Nucleophilic phosphine-catalyzed intramolecular michael reactions of N-allylic substituted α-amino nitriles: Construction of functionalized pyrrolidine rings via 5-endo-trig cyclizations

Article abstract of DOI:10.1021/jo500418s

Pyrrolidine rings are common moieties for pharmaceutical candidates and natural compounds, and the construction of these skeletons has received much attention. α-Amino nitriles are versatile intermediates in synthetic chemistry and have been widely used in the generation of multiple polyfunctional structures. Herein, a novel nucleophilic phosphine-catalyzed intramolecular Michael reaction of N-allylic substituted α-amino nitriles has been developed for the efficient construction of functionalized 2,4-disubstituted pyrrolidines (N-heterocyclic α-amino nitriles) via 5-endo-trig cyclization. Furthermore, the one-pot sequence of the synthesis of pyrrolidine and the subsequent transformations of the functionalized products have also been demonstrated.

Full text of DOI:10.1021/jo500418s

Article
pubs.acs.org/joc
Nucleophilic Phosphine-Catalyzed Intramolecular Michael Reactions
of N‑Allylic Substituted α‑Amino Nitriles: Construction of
Functionalized Pyrrolidine Rings via 5-endo-trig Cyclizations
Da En,†,‡ Gong-Feng Zou,† Yuan Guo,‡ and Wei-Wei Liao*,†
†Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
‡Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and
Materials Science, Northwest University, Xi’an 710069, China
S
* Supporting Information
ABSTRACT: Pyrrolidine rings are common moieties for pharma-
ceutical candidates and natural compounds, and the construction of
these skeletons has received much attention. α-Amino nitriles are
versatile intermediates in synthetic chemistry and have been widely
used in the generation of multiple polyfunctional structures. Herein, a
novel nucleophilic phosphine-catalyzed intramolecular Michael re-
action of N-allylic substituted α-amino nitriles has been developed for
the efficient construction of functionalized 2,4-disubstituted pyrroli-
dines (N-heterocyclic α-amino nitriles) via 5-endo-trig cyclization.
Furthermore, the one-pot sequence of the synthesis of pyrrolidine and
the subsequent transformations of the functionalized products have
also been demonstrated.
to α,β-unsaturated carbonyl compounds, followed by subse-
quent reductive decyanation, resulted in polysubstituted
pyrrolidines in a one-pot reaction sequence.7 Very recently,
we have developed an efficient tertiary amine-catalyzed
multicomponent tandem reaction to prepare funcationalized
α-amino nitriles and α-methylene-γ-butyrolactams via 5-exo-trig
cyclization.8a−c However, the development of a metal-free
catalytic process to construct functionalized pyrrolidine rings
from α-amino nitriles under mild reaction conditions is
unexploited. Nucleophilic phosphine catalysis has advanced
rapidly as a powerful tool for assembling the diverse and
complex carbon frameworks in recent years.9 Among them,
phosphine-catalyzed Michael addition of nucleophiles to
electron-deficient alkenes has provided efficient C−C bond
and C−X bond formations, in which zwitterions generated
from Michael-type additions of phosphines to electron-deficient
alkenes can act as organic bases to deprotonate protic
nucleophiles (NuH) and catalyze the corresponding Michael
additions to electron-deficient alkenes.10 Herein, we describe a
nucleophilic phosphine-catalyzed intramolecular Michael re-
action of N-allylic substituted α-amino nitriles to prepare 2,4-
disubstituted pyrrolidines (N-heterocyclic α-amino nitriles) via
5-endo-trig cyclizations.
INTRODUCTION
■
Five-membered nitrogen-atom-containing heterocycles consti-
tute one of the most important classes of heterocyclic
compounds in the pharmaceutical and agrochemical industries.1
In particular, pyrrolidine rings have received considerable
attention from the synthetic community due to their frequent
occurrence in nature and wider relevance to numerous
biologically active natural products and pharmacologically
relevant therapeutic agents.2 A variety of synthetic methods
have been developed to construct these structurally useful
motifs.3 As a straightforward strategy to access these nitrogen
incorporated heterocycles, intramolecular cyclization pathways
have thus gained much interest.4 However, the construction of
pyrrolidine rings via intramolecular catalytic nucleophile-driven
5-endo-trig cyclization, which is a geometrically disfavored
process according to Baldwin’s rules, is rare, despite the fact
that the syntheses of such saturated five-membered nitrogen
heterocycles via metal-catalyzed intramolecular 5-endo-trig
cyclizations have been studied extensively in recent years.5
Within this context, the development of catalytic intramolecular
nucleophile-driven cyclization via a 5-endo-trig mode to access
pyrrolidine rings still represents a synthetic challenge and is
highly demanded.
α-Amino nitriles bearing an α-hydrogen are exceptionally
versatile intermediates in synthetic chemistry and have been
widely used in the generation of multiple polyfunctional
structures due to the powerful anion-stabilizing capacity of the
cyano group.6 Recently, Opatz et al. have reported that addition
of deprotonated α-amino nitriles by stoichiometric strong base
Received: February 20, 2014
Published: April 22, 2014
© 2014 American Chemical Society
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Article
RESULTS AND DISCUSSION
Scheme 2. Attempt of 5-endo-trig Cyclization of Compound
3
■
In our previous work, we have demonstrated a metal-free
controllable regioselective allylic alkylation and amination
reaction between MBH adducts and α-amino nitriles, which
utilized α-amino nitriles as dipronucleophiles and provided an
efficient synthetic route for the preparation of multifuncation-
alized α-amino nitriles with high selectivity via a facile and
unified approach (Scheme 1).8a−c In these works, we found that
Scheme 1. Regioselective Allylic Alkylation and 5-exo-trig
Cyclization of Compound 3
(20 mol %). Gratifyingly, this reaction gave rise to function-
alized pyrrolidine 6aa with a quaternary carbon atom
incorporated, whose structure is unambiguously supported by
1H NMR and 13C NMR spectra and X-ray analysis (see the
Supporting Information), albeit with poor yield and diaster-
eoselectivity (Table 1, entry 1). DABCO gave a similar result as
Table 1. Optimization of 5-endo-trig Cyclization of
a
Compound 4aa
b
c
entry
cat.
solvent
T (°C) t (h)
dr
yield (%)
15
C-allylic alkylation products of α-amino nitriles can undergo 5-
exo-trig cyclization to provide α-methylene-γ-butyrolactams in a
metal-free catalytic fashion, whereas 5-endo-trig cyclization has
not been observed. As part of our efforts to develop efficient
metal-free processes to prepare a variety of functionalized
nitriles incorporating quaternary carbon centers,8 we became
interested in the possibility of utilizing these functionalized
allylic substituted α-amino nitriles to furnish diverse pyrrolidine
rings bearing quaternary carbon centers through a nucleophile-
driven 5-endo-trig cyclization. First, a t-butyl ester analogue of
C-allylic alkylation product 3a, which was prepared from a
Strecker−allylic−alkylation sequence, was investigated to
achieve 5-endo-trig cyclization because the bulky substituent
of compound 3a could inhibit the occurrence of favorable 5-
exo-trig cyclization (Scheme 2). However, whether 5-exo-trig or
5-endo-trig, cyclization has not been observed with treatment of
compound 3a with a number of catalytic bases. Instead, this
reaction gave the α-amino nitrile 7 and decyanation product 8,
which may derive from a base-induced dehydrocyanation and
subsequent isomerization and recyanation. The structure of
dicyano-substituted compound 7 was confirmed further by the
conversion of 7 into ketone 9. These results indicated that
intramolecular 5-endo-trig cyclization of 3a, which was counted
on N-based nucleophilicity, was not advantaged.
