TiCl4-promoted Baylis-Hillman reactions of substituted 5-isoxazolecarboxaldehydes with cycloalkenones

Article abstract of DOI:10.1021/jo020199t

The Baylis-Hillman (BH) reaction of substituted 5-isoxazolecarboxaldehydes with cyclohexenone in the presence of TiCl₄ invariably lead to the formation of hemiacetals beside the BH adducts. A similar reaction in the presence of DABCO, DBU, or 3-HQN yielded minor quantities of phenols in addition to the usual BH adducts. Similar to 5-isoxazolecarboxaldehydes, the TiCl₄-mediated BH reaction of cyclohexenone with various benzaldehydes also furnishes hemiacetals in considerable yields. The reaction mechanism involving the formation of α-chloromethyl enone as an intermediate has been proposed. The synthesis of hemiacetals 5 and 14 from compound 4 in the presence of cyclohexenone and cyclopentenone, respectively, under acidic conditions indicates that enolization and aromatization of the cyclohexene ring are the key steps in the reaction mechanism.

Full text of DOI:10.1021/jo020199t

TiCl4-P r om oted Ba ylis-Hillm a n Rea ction s of Su bstitu ted
5-Isoxa zoleca r boxa ld eh yd es w ith Cycloa lk en on es1
Arundhati Patra,† Sanjay Batra,*,† Bhawani S. J oshi,‡ Raja Roy,‡ Bijoy Kundu,† and
Amiya P. Bhaduri†
Medicinal Chemistry and RSIC Divisions, Central Drug Research Institute, Lucknow 226 001, India
batra_san@yahoo.co.uk
Received March 21, 2002
The Baylis-Hillman (BH) reaction of substituted 5-isoxazolecarboxaldehydes with cyclohexenone
in the presence of TiCl4 invariably lead to the formation of hemiacetals beside the BH adducts. A
similar reaction in the presence of DABCO, DBU, or 3-HQN yielded minor quantities of phenols in
addition to the usual BH adducts. Similar to 5-isoxazolecarboxaldehydes, the TiCl4-mediated BH
reaction of cyclohexenone with various benzaldehydes also furnishes hemiacetals in considerable
yields. The reaction mechanism involving the formation of R-chloromethyl enone as an intermediate
has been proposed. The synthesis of hemiacetals 5 and 14 from compound 4 in the presence of
cyclohexenone and cyclopentenone, respectively, under acidic conditions indicates that enolization
and aromatization of the cyclohexene ring are the key steps in the reaction mechanism.
In tr od u ction
which can be selectively extended further. These products
have also been utilized as the building blocks for natural
products and biologically active compounds.32 However,
the slow rate of the reaction has led to number of
reports33-58 of catalysts and conditions that lead to rate
acceleration. Among these reports, the use of Lewis acids
The Baylis-Hillman (BH) reaction is one of the most
studied reactions in the last couple of years.2 The
synthetic utility of this carbon-carbon bond-forming
reaction has been exploited both in solution3-30 and solid
phase31 chemistry, since it offers a convenient route
toward generation of array of multifunctional products,
(18) Kim, J . N.; Lee, K. Y.; Kim, H. S.; Kim, T. Y. Org. Lett. 2000,
2, 343.
* Corresponding author. Tel.: +91-0522-212411-18 ext 4368, 4383.
Fax: +91-0522-223405, 229338.
(19) Kaye, P. T.; Nocanda, X. W. J . Chem. Soc., Perkin Trans. 1 2002,
1318.
(20) Kim, J . N.; Im, Y. J .; Hyeon Gong, J .; Lee, K. Y. Tetrahedron
Lett. 2001, 42, 4195.
† Medicinal Chemistry Division.
‡ RSIC Division.
(1) CDRI Communication No. 6267.
(21) Basavaiah, D.; Sreenivasulu, B.; Srivardhana Rao, J . Tetrahe-
dron Lett. 2001, 42, 1147.
(22) Kim, J . N.; Lee, H. J .; Lee, K. Y.; Kim, H. S. Tetrahedron Lett.
2001, 42, 3737.
(23) Basavaiah, D.; Bakthadoss, M.; Reddy, G. J . Synthesis 2001,
(24) Basavaiah, D.; Reddy, R. M. Tetrahedron Lett. 2001, 42, 3025.
(25) Kim, J . N.; Im, Y. J .; Hyeon Gong, J .; Lee, K. Y. Tetrahedron
Lett. 2001, 42, 4195.
(2) (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653. (b)
Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
(c) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049. (d) Zhang, A.
M.; Wang, W.; Lin, G. Q. Youji Huaxue 2001, 21, 134. (e) Iwabuchi,
Y.; Hatakeyama, S. Yuki Gosei Kagaku Kyokaishi 2002, 60 (1), 2.
(3) Basavaiah, D.; Kumaragurubaran, N.; Padmaja, K. Synlett 1999,
1630.
