68 (1H, br t, J 7.4 Hz, CH), 2.47–2.56 (1H, m, CH), 2.29– CH), 6.98 (2H, d, J 7.4 Hz, 2ꢂ CH), 5.22–9.48 (3H, br s, 3ꢂ NH),

.38 (1H, m, CH), 1.92–2.08 (2H, m, 2ꢂ CH), 1.68–1.77 (1H, m, 3.81 (1H, d, J 12.1 Hz, CH), 3.68 (1H, d, J 12.1 Hz, CH), 3.27

(1H, dd, J 4.4, 10.4 Hz, CH), 3.01–3.18 (1H, m, CH), 2.41–2.52

) 176.4, 147.7, 140.9, 139.2, 129.5, 128.8, 123.0, 122.6, (1H, m, CH), 2.18–2.33 (1H, m, CH), 1.93–2.03 (1H, m, CH),

22.5, 119.7, 64.7, 52.8, 50.2, 31.4, 24.7, 21.4, 19.6; nmax (KBr 1.73–1.86 (2H, m, 2ꢂ CH); d (CDCl ) 176.6, 147.4, 147.1,

f

0.32 (20% EA/PE); mp 136 C; [a]

D

+52.1 (CHCl

3

,

1.0 equiv.); 5 d. Extraction and column chromatography (0–

) 10.23 (1H, s, NH), 9.98 (1H, s, NH), 7.73 (2H, 50% EA in PE) gave 27b (1.63 g, 5.06 mmol) in 52% yield as

H

3

1

6

f

0.31 (20% EA/PE); [a]

D

ꢁ47.6 (CHCl , c ¼

3

2

H

3

2

CH), 1.46–1.58 (1H, m, CH), 0.74 (6H, d, J 5.1 Hz, 2ꢂ Me); d

C

(

CDCl

3

1

C

3

disk) 3350, 3261, 3050, 2829, 1791, 1680, 1588, 1301, 1079, 137.5, 129.6, 129.3, 128.5, 127.5, 123.1, 122.7, 67.2, 59.8, 54.1,

ꢁ

1

ꢁ

8

(

94 cm ; MS (EI) m/z 349.2 (3%, [M ꢁ H] ); MS (ESI) m/z 351.2 30.9, 24.1; nmax 3413, 3060, 2943, 1659, 1643, 1589, 1305, 1064,

+

ꢁ1 +

100%, [M + H] ); HRMS (ESI) m/z found 351.2183, C H N O

752 cm ; MS (ESI) m/z 323.2 (100%, [M + H] ); HRMS (ESI) m/

2

1

27 4

+

[M + H] ) requires 351.2179.

z found 323.1868, C19

H

23

N

4

O ([M + H] ) requires 323.1866.

0

(

S)-1-Cyclohexyl-N-(N,N -diphenylcarbamimidoyl)pyrrolidine-2-

(S)-N -Boc-N-carbamimidoyl-1-methylpyrrolidine-2-carboxa-

carboxamide 26d: method A. N-Cyclohexyl-L-proline 26d (1.01 g, mide 29: method A. N-Methyl-L-proline 23a (2.0 g, 15.5 mmol,

5

.07 mmol, 1.0 equiv.) DMF (5 mL); CDI (0.99 g, 6.08 mmol, 1.2 1.0 equiv.); DMF (10 mL); CDI (3.01 g, 18.6 mmol, 1.2 equiv.);

0

equiv.); 4 h; N,N -diphenylguanidine (1.07 g, 5.07 mmol, 1.0 24 h; N-Boc-guanidine (2.47 g, 15.48 mmol, 1.0 equiv.); 24 h.

equiv.); 18 h. Extraction and trituration with DE (2ꢂ 50 mL) gave Extraction and silica gel chromatography (70–100% EA in PE)

2

6d (1.67 g, 4.28 mmol) in 84% yield as an oﬀ white solid. R 0.25 gave 29 (1.58 g, 5.85 mmol) as a white solid in 38% yield. R

f

0.3

, c ¼ 1.0); mp 134 C; d

) 8.21–10.03 (3H, br s, NH, NH ), 3.00–3.07 (1H, m, CH),

.30–7.35 (4H, m, 4ꢂ CH), 7.06 (1H, t, J 7.4 Hz, CH), 7.03 (1H, t, J 2.95 (1H, dd, J 10.5, 4.8 Hz, CH), 2.31 (3H, s, CH ), 2.30–2.38

.4 Hz, CH), 6.94 (2H, d, J 7.8 Hz, 2ꢂ CH), 3.28 (1H, dd, J 3.0, (1H, m, CH), 2.15–2.26 (1H, m, CH), 1.79–1.89 (1H, m, CH),

(CDCl ) 178.0,

f

ꢀ

15

20

ꢀ

(

15% EA/PE); mp 78–79 C; [a]_D+6.5 (MeOH, c ¼ 1.0); d (CDCl ) (5% ME in CF); [a]

D

ꢁ46 (CH

2

Cl

2

H

3

1

7

9

1

0.23 (1H, s, NH), 10.02 (1H, s, NH), 7.74 (2H, d, J 7.9 Hz, 2ꢂ CH), (CDCl

3

2

3

.5 Hz, CH), 2.72 (1H, dd, J 7.5, 7.7 Hz, CH), 2.33 (1H, ddd, J 5.6, 1.64–1.97 (2H, m, 2ꢂ CH), 1.46 (9H, s, 3ꢂ Me); d

C

3

.0, 11.4, CH), 2.05–2.13 (1H, m, CH), 1.93–2.05 (2H, m, 2ꢂ CH), 163.4, 158.5, 79.4, 69.0, 56.5, 41.7, 31.3, 28.2, 24.6; nmax 3381,

.68–1.75 (1H, m, CH) 1.53–1.67 (4H, m, 6ꢂ CH), 1.42–1.52 (1H, 3293, 2974, 2871, 2794, 1704, 1649, 1619, 1430, 1135,

ꢁ

1

+

m, CH), 1.33–1.40 (1H, m, CH), 0.93–1.15 (3H, m, 3ꢂ CH), 0.81 1048 cm ; MS (ESI) m/z 171.1 (82%), 271.2 (100%, [M + H] ),

+

(

1H, dq, J 3.3, 12.4 Hz, CH), 0.67 (1H, dq, J 3.5, 12.4 Hz, CH); d

293.2 (13%, [M + Na] ), 563.3 (27%, [2 M + Na] ); HRMS (ESI) m/z

C

+

CDCl ) 176.5, 147.8, 140.9, 139.2, 129.5, 128.8, 123.0, 122.6, 122.6, found 271.1765, C12

H

23

N

4

O

3

([M + H] ) requires 271.1765.

