Controllable regioselective construction of both functional α-methylene-β- and -γ-amino acid derivatives through an organocatalyzed tandem allylic alkylation and amination

Article abstract of DOI:10.1002/ejoc.201200642

A new controllable and regioselective allylic alkylation and amination reaction has been developed for the highly selective construction of compounds containing α-alkylidene-β-amino acid and α-methylene-γ- butyrolactam moieties. Furthermore, on the basis of this controllable strategy, multicomponent tandem reactions have also been accomplished. The subsequent transformations of the densely functionalized products have readily afforded a range of useful building blocks, which have potential utility in organic synthesis. Copyright

Full text of DOI:10.1002/ejoc.201200642

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FULL PAPER
DOI: 10.1002/ejoc.201200642
Controllable Regioselective Construction of Both Functional α-Methylene-β-
and -γ-amino Acid Derivatives Through an Organocatalyzed Tandem Allylic
Alkylation and Amination
Feng Pan,[a] Jian-Ming Chen,[a] Tian-You Qin,[a] Sean Xiao-An Zhang,[a,b] and
Wei-Wei Liao*[a]
Keywords: Synthetic methods / Amino nitriles / Regioselectivity / Tandem reaction / Alkylation / Solvent effects
A new controllable and regioselective allylic alkylation and
amination reaction has been developed for the highly selec-
tive construction of compounds containing α-alkylidene-β-
amino acid and α-methylene-γ-butyrolactam moieties.
Furthermore, on the basis of this controllable strategy, multi-
component tandem reactions have also been accomplished.
The subsequent transformations of the densely function-
alized products have readily afforded a range of useful build-
ing blocks, which have potential utility in organic synthesis.
tile intermediates in synthetic chemistry and are also pro-
posed as being prebiotic precursors to porphyrins, corrins,
nicotinic acids, and nucleic acids.[6] During a survey of the
literature, we noted that despite the synthetic importance of
α-amino nitriles as carbon pronucleophiles in organic syn-
thesis,[6,7] little attention has been paid to the potential syn-
thetic utilities of α-amino nitriles as dipronucleophiles,
given the fact that nitrogen nucleophilic centers of α-amino
nitriles can display potential nucleophilicity as well. To the
best of our knowledge, the construction of the above-men-
tioned multifunctionalized compounds by utilizing α-amino
nitriles that may act as dipronucleophiles through a control-
lable regioselective strategy with a metal-free catalyst is un-
exploited.[7]
Introduction
β-Amino and γ-amino carbonyl compounds bearing an
α-alkylidene group are versatile building blocks for phar-
maceutical candidates and other important com-
pounds.[1a–1i,2] For example, β-amino carbonyl compounds
containing an α-alkylidene group are widely used in the
syntheses of medicinal compounds and natural products.[1]
Likewise, variations of the latter, such as compounds con-
taining the α-methylene-γ-lactam moiety, display a wide
variety of biological activities such as cytotoxicity[2a–2e] and
antitumor[2f] activities as well as act as an inhibitor of pro-
teasome,[2g–2h] and they exhibit less cytotoxic activity than
the corresponding α-alkylidene-γ-butyrolactones. Given
their excellent activities as potential drug candidates as well
as their versatile synthetic potential, the development of ef-
ficient methods to construct β- and γ-amino acid derivative
compounds bearing an α-alkylidene group has received
much attention over several decades.[1,3,4,5a–5j]
Results and Discussion
As part of our efforts to develop new multicomponent
reactions for the rapid buildup of molecular complexity, we
recently reported on the metal-free multicomponent tan-
dem reactions of aldehydes or amines, cyanides sources, and
MBH (Morita–Baylis–Hillman) adducts to construct highly
functionalized compounds.[8] Encouraged by the high effi-
ciency and versatile synthetic potential of these transforma-
tions, we envisaged that it would be highly attractive if
Although a number of methods have been developed, an
efficient synthetic route based on a facile and unified ap-
proach starting from readily available chemicals to access
both α-alkylidene-β-amino acid derivatives and α-methyl-
ene-γ-butyrolactams containing multiple functional groups
is still unavailable. α-Amino nitriles are exceptionally versa-
[a] Department of Organic Chemistry, College of Chemistry, Jilin changing the reaction parameters led to a switch in the regi-
University,
ochemical course from a C-allylic alkylation to N-allylic
2699 Qianjin Street, Changchun 130012, China
amination reaction. Therefore, a new controllable regiose-
lective C- and N-allylic alkylation reaction promoted by an
organocatalyst would be established by utilizing a Lewis
base catalyzed direct allylic substitution of a Morita–
Baylis–Hillman adduct with an appropriate dipronucleo-
phile,[5] which may provide a unique and facile approach
to access both highly functional α-methylene-β-amino acid
Fax: +86-431-85153812
E-mail: wliao@jlu.edu.cn
Homepage: http://supramol.jlu.edu.cn/people/zhangxiaoan/
teacher_liao_english.html
[b] State Key Laboratory of Supramolecular Structure and
Materials, College of Chemistry, Jilin University,
2699 Qianjin Street, Changchun, 130012, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200642.
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W.-W. Liao et al.
FULL PAPER
derivatives and α-methylene-γ-butyrolactams. In this proto- accord with our previous study, the desired C-allylic alkyl-
col, the allylic substitutions of α-amino nitrile I, bearing ation reaction proceeded well in polar solvents such as
both reactive carbon and nitrogen pronucleophilic centers, CH3CN and DMF (dimethylformamide, see Table 1, En-
with MBH adducts may afford targeted amino acid deriva- tries 7 and 8). α-Methylene-γ-butyrolactam 5, which had
tives in a switchable way by modulating the reaction param- been isolated by using an α-amino nitrile substituted with
eters. Meanwhile, the ready manipulation of the α-amino the N-phenyl or PMP (p-methoxyphenyl) group was not ob-
nitrile moiety and other functional groups of II or III and served.[8b] In toluene, decreasing the amount of 2a slightly
the application of robust and well-tested methodologies to increased the yield of 4a, but on the other hand, the yield
elaborate the core structure of II or III may eventually re- of 3a was lowered in CH3CN (see Table 1, Entries 5, 9, 8,
sult in the discovery of new bioactive compounds with syn- and 10). Other N-based Lewis bases such as DMAP [4-
thetic diversity. Herein, we first demonstrated a new con- (dimethylamino)pyridine] and DBU (1,8-diazabicyclo[5.4.0]
trollable regioselective allylic alkylation and amination reac- undec-7-ene) showed poor results (see Table 1, Entries 11
tion for the construction of highly functionalized β- and γ- and 12).
amino acid derivatives (Scheme 1). As will be demonstrated,
these structures are predisposed for functionalization and
may be regarded as common precursors for a range of more
Table 1. Solvent effects on controllable allylic substitution reac-
tion.[a]
complex structures, which are built around the function-
alized α-amino nitrile or γ-lactam core.
Entry Catalyst
Solvent
t [h] 4a/3a[b]
Yield [%][c]
1
2
3
4
5
6
7
8
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMAP
ClCH2CH2Cl
CHCl3
tetrahydrofuran 4.5 Ͼ20:1
5
5
Ͼ20:1
Ͼ20:1
60 (4a)
76 (4a)
56 (4a)
80 (4a)
80 (4a)
56 (4a), 35 (3a)
68 (3a)
77 (3a)
85 (4a)
benzene
PhCH3
1,4-dioxane
DMF
CH3CN
PhCH3
CH3CN
PhCH3
CH3CN
PhCH3
CH3CN
5
5
Ͼ20:1
Ͼ20:1
4.5 1.6:1
4.5
4.5
4.5 Ͼ20:1
4.5
[d]
–
–
[d]
Scheme 1. Strategy for controllable tandem allylic alkylation and
amination.
9[e]
10[e]
11[e]
[d]
–
74 (3a)
9.5 1.1:1
24 (4a), 21 (3a)
11 (3a)
A recent study in our laboratory uncovered that α-amino
nitriles 1 with N-aromatic substituents can react with MBH
adduct 2a in acetonitrile to give rise to γ-amino acid deriva-
tives in good yield.[8b] To develop the switchable strategy as
shown in Scheme 1, efforts first focused on the development
of the N-allylic alkylation of α-amino nitriles. We found
that enhanced N-regioselectivity was observed by using α-
amino nitrile 1a with the N-benzyl substituent. Therefore,
our initial investigation examined the reaction between
MBH carbonate 2a and α-amino nitrile 1a, which can be
[d]
11
11
11
–
12[e]
DBU
–
–
[f]
[f]
[f]
–
28 (3a)
[a] Reactions were performed with 1b (0.2 mmol), 2a (0.3 mmol),
molecular sieves (4 Å), and catalyst (20 mol-%) in solvent (2.0 mL)
at 30 °C. [b] Determined by 1H NMR analysis. [c] Isolated yield.
1
Yield of 3a was determined by H NMR analysis. [d] No N-allylic
alkylation product was observed. [e] 2a (0.24 mmol) was added.
