Strecker reactions of chiral N-acylhydrazones

Article abstract of DOI:10.3987/com-06-s(w)3

Development of a method for addition of trimethylsilyl cyanide to chiral oxazolidinone-derived N-acylhydrazones is described. The diastereoselectivity was found to be highly dependent on the substituent of the oxazolidinone moiety; 4-phenyl-2-oxazolidinone achieved much higher stereocontrol than four other oxazolidinones screened. The reaction gives modest selectivity with aliphatic hydrazones and excellent selectivity with hydrazones prepared from aromatic aldehydes.

Full text of DOI:10.3987/com-06-s(w)3

HETEROCYCLES, Vol. 70, 2006
185
HETEROCYCLES, Vol. 70, 2006, pp. 185 - 199. © The Japan Institute of Heterocyclic Chemistry
Received, 11th May, 2006, Accepted, 14th June, 2006, Published online, 20th June, 2006. COM-06-S(W)3
STRECKER REACTIONS OF CHIRAL N-ACYLHYDRAZONES
Hui Ding and Gregory K. Friestad*
Department of Chemistry, University of Iowa, Iowa City, Iowa, 52242 and
Department of Chemistry, University of Vermont, Burlington, Vermont, 05405,
U. S. A.
Abstract – Development of a method for addition of trimethylsilyl cyanide to
chiral oxazolidinone-derived N-acylhydrazones is described.
The
diastereoselectivity was found to be highly dependent on the substituent of the
oxazolidinone moiety; 4-phenyl-2-oxazolidinone achieved much higher
stereocontrol than four other oxazolidinones screened. The reaction gives
modest selectivity with aliphatic hydrazones and excellent selectivity with
hydrazones prepared from aromatic aldehydes.
INTRODUCTION
Strecker-type cyanide addition to C=N bonds affords straightforward access to α-amino nitrile
compounds, which offer a broad range of synthetic applications, mainly by hydrolysis, reduction or
alkylation reactions of the nitrile group.1 Recent interests on synthesis of unusual α-amino acids as key
building blocks for pharmaceuticals have prompted intense investigation of the asymmetric Strecker-type
reaction.2 Highly efficient catalytic processes have been developed for asymmetric Strecker-type
cyanation of imines; these have been based on organocatalysts,3 phase transfer catalysts,4 and metal
Lewis acid catalysts.5
NR3
NHR3
CN–
!-amino acids, vicinal diamines, and
related 1,2-difunctional compounds
R2
CN
R1 R2
R1
Strecker
reaction
!-amino nitrile
Scheme 1. The Strecker reaction and its utility
This paper is dedicated to Prof. Steven M. Weinreb on the occasion of his 65th birthday.

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HETEROCYCLES, Vol. 70, 2006
Use of enantiopure chiral auxiliaries offers a practical alternative wherein the intermediate diastereomer
separation facilitates general access to rigorously enantiopure compounds, even in cases where the
selectivity may not be optimal. Effective auxiliaries have been reviewed extensively,1,2 and selected
examples include α-substituted ethylamines, 6 1,2-amino alcohols,7 carbohydrate derivatives,8 and
sulfinimines.9 Important biologically active α,α-dialkyl amino acids have been obtained with high
selectivity using an acyloxy amino acid as a chiral auxiliary.10 Diastereoselective Strecker reactions
have also been accomplished by crystallization-induced asymmetric transformations of carbonyl
compounds in the presence of chiral amines and cyanide donors.11
Among all the previous work noted above, there have been only sporadic reports regarding
N-acylhydrazones as substrates for asymmetric Strecker-type cyanation. With their ease of preparation,
increased air and hydrolytic stability, N-acylhydrazones are superior imine surrogates.12 In 2004,
Jacobsen reported asymmetric hydrocyanation to N-acylhydrazones catalyzed by lanthanide-PYBOX
complexes. 13 Although good selectivity was observed for some aromatic and aliphatic aldehyde
hydrazones, the scope is still limited to electron-rich hydrazones. More recently, Kobayashi has
reported catalytic procedures for dual activation14 in racemic cyanation of N-acylhydrazones.15 Chiral
16
N,N-dialkylhydrazones, prepared from (S)-1-amino-2-methoxymethylindoline (SAMI)
and
(S)-1-amino-2-methoxymethyl-pyrrolidine (SAMP),17 have also been used for Strecker-type reactions.
However, the use of chiral N-acylhydrazones in Strecker reactions has not previously been reported.
O
O
O
O
O
O
O
O
LA
O
N
N
N
R1 R2
Nu
N
HN
R1
N
N
H2N
R3
2 R3
R3
Lewis acid
R1 R2
R1 R2
R
Nu
R3
1
2
3
LA = Lewis acid
Previously: Nu = H, allyl
This work: Nu = CN
Scheme 2. General chiral N-acylhydrazone approach
Our recent studies have revealed N-acylhydrazones derived from chiral oxazolidinones18 are excellent
substrates for asymmetric nucleophilic additions of hydride19 and allylsilane20 reagents to C=N bonds.21,22
The design of these chiral imino acceptors incorporates bidentate Lewis acid binding for efficient
electrophilic activation and restriction of rotamer populations (Scheme 2). Following our initial studies,
several applications of these chiral N-acylhydrazones to a variety of other addition reactions have been
reported.23 Inspired by the potential to build a general suite of reaction types around the general chiral
N-acylhydrazone approach indicated in Scheme 2, we embarked on a study of their application in
asymmetric Strecker-type reactions, and here we disclose the results of this methodology study.

