Three-component synthesis of α-amino-α-aryl carbonitriles from arynes, aroyl cyanides, and N,N-dimethylformamide

Article abstract of DOI:10.1002/ejoc.201400040

A general and efficient synthesis of α-amino-α-aryl carbonitriles through the three-component reaction of arynes, aroyl cyanides, and DMF in a single step is described. DMF was not only used as the solvent, but it also participated in the reaction as a component. Used as the cyanide sources, the aroyl cyanides solved the toxicity and solubility problems associated with the use of HCN or metal cyanides in the Strecker synthesis. This procedure furnished α-amino-α-aryl carbonitriles in moderate to good yields with broad substrate scope. Moreover, this reaction could be performed under mild conditions with high atom economy.

Full text of DOI:10.1002/ejoc.201400040

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201400040
Three-Component Synthesis of α-Amino-α-aryl Carbonitriles from Arynes,
Aroyl Cyanides, and N,N-Dimethylformamide
Chao Zhou,[a] Jing Wang,[a] Jisong Jin,[a] Ping Lu,*[a] and Yanguang Wang*[a]
Keywords: Multicomponent reactions / Arynes / Cyanides / Domino reactions / Amino carbonitriles
A general and efficient synthesis of α-amino-α-aryl carbo-
nitriles through the three-component reaction of arynes,
aroyl cyanides, and DMF in a single step is described. DMF
was not only used as the solvent, but it also participated in
the reaction as a component. Used as the cyanide sources,
the aroyl cyanides solved the toxicity and solubility problems
associated with the use of HCN or metal cyanides in the
Strecker synthesis. This procedure furnished α-amino-α-aryl
carbonitriles in moderate to good yields with broad substrate
scope. Moreover, this reaction could be performed under
mild conditions with high atom economy.
aryne and DMF were used as two components attracted
our attention (Scheme 1).[9]
Introduction
Since the first multicomponent reaction (MCR) was dis-
closed by Strecker in 1850,[1] MCRs have been widely devel-
oped and utilized in modern organic synthesis.[2] These re-
actions combine three or more components in one pot and
provide a major product through a sequential route with
high atom economy and high bond-formation efficiency.[3–8]
In this blooming field, Yoshida’s elegant design in which an
Bifunctional α-amino carbonitriles are not only key in-
termediates in the preparation of α-amino acids, but they
also play important roles in constructing various heterocy-
cles because of their dual functionality.[10] One of the most
practical methods for the preparation of α-amino car-
bonitriles is the classical Strecker synthesis, which combines
an aldehyde/ketone, ammonia, and hydrogen cyanide in one
pot to provide α-amino carbonitriles in a single step.[1]
Much effort has been devoted to the enantiomeric synthesis
of chiral α-amino carbonitriles[11] and to the disclosure
of new cyanide surrogates.[12] Only a few contributions are
related to new methodologies in constructing α-amino
carbonitriles, such as the acyl-Strecker reactions in
Scheme 1.[13]
Three kinds of cyanide sources are normally applied in
the Strecker synthesis. One is HCN, which is classically
used, but it has extremely high toxicity. The second one
is metal cyanides,[14] which are highly toxic and show low
solubility in common organic solvents. The third one is or-
ganic compounds that contain a CN group that can release
the cyanide anion uring the reaction process. In these cases,
TMSCN,[15] acetone cyanohydrin,[16] acetyl cyan-
ide,[13] ethyl carbonocyanidate,[17] and cyanobis(dibenzyl-
amino)borane[18] are extensively used. As the cyanide anion
is in situ generated and consumed during these reaction
processes, these reactions are environmentally more benign
and operationally safer than those that use HCN or metal
cyanides. Herein, we would like to report a three-compo-
nent reaction that uses benzoyl cyanide as the cyanide
source (Scheme 1).
Scheme 1. Our work leading to α-amino carbonitriles.
[a] Department of Chemistry, Zhejiang University
Hangzhou 310027, P. R. China
E-mail: pinglu@zju.edu.cn
orgwyg@zju.edu.cn
http://mypage.zju.edu.cn/en/pinglu
http://mypage.zju.edu.cn/en/orgwyg
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400040.
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Three-Component Synthesis of α-Amino-α-aryl Carbonitriles
of 1a/2a was altered to 2:1, 3a was isolated in 70% yield.
Conversely, increasing the amount of 2a decreased the yield
markedly (Table 1, Entries 12 and 13). The yield was im-
proved if the reaction was conducted under N2 (Table 1,
Entry 14). Thus, the optimal reaction conditions were es-
tablished.
Results and Discussion
The reaction was first performed by mixing 2-(trimethyl-
silyl)phenyl trifluoromethanesulfonate (1a, 1 mmol) and
benzoyl cyanide (2a, 1 mmol) in DMF (10 mL) in the pres-
ence of 4 Å molecular sieves. If CsF (2 mmol) was added to
the mixture and the resulting mixture was heated at 60 °C
for 3 h, α-amino-α-(2-benzoyloxy)phenyl carbonitrile 3a
was formed and isolated by column chromatography in
55% yield. Spectroscopy analysis of 3a indicated that DMF
participated in the reaction as a component.[19] Delighted
by this result and the potential use of α-amino-α-aryl carbo-
nitriles as effective sphingomyelin synthase inhibitors,[20]
we optimized the reaction conditions for the formation of