(4) Basavaiah, D.; Krishnamacharyulu, M.; Hyma, R. S.; Sarma, P.
K. S.; Kumaragurubaran, N. J . Org. Chem. 1999, 64, 1197.
(5) Basavaiah, D.; Hyma, R. S.; Padmaja, K.; Krishnamacharyulu,
M. Tetrahedron 1999, 55, 6971.
(6) Alcaide, B.; Almendros, P.; Aragoncillo, C. Tetrahedron Lett.
1999, 40, 7537.
(7) Pringle, W.; Sharpless, K. B. Tetrahedron Lett. 1999, 40, 5151.
(8) Basavaiah, D.; Muthukumaran, K.; Sreenivasulu, B. Synthesis
2000, 545.
(9) Wei, H. X.; Kim, S. H.; Caputo, T. D.; Purkiss, D. W.; Li, G.
Tetrahedron 2000, 56, 2397.
(10) Chamakh, A.; M’hirsi, M.: Villieras, J .; Lebreton, J .; Amri, H.
Synthesis 2000, 295.
(11) Mateus, C. R.; Almeida, W. P.; Coelho, F. Tetrahedron Lett.
2000, 41, 2533.
(12) Basavaiah, D.; Hyma, R. S.; Muthukumaran, K.; Kumargu-
rubaran, N. Synthesis 2000, 217.
(13) Lee, H. J .; Chung, Y. M.; Lee, K. Y.; Kim, J . Bull. Korean Chem.
Soc. 2000, 21, 843.
(26) Alcaide, B.; Almendros, P.; Aragoncillo, C. J . Org. Chem. 2001,
66, 1612.
(27) Ciclosi, M.; Fava, C.; Galeazzi, R.; Orena, M.; Sepulveda-Arques,
J . Tetrahedron Lett. 2002, 43, 2119.
(28) Coelho, F.; Rossi, R. C. Tetrahedron Lett. 2002, 43, 2797.
(29) Patra, A.; Batra, S.; Kundu, B.; J oshi, B. S.; Roy, R.; Bhaduri,
A. P. Synthesis 2001, 276.
(30) Garden, S. J .; Shakle, J . M. S. Tetrahedron Lett. 2002, 43, 1969.
(31) Richter, H.; J ung, G. Mol. Diversity 1998, 3, 191. (b) Kulkarni,
B. A.; Ganesan, A. J . Comb. Chem. 1999, 1, 373. (c) Richter, H.; Walk,
T.; Hoeltzel, A.; J ung, G. J . Org. Chem. 1999, 64, 1362. (d) Batra, S.;
Rastogi, S. K.; Kundu, B.; Patra, A.; Bhaduri, A. P. Tetrahedron Lett.
2000, 41, 5971. (e) Rastogi, S. K.; Gupta, P.; Srinivasan, T.; Kundu,
B. Mol. Diversity 2000, 5 (2), 91.
(32) (a) Hatakeyama, S. Farumashia 2000, 36 (12), 1033. (b) J auch,
J . Angew. Chem., Int. Ed. 2000, 39 (15), 2764. (c) J auch, J . Eur. J .
Org. Chem. 2001, 473. (d) Iwabuchi, Y.; Furukawa, M.; Esumi, T.;
Hatakeyama, S. Chem. Commun. 2001, 2030. (e) Wang, B.; Yu, X. -M.;
Lin, G.-Q. Synlett 2001, 904 (special issue). (f) Iwabuchi, Y.; Sugihara,
T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42 (44), 7867.
(g) Masunari, A.; Ishida, E.; Trazzi, G.; Almeida, W. P.; Coelho, F.
Synth. Commun. 2001, 31 (14), 2127. (h) J effrey M.; Olmstead, Marilyn
M.; Kurth, Mark J . J . Org. Chem. 2002, 67 (3), 876. (i) Xavier, F.;
Bruno, F. Tetrahedron Lett. 2002, 43 (8), 1449. (j) Kundu, M. K.;
Sundar, N.; Kumar, S. K.; Bhat, S. V.; Biswas, S.; Valecha, N. Bioorg.
Med. Chem. Lett. 1999, 9, 731.
(14) Kim, H. S.; Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H. J .;
Kim, J . N. Tetrahedron Lett. 2000, 41, 2613.
(15) Kaye, P. T.; Nocanda, X. W. J . Chem. Soc., Perkin Trans. 1 2000,
1331.
(16) Coelho, F.; Almeida, W. P. Quim. Nova 2000, 23, 98.
(17) Raecker, R.; Doering, K.; Reiser, O. J . Org. Chem. 2000, 65,
6932.
10.1021/jo020199t CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/04/2002
J . Org. Chem. 2002, 67, 5783-5788
5783

Patra et al.
