Construction of highly functional α-amino nitriles via a novel multicomponent tandem organocatalytic reaction: A facile access to α-methylene γ-lactams

Article abstract of DOI:10.1039/c2ob07112f

The first tertiary amine-catalyzed multicomponent tandem Strecker-allylic-alkylation (SAA) reaction has been developed, which provides a facile access to functionalized α-amino nitriles, which could be readily converted into α-methylene-γ-butyrolactams. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob07112f

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COMMUNICATION
Construction of highly functional α-amino nitriles via a novel
multicomponent tandem organocatalytic reaction: a facile access to
α-methylene γ-lactams†‡
Feng Pan, Jian-Ming Chen, Zhe Zhuang, Yin-Zhi Fang, Sean Xiao-An Zhang and Wei-Wei Liao*
Received 16th December 2011, Accepted 17th January 2012
DOI: 10.1039/c2ob07112f
for preparing multifunctional compounds.6 We recently reported
The first tertiary amine-catalyzed multicomponent tandem
a novel tandem cyanation–allylic-alkylation (CAA) reaction
which provided a facile access to densely functionalized products
containing O-substituted quaternary centers using amine cata-
lysts.10 Based on this work, we envisaged that an attractive mul-
ticomponent tandem reaction promoted by organocatalyst could
be established by utilizing three-component Strecker reaction
and Lewis base catalyzed allylic substitution reaction, which
may deliver highly functional α-methylene γ-lactam skeletons.
In this protocol, the α-amino nitrile I bearing an α-hydrogen is
generated from aldehyde, amine and cyanation reagent in situ.
Subsequently, the deprotonation of the acidic CH group of the
α-amino nitrile by the oxygen-based anion generated in situ
would occur, and C-selective allylic alkylation would follow to
deliver highly functionalized α-amino nitrile II, which could be
readily converted into α-methylene-γ-butyrolactams III separ-
ately or in one pot fashion. In this manner, a great pool of valu-
able densely functionalized α-amino nitriles and α-methylene-
γ-butyrolactams containing quaternary carbon centers could be
easily accessed. Meanwhile, the readily manipulated α-amino
nitrile moiety and other functional groups of II or III and the
application of robust and well-tested methodologies for the elab-
oration of the core structure of II may eventually result in the
discovery of new bioactive compounds. Herein, we report a
novel tandem organocatalytic Strecker–allylic-alkylation reaction
(SAA) and Strecker–allylic-alkylation–cyclization reaction
(SAAC) for the construction of highly functionalized α-amino
nitriles and α-methylene-γ-butyrolactams (Scheme 1).
Strecker–allylic-alkylation (SAA) reaction has been devel-
oped, which provides a facile access to functionalized
α-amino nitriles, which could be readily converted into
α-methylene-γ-butyrolactams.
Compounds containing the α-methylene γ-lactam moiety, which
are fairly common in nature,1a display a wide variety of biologi-
cal activities1 because they exhibit less cytotoxic activity than
the corresponding α-alkylidene-γ-butyrolactones. In addition, a
large variety of modulations by the nitrogen substitutions of
α-methylene γ-lactam scaffolds may help to improve the
pharmacological properties and decrease the toxicity, in contrast
to their isosteric replacement α-methylene-γ-burtyrolactones for
instance. Due to their excellent activities for potential drug can-
didates as well as their versatile synthetic potential, the construc-
tion of α-methylene γ-lactam skeletons has received much
attention over several decades.2
Although a number of methods have been developed which
mainly relied on metal reagents,2c–i an efficient synthetic route
based on metal-free catalysis to access α-methylene-γ-butyrolac-
tams, which contain quaternary carbon centers, from readily
available chemicals is still undeveloped. α-Amino nitriles are
exceptionally versatile intermediates in synthetic chemistry and
also proposed as being prebiotic precursors to porphyrins,
corrins and nicotinic acids.3 α-Amino nitriles bearing an
α-hydrogen have been widely used in the generation of multiple
polyfunctional structures.4 Interestingly, to the best of our knowl-
edge, the construction of α-amino nitriles including densely
functional quaternary carbon centers via a multicomponent
tandem reaction with a metal-free catalyst is still unexploited.5
Recently, a Lewis base assisted Brønsted base catalysis strat-
egy was been applied for direct allylic substitutions of Morita–
Baylis–Hillman (MBH) adducts, which provided a powerful tool
Our initial investigation was examined with MBH carbonate
2a and preformed α-amino nitrile 1a which can be prepared
readily from Strecker reaction (benzaldehyde, aniline and
TMSCN) in the presence of 20% DABCO (1,4-diazabicyclo
[2.2.2]octane) (Table 1).5b A wide range of solvents were
Department of Organic Chemistry, College of Chemistry, Jilin
University, 2699 Qianjin Street, Changchun 130012, China. E-mail:
wliao@jlu.edu.cn; Tel: (+86) 0431-85168420
†This work is dedicated to Prof. M. F. Semmelhack (Princeton Univer-
sity, USA) on the occasion of his 70th birthday.