1
2
DMAP
DABCO
PPh3
PBu3
DBU
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
PBu3
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
60
60
60
30
30
30
30
30
30
30
30
60
0
24
24
24
1
1.1:1
1.1:1
14
d
3
4
1.4:1
1.2:1
1.3:1
1.2:1
1.5:1
81
84
73
18
29
trace
73
72
77
89
90
92
96
5
5.5
6
3
24
24
24
7
CHCl3
THF
8
9
PhMe
10
11
12
13
14
DMF
0.5
1.6:1
t-BuOH
MeCN
MeCN
MeCN
MeCN
MeCN
7
1:1
0.5
1.5
2.5
1.5
2
1.3:1
1.5:1
1.6:1
1.6:1
−30
0
e
15
f
16
0
2:1
a
Reaction conditions: 4aa (0.2 mmol) and catalyst (20 mol %) in
b
solvent (2.0 mL). Determined by 1H NMR analysis of crude product.
c
d
e
Isolated yield. No desired product was detected. Catalyst (10 mol
f
%) was used. Catalyst (5 mol %) was used.
that of DMAP (Table 1, entry 2). In contrast, treatment of
PPh3 did not provided any desired product. To our delight,
more electron-rich PBu3 afforded the desired product efficiently
at lower temperature in markedly increased yields (Table 1,
entries 3 and 4). More basic Lewis base, such as DBU, was also
employed and gave product 6aa in good yield after a prolonged
reaction time, which indicated that the reaction may undergo a
general base-catalyzed process (Table 1, entry 5). Solvent
In view of the potential nucleophilicity of allylic substituted
α-amino nitriles 4, we conceived that the intramolecular 5-endo-
trig cyclization of compound 4 could be achieved to afford the
desired pyrrolidine rings. To assess the feasibility of this
transformation, an initial investigation was examined with
compound 4aa in acetonitrile with a catalytic amount of DMAP
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optimization showed that this cyclization reaction proceeded
well in polar solvent generally in the presence of 20 mol %
PBu3, while the diastereoselectivities of this transformation
were unaffected (Table 1, entries 6−11). Noteworthily, 5-exo-
trig cyclization of compound 4aa was not detected in all
screened reactions. Although the attempts to improve the
diastereoselectivity of this transformation by employing the
reaction at different temperatures have proven to be
unsuccessful,11 the yield of this reaction has been improved
at low temperature (Table 1, entries 12−14). The further
reducing the loading of catalyst enhanced the chemical yield
markedly, and the reaction furnished the desired product 6aa in
excellent yield in the presence of PBu3 (5 mol %) (Table 1,
entries 15 and 16).
also serve as good substrates and provided the desired products
in comparably good yields (Table 2, entries 11 and 12).
However, aliphatic substituted α-amino nitrile did not provide
any desired product, presumably due to the deficiency of the
acidity of the substrate (Table 2, entry 13).
It is worth noting that the metal-free-catalyzed intramolecular
5-endo-trig cyclization can be accomplished via a tandem
sequence (eq 1). In this manner, functionalized pyrrolidine 6aa
With optimal reaction conditions in hand, the scope and
limitation of this phosphine-catalyzed intramolecular 5-endo-trig
cyclization of functionalized α-amino nitriles 4 have been
evaluated. The results are summarized in Table 2. Besides PMP
can be readily obtained from available α-amino nitrile and
MBH adduct 2a via a one-pot reaction, which greatly enhances
the efficiency of this method.
Finally, the synthetic transformations of functionalized
pyrrolidine 6 were illustrated. The results are summarized in
Scheme 3. The treatment of 6aa with AgNO3 in THF/H2O
Table 2. Scope of 5-endo-trig Cyclization of Allylic
a
Substituted α-Amino Nitriles 4
Scheme 3. Chemical Transformations
b
c
entry
R1
R2
4
t (h)
dr
2:1
yield (%)
1
2
Ph
Ph
Ph
Ph
PMP
Ph
4aa
4ba
4ca
4da
4ab
4ac
4ad
4ae
4af
2
2
96 (6aa)
96 (6ba)
1.4:1
1.9:1
3
Bn
24
24
1
33 (6ca)
d
solution afforded the unsaturated functionalized pyrrole 10 in
62% yield. Furthermore, N-heterocyclic α-amino nitrile 6aa can
be reduced to give the decyanation pyrrolidine 11 in 85% yield
in the presence of NaBH4 and EtOH.
4
nBu
5
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
3-MeOC6H4
2-BrC6H4
2-naphthyl
2-thienyl
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
1.1:1
1.5:1
1.3:1
1.1:1
1.4:1
1.2:1
2.1:1
1.2:1
88 (6ab)
92 (6ac)
85 (6ad)
88 (6ae)
90 (6af)
86 (6ag)
81 (6ah)
6
1
7
1
8
1
CONCLUSION
9
1
■
In conclusion, we have demonstrated a novel nucleophilic
phosphine-catalyzed 5-endo-trig cyclization of N-allylic sub-
stituted α-amino nitriles with the low catalyst loading, which
provided an efficient synthetic route for the preparation of 2,4-
disubstituted pyrrolidines (N-heterocyclic α-amino nitriles)
incorporating multifunctional groups under mild reaction
conditions. Furthermore, the synthesis of 2,4-disubstituted
pyrrolidine via a one-pot sequence and the subsequent
transformations of the functionalized products have also been
demonstrated, which will find potential utility in organic
synthesis.
10
4ag
4ah
4ai
1
ef
,
11
12
13
2.5
3
ef
,
72 (6ai)
d
iPr
4aj
24
a
Reaction conditions: 4 (0.2 mmol) and PBu3 (5 mol %) in solvent
b
(2.0 mL) at 0 °C. Determined by 1H NMR analysis of crude product.
c
d
e
Isolated yield. No desired product was detected. Catalyst (10 mol
f
%) was used. Run at 30 °C.
substituted α-amino nitriles 4, N-phenyl substituted α-amino
nitrile was also a suitable substrate to give the desired product 6
in good yield, whereas the reaction of the N-benzyl analogue
proceeded sluggishly and provided the product in low yield
(Table 2, entries 2 and 3). The cyclization of allylic substituted
α-amino nitrile derived from aliphatic amine did not occur
under the optimized reaction condition (Table 2, entry 4).