3a, and the results are listed in Table 1. Without the 4 Å
molecular sieves, the yield dramatically decreased to 10%
(Table 1, Entry 2). Keeping the reaction mixture dry was
critical for a better transformation. Screening the fluoride
source, it was found that CsF was superior to all others
tested, including KF, LiF, and tetrabutylammonium fluor-
ide (TBAF; Table 1, Entries 3–5). Upon using 10 equiv. of
DMF with the supplementary addition of acetonitrile as
the solvent, 3a was not isolated, although it was detectable
by TLC analysis. By changing the solvent from acetonitrile
to THF and toluene, 3a was not detected (Table 1, En-
tries 6–8). Either raising or lowering of the reaction tem-
perature decreased the yields (Table 1, Entries 9 and 10).
By changing the amount of DMF to 3 mL, the yield of 3a
decreased to 15% (Table 1, Entry 11). Increasing the
amount of 1a significantly increased the yield. If the ratio
Table 2. Substrate scope of this three-component reaction.[a]
Table 1. Screening of the reaction conditions.[a]
Entry
Reagent
(2.0 equiv.)
DMF
[equiv.]
Solvent
T
[°C]
Yield[b]
[%]
1
2[c]
3
4
5
6
7
8
9
10
11[e]
12[f]
13[g]
14[h]
CsF
CsF
KF
–
–
–
–
–
10
10
10
–
–
–
DMF
DMF
DMF
DMF
DMF
MeCN
THF
toluene
DMF
DMF
DMF
DMF
DMF
DMF
60
60
60
60
60
60
60
60
55
70
60
60
60
60
55
10
20
LiF
15
TBAF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
Ͻ5
Ͻ5
n.d.[d]
n.d.[d]
47
46
15
70
23
74
–
–
–
[a] Unless otherwise specified, all reactions were performed with 1a
(1.0 mmol), 2a (1.0 mmol), CsF (2.0 mmol) and 4 Å molecular si-
eves (1 g) in DMF (10 mL) at 60 °C for 3 h. Tf = trifluoromethyl-
sulfonyl. [b] Yield of isolated product after silica gel column
chromatography. [c] Without 4 Å molecular sieves. [d] n.d. = not
detected. [e] DMF (3 mL). [f] 1a (2.0 mmol). [g] 2a (1.5 mmol).
[h] Under nitrogen.
[a] Reaction conditions: A mixture of 1 (1.0 mmol), 2 (0.5 mmol),
CsF (2.0 mmol), and 4 Å molecular sieves (1.0 g) in DMF (5 mL)
was heated to 60 °C for 3 h under nitrogen.
Eur. J. Org. Chem. 2014, 1832–1835
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C. Zhou, J. Wang, J. Jin, P. Lu, Y. Wang
SHORT COMMUNICATION
Scheme 2. A regioselectivity problem arises from unsymmetrical benzynes.
With the optimized reaction conditions in hand, we able. If a mixture of 10 mmol of 1a, 5 mmol of 4-(tert-but-
tested the substrate scope (Table 2). Naphthoyl cyanide pro- yl)benzoyl cyanide, and 20 mmol of CsF was heated at
duced 3b in 63% yield. Benzoyl cyanides with aliphatic 60 °C for 6 h in 50 mL of DMF in the presence of 10 g of
groups on the benzene ring, such as methyl, ethyl, and tert- 4 Å molecular sieves, 1.23 g of 3f was isolated in 73% yield.
butyl, furnished 3c, 3e, and 3f in 40, 59, and 88% yield,
Notably, the possibility of using N,N-dimethylacetamide
respectively. Altering the position of the methyl group on in place of DMF was investigated for 1a, but we did not
the benzene ring of the benzoyl cyanide from the para posi- isolate any of the desired product from the complex reac-
tion to the meta position slightly raised the yield of α-amino tion mixture.
carbonitrile 3d. Single crystal analysis of 3d further con-
On the basis of the above reactions and literature reports,
firmed that the product contained the α-amino carbonitrile we postulate a possible mechanism for the formation of the
substructure (Figure 1).[21] However, the yields were signifi- α-amino carbonitriles (Scheme 3). First, benzyne intermedi-
cantly affected by the presence of a chlorine or bromine ate A is in situ generated by treatment of benzyne surrogate
atom on the benzene ring. Thus, 3i, 3j, and 3k were ob- 1a with the fluoride anion. Then, a [2+2] cycloaddition be-
tained in 33, 32, and 37% yield, respectively. By changing tween benzyne and the carbonyl group of DMF occurs to
the benzyne surrogate, we isolated 3l, 3m, 3n, and 3o in 48, form oxetene ring B. Some oxetenes are stable and can be
40, 43, and 64% yield, respectively. Further application of isolated.[22] In this case, the benzene-fused oxetene ring is
these benzyne surrogates furnished 3p, 3q, and 3r in 71, 58, unstable, and its fragmentation leads to the formation of α-
and 29% yield, respectively. Aliphatically substituted 3p amino-α-unsaturated ketone C.[9,23] Through effective
and 3q were obtained in higher yield than bromine-substi- push–pull of the lone pair of electrons of the dimeth-
tuted 3r.
ylamino group in intermediate C, benzoyl cyanide is incor-
porated into the product through reasonable intermediate
D.
Figure 1. Crystal structure of 3d.
Upon changing the benzyne surrogate to unsymmetrical
1b, 3sa and 3ta were regioselectively prepared in 58 and
52% yield, respectively, and 3sb and 3tb were not found in
these cases (Scheme 2). The regioselectivity was confirmed
by HMBC spectroscopy (see the Supporting Information).
However, if unsymmetrical benzyne surrogate 1c was used,
Scheme 3. Proposed mechanism for the formation of α-amino
carbonitrile.
Conclusions
3ua and 3ub were obtained in 42% yield. The ratio of 3ua/
3ub was determined to be 1:2 on the basis of the H NMR constructed α-amino-α-aryl carbonitriles from benzyne sur-
spectrum. Notably, this three-component reaction is scal- rogates, aroyl cyanides, and N,N-dimethylformamide under
We developed a three-component reaction that efficiently
1
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Eur. J. Org. Chem. 2014, 1832–1835