[f] The trace amount of product was observed by TLC.
With the optimal conditions established, we next evalu-
readily prepared from a Strecker reaction [benzylamine, ated the effects of the N-substituents of α-amino nitriles
benzaldehyde, and TMSCN (trimethyl cyanide)] in the pres- 1 on the controllable allylic substitution reactions. These
ence of 20 mol-% DABCO (1,4-diazabicyclo[2.2.2]octane, substituents may influence the N-nucleophilic reactivities of
see Table 1).[9b] A wide range of solvents were screened. Al- dipronucleophiles 1. It turned out that the successful
though the substitution reactions took place in all of the switchable outcome of allylic alkylation reactions relied
screened solvents, the regioselectivity of this reaction upon the substituents on the nitrogen of α-amino nitriles 1.
showed strong solvent dependence. N-allylic alkylations Besides 1a, the regioselectivities of the allylic reaction was
were liable to occur in less polar solvents. In particular, also regulated by employing different N-substituted α-
when toluene and benzene were employed as solvents, the amino nitriles 1. For example, the reactions between α-
desired N-allylic product 4a was observed dominantly. In amino nitriles 1b with N-aliphatic substituents and 2a in a
2
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Construction of α-Methylene-β- and -γ-amino Acid Derivatives
selected solvent system provided C- and N-allylic products This reveals a dramatic dependence on the ΔpKa between
with good to high regioselectivity (see Table 2, Entry 2). the conjugate acid of the leaving group (tert-butoxide
However, with regard to N-aromatic substituents, the elec- anion) and the pronucleophile (α-hydrogen of α-amino ni-
tronic properties of the aromatic system of the amine sub- triles). MBH adducts such as ethyl ester 2b were applied
stituent in dipronucleophiles 1c–1e greatly influenced the to this switchable allylic substitution reaction and provided
regioselectivity of the allylic reactions. In toluene, α-amino desired products 3aЈ and 4aЈ in high yield with excellent
nitrile 1d and 1c, generated from anilines with electron- regioselectivity (see Table 3, Entry 2). However, the substi-
withdrawing and neutral substituents at the para position, tution reaction in CH3CN of 1e with MBH adduct 2c,
gave the regioisomers 3 and 4 with poor selectivity (see which may create adjacent quaternary and tertiary centers,
Table 2, Entries 3 and 4, Condition B), despite the fact that gave N-allylic alkylation product 4aЈЈ in low yield instead
in acetonitrile, the C-allylic alkylation products were exclu- of the desired C-allylic alkylation product 3aЈЈ (see Table 2,
sively obtained in good yield (see Table 2, Entries 3 and 4, Entry 3, Condition A). However, the reaction in toluene
Condition A). In contrast to its electron-withdrawing or provided the regioisomers 3aЈЈ and 4aЈЈ with poor selectiv-
neutral group analogy in 1d and 1c, the reaction of α-amino ity (see Table 2, Entry 3, Condition B).[10]
nitrile 1e with an electron-donating substituent ac-
Table 3. Controllable substitution reaction of α-amino nitrile 1 with
MBH adducts 2.[a]
complished switchable regioselective N- and C-allylic alkyl-
ations in a selected solvent system (see Table 2, Entry 5).
When α-amino nitrile 1f with a more electron-withdrawing
substituent was employed, the N-allylic product was ob-
tained exclusively in moderate yield (see Table 2, Entry 6).
Table 2. Effects of N-substituents of α-amino nitrile 1 on controlla-
ble allylic substitution reaction (R1 = Ph).[a]
En-
try
1
R1 R2
2
Condition t [h]
3/4[b] Yield [%][c]
[e]
1
2
3
1g
1a
1e
iPr PMP 2a
A[d]
B
17
24
4
4
15
32
–
53 (4g)
82 (4g)
71 (3aЈ)
[e]
2a
2b
2b
–
–
Entry R2
1
Condition
t [h] (3 + 5)/4[b] Yield [%][c]
[e]
Ph Bn
A[d]
B
[e]
1
2
3
4
5
6
Bn
1a
A[d]
B
4.5
4.5
–
74 (3a)[f]
85 (4a)
–
Ͼ20:1 88 (4aЈ)
[e]
Ͻ1:20
7:1
Ph PMP 2c
A
B
–
18 (4aЈЈ)
[g]
nBu
Ph
1b
1c
A[d]
B
2c
1.7:1 47 (3aЈЈ)
27 (4aЈЈ)
3.5
3
3
3
9
3.5
3.5
2.5
2.5
Ͻ1:20
70 (4b)
[e]
A
B
A
B
–
49 (3c), 45 (5c)
44 (3c), 33 (4c)[f]
86 (3d), 8 (5d)
71 (3d), 18 (4d)
58 (3e), 33 (5e)
84 (4e)
[a] Condition A: reactions were performed with 1 (0.2 mmol), 2
(0.26 mmol), and DABCO (20 mol-%) in CH3CN (2.0 mL) at
30 °C. Condition B: reactions were performed with 1 (0.2 mmol),
2 (0.24 mmol), molecular sieves (4 Å), and DABCO (20 mol-%) in
toluene (2.0 mL) at 30 °C. [b] Determined by 1H NMR analysis or
1.3:1
[e]
4-ClC6H4 1d
–
3.9:1
[e]
PMP
Ts
1e
1f
A
–
B
Ͻ1:20
1
isolated yield. [c] Isolated yield. Yield of 3a was determined by H
A[d]
B
–
–
–
[h]
NMR analysis. [d] Molecular sieves (4 Å) were added. [e] No de-
[i]
68 (4f)
sired C-allylic alkylation product was observed.
[a] Condition A: reactions were performed with 1b (0.2 mmol), 2a
(0.26 mmol), and DABCO (20 mol-%) in CH3CN (2.0 mL) at
30 °C. Condition B: reactions were performed with 1b (0.2 mmol),
2a (0.24 mmol), molecular sieves (4 Å), and DABCO (20 mol-%) in
toluene (2.0 mL) at 30 °C. [b] Determined by 1H NMR analysis
or isolated yield. [c] Isolated yield. [d] Molecular sieves (4 Å) were
added. [e] N-allylic alkylation product was not observed. [f] Deter-
mined by H NMR analysis. [g] No calculation because of the re-
sulting inseparable mixture. [h] No desired product was observed.
[i] No desired C-allylic alkylation product was observed.
Encouraged by the results achieved above, we next inves-
tigated the scope and generality of this metal-free controlla-
ble allylic amination reaction in toluene, which can provide
general access to β-amino acid derivatives bearing an α-
alkylidene group.
Considering that both α-amino nitriles 1a and 1e with
N-benzyl and N-PMP substituents, respectively, can provide
a potential handle for further elaboration because of their
1
In addition, the pKa value of the α-hydrogen in α-amino facile deprotection[11] as well as provide the desired N- and
nitriles 1 played an important role in regulating the regiose- C-allylic products with high regioselecivity in a controllable
lectivity of the allylic alkylation reactions. When α-amino way, we evaluated a variety of α-amino nitriles 1 with both
nitriles 1 with aliphatic substitutents were employed, the the N-benzyl and N-PMP substituents. The results are sum-
substitution reactions afforded only N-allylic products, irre- marized in Table 4. First, the allylic amination reactions
spective of the reaction conditions (see Table 3, Entry 1). were examined for a spectrum of aromatic- and heteroaro-
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matic-substituted α-amino nitriles 1 with the N-benzyl sub- Table 4. Synthesis of densely functionalized β-amino acid deriva-
tives 4 (R = Me).[a]
stituent. Gratifyingly, the reactions took place efficiently in
good to excellent yields for all of the investigated α-amino
nitriles 1 (see Table 4, Entries 1–7). Aromatic groups with
various substituents at the α-position to the cyano group
were well tolerated and furnished 4 in good to high yields
with excellent regioselectivities (see Table 4, Entries 2–5), ir-
respective of the effects from steric hindrance and the elec-
tronic properties of the substituents. For example, α-amino
nitriles 1 generated from aromatic aldehydes with electron-
withdrawing or -donating substituents at the para position
provided N-allylic products in good yields and high regio-
selectivities (see Table 4, Entries 2 and 3). α-Amino nitriles
Entry
1
R1
R2
t [h]
4/3[b]
Yield [%][c]
1 with an ortho-substituted aryl group, potentially causing
a steric hindrance effect, also resulted in a good yield and
regioselectivity (see Table 4, Entry 5). Under the standard
reaction conditions, the treatment of heteroaromatic-substi-
tuted α-amino nitriles 1af with MBH adduct 2a gave rise to
similar results (see Table 4, Entry 7). However, with regard
to the N-PMP-substituted α-amino nitriles 1, the regioselec-
tivities of the allylic amination reactions seemed to depend
strongly on the substitution patterns of the aromatic system
for R1. The reaction of 1eb, with an electron-withdrawing
group at the para position of R1, gave the desired product
with low regioselectivity (see Table 4, Entry 10). In ad-
dition, the reaction with 2-naphthyl-substituted α-amino ni-
trile 1ee also resulted in a low selectivity (Table 4, Entry 13).
