Chelation-controlled intermolecular alkene and alkyne hydroacylation: The utility of β-thioacetal aldehydes

Article abstract of DOI:10.1021/ol050638l

(Chemical Equation Presented) β-Thioacetal-substituted aldehydes, which are conveniently prepared from the corresponding ynals, can be combined with a range of alkynes or electron-poor alkenes to deliver intermolecular hydroacylation adducts. The reactions employ [Rh(dppe)]ClO₄ as a catalyst and are proposed to proceed via a chelated rhodium acyl intermediate. The thioacetal-containing products can be deprotected to the corresponding ketones or reduced to alkanes in good yields.

Full text of DOI:10.1021/ol050638l

ORGANIC
LETTERS
2
005
Vol. 7, No. 11
249-2251
Chelation-Controlled Intermolecular
Alkene and Alkyne Hydroacylation:
2
The Utility of
â-Thioacetal Aldehydes
Michael C. Willis,*,† Helen E. Randell-Sly, Robert L. Woodward, and
†
†
‡
Gordon S. Currie
Department of Chemistry, UniVersity of Bath, Bath, BA2 7AY, UK, and AstraZeneca,
Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
m.c.willis@bath.ac.uk
Received March 24, 2005
ABSTRACT
â
-Thioacetal-substituted aldehydes, which are conveniently prepared from the corresponding ynals, can be combined with a range of alkynes
or electron-poor alkenes to deliver intermolecular hydroacylation adducts. The reactions employ [Rh(dppe)]ClO as a catalyst and are proposed
4
to proceed via a chelated rhodium acyl intermediate. The thioacetal-containing products can be deprotected to the corresponding ketones or
reduced to alkanes in good yields.
Transition metal-catalyzed hydroacylation reactions, in which
an aldehyde is added across a C-C multiple bond, have the
potential to be useful methods for the synthesis of ketone-
containing products. Although intramolecular versions of the
reaction have been employed successfully for the synthesis
which preferentially undergo decarbonylation processes.
Stabilization of these intermediates by chelation has emerged
as a potential solution; in efforts to develop a synthetically
5
useful chelation-controlled intermolecular hydroacylation
system, we recently reported that â-methyl sulfide-substituted
aldehydes were efficient substrates for combination with a
range of electron-poor alkenes under the action of Rh(I)
1
,2
of a range of cyclopentanone systems, the synthesis of
3
larger ring systems and intermolecular reactions remain
4
6
significantly more challenging. The main obstacle with these
catalysis (Scheme 1). Although the methyl sulfide group
systems is the instability of the metal-acyl intermediates,
functions as a coordinating substituent, the opportunities for
modification of the group after the hydroacylation reaction
were relatively limited. To expand the synthetic utility of
†
7
University of Bath.
‡
AstraZeneca.
(
1) For an example of stoichiometric cyclopentanone synthesis, see:
Sakai, K.; Ide, J.; Oda, O.; Nakamura, N. Tetrahedron Lett. 1972, 1287-
290.
2) For selected recent examples of catalytic cyclopentanone synthesis,
see: (a) Gable, K. P.; Benz, G. A. Tetrahedron Lett. 1991, 32, 3473-
476. (b) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 936-945.
c) Sattelkau, T.; Eilbracht, P. Tetrahedron Lett. 1998, 39, 9647-9648.
(4) For Rh-based systems used in combination with CO or ethylene
atmopspheres, see: (a) Schwartz, J.; Cannon, J. B. J. Am. Chem. Soc. 1974,
96, 4721-4723. (b) Vora, K. P.; Lochow, C. F.; Miller, R. G. J. Organomet.
Chem. 1980, 192, 257-264. (c) Isnard, P.; Denise, B.; Sneeden, R. P. A.;
Cognio, J. M.; Dural, P. J. Organomet. Chem. 1982, 240, 285-288. (d)
Vora, K. P. Synth. Commun. 1983, 13, 99-102. (e) Marder, T. B.; Roe, D.
C.; Milstein, D. Organometallics 1988, 7, 1451-1453. For Ru-based
systems, see: (f) Kondo, T.; Tsuji, Y.; Watanabe, Y. Tetrahedron Lett.
1987, 28, 6229-6230. (g) Kondo, T.; Akazome, M.; Tsuji, Y.; Watanabe,
Y. J. Org. Chem. 1990, 55, 1286-1291. (h) Kondo, T.; Hiraishi, N.;
Morisaki, Y.; Wada, K.; Watanabe, Y.; Mitsudo, T.-A. Organometallics
1998, 17, 2131-2134. For a Co-based method, see: (i) Lenges, C. P.;
Brookhart, M. J. Am. Chem. Soc. 1997, 119, 3165-3166. (j) Lenges, C.
P.; White, P. S.; Brookhart, M. J. Am. Chem. Soc. 1998, 120, 6965-6979.
Also see ref 4a.
1
(
3
(
For examples of enantioselective cyclisations, see: (d) Ducray, P.; Rousseau,
B.; Mioskowski, C. J. Org. Chem. 1999, 64, 3800-3801. (e) Bosnich, B.
Acc. Chem. Res. 1998, 31, 667-674 and references therein. (f) Tanaka,
M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.; Wu,
X. M.; Funakoshi, K.; Sakai, K.; Suemune, H. J. Org. Chem. 2000, 65,
5
806-5816 and references therein.
3) (a) Aloise, A. D.; Layton, M. E.; Shair, M. D. J. Am. Chem. Soc.
000, 122, 12610-12611. (b) Sato, Y.; Oonishi, Y.; Mori, M. Angew.
(
2
Chem., Int. Ed. 2002, 41, 1218-1221.
1
0.1021/ol050638l CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/03/2005