HETEROCYCLES, Vol. 70, 2006
187
RESULTS AND DISCUSSION
To initiate the study, the effects of Lewis acids on TMSCN addition were examined using prototype
hydrazone (2a)22 (Table 1). A control experiment established that 2a does not react with TMSCN in the
absence of Lewis acid (Entry 1). Based on the previous success with In(III) Lewis acids,20,22b several
In(III) salts were screened. The hydrazone was indeed activated by In(OTf)3, resulting in a good yield
of α-amino nitrile (3a) (Entry 2). Comparison of In(III) halides showed that the counterion was
important; InCl3 was somewhat less active than the corresponding triflate, while InF3 was inactive
24
(Entries 3 and 4).
Nucleophilic activation of the TMSCN with tetrabutylammonium
triphenyldifluorosilicate25 (TBAT) as fluoride source also promoted the reaction in the presence of
In(OTf)3 (Entry 5), but the yield and diastereoselectivity were not competitive with In(OTf)3 alone.
Table 1. Additions with variation of Lewis acid
O
O
O
O
N
N
additive
solvent
N
HN
+
TMSCN
CH2Ph
2a
CH2Ph
Ph
Ph
CN
3a
Entry
Additives
Solvent
CH2Cl2
Conversion, %a
3a, %b
drc
1
2
3
4
5
6
7
8
9
None
0
86
62
0
91
91
89
82
nde
0
--
In(OTf)3
InCl3
InF3
In(OTf)3, TBATd
In(OTf)3
77
48
0
59
78
67
41
0
67:33
55:45
--
63:37
52:48
55:45
55:45
--
CH3CN
THF
Et2O
DMF
a Calculated from recovered hydrazone( 2a). b Percent isolated yield of 3a. c Diastereomer ratio, determined by 1H
NMR spectra prior to chromatography. d TBAT = tetrabutylammonium triphenyldifluorosilicate. e nd = not determined
Consistent with precedent,8,17 a solvent dependence was also observed under these conditions (Entries
6–9). Decreased diastereomer ratios and moderate yields were observed in acetonitrile, diethyl ether and
THF, whereas the reaction did not occur in DMF. A possible explanation is the interference with the
two-point-binding complex (Scheme 2) by more polar solvents.
Based on the above results, the optimal conditions of (Table 1, Entry 2: 1.3 equiv In(OTf)3 in CH2Cl2)
were applied for screening of auxiliaries (Table 2). For most of the oxazolidinones, yields of cyanide
adducts were in a useful range (up to 77%), but the diastereomeric ratios never exceeded 3:1. Beyond
the point of attachment, it seems that the size of the substituent on the oxazolidinone moiety does not

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HETEROCYCLES, Vol. 70, 2006
affect selectivity (compare Entries 2 and 3). This is in sharp contrast to the observations with radical
additions to a related series of hydrazones; in those reactions all of the auxiliaries were quite effective.
Table 2. Additions with variation of oxazolidinones
X*
X*
N
HN
Ph
O
In(OTf)3 (1.3 equiv)
CH2Cl2, 2 d
O
+
TMSCN
X* =
Ph
2a–2e
CN
N
R
3a–3e
Entry
Substrate
R of X*
Conversion, %a
Yield, %b
drc,d
1
2
3
2a
2b
2c
CH2Ph
i-Pr
CHPh2
86
87
72
77 (3a)
65 (3b)
44 (3c)
67:33
60:40
67:33
H
O
O
4
5
2d
2e
X* =
93
77
72 (3d)
46 (3e)
73:27
>99:1
N
H
Ph
a Calculated based on recovered substrate. b Percent isolated yield. c Diastereomer ratio, determined by 1H
NMR spectra of product mixtures prior to chromatography. d Configurations assigned by analogy with 3l (see eq 3).
Fortunately, there was
a
dramatic difference with the hydrazone (2e) derived from
(S)-4-phenyl-2-oxazolidinone, which provided excellent diastereoselectivity (>99:1 dr, 2 days, Entry 5),
albeit with moderate yield. Control experiments showed longer reaction time (7 days, 48% yield with
26% of hydrazone recovered) or increased TMSCN (10 equiv, 36% yield) did not improve the yields. A
possible explanation for the anomalous stereoselectivity with 2e is in the very small steric requirement of
the linear CN– anion, such that the sp2-hybridized phenyl substituent of 2e with unrestricted conformation
(in comparison to 2d) is the only one which can effectively block access to the imino carbon.
With outstanding stereoselectivity at hand, a survey of scope was undertaken using a series of hydrazones,
which were prepared from the corresponding aldehydes in excellent yields for the two-step sequence by
our standard procedure26 (Scheme 3).
When subjected to the standard conditions, neutral or moderately electron-rich aromatic aldehyde
hydrazones gave modest yields but excellent diastereoselectivities (Table 3, Entries 1-3).
Electron-deficient m-nitrobenzaldehyde, the hydrazone of which has been previously found unreactive
with TMSCN,13 also participated in the reaction via hydrazone (2h) (Entry 4) to give a moderate yield of
3h, but the selectivity dropped dramatically to 1.5:1. With a strong electron-donating group, there was
very low isolated yield of 3i (Entry 5), but this was in contrast to the good conversion detected by TLC,

