Steric factors direct Baylis-Hillman and aldol reactions in titanium tetrachloride mediated coupling between α-keto esters and cyclohex-2-enone derivatives

Article abstract of DOI:10.1021/jo0342424

The titanium tetrachloride mediated reaction of α-keto esters with 5,5-dimethylcyclohex-2-enone provides the corresponding Baylis-Hillman adducts exclusively whereas a similar reaction of α-keto esters with cyclohex-2-enone furnishes the corresponding aldol adducts (with high syn-diasteroe-selectivity) as the major product (along with the Baylis-Hillman adducts as the minor product), thus clearly demonstrating the role of the steric factors in directing the reaction pathway.

Full text of DOI:10.1021/jo0342424

Ster ic F a ctor s Dir ect Ba ylis-Hillm a n a n d Ald ol Rea ction s in
Tita n iu m Tetr a ch lor id e Med ia ted Cou p lin g betw een r-Keto Ester s
a n d Cycloh ex-2-en on e Der iva tives
Deevi Basavaiah,* Bandaru Sreenivasulu, and Anumolu J aganmohan Rao
School of Chemistry, University of Hyderabad, Hyderabad-500 046, India
dbsc@uohyd.ernet.in
Received February 23, 2003
The titanium tetrachloride mediated reaction of R-keto esters with 5,5-dimethylcyclohex-2-enone
provides the corresponding Baylis-Hillman adducts exclusively whereas a similar reaction of R-keto
esters with cyclohex-2-enone furnishes the corresponding aldol adducts (with high syn-diasteroe-
selectivity) as the major product (along with the Baylis-Hillman adducts as the minor product),
thus clearly demonstrating the role of the steric factors in directing the reaction pathway.
In tr od u ction
SCHEME 1. Ba ylis-Hillm a n Rea ction of
Ald eh yd es w ith Cyclic En on es a n d r-Keto Ester s/
Tr iflu or om eth yl P h en yl Keton e w ith Acyclic
En on es
The Baylis-Hillman reaction is an atom economical
carbon-carbon bond forming reaction between the R-po-
sition of activated alkenes and carbon electrophiles under
the influence of a tertiary amine catalyst (most commonly
DABCO) producing an interesting class of highly func-
tionalized molecules that have been extensively used in
various organic transformation methodologies often in-
volving high levels of stereoselectivities.1 In a broad
sense the Baylis-Hillman reaction can be regarded as a
one-pot combination of Michael and aldol reactions.
Recently, numerous non-amine catalysts/catalytic systems/
-3
2
i
reagents such as trialkylphosphines, dimethyl sulfide/
*
To whom correspondence should be addressed. Fax: +91-40-
3012460.
1) (a) Basavaiah, D.; J aganmohan Rao, A.; Satyanarayana, T.
titanium tetrachloride,2m and titanium tetrachloride4,5
2
have been employed for performing the Baylis-Hillman
reaction. During the course of our work in the titanium
tetrachloride mediated Baylis-Hillman reaction we have
observed interesting steric factors governed competition
between the Baylis-Hillman reaction and the aldol
reaction, i.e. the titanium tetrachloride mediated reaction
of R-keto esters with 5,5-dimethylcyclohex-2-enone pro-
vides the corresponding Baylis-Hillman adducts exclu-
sively whereas a similar reaction of R-keto esters with
cyclohex-2-enone furnishes the corresponding aldol ad-
ducts, with high syn-diasteroeselectivity, as the major
product (along with the Baylis-Hillman adducts as the
minor product). We herein describe these results.
(
Chem. Rev. 2003, 103, 811. (b) Ciganek, E. Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, 1997; Vol. 51, p 201. (c)
Basavaiah, D.; Dharma Rao, P.; Suguna Hyma, R. Tetrahedron 1996,
5
2, 8001. (d) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
2) (a) Lee, K. Y.; Kim, J . M.; Kim, J . N. Synlett 2003, 357. (b)
Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J . Org. Chem. 2003, 68, 692.
c) Almeida, W. P.; Coelho, F. Tetrahedron Lett. 2003, 44, 937. (d) Yang,
(
(
K.-S.; Lee, W.-D.; Pan, J .-F.; Chen, K. J . Org. Chem. 2003, 68, 915. (e)
Patra, A.; Roy, A. K.; J oshi, B. S.; Roy, R.; Batra, S.; Bhaduri, A. P.
Tetrahedron 2003, 59, 663. (f) Shi, M.; Xu, Y.-M. Angew. Chem., Int.
Ed. 2002, 41, 4507. (g) Barrett, A. G. M.; Dozzo, P.; White, A. J . P.;
Williams, D. J . Tetrahedron 2002, 58, 7303. (h) Kaye, P. T.; Nocanda,
X. W. J . Chem. Soc., Perkin Trans. 1 2002, 1318. (i) Wang, L.-C.; Luis,
A. L.; Agapiou, K.; J ang, H.-Y.; Krische, M. J . J . Am. Chem. Soc. 2002,
24, 2402. (j) Yu, C.; Hu, L. J . Org. Chem. 2002, 67, 219. (k) Ram
Reddy, M. V.; Rudd, M. T.; Ramchandran, P. V. J . Org. Chem. 2002,
7, 5382. (l) Racker, R.; Doring, K.; Reiser, O. J . Org. Chem. 2000, 65,
932. (m) Kataoka, T.; Iwama, T.; Tsujiyama, S.-i.; Iwamura, T.;
1
6
6
Li and co-workers reported an important Baylis-
Hillman reaction between aldehydes and cyclic enones
Watanabe, S.-i. Tetrahedron 1998, 54, 11813. (n) Amri, H.; El Gaied,
M. M.; Ayed, T. B.; Villieras, J . Tetrahedron Lett. 1992, 33, 7345. (o)
Hoffmann, H. M. R.; Rabe, J . Angew. Chem., Int. Ed. Engl. 1983, 22,
under the influence of titanium tetrachloride to produce
the desired adducts (Scheme 1).4 We have recently
7
95.
described an interesting titanium tetrachloride mediated
Baylis-Hillman coupling of R-keto esters and trifluo-
romethyl phenyl ketone with acyclic enones to provide
(3) (a) Basavaiah, D.; J aganmohan Rao, A. Chem. Commun. 2003,
6
4
04. (b) Basavaiah, D.; Satyanarayana, T. Tetrahedron Lett. 2002, 43,
301. (c) Basavaiah, D.; Sharada, D. S.; Kumaragurubaran, N.; Reddy,
R. M. J . Org. Chem. 2002, 67, 7135. (d) Basavaiah, D.; Satyanarayana,
T. Org. Lett. 2001, 3, 3619. (e) Basavaiah, D.; Kumaragurubaran, N.;
Sharada, D. S. Tetrahedron Lett. 2001, 42, 85. (f) Basavaiah, D.;
Krishnamacharyulu, M.; Suguna Hyma, R.; Sarma, P. K. S.; Kuma-
ragurubaran, N. J . Org. Chem. 1999, 64, 1197. (g) Basavaiah, D.;
Bakthadoss, M.; Pandiaraju, S. Chem. Commun. 1998, 1639. (h)
Basavaiah, D.; Gowriswari, V. V. L. Tetrahedron Lett. 1986, 27, 2031.
5
the functionalized tertiary alcohols (Scheme 1).
Resu lts a n d Discu ssion
During our ongoing research program on the Baylis-
Hillman reaction we required the tertiary-allylic alcohols,
1
0.1021/jo0342424 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/02/2003
J . Org. Chem. 2003, 68, 5983-5991
5983

Basavaiah et al.
SCHEME 2. Rea ction of Cycloh ex-2-en on e w ith Eth yl P h en ylglyoxyla te a n d p-Nitr oben za ld eh yd e in th e
P r esen ce of Tita n iu m Tetr a ch lor id e
with cyclohex-2-enone (Scheme 2) led us to perform the
reaction of 4-nitrobenzaldehyde with cyclohex-2-enone in
the presence of titanium tetrachloride under similar
conditions, which provided only the Baylis-Hillman
adduct8 in 50% isolated yield (Scheme 2) and did not
,9
8
,9
indicate the presence of any aldol product. This result
is in accordance with Li’s work, that is, the titanium
tetrachloride mediated reaction of 4-nitrobenzaldehyde
with cyclohex-2-enone provided the desired Baylis-
4
Hillman adduct in 56% isolated yield (Scheme 1).