SCHEME 1
with or without various other additives in the reaction
system is the most common choice for activating the
carbonyl system. The use of Lewis acids in BH reactions
at lower temperature in the presence of an additive
furnishes either halo aldol44,46,50,53 or halo methyl enone42
as the major product while, at room temperature, the
formation of the usual BH adduct has also been re-
ported.35,41 However, recently Iwamura et al. reported58
the formation of hemiacetal through aqueous workup
during boron tribromide promoted BH reaction of p-
nitrobenzaldehyde with cyclohexenone. In an earlier
observation, Li et al. too have reported40 the formation
of an unidentified side product (10%) during the TiCl4-
mediated BH reaction of p-nitrobenzaldehyde and R,
â-cycloalkenone. In the studies directed toward the BH
reaction of 5-isoxazolecarboxaldehydes we have earlier
reported that these substrates undergo fast reaction both
in solution phase29 and on solid support.31d In our
continued work in this area we have also carried out the
BH reaction with R,â-unsaturated cyclic ketones in the
presence of TiCl4. We have observed that, under our
reaction conditions when cyclohexenone was used as the
activated enone, the hemiacetal appeared right from the
onset of reaction along with the usual BH adduct. The
details of our study are presented here.
TABLE 1. Resu lts of Ba ylis-Hillm a n Rea ction of
3-Su bstitu ted P h en yl-5-isoxa zoleca r boxa ld eh yd e in th e
P r esen ce of TiCl4
time
(h)
product
(yield (%))
entry
R
alkene
1
2
3
4
5
6
7
8
C6H5
4-(CH3)C6H4
4-ClC6H4
cyclopentenone 1.5 2 (58), 3 (7)
Resu lt a n d Discu ssion
cyclopentenone
cyclopentenone
1
1
2 (69), 3 (15)
2 (50), 3 (12)
The reactions of 3-substituted phenyl-5-isoxazolecar-
boxaldehydes (1a -d ) were carried out by sequentially
adding the 1.5 equiv of unsaturated ketone and 1.0 equiv
of TiCl4 to the appropriate solution of aldehyde in
4-(OCH2C6H5)C6H4 cyclopentenone 2.2 2 (65), 3 (5)
C6H5
4-(CH3)C6H4
4-ClC6H4
4-(OCH2C6H5)C6H4 cyclohexenone
cyclohexenone
cyclohexenone
cyclohexenone
1
4 (35), 5 (20)
0.6 4 (42), 5 (33)
1
2
4 (41), 5 (21)
4 (40), 5 (25)
(33) Aggarwal, V. K.; Tarver, G. J .; McCague, R. Chem. Commun.
1996, 24, 2713.
(34) Aggarwal, V. K.; Mereu, A.; Tarver, G. J .; McCague, R. J . Org.
Chem. 1998, 63, 7183.
(35) Kataoka, T.; Iwama, T.; Tsujiyama, S.-i.; Iwamura, T.; Wa-
tanabe, S.-i. Tetrahedron 1998, 54, 11813.
dichloromethane at 0-5 °C under stirring, and the
reaction was allowed to continue at the same tempera-
ture. In the presence of cyclopentenone the usual BH
products (2a -d ) were obtained in major yields while the
R-chloromethyl enones (3a -d ) were obtained in traces
only. In contrast to this, when reactions were carried out
in the presence of cyclohexenone, in addition to the usual
BH adducts (4a -d ), hemiacetals (5a -d ) were obtained
in moderate yields (Scheme 1). Within a short duration
of time, the reactions of 5-isoxazolecarboxaldehydes with
cycloalkenones in the presence of TiCl4 went to comple-
tion (Table 1). We did not detect the presence of R-chlo-
romethyl enone (6) in any of these reactions. It is
appropriate to mention here that, during the workup, all
reactions were quenched with saturated sodium bicar-
bonate solution. All these reactions were continuously
(36) Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539.
(37) Kataoka, T.; Iwama, T.; Kinoshita, H.; Tsujiyama, S.; Tsu-
rukami, Y.; Iwamura, T.; Watanabe, S. Synlett 1999, 197.
(38) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311.
(39) Kataoka, T.; Iwama, T.; Tsujiyama, S.-i.; Kanematsu, K.;
Iwamura, T.; Watanabe, S.-i. Chem. Lett. 1999, 257.
(40) Reddy, L. R.; Rao, K. R. Org. Prep. Proced. Int. 2000, 32, 185.
(41) Li, G.; Wei, H. X.; Gao, J . J .; Caputo, T. D. Tetrahedron Lett.
2000, 41, 1.
(42) Li, G.; Gao, J .; Wei, H. X.; Enright, M. Org. Lett. 2000, 2, 617.
(43) Kataoka, T.; Iwama, T.; Kinoshita, H.; Tsurukami, Y.; Tsujiya-
ma, S.; Fujita, M.; Honda, E.; Iwamura, T.; Watanabe, S.-i. J .
Organomet. Chem. 2000, 611, 455.
(44) Shi, M.; J iang, J .-K.; Feng, Y.-S. Org. Lett. 2000, 2, 2397.
