A convenient synthesis of N-boc-protected α-aminonitriles from α-amidosulfones

Article abstract of DOI:10.1081/SCC-200028592

Synthesis of N-Boc-protected α-aminonitriles starting from N-Boc-protected α-aminosulfones is described. Treatment of the sulfone with two equivalents of potassium cyanide in 2-propanol or dichloromethane- H₂O under phase transfer condition affords crystalline N-Boc-protected α-aminonitriles in good yield. Hydrolysis of the aminonitriles provides a convenient access to racemic α-amino acids.

Full text of DOI:10.1081/SCC-200028592

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A Convenient Synthesis
of N‐Boc‐Protected
α‐Aminonitriles from
α‐Amidosulfones
Vorawit Banphavichit a , Saowaluk
Chaleawlertumpon a , Worawan Bhanthumnavin a
& Tirayut Vilaivan a
a Organic Synthesis Research Unit, Department
of Chemistry, Faculty of Science, Chulalongkorn
University, Phayathai Road, Patumwan, Bangkok,
10330, Thailand
Version of record first published: 10 Jan 2011.
To cite this article: Vorawit Banphavichit , Saowaluk Chaleawlertumpon ,
Worawan Bhanthumnavin & Tirayut Vilaivan (2004): A Convenient Synthesis of
N‐Boc‐Protected α‐Aminonitriles from α‐Amidosulfones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:17, 3147-3160
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3147–3160, 2004
A Convenient Synthesis of N-Boc-Protected
a-Aminonitriles from a-Amidosulfones
Vorawit Banphavichit, Saowaluk Chaleawlertumpon,
*
Worawan Bhanthumnavin, and Tirayut Vilaivan
Organic Synthesis Research Unit, Department of Chemistry, Faculty of
Science, Chulalongkorn University, Patumwan, Bangkok, Thailand
ABSTRACT
Synthesis of N-Boc-protecteda-aminonitriles starting from N-Boc-protected
a-aminosulfones is described. Treatment of the sulfone with two equivalents
of potassium cyanide in 2-propanol or dichloromethane-H2O under phase
transfer condition affords crystalline N-Boc-protected a-aminonitriles in
good yield. Hydrolysis of the aminonitriles provides a convenient access
to racemic a-amino acids.
Key Words: Amino acids; Imines; Nucleophilic additions; Phase-
transfer catalysis; Strecker.
*
Correspondence: Tirayut Vilaivan, Organic Synthesis Research Unit, Department of
Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Patumwan,
Bangkok 10330, Thailand; Fax: þ66-2-2187598; E-mail: vtirayut@chula.ac.th.
3147
DOI: 10.1081/SCC-200028592
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3148
Banphavichit et al.
Alpha-amino acid, an important building block for peptides, can be
obtained from hydrolysis of a-aminonitriles prepared from the Strecker reac-
tion. Classical Strecker reaction via treatment of an aldehyde or ketone, NH3,
and a CN2 source (Sch. 1) suffers drawbacks from its reversible nature.[1]
Many variants of the Strecker reaction exist, e.g., use of amines or
(NH4)2CO3 for NH3 or bisulfite adduct for free aldehydes.[2] However,
these methods are not yet sufficient in terms of efficiency or generality. Fur-
thermore, when amines other than NH3 are used, a suitable deprotection
must follow that may not be straightforward. We propose that addition of
CN2 to N-acylimines should provide an efficient entry to N-acyl-protected
a-aminonitriles. Subsequent hydrolysis should give a direct synthesis of
a-amino acids. N-protected a-aminonitriles are also starting materials for
many heterocyclic and biologically active compounds.[3,4] They are generally
obtained from a-amino acids via a-aminoamides by dehydration with
reagents such as TsCl[3a] or MsCl,[4b] TFAA,[5] cyanuric chloride,[3b,6]
oxalyl chloride,[4c,4d,7] or dialkyltin oxide.[8] In 1990, Katritzky reported an
N-acyl a-aminonitriles synthesis from a-amidobenzotriazoles and had
extended this method to peptide synthesis.[9] More recently, a-amidosulfones
1 have attracted attention as a versatile acylimine equivalent. These stable
solids are easily prepared from aldehydes, amides or carbamates, and
sodium benzenesulfinate or sodium p-toluenesulfinate.[10,11] They react with
nucleophiles such as lithium enolates,[12,13] RMgX,[14] and ZnR2,[15–17]
among others.[18–21] There has been a report on the synthesis of N-protected
a-amino acids via KMnO4-oxidation of the sodium nitronate-1 adduct.[22] We
reasoned that CN2 should be a sufficiently strong base to cause elimination of
the sulfinate ion from 1 to provide acylimines, which can then undergo irre-
versible cyanide addition to provide N-acyl a-aminonitriles. To our know-
ledge, there is no other literature report on the synthesis of a-aminonitriles
by this approach.
