Regioselective Metal-Free Decarboxylative Multicomponent Coupling of α-Amino Acids, Aldehydes and Isonitriles Leading to N-Substituted Azacyclic-2-carboxamides with Antithrombotic Activity

Article abstract of DOI:10.1021/jo502029k

An atom-economical regioselective synthesis of N-substituted prolinamides or N-substituted piperidine-2-carboxamides via a metal-free decarboxylative multicomponent coupling between l-proline or pipecolic acid, aldehydes, and isonitriles is described. The cascade event involves sequential imine formation, decarboxylation, isonitrile insertion, and hydrolysis to afford the product in one-pot. Two of the prolinamides were found to display appreciable antithrombotic activity via inhibition of platelet aggregation.

Full text of DOI:10.1021/jo502029k

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Article
Regioselective Metal-free Decarboxylative Multicomponent
Coupling of #-Amino acids, Aldehydes and Isonitriles leading to N-
substituted azacyclic-2-carboxamides with Antithrombotic activity
Shashikant Uttam Dighe, Anil Kumar K. S., Smriti Srivastava,
Pankaj Shukla, Surendra Singh, Madhu P. Dikshit, and Sanjay Batra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502029k • Publication Date (Web): 19 Nov 2014
Downloaded from http://pubs.acs.org on November 21, 2014
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The Journal of Organic Chemistry
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Regioselective Metalꢀfree Decarboxylative
Multicomponent Coupling of αꢀAmino acids, Aldehydes
and Isonitriles leading to Nꢀsubstituted azacyclicꢀ2ꢀ
carboxamides with Antithrombotic activity
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Shashikant U. Dighe, Anil Kumar K. S., Smriti Srivastava, Pankaj Shukla, Surendra Singh, Madhu
Dikshit* and Sanjay Batra*
Medicinal and Process Chemistry Division and Pharmacology Division, CSIRꢀCentral Drug Research
Institute, BSꢀ10/1, Sector 10, Jankipuram Extension, Sitapur Road, PO Box 173, Lucknow 226031,
Uttar Pradesh, India
batra_san@yahoo.co.uk (SB); madhu_dikshit@cdri.res.in (MD)
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT. An atomꢀeconomical regioselective synthesis of Nꢀsubstituted prolinamides or Nꢀ
substituted pirperidineꢀ2ꢀcarboxamides via a metalꢀfree decarboxylative multicomponent coupling
between Lꢀproline or pipecolic acid, aldehydes and isonitriles is described. The cascade event involves
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sequential imine formation, decarboxylation, isonitrile insertion and hydrolysis to afford the product in
oneꢀpot. Two of the prolinamides were found to display appreciable antithrombotic activity via
inhibition of platelet aggregation.
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KEYWORDS. Multicomponent reaction, decarboxylative coupling, isonitrile, domino, prolinamide,
antithrombotic.
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Introduction
Decarboxylative coupling reactions leading to CꢀC bond formation have emerged as exciting options
for accomplishing valuable synthetic transformations.1,2 Though these reactions are often performed in
the presence of transitionꢀmetals, the condensation of αꢀamino acids with a variety of aldehydes and
ketones to afford azomethine ylides can be achieved under metalꢀfree conditions.3 Despite their
remarkable reactivity, azomethine ylides have found applications mostly in 3+2 cycloaddition reactions
and 1,5 or 1,7ꢀelectrocyclizations.4 Nonetheless recent work of Li’s, Seidel’s and Wang’s groups have
demonstrated the utility of αꢀamino acids derived azomethine ylides for the synthesis of a variety of αꢀ
functionalized saturated cyclic amines. In a remarkably regioselective protocol they have achieved
threeꢀcomponent coupling reactions of αꢀamino acids, aldehydes and various nucleophiles under metalꢀ
free conditions or under the influence of copper or ironꢀcatalysts (Fig. 1).5ꢀ7
Prolinamide forms subunits of many natural products and pharmacologically active compounds.8ꢀ9 We
have earlier reported the potent antithrombotic and antiꢀaggregation properties of prolinamide
derivatives.10 Moreover chiral prolinamides are successfully employed in asymmetric aminocatalytic
reactions.11 Coupling of proline and amine component for the formation of the prolinamide require a
variety of coupling reagents, anhydrous conditions, and produces stoichiometric amounts of waste.12
Thus development of a new synthetic protocols for prolinamide synthesis employing readily available
starting materials is an attractive synthetic target. Considering the widespread use of isonitriles for
multicomponent reactions (MCR) and in our interest in decarboxylative reactions and isonitrile
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insertions,13ꢀ15 we envisioned that decarboxylative MCR between Lꢀproline, aldehyde and isonitrile
would offer a new metalꢀfree approach to Nꢀsubstituted prolinamides. It is worth mentioning that Ugi et
al. have reported a 4ꢀcomponent MCR between an αꢀamino acid, aldehyde, isonitrile and alcohol to
produce 1,1'ꢀiminodicarboxylic acid derivatives.16 However, the isonitrile insertion in αꢀamino acids via
azomethine ylides remain unexplored and we disclose our results related to this study herein.
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Figure 1. Synthesis of αꢀfunctionalized saturated cyclic amines via decarboxylative coupling of αꢀ
amino acids.
Results and Discussion
Our study began with the reaction of 1.2 equiv of Lꢀproline (1), 1.0 equiv (0.2 g) of 4ꢀ
o
cyanobenzaldehyde (2b) and 1.2 equiv of cyclohexyl isonitrile (3A) in toluene or nꢀBuOH at 200 C
under microwave irradiation for 20 min (Table 1, entries 1ꢀ2). Both reactions resulted in a mixture of
inseparable products, which prompted us to investigate the reaction at reduced temperature. Fortunately,
o
an identical product in 43% and 12% yields was isolated from the reactions performed at 100 C in
toluene and nꢀBuOH, respectively (entries 3,4). On the basis of the spectroscopic analysis this product
was established to be the prolinamide 4bA. Since the formation of amide would have involved
hydrolysis (vide infra), to increase the yield of the product the reaction was conducted in the presence of
water but with no impact (entry 5). Earlier, Seidel et al. discovered that addition of an acid during
analogous reactions protonates the dipole leading to the iminium ion which allows a facile nucleophilic
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Table 1. Optimization of the decarboxylative MCRa of proline, 4ꢀcyanobenzaldehyde and cyclohexyl
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3
isonitrile
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entry solvent
(mL)
additive
mode/
time
yield
temp oC
4bA(%)c
1
PhMe (2)
nꢀBuOH (2)
PhMe (2)
nꢀBuOH (2)
PhMe (2)
PhMe (2)
PhMe (5)
Xylene (5)
nꢀBuOH (5)
MeCN (5)
DMF (5)
ꢀ
20 min NDd
20 min NDd
20 min 45
20 min 12
20 min 41
20 min 20
ꢀW/ 200
ꢀW/ 200
ꢀW/ 100
ꢀW/ 100
ꢀW/ 100
ꢀW/ 100
T/ 110
2
ꢀ
3
ꢀ
4
ꢀ
5
H2O
6
PhCO2H
7b
8 b
9b
10b
11b
12b
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4 h
4 h
4 h
4 h
4 h
2 h
85
81
46
53
ꢀ
T/ 140
T/ 115
T/ 85
T/ 110
DMSO (5)
T/ 110
ꢀ
aAll reactions were performed using 0.21 g (1.83 mmol) of Lꢀproline, 0.2 g (1.52 mmol) of 4ꢀ
cyanobenzaldehyde and 0.23 mL (1.83 mmol) of cyclohexyl isonitrile. b T = Thermal heating. cYields of
chromatographically pure product. dND = Not detected
attack.6b This finding inspired us to perform the MCR in the presence of benzoic acid in toluene
(entry 6). Unfortunately 4bA was isolated in only 20% yield and therefore the use of acid was
abandoned. To improve the yield of 4bA, we next evaluated the reaction under conventional thermal
o
conditions. To our delight, the reaction at 110 C using toluene as solvent was complete in 4 h to afford
4bA in 85% yield (entry 7). Screening of different solvents for the reaction under heating revealed that
formation of 4bA in toluene was comparable to xylene but superior to nꢀBuOH and MeCN (entries 8ꢀ
10), whereas DMF and DMSO failed to produce any isolable product (entries 11ꢀ12). Therefore, the
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optimized conditions for the decarboxylative MCR which worked best were Lꢀproline (1.2 equiv),
aldehyde (1.0 equiv), and isonitrile (1.2 equiv) in toluene at 110 °C for 4 h.
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8
With the optimized conditions in hand, we set out to test the scope of the protocol with different
aldehydes and isonitriles to afford Nꢀalkyl prolinamides and the results are summarized in Table 2.