HETEROCYCLES, Vol. 70, 2006
189
suggesting the low yield may result from decomposition of the α-amino nitrile during purification.
Interestingly, (E)-cinnamyl aldehyde hydrazone (2j) (Entry 6) was unreactive. On the other hand,
aliphatic hydrazones (2k) and (2l) (Entries 7 and 8) participated in the reaction with modest
diastereoselectivity. At –55 ˚C, selectivity of addition to 2l improved slightly (not shown), but reaction
rate at this temperature was too slow to be practical.
O
O
O
O
O
O
NH2OR
RCHO, cat. TsOH
toluene
N
N
HN
N
NaH, dioxane
H2N
Ph
Ph
Ph
R
1e
R = 2-naphthyl
2f, 54%
2g, 91%
2h, 89%
2i, 95%
2j, 89%
2k, 76%
2l, 70%
R = 4-methylphenyl
R = 3-nitrophenyl
R = 4-methoxyphenyl
R = (E)-cinnamyl
R = ethyl (ref. 22b)
R = isopropyl
O
NH2
NH2OR =
O
O2N
Scheme 3. Preparation of chiral N-acylhydrazones
Table 3. Scope of addition of TMSCN to chiral N-acylhydrazones
O
O
O
O
In(OTf)3 (1.3 equiv)
N
CH2Cl2, 2 d
N
+
TMSCN
N
HN
Ph
Ph
CN
3e–3l
R
R
2e–2l
Conversion, %a
Yield, %b
drc,d
Entry
Hydrazone
R
1
2
3
4
5
6
7
8
2e
2f
2g
2h
2i
2j
2k
2l
Ph
2-naphthyl
77
80
82
100
92
58
46 (3e)
41 (3f)
34 (3g)
53 (3h)
5 (3i)
0 (3j)
37 (3k)
73 (3l)
>99:1
>95:5
>99:1
60:40
>95:5
--
4-methylphenyl
3-nitrophenyl
4-methoxyphenyl
(E)-cinnamyl
ethyl
100
100
67:33
75:25
isopropyl
a Based on recovery of 2 after chromatography. b Isolated yield of 3. c Diastereomer ratio of 3 measured by
1H NMR spectrometry prior to chromatography. d Configurations assigned by analogy with 3l (see eq 3).
The role of electronic properties in determining selectivity in the case of 2h calls for further discussion.
There are several reasonable explanations for the much lower selectivity in cyanation of the
m-nitrobenzaldehyde hydrazone (2h). The strong electron-withdrawing effect of the nitro group would

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HETEROCYCLES, Vol. 70, 2006
be expected to lower the Lewis basicity of the substrate, interfering with chelation of In(OTf)3. This
may permit a greater proportion of the reaction to take place through an unchelated structure.
Alternatives include equilibration through cyanide addition–elimination11 or product epimerization
through increased acidity at the α-carbon. To test these hypotheses, the two separable diastereomers of
3h were resubmitted to the reaction conditions (eq 1). Surprisingly, cleavage of the N–N bond to form
4-phenyl-2-oxazolidinone was observed for both diastereomers,27 and consequently no direct evidence of
equilibration between the two diastereomers of 3h was obtained. However, the N–N bond cleavage may
be considered indirect evidence of enolization; Skrydstrup and we have reported a similar N–N bond
cleavage of a related 2-hydrazinosuccinate initiated by enolization.22b,23c In that example, the hydrazine
is attached at the α-carbon of an ester; deprotonation of the α-carbon was proposed to lead to N–N bond
cleavage through β-elimination of the oxazolidinone anion (eq 2). The observed N–N bond cleavage of
3h could occur through a similar pathway. The association of both N–N bond cleavage and low
selectivity with the electron-deficient nitroaromatic therefore suggests that the addition to 2h may be
complicated by product epimerization.
O
O
O
O
N
(R,S)-3h
or
(S,S)-3h
TMSCN, In(OTf)3
CH2Cl2
HN
HN
Ph
CN
(1)
*
O2N
Ph
(only observed product)
O
N
O
O
O
N
TMS
ZnCl
N
(2)
ZnCl
+
NTMS
CO2Et
i-Pr
EtO2C
i-Pr
Skrydstrup, ref. 27
EtO2C
EtO2C
The absolute configuration of the newly formed stereocenter could be determined by chemical correlation
to the known compound (S)-(4).28 The separated major diastereomer of cyanation product (3l) was
subjected to reductive N–N bond cleavage with borane (eq 3) and the crude product was treated with
(Boc)2O to give 7% yield of a diamine (R)-(4). The R configuration was determined by comparison of
optical rotation with the literature data for (S)-4. The low yield notwithstanding, these results confirmed
the proposed configuration. This supported that the asymmetric Strecker addition to enantiopure
N-acylhydrazones was controlled by a diastereofacial differentiation in the two-point binding complex as
shown in Scheme 2.

HETEROCYCLES, Vol. 70, 2006
191
O
O
NHBoc
NHBoc
N
1) BH3•THF, reflux
HN
(3)
Ph
CN
*
2) Boc2O, NaHCO3
MeOH/H2O, ultrasound
[!]D25 +22 (c 0.1, CHCl3)
3l
(R)-4
7%
literature data for (S)-4, 95% ee:
[!]D25 –28.7 (c 1.32, CHCl3) -- ref. 28
In conclusion, examination of Strecker-type reaction of chiral N-acylhydrazones derived from various
2-oxazolidinones revealed an unusual dependence of diastereoselectivity on the oxazolidinone substituent.
Using (S)-4-phenyl-2-oxazolidinone, excellent diastereomeric ratios favoring the (R)-aminonitrile were
obtained for aromatic aldehyde hydrazones, with the exception of the hydrazone from
3-nitrobenzaldehyde. Aliphatic aldehyde hydrazones afforded modest diastereoselectivities. Improved
yields are required for practical application, but this study achieves excellent stereocontrol in Strecker
reactions of aromatic chiral N-acylhydrazones. From a broader perspective, this work extends the
general utility of the chiral N-acylhydrazones and their application for acyclic stereocontrol.
EXPERIMENTAL
Known hydrazones (2a–2e)18 and new hydrazones (2f–2l) were prepared according to General Procedure
A from the appropriate substituted 3-amino-2-oxazolidinones.
Preparation of enantiopure N-acylhydrazones (General Procedure A): To a solution of the
appropriate substituted (S)-3-amino-2-oxazolidinone (ca. 1 mmol) in toluene (ca. 0.1 M) was added
MgSO4 (200 mg), a catalytic amount of p-TsOH (ca. 5 mol %) and aldehyde (ca. 1.5 equiv). After heating
at reflux for 10 min, concentration and flash chromatography (5:1 hexane/ethyl acetate) gave pure
hydrazones.
(S)-3-(2-Naphthylmethylene)amino-4-phenyloxazolidin-2-one (2f). From 2-naphthaldehyde (0.19 g,
1.2 mmol) by General Procedure A was obtained 2f (0.28 g, 88%) as a colorless solid; mp 234–236 °C;
25
[α]D +145 (c 0.15, CHCl3); IR (film): 3041, 2988, 2923, 1765, 1752, 1457, 1405, 1311, 1225, 1098,
1
1024 cm-1; H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.78-7.72 (m, 4H),
7.45-7.34 (m, 7H), 5.33 (dd, J = 8.9, 5.8 Hz, 1H), 4.80 (dd, J = 8.8, 8.8 Hz, 1H), 4.21 (dd, J = 8.7, 5.8 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 154.6, 147.3, 137.1, 134.4, 133.0, 131.6, 129.7, 129.1, 128.3, 127.9,
127.1, 126.5, 126.0, 69.7, 59.5; MS (EI) m/z (relative intensity): 316 (M+, 20%); Anal. Calcd for
C20H16N2O2: C, 75.93; H, 5.10; N, 8.86. Found: C, 76.00; H, 5.25; N, 8.66.
(S)-3-(4-Methylbenzylidene)amino-4-phenyloxazolidin-2-one (2g). From p-methylbenzaldehyde (0.23