Initially, the N-Boc-a-amidosulfone 1a (R ¼ Ph) derived from benzal-
dehyde was treated with potassium cyanide under a variety of conditions
(Sch. 2). In lower alcohols such as methanol and ethanol, although the reaction
was fast, a significant amount of by-product derived from alkoxide substi-
tution was observed. The reaction was significantly slower in dipolar
aprotic solvents including N,N-dimethylformamide (DMF) and MeCN. The
Scheme 1.

Convenient Synthesis of N-Boc-Protected a-Aminonitriles
3149
Scheme 2.
best yield (66%) was obtained when 2-propanol was used as a solvent (method
A). At least two equivalents of KCN were required to obtain good yields. This
suggested that one equivalent of KCN may act as a base to eliminate the phe-
nylsulfinate ion to form the N-Boc imine in situ, which was then further
attacked by the second equivalent of the cyanide. Attempts to reduce the
amounts of KCN to one equivalent by addition of another external base
were marginally successful. K2CO3 was found to be an acceptable external
base, while organic bases like triethylamine were ineffective. However, the
use of two equivalents of KCN provided a better yield, hence is the preferred
method. The reaction could also be conveniently carried out under phase
transfer condition in a dichloromethane-water mixture (method B) to give
the same product in slightly better yield (73%). Both tetrabutylammonium
hydrogensulfate and benzyltriethylammonium chloride were effective phase
transfer catalysts. In both methods, the reaction rates were considerably
faster (requires less than 3 hr) than cyanide addition to Katritzky’s amidoben-
zotriazole (requires more than 10 hr to several days),[9] presumably due to the
better leaving ability of the sulfinate compared to that of benzotriazolate ions.
The opportunity of using a chiral phase transfer catalyst to induce asymmetric
cyanation was also explored. Unfortunately, the aminonitrile 2a (R ¼ Ph)
obtained from the reaction of 1 (R ¼ Ph) and potassium cyanide in the pre-
sence of N-benzylcinchonidinium chloride (10 mol %) as catalyst was found
to be racemic.
Both reaction conditions were tested with N-Boc-a-aminosulfones 1
derived from a variety of aromatic and aliphatic aldehydes. We were
pleased to find that the reaction is compatible with a wide variety of functional
groups. In most cases the stable crystalline N-Boc-a-aminonitriles 2 were
obtained after simple aqueous work-up followed by column chromatography.
All products revealed a characteristic infrared (IR) absorption around
1
2200 cm21, a pair of H resonance between 4 and 6 ppm (CaH and NH),
and a 13C resonance of C;N between 116 and 118 ppm in addition to all

3150
Banphavichit et al.
expected resonances. Both aromatic and aliphatic substrates are well tolerated.
The electronic nature and position of substituents on the aromatic ring
appeared to have little effect on the yield (ranging from 36% to 86%) and reac-
tion rate, except for those containing strong electron-withdrawing groups such
as cyano (1h) and nitro (1e–g), where the yields were only modest. In these
cases, the reaction under phase-transfer condition provided somewhat
cleaner reaction, hence better yields (ranging from 36% to 55%). Heteroaro-
matic substrates such as 2-furyl (1q) and 2-thienyl (1r) also gave satisfactory
yields (.80%). However, only complex mixtures were obtained with 2- and
4-pyridyl substrates under both conditions. It was reasoned that nucleophilic
addition may also take place on the pyridyl ring. For aliphatic substrates,
the degree of branching is well tolerated (R ¼ iPr, tBu, iBu, and cyclohexyl).
Equally good results were obtained with those easily tautomerizable substrates
bearing a-unbranched alkyl groups, especially when R ¼ PhCH2 (1z).
The N-Boc-a-aminonitriles 2 may be readily converted to the correspond-
ing amino acids by refluxing with aqueous HCl according to known pro-
cedures.[23] The amino acid hydrochlorides were obtained simply by
evaporation of the solvent and washing or recrystallizing the residue with
water. Some representative examples are summarized in Sch. 3.
