An effective synthesis of α-cyanoenamines by Peterson olefination

Article abstract of DOI:10.1055/s-2003-37119

A convenient and gentle method for the synthesis of α-cyanoenamines based on the Peterson olefination has been developed. For these sensitive, highly functionalized olefins, the present method is superior to the Horner-Emmons condensation, as manifested by the higher yields and broader scope.

Full text of DOI:10.1055/s-2003-37119

414
LETTER
An Effective Synthesis of a-Cyanoenamines by Peterson Olefination
An
Effective Synthesis
o
a
f
α
-Cyano
l
enamin
d
es by Peterso
e
n
O
lefinat
m
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax +49(931)8884756; E-mail: adam@chemie.uni-wuerzburg.de
Received 29 November 2002
was reported by Gross and Costisella2a under a variety re-
action conditions, but this reaction is not generally appli-
cable because the employed conditions are too drastic for
labile carbonyl partners. The Knoevenagel reaction was
utilized by the Ahlbrecht’s group2b with LDA and by
Jończyk2c under phase-transfer conditions, but both are
limited to N-methylanilinoacetonitrile as active methyl-
ene unit. This α-cyanoenamine method was also em-
ployed by Takahashi et al,2d who prepared a series of
homologated carboxylic acids through the hydrolysis of
the corresponding α-cyanoenamines. Their attempt to ex-
tend this methodology to other aminoacetonitriles failed
and only traces of the expected condensation products
were detected. Subsequently, Padwa and coworkers3
showed through trapping experiments with trimethylsilyl
chloride that the carbanion essential for condensation
could only be confirmed in the case of N-methylanilinoac-
etonitrile. The α-silylated product was obtained in a mere
10% yield, other aminoacetonitriles gave the respective
selfcondensation products.
Abstract: A convenient and gentle method for the synthesis of α-
cyanoenamines based on the Peterson olefination has been devel-
oped. For these sensitive, highly functionalized olefins, the present
method is superior to the Horner–Emmons condensation, as mani-
fested by the higher yields and broader scope.
Key words: α-Cyanoenamines, Peterson olefination, Horner–
Emmons condensation
During our research work we required an efficient and
gentle method for the synthesis of diverse terminally
substituted acceptor-donor olefins, in particular α-cya-
noenamines. Such doubly functionalized olefins have
been shown to be of great utility in organic synthesis, as
demonstrated by their conversion into 1,4-diones,1a 1,2-
1b,2a,d
diones,1b ketenimines,1c carboxylic acids
and lac-
tones.1d Moreover, the allylic anions derived from α-cya-
noenamines have been used for α or γ alkylation,1b,d 1,2 or
1,4 addition to enones,1d,e and as β-carboxylvinyl anion
equivalents.1o–r The noteworthy methods to prepare the
desired α-cyanoenamine in a one-pot reaction include the
Horner–Emmons, Peterson, and Knoevenagel condensa-
tions.2
A convenient synthesis of the pertinent Peterson precur-
sor, namely the silylated aminoacetonitriles 1, was pro-
vided also by Padwa’s group, who inverted the addition
order of the reagents, that is, first the trimethylsilyl chlor-
ide and subsequently LDA as base (Scheme 1). Depro-
tonation of the silammonium salt generated in situ a
nitrogen ylide intermediate, which undergoes 1,2-silyl
transposition to the desired α-silylated aminoacetonitrile
1. This reaction procedure was later optimized by Sato
Despite these popular methods which have been devel-
oped during the last decades,1,2 the synthesis of α-cyanoe-
namines under mild conditions still remains to be a
challenge in synthetic organic chemistry, as the following
brief exposition manifests. For example, the preparation
of α-cyanoenamines by the Horner–Emmons reaction
Scheme 1 Synthesis of the α-Cyanoenamines 3 from α-Dimethylamino-α(trimethylsilyl)acetonitrile (1) and Carbonyl partner 2 by the Peter-
son Olefination
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2003,0,02,0414,0416,ftx,en;G32702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
An Effective Synthesis of α-Cyanoenamines by Peterson Olefination
415
and coworkers,4 who prepared a series of α-amino-α(tri- selectively and efficiently the α-proton from the α-silylat-
methylsilyl)acetonitriles. These were converted to 1-(tri- ed N,N-dimethylacetonitrile 1 to generate the correspond-
methylsilyl)alkylamines by replacing the cyano ing carbanion; therefore, this effective base was used for
functionality of the α-silylated aminoacetonitriles by all subsequent reactions.5
alkyl groups on treatment with the corresponding Grig-