(45) Kataoka, T.; Kinoshita, H.; Iwama, T.; Tsujiyama, S.-i.; Iwa-
mura, T.; Watanabe, S.-i.; Muraoka, O.; Tanabe, G. Tetrahedron 2000,
56, 4725.
(46) Shi, M.; J iang, J .-K. Tetrahedron 2000, 56, 4793.
(47) Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Iwamura, T.; Wa-
tanabe, S.-i. Angew. Chem., Int. Ed. 2000, 39, 2358.
(48) Shi, M.; Feng, Y.-S. J . Org. Chem. 2001, 66, 406.
(49) Shi, M.; Xu, Yong, M. Chem. Commun. 2001, 1876.
(50) Shi, M.; J iang, J .-K.; Cui, S.-C.; Feng, Y.-S. J . Chem. Soc.,
Perkin Trans. 1 2001, 390.
1
monitored through TLC and H NMR. The structure of
the hemiacetal was confirmed on the basis of detailed
2D NMR spectroscopic studies. If the reactions were
subjected to only aqueous workup and left for several
hours as reported by Iwamura et al.,58 we obtained the
BH adduct (4) too, in addition to the hemiacetal (5) and
the phenol (7).
(51) Lee, W. Der.; Yang, K. S.; Chen, K. Chem. Commun. 2001, 1612.
(52) Yu, C.; Liu, B.; Hu, L. J . Org. Chem. 2001, 66, 5413.
(53) Han, Z.; Uehira, S.; Shinokubo, H.; Oshima, K. J . Org. Chem.
2001, 66, 7854.
(54) Aggarwal, V. K.; Mereu, A. Chem. Ind. 2001, 82, 595.
(55) Basavaiah, D.; Sreenivasulu, B.; Reddy, R. M.; Muthukumaran,
K. Synth. Commun. 2001, 31, 2987.
(56) Shi, M.; J iang, J .-K.; Cui, S.-C. Tetrahedron 2001, 57, 7343.
(57) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J . Org.
Chem. 2002, 67, 510.
We next examined different reaction conditions as an
alteration to the general procedure of our BH reaction
to evaluate and compare the amounts of hemiacetal and
BH adduct formed (Table 2). During a study utilizing
compound 1b as model, it was observed that if a chalco-
genide such as dimethyl sulfide (0.1 equiv) was added
(58) Iwamura, T.; Fujita, M.; Kawakita, T.; Kinoshita, S.; Watanabe,
S.-i.; Kataoka, T. Tetrahedron 2001, 57, 8455.
5784 J . Org. Chem., Vol. 67, No. 16, 2002

TiCl4-Promoted Baylis-Hillman Reactions
TABLE 2. Va r ia tion of Yield s d u r in g Ba ylis-Hillm a n Rea ction w ith Cycloh exen on e w ith Ch a n ge in Rea ction
Con d ition s
entry
conditions
time (min)
product (yield (%))
1
2
3
4
cyclohexenone (2 equiv) + Me2S (0.1 equiv) + TiCl4 (1 equiv), at 0-5 °C
cyclohexenone (2 equiv) + TiCl4 (1 equiv), at 0-5 °C
45
20
18
60
4 (64), 5 (31)
4 (48), 5 (30)
4 (50), 5 (28)
4 (39), 5 (25)
cyclohexenone (3 equiv) + TiCl4 (1 equiv), at 0-5 °C
addition of TiCl4 done at 0-5 °C and then reaction stirred at room temp
SCHEME 2
along with TiCl4 (1.0 equiv) and cyclohexenone in the
reaction (entry 1), the usual BH adduct (4b) was obtained
in better yield while the yield of hemiacetal (5b) remain
unaffected. Increasing the amount of cyclohexenone to 2
equiv (entry 2) or 3 equiv (entry 3) increased the rate of
reaction though it did not significantly affect yields of
BH adduct and hemiacetal. Escalation of the temperature
of the reaction decreased yields of the final products
(entry 4).
Interestingly, as we did not obtain the R-chloromethyl
enone (6) in any of our reactions with cyclohexenone, we
further explored various conditions under which it could
be furnished. Since it has already been reported45,58 that
the haloalkenones could be generated by reactions of BH
adduct with hydrogen halide which is liberated in situ
from the Lewis acid, we subjected compound 4b to
reaction with HCl in dichloromethane for more than 24
h Unexpectedly, this reaction instead of giving R-chlo-
romethyl enone (6) furnished the phenol (7b) exclusively
in more than 70% yield. Similar to this reaction, if the
compound 4b was further stirred with only TiCl4 in
dichloromethane, the phenol (7b) was obtained in good
yield. In contrast, if compound 2b was treated with TiCl4
or HCl, it led to formation of R-chloromethyl enone 3b
exclusively. In view of these results it was envisaged that
compound 4 could afford hemiacetal when treated with
cyclohexenone under acidic condition. Therefore, com-
pound 4b was reacted with 1.0 equiv of cyclohexenone
in the presence of HCl for more than 24 h. This reaction
as expected furnished the hemiacetal 5b in 65% yields
with minor quantities of phenol 7b (Scheme 2).