Scheme 1. S-Chelate-Controlled Alkene Hydoacylation
Table 1. Intermolecular Hydroacylation: Scope of the
Thioacetal-Substituted Aldehyde
a,b
the process, we wished to design a series of aldehyde
substrates that maintained the same stabilizing five-mem-
bered S-chelate yet offered more flexibility for synthetic
elaboration. In this Letter, we document that â-thioacetal-
substituted aldehydes fulfill these requirements.
The synthetic utility of thioacetals is well established; in
particular, they are regularly employed as carbonyl sur-
8
rogates, with a variety of hydrolysis methods available. In
addition, conditions to convert thioacetals directly to alcohols,
carboxylic acids, and alkanes are well-known. â-Thioacetal-
substituted aldehydes were thus attractive compounds to
investigate as hydoacylation substrates. The required alde-
hydes were readily available from a double conjugate
addition of a dithiol to the corresponding ynal or indirectly
via addition to an ynoate followed by reduction.9
,10
Reaction of the simple dithiane- and dithiolane-substituted
propanals with methyl acrylate under the same mild condi-
tions ([Rh(dppe)]ClO
4
, DCE, 50 °C)11 employed for the
methyl sulfide-substituted aldehydes delivered the required
hydroacylation adducts as single regioisomers in good yield
(Table 1, entries 1 and 2). It is interesting to note that methyl
sulfide-substituted propanal delivered the corresponding
methyl acrylate adduct as a 5:1 mixture of linear and
branched regioisomers. We attribute the greater selectivity
observed with the thioacetal-substituted aldehydes to the
increased steric demands around the chelating S-atom.
Having established that â-thioacetals serve as suitable
chelating groups, we explored the range of additional
functionality that could be tolerated in the aldehyde. Simple
alkyl substituents, chloro-alkyl and acetal-protected alcohols
a
Reaction conditions: aldehyde (1.0 equiv), methyl acrylate (5.0 equiv),
b
[
Rh(dppe)]ClO4 (10 mol %), acetone, 50 °C. Catalyst generated in situ
6
from [Rh(dppe)(nbd)]ClO4 and H2. Isolated yields. d Only linear isomers
c
observed.
were all tolerated well, delivering linear adducts in good
yields (entries 3-5). Reactions employing substituted alde-
hydes required longer reaction times to reach completion,
and the aldehyde bearing a phenyl substituent provided too
significant a steric barrier, with no reaction being observed
(entry 6). Finally, the use of a bis-aldehyde allowed a double
hydroacylation to provide the corresponding diketone in
excellent yield (entry 7).
(
5) (a) Suggs, J. W. J. Am. Chem. Soc. 1978, 100, 640-641. (b) Bendorf,
H. D.; Colella, C. M.; Dixon, E. C.; Marchetti, M.; Matukonis, A. N.;
Musselman, J. D.; Tiley, T. A. Tetrahedron Lett. 2002, 43, 7031-7034.
(
2
c) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem. Eur. J. 2002, 8, 2423-
428. (d) Jun, C. H.; Lee, J. H. Pure Appl. Chem. 2004, 76, 577-587 and
references therein. (e) Bendorf, H. D.; Colella, C. M.; Dixon, E. C.;
Marchetti, M.; Matukonis, A. N.; Musselman, J. D.; Tiley, T. A. Tetrahedron
Lett. 2002, 43, 7031-7034. (f) Tanaka, M.; Imai, M.; Yamamoto, Y.;
Tanaka, K.; Shimowatari, M.; Nagumo, S.; Kawahara, N.; Suemune, H.
Org. Lett. 2003, 5, 1365-1367. (g) Imai, M.; Tanaka, M.; Tanaka, K.;
Yamamoto, Y.; Imai-Ogata, N.; Shimowatari, M.; Nagumo, S.; Kawahara,
N.; Suemune, H. J. Org. Chem. 2004, 69, 1144-1150.
We next explored the scope of the process with respect to
the alkene component; the simple alkyl-substituted aldehyde
was employed as a standard (Table 2). In analogy to the
methyl sulfide-aldehydes, simple acrylates and amides were
accommodated well (entries 1-3). A lower reactivity toward
electronically neutral alkenes such as octene was observed,
with only trace amounts of product being isolated (entry 4).
However, the process was far more tolerant of electronically
(
6) Willis, M. C.; McNally, J. S.; Beswick, P. J. Angew. Chem., Int. Ed.
004, 43, 340-343.
7) Elimination of the methyl sulfide group was possible by simple
treatment with MeOTf and KHCO3.
8) For a review on the applications of 1,3-dithianes in synthesis, see:
Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147-6212.
9) (a) Gaunt, M. J.; Sneddon, H. F.; Hewitt, P. R.; Orsini, P.; Hook, D.
2
(
(
12
varied alkynes, with both electron-poor (entry 5) and
(
-neutral systems delivering the required adducts in good
yields (entry 6). Significant variation in alkyne structure was
possible, with chloro- and cyano-substituted examples per-
forming well (entries 7 and 8). Interestingly, the cyano-
substituted alkyne delivers exclusively the branched hydro-
acylation adduct, possibly resulting from interaction of the
F.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 15-16. (b) Sneddon, H. F.;
Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5, 1147-1150. (c) Kuroda, H.;
Tomita, I.; Endo, T. Synth. Commun. 1996, 26, 1539-1543. (d) Ranu, B.
C.; Bhar, S.; Chakraborti, R. J. Org. Chem. 1992, 57, 7349-7352.
(
10) See Supporting Information for details.
(11) See ref 6 for evaluation of various catalysts and reaction conditions
using the MeS-substituted aldehyde.
2250
Org. Lett., Vol. 7, No. 11, 2005

