Development of a new α-aminonitrile synthesis

Article abstract of DOI:10.1081/SCC-200043270

α-Aminonitriles are prepared upon reaction of aryl carboxaldehydes with LiHMDS and acetone cyanohydrin. This new method provides a general route to the synthesis of various substituted α-aminoarylacetonitriles in high yield and purity, and avoids the use of the highly toxic cyanide salts.

Full text of DOI:10.1081/SCC-200043270

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Development of a New
α‐Aminonitrile Synthesis
Guo‐Hua Chu a , Minghua Gu a , Baudouin Gerard a
& Roland E. Dolle a
a Department of Chemistry , Adolor Corporation ,
700 Pennsylvania Drive, Exton, Pennsylvania,
19341, USA
Published online: 10 Jan 2011.
To cite this article: Guo‐Hua Chu , Minghua Gu , Baudouin Gerard & Roland E. Dolle
(2004) Development of a New α‐Aminonitrile Synthesis, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:24, 4583-4590, DOI: 10.1081/SCC-200043270
To link to this article: http://dx.doi.org/10.1081/SCC-200043270
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4583–4590, 2004
Development of a New
a-Aminonitrile Synthesis
*
Guo-Hua Chu, Minghua Gu, Baudouin Gerard,
and Roland E. Dolle
Department of Chemistry, Adolor Corporation,
Exton, Pennsylvania, USA
ABSTRACT
a-Aminonitriles are prepared upon reaction of aryl carboxaldehydes
with LiHMDS and acetone cyanohydrin. This new method provides
a general route to the synthesis of various substituted a-amino-
arylacetonitriles in high yield and purity, and avoids the use of the
highly toxic cyanide salts.
Key Words: a-Aminonitriles; a-Amino-arylacetonitriles; Strecker
synthesis; N-Trimethylsilylimines.
*
Correspondence: Guo-Hua Chu, Department of Chemistry, Adolor Corporation,
700 Pennsylvania Drive, Exton, PA 19341, USA; Tel: 484-595-1551; Fax: 484-595-
1551; E-mail: ghchu@adolor.com.
4583
DOI: 10.1081/SCC-200043270
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4584
Chu et al.
As part of our kappa opioid receptor agonist discovery program, we
required various substituted diamines with the general structure i as key building
blocks (Sch. 1). Diamines i are derived from the LAH reduction of diamides ii,
which in turn are generated from the corresponding a-aminonitriles iii, Strecker
reaction products.[1] The classical Strecker synthesis of a-aminonitriles involves
treating aldehydes iv with NaCN/NH4Cl or KCN/NH4Cl, and although widely
used, it often gives unsatisfactory results.[2–5] Recently, a modified version of
the Strecker reaction using Me3SiCN/NH3 was reported to circumvent the
limitations of the classical reaction.[6] However, during our synthesis, both
the classical and modified Strecker reaction gave unsatisfactory results for
several substituted benzaldehydes iv of interest. Because we required various
a-aminonitriles iii for the preparation of a diverse set of diamines i, and of
the general importance of iii as intermediates in the preparation of a-amino
acids, nitrogen-containing heterocycles, and other biologically active com-
pounds,[7,8] we sought to develop a robust preparation of a-aminonitriles. We
describe here a new, high yield method for the conversion of aryl carboxalde-
hydes to a-amino-arylacetonitriles via N-trimethylsilyl imines that can be per-
formed on a large scale and avoids the use of the highly toxic cyanide salts.[9]
N-Trimethylsilylimines (N-TMS imines) first appeared in the literature in
the 1960s.[10] In the early 1980s, Hart and coworkers reported their elegant
work on the application of N-TMS imines, derived from the reaction of
LiHMDS with nonenolizable aldehydes, in the total synthesis of natural pro-
ducts.[11] The N-TMS imines were shown to undergo facile 1,2-addition of
carbon nucleophiles, including Grignard reagents and ester enolates, to give
benzylamines and b-lactams, respectively. In the intervening years, other
researchers prepared N-TMS imines from enolizable aldehydes and have like-
wise demonstrated analogous reactivity with organometallic reagents.[12]
Given this precedent, the addition of cyanide (CN2) to N-TMS imines was
investigated as a potential route to a-aminonitriles.
In our first attempt, a solution of (3-benzyloxy)benzaldehyde in THF was
treated with LiHMDS (1.2 equiv.) to form the corresponding N-TMS imine,
Scheme 1.