In conclusion, a very simple yet effective method for the synthesis of N-
Boc-a-aminonitriles based on Strecker-type reaction of N-Boc-a-aminosul-
fones with potassium cyanide is developed. Acid hydrolysis of the N-Boc-
a-aminonitriles provides a convenient preparation of racemic a-amino
acids. The procedure compares very well in terms of yield and efficiency to
other existing methods of a-amino acid synthesis, with an added advantage
of being extremely simple. It also provides access to phenylglycine deriva-
tives, which are not accessible by the alternative synthetic route involving
alkylation of glycine equivalents. Since aldehydes are widely available, this
method should provide a very convenient route to unnatural amino acids.
Scheme 3.

Convenient Synthesis of N-Boc-Protected a-Aminonitriles
3151
EXPERIMENTAL
General
Melting points were recorded on an Electrothermal 9100 melting point
apparatus and are quoted uncorrected. Elemental analyses were performed on
a Perkin-Elmer Elemental Analyzer 2400 CHNS/O at the Research Equipment
1
Centre, Chulalongkorn University. Routine H nuclear megnetic resonance
(NMR) spectra were obtained on a Varian Mercury Plus operating at 400 MHz
(1H) and 100 MHz (13C) or Bruker AMX200 operating at 200 MHz (1H) and
50MHz (13C). Chemical shifts are reported in parts per million (ppm, d) down-
field relative to the internal standard tetramethylsilane. Unless otherwise noted,
all reagent-grade chemicals and solvents were obtained from commercial suppli-
ers (Aldrich, Fluka, and Merck) and were used as received. Reactions were per-
formed under ambient conditions without the need for anhydrous solvents or
inert atmosphere.
Typical Procedure for the Synthesis
of N-Boc-a-aminonitriles (2)
Method A
The sulfone 1 (0.30mmol) and potassium cyanide (39mg, 0.60mmol) were
stirred in 2-propanol (4 mL) at room temperature for 3 hr. The solvent was
removed under reduced pressure and the residue dissolved in ethyl acetate.
The ethyl acetate solution was washed with brine, dried (MgSO4), and evapor-
ated. The crude product was purified by chromatography on silica gel.
Method B
The sulfone 1 (0.30 mmol), potassium cyanide (39 mg, 0.60 mmol), and
tetrabutylammonium hydrogensulfate (10.2 mg, 0.03 mmol) were stirred vigo-
rously in a mixture of dichloromethane (4 mL) and water (0.2 mL) at room
temperature. After usual aqueous work-up, the crude product was purified
by flash silica gel column chromatography to afford the pure product.
Spectroscopic and Analytical Data of N-Boc-a-aminonitriles
N-Boc-amino-phenylacetonitrile (2a) (R ¼ Ph)
White solid. Isolated yield: 66% (method A), 73% (method B). m.p.
1798C–1818C; 1H NMR (200 MHz, CDCl3) d 7.47–7.24 (m, 5H), 5.72

3152
Banphavichit et al.
(br d, J ¼ 8.7 Hz, 1H), 5.37 (d, J ¼ 8.7 Hz, 1H), 1.40 (s, 9H); 13C NMR
(50 MHz, CDCl3) d 154.3, 133.5, 129.4, 129.3, 126.9, 117.8, 81.5, 46.1,
28.2; m/z (EI) 232 [Mþ]; Anal. Calcd. for C13H16N2O2: C, 67.22; H, 6.94;
N, 12.06. Found: C, 67.01; H, 6.78; N, 12.14.
N-Boc-amino-(40-methylphenyl)acetonitrile (2b) (R ¼ 4-CH3C6H4)
White solid. Isolated yield: 76% (method A), 82% (method B). m.p.
1638C–1658C; 1H NMR (200 MHz, CDCl3) d 7.34 (d, J ¼ 8.0 Hz, 2H),
7.16 (d, J ¼ 8.0 Hz, 2H), 5.66 (d, J ¼ 8.0 Hz, 1H), 5.40 (d, J ¼ 8.0 Hz, 1H),
2.32 (s, 3H) 1.44 (s, 9H); 13C NMR (50 MHz, CDCl3) d 154.3, 139.4,
130.6, 129.8, 126.8, 117.9, 81.4, 45.8, 28.2, 21.1; m/z (EI) 246 [Mþ]; Anal.
Calcd. for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.36; H,
7.35; N, 11.35.
N-Boc-amino-(40-isopropylphenyl)acetonitrile (2c) (R ¼ 4-iPrC6H4)
White solid. Isolated yield: 74% (method A), 79% (method B). m.p.