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HETEROCYCLES, Vol. 70, 2006
g, 1.1 mmol) by General Procedure A was obtained 2g (0.26 g, 91%) as a colorless solid; mp
25
156–158 °C; [α]D +63 (c 0.19, CHCl3); IR (film): 3034, 3001, 2916, 1770, 1752, 1560, 1456, 1401,
1320, 1303, 1208, 1096, 1030 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.45-7.08 (m, 9H), 5.28
13
(dd, J = 8.9, 5.7 Hz, 1H), 4.76 (dd, J = 8.8, 8.8 Hz, 1H), 4.17 (dd, J = 8.8, 5.7 Hz, 1H), 2.33 (s, 3H); C
NMR (125MHz, CDCl3) δ 154.6, 147.5, 140.6, 137.2, 131.1, 129.6, 129.3, 129.0, 127.5, 126.0, 69.6, 59.4,
21.4; MS (EI) m/z (relative intensity): 280 (M+, 73%); Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N,
9.99. Found: C, 72.23; H, 5.82; N, 9.64.
(S)-3-(3-Nitrobenzylidene)amino-4-phenyl-oxazolidin-2-one (2h). From m-nitrobenzaldehyde (0.168 g,
1.10 mmol) by General Procedure A was obtained 2h (0.28 g, 89%) as a colorless solid; mp 124–126 °C;
23
1
[α]D +106 (c 0.14, CHCl3); IR (film): 3089, 2917, 1771, 1617, 1532, 1473, 1400, 1209, 1095 cm-1; H
NMR (500 MHz, CDCl3) δ 8.22 (d, J = 1.5 Hz, 1H), 7.91 (d, J = 4.4 Hz, 1H), 7.41-7.31 (m, 8H), 5.37 (dd,
J = 8.8, 5.5 Hz, 1H), 4.84 (dd, J = 8.8, 8.8 Hz, 1H), 4.21 (dd, J = 8.8, 5.4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 154.2, 148.5, 143.8, 136.6, 135.7, 132.6, 129.8, 129.6, 129.3, 126.0, 124.5, 122.2, 69.9, 59.3;
MS (EI) m/z (relative intensity): 311 (M+, 9%); Anal. Calcd for C16H13N3O4: C, 61.73; H, 4.21; N, 13.50.
Found: C, 61.99; H, 4.42; N, 13.04.
(S)-3-(4-Methoxybenzylidene)amino-4-phenyloxazolidin-2-one (2i). From p-methoxybenzaldehyde
(0.13 mL, 1.1 mmol) by General Procedure A was obtained 2i (0.28 g, 95%) as a colorless solid; mp
162–164 °C; [α]D25 +71 (c 0.5, CHCl3); IR (film): 3034, 2975, 2916, 2844, 1760, 1607, 1514, 1405, 1253,
1
1171, 1089, 1027 cm-1; H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.45-7.30
(m, 6H), 6.80 (d, J = 8.5 Hz, 2H), 5.27 (dd, J = 8.9, 5.9 Hz, 1H), 4.76 (dd, J = 8.9, 8.9 Hz, 1H), 4.16 (dd,
J = 8.9, 5.9 Hz, 1H), 3.77 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 161.5, 154.7, 147.7, 137.3, 129.6, 129.1,
128.9, 126.6, 126.1, 114.0, 69.5, 59.7, 55.4; MS (CI) m/z (relative intensity): 297 ([M+1]+, 100%);
HRMS-FAB (m/z) [M+H]+ Calcd for C17H17N2O3, 297.1239; found, 297.1239.
(S)-3-(3-Phenyl-2-(E)-propenylidene)amino-4-phenyloxazolidin-2-one
(2j).
From
trans-
cinnamaldehyde (0.13 mL, 1.0 mmol) by General Procedure A was obtained 2j (0.26 g, 89%) as a
22
colorless solid; mp 154–157 °C; [α]D +106 (c 0.1, CHCl3); IR (film): 3033, 2982, 2923, 1757, 1627,
1
1456, 1407, 1338, 1232, 1089, 1037, 978 cm-1; H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 7.8 Hz, 1H),
7.43-7.26 (m, 10H), 6.89 (dd, J = 16.0, 9.0 Hz, 1H), 6.64 (d, J = 16.0 Hz, 1H), 5.24 (dd, J = 8.7, 5.6 Hz,
1H), 4.76 (dd, J = 8.8, 8.8 Hz, 1H), 4.16 (dd, J = 8.7, 5.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 154.6,
148.9, 139.8, 136.9, 135.7, 129.7, 129.1, 129.0, 128.8, 127.0, 125.9, 125.3, 69.8, 59.2; MS (EI) m/z
(relative intensity): 292 (M+, 7%); Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C,
73.50; H, 5.33; N, 9.55.
(S)-4-Phenyl-3-(propylideneamino)oxazolidin-2-one (2k). From propionaldehyde (0.09 mL, 1.2 mmol)
by General Procedure A was obtained 2k (0.14 g, 64%) as a colorless solid; mp 92–94 °C; [α]D20 +112 (c