The substrate with an ortho substituent on the aryl group
provided high selectivity, albeit in slightly low yield (see
Table 4, Entry 12).
During the course of the investigation of the C-allylic
substitution reaction of α-amino nitrile 1e with MBH ad-
ducts 2a, we succeeded in isolating in polar solvent systems
α-methylene-γ-butyrolactam 5e, which could be generated
from the desired product 3e in the presence of base. In our
previous study, we found that α-methylene-γ-butyrolactam
5e could be readily synthesized from 3e in the presence of
catalytic amount of DBU.[8b] Further investigations have
shown that a variety of α-methylene-γ-butyrolactams 5 can
be directly accessed by submitting 1, 2, and DABCO
(20 mol-%) in CH3CN, followed by the addition DBU
(20 mol-%) in a sequential way. The results are summarized
in Table 5. The cyclization of the N-benzyl substituent of
3a gave a trace amount of 5a in the presence of DBU
(20 mol-%), whereas the treatment of 3a with pTsOH
(20 mol-%) in toluene at 80 °C furnished 5a in 52% yield.[8b]
To the best of our knowledge, this surprising solvent ef-
fect, by which the regiochemical preference of N-monosub-
stituted α-amino nitriles for C- and N-allylic alkylation is
inverted in the absence of a metal ion, is unprecedented in
the literature. The reactions of metallated N-monosubsti-
tuted α-amino nitriles have a preference for C-nucleophilic
centers.[12] For the N-monosubstituted α-amino nitriles ex-
amined in our study, we propose that the N-allylic alkyl-
ation is favored in the presence of the metal-free tert-butox-
1
2
3
4
5
6
7
8
1a
Ph
4-MeC6H4
4-ClC6H4
Bn
Bn
Bn
4.5
3.5
2.5
3.5
2.5
3
Ͼ20:1 85 (4a)
Ͼ20:1 82 (4aa)
Ͼ20:1 80 (4ab)
Ͼ20:1 88 (4ac)
Ͼ20:1 79 (4ad)
Ͼ20:1 90 (4ae)
Ͼ20:1 76 (4af)
Ͼ20:1 84 (4e)
Ͼ20:1 89 (4ea)
1aa
1ab
1ac
1ad
1ae
1af
1e
3-MeOC6H4 Bn
2-BrC6H4
2-naphthyl
2-furyl
Ph
4-MeC6H4
4-ClC6H4
3-MeOC6H4 PMP
2-BrC6H4
2-naphthyl
Bn
Bn
Bn
PMP 3.5
PMP 5.5
3
9
1ea
1eb
1ec
1ed
1ee
10
11
12
13
PMP
3
7
6.2:1
13:1
75 (4eb)
84 (4ec)
PMP 16
PMP
Ͼ20:1 61 (4ed)
7.6:1 76 (4ee)
7
[a] Reactions were performed with 1 (0.2 mmol), 2a (R2 = Bn,
0.24 mmol; R2 = PMP, 0.26 mmol), molecular sieves (4 Å), and
DABCO (20 mol-%) in toluene (2.0 mL) at 30 °C. [b] Determined
1
by H NMR analysis or isolated yield. [c] Isolated yield.
Table 5. Synthesis of densely functionalized α-methylene-γ-butyro-
lactams 5 through a one-pot reaction.[a]
Entry
1
R1
5
Yield [%][b]
1
2
3
4
5
6
7
1e
Ph
5e
89
74
91
85
35
77
41
1ea
1eb
1ec
1ed
1ee
1ef
4-MeC6H4
4-ClC6H4
3-MeOC6H4
2-BrC6H4
2-naphthyl
2-furyl
5ea
5eb
5ec
5ed
5ee
5ef
[a] Reactions were performed with 1 (0.2 mmol), 2a (0.26 mmol),
and DABCO (20 mol-%) in CH3CN (2.0 mL) at 30 °C for 3–4 h.
Subsequently, after DBU (20 mol-%) was added, the mixture was
warmed to 60 °C for about 13 h. [b] Isolated yield.
ide formed in situ in a less polar solvent to subsequently a polar aprotic solvent, which affords C-allylic alkylation
give N-allylic alkylation products 4. However, the formation products 3. Moreover, the electronic properties and steric
of the carbanion from α-amino nitriles is prone to occur in hindrance effects of the substituent system of N-nucleo-
4
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Construction of α-Methylene-β- and -γ-amino Acid Derivatives
philic and C-nucleophilic centers of α-amino nitriles also tuted product 10, whereas the treatment of the C-allylic
have a great effect on the regioselectivity of the examined product with a different base furnished several five-mem-
allylic reactions.
bered N-heterocyclic derivatives. Besides α-methylene-γ-
It is worth noting that the controllable allylic substitution butyrolactam 5e,[8b] the cyclization of 3 also gave α-methyl-
reactions can be accomplished through a multicomponent α,β-unsaturated-γ-butyrolactam 7 in 80% yield and pyrroli-
tandem Strecker–allylic-alkylation–cyclization reaction dine derivative 8 in 61% yield in the presence of KOtBu
(SAAC, see Scheme 2).[13] In this manner, both β-amino and K2CO3, respectively. Furthermore, the treatment of 3e
acid derivatives 4 bearing α-alkylidene group and α-methyl- with AgNO3 in a THF (tetrahydrofuran)/H2O solution af-
ene-γ-butyrolactam 5 can be readily obtained from an avail- forded the β,γ-unsaturated ketone 6 in 78% yield.[8b] The
able aldehyde, amine, and MBH adduct 2a through a one- deprotection of the N-PMP protecting group of α-methyl-
pot reaction, which greatly enhances the efficiency of this ene-γ-butyrolactam 5e produced compound 9, which may
method.
serve as an effective scaffold for a large variety of modula-
tions through the N-substitution of α-methylene-γ-lactams
(see Scheme 3).[8b]
Conclusions
In conclusion, we have demonstrated a metal-free, con-
trollable, regioselective allylic alkylation and amination re-
action with a MBH adduct, which provided an efficient
synthetic route for the preparation of α-methylene-β-amino
acid derivatives and α-methylene-γ-butyrolactams, incorpo-
rating multiple functional groups with high selectivity
through an facile and unified approach. This new switch-
able allylic alkylation reaction is solvent and substituent de-
Scheme 2. Controllable regioselective allylic substitution through a
multicomponent tandem reaction.
Finally, the synthetic utilities of the allylic alkylation and pendent. In less polar solvents such as toluene, the α-amino
amination products were illustrated. Significant features of nitrile with N-benzyl and N-PMP substituents provided N-
the allylic-substituted products, resulting from the control- allylic alkylation products. By contrast, C-allylic alkylation
lable reactions, are embedded in the C- or N-based pronu- products were predominant in polar solvents such as
cleophilic reactive centers, which can be involved in further CH3CN. The broad scope and versatility of the process was
chemical transformations and deliver synthetic diversity. demonstrated by the introduction of a variety of aryl, all-
The results are summarized in Scheme 3. For example, N- ylic, and heteroaryl substituents at multiple sites in the
allylic-substituted product 4e underwent further Lewis base densely functionalized products. In addition, the organocat-
catalyzed allylic substitution and provided diallyl-substi- alytic multicomponent tandem reactions based on this con-
Scheme 3. Synthetic diversity of allylic substitution adducts.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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W.-W. Liao et al.
FULL PAPER
chromatography on silica gel (EtOAc/petroleum ether, 1:12) to af-
ford the product (30 mg, 49%) as a white solid. 1H NMR
(300 MHz, CDCl3): δ = 7.61–7.58 (m, 2 H), 7.42–7.34 (m, 3 H),
7.11–7.06 (m, 2 H), 6.76–6.71 (m, 1 H), 6.52–6.47 (m, 2 H), 6.46–
6.44 (m, 1 H), 5.86 (br., 1 H), 5.73–5.72 (m, 1 H), 3.82 (s, 3 H),
3.08 (d, J = 13.8 Hz, 1 H), 3.01 (d, J = 13.8 Hz, 1 H) ppm.
trollable strategy were also achieved. Finally, the synthetic
applications of the functionalized allylic alkylation and am-
ination products were shown to readily afford a range of
useful building blocks, which will find potential utility in
organic synthesis.
4-Methylene-5-oxo-1,2-diphenylpyrrolidine-2-carbonitrile (5c): See
Table 2.[8b] The crude product was purified by column chromatog-
raphy on silica gel (EtOAc/petroleum ether = 1:8) to afford the
product (25 mg, 45%) as a white solid. 1H NMR (300 MHz,
CDCl3): δ = 7.49–7.45 (m, 2 H), 7.41–7.37 (m, 3 H), 7.31–7.20 (m,
5 H), 6.38 (t, J = 2.6 Hz, 1 H), 5.66 (t, J = 2.3 Hz, 1 H), 3.75 (dt,
J = 17.0, 2.4 Hz, 1 H), 3.32 (dt, J = 17.0, 2.7 Hz, 1 H) ppm.