3

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0

(

S)-N-(N -Boc-N-methylcarbamimidoyl)-1-methylpyrrolidine-

(CDCl

3

, c ¼ 1.0); d

H

(CDCl

3

) 10.89 (1H, br s, NH), 10.37 (1H, br s,

2

8

2

4

-carboxamide 30: method A. N-Methyl-L-proline 23a (1.12 g, NH), 7.53–7.71 (1H, m, CH), 7.15–7.42 (8H, m, 8ꢂ CH), 3.86 (1H,

.66 mmol, 1.0 equiv.); DMF (12 mL); CDI (2.42 g, 14.94 mmol, d, J 12.7 Hz, CH), 3.72 (1H, d, J 12.7 Hz, CH), 3.43 (1H, dd, J 10.6,

0

.0 equiv.); 24 h; N-Boc-N -methylguanidine (750.0 mg, 4.2 Hz, CH), 3.15 (1H, t, J 7.4, CH), 2.49–2.58 (1H, m, CH), 2.24–

.33 mmol, 3.45 equiv.); 5 d. Extraction and trituration with DE 2.39 (1H, m, CH), 1.97–2.06 (1H, m, CH), 1.73–1.90 (2H, m,

(

2ꢂ 50 mL) gave 30 (1.15 g, 4.04 mmol) in 94% yield as oﬀ white CH

2 C 3

); d (CDCl ) 175.3, 146.1, 137.3, 134.7, 129.3, 128.8, 127.8,

1

8

solid. R 0.13 (50% EA in PE); [a] ꢁ6.4 (CH Cl , c ¼ 1.1); mp 122.3, 122.3, 66.7, 60.1, 54.3, 31.1, 24.5; nmax (KBr disk) 3350,

f

D

2

ꢀ

30–132 C, d (CDCl ) 12.80 (1H, s, NH), 8.81 (1H, s, NH), 3.21– 3253, 3025, 2942, 1768, 1688, 1624, 1307, 1047, 744 cm ; MS

H 3

.28 (1H, m, CH), 2.99 (1H, dd, J 4.6, 9.9 Hz, CH), 2.95 (3H, d, J (ESI) m/z 321.2 (100%, [M + H] ); HRMS (ESI) m/z found

ꢁ1

1

3

4

+

.9 Hz, CH

3

), 2.41 (3H, s, CH

3

), 2.36–2.44 (1H, m, CH), 2.16–2.29 321.1710, C19

(S)-N-(1H-Benzo[d]imidazol-2-yl)-1-isopropylpyrrolidine-2-

) 177.7, 162.7, 156.0, 79.3, 69.5, 56.5, 41.5, 31.4, 28.4, carboxamide 34c: method A. N-Isopropyl-L-proline 23c (1.0 g,

H N O ([M + H] ) requires 321.1710.

21 4

(

1H, m, CH), 1.75–1.93 (3H, m, 3ꢂ CH), 1.51 (9H, s, 3ꢂ Me); d

CDCl

7.9, 24.5; nmax 3312, 2975, 1727, 1434, 1152, 1046 cm ; MS 6.36 mmol, 1.0 equiv.); DMF (10 mL); CDI (1.25 g, 7.63 mmol,

C

(

2

3

ꢁ

1

+

(

ESI) m/z 285.2 (100%, M + H] ), HRMS (ESI) found 285.1919, m/ 1.2 equiv.); 3 h; 2-aminobenzimidazole (0.86 g, 6.36 mmol, 1.0

+

z C H N O ([M + H] ) requires 285.1921.

equiv.); 40 h. Extraction and column chromatography (0–100%

EA in PE) gave 34c (1.48 g, 5.45 mmol) in 86% as a pale yellow

1

3

25 4 3

0

(

S)-N-(N -Cbz-N-methylcarbamimidoyl)-1-methylpyrrolidine-

ꢀ

16

2

7

2

1

-carboxamide 31: method A. N-Methyl-L-proline 23a (935.0 mg, solid. R

.24 mmol, 1.5 equiv.); DMF (12 mL); CDI (1.96 g, 12.06 mmol, (CHCl

f

0.25 (20% EA in PE); mp 112–114 C; [a]

D

ꢁ110.5

, c ¼ 1.0); d

(CDCl ) 11.05 (1H, br s, NH), 10.65 (1H, br s,

3

H

3

.5 equiv.); 24 h; N-methyl-N-Cbz-buanidine (1.0 g, 4.83 mmol, NH), 7.34–7.81 (2H, m, 2ꢂ CH), 7.19–7.247 (2H, m, 2ꢂ CH), 3.50

.0 equiv.); 4 d. Extraction and recrystallization from methanol (1H, dd, J 2.7, 10.5 Hz, CH), 3.20 (1H, br t, J 7.6 Hz, CH), 2.87

gave 31 (1.37 g, 4.30 mmol) in 89% yield as a white solid. R

f

0.23 (1H, septet, J 6.4 Hz, CH), 2.61 (1H, ddd, J 5.9, 9.3, 10.9, CH),

2

0

ꢀ

(

50% EA/PE); [a]_Dꢁ54.0 (CH Cl, c ¼ 1.1); mp 100–102 C, d

2.13–2.24 (1H, m, CH), 2.02–2.11 (1H, m, CH), 1.69–1.89 (2H, m,

3

H

(

CDCl ) 12.81 (1H, s, NH), 8.99 (1H, s, NH), 7.42 (2H, d, J 7.0 Hz, CH

2

), 1.13 (3H, d, J 6.4 Hz, Me), 1.12 (3H, d, J 6.4 Hz, Me); d

C

3

2

ꢂ CH), 7.28–7.37 (3H, m, 3ꢂ CH) 5.16 (2H, s, CH ), 3.25–3.32 (CDCl ) 176.7, 146.1, 122.3, 122.3, 64.2, 53.4, 50.9, 31.7, 24.9,

3

2

(

1H, m, CH), 3.00 (1H, dd, J 4.7, 10.0 Hz, CH), 2.97 (3H, d, J 21.5, 20.1 (1ꢂ C not observed); nmax (KBr disk) 3312, 3071, 2927,

ꢁ

1

4

.9 Hz, CH

3

), 2.43 (3H, s, CH

3

), 2.37–2.43 (1H, m, CH), 2.20–2.32 1680, 1610, 1553, 1304, 1095, 747 cm ; MS (ESI) m/z 273.2

+

(

1H, m, CH), 1.77–1.94 (3H, m, 3ꢂ CH); d

C

(CDCl

3

) 178.0, 163.0, (100%, [M + H] ), HRMS (ESI) m/z found 273.1710, C15

H

21

N

O

4

+

1

56.6, 137.0, 128.5, 128.4, 128.0, 69.6, 67.2, 56.6, 41.6, 31.5, 27.9, ([M + H] ) requires 273.1710.

2

1

+

4.5; nmax 3298, 3130, 2946, 2851, 2793, 1691, 1642, 1618, 1562,

(S)-N-(1H-Benzo[d]imidazol-2-yl)-1-cyclohexylpyrrolidine-2-

497, 1436, 1124, 1082, 874 cm ; MS (ESI) m/z 319.2 (100%, [M carboxamide 34d: method A. N-Cyclohexyl-L-proline 23d (1.0 g,

H] ), HRMS (ESI) m/z found 319.1767, C H N O ([M + H] ) 5.07 mmol, 1.0 equiv.); DMF (10 mL); CDI (0.99 g, 6.08 mmol,

16 23 4 3

ꢁ

1

+

requires 319.1765.