Development of a New a-Aminonitrile Synthesis
4585
followed by treatment with acetone cyanohydrin (2.0 equiv.), an in situ source
of CN2.[13] Upon aqueous work-up, the corresponding a-aminonitrile was
obtained in 89% isolated yield. By comparison, the same benzaldehyde sub-
strate under Strecker conditions was previously reported to give a 43%
yield of product,[2] while a 55% yield was obtained using the modified
Strecker reaction (unpublished results). To the best of our knowledge,
this is the first application of N-TMS imines in the synthesis of a-amino-
arylacetonitriles.
The reaction was then conducted with a variety of substituted benzalde-
hydes with equally satisfying results (Table 1). Substrates containing either
electron-withdrawing or electron-donating groups with differing substitution
patterns (ortho, meta, para- substituted) afforded a-amino-arylacetonitriles
in good yield (entries 1–15). The yields using the new methodology were con-
sistently superior to those previously reported for the corresponding Strecker
synthesis (entries 1, 3, 4, 5, 7–10, 12, and 13). This was particularly true for
benzaldehydes containing electron-withdrawing groups where the Strecker
synthesis gave quite poor results. One limitation of this new method is that
it did not perform well with heteroaromatic carboxaldehydes, in particular,
nitrogen-containing heteroaromatic carboxaldehydes (entries 17 and 18).
These substrates afforded a-aminonitriles in moderate-to-low yield.
Finally, this new approach is suitable for large-scale synthesis. For
example, 50 g of a-amino-(3-benzyloxyphenyl)acetonitrile (compound iii,
X ¼ 3-PhCH2O; entry 3) was efficiently prepared by this method without
attenuation in yield (89%).
In conclusion, a new a-aminonitrile synthesis has been developed based
on the addition of CN2 to N-TMS imines. The reaction is a general and effi-
cient method for preparing various substituted a-amino-arylacetonitriles,
complementing the classical Strecker reaction. This chemistry extends the
utility of N-TMS imines in synthesis.
General Procedure
Substituted benzaldehyde iv (10 mmol) was dissolved in anhydrous THF
(40 mL) and cooled to 2408C. To this solution was added dropwise lithium
bis(trimethylsilyl)amide (LiHMDS) (1.0 M solution in THF, 12 mL,
12 mmol). The reaction mixture was warmed to 258C and stirred for 4 h.
Acetone cyanohydrin (1.83 mL, 20 mmol) was then added and the reaction
mixture stirred at 258C for 12 h, and then quenched with water or saturated
aqueous NaHCO3 (40 mL). The mixture was extracted with EtOAc
(3 ꢀ 50 mL) and the combined organic extracts were dried (Na2SO4), and
concentrated in vacuo. The residue was purified by flash chromatography

4586
Chu et al.
Table 1. Preparation of a-amino-arylacetonitriles.
Yield
%b, ( )c
Yield
%b, ( )c
Entry
1
Substratesa
Entry
10
Substratesa
92 (24)[2]
82 (27)[2]
2
3
88[6]
11
12
87
89 (43)[2]
85 (27)[2]
4
5
6
7
8
9
81 (9)[2]
81 (15)[3]
90
13
14
15
16
17
18
87 (30)[2]
88
80[14]
91 (47)[4]
88 (62)[5]
86 (16)[2]
70[6]
28[15]
18[16]
aThe aldehydes, lithium bis(trimethylsilyl)amide (1.0 M solution in THF), acetone cya-
nohydrin, and anhydrous THF were purchased from Aldrich and used directly without
further purification.
bYields refer to pure isolated a-amino-arylacetonitriles. The compounds known from
the literature were characterized by comparison of their physical and spectroscopic
data with the reported data. All the new compounds (entry 6, 11, and 14) exhibited
spectroscopic data (1HNMR, 13CNMR, MS) in agreement with the structures indicated,
and gave satisfactory elemental analysis results.
cValues in parentheses are the classic Strecker reaction yields reported in the
literature.