These two different results [the titanium tetrachloride
mediated coupling of aldehydes4 with cyclohex-2-enone
,10
4
provides the desired Baylis-Hillman adducts (Scheme
1
) whereas similar coupling of ethyl phenylglyoxylate (2a )
with cyclohex-2-enone leads to the aldol reaction, Scheme
1
1
F IGURE 1. ORTEP diagram of compound 5.
2] indicate that these reactions might possibly proceed
through two different transition states, that is, through
two different titanium-enolates. It can be easily envi-
sioned that the treatment of cyclohex-2-enone with
titanium tetrachloride in principle can result either in
the formation of Michael type enolate (A) or dienolate
(aldol type) (B) thus creating a competition between
Baylis-Hillman and aldol reactions (Scheme 3).
which would be obtained via the reaction between R-keto
esters and cyclic enones. In this direction, with a view to
obtaining the desired Baylis-Hillman adducts, that is,
alkyl 2-hydroxy-2-aryl-2-(cyclohex-2-en-1-on-2-yl)etha-
noates, we first carried out the reaction between ethyl
phenylglyoxylate (2a , 1 mmol) and cyclohex-2-enone (1a ,
4
mmol) under the influence of TiCl (1 mmol) in
In fact, we have recorded the H NMR and 13C NMR
1
3
dichloromethane at room temperature for 2 h. Astonish-
spectra of the crude reaction mixture obtained by the
ingly, this reaction provided Baylis-Hillman adduct 4
treatment of cyclohex-2-enone with TiCl (1:1) for 30 min
4
1
1
only as a minor product (≈13% as evidenced by the H
at room temperature in CDCl . In the H NMR spectrum
3
NMR spectrum of the crude product) (in fact, we have
there is a considerable change (deshielding) in the
chemical shifts of R- and â-vinylic protons (from that of
cyclohex-2-enone). The 13C NMR spectrum also shows a
considerable change in the chemical shift (deshielding),
isolated 4 in 7% yield by carrying out the reaction on a
2
-mmol scale: Experimental Section). As the major
product we have obtained ethyl syn-2-hydroxy-2-phenyl-
2
8
-(cyclohex-5-en-1-on-2-yl)ethanoate (5) (aldol adduct) in
0% isolated yield after column chromatography followed
1
(
8) H NMR data (particularly the chemical shifts of benzylic and/
6
by crystallization (Scheme 2). The syn-stereochemistry,
as well as the structure of this molecule, was established
by single-crystal X-ray data (Figure 1).7
or olefinic protons) of Baylis-Hillman and aldol compounds obtained
from cyclohex-2-enone and aromatic aldehydes were reported in the
literature.
This unexpected formation of aldol adduct as the major
product in the reaction of ethyl phenylglyoxylate (2a )
(
4) Li, G.; Wei, H. X.; Gao, J .; Caputo, T. D. Tetrahedron Lett. 2000,
4
1, 1. In this paper Li and co-workers have clearly mentioned that
the electron-withdrawing group is necessary on the aromatic ring for
obtaining modest yields and a better reaction rate in the titanium
tetrachloride mediated Baylis-Hillman reaction between aromatic
aldehydes and cyclic enones and they employed 4-nitrobenzaldehyde
and 4-(trifluoromethyl)benzaldehyde as electrophiles in this reaction.
(
5) Basavaiah, D.; Sreenivasulu, B.; Reddy, R. M.; Muthukumaran,
K. Synth. Commun. 2001, 31, 2987.
6) We have assigned the syn-stereochemistry to the structure as
(
shown below [the hydroxy group and C2′ and C3′ (of the cyclohex-2-
enone moiety) are on the same side in the extended conformation].
(
9) The 1H NMR spectrum of the crude reaction mixture shows a
triplet at δ 6.81 and a singlet at δ 5.61 in the ratio of 1:1 indicating
8
(
7) Detailed X-ray crystallographic data for compound 5 is available
the presence of Baylis-Hillman compound. The absence of any other
from the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge, CB2 1EZ, U.K. (CCDC no. 184079).
peak in the δ 4.50-5.90 region indicates the absence of syn- or anti-
8
aldol adduct.
5
984 J . Org. Chem., Vol. 68, No. 15, 2003

Baylis-Hillman and Aldol Reactions
arising from the -CHCl proton. The 13C NMR spectrum
of this crude mixture shows a peak at δ 206.48 (in
addition to the peak at δ 199.41 due to the carbonyl
carbon of cyclohex-2-enone) probably arising from the
SCHEME 3. Rea ction of Cycloh ex-2-en on e w ith
Tita n iu m Tetr a ch lor id e: P ossible En ola te
F or m a tion
-
CdO carbon of 3-chlorocyclohexanone.12 These observa-
tions also indicate that there is no formation of dienolate
(B) in the reaction.
To understand the formation of enolates (A and/or B)
and also to investigate competition between Baylis-
Hillman and aldol reactions, we have treated cyclohex-
2
-enone (1a , 1 mmol) with 4-nitrobenzaldehyde (1 mmol)
appearance (broad), and size (small) of â-vinylic and
carbonyl carbons, thus probably indicating the presence
of structures C and D in equilibrium. To realize this
and ethyl phenylglyoxylate (2a , 1 mmol) in the presence
of TiCl (1 mmol). As expected the H NMR spectrum of
4
the crude mixture shows the formation of Baylis-
Hillman product 3 (derived from the enolate A) and aldol
product 5 [derived from the dienolate B, which probably
was obtained from A in the presence of keto ester
1
(Scheme 3)] in the ratio of ca. 60:40 (probably indicating
that 4-nitrobenzaldehyde is more reactive than ethyl
phenylglyoxylate). We have also noticed the formation
of ethyl 2-hydroxy-2-phenyl-2-(cyclohex-2-en-1-on-2-yl)-
ethanoate (4) (Baylis-Hillman adduct from ethyl phen-
ylglyoxylate and cyclohex-2-enone) in minor amounts (ca.
observation, we have treated the reaction mixture with
water and recorded the H NMR spectrum of the crude
mixture, which shows a multiplet at δ 4.27-4.42 probably
1
1
/7 of 5) (eq 1, competition between Baylis-Hillman and
aldol reactions).
(10) As suggested by the referee, we have also performed the
reaction between the less reactive electrophile, that is, 4-methoxyben-
zaldehyde (1 mmol), and cyclohex-2-enone (3 mmol) under the influence
of titanium tetrachloride (1 mmol, 0.5 mL of 2 M solution in CH
for 2 h at room temperature (similar conditions as in the case of
-nitrobenzaldehyde). Since 4-methoxybenzaldehyde is less reactive,
2 2
Cl )
4
we have also performed the same reaction for 5 h at room temperature.
In both cases, the 1H NMR spectrum of the crude reaction mixture
did not show the presence of either Baylis-Hillman or aldol adducts
8
1
(
absence of any peak at ca. δ 4.50-5.80) and also H NMR and TLC
4
examinations indicated a mixture of products (unidentified). Our
observation is consistent with that of Li and co-workers. Since the
4
reaction of 4-methoxybenzaldehyde with cyclohex-2-enone did not
provide any additional information, we have used benzaldehyde
(
because it is more reactive than 4-methoxybenzaldehyde and less
reactive than 4-nitrobenzaldehyde) as the electrophile in this reaction,
with a view to understand the course of the reaction. Thus, we have
performed the reaction between benzaldehyde (1 mmol) and cyclohex-
The formation of the Baylis-Hillman and aldol adducts
in the reactions of aldehydes and R-keto esters with
cyclohex-2-enone respectively possibly can be explained
by considering the transition state models I, II, III, IV,
and V. Our results as well as Li’s results indicate that
the transition state I is more favored in the case of
aldehydes leading to the formation of Baylis-Hillman
2
-enone (3 mmol) under the influence of titanium tetrachloride (1
mmol, 0.5 mL of 2 M solution in CH Cl ) for 2 h at room temperature
following similar conditions as in the case of 4-nitrobenzaldehyde).