Three-Component Synthesis of α-Amino-α-aryl Carbonitriles
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mild reaction conditions in a single step. DMF not only
worked as a component, but it also served as the solvent in
this reaction. Aroyl cyanides slowly released the cyanide
anion during the course of the reaction, which solved the
toxicity and solubility problems arising from the use of clas-
sical HCN and metal cyanides in the Strecker reaction.
Other multicomponent reactions based on benzyne and
DMF are underway.
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Experimental Section
General Methods: Unless otherwise indicated, NMR spectra were
obtained with a Bruker Avance DMX400 spectrometer operating
at 400 MHz for 1H and 100 MHz for 13C in CDCl3. Melting points
were recorded with a Büchi 535 apparatus. All HRMS measure-
ments were performed upon electron ionization (EI or ESI) with a
mass spectrometer. Flash column chromatography was performed
by employing 300–400 mesh silica gel. Thin layer chromatography
(TLC) was performed with silica gel HSGF254.
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Typical Experimental Procedure for the Preparation of 2-[Cyano(di-
methylamino)methyl]phenyl Benzoate (3a): A solution of 2-(trimeth-
ylsilyl)phenyl trifluoromethanesulfonate (298 mg, 1.0 mmol),
benzoyl cyanide (65 mg, 0.5 mmol), and 4 Å molecular sieves
(1000 mg) in DMF (5 mL) was prepared under nitrogen. After the
reaction mixture had been stirred for 2 min, CsF (302 mg,
2.0 mmol) was added. The reaction mixture was stirred at 60 °C
for 3 h. After cooling the reaction mixture to room temperature,
the excess amount of DMF was removed under reduced pressure.
The residue was purified by column chromatography (silica gel; 5%
triethylamine in hexane/ethyl acetate, 10:1) to afford 3a (104 mg,
74%) as a yellow solid. M.p. 89–91 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.19 (d, J = 7.1 Hz, 2 H), 7.65 (dd, J = 7.2, 6.5 Hz, 2
H), 7.55–7.46 (m, 3 H), 7.35 (dd, J = 7.6, 0.8 Hz, 1 H), 7.29–7.26
(m, 1 H), 5.01 (s, 1 H), 2.12 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 164.9, 149.5, 133.9, 130.6, 130.3, 129.6, 129.5, 128.9,
126.4, 126.2, 124.3, 114.7, 59.5, 41.6 ppm. HRMS (EI): calcd. for
C17H16N2O2 [M]+ 280.1212; found 280.1209.
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Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures; characterization data; cop-
ies of the NMR spectra of 1a–1f, 2b–2j, and 3a–3ub; crystallo-
graphic information of 3d.
[21] CCDC-973722 (for 3d) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
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We thank the National Nature Science Foundation of China
(21272103, 21032005) for financial support.
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Received: January 10, 2014
Published Online: February 13, 2014
Eur. J. Org. Chem. 2014, 1832–1835
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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