HETEROCYCLES, Vol. 70, 2006
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0.59, CHCl3); IR (film): 2973, 2936, 1772, 1527, 1458, 1403, 1323, 1210, 1094, 1038, 917 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.38-7.12 (m, 6H), 5.13 (dd, J = 8.5, 5.9 Hz, 1H), 4.69 (dd, J = 8.8, 8.5 Hz, 1H),
4.08 (dd, J = 8.5, 5.9 Hz, 1H), 2.25-2.16 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
154.9, 153.2, 137.0, 129.5, 128.9, 125.9, 69.6, 59.1, 26.2, 10.8; MS (CI) m/z (relative intensity): 219
([M+1]+, 100%); Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 65.96; H, 6.30; N,
12.77.
(S)-3-Isobutylideneamino-4-phenyloxazolidin-2-one (2l). From isobutyraldehyde (0.2 mL, 2.2 mmol)
by General Procedure A was obtained 2l (0.33 g, 70%) as a colorless solid; mp 110–112 °C; [α]D23 +102
(c 0.24, CHCl3); [α]D20 +127 (c 0.62, CHCl3); IR (film): 2967, 2873, 1767, 1529, 1483, 1460, 1399, 1220,
1104, 1026 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.37-7.22 (m, 4H), 6.96 (d, J = 5.8 Hz, 1H), 5.14 (dd, J =
8.4, 5.7 Hz, 1H), 4.69 (dd, J = 8.8, 8.8 Hz, 1H), 4.08 (dd, J = 8.8, 5.8 Hz, 1H), 2.50-2.41 (m, 1H), 0.85 (d,
13
J = 6.8 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H); C NMR (125 MHz, CDCl3) δ 157.3, 154.9, 136.9, 126.5,
128.9, 126.0, 69.4, 59.1, 31.9, 19.77, 19.74; MS (EI) m/z (relative intensity): 232 (M+, 31%); Anal. Calcd
for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 66.44; H, 6.85; N, 11.85.
Strecker Reaction (General Procedure B): A mixture of the hydrazone (0.2 mmol) and In(OTf)3 (0.26
mmol) in CH2Cl2 (2.5 mL) was stirred at ambient temperature for 4 h. To the resulting solution was added
TMSCN (0.08 mL, 0.6 mmol) by syringe. After 2 d at ambient temperature the reaction was quenched by
addition of saturated NaHCO3 solution (2 mL). The organic phase was separated, and the aqueous phase
was extracted with CH2Cl2. The organic phases were combined, washed with brine, and dried over
MgSO4. Filtration, concentration and flash chromatography (hexane/EtOAc) gave α-hydrazinonitriles
(3a–3l). Solid products were recrystallized from isopropanol to give colorless crystals. Infrared data for
3a–3l showed very weak (sometimes undetected) absorbance in the region from 2210–2260 cm-1, as
expected for α-aminonitriles.29
2-[(S)-(4-Benzyl-2-oxooxazolidin-3-yl)amino]-2-phenylacetonitrile (3a). From 2a (56 mg, 0.2 mmol)
by General Procedure B was obtained 3a as a colorless oil, inseparable 2:1 mixture of diastereomers; IR
(film): 3273, 3030, 2912, 2252 (w), 1760, 1603, 1496, 1454, 1237, 1104, 1026 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.70-7.10 (m, 10H), 5.31 (d, J = 2.9 Hz, 0.33H), 5.25 (d, J = 2.9 Hz, 0.67H), 4.45-4.43 (m, 1H),
4.24 (dd, J = 8.0, 8.0 Hz, 0.67H), 4.20-4.14 (m, 0.67H), 4.09-4.01 (m, 1.33H), 3.73-3.66 (m, 0.33H), 3.48
(dd, J = 13.6, 3.7 Hz, 0.33H), 3.22 (dd, J = 13.6, 3.7 Hz, 0.67H), 2.76 (dd, J = 13.6, 9.8 Hz, 0.33H), 2.55
(dd, J = 13.6, 9.5 Hz, 0.67H); 13C NMR (125 MHz, CDCl3) δ 159.3 (minor), 158.1(major), 135.5 (minor),
135.3 (major), 131.9 (minor), 131.6 (major), 130.2, 129.4, 129.2, 129.0 (major), 128.9 (minor), 128.6
(minor), 128.5 (major), 127.3 (minor), 127.2 (major), 118.2 (major), 118.1 (minor), 67.5 (minor), 66.3
(major), 59.6 (minor), 58.8 (major), 55.8 (minor), 55.7 (major), 38.0 (minor), 36.7 (major); MS (EI) m/z
(relative intensity): 307 (M+, 1%).