1408C–1418C; 1H NMR (200 MHz, CDCl3) d 7.38 (d, J ¼ 8.0 Hz, 2H), 7.25
(d, J ¼ 8.0 Hz, 2H), 5.70 (d, J ¼ 8.5 Hz, 1H), 5.44 (d, J ¼ 8.5 Hz, 1H), 2.92
(m, 1H) 1.44 (s, 9H), 1.27 (d, J ¼ 7.0 Hz, 6H); 13C NMR (50 MHz, CDCl3)
d 154.3, 150.3, 130.9, 127.3, 126.9, 117.9, 81.3, 45.8, 33.8, 28.2, 23.8; m/z
(EI) 274 [Mþ]; Anal. Calcd. for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21.
Found: C, 70.19; H, 8.08; N, 10.36.
N-Boc-amino-(40-tert-butylphenyl)acetonitrile (2d) (R ¼ 4-tBuC6H4)
White solid. Isolated yield: 74% (method A), 78% (method B). m.p.
1318C–1328C; 1H NMR (200 MHz, CDCl3) d 7.40 (m, 4H), 5.72
(d, J ¼ 8.0 Hz, 1H), 5.31 (d, J ¼ 8.0 Hz, 1H), 1.45 (s, 9H), 1.29 (s, 9H); 13C
NMR (50 MHz, CDCl3) d 154.2, 152.7, 130.5, 126.7, 126.2, 117.9, 81.4,
45.8, 34.7, 31.2, 28.2; m/z (EI) 288 [Mþ]; Anal. Calcd. for C17H24N2O2:
C, 70.80; H, 8.39; N, 9.71. Found: C, 70.91; H, 8.59; N, 9.71.
N-Boc-amino-(40-nitrophenyl)acetonitrile (2e) (R ¼ 4-O2NC6H4)
Light yellow solid. Isolated yield: 50% (method A), 55% (method B).
m.p. 1578C–1598C; 1H NMR (200 MHz, CDCl3) d 8.30 (d, J ¼ 8.0 Hz,
2H), 7.67 (d, J ¼ 8.0 Hz, 2H), 5.91 (br d, J ¼ 8.7 Hz, 1H), 5.31
(d, J ¼ 8.7 Hz, 1H), 1.46 (s, 9H); 13C NMR (50 MHz, CDCl3) d 154.0,
148.5, 140.3, 127.9, 124.5, 116.6, 82.5, 45.4, 28.2; m/z (EI) 277 [Mþ];

Convenient Synthesis of N-Boc-Protected a-Aminonitriles
3153
Anal. Calcd. for C13H15N3O4: C, 56.31; H, 5.45; N, 15.15. Found: C, 56.37; H,
5.54; N, 15.20.
N-Boc-amino-(30-nitrophenyl)acetonitrile (2f) (R ¼ 3-O2NC6H4)
Light yellow solid. Isolated yield: 36% (method A), 36% (method B).
m.p. 1448C–1468C; 1H NMR (400 MHz, CDCl3) d 8.37 (s, 1H), 8.33
(d, J ¼ 8.0 Hz, 1H), 7.83 (d, J ¼ 7.5 Hz, 1H), 7.62 (apparent t, 1H), 5.96
(br m, 1H), 5.42 (br m, 1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) d
154.0, 148.5, 136.0, 133.2, 130.1, 124.3, 122.0, 116.6, 82.2, 45.7, 28.2; m/z
(EI) 277 [Mþ]; Anal. Calcd. for C13H15N3O4: C, 56.31; H, 5.45; N, 15.15.
Found: C, 56.31; H, 5.44; N, 15.17.
N-Boc-amino-(20-nitrophenyl)acetonitrile (2g) (R ¼ 2-O2NC6H4)
Light yellow solid. Isolated yield: 36% (method A), 47% (method B).
1
m.p. 988C–998C; H NMR (400 MHz, CDCl3) d 8.18 (d, J ¼ 8.0 Hz, 1H),
7.73–7.78 (m, 2H), 7.62 (apparent t, 1H), 6.29 (d, J ¼ 8.8 Hz, 1H), 5.83 (br
m, 1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) d 154.0, 148.5, 134.8,
131.7, 131.5, 126.0, 122.0, 116.3, 82.3, 44.4, 28.1; m/z (EI) 277 [Mþ];
Anal. Calcd. for C13H15N3O4: C, 56.31; H, 5.45; N, 15.15. Found: C, 56.35;
H, 5.28; N, 15.12.