2
2
(
1
The H NMR spectrum of crude compound shows the presence of a
triplet at δ 6.73 (with a low intensity) and a singlet at δ 5.56 (with a
low intensity) (in the ratio of 1:1) indicating the presence of Baylis-
Hillman compound. In fact, we have also isolated the Baylis-Hillman
adduct, that is, 2-[hydroxy(phenyl)methyl]cyclohex-2-en-1-one (3a ), in
very low yield (10%) by performing this reaction on 5 mmol of
benzaldehyde with cyclohex-2-enone (15 mmol) in the presence of
4
titanium tetrachloride (5 mmol, 2.5 mL of 2 M solution in CH
2
5
2
Cl
h. The H NMR spectrum of crude also shows a multiplet at δ 5.42-
.52 (unidentified) (with very low intensity, the intensity ratio of singlet
2
) for
1
at δ 5.56 and this multiplet is 3:1). The absence of any peak in the δ
.70-5.20 region clearly indicates the absence of anti-aldol product.
Since the chemical shift of the multiplet, that is, δ 5.42-5.52 (observed
4
8
,11
in our case), is similar to that of syn-aldol [δ 5.55 (d, J ) 2.8 Hz)]
it may not be possible to confirm the complete absence of syn-aldol
product because of the possibility of the doublet (or dd in case
benzylic-H couples with the OH proton) hidden in this multiplet.
Because the intensity of this multiplet itself (at δ 5.42-5.52) is much
lower than that of singlet at δ 5.56, the syn-aldol product, even if
formed, might be in much smaller amounts in comparison with that
of the Baylis-Hillman adduct. These observations might, therefore,
suggest that aldehydes undergo preferentially the Baylis-Hillman
reaction.
(11) It is worth mentioning here the work of Zaidlewich and
co-workers, who reported an interesting enolization-aldolization of
cyclohex-2-enone derivatives via dienolborinates. During their studies
they also observed the formation of Baylis-Hillman adducts in minor
amounts in the case of dienolborinates derived from hindered cyclo-
hexenones (3,4,5-trisubstituted cyclohexenone derivatives) along with
major aldol adducts; see: Zaidlewicz, M.; Sokol, W.; Wojtczak, A.;
Neumann, P.; Nissinen, M. Tetrahedron Lett. 2002, 43, 3525.
J . Org. Chem, Vol. 68, No. 15, 2003 5985

Basavaiah et al.
TABLE 1. Rea ction s of r-Keto Ester s w ith 5,5-d im eth ylcycloh ex-2-en on e in th e P r esen ce of Tita n iu m Tetr a ch lor id ea -d
enone
keto ester
Ar
R
product
mp (°C)
yield (%)
aldol:BH
1
1
1
1
1
1
1
1
1
1
b
b
b
b
b
b
b
b
b
b
2a
2b
2c
2d
2e
2f
2g
2h
2i
phenyl
Et
Et
Et
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
44-46
60-62
85
81
86
85
47
80
87
53
50
82
00:100
00:100
00:100
00:100
00:100
00:100
00:100
00:100
00:100
00:100
4-methylphenyl
4-ethylphenyl
4-methoxyphenyl
2-methylphenyl
phenyl
3-methoxyphenyl
2-methylphenyl
2-methoxyphenyl
4-methylphenyl
Et
Me
Me
Me
Me
i-Pr
58-60
52-54
102-104
74-75
2j
4j
62-64
a
All reactions were carried out on a 1-mmol scale (R-keto ester). To a stirred solution of R-keto ester (1 mmol) and 5,5-dimethylcyclohex-
2
4
-enone (3 mmol) in dichloromethane was added titanium tetrachloride (1 mmol) at 0 °C stirred at room temperature for 6 h (12 h for
e,h ,i and 10 h for 4j). All the products (4a -j) were characterized by IR, 1H NMR (200 MHz), C NMR (50 MHz), and elemental
b
13
c 1
analyses; compounds 4a , 4g, and 4j were also characterized by mass spectral analysis. H NMR spectra of the crude products did not
1
indicate the formation of any aldol product. H NMR spectra of the crude products (4e,h ,i) clearly indicated the presence of the starting
materials, that is, keto esters (2e,h ,i) ≈ 38, 35, 40%, respectively. In fact, we isolated the starting materials (the R-keto esters) in 29%
(
2e), 24% (2h ), and 32% (2i) yields in the corresponding reactions. d Yields are of the pure products (4a -j) (based on R-keto esters) after
column chromatography (silica gel, 10% EtOAc in hexanes).
adducts. However, in the case of R-keto esters, the
transition states II and III leading to the Baylis-Hillman
adduct may be disfavored due to the steric interaction
between Cl and the ester (or aryl) group whereas transi-
tion states IV and V leading to the aldol product may be
favored due to the absence of any such interactions.
The above transition states clearly suggest that if we
have some group sterically more demanding than the
chloride at the fifth position of the cyclohex-2-enone there
is a possibility of obtaining Baylis-Hillman compound
predominantly. Accordingly, we have selected 5,5-dim-
ethylcyclohex-2-enone for coupling with ethyl phenylg-
esis, that is, since the gem-dimethyl group is sterically
more demanding than the Cl group the Baylis-Hillman
adduct is produced in larger amounts (here exclusively)
than the corresponding aldol product (transition states
VI, VII, VIII, and IX).
4
lyoxylate in the presence of TiCl , and in fact, this
reaction provided the corresponding Baylis-Hillman
compound exclusively as predicted. Thus the reaction of
ethyl phenylglyoxylate (2a , 1 mmol) with 5,5-dimethyl-
In fact, with a view to understanding the nature of
titanium enolate in the case of 5,5-dimethylcyclohex-2-
enone we have also recorded the H NMR and C NMR
1
13
cyclohex-2-enone (1b, 3 mmol) in the presence of TiCl
1 mmol) at room temperature for 6 h provided the
corresponding Baylis-Hillman adduct, that is, ethyl
-hydroxy-2-phenyl-2-(5,5-dimethylcyclohex-2-en-1-on-2-
yl)ethanoate (4a ), exclusively in 85% isolated yield (eq
, Baylis-Hillman reaction of 5,5-dimethylcyclohex-2-
4
(
spectra of the crude reaction mixture obtained by the
treatment of 5,5-dimethylcyclohex-2-enone with TiCl (1:
4
2
1) for 30 min at room temperature in CDCl and found
3
similar observations as in the case of cyclohex-2-enone
2
and TiCl (Experimental Section and Supporting Infor-
4
mation).
To study the generality of this reaction we have then
extended this methodology to representative R-keto esters
(
4
2b-j) to provide the expected Baylis-Hillman adducts
b-j exclusively in 47-87% yields respectively (eq 2;
Table 1). We did not observe the formation of any aldol
products in all these cases as evidenced by the H NMR
1
spectrum of the crude products. The slow reactivity and
low yields obtained in the case of R-keto esters with the
R-substituted aryl group (2e,h ,i) might be attributed to
the steric factors, and in fact, we have recovered (isolated)
substantial amounts of R-keto esters in these experi-
ments (Table 1).
Thus, we have established conditions for obtaining the
Baylis-Hillman adducts in the reaction of cyclohex-2-
enone derivatives with R-keto esters under the influence
of titanium tetrachloride. Although our main aim was
(
12) It is reported that the reaction between aldehydes and alkyl
vinyl ketones in the presence of titanium tetrachloride/amines or
12a,b
enone with R-keto esters in the presence of titanium
4
,5
1
sulfides provided the corresponding allyl chlorides or chloroaldols.
a) Shi, M.; Feng, Y.-S. J . Org. Chem. 2001, 66, 406. (b) Shi, M.; J iang,
tetrachloride; Table 1) (the H NMR spectrum of the
(
crude product did not indicate the presence of any aldol
product). This observation clearly supports our hypoth-
J .-K.; Cui, S.-C. Tetrahedron 2001, 57, 7343. (c) Shi, M.; J iang, J .-K.;
Feng, Y.-S. Org. Lett. 2000, 2, 2397.