Development of a New a-Aminonitrile Synthesis
4587
on silica gel using ethyl acetate-hexane (1 : 2–2 : 1) as eluent, furnishing the
corresponding a-aminonitrile iii. The physical and spectroscopic data of
those compounds known from the literature were compared and identical
with the reported data. All the new compounds (entry 6, 11, and 14) were
1
fully characterized by HNMR, 13CNMR, and MS, and both the free base
and the HCl salt gave satisfactory elemental analysis results.
1
1
The HNMR spectra data of those known compounds, and the HNMR,
13CNMR, and MS spectra data and CHN analysis result of the new compounds
are given below:
1
Product of entry 1: H NMR (300 MHz, CDCl3) d 2.05 (brs, 2H), 5.22
(s, 1H), 7.40–7.32 (m, 3H), 7.63 (d, 1H).
1
Product of entry 2: H NMR (300 MHz, CDCl3) d 2.0 (brs, 2H), 3.88
(s, 3H), 4.91(s, 1H), 6.96 (d, 1H), 7.12 (m, 2H), 7.38 (t, 1H).
Product of entry 3: 1H NMR (300 MHz, DMSO-d6) d 7.50–7.35
(m, 6H), 7.20 (m, 1H), 7.10 (d, 1H), 7.02 (dd, 1H), 5.12 (s, 2H), 5.02
(s, 1H), 2.83 (brs, 2H).
1
Product of entry 4: H NMR (300 MHz, CDCl3) d 2.0 (brs, 2H), 4.90
(s, 1H), 7.42–7.35 (m, 3H), 7.55 (s, 1H).
1
Product of entry 5: H NMR (300 MHz, CDCl3) d 1.98 (brs, 2H), 4.90
(s, 1H), 7.50–7.30 (m, 3H), 7.70 (s, 1H).
Product of entry 6, a-amino-(3-iodophenyl)acetonitrile: mp of the free
base: 61.5–62.58C, mp of the HCl salt: 177.5–1798C dec.; 1H NMR (400MHz,
CDCl3) d 1.96 (brs, 2H), 4.88 (s, 1H), 7.18 (t, 1H), 7.52 (d, 1H), 7.72 (d, 1H),
7.90 (s, 1H); 13C NMR (400MHz, CDCl3) d 138.28, 138.15, 135.63, 130.69,
125.94, 120.32, 94.66, 46.50; MS m/z: 259 [M þ 1]þ, 242 [M-NH2]þ; Analysis
calculated for C8H7IN2 of the free base: C, 37.23; H, 2.73; N, 10.86 Found: C,
37.12; H, 2.66; N, 10.78; Analysis calculated for C8H8ClIN2 of the HCl salt: C,
32.63; H, 2.74; N, 9.51 Found: C, 32.44; H, 2.66; N, 9.31.
1
Product of entry 7: H NMR (300 MHz, CDCl3) d 1.90 (brs, 2H), 2.38
(s, 3H), 4.88 (s, 1H), 7.21 (d, 2H), 7.40 (d, 2H).
1
Product of entry 8: H NMR (300 MHz, CDCl3) d 1.96 (brs, 2H), 3.86
(s, 3H), 4.89 (s, 1H), 6.98 (d, 2H), 7.48 (d, 2H).
1
Product of entry 9: H NMR (300 MHz, CDCl3) d 1.92 (brs, 2H), 4.90
(s, 1H), 7.40 (d, 2H), 7.50 (d, 2H).
Product of entry 10: 1H NMR (300 MHz, CDCl3) d 1.94 (brs, 2H), 4.89
(s, 1H), 4.41(d, 2H), 7.54 (d, 2H).
Product of entry 11, a-amino-(2,3-dichlorophenyl)acetonitrile: mp of
the free base: 115.5–116.58C, mp of the HCl salt: 173.5–174.58C dec.;
1H NMR (400 MHz, CDCl3) d 2.04 (brd, 2H), 5.28 (t, 1H), 7.35 (t, 1H),
7.51 (d, 1H), 7.60 (d, 1H); 13C NMR (400 MHz, CDCl3) d 136.55, 134.19,
131.29, 131.21, 128.10, 126.23, 119.50, 45.71; MS m/z: 205 [M þ 4 þ 1]þ,
203 [M þ 2 þ 1]þ, 201 [M þ 1]þ, 188 [M-NH2 þ 4]þ, 186 [M-NH2 þ 2]þ,