1.2 equiv.); 4 h; 2-aminobenzimidazole (0.71 g, 5.07 mmol, 1.0

(

S)-N-(1H-Benzo[d]imidazol-2-yl)-1-methylpyrrolidine-2-car- equiv.); 48 h. Extraction and column chromatography (0–60%

boxamide 34a: method A. N-Methyl-L-proline 23a (1.0 g, EA in PE) gave 34d (1.32 g, 4.23 mmol) in 84% as a pale yellow

ꢀ

15

7

1

.74 mmol, 1.0 equiv.); DMF (9 mL); CDI (1.51 g, 9.29 mmol, solid. R

.2 equiv.); 4 h; 2-aminobenzimidazole (1.05 g, 7.74 mmol, 1.0 ¼ 1.0); d

f

0.37 (20% EA in PE); mp 129–130 C; [a]

(CDCl

D

ꢁ105.1 (ME, c

) 8.40–12.50 (2H, br s, 2ꢂ NH) 7.36–7.67 (2H, br

H

3

equiv.); 38 h. Extraction and column chromatography (0–50% m, 2ꢂ CH), 7.22–7.27 (2H, m, 2ꢂ CH), 3.55 (1H, dd, J 2.6,

ME in EA) gave 34a (1.04 g, 4.25 mmol) in 55% yield as a pale 10.6 Hz, CH), 3.23 (1H, br t, J 7.4 Hz, CH), 2.63 (1H, ddd, J 5.7,

ꢀ

yellow solid. R 0.16 (20% ME in EA); mp 242–244 C; 8.1, 11.1, CH), 2.39–2.50 (1H, m, CH), 2.13–2.24 (1H, m, CH),

f

1

6

[

1

a] ꢁ117 (CDCl , c ¼ 1.0); d (CDCl ) 10.92 (1H, br s, NH), 2.04–2.11 (1H, m, CH), 1.94–2.02 (1H, m, CH), 1.69–1.90 (5H, m,

D

3

H

3

0.47(1H, br s, NH), 7.24–7.74 (2H, m, 2ꢂ CH), 7.06–7.22 (2H, 5ꢂ CH), 1.64 (1H, br d, J 11.1 Hz, CH), 1.18–1.33 (1H, m, 4ꢂ

(CD OD) 175.5, 147.1, 138.6,

.45 (1H, m, CH), 2.18–2.32 (1H, m, CH), 1.87–1.99 (1H, m, 123.2, 123.2, 65.4, 63.6, 52.1, 33.1, 32.2, 31.9, 27.0, 26.5, 26.4,

(CDCl

) 175.3, 146.3, 138.3, 25.5; nmax (KBr disk) 3309, 3230, 3056, 2927, 1686, 1627, 1589,

22.3, 122.3, 68.7, 56.7, 41.9, 31.4, 24.8; nmax (KBr disk) 3350, 1308, 1029, 743 cm ; MS (ESI) m/z 313.2 (100%, [M + H] );

m, 2ꢂ CH), 3.01–3.18 (2H, m, 2ꢂ CH), 2.39 (3H, s, Me), 2.33– CH), 1.05–1.18 (1H, m, CH); d

C

3

2

CH), 1.68–1.83 (2H, m, 2ꢂ CH); d

C

3

ꢁ

1

+

1

3

(

2

ꢁ

1

+

25 4

244, 3050, 2946, 1702, 1626, 1589, 1310, 1021, 861 cm ; MS HRMS (ESI) m/z found 313.2016, C18H N O [M + H] requires

+

ESI) m/z 267.1 (100%, [M + Na] ), 245.1 (55%, [M + H] ), HRMS 313.2023.

+

ESI) m/z found 245.1399, C H N O ([M + H] ) requires

(S)-N-(1H-Benzo[d]imidazol-2-yl)-1-methylpyrrolidine-2-car-

boxamide 35: method A. N-Methyl-L-proline 23a (658.2 mg,

1

3

17 4

45.1397.

(

S)-N-(1H-Benzo[d]imidazol-2-yl)-1-benzylpyrrolidine-2-car- 5.10 mmol, 1.50 equiv.); DMF (12 mL); CDI (1.38 g, 8.49 mmol,

boxamide 34b: method A. N-Benzyl-L-proline 23b (1.0 g, 2.5 equiv.); 8 h; 1-methyl-2-aminobenzimidazole (0.50 g,

.87 mmol, 1.0 equiv.); DMF (9 mL); CDI (0.95 g, 5.85 mmol, 1.2 3.40 mmol, 1.0 equiv.); 10 d. Extraction and silica gel chroma-

equiv.); 4 h; 2-aminobenzimidazole (0.69 g, 4.87 mmol, 1.0 tography, eluting with (2.5–6% ME in CF), gave 35 (357.0 mg,

equiv.); 48 h. Extraction and column chromatography (0–100% 0.138 mmol) in 41% yield as a tan coloured gum. R 0.24 (50%

(CDCl ) 9.40–

4

f

2

3

EA in PE) gave 34b (1.48 g, 4.64 mmol) in 96% as a pale yellow CHCl

3

/MeOH); [a]

D

ꢁ32.2 (CH

2

Cl

2

, c ¼ 1.6); d

H

3

ꢀ

16

solid. R 0.47 (20% EA in PE); mp 228–229 C; [a]_Dꢁ106.8 11.24 (1H, br s, NH), 7.53 (1H, br d, J 6.0 Hz, CH), 7.22–7.30 (3H,

f

m, 3ꢂ CH), 3.69 (3H, s, CH

3

), 3.26 (1H, br t, J 7.5 Hz, CH), 3.10–

22412 | RSC Adv., 2020, 10, 22397–22416

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+

3

2

3

.18 (1H, m, CH), 2.54 (3H, s, CH ), 2.40–2.51 (1H, m, CH), 2.25– 195.1 (100%, [M + H] ); HRMS (ESI) m/z found 195.1240,

+

.36 (1H, m, CH), 2.02–2.12 (1H, m, CH), 1.81–2.00 (2H, m, 2ꢂ C H N O ([M + H] ) requires 195.1241.

9

15 4

CH); d (CDCl ) 175.1 (HMBC), 155.4 (HMBC), 135.5 (HMBC),

(S)-1-Benzyl-N-(1H-imidazol-2-yl)pyrrolidine-2-carboxamide

C

3

1

2

+

22.7, 109.3, 70.2, 56.9, 41.8, 31.1, 30.1, 24.2; n

3342, 2981, 38b: method A. N-Benzyl-L-proline 23b (1.00 g, 4.87 mmol, 1.0

max

ꢁ

1

922, 2851, 1626, 1557, 1483, 1454, 1065 cm ; MS (ESI) m/z equiv.); CDI (1.44 g, 8.77 mmol, 1.80 equiv.); DMF (15 mL); 16 h;

+

59.2 (100%, [M + H] ), 539.3 (64%, [2 M + Na] ), 281.1 (59%, [M 2-aminoimidazole hemisulfate (0.772 g, 5.84 mmol, 1.2 equiv.);

+

Na] ); HRMS (ESI) m/z found 259.1555; C14

H

18

N

4

O ([M + H] ) Et

3

N (2.21 g, 21.9 mmols, 3.04 mL, 4.5 equiv.); 2 d. Extraction

requires 259.1553.

S)-N-(1H-Benzo[d]imidazol-2-yl)-N,1-dimethylpyrrolidine-2-

and column chromatography (5–80% EA in PE) gave 38b

(

(0.897 g, 3.32 mmol) in 68% yield as a white solid. R

f

0.31 (50%

ꢀ

carboxamide 36: method A. N-Methyl-L-proline 23a (1.32 g, EA in PE); mp 64 C; [a] ꢁ198 (c ¼ 1, CHCl ); d (CDCl ) 9.38–

D

3

H

3

10.19 mmol, 1.5 equiv.); DMF (11 mL); CDI (2.75 g, 16.99 mmol, 11.51 (2H, br m, 2ꢂ NH), 7.15–7.31 (5H, m, Ph), 6.76 (2H, s, 2ꢂ

2.5 equiv.); 8 h; N-methyl-1H-benzo[d]imidazol-2-amine (1.0 g, CH), 3.82 (1H, d, J 12.7 Hz, CH), 3.57 (1H, d, J 12.7 Hz, CH), 3.31

6.79 mmol, 1.0 equiv.); 3 d. Extraction and recrystallization (DE/ (1H, dd, J 4.2, 10.4 Hz, CH), 3.00–3.07 (1H, m, CH), 2.37–2.46

