Tandem molybdenum catalyzed hydrosilylations: An expedient synthesis of β-aryl aldehydes

Article abstract of DOI:10.1021/ol701812w

The synthesis of β-aryl aldehydes utilizing a tandem molybdenum catalyzed hydrosilylation is described. This new functional group interconversion provides an efficient method for the two-carbon homologation of aryl aldehydes.

Full text of DOI:10.1021/ol701812w

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4259-4261
Tandem Molybdenum Catalyzed
Hydrosilylations: An Expedient
Synthesis of
â-Aryl Aldehydes
Christopher G. Frost* and Benjamin C. Hartley
Department of Chemistry, UniVersity of Bath, Bath, BA2 7AY, U.K.
c.g.frost@bath.ac.uk
Received July 27, 2007
ABSTRACT
The synthesis of
â-aryl aldehydes utilizing a tandem molybdenum catalyzed hydrosilylation is described. This new functional group interconversion
provides an efficient method for the two-carbon homologation of aryl aldehydes.
The transition-metal-catalyzed hydrosilylation of R,â-
unsaturated esters is a well-developed and important method
in organic synthesis.1 Of notable interest is the subsequent
functionalization of the derived silylketene acetal in tandem
processes.2 Of the various transition metal reagents known
to promote this type of transformation, the air-stable,
commercially available, and inexpensive complex Mo(CO)6
is appealing yet surprisingly rarely used. Keinan and Perez
first reported the application of phenylsilane and catalytic
amounts of Mo(CO)6 in the hydrosilylation of a wide-range
of Michael acceptors including R,â-unsaturated ketones,
carboxylic acids, carboxylic esters, amides, and nitriles.3
During a recent study into the activation of Mo(CO)6 by
the oxidative removal of carbonyl ligands, we attempted the
catalytic hydrosilylation of the R,â-unsaturated Meldrum’s
acid derivative 1a in the presence of N-methylmorpholine-
N-oxide (NMO). After quenching with water, none of the
expected product 2a was observed. Interestingly, we isolated
the â-aryl aldehyde 3a as the sole product of the reaction in
excellent yield (Scheme 1). Given the ready availability of
(1) For leading references, see: (a) Keinan, E.; Greenspoon, N. J. Am.
Chem. Soc. 1986, 108, 7314. (b) Takeshita, K.; Seki, Y.; Kawamoto, K.;
Murai, S.; Sonoda, N. J. Org. Chem. 1987, 52, 4864. (c) Doyle, M. P.;
Devora, G. A.; Nefedov, A. O.; High, K. G. Organometallics 1992, 11,
549. (d) Zheng, G. Z.; Chan, T. H. Organometallics 1995, 14, 70. (e) Ito,
H.; Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett.
1997, 38, 8887. (f) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R.
Tetrahedron Lett. 1998, 39, 4627. (g) Appella, D. H.; Moritani, Y.; Shintani,
R.; Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473.
(2) (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b)
Kiyooka, S.; Shimizu, A. Tetrahedron Lett. 1998, 39, 5237. (c) Isayama,
S.; Mukaiyama, T. Chem. Lett. 1989, 2005. (d) Taylor, S. J.; Morken, J. P.
J. Am. Chem. Soc. 1999, 121, 12202. (e) Taylor, S. J.; Duffey, M. O.;
Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528. (f) Lipshutz, B. H;
Chrisman, W.; Noson, K.; Papa, P.; Sclafani, J. A.; Vivian, R. W.; Keith,
J. M. Tetrahedron 2000, 56, 2779. (g) Zhao, C. X.; Duffey, M. O.; Taylor,
S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829. (h) Baik, T.-G.; Luis, A. L.;
Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc. 2001, 123, 5112. (i) Wang,
L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang, X.; Krische,
M. J. J. Am. Chem. Soc. 2002, 124, 9448. (j) For a review and further
leading references, see: Huddleston, R. R.; Krische, M. J. Synlett 2003,
12. (k) Fuller, N. O.; Morken, J. P. Synlett 2005, 1459. (l) Nishiyama, H.;
Siomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am. Chem. Soc. 2005, 127, 6972.
(m) Lam, H.-W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225. (n) Lam, H.-W.;
Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743.
Scheme 1. The Catalytic Synthesis of â-Aryl Aldehydes
the substrates, the broad utility of the product â-aryl
aldehydes and the lack of precedent for this functional group
interconversion, we decided to investigate further. In this
(3) Keinan, E.; Perez, D. J. Org. Chem. 1987, 52, 2576.
10.1021/ol701812w CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/14/2007