5
986 J . Org. Chem., Vol. 68, No. 15, 2003

Baylis-Hillman and Aldol Reactions
TABLE 2. Rea ction s of r-Keto Ester s w ith Cycloa lk -2-en on es in th e P r esen ce of Tita n iu m Tetr a ch lor id ea -c
enone
keto ester
Ar
R
productd
mp (°C)e
yield (%)f
aldol:BHg
h
1
1
1
1
1
1
1
1
1
a
a
a
a
a
a
a
a
a
2a
2b
2d
2f
2j
2k
2l
2m
2n
2a
phenyl
Et
Et
Et
Me
i-Pr
Et
5
6
7
8
88
80
63
50
70
65
57
31
61
66
65
87:13
90:10
100:00
85:15
95:5
82:18
100:00
100:00
88:12
95:5
i
4-methylphenyl
4-methoxyphenyl
phenyl
4-methylphenyl
4-bromophenyl
naphth-1-yl
4-methylphenyl
4-ethylphenyl
phenyl
112-114
94-95
117-119
95-96
82
118-120
132-134
80-82
i
i
i
9
i
10
11
12
13
i
Et
i
Me
Me
Et
i
i,j
1
c
14
a
All reactions were carried out on a 1-mmol scale (R-keto ester). To a stirred solution of R-keto ester (1 mmol) and cycloalk-2-enone (3
b
mmol) in dichloromethane was added titanium tetrachloride (1 mmol) at 0 °C stirred at room temperature for 2 h. All the products
1
13
(
5-14) were characterized by IR, H NMR (200 MHz), C NMR (50 MHz), and elemental analyses; compounds 5 and 9-12 were also
c 1
characterized by mass spectral analysis. H NMR spectra of the crude products (6-8, 10-12, 14) clearly indicated the presence of the
starting materials, that is, keto esters (2b,d ,f, 2k -m , 2a ) in ≈ 20, 25, 8, 17, 30, 5, 5% respectively. In fact, we isolated the starting
1
materials (the R-keto esters) in 16% (2d ) and 23% (2l) yields in their respective reactions. H NMR spectra of the crude products also
indicated the formation of Baylis-Hillman adducts in small amounts. In fact, we have isolated the minor Baylis-Hillman adduct (4) in
1
7
% isolated yield as a colorless solid in the reaction between 1a and 2a and this was fully characterized. The H NMR spectrum of the
d
crude product 11 indicated the formation of presumably the anti isomer in ca. 10%. The products (5-13) were obtained as colorless
solids with pure syn-stereochemistry after column chromatography (silica gel, 5% EtOAc in hexanes) followed by crystallization (hexanes);
e
compound 14 was obtained as liquid after column chromatography (silica gel, 5% EtOAc in hexanes). Melting points are of the pure
syn-diastereomers (5-13). f Yields are of the pure syn products (5-13) (based on R-keto esters) after column chromatography followed by
g
crystallization. In the case of 14, yield is of pure syn product after column chromatography. The ratio of the Baylis-Hillman and aldol
compounds was determined by H NMR studies of the crude products. The stereochemistry7 of compound 5 was established by single
1
h
crystal (obtained from hexanes) X-ray data (Figure 1). The syn-stereochemistry was assigned in analogy to 5. The 1H NMR spectrum
of the crude product shows two singlets at δ 4.04 and 4.00 (ca. 12:88) for the OH proton. The underlined chemical shift value might be
attributed to the minor anti-diastereomer. The 1H NMR spectrum of the crude compound also shows the presence of ca. 5% Baylis-
Hillman compound as indicated by the appearance of a triplet at δ 6.68.
i
j
not directed toward aldol reaction we were fascinated by
the formation of ethyl 2-hydroxy-2-phenyl-2-(cyclohex-5-
en-1-on-2-yl)ethanoate (5), that is, the aldol adduct as
the major product with high syn-diastereoselectivity in
the titanium tetrachloride mediated reaction of cyclohex-
(cyclohex-5-en-1-on-2-yl)ethanoates (6-13) in 31-70%
yields (eq 3, reaction of cyclohex-2-enone with a-keto
2
-enone with ethyl phenylglyoxylate (2a ). A careful
literature survey reveals that although the aldehydes
have been very extensively used as electrophiles in
various stereoefficient aldol carbon-carbon bond-forming
reactions,13 applications of R-keto esters, which repre-
sent yet another potential class of electrophiles, in aldol
reactions have been relatively less studied and the aldol
reactions of R-keto esters with cyclohex-2-enone have not
been reported so far. Since tertiary R-hydroxy acids/esters
constitute an important class of molecules because of the
presence of this structural framework in various biologi-
cally active molecules and natural products,15 the devel-
opment of convenient facile methodologies for the dias-
tereoselective aldol reaction of R-keto esters with appro-
priate metal enolates to provide the desired tertiary
R-hydroxy esters is an attractive endeavor in organic
chemistry. Therefore, we have extended the above meth-
odology to representative R-keto esters (2b,d ,f, 2j-n ) to
provide the corresponding alkyl syn-2-hydroxy-2-aryl-2-
14
esters in the presence of titanium tetrachloride; Table
2
). The stereochemistry of these compounds was assigned
in analogy to that of compound 5. In some cases we have
noticed the formation of the Baylis-Hillman adducts in
small amounts (Table 2).
Then we extended this methodology to the reaction
between ethyl phenylglyoxylate (2a ) and cyclopent-2-
enone (1c) in the presence of titanium tetrachloride.
Under similar conditions, we have noticed the formation
(
13) (a) Trost, B. M.; Ito, H.; Silcoff, E. R. J . Am. Chem. Soc. 2001,
23, 3367. (b) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.;
Oshima, T.; Suzuki, T.; Shibasaki, M. J . Am. Chem. Soc. 2001, 123,
1
2
4
2
466. (c) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33,
32. (d) List, B.; Lerner, R. A.; Barbas, C. F., III J . Am. Chem. Soc.
000, 122, 2395. (e) Mahrwarld, R. Chem. Rev. 1999, 99, 1095.
(14) (a) J orgensen, K. A.; J ohannsen, M.; Yao, S.; Audrain, H.;
Thorhauge, J . Acc. Chem. Res. 1999, 32, 605. (b) Evans, D. A.;
Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J . Am. Chem.
Soc. 1997, 119, 7893. (c) Ito, Y.; Sawamura, M.; Hamashima, H.;
Emura, T.; Hayashi, T. Tetrahedron Lett. 1989, 30, 4681.
(15) (a) Saxton, J . E. Nat. Prod. Rep. 1990, 7, 191. (b) Robins, D. J .
Nat. Prod. Rep. 1989, 6, 221. (c) Vedejs, E.; Ahmed, S.; Larsen, S. D.;
Westwood, S. J . Org. Chem. 1987, 52, 3937. (d) White, J . D.; Ohira, S.
J . Org. Chem. 1986, 51, 5492.
J . Org. Chem, Vol. 68, No. 15, 2003 5987

Basavaiah et al.
Cl ) at 0 °C. After
stirring at room temperature for 6 h, the reaction mixture was
quenched with water (5 mL) and extracted with ether (3 × 10
mL). The combined organic layer was dried over anhydrous
sodium sulfate. Solvent was evaporated and the residue, thus
obtained, was purified by column chromatography (silica gel,
of presumably ca. 12% anti-isomer along with the major
ethyl syn-2-hydroxy-2-phenyl-2-(cyclopent-4-en-1-on-2-
yl)ethanoate (14) (eq 4, reaction of cyclopent-2-enone with
ethyl phenylglyoxylate in the presence of titanium tet-
rachloride). However, the pure syn-isomer was isolated
in 65% yield after column chromatography. The syn-
stereochemistry was tentatively assigned in analogy to
(1 mmol, 0.5 mL of a 2 M solution in CH
2
2
1
0% EtOAc in hexanes) to furnish the pure molecule (4a ) in
85% (0.257 g) isolated yield, as a colorless solid. IR (KBr) 3503,
1736, 1676 cm ; H NMR δ 1.04 (s, 3H), 1.08 (s, 3H), 1.26 (t,
-
1 1
5
.
3
2
7
2
1
H, J ) 7.2 Hz), 2.21 (d, 2H, J ) 4.4 Hz), 2.36 (s, 2H), 4.25 (q,
H, J ) 7.2 Hz), 4.33 (s, 1H), 6.27 (t, 1H, J ) 4.4 Hz), 7.28-
.46 (m, 3H), 7.55-7.66 (m, 2H); 13C NMR δ 13.91, 27.42,
8.54, 33.88, 39.86, 51.97, 62.00, 78.10, 126.74, 128.05, 138.06,
P ossible Exp la n a tion for Syn -Ster eoselectivity.
The syn-stereoselectivity in aldol products possibly can
be explained through a six-membered cyclic transition
state (X and XI). Due to the simultaneous coordination
+
41.53, 146.69, 173.55, 199.31; FABMS 303 (M + H). Anal.