PE) gave 36 (970.0 mg, 3.06 mmol) in 45% yield as an oﬀ-white (1H, m, CH), 2.16–2.27 (1H, m, CH), 1.87–1.97 (1H, m, CH),

ꢀ

18

solid. R

CH Cl

5

f

0.13 (3% MeOH in CHCl

3

); mp 112–114 C; [a]

D

ꢁ84.4 1.66–1.82 (2H, m, 2ꢂ CH); 174.1, 141.3, 137.6, 129.2, 128.7,

(

2

, c ¼ 1.3); d (CDCl ) 11.60 (1H, s, NH), 7.64 (1H, d, J 127.6, 66.7, 60.0, 54.0, 30.9, 24.3 (imidazole 2ꢂ CH not detec-

H

3

.8 Hz, CH), 7.39 (1H, d, J 5.8 Hz, CH), 7.16–7.25 (2H, m, 2ꢂ ted); nmax 3269, 3025, 2973, 29 251, 2804, 1665, 1571, 1525,

ꢁ1

+

CH), 3.78 (3H, s, CH ), 3.39 (1H, dd, J 7.2, 8.6 Hz, CH), 3.22–3.29 1493 cm ; MS (CI) m/z 160.1 (100%), 269.1 (40%, [M ꢁ H] )

3

+

(

1H, m, CH), 2.44 (3H, s, CH ), 2.25–2.47 (2H, m, 2ꢂ CH), 1.82– 293.1 (55% [M + Na] ); HRMS (CI) m/z found 293.1376,

3

+

2

1

2

.08 (3H, m, 3ꢂ CH); d (CDCl ) 174.9 (HMBC), 149.9, 122.3, C H N ONa ([M + Na] ) requires 293.1373.

C

3

15 18 4

18.3, 110.8, 68.0, 56.2, 41.0, 33.9, 29.7, 23.4; nmax 3361, 3055,

(S)-1-Methyl-N-(pyridine-2-yl)pyrrolidine-2-carboxamide 39a:

ꢁ1

948, 2850, 2786, 1672, 1622, 1525, 1427, 1308 cm ; MS (ESI) method A. N-Methyl-L-proline 23a (1.00 g, 7.74 mmol, 1.5

+

m/z 259.2 (100%, [M + H] ) 539.3 (16%, [2 M + Na] ), 281.1 (9%, equiv.); CDI (2.93 g, 3.5 equiv.); DMF (10 mL); 16 h; 2-amino-

+

[

M + Na] ) HRMS (ESI) m/z found 259.1555, C13

H

19

N

4

O ([M + pyridine (486.0 mg, 5.16 mmol, 1.0 equiv.); 7 d. Extraction,

column chromatography (0–50% EA in PE with 0.1% NH ) and

S)-N-(Benzo[d]thiazol-2-yl)-1-methylpyrrolidine-2-carboxamide recrystallization (CF) gave 39a (189.6 mg, 0.92 mmol) in 18%

7a: method A. (S)-1-Methylpyrrolidine-2-carboxylic acid 23a yield as pale yellow-green crystals. R 0.26 (15% EA in PE); mp

+

H] ) requires 259.1553.

3

(

3

(

f

ꢀ

20

D

1.00 g, 7.74 mmol, 1.6 equiv.); CDI (2.93 g, 3.5 equiv.); DMF (10 40–41 C; [a] ꢁ78.9 (c ¼ 1.0 in CF); d (CDCl ) 9.85 (1H, s, NH),

H

3

mL); 16 h; 2-aminobenzothiazole (786.0 mg, 1.0 equiv.); 7 d. 8.29 (H, br d, J 4.7 Hz, CH), 8.26 (1H, br d, J 8.4 Hz, CH), 7.69

Extraction and column chromatography (0–50% EA in PE with (1H, ddd, J 1.6, 7.2, 8.4 Hz, CH), 7.02 (1H, t, J 4.7, 7.2 Hz, CH),

0

.1% NH

.10 (30% EA in PE with 0.1% NH

, c ¼ 1.0); d (CDCl ) 9.82–11.72 (1H, br s, NH), 7.82 (1H, d, J CH

.9 Hz, CH), 7.78 (1H, d, J 8.1 Hz, CH), 7.44 (1H, dd (apparent t), J 119.8, 113.9, 69.5, 56.7, 41.9, 31.3, 24.6; n

3

) gave 37a (1.00 g, 3.81 mmol, 74%) as a white solid. R

f

3.17–3.22 (1H, m, CH), 2.99–3.10 (1H, m, CH), 2.46 (3H, s, Me),

ꢁ38.0 2.39–2.46 (1H, m, CH), 2.24–2.35 (1H, m, CH), 1.92–2.02 (1H, m,

), 1.77–1.88 (2H, m, CH ); d 178.4, 151.4, 148.1, 138.4,

3301, 2950, 2850,

ꢀ

19

3

); mp 79–83 C, [a]

D

(CHCl

3

H

3

2

C

7

3

2

max

ꢁ

1

.5, 8.1 Hz, CH), 7.31 (1H, dd (apparent t), J 7.5, 7.9 Hz, CH), 3.17– 2711, 1705, 1570, 1508, 1433, 1271, 765 cm ; MS (CI) m/z 228.1

+

.30 (2H, m, 2ꢂ CH), 2.49 (3H, s, CH ), 2.44–2.55 (1H, m, CH), (100%, [M + Na]), 206.1 (20%, [M + H] ); HRMS (CI) m/z found

3

+

.26–2.40 (1H, m, CH), 1.97–2.07 ((1H, m, CH), 1.76–1.92 (2H, m, 206.1289, C11

H

16

N

3

ONa ([M + H] ) requires 206.1288.

(2S,2 S)-N,N'-(Iminomethylene)bis(1-benzylpyrrolidine-2-

0

CH

); d

2 C

(CDCl

3

) 173.7, 157.7, 148.6, 132.3, 126.4, 124.1, 121.6,

1

7

21.1, 68.5, 56.7, 42.0, 31.3, 24.9; nmax 3182, 2949, 2848, 2796, 1696, carboxamide) 40b: method C. N-Benzyl-L-proline 23b (2.0 g,

600, 1628, 1445, 1352, 1316, 1263, 1156, 1048, 1016, 779, 757, 9.74 mmol, 1.0 equiv.); CDI (1.92 g, 11.7 mmol, 1.2 equiv.); DMF

ꢁ

1

+

30, 668 cm ; MS (ESI) m/z 284.1 (100%, [M + Na] ), 262.1 (95%, (6 mL); 16 h; NaH (60%, 0.234 g, 5.85 mmol, 0.60 equiv.); DMF

+

[M + H] ), 545.2 (42%, [2M + Na] ); HRMS (ESI) m/z found (10 mL); guanidinium chloride (0.97 g, 4.87 mmol, 0.50 equiv.);

+

262.1011, C H N OS ([M + H] ) requires 262.1009.