communication, we present a mechanistic rationale for the
observed products and demonstrate the scope of this poten-
tially useful transformation.
Table 1. Synthesis of â-Aryl Aldehydes by Tandem
Molybdenum Catalyzed Hydrosilylationsa
To learn more about the sequence of events in the reaction,
the incorporation of deuterium as both nucleophile and
electrophile was investigated. The molybdenum catalyzed
hydrosilylation of R,â-unsaturated Meldrum’s acid derivative
1a with phenylsilane followed by quenching with deuterium
oxide afforded the R,R′-dideuterated product 4a (Scheme 2).
Scheme 2. Regioselective Incorporation of Deuterium
The use of trideuteriophenylsilane in the reduction followed
by treatment with water led to the formation of deuterio-
aldehyde 5a with the expected deuterium atom at the
â-carbon.4 The combination of trideuteriophenylsilane and
quenching with deuterium oxide yielded 6a with four
deuterium atoms being incorporated in a manner consistent
with the previous experiments. While these experiments were
carried out to elucidate a mechanism for the formation of
the aldehyde products, the highly regioselective incorporation
of deuterium to organic molecules (as in 4a and 5a) is also
of considerable value for biosynthesis and pharmacology
research and could be exploited further.5
A mechanism consistent with the deuterium labeling
studies is shown in Figure 1 (for the preparation of 5a). The
deuteriosilylation of R,â-unsaturated Meldrum’s acid deriva-
tive 1a with trideuteriophenylsilane would be expected to
furnish the â-deuterated dioxinone 7. On heating, rapid
cycloreversion occurs to reveal the ketene 8 which is
susceptible to attack by nucleophiles.6 It is proposed that
the ketene undergoes deuteriosilylation to afford enol silane
9. On quenching, a double protonation (or deuteration in the
a Reaction conditions: 1 (1.0 equiv), phenylsilane (3.0 equiv), Mo(CO)6
(5 mol %), N-methylmorpholine-N-oxide (10 mol %), THF, 80 °C, 16 h.
b Isolated yields. c With 2.0 equiv of phenylsilane. d No added N-methyl-
morpholine-N-oxide.
case of 4a and 6a) occurs with concomitant evolution of
carbon dioxide (confirmed by limewater test) to release the
aldehyde product 5a.
The established conditions did not yield to further opti-
mization. Other silanes (Ph2SiH2, Et3SiH, and PMHS) were
significantly less reactive, and reducing the number of
(4) (a) Ojima, I.; Kogure, T. Organometallics 1982, 1, 1390. (b) Keinan,
E.; Greenspoon, N. Tetrahedron Lett. 1985, 26, 1353. (c) Mori, A.; Fujita,
A.; Kajiro, H.; Nishihara, Y.; Hiyama, T. Tetrahedron 1999, 55, 4573. (d)
Otsuka, H.; Shirakawa, E.; Hayashi, T. Chem. Commun. 2007, 1819.
(5) (a) Fate, G. D.; Benner, C. P.; Grode, S. H.; Gilbertson, T. J. J. Am.
Chem. Soc. 1996, 118, 1163. (b) Sack, I.; Balazs, Y. S.; Rahimipour, S.;
Vega, S. J. Am. Chem. Soc. 2000, 122, 12263.
(6) (a) Sato, M.; Ogasawara, H.; Sekiguchi, K.; Kaneko, C. Heterocycles
1984, 22, 2563. (b) Sato, M.; Ogasawara, H.; Kato, T. Chem. Pharm. Bull.
1984, 32, 2602. (c) Sato, M.; Yoneda, N.; Katagiri, N.; Watanabe, H.;
Kaneko, C. Synthesis 1986, 672. (d) Sato, M.; Ban, H.; Kaneko, C.
Tetrahedron Lett. 1997, 38, 6689.
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In contrast, R,â-unsaturated Meldrum’s acid derivative 1d
with the p-NO2 group on the aryl ring was significantly less
reactive under the standard reaction conditions (Table 1, entry
6). This observation can be rationalized by the inductive
deactivation of the R,â-unsaturated Meldrum’s acid deriva-
tive to the initial hydrosilylation by the electron-withdrawing
p-NO2 group. However, if 1d is reduced to 2d using sodium
borohydride and then 2d is subjected to the hydrosilylation
conditions, the â-aryl aldehyde 3d is obtained in excellent
yield (Scheme 3). Under the described reaction conditions,
Scheme 3. Reduction of 5-Monosubstituted Meldrum’s Acid
Derivative 2d
silylation of 2d would be expected to occur followed by
cycloreversion and ketene hydrosilylation. The direct reduc-
tion of 5-monosubstituted Meldrum’s acid derivatives to
â-aryl aldehydes via hydrosilylation is of significant value
in addition to the presented tandem catalytic method.
In conclusion, we have developed an efficient synthesis
of â-aryl aldehydes from R,â-unsaturated Meldrum’s acid
derivatives (prepared from aryl aldehydes) employing a
tandem molybdenum catalyzed hydrosilylation reaction. A
plausible mechanism is proposed that suggests the reaction
proceeds via the hydrosilylation of a key ketene intermediate.
The tandem reaction can tolerate a broad range of functional
groups on the aryl ring to deliver elaborated products in good
yields. Overall, this is practical method for the two-carbon
homologation of aryl aldehydes.
Figure 1. Proposed mechanism of aldehyde formation.
equivalents of silane led to lower yields (Table 1, entry 1).
The omission of N-methylmorpholine-N-oxide was detri-
mental to the reaction (Table 1, entry 2), which corresponds
to the assumption that the active catalyst is a coordinatively
unsaturated Mo(THF)n(CO)6-n complex. Having established
the basis for a useful new functional group transformation,
we next explored the scope of the process with respect to
aryl substitution (Table 1). The required R,â-unsaturated
Meldrum’s acid derivatives (1a-h) were easily prepared by
a Knoevenagel condensation of an aryl aldehyde and
Meldrum’s acid in water.7 The yields were consistently good
for a range of substrates that possess electron-donating
substituents on the aryl ring. Of particular note is the
successful tandem catalytic synthesis of â-aryl aldehydes
containing thiomethyl, dimethylamino, and trimethoxy func-
tional groups on the aryl ring (Table 1, entries 4, 5, and 10).
Acknowledgment. This work was supported by the
EPSRC. 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.
(7) (a) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori,
G. Tetrahedron Lett. 2001, 42, 5203. (b) Maggi, R.; Bigi, F.; Carloni, S.;
Mazzacani, A.; Sartori, G. Green Chem. 2001, 3, 173. (c) Frost, C. G.;
Penrose, S. D.; Lambshead, K.; Raithby, P. R.; Warren, J. E.; Gleave, R.
Org. Lett. 2007, 9, 2119.
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