Applications of the baylis-hillman adducts in organic synthesis: A facile synthesis of [E]-α-cyanocinnamyl alcohols and [E]-α-cyanocinnamic aldehydes

Article abstract of DOI:10.1055/s-1999-2893

Aqueous sulfuric acid mediated transformation of the Baylis-Hillman adducts, i.e. 3-aryl-3-hydroxy-2-methylenepropanenitriles, into [E]-α- cyanocinnamyl alcohols and subsequent oxidation with PCC leading to the formation of stereochemically pure [E]-α-cya

Full text of DOI:10.1055/s-1999-2893

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LETTER
Applications of the Baylis-Hillman Adducts in Organic Synthesis: A Facile
Synthesis of [E]-a-Cyanocinnamyl Alcohols and [E]-a-Cyanocinnamic
Aldehydes
Deevi Basavaiah,* Nagaswamy Kumaragurubaran, Kisari Padmaja
School of Chemistry, University of Hyderabad, Hyderabad- 500 046, India
Received 30 July 1999
hexanes), stereochemically pure [2E]-2-cyano-3-phenyl-
Abstract: Aqueous sulfuric acid mediated transformation of the
prop-2-enol (2a) in 60% yield.21,22 The [E]-stereochemis-
Baylis-Hillman adducts, i.e. 3-aryl-3-hydroxy-2-methylenepro-
panenitriles, into [E]-a-cyanocinnamyl alcohols and subsequent ox-
idation with PCC leading to the formation of stereochemically pure
try of this molecule was confirmed by comparing the 13C
NMR spectral data with literature values.23 This success
[E]-a-cyanocinnamic aldehydes, which represents an efficient alter- led us to transform representative 3-aryl-3-hydroxy-2-me-
native route to the Knoevenagel condensation reaction, is described.
thylenepropanenitriles (1b-1g) into stereo-chemically
pure [E]-a-cyanocinnamyl alcohols (2b-2g) (Scheme 1,
Table 1). However, our attempts to transform 3-hydroxy-
2-methylenehexanenitrile and 3-hydroxy-2-methyleneoc-
tanenitrile into the corresponding 3-substituted 2-cyano
allylic alcohols were unsuccessful.
Key words: Baylis-Hillman reaction, [E]-a-cyanocinnamyl alco-
hols, [E]-a-cyanocinnamic aldehydes, isomerization, and oxidation
Development of simple and convenient methodology for
stereo-selective synthesis of [E]-a-cyanocinnamyl alco-
hols and [E]-a-cyanocinnamic aldehydes has been an im-
portant endeavor in synthetic organic chemistry because
these molecules constitute an important class of synthons
for synthesis of various biologically active and heterocy-
clic molecules.1-8 The Baylis-Hillman reaction is a novel
carbon-carbon bond forming reaction providing a useful
class of multifunctional molecules which have been suc-
cessfully employed in several different stereoselective
processess.9-20 In continuation of our interest in the Bayl-
is-Hillman reaction,12-17 we herein report an aqueous sul-
furic acid (20%) mediated isomerization of the Baylis-
Hillman adducts, i.e. 3-aryl-3-hydroxy-2-methylenepro-
panenitriles thus providing simple and efficient methodol-
ogy for synthesis of [E]-a-cyanocinnamyl alcohols, and
their subsequent oxidation with pyridinium chlorochro-
mate (PCC) leading to the formation of stereochemically
pure [E]-a-cyanocinnamic aldehydes.
Recently Amri and coworkers2,3 reported an interesting
three step reaction sequence “bromination-formylation-
hydrolysis” for conversion of the Baylis-Hillman adducts,
3-hydroxy-2-methylenealkanenitriles, obtained from
acrylonitrile, into 3-substituted 2-cyano allylic alcohols in
good (60-100%) [E]-stereoselectivity. In view of the im-
portance of 3-substituted 2-cyano allylic alcohols we felt
that it will be highly useful if the Baylis-Hillman adducts,
3-hydroxy-2-methylenealkanenitriles can be transformed
directly into 3-substituted 2-cyano allylic alcohols in one
step with 100% stereoselectivity. During our studies in
this direction, we have examined the possible isomeriza-
tion of 3-hydroxy-2-methylene-3-phenylpropanenitrile
(1a) under a variety of conditions. The best results were
obtained when this molecule 1a (5mM) was treated with
aqueous sulfuric acid (20%, 10 mL) at reflux temperature
for 2 hours thus providing after usual workup followed by
column chromatography (silica gel, 5% ethyl acetate in
Scheme 1
The [E]-selectivity in the sulfuric acid mediated transfor-
mation of the Baylis-Hillman adducts, i.e. 3-aryl-3-hy-
droxy-2-methylenepropanenitriles
into
[E]-a-
cyanocinnamyl alcohols (2a-2g) can be possibly ex-
plained through the transition state models A and B. The
transition state A is more favored than B due to the CN
group having a smaller steric effect than the CH2OH
group.
We have successfully transformed these [E]-a-cyanocin-