48 h. Extraction and column chromatography (25–27% EA in

PE) gave 40b (1.66 g, 3.84 mmol) as an oﬀ-white solid in 79%

13 15 4

(

S)-1-Methyl-N-(1H-imidazol-2-yl)pyrrolidine-2-carboxamide

ꢀ

19

3

8a: method A. N-Methyl-L-proline 175a (1.00 g, 7.74 mmol, 1.0 yield. R

Cl

-aminoimidazole hemisulfate (1.26 g, 9.54 mmol, 1.23 equiv.); 7.39 (10H, m, 2ꢂ Ph) 3.86 (2H, d, J 12.8 Hz, 2ꢂ CH), 3.61 (2H, d, J

Et

N (3.04 mL, 34.8 mmol, 4.5 equiv); 24 h. Extraction and 12.7 Hz, 2ꢂ CH), 3.22 (2H, dd, J, 5.9, 9.7 Hz, 2ꢂ CH), 3.11–3.15

column chromatography (5–80% EA in PE with 0.1% NH

) gave (2H, m, 2ꢂ CH), 2.38–2.44 (2H, m, 2ꢂ CH), 2.17–2.28 (2H, m, 2ꢂ

70 (1.47 g, 7.57 mmol, 97%) as a oﬀ-white solid. R 0.24 (10% CH), 1.91–2.02 (2H, m, 2ꢂ CH), 1.76–1.90 (4H, m, 2ꢂ CH ); d

f

0.25 (30% EA in PE); mp 125–127 C; [a]

D

ꢁ83.3

equiv.); CDI (2.26 g, 13.94 mmol, 1.8 equiv.); DMF (15 mL); 24 h; (CH

2

, c ¼ 1.2); d (CDCl ) 8.17–11.43 (3H, br s, 3ꢂ NH), 7.19–

H

3

2

f

2

C

ꢀ

EA in ME); mp 180–182 C; [a]_Dꢁ73.3 (c ¼ 0.3, CHCl ); d

(CDCl ) 176.0, 147.8, 137.8, 129.5, 128.4, 127.4, 68.7, 59.5, 53.9,

3

H

(

3

CDCl ) 9.55–11.41 (2H, br s, 2ꢂ NH), 6.82 (2H, s, 2ꢂ CH), 3.15– 30.6, 23.8; n_m_a_x3354, 3027, 2964, 2875, 2805, 1701, 1604, 1494,

3

+

.19 (1H, m, CH), 3.08 (1H, dd, J 4.6, 10.5 Hz, CH), 2.44 (3H, s, 1260; MS (ESI) m/z 434.3 (100%, [M + H] ), 160.1 (72%); HRMS

+

Me) 2.40–2.47 (1H, m, CH) 2.23–2.33 (1H, m, CH) 1.91–1.98 (1H, (ESI) found 434.2540, C25

m, CH), 1.74–1.86 (2H, m, CH

H

31

N

5

O

2

([M + H] ) requires 434.2551.

0

2

); d

C

(CDCl

3

) 174.3, 140.5, 68.5,

(2S,2 S)-N,N'-(Iminomethylene)bis(1-isopropylpyrrolidine-2-

5

2

6.8, 42.0, 31.4, 24.8 (imidazole 2ꢂ CH not detected); nmax 3223, carboxamide) 40c: method C. N-Isopropyl-L-proline 23c (1.0 g,

ꢁ1

960, 2845, 2786, 1671, 1585, 1524, 1492 cm ; MS (ESI) m/z 6.36 mmol, 1.0 equiv); DMF (5 mL); CDI (1.24 g, 7.36 mmol, 1.2

RSC Adv., 2020, 10, 22397–22416 | 22413

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Paper

+

18 3

equiv); 24 h; guanidine hydrochloride (303.8 mg, 3.18 mmol, 0.5 HRMS (TOF ASAP) m/z found 220.1454, C12H N O ([M + H] )

equiv); DMF (10 mL); NaH (60%, 0.38 g, 9.54 mmol, 1.0 equiv.); requires 220.1444.

48 h. Extraction and column chromatography (50–100% EA in

tert-Butyl 2-(methyl-L-prolyl)hydrazine-1-carboxylate 41c:

PE) gave 40c (1.07 g, 3.17 mmol) in 93% yield as an oﬀ-white method C. N-Methyl-L-proline 23a (1.47 g, 11.35 mmol, 1.5

ꢀ

23

solid. R

f

0.13 (100% EA); mp 121–123 C; [a]

D

ꢁ129.7 equiv.); DMF (15 mL); CDI (3.07 g, 18.92 mmol, 2.5 equiv.); 8 h;

(

1

CH Cl

2

, c ¼ 1.2); d

H

(CDCl ) 10.22–12.70 (1H, br s, NH), 8.05– tert-butyl hydrazine carboxylate (1.02 g, 7.57 mmol, 1.0 equiv.); 3

3

0.22 (2H, br s, 2ꢂ NH), 3.25–3.28 (1H, m, CH), 3.04–3.16 (2H, d. Extraction and recrystallization (ME/CF) gave 41c (1.1 g, 4.52

20

m, 2ꢂ CH), 2.70–2.80 (2H, m, 2ꢂ CH), 2.46–2.52 (2H, m, 2ꢂ mmol) as a white solid in 60% yield. R

f

0.10 (EA); [a]

D

ꢁ73.3

ꢀ

CH), 2.00–2.10 (2H, m, 2ꢂ CH), 1.83–1.94 (2H, m, 2ꢂ CH), 1.64– (CH

3

Cl, c ¼ 1.08); mp 102–106 C; d

H

(CDCl ) 8.74 (1H, br s, NH),

3

1

3

1

3

.77 (4H, m, 2ꢂ CH ), 1.01 (12H, d, J 6.4 Hz, CH ); d (CDCl ) 6.47 (1H, br s, NH), 3.05–3.13 (1H, m, CH), 3.00 (1H, dd, J 4.4,

2

3

C

3

77.3, 148.3, 94.5, 64.9, 53.0, 50.5, 31.8, 24.9, 21.2, 19.9; n

10.2 Hz, CH), 2.42 (3H, s, CH ), 2.28–2.37 (1H, m, CH), 2.16–2.27

3

max

365, 2967, 2874, 1698, 1636, 1611, 1555, 1497, 1308, (1H, m, CH), 1.73–1.97 (3H, m, CH, CH ), 1.47 (9H, s, 3ꢂ CH );

2

3

ꢁ

1

+

145 cm ; MS (ESI) m/z 338.3 ([M + H] ); HRMS (ESI) m/z found

d

C

(CDCl

3

) 173.7, 155.2, 81.8, 68.3, 56.8, 41.9, 31.0, 28.3, 24.4;

+

ꢁ1

38.2553, C17

H

31

N

5

O

2

([M + H] ) requires 338.2551.

2S,2 S)-N,N'-(Iminomethylene)bis(1-cyclohexylpyrrolidine-

-carboxamide) 40d: method C. N-Cyclohexyl-L-proline 23d 244.1663, C11

nmax 3268, 2967, 2885, 2788, 1726, 1680, 1476, 1391, 1160 cm

;

0

+

(

MS (TOF ASAP) m/z 244.2 (100%, M + H] ); HRMS m/z found

+

2

22 3 3

H N O ([M + H] ) requires 244.1656.

(3.0 g, 15.21 mmol, 1.0 equiv.); CDI (2.96 g, 18.25 mmol, 1.20

Benzyl 2-(methyl-L-prolyl)hydrazine-1-carboxylate

41d:

equiv.); DMF (6 mL) 1 h; NaH (60%, 0.36 g, 9.12 mmol, 0.60 method A. N-Methyl-L-proline 23a (1.17 g, 9.03 mmol, 1.5

equiv.) DMF (10 mL); guanidinium chloride (0.73 g, 7.60 mmol, equiv.); DMF (15 mL); CDI (2.44 g, 15.0 mmol, 2.5 equiv.); 8 h;

0

1

.50 equiv.) 24 h. Extraction and column chromatography (50– benzyl hydrazinecarboxylate (1.0 g, 6.02 mmol, 1.0 equiv.); 3 d.