dienol (9) is formed through the enolization of the BH
adduct 4, which undergoes Michael addition in the
presence of cyclohexenone to form the diketone 10. This
could be followed by chlorination of the intermediate 10
with TiCl4 or HCl to afford 11. On the other hand, it can
also be proposed that the unstable R-chloromethyl enone
(6) possibly adds up another cyclohexenone to furnish the
similar intermediate 11. The subsequent removal of HCl
from 11 leads to the diketone 12. The enol of this
intermediate possibly provokes aromatization of the
cyclohexane ring to furnish 13, which subsequently
undergoes a cyclization to yield the hemiacetal 5. The
facile aromatization of the cyclohexane ring might be the
driving force toward the formation of hemiacetal. In
principle, if the aromatization of the cyclohexenone is the
key step, the TiCl4- (or acid-) mediated reaction between
the BH adduct 4 and other cycloalkenones would afford
the corresponding hemiacetals but it will not be true for
the BH adduct of any other alkenones. To ascertain this
in a model reaction, compound 4b was reacted with
cyclopentenone in the presence of TiCl4 (or HCl) under
similar conditions (Scheme 3). As anticipated, this reac-
tion led to the formation of analogous hemiacetal 14b
(Scheme 4). On the other hand, compound 2b under same
condition failed to react with cyclohexenone and afforded
compound 3b as the only product. On the basis of these
findings, it could be proposed that the R-halomethyl
enone could be a common product in Lewis acid promoted
BH reactions but in the case of cyclohexenone under
acidic condition it is unstable and transforms to furnish
either phenol or hemiacetal.
The reaction mechanism for the formation of hemiac-
etal is similar to the one proposed earlier (Scheme 3).58
However in the view of various reactions carried out
during our studies, it could be proposed that in the case
of cyclohexenone also the R-chloromethyl enone (6) is
formed but it is unstable and in the absence of cyclohex-
enone immediately transforms to intermediate 8 which
furnished the phenol 7. On the other hand, in the
presence of excess of cyclohexenone the formation of
hemiacetal is favored. It is likely that the intermediate
To confirm the role of acid toward the formation of
phenol during reactions of cyclohexenone it was consid-
ered appropriate to carry out similar reactions of 5-isox-
azolecarboxaldehyde in the presence of DABCO, DBU,
or 3-HQN. To the best of our knowledge, previous to this
work there existed only two reports56,60 where the authors
(59) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965.
(60) Basavaiah, D.; Gowriswari, V. V. L.; Rao, P. D.; Bharathi, T.
K. J . Chem. Res., Synop. 1995, 267. J . Chem. Res., Miniprint. 1995,
1656.
J . Org. Chem, Vol. 67, No. 16, 2002 5785

Patra et al.
SCHEME 3
SCHEME 4
SCHEME 5
In light of these observations we also revisited the
TiCl4-mediated BH reactions of various other aromatic
aldehydes with cyclohexenone. It was observed that
under our reaction conditions, besides the BH adducts
(16a -e), hemiacetals (17a -d ) were formed in moderate
yields invariably with all benzaldehydes, but no such
product was observed for pyridinecarboxaldehyde (Scheme
6). However, the yield of hemiacetal was better in the
benzaldehydes bearing a phenyl group with electron-
withdrawing substitution (Table 3).
Con clu sion
have carried out the BH reaction of cyclohexenone in the
presence of base reporting the formation of the usual BH
adduct. To our surprise, these reactions led to phenols
(7a -d ) in 19-25% yields besides the normal BH adducts
(4a -d ) in 59-65% yields (Scheme 5). These results
suggest that during the reactions of TiCl4 though the
acidic medium of the reaction mixture might be respon-
sible for the dehydration leading to a 1,5-shift for
aromatization by enolization of the usual BH adduct, the
phenol can also be produced by some other mechanism.
In conclusion, we have described the detailed synthetic
and mechanistic aspects of the formation of hemiacetal
during TiCl4-promoted BH reaction of substituted 5-isox-
azolecarboxaldehydes with cyclohexenone. This holds
true for reactions of other aromatic aldehydes also,
(61) Iwama, T.; Tsujiyama, S.; Kinoshita, H.; Kanematu, K.; Tsu-
rukami, Y.; Iwamura, T.; Watanbe, S.; Kataoka, T. Chem. Pharm. Bull.
1999, 47, 956.
5786 J . Org. Chem., Vol. 67, No. 16, 2002

TiCl4-Promoted Baylis-Hillman Reactions
to furnish an oily residue. Purification of the residue by column
chromatography using hexane-ethyl acetate (95:05, v/v) fur-
nished the R-chloromethyl enones (3a -d ), while further elu-
tion with 65:35 (v/v) ratio of the same solvent yielded the BH
adducts as solids (2a -d ).