nard reagents.
The scope of the successful Peterson olefination method
is displayed in Table 1, in which the set of diverse α-cya-
The Peterson-olefination procedure (Scheme 1) was noenamines 3 have been prepared. Some of them have
utilized in the present work to prepare the the α-cyano- been synthesized previously by the Horner–Emmons ole-
enamines 3 in good yields from α-silylated aminoaceto- fination. The high yields of the Peterson method confirm
nitrile 1 and the carbonyl compounds 2 (Table 1).
that this condensation procedure is superior to the Hor-
ner–Emmons one. The tested carbonyl compounds reveal
that the best yields were obtained for the reactive aromatic
and heteroaromatic aldehydes 2d–f. Although the yields
of the aliphatic α-cyanoenamines 3b,c are lower, but still
comparatively good, the diastereomeric differentiation is
much better, since E:Z ratios of 90:10 were obtained for
the derivatives 3b,c compared to about 60:40 for the aro-
matic derivatives 3d–f. In the case of acetophenone (2g)
as carbonyl partner, the low conversion manifests the gen-
eral reactivity trend of ketones versus aldehydes in such
olefinations reactions.
Table 1 Synthesis of the α-Cyanoenamine 3 by the Peterson Olefi-
nation
RCOR′
Convn
(%)a
yield of 3 E:Zd
(%)b,c
(2a)
81
69
>95:05
All in all, we demonstrated herein that the presently devel-
oped olefination is the method of choice for the prepara-
tion of α-cyanoenamines 3, as confirmed by the higher
yields and a broader scope than the Horner–Emmons re-
action. The efficacy of the Peterson methodology presum-
ably derives from the higher oxygenphilicity of silicon
versus phosphorus, which enables sufficiently gentle re-
action conditions to employ labile carbonyl compounds
and minimize as well the decomposition of the sensitive
α-cyanoenamines 3.
(2b)
(2c)
>95
>95
78 (50)
76 (69)
91:09
90:10
(2d)
(2e)
>94
>95
91 (64)
93
64:36
54:46
General Procedure for the Preparation of a-Cyanoenamine 3
A solution of 1.27 mmol of the α-dimethylamino-α(trimethyl-
silyl)acetonitrile 1 in 20 mL of abs. THF was cooled under an ar-
gon-gas atmosphere to –78 °C, 1.00 mL (1.3 M, hexane) of s-BuLi
was added dropwise by means of a syringe, and the reaction mixture
stirred magnetically for 45 min at –78 °C. To the solution was added
1.20 mmol of the corresponding carbonyl partner 2, the reaction
mixture was allowed to warm up slowly to r.t., and stirred an addi-
tional 2 h at ca. 20 °C. After addition of 20 mL of Et2O, the organic
phase was washed with H2O (2 × 20 mL), brine (1 × 20 mL), and
dried over MgSO4. The solvent was removed by distillation (20 °C,
20 mbar) and the residue submitted to silica-gel radial chromato-
graphy (Chromatotron), to afford the pure α-cyanoenamines 3
(Table 1). The α-cyanoenamine 3b–d and 3f,g are known com-
pounds and their spectral data matched those reported for the au-
thentic substances.
(2f)
>95
58
88
61:39
69:31
(2g)
43 (24)
a Conversion determined from the re-isolated carbonyl compound 2.
b Yield of the isolated α-cyanoenamine 3 after radial-chromatograph-
ic purification (Chromatotron).
c In parenthesis are given the yields for the Horner–Emmons method
(ref.2a).
d E:Z ratio determined from the areas of the olefin signals in the 1H
NMR spectrum (± 5% of the stated value).
The critical carbonyl partner was the quite labile azoalde-
hyde 2a, for which all previously reported olefination
methods have failed; therewith the need was exposed to
develop a more suitable method. Indeed, the present com-
munication demonstrates that quite a good yield (69%) of
the corresponding α-cyanoenamine 3a may be obtained,
as shown in the first entry of Table 1. Essential for success
is the proper choice of the base for the deprotonation of
(1R*,4R*,4aS*,7aR*)-2E-Dimethylamino-3-[4′,4′a-5′,6′,7′,7′a-
hexahydro-8′,8′-dimethyl-4′-phenyl-1′,4′-methano-1H-cyclo-
penta[d]pyridazin-1′-yl]acrylonitrile (3a).
According to the general procedure, the α-cyanoenamine 3a (555
mg, 1.65 mmol, 69%) was obtained as a colorless needles, mp 126–
127 °C; Rf 0.36 [silica gel, dichloromethane–n-pentane (4:1)]. IR
1
(KBr): ν (cm–1) = 2921, 2905, 2201, 1606, 1598, 1114. H NMR
(200 MHz, CDCl3): δ = 0.31 (s, 3H, 9′-H), 0.78 (s, 3 H, 10′-H),
1.12–1.82 (m, 6 H, 4′-H, 5′-H and 6′-H), 2.31 (s, 6H, NMe2), 2.85–
the α-silylated N,N-dimethylacetonitrile 1. Optimal re- 3.00 (m, 1 H, 4′a-H), 3.30–3.50 (m, 1 H, 7′a-H), 6.14 (s, 1 H, 3′-H),
sults were obtained with sec-BuLi, which deprotonated
7.28–7.32 (m, 3 H, Ph), 7.62–7.75 (m, 2 H, Ph). 13C NMR (50 MHz,
Synlett 2003, No. 3, 414–416 ISSN 0936-5214 © Thieme Stuttgart · New York