These results indicated that sp3-substituent (R2) would
decrease the acidity of the α-hydrogen of α-amino nitrile,
which hampered the desired 5-endo-trig ring closure. On the
basis of these, a variety of α-amino nitrile 4 with different
substituents located at the α-position of the cyano group were
investigated. The reaction proceeded well regardless of whether
the aromatic group has an electron-withdrawing or an electron-
donating group and whether the aromatic group is substituted
at the para-, meta-, or ortho-position (Table 2, entries 5−10). β-
Naphthyl and heteroaromatic subsititued α-amino nitrile can
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of Allylic Alkylation
Compound 4. To a dried reaction tube were added 1a (0.4 mmol),
DABCO (20%), toluene (4 mL), and 2 (0.52 mmol). The mixture was
stirred at 30 °C and was monitored by TLC. Upon completion, the
solvent was evaporated under reduced pressure to give the crude
products. The crude mixture was purified by column chromatography
(silica gel, EtOAc/petroleum (60−90 °C)) to provide the following
compounds.8b
Methyl 2-(((Cyano(4-methoxyphenyl)methyl)(4-methoxy-
phenyl)amino)methyl)acrylate (Table 2, 4ab). Purified by silica
gel chromatography using a mixture of EtOAc/petroleum ether = 1/15
1
as eluent, which afforded 119 mg of a colorless oil (81% yield). H
NMR (300 MHz, CDCl3) δ: 7.38 (d, J = 8.9 Hz, 2H), 7.01−6.94 (m,
2H), 6.89 (dd, J = 9.3, 2.6 Hz, 2H), 6.84−6.73 (m, 2H), 6.19−6.18(m,
1H), 5.71−5.70 (m, 1H), 5.47 (s, 1H), 4.08 (d, J = 16.6 Hz, 1H), 3.89
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(d, J = 16.6 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.72 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ: 166.7, 160.1, 156.1, 140.4, 136.3, 129.1,
127.4, 125.4, 123.0, 117.1, 114.6, 114.2, 59.7, 55.5, 55.4, 52.0, 50.7. IR
(KBr, cm−1): 2953, 2837, 2228, 1719, 1611, 1512, 1251, 1035, 834,
818. HRMS (ESI): calcd. for C21H23N2O4 ([M + H]+): 367.1652,
found: 367.1658.
1H). 13C NMR (125 MHz, CDCl3) δ: 171.9, 143.4, 139.2, 129.5,
129.1, 128.9, 125.2, 119.7, 119.2, 115.0, 64.9, 52.7, 52.1, 47.6, 40.1. IR
(KBr, cm−1): 2958, 2868, 2232, 1740, 1600, 1507, 1346, 1219, 754,
704. HRMS (ESI): calcd. for C19H19N2O2 ([M + H]+): 307.1441,
1
found: 307.1444. Minor diastereomer: H NMR (500 MHz, CDCl3)
δ: 7.50−7.48 (m, 2H), 7.38−7.32 (m, 3H), 7.15 (dd, J = 8.5, 7.5 Hz,
2H), 6.79 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.2 Hz, 2H), 4.22 (t, J = 8.7
Hz, 1H), 3.90 (t, J = 9.1 Hz, 1H), 3.74 (s, 3H), 3.61−3.54 (m, 1H),
3.02 (dd, J = 13.1, 7.0 Hz, 1H), 2.59 (dd, J = 13.0, 11.6 Hz, 1H). 13C
NMR (125 MHz, CDCl3) δ: 172.2, 143.8, 137.9, 129.4, 129.0, 128.9,
125.2, 119.5, 119.3, 115.5, 66.2, 53.1, 52.6, 48.7, 40.9. IR (KBr, cm−1):
2953, 2851, 2226, 1738, 1601, 1503, 1323, 1201, 752, 699. HRMS
(ESI): calcd. for C19H19N2O2 ([M + H]+): 307.1441, found: 307.1440.
Methyl 1-Benzyl-5-cyano-5-phenylpyrrolidine-3-carboxy-
late (Table 2, 6ca). Purified by silica gel chromatography using a
mixture of EtOAc/petroleum ether = 1/20 as eluent, which afforded
21 mg of a colorless oil (33% yield, dr = 1.8:1) as an unseparated
mixture. Major diastereomer: 1H NMR (300 MHz, CDCl3) δ: 7.77−
7.73 (m, 3H), 7.48−7.37 (m, 2H), 7.35−7.23 (m, 5H), 3.69 (s, 3H),
3.47−3.41 (m, 1H), 3.33−3.18 (m, 3H), 2.86−2.74 (m, 2H), 2.59 (dd,
Methyl 2-(((Cyano(4-bromophenyl)methyl)(4-methoxy-
phenyl)amino)methyl)acrylate (Table 2, 4ae). Purified by silica
gel chromatography using a mixture of EtOAc/petroleum ether = 1/15
1
as eluent, which afforded 80 mg of a light yellow oil (48% yield). H
NMR (500 MHz, CDCl3) δ: 7.50 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.3
Hz, 2H), 7.03−6.92 (m, 2H), 6.85−6.72 (m, 2H), 6.21 (s, 1H), 5.71−
5.70 (m, 1H), 5.44 (s, 1H), 4.10 (d, J = 16.1 Hz, 1H), 3.88 (d, J = 16.2
Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H). 13C NMR (125 MHz, CDCl3) δ:
166.6, 156.5, 139.9, 136.2, 132.6, 132.1, 129.5, 127.8, 123.6, 123.3,
116.6, 114.7, 59.9, 55.6, 52.1, 51.6. IR (KBr, cm−1): 2952, 2925, 2231,
1720, 1511, 1247, 1040, 832, 818. HRMS (ESI): calcd. for
C20H20BrN2O3 ([M + H]+): 415.0652, found: 415.0650.
Methyl 2-(((Cyano(thiophen-2-yl)methyl)(4-methoxy-
phenyl)amino)methyl)acrylate (Table 2, 4ai). Purified by silica
gel chromatography using a mixture of EtOAc/petroleum ether = 1/15
1
J = 13.6, 8.0 Hz, 1H). Minor diastereomer: H NMR (300 MHz,
1
as eluent, which afforded 63 mg of a light yellow oil (44% yield). H
CDCl3) δ: 7.77−7.73 (m, 3H), 7.48−7.37 (m, 2H), 7.35−7.23 (m,
5H), 3.74−3.69 (m, 3H), 3.72 (s, 3H), 3.47−3.41 (m, 1H), 3.03 (dd, J
= 13.9, 4.9 Hz, 1H), 2.86−2.74 (m, 1H), 2.39 (dd, J = 14.0, 11.2 Hz,
1H). 13C NMR (125 MHz, CDCl3) δ: 173.1, 137.9, 137.8, 129.2,
129.2, 128.8, 128.6, 128.3, 128.2, 127.6, 127.5, 126.7, 126.5, 126.4,
117.7, 71.4, 70.3, 54.3, 54.2, 53.7, 53.5, 52.4, 49.2, 45.3, 44.9, 39.8,
39.5. HRMS (ESI): calcd. for C20H21N2O2 ([M + H]+): 321.1598,
found: 321.1599.