Initially the reactions were performed using cyclohexyl isonitrile (3A) as the isonitrile component and
making changes in aldehydes (2). It was found the all benzaldehydes (2a,c-i) gave the products (4aA,
4cA-4iA) in moderate to good yields. The nature of the substitution present on the phenyl ring did not
have any significant impact on the outcome, as both electron withdrawing and electron donating
substituents gave the product in 78ꢀ85% yields. However when pyridineꢀ2ꢀcarbaldehyde (2j) and 5ꢀ
methylꢀthiopheneꢀ2ꢀcarbaldehyde (2k) were employed, the yields of the respective products (4jA-4kA)
were only 51% and 54%. When aliphatic aldehydes (2l-m) were used as the reactant we found that the
products (4lA-2mA) were isolated in low yields. In particular, with hexanal (2m) the yield of the
isolated prolinamide 4mA was 36%. We observed that monitoring of the reaction with 2m and column
chromatography of 4mA was too cumbersome. Next we employed several commercially available
isonitriles 3B-3E in the protocol and observed that in all cases except for the phenylisonitrile (3E) the
products were isolated in good yields. In general, we discovered that benzaldehydes bearing nitrile or
halogen as substituent furnished corresponding prolinamides in excellent yields whereas the
heteroaromatic aldehydes gave products in relatively lower yields. Notably we discovered that
tosylmethylisonitrile (3F) failed to undergo reaction with 2a or 2b to yield the corresponding products.
The success of the protocol with Lꢀproline prompted us to test its scope with other αꢀamino acids.
Therefore the reaction of pipecolic acid with 2a and 3A was performed under the optimized conditions
and it was pleasing to note that the corresponding product 5aA was isolated in 42% yield. Subsequently,
pipecolic acid was also reacted with 2a-b and 3B to yield the corresponding amides 5aB and 5bB albeit
in moderate yields. In contrast when sarcosine was used as the substrate, we failed to observe the
formation of corresponding amide.
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Table 2. Scope of the protocol for the synthesis of Nꢀsubstituted prolinamidesa,b
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entry aldehyde
1
isonitril Product 4/5 (yield entry aldehyde isonitri Product 4/5 (yield
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e
%)
le
%)
A
18
B
4gB (62)
4aA (62)
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3
A
A
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B
4jB (65)
4bA (85)
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4kB (63)
4cA (80)
4dA (78)
4eA (84)
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A
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C
4lB (88)
4aC (60)
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A
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A
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C
C
C
C
D
E
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4eC (76)
4gC (70)
4jC (60)
4lC (83)
4aD (66)
4fA (82)
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4aE (60)
4kA (54)
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A
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E
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9
4eE (44)
4lA (52%)
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A
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E
4mA (36%)
4lE (49)
5aA (42)
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B
B
B
B
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A
B
B
4aB (77)
32
5aB (48)
4bB (90)
33
5bB (58)
4cB (86)
4eB (86)
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The Journal of Organic Chemistry
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5
aReactions were performed with Lꢀproline 1 (1.2 equiv), arylaldehyde 2 (0.2 g, 1.0 equiv), and
isonitrile 3 (1.2 equiv) in PhMe for 4ꢀ5 h at 110 oC. bYields after column chromatography.cTosMIC (3F)
did not undergo reaction under the optimized conditions therefore there is no product corresponding to
it.
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8
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The plausible mechanism for the formation of prolinamide is analogous to the one proposed by Seidel
et al. and Li et al. and is delineated in Scheme 1. In the first step cyclic αꢀamino acid is condensed with
the arylaldehyde resulting into imine (I) with the loss of water molecule. This is followed by thermal
decarboxylation to form the azomethine ylide (II) which is a zwitterionic species. This species
undergoes nucleophilic insertion of isonitrile to furnish the intermediate III, which on hydrolysis
furnished the observed product 4. The water liberated during the formation of the imine is required for
the hydrolysis to generate the amide bond. This was ascertained by carrying out the reaction
successfully even by using dry toluene under moistureꢀfree conditions. Additionally, performing the
reaction in the presence of activated molecular sieves under inert conditions to remove the liberated
water reduced the yield of 4bA to 12% and produced a known bicyclic compound 6 as the major
product (Scheme 2). To provide further evidence that the oxygen of the amide bond is from the water
that is liberated during the imine formation, in a control experiment the reaction between proline, 4ꢀ
cyanobenzaldehyde (2b) and cyclohexyl isonitrile (3A) was performed in dry toluene in the presence of
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H2 O (97%) under conventional heating under inert conditions. On completion the reaction mixture
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was directly subjected to mass spectral analysis which displayed the presence of a mixture of O (311
amu) and 18O (313 amu) prolinamide 4bA (see SI). Next we also performed the reaction in the presence
of molecular sieves and D2O. The reaction was complete in 4 h to afford the prolinamide 4bA in 63%
1
yield with no evidence of 6. Based on the H NMR spectrum we observed approximately 46%
deuterium incorporation in amide functionality. These experiments inferred that the water released
during the imine formation is used for hydrolysis step (Scheme 3).
Scheme 1. Plausible mechanism for the formation of prolinamide via isonitrile insertion
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Scheme 2. The reaction performed in the presence of molecular sieves only
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Scheme 3. The reaction performed in the presence of H2 O and D2O to demonstrate the hydrolysis step
In order to investigate the antithrombotic properties of the prepared prolinamides, they were initially
assessed for their ability to protect the mice (in vivo) against collagenꢀepinephrine induced pulmonary
thromboembolism at 30 µM/ kg dose using Aspirin and Clopidogrel as the reference drugs.10 It was
found that compounds 4eA, 4iA, 4cB, 4eB, 4gB, 4kB and 4jC exhibited 40 % protection whereas
Aspirin and Clopidogrel displayed 40% and 60% at 170 µM/ kg and 70 µM/ kg dose, respectively
(Table 3). Investigations toward the effect of these compounds on bleeding time revealed that whereas
4iA, 4cB, 4gB, 4kB and 4jC exhibited a mild prolongation in bleeding time, 4eA and 4eB did not ensue
major effect on haemostasis and it was considerably less in comparison to the standard antiꢀplatelet
drugs Aspirin and Clopidogrel. In order to probe the possible mode of antithrombotic action of these
compounds, the in vitro investigations against Collagen, Adenosine diꢀphosphate (ADP), Thrombin
Receptor Activating Peptide (SFLLRN) or Arachidonic Acid induced human platelet aggregation were
carried out. The result of this study showed that these compounds affect only collagen induced platelet
aggregation. Amongst all evaluated compounds, 4eA and 4eB carrying 2ꢀbromo substitution on the
phenyl ring were the most potential leads as they inhibited aggregation in a concentration dependent
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The Journal of Organic Chemistry
Table 3. Results of biological assays of the synthesized compound
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2
3
4
5
entry
compd no.
in vivo (% fold
IC50
protection) increase (µM)e
6
7
8
9
at
30 in
µM/kgc
bleeding
timed
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1
Aspirina
40
2.2
>30
ꢀ
2
Clopidogrelb 60
2.3
3
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30
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30
40
20
ND
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40
30
30
ND
ND
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20
40
40
40
10
40
20
20
ꢀ
NI
NI
NI
NI
29.9
NI
ꢀ
4aA
4bA
4cA
4dA
4eA
4fA
4gA
4hA
4iA
4
ꢀ
5
ꢀ
6
ꢀ
7
1.4
8
ꢀ
9
ꢀ
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23
24
ꢀ
NI
>30
NI
NI
ꢀ
1.3
ꢀ
4jA
4kA
4lA
ꢀ
ꢀ
ꢀ
ꢀ
4mA
4aB
4bB
4cB
4eB
4gB
4jB
ꢀ
NI
NI
>30
19.8
>30
NI
>30
NI
NI
ꢀ
2.2
1.3
2.0
ꢀ
1.5
ꢀ
4kB
4lB
ꢀ
4aC
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ꢀ
NI
4eC
4gC
4jC
4lC
4aD
4aE
4bE
4lE
1
2
3
4
5
6
7
8
ND
40
ꢀ
ꢀ
1.8
>30
ND
ND
ND
ND
ND
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
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aat 170 µM/ kg; at 70 µM/ kg; ND = Not Done; only compounds showing 40% protection were
b
c
d
evaluated for effect on the bleeding time; eNI = No inhibition at 30 µM
manner with IC50 of 29.9 µM and 19.8 µM, respectively and had no effect on Thrombin time (TT),
Prothrombin time (PT) and activated partial thromboplastin time (aPTT). In contrast compounds 4iA,
4cB, 4gB, 4kB and 4jC displayed inhibition at a higher concentration which might be due to the poor
solubility of these compounds in aqueous buffer. Further from the in vivo investigations in mice model
of FeCl3 induced arterial thrombosis, it was observed that 4eA and 4eB after 1 h of oral administration
prolonged the time to occlusion (TTO) of carotid artery by 1.5 and 1.7 folds as compared to the
Clopidogrel (2.2 folds).