N-Boc-amino-(40-cyanophenyl)acetonitrile (2h) (R ¼ 4-NCC6H4)
1
White solid. Isolated yield: 42% (method B). m.p. 1068C–1078C; H
NMR (200 MHz, CDCl3) d 7.74–7.59 (2 ꢀ d, 4H), 5.87 (br d, J ¼ 8.9 Hz,
1H), 5.26 (d, J ¼ 8.9 Hz, 1H), 1.46 (s, 9H); 13C NMR (50 MHz, CDCl3) d
154.0, 138.6, 133.0, 127.6, 117.8, 116.7, 113.6, 82.3, 45.6, 28.2 (3C); m/z
(EI) 257 [Mþ]; Anal. Calcd. for C14H15N3O2: C, 65.36; H, 5.88; N, 16.33.
Found: C, 55.59; H, 5.50; N, 16.33.
N-Boc-amino-(40-fluorophenyl)acetonitrile (2i) (R ¼ 4-FC6H4)
White solid. Isolated yield: 64% (method A), 83% (method B). m.p.
1
1198C–1218C; H NMR (200 MHz, CDCl3) d 7.45 (m, 2H), 6.97 (m, 2H),
5.70 (br, 1H), 5.54 (d, J ¼ 8.0 Hz, 1H), 1.41 (s, 9H); 13C NMR (50 MHz,
1
3
CDCl3) d 163.1 (d, J13C-19F ¼ 248 Hz), 154.3, 129.5, 128.8 (d, J13C-19F
¼
2
8.5 Hz), 117.7, 116.2 (d, J13C-19F ¼ 22.0 Hz), 81.6, 45.4, 28.2; m/z (EI)
250 [Mþ]; Anal. Calcd. for C13H15N2O2F: C, 62.39; H, 6.04; N, 11.19.
Found: C, 62.48; H, 6.03; N, 11.08.

3154
Banphavichit et al.
N-Boc-amino-(40-chlorophenyl)acetonitrile (2j) (R ¼ 4-ClC6H4)
White solid. Isolated yield: 60% (method A), 84% (method B). m.p.
1
1558C–1578C; H NMR (200 MHz, CDCl3) d 7.38 (m, 4H), 5.74 (br d,
J ¼ 8.5 Hz, 1H), 5.43 (d, J ¼ 8.5 Hz, 1H), 1.42 (s, 9H); 13C NMR (50 MHz,
CDCl3) d 154.2, 135.5, 132.1, 129.4, 128.2, 117.4, 81.7, 45.4, 28.2; m/z
(EI) 266 [Mþ]; Anal. Calcd. for C13H15N2O2Cl: C, 58.54; H, 5.67; N,
10.50. Found: C, 58.52; H, 5.63; N, 10.64.
N-Boc-amino-(40-bromophenyl)acetonitrile (2k) (R ¼ 4-BrC6H4)
White solid. Isolated yield: 63% (method A), 83% (method B). m.p.
1688C–1698C; 1H NMR (200 MHz, CDCl3) d 7.50 (d, J ¼ 8.0 Hz, 2H),
7.28 (d, J ¼ 8.0 Hz, 2H), 5.73 (br d, J ¼ 8.1 Hz, 1H), 5.32 (d, J ¼ 8.5 Hz,
1H), 1.44 (s, 9H); 13C NMR (50 MHz, CDCl3) d 154.1, 132.4, 128.5, 123.7,
117.3, 81.9, 45.5, 28.2 (3C); m/z (EI) 310 and 312 [Mþ]; Anal. Calcd. for
C13H15N2O2Br: C, 50.18; H, 4.86; N, 9.00. Found: C, 50.19; H, 4.83; N,
9.02. m.p. 1688C–1698C.
N-Boc-amino-(30-hydroxyphenyl)acetonitrile (2l) (R ¼ 3-HOC6H4)
White solid. Isolated yield: 74% (method A), 81% (method B). m.p.
1
1428C–1438C; H NMR (200 MHz, DMSO-d6) d 9.68 (s, 1H), 8.33 (br d,
1H), 7.20 (apparent t, 1H), 6.85–6.73 (m, 3H), 5.70–5.90 (m, 2H), 1.40
(s, 9H); 13C NMR (50 MHz, DMSO-d6) d 157.6, 154.6, 136.0, 129.9, 118.8,
117.2, 115.6, 113.6, 79.5, 44.9, 28.0; m/z (EI) 248 [Mþ]; Anal. Calcd. for
C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C, 62.85; H, 6.54; N, 11.35.