Experimental Section
General Procedure for Controllable Allylic Substitution Reaction of
α-Amino Nitrile 1 with MBH Adduct 2: All reactions were carried
out under a nitrogen atmosphere. Condition A: To a dried flask
were added 1 (0.2 mmol), DABCO (20 mol-%), CH3CN (2 mL),
and 2 (0.26 mmol). The mixture was stirred at 30 °C, and the reac-
tion was monitored by TLC. Upon completion, the resulting mix-
ture was concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel (EtOAc/petroleum
ether) to provide 3. Condition B: To a dried flask were added 1
(0.2 mmol), DABCO (20 mol-%), MS (molecular sieves, 4 Å,
80 mg), toluene (2 mL), and 2 (0.24 mmol). The mixture was stirred
at 30 °C and was monitored by TLC. Upon completion, the mix-
ture was filtered, and the solvent was removed under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (EtOAc/petroleum ether) to provide compound 4.
Methyl 4-(4-Chlorophenylamino)-4-cyano-2-methylene-4-phenylbut-
anoate (3d): See Table 2.[8b] The crude product was purified by col-
umn chromatography on silica gel (EtOAc/petroleum ether, 1:12)
to afford the product (59 mg, 86%) as a white solid. 1H NMR
(300 MHz, CDCl3): δ = 7.57–7.54 (m, 2 H), 7.43–7.35 (m, 3 H),
7.03 (d, J = 8.7 Hz, 2 H), 6.46 (s, 1 H), 6.42 (d, J = 8.6 Hz, 2 H),
6.07 (br., 1 H), 5.74 (s, 1 H), 3.83 (s, 3 H), 3.06 (d, J = 13.9 Hz, 1
H), 2.98 (d, J = 13.9 Hz, 1 H) ppm.
Methyl 2-({(4-Chlorophenyl)[cyano(phenyl)methyl]amino}methyl)ac-
rylate (4d): See Table 2. According to the general procedure de-
scribed above (silica gel, EtOAc/petroleum ether, 1:13), the title
Methyl 2-({Benzyl[cyano(phenyl)methyl]amino}methyl)acrylate (4a):
See Table 2. The crude product was purified by column chromatog-
raphy on silica gel (EtOAc/petroleum ether, 1:13) to afford the
product (55 mg, 85%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ = 7.53 (d, J = 6.7 Hz, 2 H), 7.41–7.28 (m, 8 H), 6.31 (s,
1 H), 5.92 (s, 1 H), 4.97 (s, 1 H), 3.96 (d, J = 13.6 Hz, 1 H), 3.69
(s, 3 H), 3.52 (d, J = 14.8 Hz, 1 H), 3.45 (d, J = 13.6 Hz, 1 H),
3.31 (d, J = 15.0 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 166.76, 137.30, 137.22, 133.62, 128.91, 128.87, 128.77, 128.68,
127.83, 127.75, 127.51, 115.52, 57.64, 55.46, 51.88, 51.46 ppm. IR
compound was prepared as an inseparable mixture of 4d (18%
1
yield based on H NMR analysis) and ether 11 (4d/11, 2:1).[14] 1
H
NMR (300 MHz, CDCl3): δ = 7.50–7.38 (m, 5 H), 7.24–7.19 (m, 2
H), 6.89–6.84 (m, 2 H), 6.27–6.25 (m, 1 H), 5.76 (s, 1 H), 5.73–5.71
(m, 1 H), 4.18 (d, J = 17.7 Hz, 1 H), 4.07 (d, J = 17.8 Hz, 1 H),
3.75 (s, 3 H) ppm. HRMS (ESI): calcd. for C19H18ClN2O2 [M +
H]+ 341.1051; found 341.1050.
Methyl 4-Cyano-4-(4-methoxyphenylamino)-2-methylene-4-phenyl-
butanoate (3e): See Table 2.[8b] The crude product was purified by
column chromatography on silica gel (EtOAc/petroleum ether,
1:13) to afford the product (39 mg, 58%) as a white solid. 1H NMR
(300 MHz, CDCl3): δ = 7.61–7.57 (m, 2 H), 7.42–7.34 (m, 3 H),
6.68–6.65 (m, 2 H), 6.47–6.44 (m, 2 H), 6.43–6.41 (m, 1 H), 5.67–
5.66 (m, 1 H), 5.42 (br., 1 H), 3.80 (s, 3 H), 3.68 (s, 3 H), 3.04 (s,
2 H) ppm.
(KBr): ν = 3088, 3058, 3029, 3001, 2951, 2926, 2833, 2224, 1712,
˜
1634, 1494, 1451, 1159, 823, 742, 699 cm–1. HRMS (ESI): calcd.
for C20H21N2O2 [M + H]+ 321.1598; found 321.1594.
Methyl
4-(Benzylamino)-4-cyano-2-methylene-4-phenylbutanoate
(3a): See Table 2.[8b] According to the general procedure described
above (silica gel, EtOAc/petroleum ether, 1:13), the title compound
was prepared as an inseparable mixture of 3a (74% yield based on
1H NMR analysis) and ether 11 (3a/11, 5.3:1).[14] 1H NMR
(300 MHz, CDCl3): δ = 7.66–7.63 (m, 2 H), 7.43–7.24 (m, 8 H),
6.28 (d, J = 1.0 Hz, 1 H), 5.46–5.44 (m, 1 H), 3.86 (dd, J = 12.6,
4.1 Hz, 1 H), 3.63 (s, 3 H), 3.56–2.52 (m, 1 H), 3.14 (dd, J = 13.5,
0.8 Hz, 1 H), 2.94 (dd, J = 13.5, 0.8 Hz, 1 H), 2.16 (m, 1 H) ppm.
Methyl 2-({[Cyano(phenyl)methyl](4-methoxyphenyl)amino}methyl)-
acrylate (4e): See Table 2. The crude product was purified by col-
umn chromatography on silica gel (EtOAc/petroleum ether, 1:13)
to afford the product (57 mg, 84%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.51–7.48 (m, 2 H), 7.42–7.36 (m, 3 H),
7.01–6.98 (m, 2 H), 6.83–6.79 (m, 2 H), 6.22–6.19 (m, 1 H), 5.74–
5.72 (m, 1 H), 5.54 (s, 1 H), 4.12 (dt, J = 16.8, 1.2 Hz, 1 H), 3.90
(dt, J = 16.5, 1.5 Hz, 1 H), 3.76 (s, 3 H), 3.73 (s, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.45, 155.85, 140.11, 135.97,
133.24, 128.91, 128.74, 127.53, 127.36, 122.68, 116.70, 114.38,
Methyl 2-({Butyl[cyano(phenyl)methyl]amino}methyl)acrylate (4b):
See Table 2. The crude product was purified by column chromatog-
raphy on silica gel (EtOAc/petroleum ether, 1:13) to afford the
product (40 mg, 70%) as a light yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 7.52–7.49 (m, 2 H), 7.41–7.35 (m, 3 H), 6.27 (t, J =
1.2 Hz, 1 H), 5.86–5.85 (m, 1 H), 5.03 (s, 1 H), 3.74 (s, 3 H), 3.58
(dt, J = 15.1, 1.6 Hz, 1 H), 3.24 (d, J = 14.7 Hz, 1 H), 2.59–2.42
(m, 2 H), 1.51–1.41 (m, 2 H), 1.37–1.11 (m, 2 H), 0.81 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.90,
137.59, 133.90, 128.73, 128.65, 127.73, 127.19, 115.98, 58.36, 52.37,
60.09, 55.32, 51.80, 50.71 ppm. IR (KBr): ν = 2996, 2591, 2834,
˜
1718, 1635, 1515, 1193, 1137, 816, 700 cm–1. HRMS (ESI): calcd.
for C20H20N2NaO3 [M + Na]+ 359.1366; found 359.1359.
Methyl 2-({N-[Cyano(phenyl)methyl]-4-methylphenylsulfonamido}-
methyl)acrylate (4f): See Table 2. The crude product was purified
by column chromatography on silica gel (EtOAc/petroleum ether,
1:13) to afford the product (52 mg, 68%) as a white solid; m.p. 92–
51.86, 50.56, 29.62, 20.10, 13.79 ppm. IR (KBr): ν = 3089, 3063,
˜
3033, 2957, 2872, 2227, 1724, 1635, 1495, 1451, 1156, 739,
697 cm–1. HRMS (ESI): calcd. for C17H23N2O2 [M + H]+ 287.1754;
found 287.1750.