SCHEME 6
2b: 69% as a pale yellow solid, mp 88-90 °C; IR (KBr) 1689,
3362 cm-1 1H NMR (CDCl3) δ 2.39 (s, 3H, CH3), 2.49-2.54
;
(m, 2H, CH2), 2.68-271 (m, 2H, CH2), 3.98 (d, 1H, J ) 6.3 Hz,
OH), 5.76 (d, 1H, J ) 6.0 Hz, CH), 6.60 (s, 1H, dCH), 7.25 (d,
2H, J ) 8.0 Hz, Ar H), 7.62 (t, 1H, J ) 1.8 Hz, dCH), 7.68 (d,
2H, J ) 8.0 Hz, Ar H); mass (EI) m/z 269 (M+, 45), 158 (100).
Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found:
C, 71.54; H, 5.77; N, 5.1.
3b: 15% as white solid, mp 118-120 °C; IR (KBr) 1708
cm-1; 1H NMR (CDCl3) δ 2.41 (s, 3H, CH3), 2.45-259 (m, 3H,
CH2), 2.77-2.90 (m, 1H, CH2), 5.70-5.72 (m, 1H, CHCl), 6.95
(s, 1H, dCH), 7.26-7.30 (m, 3H, dCH and Ar H), 7.71 (d, 2H,
J ) 8.0 Hz, Ar H); mass (FAB+) m/z 288 (M+ + 1). Anal. Calcd
for C16H14ClNO3: C, 66.78; H, 4.90; N, 4.86. Found: C, 66.74;
H, 5.07; N, 4.67.
TABLE 3. Rea ction of Va r iou s Ald eh yd es w ith
Cycloh exen on e in th e P r esen ce of TiCl4
Gen er a l P r oced u r e for TiCl4-P r om oted Rea ction s of
3-Su bstitu ted P h en yl-5-isoxa zoleca r boxa ld eh yd es w ith
Cycloh exen on e. To a stirred solution of the appropriate
compound from 1a -d (0.5 mmol) and cyclohexenone (1.0
mmol) in dry DCM (1.5 mL) was added TiCl4 (89.3 µL, 0.5
mmol in 0.5 mL of DCM) at 0-5 °C. The stirring was continued
at same temperature for the time given in Table 1 (entries
5-8). Thereafter, the reaction mixture was quenched with
saturated aqueous NaHCO3 solution and stirred further for
30 min. The precipitate of inorganic material was removed by
filtration through Celite using DCM. The organic layer was
separated, dried over Na2SO4, and evaporated to furnish an
oily residue. This residue was purified by column chromatog-
raphy using hexane-ethyl acetate (90:10, v/v), which furnished
the hemiacetal (5a -d ) as pale yellow solids, while further
elution with a 70:30 (v/v) solvent mixture furnished the BH
adduct (4a -d ) as oil or solid.
entry
R
time (h)
product (yield (%))
1
2
3
4
5
C6H5
24
36
2.15
2.30
1.3
16a 60 (15), 17a (7)
16b60 (10), 17b (10)
16c35,41 (48), 17c58 (30)
16d 61 (50), 17d (28)
16 (58)
4-(CH3)C6H4
4-(NO2)C6H4
4-(CF3)C6H4
pyridine-3-
though the reaction times were higher. The yields of such
hemiacetals are significant for aldehydes bearing an
electron-withdrawing group on the phenyl ring. It is
confirmed through our studies that a slight excess of
cyclohexenone and the acidic medium of the reaction is
sufficient for the generation of hemiacetal. During this
study we have observed that minor quantities of corre-
sponding phenols are also formed during the base-
promoted BH reaction of aldehyde with cyclohexenone.
This indicates that it is not only the acidic condition that
is responsible for the generation of phenol but also some
other mechanism in the presence of base that could form
phenol.
4b: 42% as pale yellow solid, mp 108-110 °C; IR (KBr)
1653, 3377 cm-1 1H NMR (CDCl3) δ 2.04 (quintet, 2H, J )
;
6.2 Hz, CH2), 2.39 (s, 3H, CH3), 2.43-2.53 (m, 4H, 2 × CH2),
5.56 (s, 1H, CH), 6.58 (s, 1H, dCH), 7.01 (t, 1H, J ) 4.0 Hz,
dCH), 7.24 (d, 2H, J ) 8.0 Hz, Ar H), 7.68 (d, 2H, J ) 8.0 Hz,
Ar H); mass (EI) m/z 283 (M+, 44), 199 (80), 158 (100). Anal.
Calcd for C17H17NO3: C, 72.06; H, 6.04; N, 4.94. Found: C,
71.77; H, 6.14; N, 4.78.