00% EA in PE) gave 40d (0.50 g, 16% yield, together with 1.87 g, Extraction and trituration (DE 3ꢂ 50 mL) gave 41d (1.5 g, 5.41

ca. 46% yield (ca. 95% pure)) as pale yellow crystals. R

f

0.30 (5% mmol) as a pale yellow viscous liquid in 90% yield. R

f

0.13 (EA);

) 8.82 (1H, s, NH), 7.41–

) 10.44–12.71 (1H, br s, NH), 8.26–10.44 (2H, br s, 2ꢂ 7.29 (5H, m, Ph), 6.75 (1H, s, NH), 5.16 (2H, s, CH ), 3.15–3.06

NH), 3.37 (2H, dd, J 3.2, 10.3 Hz, 2ꢂ CH), 3.15–3.25 (2H, m, 2ꢂ (1H, m, CH ), 3.05–2.95 (1H, m, CH), 2.42 (3H, s, CH ), 2.34 (1H,

CH), 2.52–2.62 (2H, m, 2ꢂ CH), 2.32–2.45 (2H, m, 2ꢂ CH) 2.04– m, CH), 2.27–2.13 (1H, m, CH), 2.00–1.87 (1H, m, CH), 1.83–1.67

.17 (2H, m, 2ꢂ CH), 1.87–1.98 (4H, m, 4ꢂ CH), 1.69–1.85 (10H, (2H, m, CH ); d (CDCl ) 156.1, 135.7, 128.7, 128.5, 128.3, 68.3,

ꢀ

17

D

21

D

ME in EA); mp 157–159 C; [a]

CDCl

ꢁ53.9 (CH

2

Cl

2

, c ¼ 1.0); d

H

[a]

ꢁ61.3 (CH

3

H 3

Cl, c ¼ 0.45); d (CDCl

(

3

2

3

2

C

3

m, 10ꢂ CH), 1.61 (2H, br d, J 12.1 Hz, 2ꢂ CH), 1.03–1.31 (10H, 68.0, 56.7, 41.8, 31.0, 24.4; n

3265, 2967, 2885, 2791, 1735,

3

) 177.2, 150.6, 65.3, 62.0, 50.8, 31.7, 31.5, 1685, 1466, 1385, 1025 cm ; MS (ASAP) m/z 278.2 (100%, [M +

max

ꢁ1

m, 10ꢂ CH); d

C

(CDCl

+

3

1

0.6, 26.1, 25.6, 25.5, 24.5; nmax 3348, 2965, 2926, 2851, 1693, H] ), 220.2 (58%); HRMS (ASAP) m/z found 278.1505,

660, 1605, 1462, 108; MS (ESI) m/z 418.3 (100%, [M + H] ), 152.2

+

14 20 3 3

C H N O ([M + H] ) requires 278.1499.

+

0

(49%); HRMS (ESI) m/z found 418.3168, C23

H

39

N

5

O

2

([M + H] ),

(S)-N-Cbz-N -carbamimidoyl-2-(dimethylamino)propanamide

requires 418.3177.

43a. Method A. N,N-Dimethyl-L-alanine 42a (727.6 mg,

(

S)-1-Methylpyrrolidine-2-carbohydrazide 41a: method D. R

6.21 mmol, 1.2 equiv.); DMF (15 mL); CDI (1.43 g, 8.80 mmol, 1.7

f

2

0

1

.24 (5% ME in CF with 1% NEt ); [a] ꢁ121.6 (CH Cl , c ¼ equiv.); 24 h; N-Cbz-guanidine (1.0 g, 5.18 mmol, 1.0 equiv.); 4 d.

3

D

2

.28); d_H(CDCl ) 8.25 (1H, br s, NH), 3.74 (2H, br s, NH ), 3.04 Extraction and column chromatography (30–50% EA in PE) gave

3

2

(

f

1H, ddd, J 2.2, 6.5, 8.5 Hz, CH), 2.93 (1H, dd, J 5.1, 10.3 Hz, CH), 43a (1.50 g, 5.13 mmol) in 99% yield as a white solid. R 0.15

2

3

ꢀ

2

1

3

.32 (3H, s, CH

.66–1.84 (3H, m, CH, CH

0.9, 24.4; nmax 3297, 2967, 2884, 2785, 1650, 1464, 1085 cm

3

), 2.25–2.32 (1H, m, CH), 2.12–2.22 (1H, m, CH), (100% EA); [a]

); d (CDCl ) 174.6, 68.1, 56.7, 41.9, (CDCl

) 8.45–10.94 (3H, br s, 3ꢂ NH), 7.23–7.41 (5H, m, CH), 5.11

(2H, s, CH ), 1.19

), 3.13 (1H, q, J 7.0 Hz, CH), 2.21 (6H, s, 2ꢂ CH

); d (CDCl ) 177.2, 163.8, 158.9, 136.6, 128.4,

D

+31.3 (CH

2

Cl

2

, c ¼ 1.8); mp 112–114 C, d

H

2

C

3

ꢁ1

;

2

3

+

MS (ESI) m/z 144.1 (51%, [M + H] ); HRMS (ESI) m/z found (3H, d, J 7.0 Hz, CH

1

3

C

3

+

44.1128, C H N O ([M + H] ) requires 144.1131.

(

128.1, 127.9, 66.9, 64.6, 41.8, 9.5; n_m_a_x3378, 3286, 3033, 2980,

6

14 3

0

S)-1-Methyl-N -phenylpyrrolidine-2-carbohydrazide

41b: 2944, 2872, 2833, 2789, 1708, 1649, 1619, 1528, 1498, 1439, 1263,

ꢁ

1

+

method A. N-Methyl-L-proline 23a (1.79 g, 13.87 mmol, 1.5 1082 cm ; MS (ESI) m/z 293.2 (100%, [M + H] ); HRMS (ESI)

equiv.); DMF (12 mL); CDI (3.75 g, 23.1 mmol, 2.5 equiv.); 24 h; found 293.1614, m/z C14

phenyl hydrazine (1.0 g, 9.25 mmol, 1.38 mL, 1.0 equiv.) 2 d.

Extraction and column chromatography (3–5% ME in CHCl

gave 41b (1.0 g, 4.56 mmol) as a yellow solid in 50% yield. R

+

3

+

21 4

H N O

[M + H] requires 293.1614.

0

(S)-N-Cbz-N -carbamimidoyl-2-(dimethylamino)-3-phenyl-

3

), propanamide 43b: method A. N-Dimethyl-L-phenylalanine 42b

f

ꢀ

0.25 (800.2 mg, 4.14 mmol, 1.0 equiv.); DMF (15 mL); CDI (1.43 g,

2

0

(5% ME in EA), [a]

D

ꢁ64.6 (CH

3

Cl, c ¼ 1.05); mp 101–103 C; d

H

8.28 mmol, 2.0 equiv.); 24 h; N-Cbz-guanidine (800.0 mg,

(

CDCl ) 8.90 (1H, s, NH), 7.21 (2H, d, J 7.6 Hz, CH), 6.89 (1H, t, J 4.14 mmol, 1.0 equiv.); 6 d. Extraction and column chroma-

3

7

.3 Hz, CH), 6.81 (2H, d, J 8.0 Hz, CH), 6.15 (1H, s, NH), 3.14 (1H, tography (33–42% EA in PE) gave 43b (1.20 g, 3.26 mmol) as

2

3

m, CH ), 3.07 (1H, dd, J 10.2, 4.8 Hz,CH ), 2.47 (3H, s, CH ), 2.38 a white solid in 79% yield. R 0.1 (50% EA in PE); [a] +30.0