NMR (500 MHz, CDCl3) δ: 7.33 (d, J = 5.0 Hz, 1H), 7.23−7.22 (m,
1H), 7.08−7.04 (m, 2H), 6.97 (dd, J = 5.0, 3.7 Hz, 1H), 6.87−6.80
(m, 2H), 6.24 (s, 1H), 5.78−5.77 (m, 1H), 5.61 (s, 1H), 4.16 (d, J =
16.6 Hz, 1H), 3.91 (d, J = 16.6 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H).
13C NMR (125 MHz, CDCl3) δ: 166.7, 156.6, 140.0, 137.5, 136.0,
127.7, 127.7, 127.3, 126.9, 123.5, 116.3, 114.7, 56.9, 55.6, 52.1, 50.3. IR
(KBr, cm−1): 2951, 2837, 2232, 1719, 1511, 1247, 1040, 837, 818.
HRMS (ESI): calcd. for C18H19N2O3S ([M + H]+): 343.1111, found:
343.1112.
General Procedure for the Synthesis of Pyrrolidine
Derivatives 6. All reactions were carried out under a nitrogen
atmosphere. To a dried reaction tube were added 4 (0.2 mmol),
CH3CN (2 mL), and PBu3 (5%) at 0 °C. The reaction was monitored
by TLC. Upon completion, the solvent was evaporated under reduced
pressure to give the crude products. The crude mixture was purified by
column chromatography (silica gel, EtOAc/petroleum (60−90 °C)) to
provide 6.
Methyl 5-Cyano-1,5-bis(4-methoxyphenyl)pyrrolidine-3-
carboxylate (Table 2, 6ab). Purified by silica gel chromatography
using a mixture of EtOAc/petroleum ether = 1/25 as eluent, which
afforded 65 mg of a colorless oil (88% yield, dr = 1.1:1). Major
1
diastereomer: H NMR (500 MHz, CDCl3) δ: 7.40−7.36 (m, 2H),
6.92−6.88 (m, 2H), 6.77−6.72 (m, 2H), 6.60−6.55 (m, 2H), 4.02 (dd,
J = 8.8, 8.1 Hz, 1H), 3.87−3.83 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H),
3.71 (s, 3H), 3.35−3.28 (m, 1H), 3.19 (dd, J = 13.0, 8.6 Hz, 1H), 2.55
(dd, J = 13.0, 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ: 172.2,
159.9, 153.4, 137.9, 131.4, 126.7, 116.9, 114.7, 114.6, 114.5, 65.4, 55.7,
55.5, 52.7, 52.6, 47.5, 40.2. IR (KBr, cm−1): 2999, 2953, 2929, 2837,
2232, 1737, 1513, 1250, 1034, 833, 820. HRMS (ESI): calcd. for
C21H23N2O4 ([M + H]+): 367.1652, found: 367.1652. Minor
Methyl 5-Cyano-1-(4-methoxyphenyl)-5-phenylpyrrolidine-
3-carboxylate (Table 2, 6aa). Purified by silica gel chromatography
using a mixture of EtOAc/petroleum ether = 1/20 as eluent, which
afforded 65 mg of a colorless oil (97% yield, dr (cis/trans) = 2/1).
1
diastereomer: H NMR (500 MHz, CDCl3) δ: 7.44−7.39 (m, 2H),
1
Major diastereomer (6aa-cis): a colorless oil. H NMR (300 MHz,
6.91−6.85 (m, 2H), 6.74−6.69 (m, 2H), 6.60−6.54 (m, 2H), 4.18 (dd,
J = 9.2, 7.3 Hz, 1H), 3.79 (s, 3H), 3.76−3.75 (m, 1H), 3.74 (s, 3H),
3.69 (s, 3H), 3.55−3.48 (m, 1H), 2.95 (dd, J = 13.1, 7.4 Hz, 1H), 2.56
(dd, J = 13.1, 10.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ: 172.7,
159.9, 153.3, 138.1, 129.8, 126.7, 119.7, 117.3, 114.7, 114.4, 66.6, 55.6,
55.5, 53.6, 52.6, 48.4, 40.5. IR (KBr, cm−1): 2953, 2924, 2224, 1737,
1513, 1250, 1177, 833, 819. HRMS (ESI): calcd. for C21H23N2O4 ([M
+ H]+): 367.1652, found: 367.1653.
CDCl3) δ: 7.52−7.44 (m, 2H), 7.44−7.31 (m, 3H), 6.79−6.70 (m,
2H), 6.62−6.52 (m, 2H), 4.05 (dd, J = 9.2, 7.6 Hz, 1H), 3.89−3.83
(m, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.39−3.28 (m, 1H), 3.23 (dd, J =
12.8, 8.5 Hz, 1H), 2.58 (dd, J = 12.8, 7.7 Hz, 1H). 13C NMR (125
MHz, CDCl3) δ: 172.1, 153.4, 139.6, 137.7, 129.4, 128.8, 125.3, 119.8,
116.7, 114.6, 65.8, 55.7, 52.8, 52.6, 47.5, 40.2. IR (KBr, cm−1): 2953,
2835, 2231, 1738, 1512, 1247, 1036, 819, 778. HRMS (ESI): calcd. for
C20H21N2O3 ([M + H]+): 337.1547, found: 337.1548. Minor
diastereomer (6aa-trans): a white amorphous solid, mp: 105−107
Methyl 5-Cyano-1-(4-methoxyphenyl)-5-p-tolylpyrrolidine-
3-carboxylate (Table 2, 6ac). Purified by silica gel chromatography
using a mixture of EtOAc/petroleum ether = 1/25 as eluent, which
afforded 65 mg of a yellow oil (92% yield, dr = 1.5:1). Major
1
°C. H NMR (300 MHz, CDCl3) δ: 7.54−7.47 (m, 2H), 7.40−7.31
(m, 3H), 6.78−6.64 (m, 2H), 6.63−6.50 (m, 2H), 4.20 (dd, J = 9.3,
7.3 Hz, 1H), 3.80 (t, J = 9.2 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.62−
3.47 (m, 1H), 2.99 (dd, J = 13.1, 7.3 Hz, 1H), 2.59 (dd, J = 13.1, 10.9
Hz, 1H). 13C NMR (125 MHz, CDCl3) δ: 172.6, 153.3, 138.0, 138.0,
129.3, 128.9, 125.3, 119.6, 117.1, 114.5, 66.9, 55.6, 53.6, 52.5, 48.4,
40.6. IR (KBr, cm−1): 2999, 2957, 2834, 2218, 1735, 1512, 1249, 1041,
819. HRMS (ESI): calcd. for C20H21N2O3 ([M + H]+): 337.1547,
found: 337.1546.