N-Boc-amino-(40-methoxyphenyl)acetonitrile (2m) (R ¼ 4-CH3OC6H4)
White solid. Isolated yield: 76% (method A), 79% (method B). m.p.
1348C–1358C; 1H NMR (200 MHz, CDCl3) d 7.38 (d, J ¼ 8.0 Hz, 2H),
6.95 (d, J ¼ 8.0 Hz, 2H), 5.66 (br d, J ¼ 7.4 Hz, 1H), 5.19 (br m, 1H), 3.80
(s, 3H), 1.45 (s, 9H); 13C NMR (50 MHz, CDCl3) d 160.4, 154.2, 128.3,
125.5, 118.0, 114.6, 81.5, 55.4, 45.6, 28.2; m/z (EI) 262 [Mþ]; Anal. Calcd.
for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.03; H, 6.77; N,
10.69.
N-Boc-amino-(30-methoxyphenyl)acetonitrile (2n) (R ¼ 3-CH3OC6H4)
White solid. Isolated yield: 80% (method A), 82% (method B).
1
m.p. 1028C–1038C; H NMR (200 MHz, CDCl3) d 7.27 (apparent t, 1H),

Convenient Synthesis of N-Boc-Protected a-Aminonitriles
3155
7.02–6.83 (m, 3H), 5.69 (d, J ¼ 8.1 Hz, 1H), 5.51 (d, J ¼ 8.3 Hz, 1H), 3.75
(s, 3H), 1.42 (s, 9H); 13C NMR (50 MHz, CDCl3) d 160.0, 154.4, 134.9,
130.3, 118.9, 117.8, 114.9, 112.5, 81.5, 55.4, 45.9, 28.2; m/z (EI) 262
[Mþ]; Anal. Calcd. for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C,
64.19; H, 6.77; N, 10.69.
N-Boc-amino-(20-methoxyphenyl)acetonitrile (2o) (R ¼ 2-CH3OC6H4)
White solid. Isolated yield: 62% (method A), 74% (method B). m.p.
1
948C–968C; H NMR (200 MHz, CDCl3) d 7.30–7.35 (m, 2H), 6.90–7.05
(m, 2H), 5.77 (d, J ¼ 8.5 Hz, 1H), 5.57 (br, 1H), 3.90 (s, 3H), 1.43 (s, 9H);
13C NMR (50 MHz, CDCl3) d 157.0, 154.1, 131.2, 129.0, 121.9, 121.0,
118.1, 111.4, 81.1, 55.8, 42.9, 28.2; m/z (EI) 262 [Mþ]; Anal. Calcd. for
C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.11; H, 6.92; N, 10.68.
N-Boc-amino-(1-naphthyl)acetonitrile (2p) (R ¼ 1-naphthyl)
White solid. Isolated yield: 73% (method A), 80% (method B). m.p.
1908C–1928C; 1H NMR (200 MHz, CDCl3) d 7.94–7.41 (m, 7H), 5.40
(d, J ¼ 8.5 Hz, 1H), 5.26 (br, 1H), 1.46 (s, 9H); 13C NMR (50 MHz, CDCl3)
d 154.1, 134.0, 130.7, 129.8, 129.1, 128.7, 127.6, 126.6, 126.1, 125.1,
122.5, 118.0, 81.6, 44.4, 28.2; m/z (EI) 282 [Mþ]; Anal. Calcd. for
C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C, 72.38; H, 6.52; N, 10.00.
N-Boc-amino-(2-furyl)acetonitrile (2q) (R ¼ 2-furyl)
White solid. Isolated yield: 81% (method A), 84% (method B). m.p.
1
768C–788C; H NMR (400 MHz, CDCl3) d 7.42 (m, 1H), 6.58 (m, 1H),
6.42 (m, 1H), 5.82 (br, 1H), 5.26 (br, 1H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 154.1, 145.8, 144.0, 116.1, 111.1, 109.8, 82.2, 40.1,
28.2; m/z (EI) 222 [Mþ]; Anal. Calcd. for C11H14N2O3: C, 59.45; H, 6.35;
N, 12.61. Found: C, 59.15; H, 6.36; N, 12.62.
N-Boc-amino-(2-thienyl)acetonitrile (2r) (R ¼ 2-thienyl)
White solid. Isolated yield: 80% (method A), 84% (method B). m.p.