2

3

f

D

ꢀ

(

1H, m, CH), 2.33–2.19 (1H, m, CH), 1.98–1.76 (3H, m, CH + (CH

CH ); d (CDCl

2.2, 31.2, 24.6; nmax 3267, 2965, 2849, 2788, 1672, 1602, 1495, (1H, dd, J 5.8, 7.4 Hz, CH), 3.04 (1H, dd, J 7.4, 14.0 Hz, CH), 2.85

2

Cl

2

, c ¼ 3.0); mp 141–143 C, d

H

(CDCl

3

) 7.99–10.49 (3H,

2

C

3

) 173.9, 148.2, 129.2, 121.1, 113.6, 68.3, 56.8, br s, 3ꢂ NH) 7.11–7.32 (10H, m, 2ꢂ Ph) 5.05 (2H, s, CH

2

), 3.36

4

1

ꢁ

1

+

351, 1084 cm ; MS (TOF ASAP) m/z 220.2 (100%, [M + H] ); (1H, dd, J 5.8, 14.0 Hz, CH), 2.23 (6H, s, 2ꢂ CH

3

); d

C

(CDCl

3

)

1

75.8, 163.6, 158.8, 138.9, 136.6, 129.1, 128.7, 128.5, 128.2,

22414 | RSC Adv., 2020, 10, 22397–22416

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2

0

ꢀ

1

2

1

28.0, 126.6, 71.3, 67.1, 42.0, 31.3; nmax 3381, 3284, 3063, 3030,

R

f

0.10 (EA); [a]

D

+24.3 (CH

3

Cl, c ¼ 1.07); mp 208–210 C; d

H

929, 2789, 1704, 1650, 1621, 1530, 1496, 1453, 1268, (D DMSO) 12.08 (1H, br s, NH), 11.20 (1H, br s, NH), 7.37–7.50

6-

ꢁ

1

+

165 cm ; MS (ESI) m/z 385.2 (100%, [M + H O–H] ), 369.2 (2H, m, 2ꢂ CH), 7.07–7.09 (2H, m, 2 ꢂ CH), 3.32 (1H, q, J 6.8 Hz,

2

+

(43%, [M + H] ); HRMS (ESI) m/z found 369.1926, C H N O

CH), 2.28 (6H, s, 2ꢂ CH ), 1.20 (3H, d, J 6.8 Hz, CH ); d (CDCl )

2

0

25

4

3

C

3

+

[M + H] requires 369.1921.

172.5, 146.2, 140.5 (HMBC), 134.4 (HMBC), 121.0, 62.2, 41.2, 12.4;

nmax 3335, 3100, 2978, 2942, 2870, 2826, 2782, 1683, 1562, 1520,

0

(

S)-N-Boc-N -carbamimidoyl-2-(dimethylamino)propanamide

ꢁ1

+

4

1

4a: method A. N-Methyl-L-alanine 42a (883.1 mg, 7.54 mmol, 1455, 1222 cm ; MS (ESI) m/z 233.1 (100%, [M + H] ), 161.1 (44%);

.2 equiv.) DMF (20 mL); CDI (1.73 g, 10.68 mmol, 1.7 equiv.) 6 h; HRMS (ESI) m/z found 233.1404, C12H N O ([M + H] ) requires

17 4

+

N-Boc-guanidine (1.0 g, 6.28 mmol, 1.0 equiv.); 4 d. Extraction 233.1402.

and column chromatography (0–0.5% ME in CF) gave 44a (S)-N-(1H-Benzo[d]imidazol-2-yl)-2-(dimethylamino)-3-phe-

0.65 g, 2.52 mmol) as a white solid in 40% yield. R 0.14 (DE); nylpropanamide 46b: method A. N,N-Dimethyl-L-phenylala-

(

f

1

8

ꢀ

[

(

a] +27.8 (CH Cl , c ¼ 1.05); mp 119–120 C; d (CDCl ) 8.96 nine 42b (800.0 mg, 4.14 mmol, 1.0 equiv.); DMF (15 mL); CDI

D

2

H

3

3H, br s, 3ꢂ NH), 3.12 (1H, q, J 6.9 Hz, CH), 2.22 (6H, s, CH

3

), (1.64 g, 10.10 mmol, 2.44 equiv.); 24 h; 2-aminobenzimidazole

) 177.3, (551.2 mg, 4.14 mmol, 1.0 equiv.); 7 d. Brine (100 mL) was

58.6, 79.5, 64.9, 41.9, 28.3, 9.8; nmax 3380, 3129, 2972, 2938, added, extraction and column chromatography (0–30% EA in

1

2

.49 (3H, s, 3ꢂ Me), 1.20 (3H, d, J 7.0 Hz, CH

3 C 3

); d (CDCl

ꢁ

1

871, 2832, 2791, 1712, 1653, 1564, 1478, 1136, 1049 cm ; MS DE) gave 46b (540.0 mg, 1.75 mmol) as a white solid in 42%

+

20

ꢀ

(

ESI) m/z 275.2 (100%, [M + H

2

O–H] ), 259.3 (43%, [M + H] ); yield. R

f

0.06 (DE); [a]

D

+33.5 (MeOH, c ¼ 2.6); mp 133–136 C;

+

HRMS (ESI) m/z found 259.1768, C H N O ([M + H] ) requires

2

d

(CDCl ) 10.32 (2H, br s, 2ꢂ NH), 7.44–7.46 (2H, m, 2ꢂ CH),

1

23

4

3

H

3

59.1765.

S)-N-Boc-N -carbamimidoyl-2-(dimethylamino)-3-phenylpro- 3.21 (1H, dd, J 7.8, 13.9 Hz, CH), 2.97 (1H, dd, J 5.7, 13.9 Hz,

); d (CDCl ) 172.9, 146.7, 141.0

.17 mmol, 1.0 equiv.); DMF (20 mL); CDI (1.30 g, 7.76 mmol, (HMBC), 138.7, 129.0, 128.5, 126.5, 122.3, 70.6, 42.0, 32.5; nmax

.55 equiv.); 24 h; N-Boc-guanidine (823.8 mg, 5.17 mmol, 1.0 3372, 3027, 2885, 2785, 1682, 1630, 1561, 1519, 1455,

7.13–7.25 (7H, m, Ph, 2ꢂ CH), 3.57 (1H, dd, J 5.7, 7.8 Hz, CH),

0

(

panamide 44b: method A. N-Methyl-L-phenylalanine 42b (1.00 g, CH), 2.35 (6H, s, 2ꢂ CH

3

C

3

5

1

ꢁ1

+

equiv.); 13 d. Extraction and column chromatography (17–28% 1272 cm ; MS (ESI) m/z 309.2 (100%, [M + H] ); HRMS (ESI) m/

EA in PE) gave 44b (1.5 g, 4.49 mmol) as a white solid in 87% z found 309.1712, C18

+

H

21

N

4

O ([M + H] ) requires 309.1710.