Conclusions
In summary, we have developed a metalꢀfree decarboxylative multicomponent reaction involving Lꢀ
proline or pipecolic acid, aldehydes and isonitriles for the synthesis of Nꢀsubstitutedꢀ2ꢀprolinamides or
Nꢀsubstitutedꢀpiperidineꢀ2ꢀcarboxamides. This reaction proceeds via a cascade process involving
intermolecular imine formation, decarboxylation, isonitrile insertion and hydrolysis to furnish the
product. The protocol described herein is attractive as it is metal or additiveꢀfree and can be readily
performed via commercially available reagents. The antithrombotic assessment of products led to
identification of two prolinamides with appreciable activity which is attributable to collagen induced
platelet aggregation.
Experimental
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General. All experiments were monitored by analytical thin layer chromatography (TLC) performed
on preꢀcoated silica gel plates. After elution, plate was visualized under UV illumination at 254 nm for
UV active materials. Further visualization was achieved by staining with KMnO4 and charring on a hot
plate.Column chromatography was performed on silica gel (230ꢀ400 mesh) by standard techniques
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eluting with solvents as indicated. IR spectra were recorded using a FTIR spectrophotometer. H NMR
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and 13C NMR spectra were recorded on 400 MHz spectrometer, using TMS as an internal standard
(chemical shifts in δ). Peak multiplicities of NMR signals were designated as s (singlet), bs (broad
singlet), d (doublet), dd (doublet of doublet), t (triplet), m (multiplet) etc. The ESIꢀMS were recorded on
Ion Trap Mass spectrometer and the HRMS spectra were recorded as ESIꢀHRMS on a QꢀTOF LCꢀ
MS/MS mass spectrometer. Commercial grade reagents and solvents were used without further
18
purification. H2 O (97 %) was purchased from Cambridge Isotope Laboratories, USA. All reactions
were carried out in flameꢀdried reaction vessels with Teflon screw caps. The reactions via microwave
heating were carried out in Biotage initiator 2.5 microwave synthesizer under sealed vessel conditions
using the temperature control mode and the magnetic stirring option. The temperature in this instrument
is determined by a calibrated external infrared sensor. The experimental studies involving human
platelet rich plasma and Swiss mice were performed in accordance with the Indian Council of Medical
Research, New Delhi norms and GCP guidelines. Ethical committees of King Gorge’s Medical
University, Lucknow and CSIRꢀCDRI, approved the protocols used for the experiments and informed
consent was obtained from all the healthy subjects.
General procedure for the synthesis of pyrrolidine-2-carboxamides as exemplified for 1-(4-
cyanobenzyl)-Ncyclohexylpyrrolidine-2-carboxamide 4bA.
To a stirred solution of aldehyde 2b (0.2 g, 1.52 mmol) and Lꢀproline (0.21 g, 1.83 mmol) in dry
toulene (5.0 mL) was added cyclohexyl isonitrile 3A (0.23 ml, 1.83mmol) at room temperature. The
reaction mixture was stirred at 110 oC for 5 h. After the reaction was completed (as determined by TLC)
it was quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic
layer was dried over anhyd. Na2SO4 and concentrated under reduced pressure to obtain a residue. The
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residue was purified through column chromatography on silica gel using hexanes/ EtOAc (6:4, v/v) as
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eluent to furnish 4bA (0.382 g, 82%) as a colorless oil.
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1-Benzyl-N-cyclohexylpyrrolidine-2-carboxamide (4aA).17 Yield: 62% (0.334 g from 0.2 g);
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8
9
1
colorless oil; Rf = 0.48 (hexanes: EtOAc, 6:4, v/v); IR (neat)
NMR (400 MHz, CDCl3):
ν
max: 1217, 1520, 1660, 3345 cmꢀ1. H
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δ
= 1.12ꢀ1.38 (m, 7H), 1.59ꢀ1.72 (m, 4H), 1.85ꢀ1.89 (m, 2H), 2.22ꢀ2.38 (m,
2H), 3.02ꢀ3.06 (m, 1H), 3.21 (dd, J1 = 5.1 Hz, J2 = 5.1Hz, 1H), 3.48 (d, J = 12.8 Hz, 1H), 3.71ꢀ3.79 (m,
1H), 3.88 (d, J = 12.9 Hz, 1H), 7.28ꢀ7.36 (m, 6H); 13C NMR (100 MHz, CDCl3): 23.1, 24.4, 24.7, 25.5,
29.9, 32.5, 47.2, 54.6, 58.7, 67.7, 127.1, 127.4, 128.5, 128.6, 128.7, 137.1, 172.3. MS (ESI+): m/z =
287.1. ESIꢀHRꢀMS calculated for C18H26N2O (M++H): 287.2123, found: 287.2119.
1-(4-Cyanobenzyl)-N-cyclohexylpyrrolidine-2-carboxamide (4bA).17 Yield: 85% (0.395 g from 0.2
1
g); colorless oil; Rf = 0.42 (hexanes: EtOAc, 6:4, v/v); IR (neat)
NMR (400 MHz, CDCl3):
ν
max: 891, 1251, 1657, 3351 cmꢀ1. H
δ
= 1.02ꢀ1.14 (m, 3H), 1.26ꢀ1.34 (m, 2H), 1.52ꢀ1.87 (m, 8H), 2.13ꢀ2.30 (m,
2H), 2.93ꢀ2.96 (m, 1H), 3.11 (dd, J1 = 5.3 Hz, J2 = 5.3 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 3.61ꢀ3.69 (m,
1H), 3.84 (d, J = 13.6 Hz, 1H), 7.05 (s, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.57 (dd, J1= 1.7 Hz, J2 = 1.7 Hz,
2H); 13C NMR (100 MHz, CDCl3): 24.1, 24.6, 24.7, 25.5, 30.7, 33.4, 47.3, 54.1, 59.5, 67.8, 111.3,
118.6, 129.2, 132.4, 144.2, 173.0. MS (ESI+): m/z = 312.1. ESIꢀHRꢀMS calculated for C19H25N3O
(M++H): 312.2076, found: 312.2077.
N-cyclohexyl-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide (4cA). Yield: 80% (0.325 g
from 0.2 g); colorless oil; Rf = 0.44 (hexanes: EtOAc, 6:4, v/v); IR (neat)
2858, 3409 cmꢀ1. 1H NMR (400 MHz, CDCl3):
νmax: 1067, 1214, 1526, 1669,
δ
= 1.14ꢀ1.67 (m, 3H), 1.26ꢀ1.32 (m, 2H), 1.57ꢀ1.60 (m,
2H), 1.67ꢀ1.71 (m, 4H), 1.88ꢀ2.06 (m, 5H), 2.39 (t, J = 4.4 Hz, 1H), 3.41ꢀ3.43 (m, 1H), 3.61 (d, J = 2.3
Hz, 1H), 4.19 (d, J = 9.7 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 6.0 Hz,
13
1H); C NMR (100 MHz, CDCl3): 24.6, 24.7, 25.3, 25.5, 29.6, 32.4, 32.5, 33.7, 48.5, 54.1, 57.4, 66.5,
122.4, 125.2, 125.8, 130.4, 142.3, 173.5. MS (ESI+): m/z = 355.1. ESIꢀHRꢀMS calculated for
C19H25F3N2O (M++H): 355.1997, found: 355.1995.
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N-cyclohexyl-1-(2-nitrobenzyl)pyrrolidine-2-carboxamide (4dA). Yield: 78% (0.427 g from 0.25
1
2
3
4
5
1
g); brown oil; Rf = 0.43 (hexanes: EtOAc, 6:4, v/v); IR (neat)
NMR (400 MHz, CDCl3):
ν
max: 859, 1528, 1648, 3379 cmꢀ1. H
δ
= 1.05ꢀ1.20 (m, 3H), 1.29ꢀ1.32 (m, 2H), 1.55ꢀ1.78 (m, 7H), 1.84ꢀ1.90 (m,
6
7
8
9
1H), 2.16ꢀ2.26 (m, 1H), 2.30ꢀ2.37 (m, 1H), 2.92ꢀ2.96 (m, 1H), 3.16 (dd, J1 = 4.8 Hz, J2 = 4.8 Hz, 1H),
3.54ꢀ3.60 (m, 1H), 3.85 (dd, J1 = 12.0 Hz, J2 = 12.0 Hz, 2H), 7.28 (s, 1H), 7.41ꢀ7.42 (m, 2H), 7.53ꢀ7.57
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(m, 1H), 7.82 (dd, J1 = 1.1 Hz, J2 = 1.2 Hz, 1H); C NMR (100 MHz, CDCl3): 22.8, 23.8, 23.9, 24.4,
29.8, 31.5, 31.8, 46.6, 53.9, 56.4, 123.4, 127.5, 130.4, 131.8, 148.6, 171.9. MS (ESI+): m/z = 332.1.