namyl alcohols (2a-2g) by treating with pyridinium chlo-
rochromate (PCC) into [E]-a-cyanocinnamic aldehydes
(3a-3g) (Scheme 1, Table 1). It is worth mentioning here
that the a-cyanocinnamic aldehydes were earlier prepared
either by the base catalyzed condensation of appropriate
aromatic aldehydes with 3-oxopropanenitrile, generated
in situ from isoxazole7,8 or by condensation of 3,3-
dimethoxypropanenitrile with aldehydes followed by acid
hydrolysis.5 However, the stereochemistry of these mole-
cules has not been reported.5,7,8 Thus our methodology
Synlett 1999, No. 10, 1630–1632 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Applications of the Baylis-Hillman Adducts in Organic Synthesis
1631
a) All reactions were carried out on a 5 mM scale of the allyl alcohol with 10 mL of aq. sulfuric
acid (20%) at reflux temperature.24
b) Products 2a, 2d, and 2e were isolated as colorless liquids and 2b, 2c, 2f and 2g were isolated
as solids after silica gel column chromatography (5% EtOAc in hexanes). All these molecules
2a-2g were characterized by IR, 1H NMR (200 MHz), 13C NMR (50 MHz) spectral data and
elemental analyses.
c) 1H and 13C NMR spectra indicate the absence of any [Z]-isomer.
d) Isolated yields of products either after column chromatography (2a, 2d and 2e) (silica gel, 5%
EtOAc in hexanes) or after column chromatography followed by crystallization (2b, 2c, 2f and
2g) from EtOAc in hexanes.
e) Oxidation of cinnamyl alcohols 2a-2g was carried out on a 2 mM scale with PCC (3 mM) at
room temperature for 2 hours in dichloromethane. Products 3a-3c, 3e-3g were isolated as
solids and the compound 3d was isolated as colorless liquid. All these molecules 3a-3g gave
satisfactory spectral [IR, 1H NMR (200 MHz), 13C NMR (50 MHz)] data and elemental
analyses. Molecules 3a-3d, and 3f-3g were known in the literature but their stereochemical
assignment has not been reported.5,7,8
f) Isolated yields of the pure aldehydes obtained either after crystallization (3a-3c, 3e-3g) from
EtOAc:hexanes (1:2) or after silica gel column chromatography (3d) (2% EtOAc in hexanes).
g) These molecules (2a-2c) are known in literature. Spectral data of 2a-2c is in agreement with
literature data.1-3
h) The [E]-stereochemistry of the molecule 3a was assigned by a 2D NOESY experiment.
i) The [E]-stereochemistry of the molecules 3b-3g was assigned in analogy with 3a.
j) The [E]-stereochemistry of the molecules 2d-2g was assigned by comparing the 13C NMR
chemical shift value of allylic methylene carbon with that of 2a.
represents an efficient alternative route to Knoevenagel References and Notes
condensation reaction for obtaining stereochemically pure
[E]-a-cyanocinnamic aldehydes.
(1) Aiai, M.; Floc’h, M. B.; Robert, A.; Le Grel, P. Synthesis,
1996, 403 and references cited therein.
(2) Hbaieb, S.; Ben Ayed, T.; Amri, H. Synth. Commun., 1997,
27, 2825 and references cited therein.
In conclusion, this methodology describes a facile aque-
ous sulfuric acid mediated one-step conversion of the
Baylis-Hillman adducts i.e., 3-aryl-3-hydroxy-2-methyl-
enepropanenitriles into [E]-a-cyanocinnamyl alcohols
and subsequent oxidation with PCC leading to the forma-
tion of [E]-a-cyanocinnamic aldehydes, thus demonstrat-
ing the synthetic potential of the Baylis-Hillman adducts.
(3) Beltaief, I.; Hbaieb, S.; Besbes, R.; Amri, H.; Villieras, M.;
Villieras, J. Synthesis, 1998, 1765 and references cited therein.
(4) Campi, E. M.; Dyall, K.; Fallon, G.; Jackson, W. R.;
Perlmutter, P.; Smallridge, A. J. Synthesis, 1990, 855.
(5) Elliott, A. J.; Morris, P. E.; Petty, S. L.; Williams, C. H. J.
Org. Chem., 1997, 62, 8071.
(6) Elliott, A. J.; Walsh, D. A.; Morris, P. E. PCT Int. Appl. WO
97 21,653, Chem. Abstr., 1997, 127, 121751v.
Acknowledgement
(7) Ciller, J. A.; Martin, N.; Seoane, C.; Soto, J. L. J. Chem. Soc.,
Perkin Trans. 1, 1985, 2581.
(8) Herbert, A. (BASF A.-G.) Ger. Offen. 2,623,170, Chem.
Abstr., 1978, 88, 62159j.
(9) Ciganek, E. Organic Reactions; Paquette, L. A. Ed.; John
Wiley & Sons, New York, 1997, Vol 51, pp 201.
(10) Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R.
Tetrahedron, 1996, 52, 8001.
We thank DST (New Delhi) for funding this project. We also thank
the UGC (New Delhi) for the Special Assistance Program in orga-
nic chemistry in the School of Chemistry, University of Hyderabad,
Hyderabad. NK and KP thank UGC (New Delhi) for research fel-
lowship.
(11) Drewes, S. E.; Roos, G. H. P. Tetrahedron, 1988, 44, 4653.
Synlett 1999, No. 10, 1630–1632 ISSN 0936-5214 © Thieme Stuttgart · New York