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2-[(S)-(4-Isopropyl-2-oxooxazolidin-3-yl)amino]-2-phenylacetonitrile (3b). From 2b (44 mg, 0.19
mmol) by General Procedure B was obtained 3b as a 1.5:1 mixture of diastereomers (32 mg, 65%, major
20
diastereomer separable); Major: colorless oil. [α]D –87 (c 0.35, CHCl3); IR (film): 3272, 2964, 2877,
2250 (w), 1756, 1483, 1456, 1406, 1220, 1100 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.57-7.41 (m, 5H),
5.24 (d, J = 2.7 Hz, 1H), 4.35 (dd, J = 8.7, 8.7 Hz, 1H), 4.25 (d, J = 2.4 Hz, 1H), 4.11 (dd, J = 9.1, 4.3 Hz,
1H), 3.98 (dd, J = 8.2, 4.0 Hz, 1H), 2.28-2.22 (m, 1H), 0.90 (d, J = 7.0 Hz, 3H), 0.81 (d, J = 6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 158.3, 131.5, 130.2, 129.4, 128.5, 118.4, 63.6, 61.4, 55.6, 28.9, 27.9, 17.6,
15.3; MS (EI) m/z (relative intensity): 259 (M+, 3%); Anal. Calcd for C14H17N3O2: C, 64.85; H, 6.61; N,
16.21. Found: C, 64.93; H, 6.62; N, 16.02.
2-[(S)-(4-Diphenylmethyl-2-oxooxazolidin-3-yl)amino]-2-phenylacetonitrile (3c). From 2c (36 mg, 0.1
mmol) by General Procedure B was obtained 3c (17 mg, 44%) as a colorless solid, inseparable 2:1
mixture of diastereomers; IR (film): 3283, 3060, 2922, 1759, 1652, 1593, 1494, 1216, 1102, 1023 cm-1;
1
Major: H NMR (500 MHz, CDCl3) δ 7.36-7.11 (m, 15H), 4.97-4.93 (m, 1H), 4.85 (d, J = 4.8 Hz, 1H),
13
4.42-4.34 (m, 2H), 4.19-4.15 (m, 1H), 4.08-4.03 (m, 1H); C NMR (125 MHz, CDCl3) δ 158.1, 140.5,
139.3, 131.8, 131.1, 129.1, 129.0, 128.8, 128.6, 128.3, 127.6, 127.2, 126.9, 118.2, 65.9, 60.0, 55.3, 54.1;
MS (EI) m/z (relative intensity): 383 (M+, 4%); Anal. Calcd for C24H21N3O2: C, 75.18; H, 5.52; N, 10.96.
Found: C, 75.08; H, 5.74; N, 10.61.
2-Hydrazino phenylacetonitrile (3d). From 2d (56 mg, 0.2 mmol) by General Procedure B was obtained
20
3d (44 mg, 72%) as a separable 2.7:1 mixture of diastereomers; Major: colorless oil; [α]D +39 (c 0.1,
CHCl3); IR (film): 3276, 3071, 3031, 2932, 2248 (w), 1754, 1650, 1459, 1383, 1201, 1113, 1032 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.62-7.20 (m, 9H), 5.39-5.34 (m, 2H), 5.31 (d, J = 2.2 Hz, 1H), 4.29(s, 1H),
3.41-3.29 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 157.5, 140.0, 137.6, 131.4, 130.2, 129.8, 129.4, 128.5,
127.6, 126.1, 125.5, 118.5, 77.8, 65.3, 55.9, 38.3; MS (EI) m/z (relative intensity): 305 (M+, 1%); Anal.
Calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C, 70.42; H, 5.01; N, 13.46. Minor: colorless
20
oil; [α]D +37 (c 0.04, CHCl3); IR (film): 3275, 3034, 2924, 2248 (w), 1752, 1458, 1384, 1202, 1115,
1034 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.61-7.23 (m, 9H), 5.27 (d, J = 4.1 Hz, 1H), 5.08 (ddd, J = 7.1,
13
7.1, 2.2 Hz, 1H), 4.69 (d, J = 4.1 Hz, 1H), 4.62 (d, J = 7.0 Hz, 1H), 3.34-3.23 (m, 2H); C NMR (125
MHz, CDCl3) δ 157.4, 140.0, 137.4, 132.5, 130.1, 129.9, 129.3, 128.7, 127.6, 126.2, 125.5, 117.3, 77.5,
65.2, 54.4, 38.8; MS (EI) m/z (relative intensity): 305 (M+, 2%); Anal. Calcd for C18H15N3O2: C, 70.81; H,
4.95; N, 13.76. Found: C, 70.78; H, 5.01; N, 13.49.
2-[(S)-(2-Oxo-4-phenyloxazolidin-3-yl)amino]-2-phenylacetonitrile (3e). From 2e (53 mg, 0.2 mmol)
by General Procedure B was obtained 3e (27 mg, 46%) as a colorless solid; mp 176–178 °C; [α]D23 +60 (c
0.06, CHCl3); IR (film): 3263, 2982, 2903, 2227 (w), 1756, 1495, 1456, 1103, 1025 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.42-7.30 (m, 10H), 5.02 (d, J = 4.9 Hz, 1H), 4.97 (dd, J = 8.2, 6.0 Hz, 1H), 4.68 (dd, J =