1
1158C–1168C; H NMR (400 MHz, CDCl3) d 7.38 (d, 1H), 7.26 (d, 1H),
7.10 (m, 1H), 5.82 (br, 1H), 5.37 (br, 1H), 1.46 (s, 9H); 13C NMR (50 MHz,
CDCl3) d 154.3, 146.2, 127.8, 127.7, 127.4, 116.5, 82.2, 42.1, 28.2; m/z
(EI) 238 [Mþ]; Anal. Calcd. for C11H14N2O2S: C, 55.44; H, 5.92; N, 11.76.
Found: C, 55.46; H, 6.02; N, 11.75.

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Banphavichit et al.
N-Boc-2-amino-butyronitrile (2s) (R ¼ Et)
White solid. Isolated yield: 72% (method A), 78% (method B). m.p.
1
958C–968C; H NMR (200 MHz, CDCl3) d 5.02 (br m, 1H), 4.48 (br m,
1H), 1.79 (m, 2H), 1.46 (s, 9H), 1.05 (t, J ¼ 7.0 Hz, 3H); 13C NMR (50
MHz, CDCl3) d 154.4, 118.8, 81.1, 43.6, 28.2, 26.8, 9.8; m/z (EI) 184
[Mþ]; Anal. Calcd. for C9H16N2O2: C, 58.67; H, 8.75; N, 15.21. Found:
C, 58.59; H, 8.72; N, 15.37.
N-Boc-2-amino-valeronitrile (2t) (R ¼ nPr)
White solid. Isolated yield: 76% (method A), 81% (method B). m.p.
1
658C–668C; H NMR (200 MHz, CDCl3) d 5.18 (br m, 1H), 4.50 (br m,
1H), 1.73 (m, 2H), 1.46 (s, 9H), 1.36 (m, 2H), 1.00 (t, J ¼ 7.5 Hz, 3H); 13C
NMR (50 MHz, CDCl3) d 154.4, 119.0, 80.9, 42.0, 35.17, 28.2, 18.6, 13.2;
m/z (EI) 198 [Mþ]; Anal. Calcd. for C10H18N2O2: C, 60.58; H, 9.15;
N, 14.13. Found: C, 60.57; H, 9.24; N, 14.21.
N-Boc-2-amino-3-methyl-butyronitrile (2u) (R ¼ iPr)
White solid. Isolated yield: 72% (method A), 81% (method B). m.p.
1
918C–928C; H NMR (200 MHz, CDCl3) d 5.16 (br m, 1H), 4.39 (br m,
1H), 1.96 (m, 1H), 1.37 (s, 9H), 1.04 (2 ꢀ d, 6H); 13C NMR (50 MHz,
CDCl3) d 154.5, 118.0, 81.0, 48.4, 31.7, 28.2, 18.5, 17.9; m/z (EI) 198
[Mþ]; Anal. Calcd. for C10H18N2O2: C, 60.58; H, 9.15; N, 14.13. Found:
C, 60.59; H, 9.09; N, 14.39.
N-Boc-2-amino-hexanenitrile (2v) (R ¼ nBu)
Colorless oil. Isolated yield: 73% (method A), 79% (method B). 1H NMR
(200 MHz, CDCl3) d 4.96 (br m, 1H), 4.50 (br m, 1H), 1.78 (m, 2H), 1.47
(s, 9H), 1.29–1.33 (m, 4H), 0.96 (t, 3H); 13C NMR (50 MHz, CDCl3) d
154.3, 119.0, 81.1, 42.3, 33.0, 28.2, 27.3, 21.9, 13.7; m/z (EI) 212 [Mþ];
Anal. Calcd. for C11H20N2O2: C, 62.24; H, 9.50; N, 13.20. Found: C, 62.24;
H, 9.64; N, 13.21.
N-Boc-2-amino-undecanenitrile (2w) (R ¼ nC9H19)
White solid. Isolated yield: 86% (method A), 88% (method B). m.p.
1
448C–458C; H NMR (200 MHz, CDCl3) d 5.17 (br m, 1H), 4.47 (br m,
1H), 1.75 (m, 2H), 1.45 (s, 9H), 1.36–1.20 (m, 14H), 0.82 (t, J ¼ 7.0 Hz,
3H); 13C NMR (50 MHz, CDCl3) d 154.4, 119.0, 80.9, 42.2, 33.3, 31.8,

Convenient Synthesis of N-Boc-Protected a-Aminonitriles
3157
29.3, 29.2, 29.1, 28.7, 28.2, 25.3, 22.6, 14.0; m/z (EI) 282 [Mþ]; Anal. Calcd.
for C16H30N2O2: C, 68.04; H, 10.71; N, 9.92. Found: C, 68.12; H, 10.79;
N, 9.96.