‡Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob07112f
Scheme 1 Strategy of tandem Strecker–allylic-alkylation–cyclization
reaction for α-methylene-γ-butyrolactams.
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Table 1 Optimization of Lewis base catalyzed direct allylic alkylation
of α-amino nitrile 1a with MBH carbonate 2a
Table 2 Synthesis of densely functionalized α-amino nitrile 1a via
multicomponent tandem reaction (SAA)a
Entry
Catalyst
Solvent
t (h)
Yieldb (%)
1
2
3
4
5
6
7
8
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMAP
PhCH3
DCM
THF
4
9
4
20
15
9
52(3aa)
50(3aa)
36(3aa)
40(3aa)
62(3aa)
56(3aa)
79(3aa); 5(4a)
32(3aa); 50(4a)
93(3aa)
Entry R1
NR2 R3(5)
NHPh
NH(C6H4Cl-p) 2a 3ab 2.5
NHBn
2
3
t (h) Yieldb (%)
CHCl3
1
2
Ph
Ph
2a 3aa 2.5
95
85
77c
96
1,4-Dioxane
t-BuOH
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
3
4
Ph
Ph
2a 3ac
2a 3ad 2.5
2b
4
2
NHPMP
NMeBn
3.5
14
22
2.5
2.5
d
9c
10d
11
12
5
Ph
—
—
—
6
7
8
9
10
11
12
13
14
15
Ph
N-Morpholinyl 2a 3ae 14
67
70
91
79
78c
83
76
95
94
9
35(3aa)
44(3aa); 50(4a)
50(3aa)
4-ClC6H4
4-MeC6H4
3-MeOC6H4 NHPMP
2-BrC6H4
2-Naphyl
2-Furyl
Ph
NHPMP
NHPMP
2a 3b
2a 3c
2a 3d
2a 3f
1.5
2
2
3.5
2
Ph3P
a Unless otherwise noted, reactions were performed with 0.3 mmol of
1a, 0.45 mmol of 2a, and 20 mol% of DABCO in 3.0 mL of solvent at
30 °C. b Isolated yield. c 4 Å molecular sieve was added and the reaction
was performed at 0 °C. d MBH acetate 2e (0.45 mmol) was employed.
NHPMP
NHPMP
NHPMP
NHPMP
NHPMP
NHPh
2a 3g
2a 3h
2b 3af
2c 3ag
2d 3ah
2
2
4
4
Ph
Ph
a Aldehydes (0.3 mmol), amine (1.05 equiv.) and TMSCN (1.1 equiv.)
were stirred at 30 °C for 50 min. DABCO (20 mol%) and solvent were
added. The mixture was stirred for the mentioned reaction times at
30 °C. b Isolated yield. c Based on 1H NMR (see the ESI†). d No desired
product was detected. PMP: p-methoxyphenyl.
screened. Although the substitution reactions took place in all
screened solvents, the regioselectivity of this reaction showed
strong solvent-dependence. Besides the desired product 3aa, the
N-alkylation and simultaneous C- and N-alkylation also were
observed in less polar solvents.7 The desired C-allylic alkylation
proceeded well in polar solvents such as CH3CN and DMF
(Table 1, entries 7 and 8). While exploring the reaction con-
ditions of this allylic alkylation reaction, α-methylene-γ-butyro-
lactam 4a was isolated, which could be generated from desired
product 3aa in the presence of base (Table 1, entries 7, 8 and
11). Performing this reaction at 0 °C in the presence of molecule
sieves can significantly increase the yield of 3aa (Table 1, entry
9). MBH adduct 2e can also react with 1a to furnish 3aa, albeit
in low yield (Table 1, entry 10). Other Lewis bases such as
DMAP and Ph3P have also been tested. DMAP exhibited
efficiency comparable with that of DABCO, while Ph3P afforded
allylic product in decreased yield (Table 1, entries 11 and 12).
With these preliminary results in hand, next we investigated
the feasibility of the multicomponent tandem SAA reaction.
Straightforwardly mixing benzaldehyde, aniline, TMSCN,
DABCO (20%) and MBH adduct 2a in one flask in CH3CN
resulted in the desired product 3aa in low yield (44%) and side
product formation. We hypothesized that the order of reagent
mixing may be crucial in order to increase the production of 3.
Indeed, submitting benzaldehyde, aniline and TMSCN in one
flask, and subsequently adding DABCO (20%), MBH adduct 2a
and the optimum solvent, readily furnished the desired product
3aa in high yield with a trace amount of α-methylene-γ-butyro-
lactam 4a. The scope and generality of this novel tandem SAA
reaction was evaluated. Firstly, the reactions of different primary
amines with benzaldehyde, TMSCN and MBH adduct 2a were
examined. Noteworthily, anilines with electron-withdrawing or
-donating substituents at the para-position can be smoothly
employed in SAA reaction to furnish 3 in good to high yield
(Table 2, entries 1, 2 and 4). The electronic properties of the aro-
matic system of the amine component do not seem to influence
the yield. N-Benzyl protected 3ac also could be obtained in 77%
yield when benzylamine was used (Table 2, entry 3). N-PMP
and N-benzyl substitutions of 3 may provide a potential handle
for further elaboration, due to their facile deprotection.8 When a
secondary amine such as N-methylbenzylamine was used, SAA
reactions didn’t provide desired product, while morpholine gave
rise to 3ae in moderate yield (Table 2, entry 6). A variety of aro-
matic and heteroaromatic aldehydes were evaluated next with p-
anisidine as the amine component. Gratifyingly, the reactions
took place efficiently in good to excellent yields for all studied
aldehydes (Table 2, entries 7–12). An aromatic aldehyde with an
ortho-substituent on the aryl group, which potentially causes
steric hindrance effects, also gave good yield (Table 2, entry 10).