1
94 °C. H NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 8.3 Hz, 2 H),
7.47–7.36 (m, 7 H), 6.21 (s, 1 H), 6.01 (s, 1 H), 5.60 (s, 1 H), 4.21
(d, J = 17.1 Hz, 1 H), 3.87 (d, J = 17.1 Hz, 1 H), 3.61 (s, 3 H),
Methyl
(3c): See Table 2.[8b] The crude product was purified by column
4-Cyano-2-methylene-4-phenyl-4-(phenylamino)butanoate 2.47 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.56,
144.94, 134.46, 134.36, 131.07, 130.23, 129.73, 129.08, 128.66,
6
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Construction of α-Methylene-β- and -γ-amino Acid Derivatives
128.03, 127.71, 114.77, 53.41, 51.87, 46.01, 21.70 ppm. IR (KBr):
(125 MHz, CDCl3): δ = 166.55, 154.28, 137.93, 137.28, 136.79,
ν = 3061, 3032, 2953, 2919, 2850, 1724, 1636, 1495, 1446, 1165,
136.38, 129.90, 129.65, 129.35, 128.87, 128.68, 127.30, 119.45,
˜
812, 741, 697 cm–1. HRMS (ESI): calcd. for C20H21N2O4S [M +
H]+ 385.1217; found 385.1210.
118.97, 114.28, 65.58, 55.65, 55.43, 52.10 ppm. IR (KBr): ν = 3062,
˜
3033, 3004, 2947, 2834, 1727, 1624, 1513, 1494, 1249, 1147,
825 cm–1. HRMS (ESI): calcd. for C26H25N2O3 [M + H]+ 413.1860;
found 413.1863.
Methyl 2-{[(1-Cyano-2-methylpropyl)(4-methoxyphenyl)amino]meth-
yl}acrylate (4g): See Table 3. According to the general procedure
described above (silica gel, EtOAc/petroleum ether, 1:13), the title
compound was prepared as inseparable mixture of 4g (82% yield
based on 1H NMR analysis) and ether 11 (4g/11, 25:1).[14] 1H
NMR (300 MHz, CDCl3): δ = 7.08 (d, J = 8.9 Hz, 2 H), 6.84 (d,
J = 8.9 Hz, 2 H), 6.21 (s, 1 H), 5.67 (s, 1 H), 4.04 (d, J = 16.2 Hz,
1 H), 3.96 (d, J = 16.0 Hz, 1 H), 3.78 (s, 3 H), 3.65 (d, J = 10.5 Hz,
1 H), 2.06 (m, 1 H), 1.11 (d, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.5 Hz,
3 H) ppm. HRMS (ESI): calcd. for C17H23N2O3 [M + H]+
303.1703; found 303.1700.
Methyl
2-({Benzyl[cyano(p-tolyl)methyl]amino}methyl)acrylate
(4aa): See Table 4. The crude product was purified by column
chromatography on silica gel (EtOAc/petroleum ether, 1:13) to af-
ford the product (55 mg, 82%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.40 (d, J = 7.8 Hz, 2 H), 7.35–7.26 (m, 5
H), 7.19 (d, J = 7.7 Hz, 2 H), 6.31 (s, 1 H), 5.93 (s, 1 H), 4.94 (s,
1 H), 3.95 (d, J = 13.4 Hz, 1 H), 3.70 (s, 3 H), 3.50 (d, J = 14.8 Hz,
1 H), 3.43 (d, J = 13.7 Hz, 1 H), 3.29 (d, J = 14.9 Hz, 1 H), 2.35
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.82, 138.77,
137.36, 137.23, 130.51, 129.41, 128.80, 128.61, 127.73, 127.61,
Ethyl
4-(Benzylamino)-4-cyano-2-methylene-4-phenylbutanoate
127.38, 115.70, 57.37, 55.32, 51.85, 51.32, 21.13 ppm. IR (KBr): ν
(3aЈ): See Table 3. The crude product was purified by column
chromatography on silica gel (EtOAc/petroleum ether, 1:13) to af-
ford the product (48 mg, 71%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.66–7.63 (m, 2 H), 7.43–7.23 (m, 8 H),
6.29 (d, J = 1.0 Hz, 1 H), 5.45 (d, J = 0.9 Hz, 1 H), 4.13–3.98 (m,
2 H), 3.86 (d, J = 12.6 Hz, 1 H), 3.55 (d, J = 12.5 Hz, 1 H), 3.15
(d, J = 13.4 Hz, 1 H), 2.93 (d, J = 13.5 Hz, 1 H), 2.17 (br., 1 H),
1.21 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
166.73, 138.97, 137.23, 134.24, 130.58, 128.84, 128.71, 128.50,
128.08, 127.35, 126.54, 120.02, 64.95, 61.21, 49.06, 44.43,
˜
= 3030, 2951, 2924, 2846, 1724, 1635, 1513, 1495, 1157, 816, 744,
700 cm–1. HRMS (ESI): calcd. for C21H23N2O2 [M + H]+ 335.1754;
found 335.1752.
Methyl
2-({Benzyl[(4-chlorophenyl)(cyano)methyl]amino}methyl)-
acrylate (4ab): See Table 4. The crude product was purified by col-
umn chromatography on silica gel (EtOAc/petroleum ether, 1:13)
to afford the product (57 mg, 80%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.48–7.44 (m, 2 H), 7.38–7.29 (m, 7 H),
6.31 (t, J = 1.3 Hz, 1 H), 5.90–5.88 (m, 1 H), 4.92 (s, 1 H), 3.95 (d,
J = 13.5 Hz, 1 H), 3.70 (s, 3 H), 3.52–3.41 (m, 2 H), 3.29 (d, J =
14.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.67,
137.01, 134.90, 132.17, 129.08, 128.95, 128.83, 128.73, 127.93,
14.05 ppm. IR (KBr): ν = 3320, 3063, 3030, 2981, 2936, 2225, 1717,
˜
1630, 1495, 1452, 1152, 727, 701 cm–1. HRMS (ESI): calcd. for
C21H23N2O2 [M + H]+ 335.1754; found 335.1750.
Ethyl 2-({Benzyl[cyano(phenyl)methyl]amino}methyl)acrylate (4aЈ):
See Table 3. The crude product was purified by column chromatog-
raphy on silica gel (EtOAc/petroleum ether, 1:13) to afford the
product (59 mg, 88%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ = 7.55–7.52 (m, 2 H), 7.42–7.27 (m, 8 H), 6.30 (s, 1 H),
5.92 (s, 1 H), 4.99 (s, 1 H), 4.27–4.12 (m, 2 H), 3.96 (d, J = 13.6 Hz,
1 H), 3.54–3.49 (m, 1 H), 3.45 (d, J = 13.6 Hz, 1 H), 3.32 (d, J =
15.0 Hz, 1 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 166.34, 137.48, 137.32, 133.60, 128.89, 128.81, 128.77,
128.66, 127.78, 127.69, 127.23, 115.54, 60.87, 57.67, 55.45, 51.46,
127.75, 115.15, 57.07, 55.48, 51.92, 51.53 ppm. IR (KBr): ν = 3063,
˜
3030, 2952, 2925, 2851, 2231, 1725, 1635, 1598, 1492, 1158, 817,
746, 700 cm–1. HRMS (ESI): calcd. for C20H20ClN2O2 [M + H]+
355.1208; found 355.1206.
Methyl 2-({Benzyl[cyano(3-methoxyphenyl)methyl]amino}methyl)-
acrylate (4ac): See Table 4. The crude product was purified by col-
umn chromatography on silica gel (EtOAc/petroleum ether, 1:13)
to afford the product (62 mg, 88%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.38–7.27 (m, 6 H), 7.14–7.08 (m, 2 H),
6.88 (dd, J = 8.2, 2.5 Hz, 1 H), 6.31 (t, J = 1.4 Hz, 1 H), 5.93–5.91
(m, 1 H), 4.95 (s, 1 H), 3.97 (d, J = 13.6 Hz, 1 H), 3.82 (s, 3 H),
3.70 (s, 3 H), 3.52 (dt, J = 15.0, 1.5 Hz, 1 H), 3.45 (d, J = 13.6 Hz,
1 H), 3.31 (d, J = 15.0 Hz, 1 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 166.78, 159.90, 137.23, 137.20, 135.10, 129.78, 128.82,
128.66, 127.80, 127.44, 119.88, 115.50, 114.26, 113.43, 57.56, 55.46,
14.21 ppm. IR (KBr): ν = 3063, 3031, 2981, 2928, 2841, 2228, 1719,
˜
1635, 1602, 1507, 1495, 1452, 1263, 1159, 750, 699 cm–1. HRMS
(ESI): calcd. for C21H23N2O2 [M + H]+ 335.1754; found 335.1752.
Methyl
4-Cyano-4-(4-methoxyphenylamino)-2-methylene-3,4-di-
phenylbutanoate (3aЈЈ): See Table 3. The crude product was purified
by column chromatography on silica gel (EtOAc/petroleum ether,
1:12) to afford the product (39 mg, 47%) as a colorless oil. 1H
NMR (300 MHz, C6D6): δ = 7.43–7.40 (m, 2 H), 7.14–7.12 (m, 2
H), 6.94–6.88 (m, 6 H), 6.71 (s, 1 H), 6.54 (s, 1 H), 6.51 (s, 4 H),
4.79 (br., 1 H), 4.76 (s, 1 H), 3.18 (s, 3 H), 3.16 (s, 3 H) ppm. 13C
NMR (125 MHz, C6D6): δ = 166.69, 154.19, 138.30, 138.27,
137.03, 135.13, 130.21, 128.36, 128.30, 127.95, 127.30, 126.98,
119.17, 117.99, 114.47, 65.25, 57.73, 54.58, 51.66 ppm. IR (KBr):
55.30, 51.87, 51.51 ppm. IR (KBr): ν = 3062, 3030, 3004, 2951,
˜
2837, 2229, 1724, 1635, 1603, 1587, 1491, 1453, 1263, 1199, 1158,
816, 769, 700 cm–1. HRMS (ESI): calcd. for C21H23N2O3 [M +
H]+ 351.1703; found 351.1697.