however, lower loadings are possible. For example, the
reaction between dithiane-substituted propanal and methyl
acrylate (Table 1, entry 1) using 2.5 mol % catalyst delivers
Table 2. Intermolecular Hydroacylation: Scope of Alkene or
Alkyne Componenta,b
7
8% product after 24 h at 50 °C. The same reaction
employing 1.0 mol % catalyst provides 70% product after
8 h.
Finally, to demonstrate the potential synthetic utility of
the hydroacylation adducts, thioacetal 1 was treated with
NBS/AgNO to deliver diketone 2 or alternatively reduced
4
3
with Raney nickel to generate ketone 3 (Scheme 2).
Scheme 2. Modification of Thioacetal 1
In conclusion, we have demonstrated that synthetically
flexible â-thioacetal-substituted aldehydes are efficient sub-
strates for intermolecular rhodium-catalyzed hydroacylation
of alkenes and alkynes. Reactions are conducted under mild
conditions, can tolerate a variety of reactive functionality
and deliver highly functionalized products. The adducts are
obtained in good yields and in general with high levels of
regioselectivity. The greater reactivity of alkynes allows
disubstituted (internal) examples to be employed.
Acknowledgment. This work was supported by the
EPSRC and AstraZeneca. The EPSRC Mass Spectrometry
Service at the University of Wales Swansea is also thanked
for their assistance.
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a
Reaction conditions: aldehyde (1.0 equiv), alkene or alkyne (5.0 equiv),
b
[
Rh(dppe)]ClO4 (10 mol %), acetone, 50 °C. Catalyst generated in situ
from [Rh(dppe)(nbd)]ClO4 and H2. Isolated yields. Only linear isomers
observed. Performed with 5.0 mol % catalyst. Isolated as a 4:1 mix of
E:Z isomers (major isomer shown). Isolated as a 3:1 mix of Z:E isomers.
c
d
e
f
g
OL050638L
cyano group with the rhodium center. The final two examples
demonstrate that internal alkynes are also excellent hydro-
acylation substrates, with the final entry also illustrating the
tolerance of the process toward hydroxyl functionality.
To achieve convenient reaction times, all of the examples
described involving alkene substrates employed 10 mol %
catalyst, while alkyne substrates used 5 mol % catalyst,
(
12) For an example of intramolecular alkyne hydroacylation, see: (a)
Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 11492-11493.
Intramolecular enantioselective alkyne hydroacylation: (b) Tanaka, K.; Fu,
G. C. J. Am. Chem. Soc. 2002, 124, 10296-10297. For intermolecular
alkyne hydroacylation, see: (c) Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org.
Chem. 1990, 55, 2554-2558. (d) Kokubo, K.; Matsumasa, K.; Nishinaka,
Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 303-311. (e)
Lee, D.-Y.; Hong, B.-S.; Cho, E.-G.; Lee, H.; Jun, C.-H. J. Am. Chem.
Soc. 2003, 125, 6372.
Org. Lett., Vol. 7, No. 11, 2005
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