N-Boc-2-amino-3,3-dimethyl-butyronitrile (2x) (R ¼ tBu)
White solid. Isolated yield: 78% (method A), 82% (method B). m.p.
1
1248C–1258C; H NMR (400 MHz, CDCl3) d 4.87 (br d, J ¼ 8.3 Hz, 1H),
4.3 (d, J ¼ 8.1 Hz, 1H), 1.47 (s, 9H), 1.16 (s, 9H); 13C NMR (50 MHz,
CDCl3) d 154.6, 118.0, 81.1, 52.2, 34.9, 28.2, 25.6; m/z (EI) 212 [Mþ];
Anal. Calcd. for C11H20N2O2: C, 62.24; H, 9.50; N, 13.20. Found: C, 62.31;
H, 9.55; N, 13.21.
N-Boc-2-amino-4-methyl-valeronitrile (2y) (R ¼ iBu)
White solid. Isolated yield: 74% (method A), 80% (method B). m.p.
1798C–1818C; 1H NMR (400 MHz, CDCl3) d 4.81 (d, J ¼ 8.4 Hz, 1H),
4.58 (m, 1H), 1.84 (m, 1H), 1.65 (m, 2H), 1.47 (s, 9H), 0.98 (d, J ¼ 7.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) d 154.3, 119.0, 81.7, 42.3, 40.8, 28.2,
24.3, 21.9, 21.7; m/z (EI) 212 [Mþ]; Anal. Calcd. for C11H20N2O2:
C, 62.24; H, 9.50; N, 13.20. Found: C, 62.19; H, 9.53; N, 13.18.
N-Boc-2-amino-3-phenyl-propionitrile (2z) (R ¼ PhCH2)
White solid. Isolated yield: 75% (method A), 81% (method B). m.p.
1
1188C–1198C; H NMR (400 MHz, CDCl3) d 7.41–7.22 (m, 5H), 4.97 (br,
1H), 4.83 (br, 1H), 3.22 (m, 2H), 1.47 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 154.6, 134.0, 129.8, 129.1, 128.0, 118.2, 81.8, 43.8, 38.7, 28.2;
m/z (EI) 246 [Mþ]; Anal. Calcd. for C14H18N2O2: C, 68.27; H, 7.37;
N, 11.37. Found: C, 68.38; H, 7.22; N, 11.50.
N-Boc-2-amino-4-phenyl-butyronitrile (2aa) (R ¼ PhCH2CH2)
White solid. Isolated yield: 75% (method A), 82% (method B). m.p.
1
1148C–1158C; H NMR (400 Mz, CDCl3) d 7.38–7.18 (m, 5H), 5.12 (br,
1H), 4.57 (br, 1H), 2.81 (m, 2H), 2.15 (m, 2H), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 154.3, 139.4, 129.1, 128.8, 126.2, 119.1, 81.6, 42.2,
35.1, 31.7, 28.2; m/z (EI) 260 [Mþ]; Anal. Calcd. for C15H20N2O2:
C, 69.20; H, 7.74; N, 10.76. Found: C, 69.24; H, 7.35; N, 10.79.

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N-Boc-2-amino-cyclohexylacetonitrile (2bb) (R ¼ cHex)
White solid. Isolated yield: 82% (method A), 85% (method B). m.p.
1
1108C–1118C; H NMR (400 MHz, CDCl3) d 4.96 (br m, 1H), 4.44 (br m,
1H), 1.90–1.00 (m, 11H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) d
154.3, 119.0, 81.6, 47.9, 41.3, 29.2, 28.5, 28.2, 25.9, 25.1; m/z (EI) 238
[Mþ]; Anal. Calcd. for C13H22N2O2: C, 65.51; H, 9.30; N, 11.75. Found:
C, 65.53; H, 9.39; N, 11.80.
ACKNOWLEDGMENT
Financial support comes from the Department of Chemistry and Rachada-
phisek Somphot Endowment grant from Chulalongkorn University. We also
thank Professor Somsak Ruchirawat, Chulabhorn Research Institute,
Bangkok, Thailand, for providing the mass spectrometry facility.
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Received in India March 6, 2004