Methyl 2-({Benzyl[(2-bromophenyl)(cyano)methyl]amino}methyl)-
acrylate (4ad): See Table 4. The crude product was purified by col-
umn chromatography on silica gel (EtOAc/petroleum ether, 1:13)
to afford the product (63 mg, 79%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.69 (dd, J = 7.7, 1.6 Hz, 1 H), 7.58 (dd,
J = 7.9, 1.3 Hz, 1 H), 7.36 (dd, J = 7.5, 1.3 Hz, 1 H), 7.32–7.25
(m, 5 H), 7.21 (dd, J = 7.6, 1.6 Hz, 1 H), 6.29 (s, 1 H), 5.83–5.81
(m, 1 H), 5.23 (s, 1 H), 3.90 (d, J = 13.2 Hz, 1 H), 3.69–3.64 (m, 4
ν = 3074, 3029, 3006, 2989, 2949, 2928, 2837, 2238, 1725, 1628,
˜
1518, 1491, 1447, 1153, 819, 765, 701 cm–1. HRMS (ESI): calcd.
for C26H25N2O3 [M + H]+ 413.1860; found 413.1857.
Methyl 2-({[Cyano(phenyl)methyl](4-methoxyphenyl)amino}(phenyl)-
methyl)acrylate (4aЈЈ): See Table 3. The crude product was purified
by column chromatography on silica gel (EtOAc/petroleum ether,
1:13) to afford the product (22 mg, 27%) as a colorless oil. 1H
NMR (300 MHz, CDCl3): δ = 7.68–7.63 (m, 4 H), 7.47–7.35 (m, 6
H), 3.47 (d, J = 13.2 Hz, 1 H), 3.22 (d, J = 14.4 Hz, 1 H) ppm. 13
C
NMR (125 MHz, CDCl3): δ = 166.90, 136.58, 136.56, 133.95,
132.64, 131.07, 130.68, 129.70, 128.86, 128.20, 127.73, 127.40,
H), 6.62–6.56 (m, 2 H), 6.51 (s, 1 H), 6.33–6.28 (m, 3 H), 4.78 (s, 124.44, 115.42, 58.11, 55.47, 51.79, 51.78 ppm. IR (KBr): ν = 3063,
˜
1 H), 4.17 (s, 1 H), 3.65 (s, 3 H), 3.43 (s, 3 H) ppm. 13C NMR 3029, 2949, 2838, 2226, 1724, 1637, 1571, 1495, 1471, 1199, 1160,
Eur. J. Org. Chem. 0000, 0–0
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W.-W. Liao et al.
FULL PAPER
817, 757 cm–1. HRMS (ESI): calcd. for C20H20BrN2O2 [M + H]+
399.0703; found 399.0702.
6.98 (m, 4 H), 6.89 (dd, J = 8.2, 2.4 Hz, 1 H), 6.84–6.77 (m, 2 H),
6.22–6.20 (m, 1 H), 5.74–5.72 (m, 1 H), 5.52 (s, 1 H), 4.12 (d, J =
16.6, Hz, 1 H), 3.90 (d, J = 16.5, 1.5 Hz, 1 H), 3.79 (s, 3 H), 3.76
(s, 3 H), 3.73 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
166.57, 159.97, 155.94, 140.28, 136.11, 134.89, 129.92, 127.44,
122.60, 119.79, 116.77, 114.54, 113.19, 60.18, 55.45, 55.33, 51.90,
Methyl
2-({Benzyl[cyano(naphthalen-2-yl)methyl]amino}methyl)-
acrylate (4ae): See Table 4. The crude product was purified by col-
umn chromatography on silica gel (EtOAc/petroleum ether, 1:13)
to afford the product (67 mg, 90%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.89–7.82 (m, 3 H), 7.55–
7.49 (m, 3 H), 7.40–7.28 (m, 5 H), 6.31 (s, 1 H), 5.94 (s, 1 H), 5.12
(s, 1 H), 4.00 (d, J = 13.5 Hz, 1 H), 3.66 (s, 3 H), 3.56 (d, J =
14.8 Hz, 1 H), 3.48 (d, J = 13.5 Hz, 1 H), 3.34 (d, J = 15.0 Hz, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.81, 137.25, 137.20,
133.34, 132.89, 130.98, 128.94, 128.70, 128.19, 127.86, 127.69,
127.65, 127.14, 126.84, 126.73, 125.08, 115.58, 57.81, 55.52, 51.88,
50.74 ppm. IR (KBr): ν = 3001, 2952, 2836, 2232, 1720, 1635, 1511,
˜
1490, 1454, 1247, 1192, 1153, 818, 773, 690 cm–1. HRMS (ESI):
calcd. for C21H23N2O4 [M + H]+ 367.1652; found 367.1645.
Methyl
2-({[(3-Bromophenyl)(cyano)methyl](4-methoxyphenyl)-
amino}methyl)acrylate (4ed): See Table 4. The crude product was
purified by column chromatography on silica gel (EtOAc/petroleum
ether, 1:13) to afford the product (51 mg, 61%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.62 (dd, J = 7.4, 1.8 Hz, 1 H),
7.48 (dd, J = 7.4, 1.9 Hz, 1 H), 7.32–7.21 (m, 2 H), 7.07–6.99 (m,
2 H), 6.84–6.76 (m, 2 H), 6.13 (dd, J = 2.4, 1.1 Hz, 1 H), 5.73–5.72
(m, 2 H), 4.04–4.02 (m, 2 H), 3.77 (s, 3 H), 3.69 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 166.53, 156.35, 140.23, 136.02,
133.64, 132.58, 130.98, 130.84, 127.69, 127.61, 124.55, 123.33,
51.47 ppm. IR (KBr): ν = 3060, 3029, 2950, 2839, 1724, 1635, 1602,
˜
1495, 1157, 740, 700 cm–1. HRMS (ESI): calcd. for C24H23N2O2
[M + H]+ 371.1754; found 371.1751.
Methyl 2-({Benzyl[cyano(furan-2-yl)methyl]amino}methyl)acrylate
(4af): See Table 4. The crude product was purified by column
chromatography on silica gel (EtOAc/petroleum ether, 1:13) to af-
ford the product (47 mg, 76%) as a yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 7.45–7.44 (m, 1 H), 7.35–7.27 (m, 5 H), 6.55 (dt, J =
3.3, 0.9 Hz, 1 H), 6.37 (dd, J = 3.3, 1.9 Hz, 1 H), 6.31–6.30 (m, 1
H), 5.97–5.95 (m, 1 H), 4.96 (s, 1 H), 3.94 (d, J = 13.9 Hz, 1 H),
3.72 (s, 3 H), 3.60–3.51 (m, 2 H), 3.38 (d, J = 15.5 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 166.74, 146.57, 143.76, 137.12,
136.78, 128.63, 127.75, 127.17, 114.55, 110.60, 110.53, 55.40, 51.92,
116.75, 114.38, 59.46, 55.43, 51.85, 51.19 ppm. IR (KBr): ν = 2998,
˜
2952, 2837, 2230, 1720, 1639, 1607, 1513, 1470, 1193, 1155, 819,
748 cm–1. HRMS (ESI): calcd. for C20H20BrN2O3 [M + H]+
415.0652; found 415.0645.
Methyl
2-({[Cyano(naphthalen-2-yl)methyl](4-methoxyphenyl)-
amino}methyl)acrylate (4ee): See Table 4. The crude product was
purified by column chromatography on silica gel (EtOAc/petroleum
51.81, 51.35 ppm. IR (KBr): ν = 3120, 3063, 3030, 2952, 2925,
˜
1
ether, 1:13) to afford the product (59 mg, 76%) as a yellow oil. H
2843, 2234, 1724, 1634, 1496, 1158, 743, 700 cm–1. HRMS (ESI):
calcd. for C18H19N2O3 [M + H]+ 311.1390; found 311.1386.