ESIꢀHRꢀMS calculated for C18H25N3O3 (M++H): 332.1974, found: 332.1973.
1-(2-Bromobenzyl)-N-cyclohexylpyrrolidine-2-carboxamide (4eA). Yield: 84% (0.330 g from 0.2
1
g); pale yellow oil; Rf = 0.45 (hexanes: EtOAc, 6:4, v/v); IR (neat)
NMR (400 MHz, CDCl3):
ν
max: 1252, 1646, 3312 cmꢀ1. H
δ
= 0.86ꢀ0.98 (m,1H), 1.06ꢀ1.16 (m, 2H), 1.26ꢀ1.34 (m, 2H), 1.55ꢀ1.72 (m,
5H), 1.73ꢀ1.82 (m, 2H), 1.87ꢀ1.95 (m, 1H), 2.19ꢀ2.23 (m, 1H), 2.45ꢀ2.52 (m, 1H), 3.11 (t, J = 6.7 Hz,
1H), 3.22 (dd, J1= 4.1 Hz, J2 = 4.1 Hz, 1H), 3.56ꢀ3.58 (m,1H), 3.78 (dd, J1 = 13.1 Hz, J2 = 13.1 Hz, 2H),
13
7.14ꢀ7.16 (m, 1H), 7.25ꢀ7.32 (m, 3H), 7.54 (dd, J1 = 1.1 Hz, J2 = 1.1 Hz, 1H); C NMR (100 MHz,
CDCl3): 24.2, 24.8, 24.9, 25.5, 31.1, 32.7, 33.1, 47.4, 54.8, 60.2, 67.3, 124.9, 127.6, 129.0, 131.2, 133.0,
137.8, 173.5. MS (ESI+): m/z = 365.0. ESIꢀHRꢀMS calculated for C18H25BrN2O (M++H): 365.1229,
found: 365.1242.
N-cyclohexyl-1-(2-methylbenzyl)pyrrolidine-2-carboxamide (4fA).17 Yield: 82% (0.335 g from 0.2
g); pale yellow; Rf = 0.49 (hexanes: EtOAc, 6:4, v/v); IR (neat)
1H NMR (400 MHz, CDCl3):
ν
max: 928, 1159, 1520, 1654, 3412 cmꢀ1.
δ
= 1.22ꢀ1.78, (m, 3H), 1.34ꢀ1.38 (m, 2H), 1.61ꢀ1.73 (m, 4H), 1.85ꢀ1.88
(m, 2H), 2.21ꢀ2.24 (m, 1H), 2.33 (bs, 1H),2.36 (s, 3H), 3.05 (t, J = 1.7 Hz, 1H), 3.18 (dd, J1 = 4.9 Hz, J2
= 5.0 Hz, 1H), 3.44 (d, J = 12.8 Hz, 1H), 3.44ꢀ3.78 (m, 1H), 3.84 (d, J = 12.8 Hz, 1H), 7.16ꢀ7.19 (m,
3H), 7.28ꢀ7.31 (m,1H), 7.37 (s, 1H); 13C NMR (100 MHz, CDCl3): 18.8, 23.6, 24.4, 24.3, 24.9, 30.5,
32.1, 32.5, 46.8, 54.2, 59.6, 66.7, 124.3, 126.9, 128.4, 130.5, 132.4, 134.1, 172.9. MS (ESI+): m/z =
301.2. ESIꢀHRꢀMS calculated for C19H28N2O (M++H): 301.2280, found: 301.2282.
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N-cyclohexyl-1-(2-methoxybenzyl)pyrrolidine-2-carboxamide (4gA). Yield: 78% (0.362 g from
1
2
3
4
5
0.2 g); colorless oil; Rf = 0.46 (hexanes: EtOAc, 6:4, v/v); IR (neat)
cmꢀ1. 1H NMR (400 MHz, CDCl3):
νmax: 919, 1161, 1529, 1648, 3422
δ
= 1.08ꢀ1.21, (m, 3H), 1.29ꢀ1.41(m, 3H), 1.57ꢀ1.68 (m, 4H), 1.77ꢀ
6
7
8
9
1.86 (m, 4H), 2.13ꢀ2.24 (m, 1H), 2.97ꢀ3.02 (m, 1H), 3.12 (dd, J1 = 4.9 Hz, J2 = 5.0 Hz, 1H), 3.40 (d, J =
12.8 Hz, 1H), 3.66ꢀ3.72 (m, 1H), 3.78 (d, J = 12.8 Hz, 1H), 3.86 (s, 3H), 7.14 (d, J = 7.3 Hz, 2H), 7.23
(d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): 24.1, 24.6, 24.7, 25.5, 30.7,
32.9, 33.1, 47.3, 53.9, 59.6, 64.7, 67.3, 110.9, 126.6, 128.6, 135.6, 136.8, 138.4, 147.9, 174.1. MS
(ESI+): m/z = 317.1. ESIꢀHRꢀMS calculated for C19H28N2O2 (M++H): 317.2229, found: 317.2187.
1-(5-Chloro-2-nitrobenzyl)-N-cyclohexylpyrrolidine-2-carboxamide (4hA). Yield: 71% (0.28 g
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from 0.2 g); colorless oil; Rf = 0.41 (hexanes: EtOAc, 6:4, v/v); IR (neat)
1H NMR (400 MHz, CDCl3):
ν
max: 1263, 1648, 3334 cmꢀ1.
δ
= 1.05ꢀ1.19 (m, 3H), 1.25ꢀ1.37 (m, 2H), 1.57ꢀ1.62 (m, 2H),1.66ꢀ1.73
(m, 4H), 2.22ꢀ2.32 (m, 1H), 2.42ꢀ2.49 (m, 1H), 3.05ꢀ3.09 (m, 1H), 3.27 (dd, J1 = 4.6 Hz, J2 = 4.6 Hz,
1H), 3.63ꢀ3.71 (m, 1H), 3.87 (dd, J1 = 13.8 Hz, J2 = 13.8 Hz, 2H), 7.18 (d, J = 8.1 Hz, 1H), 7.55 (d, J =
13
8.6 Hz, 1H), 8.11 (dd, J1 = 2.7 Hz, J2 = 2.7 Hz, 1H), 8.26 (d, J = 2.6 Hz, 1H); C NMR (100 MHz,
CDCl3): 24.2, 24.9, 25.5, 25.6, 30.9, 33.9, 47.5, 54.6, 57.3, 67.9, 123.5, 125.4, 130.7, 138.3, 141.1,
146.7, 172.9.MS (ESI+): m/z = 366.1. ESIꢀHRꢀMS calculated for C18H24ClN3O3 (M++H): 366.1584,
found: 366.1588.
1-(2-Bromo-5-fluorobenzyl)-N-cyclohexylpyrrolidine-2-carboxamide (4iA). Yield: 68% (0.255 g
from 0.2 g); colorless oil; Rf = 0.42 (hexanes: EtOAc, 6:4, v/v); IR (neat)
1H NMR (400 MHz, CDCl3):
ν
max: 1258, 1650, 3332 cmꢀ1.
δ
= 1.08ꢀ1.26 (m, 1H), 1.29ꢀ1.36 (m, 2H), 1.58ꢀ1.71 (m, 6H), 2.19ꢀ2.29
(m, 1H), 2.43ꢀ2.49 (m, 1H), 3.13 (t, J = 6.9 Hz, 1H), 3.21ꢀ3.24 (m, 1H), 2.19ꢀ2.23 (m, 1H), 2.45ꢀ2.52
(m, 1H), 3.11 (t, J = 6.7 Hz, 1H), 3.22 (dd, J1 = 4.1 Hz, J2 = 4.1 Hz, 1H), 3.58ꢀ3.66 (m,1H), 3.57 (s,2H),
6.86ꢀ6.90 (m, 1H), 7.08 (dd, J1 = 2.8 Hz, J2 = 2.8 Hz, 2H), 7.21 (d, J = 6.9 Hz, 1H), 7.50 (dd, J1 = 5.3
Hz, J2 = 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3): 24.2, 24.7, 24.8, 24.9, 25.5, 31.1, 47.4, 54.7, 59.9,
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67.6, 116.0 (d, J = 22.0 Hz), 117.7 (d, J = 23.0 Hz), 134.1, 134.2, 140.0, 140.1, 160.7, 173.3MS (ESI+):
m/z = 383.1. ESIꢀHRꢀMS calculated for C18H24BrFN2O (M++H): 383.1134, found: 383.1136.