1
diastereomer: H NMR (300 MHz, CDCl3) δ: 7.35 (d, J = 8.3 Hz,
2H), 7.18 (d, J = 8.0 Hz, 2H), 6.76−6.72 (m, 2H), 6.60−6.54 (m,
2H), 4.04 (dd, J = 9.0, 7.6 Hz, 1H), 3.88−3.81 (m, 1H), 3.76 (s, 3H),
3.70 (s, 3H), 3.38−3.27 (m, 1H), 3.20 (dd, J = 12.8, 8.6 Hz, 1H), 2.55
(dd, J = 12.9, 7.7 Hz, 1H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ: 172.2, 153.4, 138.8, 137.9, 136.7, 130.1, 125.3, 119.9, 116.7, 114.6,
65.6, 55.7, 52.8, 52.6, 47.5, 40.2, 21.2. IR (KBr, cm−1): 2953, 2922,
2851, 2233, 1738, 1513, 1247, 1038, 817. HRMS (ESI): calcd. for
C21H23N2O3 ([M + H]+): 351.1703, found: 351.1703. Major
Methyl 5-Cyano-1,5-diphenylpyrrolidine-3-carboxylate
(Table 2, 6ba). Purified by silica gel chromatography using a mixture
of EtOAc/petroleum ether = 1/25 as eluent, which afforded 59 mg of
a colorless oil (96% yield, dr = 1.4:1). Major diastereomer: 1H NMR
(500 MHz, CDCl3) δ: 7.45−7.43 (m, 2H), 7.40−7.32 (m, 3H), 7.19−
7.15 (m, 2H), 6.81 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 8.0 Hz, 2H), 4.09
(dd, J = 9.1, 7.6 Hz, 1H), 3.97−3.93 (m, 1H), 3.76 (s, 3H), 3.35−3.29
(m, 1H), 3.25 (dd, J = 12.6, 8.9 Hz, 1H), 2.60 (dd, J = 12.5, 7.0 Hz,
1
diastereomer: H NMR (500 MHz, CDCl3) δ: 7.38 (d, J = 8.2 Hz,
2H), 7.16 (d, J = 8.0 Hz, 2H), 6.73−6.70 (m, 2H), 6.58−6.54 (m,
2H), 4.19 (dd, J = 9.2, 7.5 Hz, 1H), 3.78 (t, J = 9.4 Hz, 1H), 3.74 (s,
3H), 3.69 (s, 3H), 3.56−3.49 (m, 1H), 2.96 (dd, J = 13.1, 7.3 Hz, 1H),
2.56 (dd, J = 13.1, 11.0 Hz, 1H), 2.33 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ: 172.7, 153.3, 138.8, 138.1, 135.0, 130.0, 125.3, 119.7, 117.2,
4459
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114.5, 66.8, 55.6, 53.6, 52.5, 48.5, 40.6, 21.2. IR (KBr, cm−1): 2950,
2925, 2930, 2226, 1731, 1512, 1243, 1039, 820. HRMS (ESI): calcd.
for C21H23N2O3 ([M + H]+): 351.1703, found: 351.1704.
Methyl 5-(2-Bromophenyl)-5-cyano-1-(4-methoxyphenyl)-
pyrrolidine-3-carboxylate (Table 2, 6ag). Purified by silica gel
chromatography using a mixture of EtOAc/petroleum ether = 1/20 as
eluent, which afforded 71 mg of a light yellow oil (86% yield, dr =
Methyl 5-(4-Chlorophenyl)-5-cyano-1-(4-methoxyphenyl)-
pyrrolidine-3-carboxylate (Table 2, 6ad). Purified by silica gel
chromatography using a mixture of EtOAc/petroleum ether = 1/25 as
eluent, which afforded 63 mg of a light yellow oil (85% yield, dr =
1.3:1). Major diastereomer: 1H NMR (500 MHz, CDCl3) δ: 7.43 (d,
J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H),
6.56 (d, J = 9.0 Hz, 2H), 4.05 (t, J = 8.4 Hz, 1H), 3.85 (t, J = 8.6 Hz,
1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.36−3.27 (m, 1H), 3.23 (dd, J = 13.0,
8.3 Hz, 1H), 2.53 (dd, J = 13.0, 8.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ: 171.9, 153.7, 138.2, 137.5, 134.6, 129.6, 126.8, 119.4, 117.0,
114.6, 65.4, 55.7, 52.9, 52.7, 47.4, 40.2. IR (KBr, cm−1): 2954, 2923,
2851, 2228, 1738, 1513, 1248, 1038, 812. HRMS (ESI): calcd. for
C20H20ClN2O3 1 ([M + H]+): 371.1157, found: 371.1153. Minor
diastereomer: H NMR (300 MHz, CDCl3) δ: 7.50−7.42 (m, 2H),
7.37−7.31 (m, 2H), 6.74−6.70 (m, 2H), 6.57−6.51 (m, 2H), 4.19 (dd,
J = 9.3, 7.1 Hz, 1H), 3.84−3.75 (m, 1H), 3.75 (s, 3H), 3.70 (s, 3H),
3.58−3.47 (m, 1H), 2.98 (dd, J = 13.2, 7.4 Hz, 1H), 2.55 (dd, J = 13.2,
10.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ: 172.5, 153.6, 137.7,
136.7, 134.8, 129.6, 126.9, 119.2, 117.4, 114.6, 66.5, 55.6, 53.7, 52.6,
48.3, 40.6. IR (KBr, cm−1): 2955, 2924, 2853, 2224, 1738, 1513, 1248,
1038, 819. HRMS (ESI): calcd. for C20H20ClN2O3 ([M + H]+):
371.1157, found: 371.1153.
Methyl 5-(4-Bromophenyl)-5-cyano-1-(4-methoxyphenyl)-
pyrrolidine-3-carboxylate (Table 2, 6ae). Purified by silica gel
chromatography using a mixture of EtOAc/petroleum ether = 1/25 as
eluent, which afforded 73 mg of a light yellow oil (88% yield, dr =
1.1:1). Major diastereomer: 1H NMR (500 MHz, CDCl3) δ: 7.52 (d,
J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 6.78−6.72 (m, 2H), 6.60−
6.51 (m, 2H), 4.08−4.02 (m, 1H), 3.87−3.82 (m, 1H), 3.77 (s, 3H),
3.71 (s, 3H), 3.34−3.28 (m, 1H), 3.22 (dd, J = 13.1, 8.2 Hz, 1H), 2.53
(dd, J = 13.0, 8.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ: 171.9,
153.7, 138.8, 137.4, 132.6, 127.1, 123.0, 119.3, 117.0, 114.6, 65.4, 55.7,
52.9, 52.7, 47.3, 40.2. IR (KBr, cm−1): 2997, 2954, 2927, 2852, 2234,
1737, 1513, 1247, 1036, 819. HRMS (ESI): calcd. for C20H20BrN21O3
([M + H]+): 415.0652, found: 415.0647. Minor diastereomer: H
NMR (300 MHz, CDCl3) δ: 7.51−7.48 (m, 2H), 7.40−7.37 (m, 2H),
6.76−6.70 (m, 2H), 6.57−6.51 (m, 2H), 4.19 (dd, J = 9.4, 7.1 Hz,
1H), 3.82−3.77 (m, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.58−3.47 (m,
1H), 2.97 (dd, J = 13.0, 7.5 Hz, 1H), 2.55 (dd, J = 13.2, 10.6 Hz, 1H).