NMR (300 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.87–7.83 (m, 3 H),
7.58–7.50 (m, 3 H), 7.08–7.02 (m, 2 H), 6.85–6.78 (m, 2 H), 6.21–
6.19 (m, 1 H), 5.76–5.74 (m, 1 H), 5.69 (s, 1 H), 4.18–4.13 (m, 1
H), 3.93 (dt, J = 16.5, 1.6 Hz, 1 H), 3.76 (s, 3 H), 3.69 (s, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 166.57, 156.07, 140.31, 136.11,
133.35, 132.95, 130.80, 128.87, 128.29, 127.71, 127.57, 127.09,
126.94, 126.77, 124.91, 122.91, 116.84, 114.58, 60.52, 55.45, 51.89,
Methyl 2-({[Cyano(p-tolyl)methyl](4-methoxyphenyl)amino}methyl)-
acrylate (4ea): See Table 4. The crude product was purified by col-
umn chromatography on silica gel (EtOAc/petroleum ether, 1:13)
to afford the product (62 mg, 89%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.37 (d, J = 8.1 Hz, 2 H), 7.17 (d, J =
8.1 Hz, 2 H), 7.01–6.96 (m, 2 H), 6.83–6.78 (m, 2 H), 6.21–6.18 (m,
1 H), 5.73–5.71 (m, 1 H), 5.50 (s, 1 H), 4.10 (d, J = 16.6 Hz, 1 H),
3.88 (d, J = 16.6 Hz, 1 H), 3.76 (s, 3 H), 3.72 (s, 3 H), 2.35 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.60, 155.88, 140.33,
138.95, 136.13, 130.32, 129.52, 127.56, 127.37, 122.65, 116.97,
50.71 ppm. IR (KBr): ν = 3001, 2952, 2836, 2224, 1719, 1636, 1603,
˜
1587, 1511, 1491, 1247, 1154, 819 cm–1. HRMS (ESI): calcd. for
C24H23N2O3 [M + H]+ 387.1703; found 387.1701.
General Procedure for the Preparation of Densely Functionalized α-
Methylene-γ-butyrolactam 5 Through a One-Pot Reaction: See
Table 5. To a dried flask were added 1 (0.2 mmol), DABCO
(20 mol-%), CH3CN (2 mL), and 2a (0.26 mmol). After the mixture
was stirred at 30 °C for 3–4 h, DBU (20 mol-%) was added, and the
temperature was warmed to 60 °C. Upon completion, the resulting
mixture was concentrated under reduced pressure, and the residue
was purified through column chromatography on silica gel (EtOAc/
petroleum ether) to provide 5.
114.50, 59.97, 55.45, 51.88, 50.54, 21.15 ppm. IR (KBr): ν = 3000,
˜
2952, 2926, 2837, 2229, 1717, 1636, 1582, 1510, 1247, 1183,
818 cm–1. HRMS (ESI): calcd. for C21H23N2O3 [M + H]+ 351.1703;
found 351.1699.
Methyl
2-({[(4-Chlorophenyl)(cyano)methyl](4-methoxyphenyl)-
amino}methyl)acrylate (4eb): See Table 4. The crude product was
purified by column chromatography on silica gel (EtOAc/petroleum
ether, 1:13) to afford the product (56 mg, 75%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.45–7.40 (m, 2 H), 7.37–7.33
(m, 2 H), 6.99 (d, J = 9.0 Hz, 2 H), 6.80 (d, J = 9.0 Hz, 2 H), 6.22–
6.20 (m, 1 H), 5.73–5.70 (m, 1 H), 5.46 (s, 1 H), 4.10 (dt, J = 15.9,
0.9 Hz, 1 H), 3.88 (dt, J = 16.2, 1.5 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.52, 156.33, 139.86,
136.10, 135.04, 132.00, 129.07, 129.06, 127.72, 123.46, 116.51,
1-(4-Methoxyphenyl)-4-methylene-5-oxo-2-phenylpyrrolidine-2-carbo-
nitrile (5e): See Table 5.[8b] The crude product was purified by col-
umn chromatography on silica gel (EtOAc/petroleum ether, 1:8) to
afford the product (54 mg, 89 %) as a white solid. 1H NMR
(300 MHz, CDCl3): δ = 7.48–7.44 (m, 2 H), 7.40–7.37 (m, 3 H),
7.05 (d, J = 9.0 Hz, 2 H), 6.77 (d, J = 9.1 Hz, 2 H), 6.34 (t, J =
2.7 Hz, 1 H), 5.63 (t, J = 2.3 Hz, 1 H), 3.76–3.69 (m, 1 H), 3.71 (s,
3 H), 3.33 (dt, J = 17.2, 2.6 Hz, 1 H) ppm.
114.54, 59.70, 55.44, 51.96, 51.44 ppm. IR (KBr): ν = 3001, 2954,
˜
2929, 1718, 1635, 1512, 1490, 1456, 1246, 1154, 818 cm–1. HRMS
(ESI): calcd. for C20H20ClN2O3 [M + H]+ 371.1157; found
371.1153.
1-(4-Methoxyphenyl)-4-methylene-5-oxo-2-p-tolylpyrrolidine-2-carbo-
nitrile (5ea): See Table 5.[8b] The crude product was purified by col-
Methyl
2-({[Cyano(3-methoxyphenyl)methyl](4-methoxyphenyl)- umn chromatography on silica gel (EtOAc/petroleum ether, 1:8) to
amino}methyl)acrylate (4ec): See Table 4. The crude product was
purified by column chromatography on silica gel (EtOAc/petroleum
ether, 1:13) to afford the product (62 mg, 84%) as a light yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.32–7.26 (m, 1 H), 7.11–
afford the product (47 mg, 74 %) as a white solid. 1H NMR
(300 MHz, CDCl3): δ = 7.34 (d, J = 8.4 Hz, 2 H), 7.18 (d, J =
8.1 Hz, 2 H), 7.05 (d, J = 9.0 Hz, 2 H), 6.78 (d, J = 9.0 Hz, 2 H),
6.34 (t, J = 2.7 Hz, 1 H), 5.63 (t, J = 2.3 Hz, 1 H), 3.76–3.68 (m,
8
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Job/Unit: O20642
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Date: 13-08-12 12:09:59
Pages: 12
Construction of α-Methylene-β- and -γ-amino Acid Derivatives
1 H), 3.74 (s, 3 H), 3.31 (dt, J = 17.1, 2.6 Hz, 1 H), 2.35 (s, 3
H) ppm.
quenched with brine, and the aqueous mixture was extracted with
ethyl acetate. The combined organic extracts were dried with
Na2SO4, filtered, and concentrated in vacuo. The crude mixture
was purified by column chromatography on silica gel (EtOAc/pe-
troleum ether, 1:5) to provide 7 (24 mg, 80%) as a yellow oil. 1H
NMR (300 MHz, CDCl3): δ = 7.40–7.35 (m, 5 H), 7.04 (d, J =
8.9 Hz, 2 H), 6.80 (d, J = 8.9 Hz, 3 H), 3.75 (s, 3 H), 2.12 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.48, 157.19, 136.86,
134.96, 130.38, 128.17, 127.59, 126.27, 125.78, 124.47, 114.00,
2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-methylene-5-oxopyrrolid-
ine-2-carbonitrile (5eb): See Table 5.[8b] The crude product was puri-
fied by column chromatography on silica gel (EtOAc/petroleum
1
ether, 1:8) to afford the product (61 mg, 91%) as a white solid. H
NMR (300 MHz, CDCl3): δ = 7.42–7.35 (m, 4 H), 7.05 (d, J =
9.0 Hz, 2 H), 6.80 (d, J = 9.0 Hz, 2 H), 6.37 (t, J = 2.7 Hz, 1 H),
5.66 (t, J = 2.3 Hz, 1 H), 3.78–3.71 (m, 1 H), 3.75 (s, 3 H), 3.28
(dt, J = 17.1, 2.6 Hz, 1 H) ppm.
112.78, 65.37, 53.58, 9.50 ppm. IR (KBr): ν = 3055, 2962, 2917,
˜
2839, 1710, 1513, 1454, 823, 740, 697 cm–1. HRMS (ESI): calcd.
for C19H17N2O2 [M + H]+ 305.1285; found 305.1280.
2-(3-Methoxyphenyl)-1-(4-methoxyphenyl)-4-methylene-5-oxopyrro-
lidine-2-carbonitrile (5ec): See Table 5.[8b] The crude product was
purified by column chromatography on silica gel (EtOAc/petroleum
Methyl 5-Cyano-1-(4-methoxyphenyl)-5-phenylpyrrolidine-3-carb-
oxylate (8): See Scheme 3. To a solution of 3e (101 mg, 0.3 mmol)
in CH3OH (1.5 mL) was added K2CO3 (62 mg, 0.45 mmol), and
the reaction mixture was stirred at 50 °C for 4 h. The mixture was
filtered through a pad of Celite, and the precipitate was washed
with dichloromethane. The organic phase was evaporated in vacuo,
and the residue was purified by chromatography on silica gel
(EtOAc/petroleum ether, 1:10) to give 8 [62 mg, 61%; dr (dia-
stereomeric ratio), 2.6:1] as a yellow oil. Data for 8a (major): 1H
NMR (300 MHz, CDCl3): δ = 7.54–7.50 (m, 2 H), 7.38–7.31 (m, 3
H), 7.09 (d, J = 9.1 Hz, 2 H), 6.74 (d, J = 9.1 Hz, 2 H), 3.95 (dd,
J = 9.5, 4.4 Hz, 1 H), 3.72–3.68 (m, 1 H), 3.71 (s, 3 H), 3.44 (s, 3
H), 3.23–3.14 (m, 1 H), 3.01 (dd, J = 13.4, 8.7 Hz, 1 H), 2.73 (dd,
J = 13.4, 11.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
168.71, 153.43, 130.95, 124.19, 123.76, 123.12, 122.74, 121.32,
114.34, 109.05, 64.84, 60.12, 54.09, 50.03, 36.67, 34.88 ppm. IR
1
ether, 1:8) to afford the product (57 mg, 85%) as a white solid. H
NMR (300 MHz, CDCl3): δ = 7.31 (t, J = 8.0 Hz, 1 H), 7.12–7.08
(m, 2 H), 7.06–7.03 (m, 1 H), 6.98–6.96 (m, 1 H), 6.91–6.88 (m, 1
H), 6.82–6.79 (m, 2 H), 6.35 (t, J = 2.7 Hz, 1 H), 5.64 (t, J =
2.3 Hz, 1 H), 3.78 (s, 3 H), 3.76–3.68 (m, 1 H), 3.75 (s, 3 H), 3.31
(dt, J = 17.2, 2.6 Hz, 1 H) ppm.