HETEROCYCLES, Vol. 70, 2006
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13
8.5, 8.5 Hz, 1H), 4.30-4.28 (m, 2H); C NMR (125 MHz, CDCl3) δ 158.1, 136.8, 131.3, 130.0, 129.4,
129.2, 128.3, 127.3, 118.3, 69.2, 62.1, 55.7; MS (EI) m/z (relative intensity): 293 (M+, 2%); Anal. Calcd
for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C, 69.73; H, 5.29; N, 14.32.
2-(Naphthalen-2-yl)-2-[(S)-(2-oxo-4-phenyloxazolidin-3-yl)amino]acetonitrile (3f). From 2f (61 mg,
0.19 mmol) by General Procedure B was obtained 3f (27 mg, 46%) as a colorless solid; mp 157–159 °C;
23
[α]D +49 (c 0.07, CHCl3); IR (film): 3280, 3060, 2923, 2852, 2252 (w), 1761, 1458, 1398, 1212, 1100,
1023 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.82-7.29 (m, 11H), 5.18 (d, J = 4.7 Hz, 1H), 4.97
(dd, J = 8.1, 6.0 Hz, 1H), 4.68 (dd, J = 8.7, 8.7 Hz, 1H), 4.41 (d, J = 6.2 Hz, 1H), 4.29 (dd, J = 8.9, 6.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 158.3, 143.9, 136.8, 133.7, 132.9, 129.4, 129.3, 129.2, 128.5, 128.3,
128.1, 127.7, 127.3, 127.0, 125.0, 118.3, 69.2, 62.2, 55.8; MS (EI) m/z (relative intensity): 343 (M+, 3%);
Anal. Calcd for C21H17N3O2: C, 73.45; H, 4.99; N, 12.24. Found: C, 73.68; H, 4.91; N, 12.19.
2-[(S)-(2-Oxo-4-phenyloxazolidin-3-yl)amino]-2-(p-tolyl)acetonitrile (3g). From 2g (56 mg, 0.2 mmol)
by General Procedure B was obtained 3g (21 mg, 34%) as a colorless solid; mp 122–125 °C; [α]D20 +48 (c
0.09, CHCl3); IR (film): 3281, 3034, 2922, 2250 (w), 1762, 1608, 1528, 1458, 1399, 1358, 1264, 1100,
1023 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.39-7.30 (m, 7H), 7.14 (d, J = 7.6 Hz, 2H), 4.99-4.96 (m, 2H),
13
4.67 (dd, J = 8.9, 8.4 Hz, 1H), 4.28 (dd, J = 8.9, 5.9 Hz, 1H), 4.24 (d, J = 3.8 Hz, 1H), 2.32 (s, 3H); C
NMR (125 MHz, CDCl3) δ 158.1, 140.1, 136.9, 129.8, 129.3, 128.3, 128.2, 127.3, 118.5, 69.2, 62.1, 55.4,
21.2; MS (CI) m/z (relative intensity): 308 ([M+1]+, 52%); Anal. Calcd for C18H17N3O2: C, 70.34; H, 5.58;
N, 13.67. Found: C, 70.04; H, 5.83; N, 13.08.
2-(3-Nitrophenyl)-2-[(S)-(2-oxo-4-phenyloxazolidin-3-yl)amino]acetonitrile (3h). From 2h (62 mg, 0.2
mmol) by General Procedure B was obtained 3h (36 mg, dr = 1.5:1, 53%) as two separable diastereomers.
20
Major: Colorless solid; mp 96–98 °C; [α]D +58 (c 0.05, CHCl3); IR (film): 3300, 3093, 2922, 2857,
1
2232 (w), 1752, 1532, 1351, 1241, 1099, 1025 cm-1; H NMR (500 MHz, CDCl3) δ 8.22-8.19 (m, 2H),
7.75 (d, J = 4.8 Hz, 1H), 7.76-7.21 (m, 6H), 5.10 (d, J = 5.2 Hz, 1H), 4.91 (dd, J = 8.8, 6.8 Hz, 1H), 4.67
13
(dd, J = 8.8, 8.5 Hz, 1H), 4.58 (d, J = 5.1 Hz, 1H), 4.30 (dd, J = 9.0, 6.7 Hz, 1H); C NMR (125 MHz,
CDCl3) δ 158.5, 148.6, 136.1, 134.2, 133.6, 130.3, 129.6, 129.4, 127.4, 124.9, 123.4, 117.0, 69.2, 62.6,
54.8; MS (CI) m/z (relative intensity): 312 ([M-CN]+, 100%); Anal. Calcd for C17H14N4O4: C, 60.35; H,
4.17; N, 16.56. Found: C, 60.07; H, 4.35; N, 16.42. Minor: Colorless solid; mp 125-127 °C; [α]D23 +237
1
(c 0.06, CHCl3); H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.80
(dd, J = 8.0, 1.2 Hz, 1H), 7.56 (dd, J = 8.0, 8.0 Hz, 1H), 7.36-7.24 (m, 5H), 5.22 (d, J = 3.8 Hz, 1H),
13
4.67-4.62 (m, 2H), 4.53 (dd, J = 8.9, 8.4 Hz, 1H), 4.25 (dd, J = 9.0, 7.2 Hz, 1H); C NMR (125 MHz,
CDCl3) δ 159.1, 148.5, 135.5, 134.6, 134.1, 130.1, 129.7, 129.3, 127.7, 124.7, 123.4, 116.4, 69.2, 63.0,
54.3; MS (CI) m/z (relative intensity): 312 ([M-CN]+, 100%); Anal. Calcd for C17H14N4O4: C, 60.35; H,
4.17; N, 16.56. Found: C, 60.58; H, 4.23; N, 16.38.

