Thiol addition to aryl propargyl alcohols under mild conditions: An accelerating neighboring group effect

Article abstract of DOI:10.1016/S0040-4039(99)02040-7

Aryl alkynols provide a convenient entry into α-hydroxyketones via thiol addition followed by hydrolysis. Thiols have been added to several non- activated alkynes under mild, basic conditions. A coordinating functional group in close proximity to the triple bond facilitates this reaction.

Full text of DOI:10.1016/S0040-4039(99)02040-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 141–144
Thiol addition to aryl propargyl alcohols under mild conditions:
an accelerating neighboring group effect
Marjorie See Waters,∗ Jennifer A. Cowen, J. Christopher McWilliams, Peter E. Maligres and
David Askin
Department of Process Research, Merck Research Laboratory, Merck & Co. Inc., PO Box 2000, Rahway, New Jersey 07065,
USA
Received 15 October 1999; accepted 28 October 1999
Abstract
Aryl alkynols provide a convenient entry into α-hydroxyketones via thiol addition followed by hydrolysis. Thiols
have been added to several non-activated alkynes under mild, basic conditions. A coordinating functional group in
close proximity to the triple bond facilitates this reaction. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: vinyl sulfides; propargylic alcohols; neighboring group effects; hydroxyketones.
α-Hydroxy ketones are versatile intermediates in the synthesis of biologically active compounds,
heterocycles, and pharmaceutical products. These compounds have previously been prepared by the
selective oxidation of 1,2-diols,1 often in low yields. Hydroxy ketones have also been prepared from
alkenes by treatment with an oxidizing agent and catalytic osmium2 and with permanganate in acetic
acid.3 In addition, they have been prepared by the rearrangement of α-hydroxy epoxides with palladium.4
We required hydroxymethyl-α-aryl ketones of the general structure 3 as pharmaceutical intermediates,
and sought a method that would not require harsh oxidative conditions. Specifically, we were interested
in the 4-cyanobenzyl ketone 3b (R_CN).
Recently, α-aryl ketones were prepared by the palladium catalyzed arylation of ketones under mild
basic conditions; selective reactions were observed with several alkyl and aryl methyl ketones.5 Unfor-
tunately, we found that α-hydroxy ketones were not good substrates with this method, resulting in no
reaction or complex mixtures. Alkynols 1, already in the required oxidation state, are readily available
via Castro–Stephens6 coupling of the acetylenes with aryl halides; thus the regioselective formal addition
of water to 1 would provide the desired hydroxy ketones 3.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02040-7
tetl 15968