Calcd for C18
.27.
Eth yl 2-h yd r oxy-2-(4-m eth ylp h en yl)-2-(5,5-d im eth yl-
cycloh ex-2-en -1-on -2-yl)eth a n oa te (4b): IR (KBr) 3504,
22 4
H O : C, 71.50; H, 7.33. Found: C, 71.66; H,
7
-
1 1
1
3
2
2
2
1
736, 1676 cm ; H NMR δ 1.03 (s, 3H), 1.07 (s, 3H), 1.25 (t,
H, J ) 6.9 Hz), 2.21 (d, 2H, J ) 4.0 Hz), 2.35 (s, 5H), 4.24 (q,
H, J ) 6.9 Hz), 4.30 (s, 1H), 6.30 (t, 1H, J ) 4.0 Hz), 7.18 (d,
H, J ) 8.2 Hz), 7.46 (d, 2H, J ) 8.2 Hz); 13C NMR δ 13.98,
1.01, 27.42, 28.62, 33.97, 39.84, 51.96, 62.05, 77.97, 126.63,
28.84, 134.90, 137.76, 141.47, 146.93, 173.77, 199.60. Anal.
Calcd for C19
.68.
Eth yl 2-h yd r oxy-2-(4-eth ylp h en yl)-2-(5,5-d im eth ylcy-
cloh ex-2-en -1-on -2-yl)eth a n oa te (4c): IR (neat) 3503, 1736,
24 4
H O : C, 72.13; H, 7.65. Found: C, 72.25; H.
of Ti with carbonyl oxygens of the ester and keto groups,
the 1,3-interactions between the ester group and Cl in
transition state X may be more dominating than the 1,3-
interactions between the aryl group and Cl in the
transition state XI, thus leading to the formation of syn-
product.
7
-
1 1
1678 cm ; H NMR δ 1.03 (s, 3H), 1.07 (s, 3H), 1.24 (t, 3H, J
)
7.2 Hz), 1.26 (t, 3H, J ) 7.2 Hz), 2.21 (d, 2H, J ) 4.2 Hz),
2
4
7
2
.35 (s, 2H), 2.66 (q, 2H, J ) 7.2 Hz), 4.24 (q, 2H, J ) 7.2 Hz),
.30 (s, 1H), 6.30 (t, 1H, J ) 4.2 Hz), 7.20 (d, 2H, J ) 8.0 Hz),
In conclusion, our work describes the role of steric
factors in the selection of reaction pathways, that is,
Baylis-Hillman or aldol reactions, particularly in the
reaction between R-keto esters and cyclohex-2-enone
derivatives. Thus we have successfully demonstrated that
the reaction of 5,5-dimethylcyclohex-2-enone with R-keto
esters in the presence of titanium tetrachloride proceeds
in the Baylis-Hillman fashion affording the correspond-
ing adducts alkyl 2-hydroxy-2-phenyl-2-(5,5-dimethyl-
cyclohex-2-en-1-on-2-yl)ethanoates exclusively, whereas
a similar reaction between R-keto esters and cyclohex-
13
.48 (d, 2H, J ) 8.0 Hz); C NMR δ 13.99, 15.34, 27.41, 28.40,
8.64, 33.98, 39.84, 51.96, 62.06, 77.99, 126.69, 127.62, 135.09,
141.48, 144.07, 146.97, 173.79, 199.61. Anal. Calcd for
: C, 72.70; H, 7.93. Found: C, 72.95; H, 7.80.
Eth yl 2-h yd r oxy-2-(4-m eth oxyp h en yl)-2-(5,5-d im eth -
ylcycloh ex-2-en -1-on -2-yl)eth a n oa te (4d ): IR (neat) 3489,
20 26 4
C H O
-
1 1
1
3
3
736, 1678 cm ; H NMR δ 1.04 (s, 3H), 1.07 (s, 3H), 1.26 (t,
H, J ) 7.4 Hz), 2.22 (d, 2H, J ) 4.0 Hz), 2.35 (s, 2H), 3.82 (s,
H), 4.24 (q, 2H, J ) 7.4 Hz), 4.30 (s, 1H), 6.31 (t, 1H, J ) 4.0
13
Hz), 6.90 (d, 2H, J ) 8.7 Hz), 7.50 (d, 2H, J ) 8.7 Hz);
C
NMR δ 13.99, 27.43, 28.62, 33.98, 39.87, 51.97, 55.22, 62.04,
77.76, 113.54, 127.99, 129.88, 141.61, 146.86, 159.43, 173.81,
2
-enone in the presence of titanium tetrachloride pro-
199.61. Anal. Calcd for C19
C, 68.39; H, 7.36.
24 5
H O : C, 68.66; H, 7.28. Found:
ceeds in the highly syn-diastereoselective aldol fashion
thus for the first time providing a convenient methodol-
ogy for synthesis of pure alkyl syn-2-hydroxy-2-aryl-2-
Eth yl 2-h yd r oxy-2-(2-m eth ylp h en yl)-2-(5,5-d im eth yl-
cycloh ex-2-en -1-on -2-yl)eth a n oa te (4e): reaction time 12
-
1
1
h; IR (neat) 3495, 1732, 1664 cm ; H NMR δ 1.07 (s, 6H),
(cyclohex-5-en-1-on-2-yl)ethanoates. Further work in un-
1
2
4
2
1
.30 (t, 3H, J ) 7.4 Hz), 2.25 (d, 2H, J ) 4.0 Hz), 2.38 (s, 3H),
.39 (s, 2H), 4.24-4.48 (m, 2H), 4.85 (s, 1H), 6.22 (t, 1H, J )
derstanding and exploring the various aspects of steric
factors in directing the reaction pathway is in progress
in our laboratory.
13
.0 Hz), 7.11-7.34 (m, 4H); C NMR δ 14.05, 22.04, 27.64,
8.55, 34.23, 40.06, 52.29, 62.05, 81.73, 125.63, 127.18, 128.25,
32.58, 136.15, 138.13, 138.34, 147.30, 173.67, 201.05. Anal.
Calcd for C19
7.76.
24 4
H O : C, 72.13; H, 7.65. Found: C, 72.35; H.
Exp er im en ta l Section
Met h yl 2-h yd r oxy-2-p h en yl-2-(5,5-d im et h ylcycloh ex-
Gen er a l. Melting points were uncorrected. IR spectra were
2-en -1-on -2-yl)eth a n oa te (4f): IR (KBr) 3449, 1745, 1672
cm ; H NMR δ 0.95 (s, 3H), 0.99 (s, 3H), 2.07 and 2.19
-
1
1
recorded on a FT-IR spectrometer with samples as KBr plates
1
(
solids) and liquid samples as neat. H NMR (200 MHz) and
(doublet of ABq, 2H, J ) 4.0 and 18.8 Hz), 2.23 and 2.32 (ABq,
2H, J ) 16.0 Hz), 3.68 (s, 3H), 4.30 (s, 1H), 6.20 (t, 1H, J )
1
3
C NMR (50 MHz) spectra were recorded in deuteriochloro-
1
3
form (CDCl
3
) with tetramethylsilane (TMS, δ ) 0) as an
4.0 Hz), 7.19-7.38 (m, 3H), 7.45-7.55 (m, 2H); C NMR δ
27.72, 28.39, 33.98, 39.86, 51.92, 53.03, 78.29, 126.71, 128.21,
137.74, 141.35, 147.20, 174.19, 199.89. Anal. Calcd for
internal standard. Elemental analyses were recorded on a
CHN analyzer. Mass spectra were recorded on a micromass
instrument. The X-ray diffraction measurements were carried
out at 293 K, using graphite monochromated, Mo KR (λ )
C
17
H
20
O
4
: C, 70.81; H, 6.99. Found: C, 70.52; H, 7.02.
Meth yl 2-h yd r oxy-2-(3-m eth oxyp h en yl)-2-(5,5-d im eth -
ylcycloh ex-2-en -1-on -2-yl)eth a n oa te (4g): IR (KBr) 3501,
0
.71073 Å) radiation with CAD4 software.