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2-(4-Methoxyphenyl)-2-[(S)-(2-oxo-4-phenyloxazolidin-3-yl)amino]acetonitrile (3i). From 2i (60 mg,
20
0.2 mmol) by General Procedure B was obtained 3i (2 mg, 5%) as a colorless oil; [α]D +22 (c 0.13,
CHCl3); IR (film): 3276, 2969, 2923, 2844, 2246, 1761, 1615, 1514, 1456, 1398, 1252, 1176, 1098, 1028
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.47-7.29 (m, 7H), 6.85 (d, J = 7.5 Hz, 2H), 5.02-4.97 (m, 2H), 4.68
(dd, J = 9.0, 8.4 Hz, 1H), 4.28 (dd, J = 9.0, 5.7 Hz, 1H), 4.24-4.20 (m, 1H), 3.77 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 160.6, 158.1, 136.9, 129.7, 129.3, 127.3, 123.7, 118.5, 114.5, 69.2, 62.1, 55.4, 55.1; MS
(CI) m/z (relative intensity): 324 ([M+1]+, 36%); HRMS-FAB (m/z) [M+H]+ Calcd for C18H18N3O3,
324.1348; found, 324.1356.
2-[(S)-(2-Oxo-4-phenyloxazolidin-3-yl)amino]butyronitrile (3k). From 2k (43 mg, 0.2 mmol) by
General Procedure B was obtained 3k (18 mg, dr = 2:1, 37%) as a colorless oil, separable 2:1 mixture of
20
diastereomers; Major: [α]D +38 (c 0.65, CHCl3); IR (film): 3283, 2975, 2929, 2877, 2252 (w), 1762,
1
1458, 1399, 1211, 1097, 1023 cm-1; H NMR (500 MHz, CDCl3) δ 7.47-7.33 (m, 5H), 4.98 (dd, J = 8.1,
6.2 Hz, 1H), 4.65 (dd, J = 8.8, 8.1 Hz, 1H), 4.27(dd, J = 8.8, 6.2 Hz, 1H), 4.15-4.10 (m, 1H), 3.81-3.79
(m, 1H), 1.69-1.61 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.1, 136.8, 129.4,
129.3, 127.4, 119.2, 69.1, 62.2, 53.4, 24.4, 9.7; MS (CI) m/z (relative intensity): 246 ([M+1]+, 43%);
HRMS-FAB (m/z) [M+H]+ Calcd for C13H16N3O2, 246.1243; found, 246.1234. Minor: [α]D20 +53 (c 0.25,
CHCl3); IR (film): 3289, 2975, 2922, 2877, 2252 (w), 1762, 1453, 1394, 1212, 1091, 1023 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.42-7.28 (m, 5H), 4.89 (dd, J = 8.1, 6.2 Hz, 1H), 4.63 (dd, J = 8.8, 8.1 Hz, 1H),
4.30 (dd, J = 8.8, 6.2 Hz, 1H), 4.18 (br s, 1H), 3.88-3.78 (m, 1H), 1.79-1.71 (m, 2H), 1.03 (t, J = 7.4 Hz,
13
3H); C NMR (125 MHz, CDCl3) δ 158.9, 136.1, 129.6, 129.4, 127.7, 118.7, 68.9, 62.2, 53.2, 24.9, 9.9;
MS (CI) m/z (relative intensity): 246 ([M+1]+, 32%); HRMS-FAB (m/z) [M+H]+ Calcd for C13H16N3O2,
246.1243; found, 246.1241.3-Methyl-2-[(S)-(2-oxo-4-phenyloxazolidin-3-yl)amino]butyronitrile (3l).
From 2l (46 mg, 0.2 mmol) by General Procedure B was obtained 3l (38 mg, dr = 3:1, 73%) as separable
diastereomers. Major: Colorless solid; mp 98–100 °C; [α]D23 +52 (c 0.13, CHCl3); IR (film): 3258, 2965,
2916, 2238 (w), 1758, 1459, 1408, 1364, 1245, 1106, 1025 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.42-7.33
(m, 5H), 4.96 (dd, J = 8.3, 6.1 Hz, 1H), 4.64 (dd, J = 8.8, 8.3 Hz, 1H), 4.28 (dd, J = 8.9, 6.1 Hz, 1H), 4.11
(d, J = 6.1 Hz, 1H), 3.69 (dd, J = 5.9, 5.9 Hz, 1H), 1.87-1.82 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.91 (d, J
= 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.1, 136.7, 129.4, 129.3, 127.4, 118.4, 69.0, 62.2, 58.4,
29.8, 19.1, 17.8; MS (EI) m/z (relative intensity): 259 (M+, 7%); Anal. Calcd for C14H17N3O2: C, 64.85; H,
20
6.61; N, 16.21. Found: C, 65.08; H, 6.47; N, 16.22. Minor: Colorless oil; [α]D –15 (c 0.02, CHCl3); IR
(film): 3286, 2966, 2955, 2259 (w), 1762, 1497, 1458, 1397, 1211, 1100, 1024 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.42-7.33 (m, 5H), 4.83 (dd, J = 8.2, 6.3 Hz, 1H), 4.61 (dd, J = 9.0, 8.2 Hz, 1H), 4.29 (dd, J =
8.2, 6.3 Hz, 1H), 4.21 (d, J = 4.8 Hz, 1H), 3.70 (dd, J = 5.8, 5.8 Hz, 1H), 1.99-1.93 (m, 1H), 1.04 (d, J =
13
6.7 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H); C NMR (125 MHz, CDCl3) δ 158.9, 136.1, 129.6, 129.3, 127.7,

HETEROCYCLES, Vol. 70, 2006
197
117.6, 68.9, 62.3, 58.2, 29.8, 19.3, 17.8; MS (EI) m/z (relative intensity): 259 (M+, 11%); Anal. Calcd
for C14H17N3O2: C, 64.85; H, 6.61; N, 16.21. Found: C, 65.15; H, 6.75; N, 15.94.
Stereochemical Proof for Strecker Product (3l). The major product (3l) was subjected to reduction
conditions: A mixture of 3l (major diastereomer, 36 mg, 0.14 mmol) and BH3•THF (4.2 mL, 1.0 M in
THF, 4.2 mmol) in THF (3 mL) was heated to reflux. After 3 d, 3 M HCl (4 mL) was added to the
mixture dropwise under ice-bath. The resulting mixture was stirred at 0 °C for 3 h, then at ambient
temperature for 4 h. Solvent was removed and the residue was partitioned between basic brine and
1
CH2Cl2. The organic phase was washed with brine, dried (MgSO4) and concentrated. H NMR showed
that all 3l had been consumed. To a solution of this crude mixture in MeOH (3 mL) was added (Boc)2O
(250 mg, 1.1 mmol), NaHCO3 (170 mg, 2.0 mmol) and water (0.3 mL). The mixture was sonicated for 90
min, stirred at ambient temperature overnight, filtered through celite, concentrated, and dried. Flash
chromatography gave (R)-4 (2 mg, 7% from 3l) as a colorless oil; [α]D25 +22 (c 0.1, CHCl3) (Lit.,28 value
for (S)-4: [α]D25 –28.7 (c 1.32, CHCl3, 95% ee)). Spectral data matched the literature.28
ACKNOWLEDGEMENTS
We thank NIH (R01 GM67817) for generous support.
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