13C NMR (125 MHz, CDCl3) δ: 172.5, 153.6, 137.6, 137.3, 132.6,
1
1.2:1). Major diastereomer: H NMR (300 MHz, CDCl3) δ: 7.69
(dd, J = 7.6, 1.5 Hz, 1H), 7.48−7.45 (m, 1H), 7.33−7.26 (m, 1H),
7.25−7.20 (m, 1H), 6.85−6.75 (m, 2H), 6.62−6.53 (m, 2H), 4.05−
3.97 (m, 1H), 3.90−3.84 (m, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 3.30−
3.12 (m, 2H), 3.05−2.96 (m, 1H). 13C NMR (125 MHz, CDCl3) δ:
171.8, 153.4, 137.3, 135.9, 135.7, 130.6, 129.6, 127.8, 120.1, 118.5,
116.4, 114.5, 55.7, 52.6, 52.2, 44.5, 40.5. IR (KBr, cm−1): 2953, 2926,
2853, 2232, 1738, 1513, 1248, 1030, 818, 761. HRMS (ESI): calcd. for
C20H20BrN2O3 1 ([M + H]+): 415.0652, found: 415.0654. Minor
diastereomer: H NMR (500 MHz, CDCl3) δ: 7.60 (d, J = 7.6 Hz,
2H), 7.32−7.29 (m, 1H), 7.19 (td, J = 7.7, 1.6 Hz, 1H), 6.75 (d, J = 8.9
Hz, 2H), 6.54 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 7.9 Hz, 1H), 3.79 (t, J =
8.8 Hz, 1H), 3.70 (s, 3H), 3.67 (brs, 3H), 3.61−3.48 (m, 1H), 3.31−
3.07 (m, 1H), 3.01−2.85 (m, 1H). 13C NMR (125 MHz, CDCl3) δ:
172.1, 153.1, 130.5, 127.9, 114.5, 55.6, 52.5, 43.9, 40.8. IR (KBr,
cm−1): 2952, 2925, 2853, 2224, 1738, 1513, 1248, 1033, 817, 760.
HRMS (ESI): calcd. for C20H20BrN2O3 ([M + H]+): 415.0652, found:
415.0655.
Methyl 5-Cyano-1-(4-methoxyphenyl)-5-(naphthalen-2-yl)-
pyrrolidine-3-carboxylate (Table 2, 6ah). Purified by silica gel
chromatography using a mixture of EtOAc/petroleum ether = 1/25 as
eluent, which afforded 63 mg of a white amorphous solid (81% yield,
1
dr = 2.1:1). Major diastereomer: mp 119−121 °C. H NMR (500
MHz, CDCl3) δ: 8.00 (s, 1H), 7.91−7.82 (m, 3H), 7.57−7.50 (m,
3H), 6.73−6.69 (m, 2H), 6.65−6.60 (m, 2H), 4.15−4.10 (m, 1H),
3.91 (t, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.68 (s, 3H), 3.40 (p, J = 8.0 Hz,
1H), 3.43−3.37 (m, 1H), 2.65 (dd, J = 13.2, 8.1 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ: 172.1, 153.6, 137.9, 137.0, 133.4, 133.3, 129.7,
128.4, 127.9, 127.0, 127.0, 124.9, 122.5, 119.8, 117.0, 114.6, 66.2, 55.6,
53.0, 52.7, 47.4, 40.4. IR (KBr, cm−1): 2956, 2927, 2853, 2226, 1739,
1514, 1255, 1033, 818, 764. HRMS (ESI): calcd. for C24H23N2O3 ([M
+ H]+): 387.1703, found: 387.1702. Minor diastereomer: mp 121−
1
123 °C. H NMR (300 MHz, CDCl3) δ: 8.09 (d, J = 1.8 Hz, 1H),
7.87−7.81 (m, 3H), 7.55−7.47 (m, 3H), 6.71−6.66 (m, 2H), 6.63−
6.57 (m, 2H), 4.26 (dd, J = 9.3, 7.2 Hz, 1H), 3.85 (t, J = 9.2 Hz, 1H),
3.74 (s, 3H), 3.66 (s, 3H), 3.62−3.54 (m, 1H), 3.03 (dd, J = 13.2, 7.4
Hz, 1H), 2.69 (dd, J = 13.2, 10.7 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ: 172.7, 153.4, 138.0, 135.6, 133.4, 133.3, 129.7, 128.3, 127.8,
126.9, 125.1, 122.3, 120.1, 119.6, 117.2, 114.5, 67.2, 55.6, 53.7, 52.6,
48.2, 40.7. IR (KBr, cm−1): 2952, 2924, 2853, 2224, 1730, 1513, 1238,
1033, 815, 763. HRMS (ESI): calcd. for C24H23N2O3 ([M + H]+):
387.1703, found: 387.1701.
Methyl 5-Cyano-1-(4-methoxyphenyl)-5-(thiophen-2-yl)-
pyrrolidine-3-carboxylate (Table 2, 6ai). Purified by silica gel
chromatography using a mixture of EtOAc/petroleum ether = 1/25 as
eluent, which afforded 49 mg of a light yellow oil (72% yield, dr =
1.4:1.) as an unseparated mixture. Major diastereomer: 1H NMR
(300 MHz, CDCl3) δ: 7.30−7.25 (m, 1H), 7.23 (dd, J = 3.7, 1.3 Hz,
1H), 6.99 (dd, J = 5.1, 3.7 Hz, 1H), 6.79−6.70 (m, 4H), 3.99−3.93
(m, 1H), 3.78 (s, 3H), 3.77−3.73 (m, 1H), 3.72 (s, 3H), 3.53−3.42
(m, 1H), 3.23 (dd, J = 13.2, 8.9 Hz, 1H), 2.72 (dd, J = 13.3, 8.1 Hz,
1H). Minor diastereomer: 1H NMR (300 MHz, CDCl3) δ: 7.30−7.25
(m, 2H), 6.95 (dd, J = 5.1, 3.6 Hz, 1H), 6.79−6.70 (m, 4H), 4.14 (dd,
J = 9.4, 6.9 Hz, 1H), 3.77−3.73 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H),
3.53−3.42 (m, 1H), 3.05 (dd, J = 13.2, 7.4 Hz, 1H), 2.80 (dd, J = 13.2,
10.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ: 172.5, 172.0, 154.2,
154.1, 145.6, 143.2, 138.0, 137.7, 127.4, 126.9, 126.8, 126.6, 126.2,
125.2, 119.0, 118.1, 117.6, 114.6, 114.5, 114.4, 63.8, 63.0, 62.9, 55.6,
55.6, 53.6, 52.8, 52.6, 48.6, 47.7, 40.4, 40.3. HRMS (ESI): calcd. for
C18H19N2O3S ([M + H]+): 343.1111, found: 343.1112.
