The use of acetylenic aldehydes in Baylis-Hillman reactions: Synthesis of versatile allyl propargyl alcohols

Article abstract of DOI:10.1016/S0040-4039(03)01169-9

The utility of acetylenic aldehydes in Baylis-Hillman reactions giving allyl propargyl alcohols in moderate to good yields is reported.

Full text of DOI:10.1016/S0040-4039(03)01169-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4973–4975
The use of acetylenic aldehydes in Baylis–Hillman reactions:
synthesis of versatile allyl propargyl alcoholsꢀ
Palakodety Radha Krishna,* Empati Raja Sekhar and V. Kannan
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad-500 007,
India
Received 10 April 2003; revised 2 May 2003; accepted 9 May 2003
Abstract—The utility of acetylenic aldehydes in Baylis–Hillman reactions giving allyl propargyl alcohols in moderate to good
yields is reported. © 2003 Elsevier Science Ltd. All rights reserved.
Chiral propargyl and allyl propargyl alcohols are
important intermediates for the synthesis of hydroxyl-
ated fatty acids,1 natural products such as alkaloids,2
pyrethroids,3 avenaciolide,4 steroids,5 pheromones,6
vitamin E,7 and prostaglandins,8 and biologically active
prostacyclin mimetics.9 The Baylis–Hillman reaction of
an acetylenic carbonyl compound with an activated
alkene could be utilized for the formation of allyl
propargyl alcohols. However, acetylenic compounds
have less frequently been used in Baylis–Hillman reac-
tions. For instance, the reaction of 3-butyn-2-one10 with
ethyl acrylate in the presence of DABCO did not
provide the expected Baylis–Hillman adduct, but
resulted in self condensation to form a divinyl ether.
However, prop-2-yn-1-al and 1-phenylprop-2-yn-1-one
have been used in the chalcogen Baylis–Hillman reac-
tion.11 In continuation of our work on chiral allyl
propargyl alcohols12 and Baylis–Hillman reactions,13
herein a study on the use of acetylenic aldehydes for the
synthesis of allyl propargyl alcohols by Baylis–Hillman
reactions is reported (Eq. (1)). It is interesting to note
that tertiary hydroxy esters14 which form an important
part of the structures of many natural products such as
S-oxybutynin, may be accessed from these adducts.
All the primary alkynyl alcohols, the precursors of the
acetylenic aldehydes used in this study, were synthe-
sized from the commercially available terminal alkynes
by reported procedures.15 For example, phenyl acetyl-
ene on reaction with EtMgBr under Grignard condi-
tions followed by treatment with formaldehyde gave the
corresponding primary alkynyl alcohol. The alkynyl
alcohol thus obtained on oxidation with iodoxybenzoic
acid (IBX) provided 3-phenyl-2-propynal 1 in 90%
yield, which was subjected to a Baylis–Hillman reaction
with ethyl acrylate 4 in the presence of DABCO (0.5
equiv.) in THF at room temperature. The reaction gave
only a moderate yield of the adduct 7a in 45% yield
after two days, but the same reaction was completed
within 15 h in DMSO in the presence of 50 mol% of
DABCO giving a 74% yield of the product 7a. Subse-
quently, the aldehyde 1 when treated with methyl vinyl
ketone 5 and 1,2:5,6-di-O-isopropylidene-3-O-acrylate-
a-D-glucopentoaldo-1,4-furanose 6 in DMSO afforded
the corresponding Baylis–Hillman adducts 7b and 7c in
good yields (Scheme 1, Table 1).
This method was then extended to other acetylenic
aldehydes such as 2-nonynal 2 and 5-benzyloxy-2-pen-
tynal 3 to provide the desired products 8a–c, and 9a–c,
respectively (Table 1). To increase the scope of this
methodology for realizing the synthesis of chiral allyl
propargyl alcohols, this reaction was performed using 6
as a chiral acrylate. The diastereoselectivity observed in
the adducts 7c, 8c and 9c corresponded to 30, 44 and
(1)
1
24% de’s, respectively, as determined by H NMR. The
Keywords: chiral allyl propargyl alcohols; acetylenic aldehydes; Bay-
lis–Hillman reactions; DABCO and chiral acrylates.
ꢀ IICT Communication No. 030318.
* Corresponding author. Fax: 91-40-27160387/27160757; e-mail:
prkgenius@iict.ap.nic.in
absolute stereochemistry at the newly created center of
the major isomer was assigned based on our earlier
report,13 which describes the use of the same chiral
acrylate 6 for asymmetric Baylis–Hillman reactions
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01169-9