Typ ica l Exp er im en ta l P r oced u r e: Eth yl 2-Hyd r oxy-
-p h e n yl-2-(5,5-d im e t h ylcycloh e x-2-e n -1-on -2-yl)e t h -
a n oa te (4a ). To a stirred solution of ethyl phenylglyoxylate
1 mmol, 0.178 g) and 5,5-dimethylcyclohex-2-enone (3 mmol,
-
1
1
1724, 1657 cm ; H NMR δ 1.03 (s, 3H), 1.07 (s, 3H), 2.17
and 2.28 (doublet of ABq, 2H, J ) 4.0 and 19.0 Hz), 2.31 and
2.41 (ABq, 2H, J ) 16.0 Hz), 3.78 (s, 3H), 3.82 (s, 3H), 4.38 (s,
1H), 6.32 (t, 1H, J ) 4.0 Hz), 6.86-6.94 (m, 1H), 7.08-7.35
(m, 3H); 13C NMR δ 27.66, 28.33, 33.92, 39.82, 51.87, 52.96,
2
(
0
.372 g) in CH
2 2
Cl (3 mL) was added titanium tetrachloride
5
988 J . Org. Chem., Vol. 68, No. 15, 2003

Baylis-Hillman and Aldol Reactions
5
1
5.21, 78.19, 112.53, 113.67, 119.04, 129.09, 139.37, 141.14,
139.55, 150.66, 174.75, 198.94; FABMS 275 (M+ + H). Anal.
Calcd for C16 : C, 70.06; H, 6.61. Found: C, 70.14; H,
6.63. Crystal data for 5: empirical formula, C16 ; formula
+
47.19, 159.63, 174.03, 199.76; FABMS 319 (M + H). Anal.
18 4
H O
Calcd for C18
.89.
Met h yl 2-h yd r oxy-2-(2-m et h ylp h en yl)-2-(5,5-d im et h -
ylcycloh ex-2-en -1-on -2-yl)eth a n oa te (4h ): reaction time 12
H
22
O
5
: C, 67.91; H, 6.97. Found: C, 67.85; H,
18 4
H O
6
weight, 274.30; crystal color and habit, colorless, needle; crystal
dimensions, 0.40 × 0.15 × 0.15 mm; crystal system, mono-
clinic; lattice type, primitive; lattice parameters, a ) 8.7653-
(18) Å, b ) 9.2536(19) Å, c ) 17.751(4) Å; â ) 93.18(3)°; V )
-
1
1
h; IR (KBr) 3472, 1745, 1647 cm ; H NMR δ 1.07 (s, 6H),
3
3
2
3
.25 (d, 2H, J ) 4.0 Hz), 2.35 (s, 3H), 2.40 (s, 2H), 3.83 (s,
H), 4.96 (s, 1H), 6.22 (t, 1H, J ) 4.0 Hz), 7.10-7.30 (m, 4H);
C NMR δ 21.93, 27.81, 28.38, 34.21, 40.08, 52.25, 52.87,
1.90, 125.71, 127.16, 128.33, 132.56, 136.03, 137.98, 138.15,
1437.6(5) Å ; space group, P2
F
0.1783.
1
/n; Z ) 4; Dcalcd ) 1.267 g/cm ;
2
ooo ) 584.00; λ(Mo KR) ) 0.71073 Å; R ) 0.0605, wR
)
1
3
8
1
7
Typ ica l Exp er im en ta l P r oced u r e for th e Isola tion of
E t h yl 2-H yd r oxy-2-p h en yl-2-(cycloh ex-2-en -1-on -2-yl)-
eth a n oa te (4) (m in or Ba ylis-Hillm a n a d d u ct). To a
stirred solution of ethyl phenylglyoxylate (2 mmol, 0.356 g)
47.50, 174.12, 201.38. Anal. Calcd for C18
.33. Found: C, 71.69; H, 7.38.
22 4
H O : C, 71.50; H,
Meth yl 2-h yd r oxy-2-(2-m eth oxyp h en yl)-2-(5,5-d im eth -
ylcycloh ex-2-en -1-on -2-yl)eth a n oa te (4i): reaction time 12
h; IR (KBr) 3416, 1734, 1655 cm ; H NMR δ 0.97 (s, 3H),
1
1
3
and cyclohex-2-enone (6 mmol, 0.576 g, 0.58 mL) in CH
mL) was added titanium tetrachloride (2 mmol, 1 mL of a 2
M solution in CH Cl ) at 0 °C and stirred for 2 h at room
2 2
Cl (5
-
1
1
.07 (s, 3H), 2.17 and 2.31 (doublet of ABq, 2H, J ) 4.1 and
9.0 Hz), 2.32 and 2.55 (ABq, 2H, J ) 15.9 Hz), 3.67 (s, 3H),
.71 (s, 3H), 6.02 (s, 1H), 6.20 (t, 1H, J ) 4.1 Hz), 6.87 (d, 1H,
2
2
temperature. Compound 4 was isolated (following a similar
workup procedure as described for 5) after column chroma-
tography (silica gel, 8% EtOAc in hexanes) in 7% (0.038 g) yield
along with major aldol adduct 5 in 81% (0.445 g) isolated yield.
J ) 8.0 Hz), 6.95-7.05 (m, 1H), 7.21-7.35 (m, 1H), 7.54 (d,
H, J ) 8.0 Hz); 13C NMR δ 27.78, 28.44, 34.04, 40.15, 52.41,
2.51, 55.70, 79.04, 111.34, 121.34, 128.03, 128.18, 129.59,
36.96, 147.13, 156.35, 173.39, 202.35. Anal. Calcd for
1
5
1
-1 1
mp 56-58 °C; IR (KBr) 3449, 1743, 1664 cm ; H NMR δ 1.26
(t, 3H, J ) 6.8 Hz), 1.94-2.13 (m, 2H), 2.25-2.42 (m, 2H),
2.45-2.60 (m, 2H), 4.15-4.34 (m, 2H), 4.37 (s, 1H), 6.40 (t,
C
18
H
22
O
5
: C, 67.91; H, 6.97. Found: C, 67.70; H, 6.93.
1
3
1
H, J ) 4.0 Hz), 7.27-7.49 (m, 3H), 7.56-7.65 (m, 2H);
C
Isop r op yl 2-h yd r oxy-2-(4-m eth ylp h en yl)-2-(5,5-d im e-
NMR δ 13.98, 22.39, 25.86, 38.42, 62.15, 78.41, 126.88, 128.15,
th ylcycloh ex-2-en -1-on -2-yl)eth a n oa te (4j): reaction time
+
0 h; IR (KBr) 3522, 1728, 1672 cm-1; 1H NMR δ 1.04 (s, 3H),
138.07, 142.53, 149.01, 173.60, 199.32; FABMS 275 (M + H).
1
1
2
1
Anal. Calcd for C16
H, 6.57.
18 4
H O : C, 70.06; H, 6.61. Found: C, 70.25;
.07 (s, 3H), 1.21 (d, 3H, J ) 6.0 Hz), 1.26 (d, 3H, J ) 6.0 Hz),
.20 (d, 2H, J ) 4.0 Hz), 2.35 (s, 2H), 2.36 (s, 3H), 4.26 (s,
H), 5.09 (sept, 1H, J ) 6.0 Hz), 6.29 (t, 1H, J ) 4.0 Hz), 7.18
Eth yl syn -2-h yd r oxy-2-(4-m eth ylp h en yl)-2-(cycloh ex-
5-en -1-on -2-yl)eth a n oa te (6): IR (KBr) 3452, 1720, 1662
1
3
(d, 2H, J ) 8.1 Hz), 7.48 (d, 2H, J ) 8.1 Hz); C NMR δ 21.02,
-
1 1
2
1
3
1.56, 27.18, 28.87, 33.97, 39.83, 51.99, 69.86, 77.75, 126.67,
28.78, 135.05, 137.68, 141.51, 146.77, 173.26, 199.23; FABMS
cm ; H NMR δ 1.27 (t, 3H, J ) 7.4 Hz), 1.55-1.70 (m, 1H),
1.78-2.05 (m, 1H), 2.28-2.50 (m, 5H), 3.45 (dd, 1H, J ) 4.4
and 14.0 Hz), 3.80 (s, 1H), 4.24 (q, 2H, J ) 7.4 Hz), 5.98-6.10
(m, 1H), 6.92-7.05 (m, 1H), 7.16 (d, 2H, J ) 8.0 Hz), 7.51 (d,
+
31 (M + H). Anal. Calcd for C20
26 4
H O : C, 72.70; H, 7.93.