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Since addition of water directly to an alkyne typically requires the use of heavy metal catalysts such
as mercury or palladium salts,7 an indirect hydration method was sought. Both alkyl and aryl thiols have
been shown to add to alkynes to give vinyl sulfides. With activated alkynes such as α,β-acetylenic esters
and ketones, the addition has been performed under basic conditions, using reagents such as KOH8 and
triethylamine.9 However, for unactivated alkynes, radical initiators,10 transition metal catalysts11 and
high temperatures12 have been required. In our work, we have found that under mild, basic conditions
thiols add to unactivated aryl alkynols 1, facilitated by a neighboring group effect.13 The vinyl sulfides
can then be hydrolyzed under a variety of conditions to provide the desired hydroxy-ketone.14
We anticipated that the cyanophenyl alkyne 1b would be sufficiently electron deficient to allow facile
nucleophilic addition of a thiol to the alkyne. Reaction of 1b with n-butanethiol and NaOH in acetonitrile
at room temperature gave the vinyl sulfide 2b in 90% yield. Remarkably, reaction of 1a bearing only
a phenyl group without a strongly electron withdrawing functionality with butanethiol and NaOH in
acetonitrile at 75°C gave the vinyl sulfide 2a in 86% yield.15 As in previous reports, in both cases we saw
almost exclusively the Z product in the crude 1H NMR (6.8 ppm Z, 6.4 ppm E). In addition, we saw very
high selectivity (100:1) for addition of the thiol β to the phenyl group. The vinyl sulfides 2a and 2b were
then hydrolyzed using 0.4 M H2SO4 in 4:1 ethanol/water at 50°C overnight,16 giving 1-hydroxy-3-aryl-
propan-2-one (3a and 3b) in 83 and 85% yields respectively. The unanticipated ease of thiol addition
to 1a prompted us to study the scope of the reaction with several substituted alkynes.17 The results are
shown in Table 1.
The more electron deficient alkyne (1c) reacted with butanethiol exothermically even at room tempe-
rature, with the thiol adding exclusively β to the aryl group. However, the less electron deficient alkyne
(1d) required 5 h at 75°C to react and was slightly less selective in the β/α ratio. Increased branching
at the carbon bearing the hydroxyl group (1e and 1f) lead to reduced reactivity. In the tertiary alcohol
case, fragmentation to the ketone and acetylide became the major pathway. Surprisingly, even when the
moderately electron-withdrawing aryl group was absent, reaction with butanethiol still occurred under
the mild, basic conditions. Addition of butanethiol to 2-butyn-1-ol (1g) gave 70% conversion after 24
h with only moderate β/α selectivity. With butynediol 1h, the reaction was complete in only 3 h; in
contrast, addition to phenylbutyne 1i led to only 7% conversion by 1H NMR after 24 h.13 This profound
difference in reactivity shows that the presence of the neighboring alcohol group has a significant effect
in the thiolation of alkynes. The data indicates that the neighboring group is relatively weak in directing
the regiochemistry, but is clearly accelerating the reaction.
A possible mechanistic explanation for the acceleration in which the alcohol group coordinates with
the metal of BuS−Na+ is indicated below. Interestingly, when butanethiol was added to 1a with CsOH
or KOH as the base, the reaction was complete in 20 min,18 NaOH required 90 min, and with LiOH the
reaction required over 24 h. The identity of the base had no significant effect on the yield and the Z/E and
β/α selectivity.
Increasing the distance between the alcohol group and the alkyne through methylene spacers also
reduced the reactivity (1j and 1k); nevertheless, both products were isolated after completion in good
yields. Phenyl alkynes with other functional groups that can provide coordination to a metal cation
showed good reactivity with butanethiol (1l and 1m).19 In conclusion, aryl alkynols provide a convenient
entry into aryl ketones via the vinylic sulfides, avoiding the use of strong oxidizing agents. The base

143
Table 1
Addition of thiols to alkynesa
catalyzed addition of thiols to alkynes takes place under mild conditions due to acceleration by the
neighboring hydroxyl group.
Acknowledgements
We wish to thank Peter Dormer for his NMR support.
References
1. Sakata, Y.; Ishii, Y. J. Org. Chem. 1991, 56, 6233–6235. Navarro, M.; De Giovani, W. F.; Romero, J. R. Tetrahedron 1991,
47, 851–857. Rozen, S.; Bareket, Y.; Kol, M. Tetrahedron 1993, 49, 8169–8178.