N-cyclohexyl-1-(pyridin-2-ylmethyl)pyrrolidine-2-carboxamide (4jA). Yield: 51% (0.274 g from
1
2
3
4
5
6
7
8
9
0.2 g); colorless oil; Rf = 0.31 (hexanes: EtOAc, 6:4, v/v); IR (neat)
cmꢀ1. 1H NMR (400 MHz, CDCl3):
νmax: 928, 1072, 1522, 1653, 3409
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δ
= 1.07ꢀ1.33 (m, 5H), 1.55ꢀ1.89 (m, 8H), 2.18ꢀ2.25 (m, 1H), 2.46ꢀ
2.48 (m, 1H), 3.06 (t, J = 8.0 Hz, 1H), 3.26ꢀ3.30 (m, 1H), 3.69 (s, 1H), 3.81 (dd, J1 = 12.0 Hz, J2 = 12.0
Hz, 2H), 7.16ꢀ7.23 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): 24.2, 24.7, 25.7, 29.7, 30.7, 32.8, 33.0, 47.4, 53.2 61.1, 67.4, 122.3,
122.7, 136.6, 149.5, 158.6, 173.4. MS (ESI+): m/z = 288.1. ESIꢀHRꢀMS calculated for C17H25N3O
(M++H): 288.2076, found: 288.2066.
N-cyclohexyl-1-((5-methylthiophen-2-yl)methyl)pyrrolidine-2-carboxamide (4kA). Yield: 54%
(0.262 g. from 0.2 g); colorless oil; Rf = 0.31 (hexanes: EtOAc, 6:4, v/v); IR (neat) νmax: 1061, 1215,
1
1519, 1648, 2312 cmꢀ1. H NMR (400 MHz, CDCl3):
δ = 1.88ꢀ1.22 (m, 4H), 1.35ꢀ1.38 (m, 2H), 1.58ꢀ
1.72 (m, 1H), 1.84ꢀ1.86 (m, 1H), 2.16ꢀ2.22 (m, 1H), 2.44 (s, 3H), 3.09ꢀ3.18 (m, 2H), 3.63 (d, J = 13.7
Hz, 1H), 3.72ꢀ3.74 (m, 1H), 3.88 (d, J = 13.7 Hz, 1H), 6.55 (dd, J1 = 1.1 Hz, J2 = 1.1 Hz, 2H), 6.65 (d, J
= 3.3 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): 15.4, 24.1, 24.7, 25.6, 28.4, 29.6,
30.7, 32.9, 33.1, 47.3, 53.7, 54.1, 66.9, 76.8, 77.2, 77.5, 124.6, 125.5, 139.4, 139.9, 173.4. MS (ESI+):
m/z = 307.0. ESIꢀHRꢀMS calculated for C17H26N2OS (M++H): 307.1844, found: 307.1841.
1-Cinnamyl-N-cyclohexylpyrrolidine-2-carboxamide (4lA). Yield: 52% (0.246 g from 0.2 g);
colorless oil; Rf = 0.43 (hexanes: EtOAc, 6:4, v/v); IR (neat)
NMR (400 MHz, CDCl3): = 1.16ꢀ1.22 (m, 2H), 1.37ꢀ1.47 (m, 2H), 1.61ꢀ1.68 (m, 4H), 1.77ꢀ1.89 (m,
ν
max: 890, 961, 1251, 1653, 3333 cmꢀ1. 1H
δ
4H), 2.16ꢀ2.19 (m, 1H), 2.22ꢀ2.45 (m, 1H), 3.12ꢀ3.22 (m, 3H), 3.23ꢀ3.25 (m, 1H), 3.40ꢀ3.76 (m, 1H),
4.33 (dd, J1 = 1.3 Hz, J2 = 1.3 Hz, 1H), 6.20ꢀ6.26 (m,1H), 6.53 (d, J = 15.8 Hz, 1H), 7.24ꢀ7.37 (m, 8H);
13C NMR (100 MHz, CDCl3): 22.2, 24.8, 24.9, 25.6, 30.8, 33.2, 33.3, 47.3, 54.1, 57.6, 67.1, 126.4,
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126.5, 126.7, 127.7, 128.6, 129.4, 132.6, 136.9, 173.7. MS (ESI+): m/z = 313.3. ESIꢀHRꢀMS calculated
1
2
3
for C20H28N2O (M++H): 313.2280, found: 313.2264.
4
5
6
N-cyclohexyl-1-hexylpyrrolidine-2-carboxamide (4mA). Yield: 36% (0.202 g from 0.2 g); colorless
7
8
9
1
oil; Rf = 0.47 (hexanes: EtOAc, 6:4, v/v); IR (neat)
MHz, CDCl3):
ν
max: 942, 1245, 1660, 3330 cmꢀ1. H NMR (400
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δ
= 0.92 (t, J = 6.3 Hz, 3H), 1.27ꢀ1.38 (m, 7H), 1.62ꢀ1.96 (m, 12H), 2.09ꢀ2.19 (m, 2H),
2.29ꢀ2.37 (m, 2H), 3.17ꢀ3.27 (m, 3H), 3.74 (bs, 2H), 7.43 (bs, 1H); 13C NMR (100 MHz, CDCl3): 14.2,
22.7, 24.2, 24.7, 24.8, 25.7, 27.3, 29.8, 30.6, 31.8, 33.1, 33.2, 34.1, 47.1, 53.9, 56.1, 173.5. MS (ESI+):
m/z = 281.9. ESIꢀHRꢀMS calculated for C17H32N2O (M++H): 281.2593, found: 281.2585.
1-Benzyl-N-tert-butylpyrrolidine-2-carboxamide (4aB)18 Yield: 77% (0.377 g from 0.2 g);
colorless oil; Rf = 0.50 (hexanes: EtOAc, 6:4, v/v); IR (neat) ν
max: 1554, 1648, 3348 cmꢀ1. 1H NMR (400
MHz, CDCl3):
δ
= 1.28 (s, 9H), 1.66ꢀ1.75 (m, 2H), 1.81ꢀ1.86 (m, 1H), 2.16ꢀ2.22 (m, 1H), 2.31ꢀ2.37 (m,
13
1H), 3.03ꢀ3.06 (m, 2H), 3.63 (dd, J1 = 12.9 Hz, J2 = 12.9 Hz, 2H), 7.25ꢀ7.36 (m, 6H); C NMR (100
MHz, CDCl3): 23.9, 28.4, 30.7, 50.1, 54.2, 59.9, 68.1, 126.9, 127.3, 128.4, 128.5, 128.6, 138.8, 173.9.
MS (ESI+): m/z = 261.0. ESIꢀHRꢀMS calculated for C16H24N2O (M++H): 261.1967, found: 261.1972.
N-tert-butyl-1-(4-cyanobenzyl)pyrrolidine-2-carboxamide (4bB). Yield: 90% (0.377 g from 0.2 g);
colorless oil; Rf = 0.47 (hexanes: EtOAc, 6:4, v/v); IR (neat)
NMR (400 MHz, CDCl3): = 1.31 (s, 9H), 1.69ꢀ1.91 (m, 3H), 2.19ꢀ2.29 (m, 1H), 2.34ꢀ2.41 (m, 1H),
ν
max: 929, 1067, 1655, 2400, 3363 cmꢀ1. 1H
δ
3.01ꢀ3.11 (m, 2H), 3.73 (dd, J1 = 13.3 Hz, J2 = 13.3 Hz, 2H), 7.18 (s, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.61
(d, J = 7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3): 24.8, 28.7, 30.7, 50.3, 54.1, 59.9, 68.2, 112.5, 119.2,
129.7, 133.0, 144.2, 173.8.MS (ESI+): m/z = 286.1. ESIꢀHRꢀMS calculated for C17H23N3O (M++H):
286.1919, found: 286.1929.