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D. Basavaiah et al.
LETTER
(12) Basavaiah, D.; Gowriswari, V. V. L. Synth. Commun., 1987,
17, 587.
(13) Basavaiah, D.; Gowriswari, V. V. L.; Sarma, P. K. S.; Dharma
Rao, P. Tetrahedron Lett., 1990, 31, 1621.
MHz) (CDCl3): d 64.00, 110.52, 117.79, 128.74, 130.40,
132.93, 143.90; IR (neat): 3410, 2216 cm-1; Elemental
analysis calculated for C10H9NO: C, 75.45; H, 5.70; N, 8.80
and found C, 75.31; H, 5.72; N, 8.87.
(14) Basavaiah, D.; Sarma, P. K. S.; Bhavani, A. K. D. J. Chem.
Soc., Chem. Commun., 1994, 1091.
(15) Basavaiah, D.; Krishnamacharyulu, M.; Suguna Hyma, R.;
Pandiaraju, S. Tetrahedron Lett., 1997, 38, 2141.
(16) Basavaiah, D.; Bakthadoss, M.; Pandiaraju, S. Chem.
Commun., 1998, 1639.
(17) Basavaiah, D.; Krishnamacharyulu, M.; Suguna Hyma, R.;
Sarma, P. K. S.; Kumaragurubaran, N. J. Org. Chem., 1999,
64, 1197.
(18) Matsumoto, S.; Okubo, Y.; Mikami, K. J. Am. Chem. Soc.,
1998, 120, 4015.
(23) Both [E]- & [Z]-isomers of 2-cyano-3-phenylprop-2-enol are
known in the literature.1-3 In the 13C NMR spectrum the allylic
methylene carbon of the [E]- isomer appears at ª d 64.00 while
that of the [Z]- isomer appears at ª d 57.00. In the case of
molecule 2a, the allylic methylene carbon appears at d 64.00.
We have therefore assigned [E]- stereochemistry to 2a.
(24) In all the cases, the 1H NMR spectrum of the crude product
shows the presence of ª5-20% unreacted starting material.
(25) Spectral data for 3a: mp.: 94-96 ∞C {lit.5 96-97 ∞C}; 1H
NMR (200 MHz) (CDCl3): d 7.48-7.70 (m, 3H), 7.92 (s, 1H),
8.02-8.15 (m, 2H), 9.60 (s, 1H); 13C NMR (50 MHz) (CDCl3):
d 112.40, 114.06, 129.49, 131.30, 134.28, 159.37, 187.05; IR
(KBr): 2222, 1691 cm-1; Elemental analysis calculated for
C10H7NO: C, 76.42; H, 4.49; N, 8.91 and found C, 76.52; H,
4.48; N, 8.93.
(19) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. J.
Org. Chem., 1998, 63, 7183.
(20) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem.
Commun., 1998, 2533.
(21) 1H NMR spectrum of the crude product 2a shows the presence
of ª 15% unreacted starting material.
(22) Spectral data for 2a: 1H NMR (200 MHz) (CDCl3): d 2.76 (t,
1H, J = 6.0 Hz, D2O washable), 4.40 (d, 2H, J = 6.0 Hz), 7.20
(s, 1H), 7.35-7.50 (m, 3H), 7.70-7.82 (m, 2H); 13C NMR (50
Article Identifier:
1437-2096,E;1999,0,10,1630,1632,ftx,en;L07899ST.pdf
Synlett 1999, No. 10, 1630–1632 ISSN 0936-5214 © Thieme Stuttgart · New York