144
2. Murahashi, S. I.; Naota, T.; Hanaoka, H. Chem. Lett. 1993, 10, 1767–1770. Takai, T.; Yamada, T.; Mukaiyama, T. Chem.
Lett. 1991, 9, 1499–1502.
3. Srinivasan, N. S.; Lee, D. G. Synthesis 1979, 520–521.
4. Vankar, Y. D.; Chaudhuri, N. C.; Singh, S. P. Synthetic Commun. 1986, 16, 1621–1626. Kulasegaram, S.; Kulawiec, R. J. J.
Org. Chem. 1994, 59, 7195.
5. Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108–11109. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc.
1997, 119, 12382–12383.
6. Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163; Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28,
3313–3315.
7. Hudrlik, P. F.; Hudrlik, A. M. In The Chemistry of the Carbon–Carbon Triple Bond; Patai, Ed.; John Wiley & Sons: 1978;
Part 1, Chapter 7. Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 3127–3130.
8. Wadsworth, D. H.; Detty, M. R. J. Org. Chem. 1980, 45, 4611–4615. Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1974,
705–708.
9. Dieter, R. K.; Silks, L. A. III; Fishpaugh, J. R.; Kastner, M. E. J. Am. Chem. Soc. 1985, 107, 4679–4692.
10. Galambos, G.; Csokasi, P.; Szantay, C. J.; Czira, G.; Szantay, C. Heterocycles 1994, 38, 1459–1464. Montevecchi, P. C.;
Navacchia, M. L. Tetrahedron Lett. 1998, 39, 9077–9080.
11. Kuniyasu, H.; Ogawa, A.; Sato, K. I.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1992, 114, 5902–5903. Ishino, Y.; Masaoka,
T.; Hirashima, T. Chem. Lett. 1990, 7, 1185–1188. Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem. Soc. 1999, 121,
5108–5114.
12. Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin Trans. 1 1991, 9, 2103–2109.
13. On a similar system, Schroth found that phenylmethanethiol added to 1-(2-thiomethoxy)-phenyl-1-propyn-3-ol using KOH
in DMF, while addition of the same thiol to an alkyne in which the alcohol is replaced by a methyl group required heating
to reflux with KOH and 18-crown-6 in benzene/water: Schroth, W.; Jordan, H.; Spitzer, R. Tetrahedron Lett. 1995, 36,
1421–1424.
14. Grobel, B.; Seebach, D. Synthesis 1977, 357–402.
15. Preparation of 2a: 1-Phenyl-1-propyn-3-ol (0.67 g, 5.0 mmol) and powdered NaOH (0.21 g, 5.2 mmol) were combined in
5 mL of MeCN. Butanethiol (0.70 mL, 6.5 mmol) was added via syringe. The slurry was heated to 75°C for 3 h. The crude
reaction was concentrated to a dark orange oil. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes)
to provide 2a as a colorless oil (0.96 g, 86% yield): 1H NMR (250 MHz, CDCl3) δ 7.63–7.24 (m, 5H), 6.82 (s, 1H), 4.35 (s,
2H), 2.77 (t, 2H, 7.26 Hz), 2.28 (s, 1H), 1.53 (m, 2H), 1.36 (m, 2H), 0.87 (t, 3H, 7.26 Hz); 13C NMR (62.5 MHz, CDCl3)
δC 136.2, 135.6, 129.6, 129.4, 128.1, 127.3, 68.8, 31.9, 30.9, 21.9, 13.6.
16. Preparation of 3a: Compound 2a (0.24 g, 1.1 mmol) was diluted with 4 mL of a stock solution of 4:1 ethanol/1N H2SO4.
The biphasic mixture was heated to 50°C forming a homogenous solution which was stirred for 16 h at 50°C. The solution
was cooled to room temperature and brine (5 mL) added. The organic layer was separated and concentrated to a yellow oil.
The residue was purified by flash chromatography (silica gel, chloroform) to give 3a as a colorless solid (0.14 g , 83% yield):
1H NMR (250 MHz, CDCl3) δ 7.35–7.19 (m, 5H), 4.28 (s, 2H), 3.72 (s, 2H), 3.08 (s, 1H); 13C NMR (62.5 MHz, CDCl3) δ
207.4, 132.8, 129.3, 128.9, 127.5, 67.7, 45.8.
17. Many of the alkynes used were commercially available from Aldrich (1i, 1h), Acros (1g), Lancaster (1a, 1e), Chemsampco
(1f), TCI (1k), RBI (1m) and Maybridge (1b, 1c). The methyl ether (1l) was prepared from 1a by reaction with MeI and
NaH. Compound 1j was prepared by Castro–Stephens coupling of bromobenzene with 3-butyn-1-ol (PdCl2, CuI, PPh3,
and butylamine in MTBE at 50°C). Compound 1d was prepared by reaction of lithium 4-methoxy-phenylacetylide with
formaldehyde in THF.
18. Further optimization of the reaction conditions was performed after the experiments with alkynes 1a–1m with regard to
reaction time. The ideal conditions for the preparation of 2b are as follows: 1-(4-Cyano)-phenyl-1-propyn-3-ol (7.86 g, 50.0
mmol) and 45% KOH (1.28 g, 10.2 mmol) were combined in 50 mL of MeCN at 20°C. n-Butanethiol (7.0 mL, 64 mmol)
was added via syringe over 30 min with a slight exotherm. After 1 h the crude reaction was concentrated to a dark orange
oil. The residue was purified by flash chromatography (silica gel, t-BuOMe/hexanes) to provide 2b as a colorless oil (11.7
g, 95%).
19. Phenylpropiolic acid shows very high reactivity with reaction complete in only 2 h, giving the α product exclusively, as
would be expected due to the relatively more electron deficient character of the carboxylic acid.