N-tert-butyl-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide (4cB). Yield: 86% (0.324 g
from 0.2 g); colorless oil; Rf = 0.44 (hexanes: EtOAc, 6:4, v/v); IR (neat)
cmꢀ1. 1H NMR (400 MHz, CDCl3):
νmax: 1119, 1256, 1665, 3329
δ
= 1.28 (s, 9H),1.69ꢀ1.87 (m, 3H), 2.19ꢀ2.25 (m, 1H),2.32ꢀ2.38 (m,
1H), 3.05 (t, J = 5.4 Hz, 2H), 3.78 (dd, J1= 13.3 Hz, J2 = 13.3 Hz, 2H), 7.16 (s, 1H), 7.39 (d, J = 7.9 Hz,
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2H), 7.59 (d, J = 7.9 Hz, 2H); C NMR (100 MHz, CDCl3): 23.9, 28.6, 30.7, 50.2, 54.3, 59.5, 68.3,
125.5, 125.6, 126.8, 128.8, 142.9, 173.5.MS (ESI+): m/z = 329.1. ESIꢀHRꢀMS calculated for
C17H23F3N2O (M++H) 329.1841, found: 329.1844
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1-(2-Bromobenzyl)-N-tert-butylpyrrolidine-2-carboxamide (4eB). Yield: 86% (0.365 g from 0.2
9
1
g); pale yellow oil; Rf = 0.50 (hexanes: EtOAc, 6:4, v/v); IR (neat)
NMR (400 MHz, CDCl3):
ν
max: 1253, 1656, 3326 cmꢀ1. H
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δ
= 1.14 (s, 9H), 1.69ꢀ1.77 (m, 2H), 1.84ꢀ1.90 (m, 1H), 2.15 ꢀ2.25 (m, 1H),
2.46ꢀ2.52 (m, 1H), 3.08 (dd, J1 = 4.1 Hz, J2 = 4.1 Hz, 1H), 3.15 (t, J = 7.5 Hz, 1H), 3.66 (dd, J1 = 13.0
13
Hz, J2 = 13.1 Hz, 2H), 7.11ꢀ7.15 (m, 2H), 7.23ꢀ7.31 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H); C NMR (100
MHz, CDCl3): 24.2, 28.5, 31.2, 49.8, 55.1, 60.3, 68.0, 124.9, 127.6, 129.0, 131.1, 132.9, 137.9, 173.6.
MS (ESI+): m/z= 339.0. ESIꢀHRꢀMS calculated for C16H23BrN2O (M++H): 339.1072, found: 339.1075.
N-tert-butyl-1-(2-methoxybenzyl)pyrrolidine-2-carboxamide (4gB). Yield: 62% (0.330 g from
0.25 g); colorless oil; Rf = 0.45 (hexanes: EtOAc, 6:4, v/v); IR (neat)
1H NMR (400 MHz, CDCl3):
ν
max: 1116, 1549, 1639, 3321 cmꢀ1.
δ
= 1.26 (s, 9H), 1.68ꢀ1.75 (m, 2H), 1.82ꢀ1.88 (m, 1H), 2.17ꢀ2.23 (m, 1H),
2.38ꢀ2.45 (m, 1H), 3.03ꢀ3.09 (m, 2H), 3.72 (dd, J1 = 9.9 Hz, J2 = 12.9 Hz, 2H), 3.85 (s, 3H), 6.88ꢀ6.94
(m, 2H), 7.24ꢀ7.32 (m, 2H), 7.32 (s, 1H); 13C NMR (100 MHz, CDCl3): 23.9, 28.6, 30.9, 49.9, 54.2,
54.5, 55.4, 67.9, 110.6, 120.5, 127.0, 128.5, 130.6, 157.7, 174.1. MS (ESI+): m/z= 291.1. ESIꢀHRꢀMS
calculated for C17H26N2O2 (M++H): 291.2073, found: 291.2077.
N-tert-butyl-1-(pyridin-2-ylmethyl)pyrrolidine-2-carboxamide (4jB). Yield: 79% (0.384 g from
0.2 g); colorless oil; Rf = 0.3 (hexanes: EtOAc, 6:4, v/v); IR (neat) νmax: 1059, 1217, 1523, 1650, 3408
1
cmꢀ1. H NMR (400 MHz, CDCl3):
δ = 1.29 (s, 9H), 1.75ꢀ1.77 (m, 2H), 1.87ꢀ1.91 (m, 1H), 2.17ꢀ2.25
(m, 1H), 2.45ꢀ2.52 (m, 1H), 3.08ꢀ3.19 (m, 2H), 3.81 (dd, J1 = 13.4 Hz, J2 = 13.4 Hz, 2H), 7.18ꢀ7.23 (m,
1H), 7.25ꢀ7.29 (m, 1H), 7.64ꢀ7.69 (m, 2H), 8.56 (t, J = 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): 24.2,
28.8, 30.8, 50.3, 54.6, 61.5, 68.2, 122.4, 122.8, 136.7, 140.7, 158.9, 173.9. MS (ESI+): m/z = 262.1.
ESIꢀHRꢀMS calculated for C15H23N3O (M++H): 262.1919, found: 262.1917.
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N-tert-butyl-1-((5-methylthiophen-2-yl)methyl)pyrrolidine-2-carboxamide(4kB). Yield: 63%
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5
(0.279 g from 0.2 g); colorless oil; Rf = 0.43 (hexanes: EtOAc, 6:4, v/v); IR (neat) νmax: 1554, 1664,
1
3348 cmꢀ1. H NMR (400 MHz, CDCl3):
δ = 1.35 (s, 9H), 1.72ꢀ1.75 (m, 2H), 1.83ꢀ1.87 (m, 1H), 2.17ꢀ
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2.22 (m, 1H), 2.35ꢀ2.39 (m, 1H), 2.46 (s, 3H), 3.04ꢀ3.07 (m, 1H), 3.13 (t, J = 6.6 Hz, 1H), 3.76 (dd, J1=
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13.8 Hz, J2 = 13.7 Hz, 2H), 6.56ꢀ6.57 (m, 1H), 6.67 (d, J = 3.2 Hz, 1H), 7.33 (s, 1H); C NMR (100
MHz, CDCl3): 15.4, 24.0, 28.7, 30.7, 50.2, 53.8, 54.2, 67.7, 124.6, 125.4, 139.4, 140.2, 173.7. MS
(ESI+): m/z = 281.2. ESIꢀHRꢀMS calculated forC15H24N2OS (M++H): 281.1688, found: 281.1690.
N-tert-butyl-1-(2,3-dichlorobenzyl)pyrrolidine-2-carboxamide (4lB). Yield: 88% (0.329 g from 0.2
1
g); colorless oil; Rf = 0.48 (hexanes: EtOAc, 6:4, v/v); IR (neat)
(400 MHz, CDCl3):
ν
max: 1568, 1649, 3327cmꢀ1. H NMR
δ
= 1.17 (s, 9H), 1.65ꢀ1.82 (m, 2H), 1.84ꢀ1.98 (m, 1H), 2.17ꢀ2.27 (m, 1H), 2.45ꢀ
2.51 (m, 1H), 3.07 (dd, J1= 4.2 Hz, J2 = 4.2 Hz, 1H), 3.14 (t, J = 7.8 Hz, 1H), 3.80 (dd, J1 = 12.9 Hz, J2
= 12.9 Hz, 2H), 7.08 (s, 1H), 7.15ꢀ7.23 (m, 2H), 7.41 (dd, J1 = 1.6 Hz, J2 = 1.6 Hz, 1H); 13C NMR (100
MHz, CDCl3): 24.2, 28.5, 31.2, 49.9, 55.2, 58.8, 68.1, 127.4, 129.2, 129.7, 132.8, 133.4, 138.7, 173.7.
MS (ESI+): m/z = 329.1. ESIꢀHRꢀMS calculated for C16H22Cl2N2O (M++H): 329.1187, found:
329.1182.
N,1-dibenzylpyrrolidine-2-carboxamide (4aC).19 Yield: 60% (0.332 g from 0.2 g); colorless oil; Rf
= 0.46 (hexanes: EtOAc, 6:4, v/v); IR (neat)
= 1.76ꢀ1.79 (m, 2H), 1.87ꢀ1.95 (m, 1H), 2.18ꢀ2.27 (m, 1H), 2.33ꢀ2.39 (m, 1H), 2.96ꢀ3.01 (m, 1H),
ν
max: 1226, 1648, 3416 cmꢀ1. 1H NMR (400 MHz, CDCl3):
δ
3.26 (dd, J1 = 4.8 Hz, J2 = 4.8 Hz, 1H), 3.64 (d, J1 = 12.8 Hz, J2 = 12.8 Hz, 2H), 4.38 (d, J = 5.8 Hz,
1H), 7.23ꢀ7.27 (m, 5H), 7.32ꢀ7.36 (m, 5H), 7.72 (s, 1H); 13C NMR (100 MHz, CDCl3): 24.2, 30.7, 43.1,
54.0, 60.0, 65.2, 67.4, 126.9, 127.3, 127.4, 127.5, 127.6, 127.9, 128.5, 128.6, 128.7, 128.8, 138.4, 138.5,
141.2, 174.8. MS (ESI+): m/z = 295.2. ESIꢀHRꢀMS calculated for C19H22N2O (M++H): 295.1810,
found: 295.1809.