Found: C, 72.75; H, 7.91.
2
H, J ) 8.0 Hz); 13C NMR δ 13.95, 20.99, 22.89, 26.06, 55.06,
2
-[H yd r oxy(4-n it r op h e n yl)m e t h yl]cycloh e x-2-e n -1-
2
m
62.22, 77.40, 125.60, 129.05, 129.88, 136.51, 137.43, 150.62,
on e (3): mp 84-86 °C (lit. mp 87-89 °C); IR (KBr) 3402,
1
3
-
1
1
174.84, 198.98. Anal. Calcd for C17
Found: C, 70.58; H, 7.03.
20 4
H O : C, 70.81; H, 6.99.
649 cm ; H NMR δ 1.95-2.10 (m, 2H), 2.38-2.55 (m, 4H),
.52 (d, 1H, J ) 6.0 Hz), 5.61 (d, 1H, J ) 6.0 Hz), 6.81 (t, 1H,
J ) 4.0 Hz), 7.55 (d, 2H, J ) 8.6 Hz), 8.20 (d, 2H, J ) 8.6 Hz);
Eth yl syn -2-h yd r oxy-2-(4-m eth oxyp h en yl)-2-(cycloh ex-
5-en -1-on -2-yl)eth a n oa te (7): IR (KBr) 3443, 1718, 1662
1
3
C NMR δ 22.27, 25.68, 38.27, 71.19, 123.31, 127.08, 140.20,
47.02, 148.11, 149.67, 199.76. Anal. Calcd for C13 : C,
3.15; H, 5.30; N, 5.66. Found: C, 63.40; H, 5.31; N, 5.63. This
-
1 1
1
6
H
13NO
4
cm ; H NMR δ 1.28 (t, 3H, J ) 7.0 Hz), 1.54-1.68 (m, 1H),
1.78-2.05 (m, 1H), 2.25-2.42 (m, 2H), 3.43 (dd, 1H, J ) 4.6
and 13.8 Hz), 3.81 (s, 4H), 4.25 (q, 2H, J ) 7.0 Hz), 5.96-6.08
2
m,4
molecule is known in the literature
are consistent with reported data.
and our spectral data
1
3
(m, 1H), 6.84-7.02 (m, 3H), 7.54 (d, 2H, J ) 8.8 Hz); C NMR
δ 13.96, 22.88, 26.06, 55.06, 55.25, 62.18, 77.22, 113.73, 126.93,
129.92, 131.46, 150.57, 159.24, 174.88, 198.94. Anal. Calcd for
1
0
2
-[Hyd r oxy(p h en yl)m eth yl]cycloh ex-2-en -1-on e (3a ):
-
1
1
yield 10%; IR (neat) 3404, 1656 cm ; H NMR δ 1.90-2.08
17 20 5
C H O : C, 67.09; H, 6.62. Found: C, 66.88; H, 6.57.
(
m, 2H), 2.32-2.53 (m, 4H), 3.43 (d, 1H, J ) 4.8 Hz), 5.56 (d,
1
H, J ) 4.8 Hz), 6.73 (t, 1H, J ) 4.0 Hz), 7.18-7.43 (m, 5H);
C NMR δ 22.47, 25.71, 38.48, 72.09, 126.43, 127.36, 128.21,
41.13, 141.88, 147.17, 200.12. This molecule is known in the
Meth yl syn -2-h yd r oxy-2-p h en yl-2-(cycloh ex-5-en -1-on -
1
3
2-yl)eth a n oa te (8): IR (KBr) 3431, 1730, 1658 cm-1
;
1
H NMR
1
δ 1.47-1.64 (m, 1H), 1.77-2.05 (m, 1H), 2.28-2.42 (m, 2H),
3.48 (dd, 1H, J ) 4.6 and 13.8 Hz), 3.79 (s, 3H), 3.81 (s, 1H),
5.98-6.10 (m, 1H), 6.89-7.02 (m, 1H), 7.22-7.42 (m, 3H),
2
m
literature and our spectral data are consistent with reported
data.
Typ ica l Exp er im en ta l P r oced u r e: Eth yl syn -2-Hy-
d r oxy-2-p h en yl-2-(cycloh ex-5-en -1-on -2-yl)eth a n oa te (5).
To a stirred solution of ethyl phenylglyoxylate (1 mmol, 0.178
7
1
.60-7.70 (m, 2H); 13C NMR δ 22.86, 26.05, 53.14, 55.24, 77.57,
25.69, 127.82, 128.40, 129.85, 139.34, 150.71, 175.26, 199.01.
Anal. Calcd for C15
H, 6.23.
16 4
H O : C, 69.22; H, 6.20. Found: C, 69.48;
g) and cyclohex-2-enone (3 mmol, 0.288 g, 0.29 mL) in CH
3 mL) was added titanium tetrachloride (1 mmol, 0.5 mL of
a 2 M solution in CH Cl ) at 0 °C. After stirring at room
2 2
Cl
(
Isop r op yl syn -2-h yd r oxy-2-(4-m eth ylp h en yl)-2-(cyclo-
h ex-5-en -1-on -2-yl)eth a n oa te (9): IR (KBr) 3503, 1722, 1678
2
2
-
1
1
temperature for 2 h, the reaction mixture was quenched with
water (5 mL) and extracted with ether (3 × 10 mL). The
combined organic layer was dried over anhydrous sodium
sulfate. Solvent was evaporated and the residue, thus obtained,
was purified by column chromatography (silica gel, 5% EtOAc
in hexanes) followed by crystallization from hexanes to furnish
the pure molecule (5) in 80% (0.219 g) yield, as a colorless solid.
cm ; H NMR δ 1.23 and 1.27 (2d, 6H, J ) 6.0 Hz), 1.51-
1.68 (m, 1H), 1.77-2.04 (m, 1H), 2.25-2.43 (m, 5H), 3.42 (dd,
1H, J ) 4.4 and 13.8 Hz), 3.83 (s, 1H), 5.08 (sept, 1H, J ) 6.0
Hz), 5.96-6.10 (m, 1H), 6.88-7.04 (m, 1H), 7.16 (d, 2H, J )
8.2 Hz), 7.52 (d, 2H, J ) 8.2 Hz); 13C NMR δ 21.01, 21.53,
22.97, 26.06, 54.95, 70.02, 77.42, 125.64, 128.99, 129.96,
+
136.77, 137.34, 150.48, 174.31, 198.69; FABMS 303 (M + H).
-
1
1
18 22 4
Anal. Calcd for C H O : C, 71.50; H, 7.33. Found: C, 71.38;
IR (KBr) 3520, 1724, 1674 cm ; H NMR δ 1.28 (t, 3H, J )
7
2
2
7
2
.2 Hz), 1.48-1.72 (m, 1H), 1.78-2.05 (m, 1H), 2.27-2.48 (m,
H), 3.48 (dd, 1H, J ) 4.5 and 13.8 Hz), 3.85 (s, 1H), 4.26 (q,
H, J ) 7.2 Hz), 5.98-6.12 (m, 1H), 6.88-7.09 (m, 1H), 7.22-
.48 (m, 3H), 7.59-7.72 (m, 2H); 13C NMR δ 13.99, 22.95,
6.09, 55.18, 62.35, 77.56, 125.75, 127.79, 128.38, 129.93,
H, 7.28.
Eth yl syn -2-h yd r oxy-2-(4-br om op h en yl)-2-(cycloh ex-5-
-
1
en -1-on -2-yl)eth a n oa te (10): IR (KBr) 3414, 1739, 1662 cm
;
1
H NMR δ 1.27 (t, 3H, J ) 7.2 Hz), 1.46-1.66 (m, 1H), 1.76-
2.06 (m, 1H), 2.25-2.45 (m, 2H), 3.41 (dd, 1H, J ) 4.3 and
J . Org. Chem, Vol. 68, No. 15, 2003 5989

Basavaiah et al.