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P. Radha Krishna et al. / Tetrahedron Letters 44 (2003) 4973–4975
Scheme 1.
Table 1. Baylis–Hillman reaction of acetylenic aldehydes
2. Overman, L. E.; Bell, K. L. J. Am. Chem. Soc. 1981, 103,
1851.
with activated alkenes16,17
3. (a) Matsuo, T.; Nishioka, T.; Hirano, M.; Suzuki, T.;
Tsushima, K.; Itaya, N.; Yoshika, M. Pesticide Sci. 1980,
11, 202; (b) Franck-Neumann, M.; Sedrati, M.; Vigneron,
J. P.; Bloy, V. Angew. Chem., Int. Ed. 1985, 24, 996; (c)
Sugai, T.; Kuwahara, S.; Hishino, C.; Matsuo, N.; Mori,
K. Agric. Biol. Chem. 1982, 46, 2579.
4. Mukaiyama, T.; Suzuki, K. Chem. Lett. 1980, 255.
5. Johnson, W. S.; Frei, B.; Gopalan, A. S. J. Org. Chem.
1981, 46, 1512.
6. (a) Pirkle, W. H.; Boeder, C. W. J. Org. Chem. 1978, 43,
2091; (b) Mori, K.; Akao, H. Tetrahedron Lett. 1978, 19,
4127; (c) Sato, K.; Nakayama, T.; Mori, K. Agric. Biol.
Chem. 1979, 43, 1571.
S. No.
Acetylenic
aldehyde
Activated
alkene
Yielda (%)
1
2
3
4
5
6
7
8
9
1
2
3
1
2
3
1
2
3
4
4
4
5
5
5
6
6
6
7a, 74
8a, 80
9a, 75
7b, 67
8b, 59
9b, 61
7c, 58 (30% de)b
8c, 64 (44% de)b
9c, 72 (24% de)b
a Yields of isolated products.
b As determined by 1H NMR.
7. Chan, K. K.; Cohen, N. C.; Denoble, J. P.; Specian, A.
C.; Saucy, G. J. Org. Chem. 1976, 41, 3497.
8. Patridge, J. J.; Chandha, N. K.; Uskokovic, M. R. J. Am.
Chem. Soc. 1973, 95, 7171.
9. Kluge, A. F.; Kertesz, D. J.; Yang, C. O.; Wu, H. Y. J.
Org. Chem. 1987, 52, 2860.
10. Ramachandran, P. V.; Rudd, M. T.; Ram Reddy, M. V.
Tetrahedron Lett. 1999, 40, 3819.
11. Medvedeva, A. S.; Demina, M. M.; Novopashin, P. S.;
Sarapulova, G. I.; Afonin, A. V. Mendeleev Commun.
2002, 110.
with aromatic aldehydes. It is pertinent to mention that
the earlier study resulted in establishing the stereochem-
istry as R by chemical correlation with an indepen-
dently synthesized optically pure compound. Similarly,
the absolute stereochemistry at the newly created center
of the major isomer of all adducts obtained in the
present study was assigned as (R)-7c, (R)-8c and (R)-
9c.
12. (a) Rama Rao, A. V.; Khrimian, A. P.; Radha Krishna,
P.; Yadagiri, P.; Yadav, J. S. Synth. Commun. 1988, 18,
2325; (b) Rama Rao, A. V.; Radha Krishna, P.; Yadav,
J. S. Tetrahedron Lett. 1989, 30, 1669.
13. (a) Radha Krishna, P.; Kannan, V.; Ilangovan, A.;
Sharma, G. V. M. Tetrahedron: Asymmetry 2001, 12, 829;
(b) Radha Krishna, P.; Kannan, V.; Sharma, G. V. M.;
Ramana Rao, M. H. V. Synlett 2003, 888.
In conclusion, it has successfully been demonstrated
that acetylenic aldehydes can be used in Baylis–Hillman
reactions for the synthesis of allyl propargyl alcohols.
The asymmetric version of this reaction using other
chiral acrylates is currently under investigation.
Acknowledgements
14. Senanayake, C. H.; Fang, K.; Grover, P.; Bakale, R. P.;
Vandenbossche, C. P.; Wald, S. A. Tetrahedron Lett.
1999, 40, 819.
The authors acknowledge Drs. J.S. Yadav and G.V.M.
Sharma for their keen interest in this work. E.R.S. and
V.K. acknowledge the financial support from the CSIR,
New Delhi, India.
15. Brandsma, L. Preparative Acetylenic Chemistry, 2nd ed.;
Elsevier Science: Amsterdam, 1988; p. 92.
16. General experimental procedure: To the acetylenic alde-
hyde (1 mmol) in DMSO (1 mL), DABCO (0.5 mmol)
and activated alkene (1.2 mmol) were added and the
reaction mixture stirred for 15 h at room temperature.
Then the reaction mixture was partitioned between ether
(3×15 mL) and water (25 mL), the collected organic layer
References
1. Midland, M. M.; Lee, P. E. J. Org. Chem. 1981, 46, 3934.