4588
Chu et al.
184 [M-NH2]þ; Analysis calculated for C8H6Cl2N2 of the free base: C, 47.79;
H, 3.01; N 13.93 Found: C, 47.96; H, 3.07; N, 13.94; Analysis calculated for
C8H7Cl3N2 of the HCl salt: C, 40.46; H, 2.97; N 11.79 Found: C, 40.47; H,
2.97; N, 11.76.
Product of entry 12: 1H NMR (300 MHz, CDCl3) d 2.32 (brs, 2H), 5.70
(s, 1H), 7.26 (t, 1H), 7.40 (d, 2H).
Product of entry 13: 1H NMR (300 MHz, CDCl3) d 1.98 (brs, 2H), 3.91
(s, 3H), 3.95 (s, 3H), 4.90 (s, 1H), 6.90 (d, 1H), 7.05 (d, 1H), 7.10 (dd, 1H).
Product of entry 14, a-Amino-(3-bromo-4-methoxy-phenyl)acetonitrile:
mp of the free base: 108.5–109.58C, mp of the HCl salt: 174–1768C dec.;
1H NMR (400 MHz, CDCl3) d 1.93 (brs, 2H), 3.91 (s, 3H), 4.87 (s, 1H),
6.92 (d, 1H), 7.44 (dd, 1H), 7.73 (d, 1H); 13C NMR (400 MHz, CDCl3) d
156.37, 131.70, 129.68, 126.89, 120.66, 112.17, 111.96, 56.39, 46.17; MS
m/z: 226 [M-NH2 þ 2]þ, 224 [M-NH2]þ; Analysis calculated for
C9H9BrN2O of the free base: C, 44.84; H, 3.76; N 11.62 Found: C, 44.60;
H, 3.70; N, 11.49; Analysis calculated for C9H10BrClN2O of the HCl salt:
C, 38.95; H, 3.63; N 10.09 Found: C, 38.73; H, 3.55; N, 9.92.
1
Product of entry 15: H NMR (300 MHz, CDCl3) d 2.0 (brs, 2H), 4.90
(s, 1H), 7.28 (m, 2H), 7.42 (dd, 1H).
Product of entry 16: 1H NMR (300 MHz, CDCl3) d 2.10 (brs, 2H), 5.10
(s, 1H), 7.0 (m, 1H), 7.23 (d, 1H), 7.33 (d, 1H).
1
Product of entry 17: H NMR (300 MHz, CDCl3) d 2.0 (brs, 2H), 4.98
(s, 1H), 7.35 (m, 1H), 7.88 (m, 1H), 8.62 (m, 1H), 8.77 (d, 1H).
Product of entry 18: 1H NMR (300 MHz, CDCl3) d 2.22 (brs, 2H), 5.03
(s, 1H), 7.30 (m, 1H), 7.52 (d, 1H), 7.79 (m, 1H), 8.69 (d, 1H).
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Received in the USA August 24, 2004