Com p lex ( H a n d 13C
1
SCHEME 4. Ch em ica l Sh ifts of Cycloh ex-2-en on e a n d th e Cycloh ex-2-en on e-TiCl
NMR)
4
SCHEME 5. Ch em ica l Sh ifts of 5,5-Dim eth ylcycloh ex-2-en on e a n d th e 5,5-Dim eth ylcycloh ex-2-en on e-TiCl
4
1
13
Com p lex ( H a n d C NMR)
1
1
2
1
3
4
4.0 Hz), 3.84 (s, 1H), 4.25 (q, 2H, J ) 7.2 Hz), 5.97-6.08 (m,
H), 6.90-7.07 (m, 1H), 7.45-7.58 (m, 4H); 13C NMR δ 13.95,
2.83, 25.99, 55.06, 62.50, 77.35, 122.05, 127.64, 129.82,
Eth yl syn -2-h yd r oxy-2-p h en yl-2-(cyclop en t-4-en -1-on -
-1
1
2-yl)eth a n oa te (14): IR (neat) 3522, 1724, 1672 cm
; H
NMR δ 1.33 (t, 3H, J ) 7.2 Hz), 2.47-2.61 (m, 2H), 3.56 (dd,
1H, J ) 4.0 and 6.0 Hz), 3.99 (s, 1H), 4.18-4.51 (m, 2H), 6.19
(td, 1H, J ) 2.0 and 6.0 Hz), 7.27-7.43 (m, 3H), 7.59-7.72
(m, 3H); 13C NMR δ 14.02, 31.97, 52.37, 62.98, 77.44, 125.92,
127.99, 128.42, 134.18, 140.50, 164.45, 174.33, 208.02. Anal.
+
31.48, 138.75, 150.67, 174.23, 198.50; FABMS 353 (M + H),
+
55 (M + H + 2). Anal. Calcd for C16
17 4
H O Br: C, 54.41; H,
.85. Found: C, 54.53; H, 4.88.
Eth yl syn -2-h yd r oxy-2-(n a p h th -1-yl)-2-(cycloh ex-5-en -
-
1
15 16 4
Calcd for C H O : C, 69.22; H, 6.20. Found: C, 68.94; H,
1
-on -2-yl)eth a n oa te (11): IR (KBr) 3510, 1730, 1666 cm
;
1
6.25.
H NMR δ 1.22 (t, 3H, J ) 7.6 Hz), 1.48-1.68 (m, 1H), 1.78-
1H NMR Da ta of Cr u d e Com p ou n d s. In the 1H NMR
spectrum of the crude products (5-13) the methine proton (at
2
.10 (m, 1H), 2.25-2.40 (m, 2H), 4.09 (dd, 1H, J ) 4.4 and
3.8 Hz), 4.18-4.36 (m, 3H), 6.07-6.16 (m, 1H), 6.88-7.02 (m,
H), 7.42-7.54 (m, 3H), 7.77-7.90 (m, 2H), 8.00 (d, 1H, J )
1
1
7
5
1
C
2
) in aldol products appears at ca. δ 3.40-3.50 (dd, 1H) (in
the case of 11, the doublet of doublet appears at ca. δ 4.09)
and the â-vinylic proton (at C ) in the Baylis-Hillman products
.2 Hz), 8.79-8.91 (m, 1H); 13C NMR δ 13.94, 23.68, 26.25,
4.15, 62.33, 79.70, 125.07, 125.33, 125.88, 126.06, 129.22,
29.63, 130.04, 131.06, 134.34, 134.75, 150.58, 174.08, 200.04;
3
appears at ca. δ 6.40-6.50 (t, 1H). The integration of these
protons provides the ratio of aldol and Baylis-Hillman
products in 82-100:0-18%, respectively.
+
FABMS 325 (M + H). Anal. Calcd for C20
6
20 4
H O : C, 74.06; H,
.21. Found: C, 73.90; H, 6.19.
Meth yl syn -2-h yd r oxy-2-(4-m eth ylp h en yl)-2-(cycloh ex-
-en -1-on -2-yl)eth a n oa te (12): IR (KBr) 3425, 1730, 1660
5
-1 1
cm ; H NMR δ 1.50-1.68 (m, 1H), 1.78-2.06 (m, 1H), 2.24-
2
5
.40 (m, 5H), 3.47 (dd, 1H, J ) 4.5 and 14.0 Hz), 3.78 (s, 4H),
.97-6.09 (m, 1H), 6.90-7.02 (m, 1H), 7.17 (d, 2H, J ) 8.0
1
Hz), 7.51 (d, 2H, J ) 8.0 Hz); in the H NMR spectrum of the
3
compound (5 mg) in the presence of Eu(fod) (4 mg) the singlet
originally at δ 3.78 separated into two singlets at δ 4.36 and
1
δ 6.10 in the ratio of 3:1 indicating that original singlet
The H NMR spectrum of crude compounds (4a -j) did not
1
3
contains four protons (COOCH
2
1
3
+ OH); C NMR δ 21.00,
indicate the formation of any aldol product as evidenced by
the absence of methine proton peaks. The H NMR spectra of
the crude products (5-10, 12, and 13) do not show the presence
of any other diastereomers (anti). The H NMR spectrum of
the crude product 11 shows a doublet of doublet at ca. δ 4.09
for methine proton of the syn-aldol compound) and a multiplet
at ca. δ 3.48-3.72 in the ratio of ca. 90:10 ( H NMR spectrum
of the mother liquor also shows the presence of a multiplet at
ca. δ 3.48-3.72). We have assigned a minimum of 90% syn-
selectivity (even if the doublet of doublet arising from the
methine proton of the anti-aldol product is hidden in the
multiplet at δ 3.48-3.72).
See Scheme 4 for the chemical shifts of cyclohex-2-enone
and the cyclohex-2-enone-TiCl
chemical shifts of 5,5-dimethylcyclohex-2-enone and the 5,5-
1
2.84, 26.07, 53.12, 55.14, 77.43, 125.58, 129.12, 129.85,
+
36.29, 137.54, 150.77, 175.41, 199.17; FABMS 275 (M + H).
1
Anal. Calcd for C16
H, 6.64.
H
18
O
4
: C, 70.06; H, 6.61. Found: C, 69.87;
(
Meth yl syn -2-h yd r oxy-2-(4-eth ylp h en yl)-2-(cycloh ex-5-
1
-
1
en -1-on -2-yl)eth a n oa te (13): IR (KBr) 3441, 1736, 1658 cm
;
1
H NMR δ 1.23 (t, 3H, J ) 7.6 Hz), 1.52-1.70 (m, 1H), 1.78-
2
(
6
8
.04 (m, 1H), 2.26-2.40 (m, 2H), 2.64 (q, 2H, J ) 7.6 Hz), 3.46
dd, 1H, J ) 4.6 and 14.0 Hz), 3.78 (s, 4H), 5.98-6.08 (m, 1H),
.90-7.02 (m, 1H), 7.18 (d, 2H, J ) 8.0 Hz), 7.52 (d, 2H, J )
1
.0 Hz); in the H NMR spectrum of the compound (5 mg) in
(4 mg) the singlet originally at δ 3.78
separated into two singlets at δ 3.82 and δ 3.89 in the ratio of
:1 indicating that the original singlet contains four protons
the presence of Eu(fod)
3
4
complex and Scheme 5 for the
3
1
3
dimethylcyclohex-2-enone-TiCl complex.
(COOCH
3
+ OH); C NMR δ 15.23, 22.85, 26.04, 28.34, 52.97,
5.17, 77.49, 125.61, 127.83, 129.88, 136.56, 143.76, 150.47,
75.32, 199.00. Anal. Calcd for C17 : C, 70.81; H, 6.99.
4
5
1
H
20
O
4
Ack n ow led gm en t. We thank DST (New Delhi) for
Found: C, 70.83; H, 6.97.
funding this project. We thank UGC (New Delhi) for a
5
990 J . Org. Chem., Vol. 68, No. 15, 2003

Baylis-Hillman and Aldol Reactions
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
Special Assistance Program in Organic Chemistry in the
School of Chemistry, University of Hyderabad. B.S. and
A.J .R. thank CSIR (New Delhi) for their research
fellowship. We also thank the National Single Crystal
X-ray Facility, School of Chemistry, University of Hy-
derabad funded by DST (New Delhi). We thank Dr. T.
P. Radhakrishnan for helpful discussions regarding the
X-ray crystal structure.
1
3
all the compounds (3, 3a , 4, 4a -j, 5-14); C NMR spectra of
cyclohex-2-enone and its TiCl
complex; 13C NMR spectra of
5,5-dimethylcyclohex-2-enone and its TiCl complex; crystal-
4
4
lographic information data file for 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0342424
J . Org. Chem, Vol. 68, No. 15, 2003 5991