127.2, 122.9, 119.2, 117.4, 114.6, 66.5, 55.6, 53.7, 52.6, 48.2, 40.6. IR
(KBr, cm−1): 2952, 2923, 2852, 2225, 1737, 1513, 1248, 1036, 819.
HRMS (ESI): calcd. for C20H20BrN2O3 ([M + H]+): 415.0652, found:
415.0645.
Methyl 5-Cyano-5-(3-methoxyphenyl)-1-(4-methoxy-
phenyl)pyrrolidine-3-carboxylate (Table 2, 6af). Purified by
silica gel chromatography using a mixture of EtOAc/petroleum ether =
1/20 as eluent, which afforded 66 mg of a colorless oil (90% yield, dr =
1
1.4:1). Major diastereomer: H NMR (500 MHz, CDCl3) δ: 7.33−
7.28 (m, 1H), 7.09−7.02 (m, 2H), 6.89−6.85 (m, 1H), 6.78−6.72 (m,
2H), 6.61−6.54 (m, 2H), 4.07−4.02 (m, 1H), 3.87−3.81 (m, 1H),
3.79 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 3.38−3.30 (m, 1H), 3.21 (dd,
J = 13.1, 8.7 Hz, 1H), 2.58 (dd, J = 13.1, 8.0 Hz, 1H). 13C NMR (125
MHz, CDCl3) δ: 172.1, 160.5, 153.4, 141.4, 137.8, 130.5, 119.8, 117.5,
116.7, 114.6, 114.0, 111.2, 65.8, 55.7, 55.5, 52.8, 52.6, 47.4, 40.3. IR
(KBr, cm−1): 2924, 2851, 2230, 1738, 1514, 1248, 1040, 820. HRMS
(ESI): calcd. for C21H23N2O4 ([M + H]+): 367.1652, found: 367.1653.
Minor diastereomer: 1H NMR (500 MHz, CDCl3) δ: 7.28 (d, J = 8.0
Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.04−7.03 (m, 1H), 6.85 (dd, J =
8.2, 2.3 Hz, 1H), 6.74−6.71 (m, 2H), 6.58−6.55 (m, 2H), 4.19 (dd, J
= 9.2, 7.3 Hz, 1H), 3.80−3.78 (m, 1H), 3.77 (s, 3H), 3.74 (s, 3H),
3.70 (s, 3H), 3.56−3.49 (m, 1H), 2.98 (dd, J = 13.1, 7.4 Hz, 1H), 2.59
(dt, J = 13.0, 9.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ: 172.6,
160.4, 153.3, 139.8, 138.1, 130.5, 119.6, 117.6, 117.1, 114.5, 114.2,
111.1, 66.9, 55.6, 55.5, 53.6, 52.6, 48.3, 40.6. IR (KBr, cm−1): 2954,
2924, 2851, 2274, 1738, 1513, 1248, 1038, 818. HRMS (ESI): calcd.
for C21H23N2O4 ([M + H]+): 367.1652, found: 367.1658.
tert-Butyl 4-Cyano-2-(cyanomethyl)-4-(4-methoxyphenyl-
amino)-4-phenylbutanoate (Scheme 2, 7). To a dried flask
were added 3aa (0.2 mmol), DBU (20%), and CH3CN (2 mL) under
a nitrogen atmosphere. The mixture was stirred at 60 °C, and the
reaction was monitored by TLC. Upon completion, the resulting
mixture was concentrated under reduced pressure, and the residue was
4460
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Article
purified through column chromatography on silica gel (EtOAc/
petroleum ether = 1/10) to provide compounds 7 and 8.
(1-(4-Methoxyphenyl)-5-phenylpyrrolidin-3-yl)methanol
(Scheme 2, 11). 6aa (33.6 mg, 0.1 mmol) was dissolved in THF (0.1
mL) and treated with an EtOH solution (0.1 mL) of NaBH4 (11 mg,
0.3 mmol). After stirring at 40 °C for 2 h, the solution was treated with
1 N HCl (5 mL). The aqueous phase was extracted with EtOAc (3 × 5
mL). The combined organic phases were washed with brine (2 × 5
mL) and water (5 mL), dried over anhydrous Na2SO4, and filtered,
and the solvent was removed in vacuo. Purification by flash
chromatography (silica gel, EtOAc/petroleum = 1/3) afforded the
product 11 (23 mg, 85% yield, dr = 3.9/1) as an unseparated mixture.
Compound 7: an unseparated mixture (a colorless oil, 40 mg, 49%
yield. dr = 1.7/1). Major diastereomer: 1H NMR (300 MHz, CDCl3)
δ: 7.93−7.78 (m, 1H), 7.48−7.46 (m, 2H), 7.13−7.09 (m, 2H), 6.68−
6.65 (m, 2H), 6.54−6.51 (m, 2H), 3.71 (s, 3H), 3.37−3.18 (m, 2H),
3.11−3.03 (m, 1H), 2.93 (s, 1H), 2.88−2.81 (m, 1H), 2.32 (dd, J =
6.7, 3.8 Hz, 1H), 1.48 (s, 9H). Minor diastereomer:1H NMR (300
MHz, CDCl3) δ: 7.28−7.23 (m, 5H), 6.94−6.91 (m, 2H), 6.76−6.73
(m, 2H), 3.82 (s, 3H), 3.74−3.68 (m, 1H), 3.37−3.18 (m, 2H), 3.04−
2.97 (m, 1H), 2.93−2.91 (m, 1H), 1.37 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ: 171.4, 170.4, 167.1, 166.3, 156.4, 156.1, 143.6, 143.2, 138.2,
137.5, 130.8, 128.9, 128.9, 128.5, 127.8, 127.7, 125.8, 122.3, 120.4,
118.4, 114.7, 114.0, 83.0, 82.0, 55.6, 55.4, 40.6, 40.6, 39.2, 31.2, 28.1,
28.0, 19.5, 19.2. HRMS (ESI): calcd. for C24H28N3O3 ([M + H]+):
406.2125, found 406.2114.
tert-Butyl 4-(4-Methoxyphenylimino)-2-methyl-4-phenyl-
but-2-enoate (Scheme 2, 8). A colorless oil (29 mg, 42% yield).