416
W. Adam, C. M. Ortega-Schulte
LETTER
CDCl3): δ = 18.3, 19.0, 26.6, 27.1, 29.8, 42.2, 50.2, 51.2, 68.6, 97.5,
98.3, 111.5, 115.2, 117.3, 128.4, 129.5, 129.6, 130.2, 138.3. Anal.
Calcd for C21H26N4 (334.4): C, 75.41; H, 7.84; N, 16.75. Found: C,
75.45; H, 7.69; N, 17.22.
References
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2-Dimethylamino-3-(4-methoxyphenyl)acrylonitrile (3e).
According to the general procedure, a E/Z (54:46) mixture of the α-
cyanoenamine 3e (226 mg, 1.12 mmol, 93%) was obtained as a col-
orless oil; Rf = 0.56 (silica gel, CH2Cl2). IR (KBr): ν (cm–1) = 2915,
1
2910, 2205, 2195, 1590, 1500, 1030. E-Isomer: H NMR (200
MHz, CDCl3): δ = 2.58 (s, 6 H, NMe2), 3.83 (s, 3 H, OMe), 6.36 (s,
1 H), 6.87 (d, 3J = 8.8 Hz, 2 H, Ar), 7.67 (d, 3J = 8.8 Hz, 2 H, Ar).
13C NMR (50 MHz, CDCl3): δ = 40.1, 54.7, 113.8, 116.2, 122.4,
126.4, 128.0, 131.9, 160.3. Z-Isomer: 1H NMR (200 MHz, CDCl3):
δ = 2.84 (s, 6 H, NMe2), 3.81 (s, 3 H, OMe), 5.97 (s, 1 H), 6.88 (d,
3J = 8.8 Hz, 2 H Ar), 7.47 (d, 3J = 8.8 Hz, 2 H, Ar). 13C NMR (50
MHz, CDCl3): δ = 42.4, 55.7, 113.9, 116.1, 121.4, 127.0, 128.9,
131.2, 159.0. Anal. Calcd for C12H14N2O (202.3): C, 71.26; H, 6.98;
N, 13.85. Found: C, 71.02; H, 7.04; N, 13.81.
Acknowledgment
We are grateful to the Deutsche Forschungsgemeinschaft, the
Volkswagen Stiftung, and the Fonds der Chemischen Industrie for
generous financial support.
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(3) Padwa, A.; Eisenbarth, P.; Venkatramanan, M. K.; Wong, G.
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(4) Okazaki, S.; Sato, Y. Synthesis 1990, 36.
(5) In our preliminary attempts on the Peterson olefination, we
have employed n-BuLi and LDA for the reaction with the
aldehyde 2a, but obtained poor yields of the desired α
cyanoenamine 3a, e.g., none with n-BuLi and only a 7%
yield in the case of LDA.
Synlett 2003, No. 3, 414–416 ISSN 0936-5214 © Thieme Stuttgart · New York