(S)-N-(Amino((S)-2-(dimethylamino)-3-phenylpropanamido)

03 C; d (CDCl ) 8.95 (3H, br s, NH), 7.30–7.15 (5H, m, CH), methylene)-2-(dimethylamino)-3-phenylpropanamide 47b

.42–3.35 (1H, m, CH), 3.08 (1H, dd, J 14.0, 7.4 Hz, CH ), 2.88 method C. N,N-Dimethyl-L-phenylalanine 42b (1.0 g, 5.17 mmol,

1

8

yield. R 0.16 (50% EA/PE); [a] +37.0 (CH Cl , c ¼ 1.9); mp 101–

f

D

2

ꢀ

1

3

H

3

2

(

4

1

1H, d, J 5.9 Hz, CH

CDCl ) 176.0, 162.9, 158.4, 138.9, 129.1, 128.6, 126.5, 79.5, 71.4, 24 h; guanidinium hydrochloride (247.2 mg, 2.59 mmol, 0.5

2.0, 31.5, 28.2; nmax 3386, 3285, 2975, 2935, 2832, 2789, 1702, equiv.); DMF (10 mL); NaH (60%, 124.1 mg, 9.54 mmol, 3.1

2

), 2.27 (6H, s, CH

3

), 1.47 (9H, s, CH

3

); d

C

1.0 equiv.); DMF (10 mL); CDI (1.43 g, 8.80 mmol, 1.7 equiv.);

3

ꢁ

1

654, 1620, 1561, 1530, 1495, 1293 cm ; MS (ESI) 351.2 (100%, equiv.), 7 d. Extraction and column chromatography (90–100%

+

2 3

[M + H O–H] ), 335.2 (100%, [M + H] ); HRMS (ESI) m/z found DE in PE; 0–100% EA in DE with Et N (3 drop per litre)) gave 47b

+

3

35.2082, C H N O ([M + H] ), requires 335.2078.

(

(820.0 mg, 2.00 mmol) as an oﬀ-white wax in 77% yield. R 0.15

1

7

27

4

3

f

0

21

S)-2-(Dimethylamino)-3-phenyl-N-(N -phenylcarbamimidoyl)

(100% EA + 3 drops NH OH); [a] +61.9 (CH Cl , c ¼ 1.38); d

4

D

2

H

propanamide 45b method B. N,N-Dimethyl-L-phenylalanine 42b (CDCl ) 8.06–10.04 (2H, s, 2ꢂ NH), 7.20–7.24 (10H, m, 2ꢂ Ph),

3

(

1

1.0 g, 5.17 mmol, 1.0 equiv.); DMF (15 mL), CDI (1.82 g, 3.39 (2H, dd, J 5.3, 8.5 Hz, 2ꢂ CH), 3.12 (2H, dd, J 8.6, 13.6 Hz,

1.21 mmol, 2.6 equiv.); 24 h; NaH (60%, 155.2 mg, 3.88 mmol, 2ꢂ CH), 2.98 (2H, dd, J 5.3, 13.6 Hz, 2ꢂ CH), 2.41 (12H, s, 4ꢂ

.0 equiv.); DMF (15 mL); phenylguanidinium carbonate CH ); d (CDCl ) 178.8, 157.9, 139.2, 129.3, 128.5, 126.4, 73.1,

3

C

3

(

850.4 mg, 4.31 mmol, 1.0 equiv.); 4 d. Extraction and column 42.4, 33.1; nmax 3365, 3062, 2965, 2935, 2829, 2785, 1703, 1633,

ꢁ

1

chromatography (50–100% EA in PE) gave 45b (0.61 g, 1.97 1602, 1450, 1453, 1078 cm ; MS (ESI) m/z 410.3 (100%, [M +

mmol) as a pale yellow gum in 46% yield. R 0.1 (EA); [a] +49.7 H] ); HRMS (ESI) m/z found 410.2543, C H N O ([M + H] )

1

9

+

f

D

23 31 5 2

(

3

CH Cl , c ¼ 2.15); d (CDCl ) 7.09–7.51 (11H, m, NH, NH , Ph, requires 410.2551.

2

H

3

2

ꢂ CH), 7.02 (2H, br d, J 8 Hz, 2ꢂ CH), 3.50 (1H, dd, J 6.2, 7.1 Hz,

CH), 3.22 (1H, dd, J 7.1, 14.2 Hz, CH), 2.95 (1H, dd, J 6.2, 14.1, Hz,

); d (CDCl ) 175.3, 149.6, 144.6, 139.4,

29.8, 129.2, 128.7, 126.5, 124.2, 123.3, 71.5, 42.1, 31.8; nmax 3309,

General method for the reaction of 2-hydroxy-1,4-

CH), 2.38 (6H, s, 2ꢂ CH

3

C

3

naphthoquinone 93 with b-nitrostyrene 52

1

3

1

060, 3027, 2940, 2866, 2830, 2785, 1655, 1589, 1561, 1509, 1493, 2-Hydroxy-1,4-napthoquinone 1 (100 mg, 0.574 mmol) and the

ꢁ

1

ꢁ

077 cm ; MS (ESI ꢁve) m/z 345.2 (52%, [M + Cl] ), 309.2 (77%, required catalyst (0.04–0.1 equiv.) were dissolved in the required

ꢀ

[

M ꢁ H] ), 264 (100%); HRMS (ESI ꢁve) m/z found 309.1720, solvent and cooled to the required temperature (ꢁ20 to 0 C, see

ꢁ ꢁ

C H N O ([M ꢁ H] ) requires 309.1721.

Table 1). b-Nitrostyrene 2 (128.5 mg, 0.861 mmol, 1.5 equiv.)

S)-N-(1H-Benzo[d]imidazol-2-yl)-2-(dimethylamino)propa- was then added and the mixture stirred for the required time

namide 46a: method A. N,N-Dimethyl-L-alanine 42a (500.0 mg, and temperature. Reaction progress was determined by

.76 mmol, 1.0 equiv.); DMF (7 mL); CDI (1.52 g, 9.39 mmol, 2.5 sampling and H NMR analysis. On completion the solvent was

1

8

21 4

(

3

equiv.); 24 h; 2-aminobenzimidazole (659.8 mg, 5.63 mmol, 1.5 evaporated to give a deep red residue which was puried by

equiv.) 24 h. Extraction and column chromatography (60–90% EA column chromatography eluting rstly with 2–4% EA in petrol

in PE) gave 46a (800.0 mg, 3.44 mmol) as a white solid in 92% yield. to remove excess 2 then followed with DCM to give the product 5

RSC Adv., 2020, 10, 22397–22416 | 22415

View Article Online

RSC Advances

Paper

as a yellow solid. Illustrative example from catalyst 25a; 56% ee,

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2

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17

[

1

a] ꢁ16.0 (acetone, c ¼ 1.46); lit. [a] ꢁ44.8 (acetone, c ¼

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15

14

25

D

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ꢀ

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4

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ꢁ1

ꢀ

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1

2

1

16

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1

7

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19

20

using SHELXT and SHELXL-2014 within OLEX-2.

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Conﬂicts of interest

There are no conicts to declare.

Acknowledgements

We thank the EPSRC (DE, EP/J01821X/1), the ERASMUS and

SOCRATES schemes (FFJDK), BEACON (ERDF; DE, PJM), the

Iraqi government (ZSSA-T) and the government of Saudi Arabia 18 G. Winter, J. Appl. Crystallogr., 2010, 43, 186–190.

YTHM) for funding and support. This work was carried out 19 G. M. Sheldrick, Acta Crystallogr., Sect. C: Struct. Chem., 2015,

(

with the support of the Diamond Light Source, instrument I19

proposal MT15762). We also thank the EPSRC National Crys-

71, 3–8.

2

0 O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard

(

and H. J. Puschmann, Appl. Crystallogr., 2009, 42, 339–341.

tallography Service at the University of Southampton and the

National Mass Spectrometry Facility at Swansea for their excel-

lent work.

22416 | RSC Adv., 2020, 10, 22397–22416

Article Doi

Proline derived guanidine catalysts forge extensive H-bonded architectures: A solution and solid state study

DOI: 10.1039/c9ra07508a

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