1H NMR (300 MHz, CDCl3) δ: 7.85−7.82 (m, 2H), 7.47−7.30 (m,
3H), 7.21−7.20 (m, 3H),, 6.91−6.83 (m, 4H), 3.81 (s, 3H), 1.53 (d, J
= 1.3 Hz, 3H), 1.47 (s, 9H). 13C NMR (125 MHz, CDCl3) δ: 166.3,
164.2, 157.0, 143.9, 138.3, 134.9, 134.2, 130.8, 128.7, 128.1, 122.5,
114.0, 81.2, 55.6, 28.2, 15.5. IR (KBr, cm−1): 2977, 2932, 2835, 1709,
1606, 1503, 1245, 1168, 1123, 1036, 848, 746. HRMS (ESI): calcd. for
C22H26NO3 ([M + H]+): 352.1907, found: 352.1906.
1
Major diastereomer: H NMR (500 MHz, CDCl3) δ: 7.34−7.19 (m,
5H), 6.72 (d, J = 9.0 Hz, 2H), 6.45 (d, J = 8.9 Hz, 2H), 4.61 (t, J = 7.3
Hz, 1H), 3.69 (s, 3H), 3.66−3.64 (m, 3H), 3.57−3.60 (m, 1H), 2.63−
1
2.52 (m, 2H), 1.78−1.73 (m, 1H). Minor diastereomer: H NMR
(500 MHz, CDCl3) δ: 7.34−7.19 (m, 5H), 6.75 (d, J = 9.0 Hz, 2H),
6.42 (d, J = 9.0 Hz, 2H), 4.71 (d, J = 7.3 Hz, 1H), 3.84−3.81 (m, 1H),
3.70 (s, 3H), 3.66−3.64 (m, 2H), 3.18 (t, J = 8.8 Hz, 1H), 2.69−2.65
(m, 1H), 2.24−2.17 (m, 1H), 2.01−1.98 (m, 1H). 13C NMR (125
MHz, CDCl3) δ: 151.3, 144.8, 142.5, 128.8, 128.7, 126.8, 126.0, 126.0,
116.7, 115.0, 114.7, 114.5, 113.0, 106.5, 65.5, 65.1, 63.8, 63.4, 56.0,
55.9, 54.4, 52.7, 40.5, 40.2, 39.1, 38.9. HRMS (ESI): calcd. for
C18H22NO2 ([M + H]+): 284.1645, found: 284.1649.
ASSOCIATED CONTENT
* Supporting Information
■
S
tert-Butyl 2-(Cyanomethyl)-4-oxo-4-phenylbutanoate
(Scheme 2, 9). Compound 7 (37.8 mg, 0.1 mmol) was dissolved
in THF (0.68 mL) and treated with an aqueous solution (0.1 mL) of
AgNO3 (33.9 mg, 0.2 mmol).12 After stirring at room temperature for
2 h, the mixture was filtrated through a pad of Celite and the
precipitate was washed with ether (2 × 5 mL) and water (5 mL). The
aqueous phase was extracted with ether (3 × 5 mL). The combined
organic phases were washed with brine (2 × 5 mL) and water (5 mL),
dried over anhydrous Na2SO4, and filtered, and the solvent was
removed in vacuo. Purification by flash chromatography (silica gel,
EtOAc/petroleum 1/8) afforded compound 9 (21 mg, 78%) as a
NMR spectra of products 4ab, 4ae, 4ai, 6aa−6ca, 6ab−6ai, 7,
8, 9, 10, and 11, as well as X-ray structure of compound 6aa-
trans. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wliao@jlu.edu.cn.
■
Notes
1
The authors declare no competing financial interest.
colorless oil. H NMR (300 MHz, CDCl3) δ: 8.01−7.94 (m, 2H),
7.64−7.56 (m, 1H), 7.53−7.45 (m, 2H), 3.57 (dd, J = 17.7, 5.3 Hz,
1H), 3.37−3.22 (m, 3H), 2.82 (d, J = 6.2 Hz, 2H), 1.46 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ: 196.9, 170.8, 136.3, 133.8, 128.9, 128.2,
118.0, 82.6, 38.7, 37.9, 28.0, 19.4. IR (KBr, cm−1): 2979, 2922, 2851,
2248, 1730, 1685, 1369, 1156, 846, 755. HRMS (ESI): calcd. for
C16H20NO3 ([M + H]+): 274.1438, found: 274.1438.
ACKNOWLEDGMENTS
■
W.-W.L. thanks NSFC (No. 21372096) for financial support.
We also thank Mr. Jian-Ming Chen, Ms. Yan-Jing Zhang, and
Ms. Qiu-Qin Xu for the NMR and MS analytical support.
General Procedure for the Tandem Sequence (eq 1). To a
dried reaction tube were added 1a (48 mg, 0.2 mmol), DABCO
(20%), toluene (1 mL), and 2a (56 mg, 0.26 mmol) under a nitrogen
atmosphere. The mixture was stirred at 30 °C and was monitored by
TLC. Upon completion, CH3CN (1 mL) and PBu3 (20%) were added
in turn at 0 °C. After 2.5 h, the mixture was concentrated under
reduced pressure and purified by column chromatography (silica gel,
EtOAc/petroleum (60−90 °C)) to provide compound 6aa (38 mg,
56% yield).
Methyl 1-(4-Methoxyphenyl)-5-phenyl-1H-pyrrole-3-car-
boxylate (Scheme 3, 10). 6aa (33.6 mg, 0.1 mmol) was dissolved
in THF (0.68 mL) and treated with an aqueous solution (0.1 mL) of
AgNO3 (33.9 mg, 0.2 mmol). After stirring at room temperature for 5
h, the solution was filtrated through a pad of Celite and the precipitate
was washed with ether (2 × 5 mL) and water (5 mL). The aqueous
phase was extracted with ether (3 × 5 mL). The combined organic
phases were washed with brine (2 × 5 mL) and water (5 mL), dried
over anhydrous Na2SO4, and filtered, and the solvent was removed in
vacuo. Purification by flash chromatography (silica gel, EtOAc/
petroleum = 1/10) afforded compound 10 (19 mg, 62% yield) as a
colorless oil. 1H NMR (500 MHz, CDCl3) δ: 7.49 (s, 1H), 7.25−7.20
(m, 3H), 7.12−7.11 (m, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6
Hz, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H). 13C NMR (125
MHz, CDCl3) δ: 165.4, 159.0, 135.2, 132.7, 132.1, 129.1, 128.5, 128.3,
127.1, 127.1, 116.3, 114.4, 110.7, 55.6, 51.3. IR (KBr, cm−1): 2952,
2932, 2853, 1718, 1513, 1249, 1154, 1033, 837, 762, 697. HRMS
(ESI): calcd. for C19H18NO3 ([M + H]+): 308.1281, found: 308.1284.
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