P. Radha Krishna et al. / Tetrahedron Letters 44 (2003) 4973–4975
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was washed with brine (30 mL), dried (Na2SO4) and
concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, 60–120
mesh, EtOAc:hexane, 1:9) to afford adducts 7a–c, 8a–c and
9a–c in 58–80% yield.
olefinic), 6.00 (s, 1H, olefinic), 5.62 (s, 1H, allylic), 2.38 (s,
3H, -CH3); FABMS: m/z 202 (M++2). Anal. calcd for
C13H12O2: C, 77.98, H, 6.04. Found: C, 77.87, H, 6.06. 7c.
[h]D=−20.73 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3,
TMS): l 7.52–7.24 (m, 5H, Ar-H), 6.37 (s, 0.65H, olefinic),
6.35 (s, 0.35H, olefinic), 6.24 (s, 0.65H, olefinic), 6.08 (s,
0.35H, olefinic), 5.80 (d, 1H, J=4.2 Hz, H-1), 5.42 (s,
0.65H, allylic), 5.27 (s, 0.35H, allylic), 5.24 (d, 1H, J=2.5
Hz, H-3), 4.58 (d, 0.65H, J=4.2 Hz, H-2), 4.54 (d, 0.35H,
J=4.2 Hz, H-2), 4.24–4.16 (m, 2H, H-4, 5), 4.08–3.94 (m,
2H, H-6,6%), 1.50 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.24 (s,
6H, 2×CH3); FABMS: m/z 444 (M+). Anal. calcd for
C24H28O8: C, 64.85, H, 6.35. Found: C, 64.79, H, 6.27.
1
17. Spectral data for selected compounds: 7a. H NMR (300
MHz, CDCl3, TMS): l 7.50–7.40 (m, 2H, Ar-H), 7.38–7.25
(m, 3H, Ar-H), 6.34 (s, 1H, olefinic), 6.18 (s, 1H, olefinic),
5.39 (s, 1H, allylic), 4.30 (q, 2H, J=7.5 Hz, -CH2-), 3.12
(br. s, 1H, -OH), 1.40 (t, 3H, J=7.5 Hz, -CH3); FABMS:
m/z 229 (M+−1). Anal. calcd for C14H14O3: C, 73.03, H,
1
6.13. Found: C, 73.15, H, 6.08. 7b. H NMR (300 MHz,
CDCl3, TMS): l 7.48–7.29 (m, 5H, Ar-H), 6.80 (s, 1H,