N-benzyl-1-(2-bromobenzyl)pyrrolidine-2-carboxamide (4eC). Yield: 76% (0.305 g from 0.2 g);
1
colorless oil; Rf = 0.45 (hexanes: EtOAc, 6:4, v/v); IR (neat)
ν
max: 1061, 1220, 1641, 3412 cmꢀ1. H
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NMR (400 MHz, CDCl3):
δ
= 1.77ꢀ1.81 (m,2H), 1.97ꢀ2.02 (m, 1H), 2.25ꢀ2.31 (m, 1H), 2.46ꢀ2.48 (m,
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1H), 3.03 (dd, J1 = 7.2 Hz, J2 = 1.4 Hz, 1H), 3.29ꢀ3.32 (m, 1H), 3.78 (dd, J1 = 12.8 Hz, J2 = 12.8 Hz,
2H), 4.21ꢀ4.24 (m, 1H), 4.39 (dd, J1 = 6.2 Hz, J2 = 6.3 Hz, 1H), 7.08ꢀ7.12 (m, 1H), 7.71ꢀ7.32 (m, 7H),
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7.46 (dd, J1 = 0.9 Hz, J2 = 1.1 Hz, 1H), 7.79 (s, 1H); C NMR (100 MHz, CDCl3): 24.3, 30.9, 42.9,
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54.6, 60.1, 67.4, 124.7, 127.3, 127.5, 127.7, 128.6, 129.2, 131.4, 132.9, 137.5, 138.4. MS (ESI+): m/z =
373.0. ESIꢀHRꢀMS calculated for C19H21BrN2O (M++H): 373.0916, found: 373.0920.
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N-benzyl-1-(2-methoxybenzyl)pyrrolidine-2-carboxamide (4gC). Yield: 70% (0.329 g from 0.2 g);
colorless oil; Rf = 0.44 (hexanes: EtOAc, 6:4, v/v); IR (neat)
MHz, CDCl3): = 1.71ꢀ1.78 (m, 2H), 1.97ꢀ2.01 (m, 1H), 2.27ꢀ2.32 (m, 1H), 2.35ꢀ2.42 (m, 1H), 2.87ꢀ
ν
max: 1539, 1649, 3345 cmꢀ1. 1H NMR (400
δ
2.92 (m, 1H), 3.27 (dd, J1 = 5.1 Hz, J2 = 5.1 Hz, 1H), 3.41 (d, J = 12.2 Hz, 1H), 3.55 (s, 3H), 4.04 (d, J
= 12.2 Hz, 1H), 4.41 (dd, J1 = 5.6 Hz, J2 = 5.6 Hz, 1H), 4.57 (dd, J1 = 6.5 Hz, J2 = 6.5 Hz, 1H), 6.82 (d,
J = 8.2 Hz, 1H), 6.88ꢀ6.92 (m, 1H), 7.17 (dd, J1 = 1.7 Hz, J2 = 1.7 Hz, 1H), 7.24ꢀ7.36 (m, 6H), 8.22 (s,
13
1H); C NMR (100 MHz, CDCl3): 23.9, 30.9, 42.9, 54.1, 55.2, 55.5, 67.2, 110.6, 120.5, 126.8, 127.3,
127.4, 128.7, 128.9, 131.1, 138.9, 157.9, 175.0. MS (ESI+): m/z = 325.2. ESIꢀHRꢀMS calculated for
C20H24N2O2 (M++H): 325.1916, found: 325.1913.
N-benzyl-1-(pyridin-2-ylmethyl)pyrrolidine-2-carboxamide (4jC). Yield: 74% (0.408 g from 0.2
g); colorless oil; Rf = 0.25 (hexanes: EtOAc, 6:4, v/v); IR (neat)
3348 cmꢀ1. 1H NMR (400 MHz, CDCl3):
νmax: 928, 1069, 1159, 1521, 1659,
δ
= 1.79ꢀ1.82 (m, 2H), 2.01ꢀ2.04 (m, 1H), 2.26ꢀ2.32 (m, 1H),
2.49ꢀ2.56 (m, 1H), 3.06ꢀ3.11 (m, 1H), 3.45 (dd, J1 = 4.8 Hz, J2 = 4.8 Hz, 1H), 3.85 (dd, J1 = 13.4 Hz, J2
= 13.4 Hz, 2H), 4.35ꢀ4.48 (m, 2H), 7.14 (d, J = 7.6 Hz, 2H), 7.26ꢀ7.32 (m, 5H), 7.56ꢀ7.60 (m, 1H), 8.41
(d, J = 4.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): 24.4, 30.7, 43.1, 54.3, 61.2, 67.4, 122.3, 122.7, 127.2,
127.7, 128.5, 136.5, 138.7, 149.5, 158.5, 174.6. MS (ESI+): m/z = 296.1. ESIꢀHRꢀMS calculated for
C18H21N3O (M++H): 296.1763, found: 296.1759.
N-benzyl-1-(2,3-dichlorobenzyl)pyrrolidine-2-carboxamide (4lC). Yield: 83% (0.343 g from 0.2
1
g); colorless oil; Rf = 0.41 (hexanes: EtOAc, 6:4, v/v); IR (neat)
ν
max: 1256, 1558, 1660, 3356 cmꢀ1. H
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NMR (400 MHz, CDCl3):
δ = 1.72ꢀ1.81 (m, 2H), 1.96ꢀ1.98 (m, 1H), 2.25ꢀ2.31 (m, 1H), 2.41ꢀ2.45 (m,
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1H), 2.99ꢀ3.03 (m, 1H), 3.29 (dd, J1 = 4.5 Hz, J2 = 4.5 Hz, 1H), 3.81(dd, J1 = 13.0 Hz, J2 = 13.0 Hz,
2H), 4.21 (dd, J1 = 5.6 Hz, J2 = 5.6 Hz, 1H), 4.41 (dd, J1 = 6.5 Hz, J2 = 6.5 Hz, 1H), 7.11 (t, J = 7.7 Hz,
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1H), 7.16ꢀ7.19 (m, 3H), 7.25ꢀ7.33 (m, 3H), 7.36 (dd, J1 = 1.7 Hz, J2 = 1.7 Hz, 1H), 7.68 (s, 1H); C
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NMR (100 MHz, CDCl3): δ (ppm) = 24.3, 31.1, 43.1, 54.6, 58.5, 67.6, 127.4, 127.5, 127.7, 128.7,
129.3, 129.8, 132.6, 133.5, 138.4, 174.4. MS (ESI+): m/z = 363.1. ESIꢀHRꢀMS calculated for
C19H20Cl2N2O (M++H): 363.1031, found: 363.1034.
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Ethyl 2-(1-benzylpyrrolidine-2-carboxamido)acetate (4aD). Yield: 66% (0.361 g from 0.2 g);
1
brown oil; Rf = 0.41 (hexanes: EtOAc, 6:4, v/v); IR (neat)
MHz, CDCl3):
ν
max: 1639, 1741, 3418 cmꢀ1. H NMR (400
δ
= 1.17 (t, J = 7.2 Hz, 3H), 1.69ꢀ1.76 (m, 3H), 2.03ꢀ2.11 (m, 1H), 2.21ꢀ2.27 (m, 1H),
2.83ꢀ2.86 (m, 1H), 3.06 (dd, J1 = 5.5 Hz, J2 = 5.8 Hz, 1H), 4.03ꢀ4.13 (m, 1H), 7.23ꢀ7.34 (m, 5H), 8.16
(s, 1H); 13C NMR (100 MHz, CDCl3): 14.5, 23.6, 30.2, 41.1, 53.2, 59.1, 60.9, 67.4, 127.4, 128.5, 129.4,
139.1, 170.4, 174.5. MS (ESI+): m/z = 291.0. ESIꢀHRꢀMS calculated for C16H22N2O3 (M++H):
291.1709, found: 291.1708.