2-(2-Bromophenyl)-1-(4-methoxyphenyl)-4-methylene-5-oxopyrrolid-
ine-2-carbonitrile (5ed): See Table 5.[8b] The crude product was puri-
fied by column chromatography on silica gel (EtOAc/petroleum
ether, 1:8) to afford the product (27 mg, 35%) as a colorless oil. 1H
NMR (300 MHz, CDCl3): δ = 7.77–7.74 (m, 1 H), 7.67–7.64 (m, 1
H), 7.35–7.30 (m, 1 H), 7.28–7.21 (m, 3 H), 6.82–6.77 (m, 2 H),
6.37 (t, J = 2.6 Hz, 1 H), 5.64 (t, J = 2.3 Hz, 1 H), 3.79 (dt, J
= 17.6, 2.7 Hz, 1 H), 3.73 (s, 3 H), 3.67 (dt, J = 17.6, 2.2 Hz, 1
H) ppm.
(KBr): ν = 3058, 2960, 2921, 2847, 1714, 1512, 1251, 826, 743,
˜
1-(4-Methoxyphenyl)-4-methylene-2-(naphthalen-2-yl)-5-oxopyrrol- 701 cm–1. HRMS (ESI): calcd. for C20H21N2O3 [M + H]+ 337.1547;
idine-2-carbonitrile (5ee): See Table 5.[8b] The crude product was
found 337.1542.
purified by column chromatography on silica gel (EtOAc/petroleum
ether, 1:8) to afford the product (54 mg, 77%) as a white solid. H
Methyl 4-Cyano-4-{[2-(methoxycarbonyl)allyl](4-methoxyphenyl)-
amino}-2-methylene-4-phenylbutanoate (10): See Scheme 3. To a
dried flask were added 4e (0.2 mmol), DABCO (20 mol-%),
CH3CN (2 mL), MS (4 Å, 80 mg), and 2a (0.24 mmol). The reac-
tion mixture was stirred at 30 °C. Upon completion, the mixture
was filtered, and the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/petroleum
ether, 1:13) to provide compound 10 (37 mg, 37%) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.69 (m, 2 H), 7.44 (d, J =
8.9 Hz, 2 H), 7.39–7.33 (m, 3 H), 6.89 (d, J = 8.9 Hz, 2 H), 6.08
(s, 1 H), 6.06–6.05 (m, 1 H), 5.61 (s, 1 H), 5.40 (s, 1 H), 3.97 (d, J
= 14.6 Hz, 1 H), 3.81 (s, 3 H), 3.64 (s, 3 H), 3.63 (d, J = 14.6 Hz,
1 H), 3.34 (s, 3 H), 2.89 (d, J = 13.0 Hz, 1 H), 2.46 (d, J = 13.0 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.64, 166.54,
158.54, 137.64, 136.72, 136.56, 134.26, 130.18, 129.98, 128.91,
128.44, 128.20, 127.67, 118.84, 114.26, 71.34, 55.37, 52.71, 51.68,
1
NMR (300 MHz, CDCl3): δ = 8.00–7.99 (m, 1 H), 7.90 (d, J =
8.7 Hz, 1 H), 7.86–7.82 (m, 2 H), 7.59–7.51 (m, 2 H), 7.45 (dd, J
= 8.8, 2.1 Hz, 1 H), 7.08 (d, J = 9.1 Hz, 2 H), 6.74 (d, J = 9.1 Hz,
2 H), 6.40 (t, J = 2.6 Hz, 1 H), 5.67 (t, J = 2.2 Hz, 1 H), 3.80 (dt,
J = 17.3, 2.3 Hz, 1 H), 3.70 (s, 3 H), 3.42 (dt, J = 17.3, 2.6 Hz, 1
H) ppm.
2-(Furan-2-yl)-1-(4-methoxyphenyl)-4-methylene-5-oxopyrrolidine-2-
carbonitrile (5ef): See Table 5.[8b] The crude product was purified
by column chromatography on silica gel (EtOAc/petroleum ether,
1
1:8) to afford the product (24 mg, 41%) as a yellow oil. H NMR
(300 MHz, CDCl3): δ = 7.47 (dd, J = 1.9, 0.9 Hz, 1 H), 6.93–6.89
(m, 2 H), 6.87–6.82 (m, 2 H), 6.48 (dd, J = 3.4, 0.9 Hz, 1 H), 6.34–
6.32 (m, 2 H), 5.66 (t, J = 2.3 Hz, 1 H), 3.78 (s, 3 H), 3.64 (dt, J
= 17.1, 2.7 Hz, 1 H), 3.56 (dt, J = 16.8, 2.1 Hz, 1 H) ppm.
51.65, 42.76 ppm. IR (KBr): ν = 2951, 2840, 1725, 1633, 1510,
˜
General Procedure for Multicomponent Tandem Allylic Amination
Reaction: See Scheme 2. To a dried flask were added PhCHO
(0.2 mmol) and BnNH2 (0.21 mmol). After the mixture was stirred
at room temp. for 20 min, TMSCN (0.22 mmol) was added, and
the mixture was vigorously stirred. After 50 min, PhCH3 (2 mL),
DABCO (20 mol-%), and compound 2a (0.24 mmol) were added.
The reaction was monitored by TLC. Upon completion, the re-
sulting mixture was concentrated under reduced pressure, and the
residue was purified by column chromatography on silica gel
(EtOAc/petroleum ether, 1:13) to provide 4a (51 mg, 80%).
1199, 1151, 814, 756, 699 cm–1. HRMS (ESI): calcd. for
C25H27N2O5 [M + H]+ 435.1914; found 435.1915.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of products 3a, 3c,
3d–3e, 3aЈ–3aЈЈ, 4a–4b, 4d–4g, 4aЈ–4aЈЈ, 4aa–4af, 4ea–4ee, 5e, 5ea–
5ef, 7, 8, and 10.
Acknowledgments
1-(4-Methoxyphenyl)-4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyr-
role-2-carbonitrile (7): See Scheme 3. To a dried flask were added
3e (34 mg, 0.1 mmol), MeCN (1 mL), and KOtBu (0.2 equiv.) at
0 °C, and the mixture was warmed to room temperature. After stir-
ring at room temperature for 2 h, the reaction mixture was
This work is supported by the National Natural Science Founda-
tion of China (NSFC) (grant number 21102054) and the Open Pro-
ject of State Key Laboratory for Supramolecular Structure and
Materials (sklssm201220).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

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/KAP1
Date: 13-08-12 12:09:59
Pages: 12
W.-W. Liao et al.
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10
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www.eurjoc.org
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20642
/KAP1
Date: 13-08-12 12:09:59
Pages: 12
Construction of α-Methylene-β- and -γ-amino Acid Derivatives
Lopez, R. Herranz, Mini-Rev. Org. Chem. 2008, 5, 209–221; k)
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conditions as mentioned in Table 3, the reaction of 1a with
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Received: May 14, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O20642
/KAP1
Date: 13-08-12 12:09:59
Pages: 12
W.-W. Liao et al.
FULL PAPER
Amino Acid Derivatives
F. Pan, J.-M. Chen, T.-Y. Qin,
S. X.-A. Zhang, W.-W. Liao* .......... 1–12
Controllable Regioselective Construction
of Both Functional α-Methylene-β- and -γ-
amino Acid Derivatives Through an Or-
ganocatalyzed Tandem Allylic Alkylation
and Amination
Keywords: Synthetic methods / Amino ni-
triles / Regioselectivity / Tandem reaction /
Alkylation / Solvent effects
A controllable regioselective allylic alk-
ylation and amination reaction has been
developed by using α-amino nitriles for the
highly selective construction of β- and γ-
amino acid derivatives incorporating mul-
tiple functional groups. Subsequent multi-
component tandem reactions and trans-
formations of the densely functionalized
products were shown to readily afford a
range of useful building blocks.
12
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