Exp er im en ta l Section
1
5b: 33% as pale yellow oil; IR (neat) 3352 cm-1; H NMR
(CDCl3) δ 1.54-1.77 (m, 5H, 2 × CH2 and 1H other CH2),
1.97-2.08 (m, 3H, 1 CH2 and 1H of other CH2), 2.36 (s, 3H,
CH3), 3.19 (t, 1H, J ) 3 Hz, CH), 4.00 and 4.11 (2d, each 1H,
J ) 10 Hz, benzylic CH2), 6.20 (s, 1H, dCH), 6.79 (t, 1H, J )
7.4 Hz, dCH), 6.95 (dd, 1H, J 1 ) 1.5 Hz, J 2 ) 7.4 Hz, Ar H),
7.05 (dd, J 1 ) 1.5 Hz, J 2 ) 7.4 Hz, Ar H), 7.20 (d, 2H, J ) 8.0
Hz, Ar H), 7.62 (d, 2H, J ) 8.0 Hz, Ar H); 13C NMR (CDCl3,
75.6 MHz) δ 21.78 (CH3), 22.69 (CH2), 38.68 (CH2), 67.95 (CH),
100.27 (CHd), 126.48 (C), 127.12 (2 × CH), 129.96 (2 × CH),
137.51 (C), 140.52 (C), 149.67 (CH), 162.79 (C), 173.25 (C),
200.42 (CO); mass (FAB+) m/z 362 (M+ + 1). Anal. Calcd for
Gen er a l Meth od s. Reactions were run in oven-dried
glassware, and dried dichloromethane was prepared by distil-
lation over P2O5. All column chromatography was carried on
flash silica gel (230-400 mesh) using distilled solvents.
Melting points are uncorrected and were determined in
capillary tubes on a hot stage apparatus containing silicon oil.
IR spectra were recorded using an FTIR spectrophotometer.
1H NMR and 13C NMR spectra were run in CDCl3 and recorded
on either a 300 or a 200 MHz FT spectrometer, using TMS as
an internal standard (chemical shifts in δ values, J in Hz).
The EIMS and FABMS were recorded on appropriate spec-
trometers, and ESMS were recorded through direct injections
in an LCMS system. Elemental analyses were performed on
a microanalyzer.
Gen er a l P r oced u r e for Rea ction s of 3-Su bstitu ted
P h en yl-5-isoxa zoleca r boxa ld eh yd es w ith Cyclop en ten -
on e. To a stirred solution of the appropriate compound from
1a -d (0.5 mmol) and cyclopentenone (1.06 mmol) in dry
dichloromethane (DCM) (1.5 mL) was added TiCl4 (89.3 µL,
0.5 mmol in 0.5 mL of DCM) at 0-5 °C. The stirring was
continued at the same temperature for the time given in Table
1 (entries 1-4). Thereafter, the reaction mixture was quenched
by addition of saturated aqueous NaHCO3 solution and stirred
further for 30 min. The inorganic precipitate was filtered out
with a Celite bed using DCM. The organic layer was separated,
dried over Na2SO4, and evaporated under reduced pressure
C
23H23NO3: C, 76.43; H, 6.41; N, 3.87. Found: C, 76.12; H,
6.44; N, 4.05.
Gen er a l P r oced u r e for TiCl4-P r om oted Rea ction s of
Com p ou n d 4b w ith Cycloa lk en on es. To a stirred solution
of compound 4b (0.35 mmol) and appropriate cycloalkenone
(1.0 mmol) in dry DCM (1.5 mL) was added TiCl4 (38 µL, 0.34
mmol in 0.5 mL of DCM) at 0-5 °C. The reaction was
continued at the same temperature for 1 h, and then it was
quenched with saturated aqueous NaHCO3 solution and
stirred further for 30 min. The precipitate of inorganic material
was removed by filtration through Celite using DCM. The
organic layer was separated, dried over Na2SO4, and evapo-
rated to furnish an oily residue. The residue obtained from
the reaction of cyclopentenone was purified by column chro-
matography using hexane-ethyl acetate (95:5, v/v) that fur-
J . Org. Chem, Vol. 67, No. 16, 2002 5787

Patra et al.
nished the phenol 7b in 7% yield, while elution with 90:10
(v/v) of the same solvent yielded the hemiacetal (14b) in 18%
yield as a pale yellow oil. In the case for the residue from the
reaction of cyclohexenone also, elution with hexane-ethyl
acetate (95:5, v/v) gave the phenol 7b in 19% yield and further
elution with 90:10 (v/v) hexane-ethyl acetate afforded the
hemiacetal (5b) in 22% yield. Elution with a mixture of 70:30
(v/v) of the same solvents furnished the unreacted starting
material in 52% yields. (This reaction if continued for more
than 24 h did not give any starting material.)