When an aromatic aldehyde with an electron-withdrawing substi-
tuent was employed, a slight decrease in yield was observed
(Table 2, entry 7). In addition, MBH adducts such as ethyl and
t-butyl esters also were applied in the SAA reaction and both of
them provided desired products 3 in high yield (Table 2, entries
13 and 14), while SAA reaction with MBH adduct 2d, which
may create adjacent quaternary and tertiary centers, gave desired
product 3ah in low yield (Table 2, entry 15).
We next focused our attention on the synthesis of highly func-
tionalized α-methylene-γ-butyrolactams 4 based on SAA reac-
tion. After several attempts at the cyclization of α-amino nitriles
3, α-methylene-γ-butyrolactam 4a could be readily synthesized
from 3aa in the presence of a catalytic amount of DBU (Table 3,
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(Scheme 3).9 The deprotection of the N-PMP protecting group
of α-methylene-γ-butyrolactam 4c produced compound 7, which
may serve as an effective scaffold for a large variety of modu-
lations by the N-substitution of α-methylene γ-lactams
(Scheme 3).8
Table 3 Synthesis
of
densely
functionalized
α-methylene-
γ-butyrolactams 4 from α-amino nitrile 3 catalyzed by Lewis basea
In conclusion, we have demonstrated an organocatalytic
Strecker–allylic-alkylation reaction with aldehydes, amines and
MBH adducts, which provided an efficient synthetic route for
the preparation of densely functionalized α-amino nitriles
bearing an N-substituted quaternary carbon center, which could
be readily converted into α-methylene-γ-butyrolactams separ-
ately or in one-pot fashion. A number of aromatic aldehydes
could be successfully applied to give multifunctional desired
products. The potential synthetic applications of SAA products
have also been displayed, which have potential utility in organic
synthesis. Further studies on synthetic applications and asym-
metric catalysis are ongoing in our laboratories and will be
reported in due course.
Entry
R1
R2
4
t (h)
Yieldb (%)
1
2
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
13
13
18
56
13
18
13
18
12
15
89
66
92
52
82
81
70
58
85
55
4-ClC6H4
4-MeOC6H4
Bn
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3
4c
5
4-ClC6H4
4-MeC6H4
3-MeOC6H4
2-BrC6H4
2-Naphthyl
2-Furyl
6
7
8
9
10
4j
a Unless otherwise noted, reactions were performed with 0.2 mmol of 3
and 20 mol% of DBU in CH3CN (2.0 mL) at 30 °C. b Isolated yield.
c The reaction was performed with 0.2 mmol of 3 and 20 mol% of
p-TsOH in toluene (2.0 mL) at 80 °C.
Acknowledgements
Support of this work by NSFC (No. 21102054) is greatly
appreciated.
entry 1). It turned out that the electronic properties of the N-sub-
stituent of 3 seemed to influence the yield. When N-substitutions
with neutral or electron-donating groups on 3 were employed,
the cyclization reactions worked well and gave the products in
high yields (Table 3, entries 1 and 3). Compound 3ab with elec-
tron-withdrawing group afforded the product 4b in moderate
yield (Table 3, entry 2). The cyclization of N-benzyl substituted
3ac gave a trace amount of 4d in the presence of DBU (20%),
while the treatment of 3ac with p-TsOH (20%) in toluene at
80 °C furnished 4d in 52% yield. A variety of above mentioned
α-amino nitriles 3 can be employed for the cyclization success-
fully. Noteworthily, based on this, a novel multicomponent
tandem SAAC reaction has also been developed. In this manner,
α-methylene-γ-butyrolactam 4a can be readily obtained from
available aldehyde 1, amine 5 and MBH adduct 2a in a one-pot
reaction (Scheme 2).11
Notes and references
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Scheme 2 Multicomponent
cyclization reaction (SAAC).
tandem
Strecker–allylic-alkylation–
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Scheme 3 Synthetic applications of the SAA substitution adduct.
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11 Under standard reaction conditions as mentioned in Table 1, direct allylic
alkylation of α-amino nitrile 1a with MBH carbonate 2a provided 3aa in
19% yield and 4a in 55% yield in the presence of DBU (20%) after
3 hours. However, submitting benzaldehyde, aniline and TMSCN in one
flask, subsequently adding DBU (20%), MBH adduct 2a and CH3CN
(under standard reaction conditions as mentioned in Table 2), gave rise to
α-methylene-γ-butyrolactam 4a in 54% yield with small amount of
unidentified substance after 25 hours.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2214–2217 | 2217