1-Benzyl-N-phenylpyrrolidine-2-carboxamide (4aE). Yield: 60% (0.318 g from 0.2 g); colorless
1
oil; Rf = 0.39 (hexanes: EtOAc, 6:4, v/v); IR (neat)
(400 MHz, CDCl3):
ν
max: 950, 1259, 1560, 1663, 3335 cmꢀ1. H NMR
δ
= 1.76ꢀ1.77 (m, 1H), 2.05 (bs, 1H), 2.25ꢀ2.34 (m, 2H), 3.01ꢀ3.07 (m, 2H), 3.86
(bs, 1H), 4.70 (s, 2H), 7.11ꢀ7.12 (m, 1H), 7.27ꢀ7.38 (m, 7H), 7.61 (d, J = 7.2 Hz, 2H), 9.74 (s, 1H); 13C
NMR (100 MHz, CDCl3): 29.7, 30.7, 47.3, 61.1, 65.3, 119.3, 123.9, 126.9, 127.6, 128.5, 128.9, 137.8,
141.0, 173.4. MS (ESI+): m/z = 281.7. ESIꢀHRꢀMS calculated for C18H20N2O (M++H): 281.1654,
found: 281.1653
1-(2-Bromobenzyl)-N-phenylpyrrolidine-2-carboxamide (4eE). Yield: 44% (0.172 g from 0.2 g);
colorless oil; Rf = 0.37 (hexanes: EtOAc, 6:4, v/v); IR (neat)
1. 1H NMR (400 MHz, CDCl3):
ν
max: 868, 961, 1240, 1544, 1657, 3369 cmꢀ
δ
= 1.75ꢀ1.85 (m, 1H), 2.03ꢀ2.22 (m, 1H), 2.23ꢀ2.40 (m, 2H), 2.49ꢀ2.55
(m, 1H), 3.85ꢀ3.95 (m, 1H), 3.90 (dd, J1 = 13.0 Hz, J2 = 12.8 Hz, 1H), 4.14 (dd, J1 = 7.1 Hz, J2 = 8.2 Hz,
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1H), 4.77 (s, 2H), 7.04ꢀ7.20 (m, 3H), 7.27ꢀ7.36 (m, 2H), 7.50ꢀ7.66 (m, 4H), 9.34 (s, 1H); 13C NMR (100
MHz, CDCl3): 22.6, 25.1, 29.7, 49.5, 65.1, 119.3, 121.8, 125.1, 127.6, 128.7, 128.9, 129.1, 132.6, 133.4,
139.7, 176.2. MS (ESI+): m/z = 359.5. ESIꢀHRꢀMS calculated for C18H19BrN2O (M++H): 359.0759,
found: 359.0744.
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1-Cinnamyl-N-phenylpyrrolidine-2-carboxamide (4lE). Yield: 49% (0.227 g from 0.2 g); colorless
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1
oil; Rf = 0.32 (hexanes: EtOAc, 6:4, v/v); IR (neat)
(400 MHz, CDCl3):
ν
max: 951, 1255, 1560, 1668, 3325 cmꢀ1. H NMR
δ
= 1.77ꢀ1.81 (m, 2H), 1.97ꢀ2.01 (m, 1H), 2.19ꢀ2.27 (m, 1H), 2.47ꢀ2.53 (m, 1H),
3.25ꢀ3.32 (m, 3H), 3.46ꢀ3.52 (m, 1H), 6.22ꢀ6.29 (m, 1H), 6.55 (d, J = 15.7 Hz, 1H), 7.08 (d, J = 7.3 Hz,
1H), 7.19ꢀ7.34 (m, 7H), 7.58 (d, J = 7.8 Hz, 1H), 9.34 (s, 1H); 13C NMR (100 MHz, CDCl3): 24.4, 30.7,
54.0, 57.5, 67.3, 119.4, 124.1, 126.2, 126.4, 127.7, 128.6, 128.9, 132.9, 136.6, 137.7, 172.9. MS (ESI+):
m/z = 307.3. ESIꢀHRꢀMS calculated for C20H22N2O (M++H): 307.1810, found: 307.17990.
1-Benzyl-N-cyclohexylpiperidine-2-carboxamide (5aA). Yield: 42% (0.237 g from 0.2 g); colorless
1
oil; Rf = 0.37 (hexanes: EtOAc, 6:4, v/v); IR (neat)
ν
max: 869, 1259, 1498, 1662, 3306 cmꢀ1. H NMR
(400 MHz, CDCl3):
δ
= 1.90ꢀ1.30 (m, 3H), 1.31ꢀ1.41 (m, 4H), 1.57ꢀ1.72 (m, 4H), 1.77ꢀ1.95 (m, 4H),
13
2.60ꢀ2.69 (m, 3H), 3.11ꢀ3.14 (m, 1H), 3.67ꢀ3.87 (m, 3H), 7.26ꢀ7.36 (m, 5H), 7.82 (bs, 1H); C NMR
(100 MHz, CDCl3): 24.1, 24.7, 24.8, 25.5, 25.8, 30.2, 32.8, 32.9, 45.7, 47.6, 60.4, 64.8, 126.8, 127.3,
128.4, 141.3, 173.2. MS (ESI+): m/z = 301.1. ESIꢀHRꢀMS calculated for C19H28N2O (M++H):
301.2280, found: 301.2256.
1-Benzyl-N-tert-butylpiperidine-2-carboxamide (5aB). Yield: 48% (0.248 g from 0.2 g); colorless
1
oil; Rf = 0.34 (hexanes: EtOAc, 6:4, v/v); IR (neat)
ν
max: 923, 1256, 1562, 1668, 3323 cmꢀ1. H NMR
(400 MHz, CDCl3):
δ
= 1.35 (s, 9H), 1.37ꢀ1.39 (m, 2H), 1.56ꢀ1.57 (m, 2H), 1.77ꢀ1.94 (m, 2H), 2.61ꢀ
13
2.66 (m, 1H), 2.99ꢀ3.08 (m, 2H), 3.40 (bs, 2H), 7.28ꢀ7.36 (m, 5H), 7.56 (bs, 1H); C NMR (100 MHz,
CDCl3): 23.9, 25.7, 28.7, 29.9, 45.7, 50.6, 60.8, 65.1, 126.9, 127.4, 128.5, 141.2, 173.3. MS (ESI+): m/z
= 275.0. ESIꢀHRꢀMS calculated for C17H26N2O (M++H): 275.2123, found: 275.2118.
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N-tert-butyl-1-(4-cyanobenzyl)piperidine-2-carboxamide (5bB). Yield: 58% (0.264 g from 0.2 g);
max: 896, 1262, 1548, 1659, 3340 cmꢀ1. 1H
1
2
3
4
colorless oil; Rf = 0.32 (hexanes: EtOAc, 6:4, v/v); IR (neat)
ν
5
6
NMR (400 MHz, CDCl3):
δ = 1.28 (s, 9H), 1.66ꢀ1.75 (s, 3H), 1.81ꢀ1.86 (m, 2H), 2.16ꢀ2.22 (m, 1H),
7
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2.31ꢀ2.37 (m, 1H), 3.02ꢀ3.06 (m, 2H), 3.39 (d, J = 13.2 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H), 7.27 (bs,
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1H), 7.38 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H); C NMR (100 MHz, CDCl3): 24.0, 26.8, 28.7,
30.7, 50.2, 53.8, 61.5, 67.7, 112.8, 119.6, 130.7, 133.8, 143.9, 173.6. MS (ESI+): m/z = 300.1. ESIꢀHRꢀ
MS calculated for C18H25N3O (M++H): 300.2076, found: 300.2061.
4,4'-(Hexahydropyrrolo[2,1-b]oxazole-2,3-diyl)dibenzonitrile20 (6). Yield: 30% (0.036 g from 0.05
o
g); white solid; mp >200 C; Rf = 0.42 (hexanes: EtOAc, 6:4, v/v); IR (neat)
ν
max: 960, 1423, 1553,
1612 cmꢀ1. 1H NMR (400 MHz, CDCl3):
δ = 1.78ꢀ1.84 (m, 1H), 1.97ꢀ2.14 (m, 3H), 2.73ꢀ2.78 (m, 1H),
3.04ꢀ3.10 (m, 1H), 3.71 (d, J = 7.9 Hz, 1H), 4.55 (d, J = 7.9 Hz, 1H), 5.22 (dd, J1 = 7.9 Hz, J2 = 7.9 Hz,
1H), 7.24 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 6.5 Hz, 2H), 7.56 (d, J = 6.2 Hz, 2H);
13C NMR (100 MHz, CDCl3): 24.2, 31.7, 55.9, 78.7, 87.7, 99.3, 111.7, 112.4, 118.6, 118.8, 127.1,
128.1, 132.5, 132.6, 143.8, 146.3.
ACKNOWLEDGMENT. One of the authors (SUD) acknowledges the financial support in the form of
fellowship from CSIR, New Delhi. Authors acknowledge the SAIF division for providing the
spectroscopic data. One of the authors (MD) acknowledges a financial grant from the CSIRꢀNetwork
project BSC0102. Authors acknowledge the anonymous reviewers for their suggestions to improve the
manuscript.
This is CDRI Communication No. 283/2014/SB.
SUPPORTING INFORMATION. Experiment to ascertain the in situ liberation of water for
hydrolysis, procedures for bioassays, and copies of 1H, 13Cꢀ NMR and HRMS spectra are included. This
material is available free of charge via the Internet at http://pubs.acs.org.
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