Gen er a l P r oced u r e for DABCO-, DBU-, or 3-HQN-
Med ia ted Rea ction s of 3-Su bstitu ted P h en yl-5-isoxa zole-
ca r boxa ld eh yd es w ith Cycloh exen on e. To a prestirred
mixture of DABCO, DBU, or 3-HQN (0.15 mmol) and cyclo-
hexenone (0.15 mL, 1.5 mmol) was added the appropriate
aldehyde from 1a -d , and the stirring was continued at room
temperature for 18 h. Thereafter, the reaction mixture was
extracted with ethyl acetate (2 × 15 mL) and washed with
water (15 mL). The organic layers were pooled, dried over Na2-
SO4, and evaporated under reduced pressure to furnish an oily
residue that was purified by column chromatography. Elution
with hexane-ethyl acetate (90:10, v/v) gave the phenols (7a -
d ) as white solids, while further elution with 70:30 (v/v) solvent
yielded the BH adduct as a light yellow solid.
7b: 25% as a white solid, mp 108-110 °C; IR (KBr) 3432
cm-1; 1H NMR (CDCl3) δ 2.35 (s, 3H, CH3), 4.01 (d, J ) 10 Hz,
1H of benzylic CH2), 4.13 (d, J ) 10 Hz, 1H of benzylic CH2),
6.21 (s, 1H, dCH), 6.81-6.93 (m, 2H, Ar H), 7.10-7.28 (m,
4H, Ar H), 7.62 (d, 2H, J ) 8.0 Hz, Ar H); 13C NMR (CDCl3,
75.6 MHz) δ 21.4 (CH3), 27.7 (CH2), 99.8 (CH), 115.7 (CH),
121.1 (CH), 122.7 (C), 126.7 (2 × CH), 128.6 (CH), 129.5 (2 ×
CH), 130.9 (CH), 139.9 (C), 153.7 (C), 162.5 (C), 1732.2 (C);
mass (FAB+) m/z 266 (M+ + 1). Anal. Calcd for C17H17NO3:
C, 76.95; H, 5.69; N, 5.28. Found: C, 76.67; H, 6.04; N, 5.20.
1
14b: 18% as pale yellow oil; IR (neat) 3376 cm-1; H NMR
(CDCl3) δ 1.59-1.69 (m, 2H, CH2), 1.99-2.08 (m, 2H, CH2),
2.29-2.41 (m, 4H, 1 CH3 and 1H of CH2), 2.67 (dd, 1H, J 1
)
7.5 Hz, J 2 ) 17.5 Hz, 1H of CH2), 3.67-3.72 (m, 1H, CH), 4.12
(s, 2H, benzylic CH2), 6.21(s, 1H, dCH), 6.93 (t, 1H, J ) 8.0
Hz, Ar H), 7.10-7.15 (m, 2H, Ar H), 7.21 (d, 2H, J ) 8.0 Hz,
Ar H), 7.61 (d, 2H, J ) 8.0 Hz, Ar H); mass (FAB+) m/z 348
(M+ + 1). Anal. Calcd for C22H21NO3: C, 76.27; H, 5.81; N,
4.04. Found: C, 76.12; H, 6.04; N, 4.05.
Gen er a l P r oced u r e for H Cl-Med ia t ed R ea ct ion s.
Method A. To a stirred solution of compound 4b (0.1 mmol)
and appropriate cycloalkenone (0.1 mmol) in dry DCM (1.5 mL)
was added HCl (30 µL, 0.36 mmol) at room temperature. The
reaction was continued for 24 h, dichloromethane was evapo-
rated, and the residue was extracted with ethyl acetate (2 ×
10 mL). The organic layers were combined, dried over anhy-
drous Na2SO4, and evaporated under vacuum. The residues
from cyclopentenone and cyclohexenone were subjected to
column chromatography, and the respective products (5b and
14b) were isolated as described above for TiCl4-mediated
reactions.
Meth od B. To a stirred solution of appropriate compound
from 2b or 4b (0.1 mmol) in dry DCM (1.5 mL) was added
HCl (30 `ıL, 0.36 mmol) at room temperature. The reaction was
continued for 24 h, DCM was evaporated, and the residue was
extracted with ethyl acetate (2 × 10 mL). The organic layers
were combined, dried over anhydrous Na2SO4, and evaporated
under vacuum. The R-chloromethyl enone (3b) in the case of
2b or phenol 7b in the case of 4b was isolated by column
chromatography as described above.
Ack n ow led gm en t. A.P. and B.S.J . gratefully ac-
knowledge the financial support from the CSIR of India
in the form of a fellowship.
Su p p or tin g In for m a tion Ava ila ble: Physical and spec-
troscopic data for compounds 2a ,c,d , 3a ,c,d , 4a ,c,d , 5a ,c,d ,
1
7a ,c, 16e, and 17a -c, H NMR spectral charts of compounds
2b, 3b, 4b, 5b, 7b, 14b, and 17, 13C NMR spectral charts of
compounds 4b and 5b, and 2D COSY (HMQC and HMBC)
charts used for characterization of hemiacetal 5b . This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O020199T
5788 J . Org. Chem., Vol. 67, No. 16, 2002