SCHEME 3. Triethylamine-Promoted Reduction of Cyclic
Malonates
SCHEME 5. Ketene Hydrosilylation Mechanistic Proposal
SCHEME 4. Triethylamine-Promoted Reduction of Cyclic
Malonates
of cyclic malonates to provide a convenient synthesis of
ꢀ-substituted aldehydes and γ-substituted propylamines.
Initially, the hydrosilylation of 5-(4-methoxybenzyl)-2,2-
dimethyl-1,3-dioxane-4,6-dione (3b) was examined in the
presence of various Lewis bases and organosilanes. We were
pleased to note that when 3b was exposed to a mixture of
triethylamine and phenylsilane in THF followed by hydrolysis
the desired aldehyde 2b was obtained in good yield, 84%
(Scheme 3). No aldehyde was observed when less reactive
silanes were employed (Et3SiH, (EtO)2MeSiH, and PMHS) and
only a low conversion (<10%) was achieved with trichlorosi-
lane. Similarly, no reaction was detected in the absence of amine
base. Using substoichiometric amounts of triethylamine led to
lower conversions to product (49% with 0.5 equiv). 4-(N,N-
Dimethylamino)pyridine (DMAP) and N-methylmorpholine
N-oxide (NMO) provided similar results to triethylamine. Other
amines proved less effective in this reaction while N,N-
dimethylformamide, dimethyl sulfoxide, triphenylphosphine, and
K2CO3 all gave no conversion to product.8
We propose that triethylamine has two roles in this process:
first, substrate deprotonation leading to R-oxoketene formation,
and second, the activation of phenylsilane enabling ketene
hydrosilylation.
To gain insight into the reaction mechanism, isotopic labeling
studies were carried out with deuterium as both an electrophile
and a nucleophile (Scheme 4). Reaction of Meldrum’s acid
derivative 3b with phenylsilane followed by hydrolysis with
deuterium oxide afforded the R,R′-dideuteriated product 4b. The
use of trideuteriophenylsilane followed by water led to the
formation deuterioaldehyde 5b with no other deuterium incor-
poration being observed. These observations are consistent with
the mechanism shown in Scheme 5. First, addition of triethy-
lamine gives silyl ketene acetal I, which undergoes cyclorever-
sion to reveal the R-oxoketene II. Ketene hydrosilylation occurs
giving enol silane III, which remains in solution until decar-
boxylative protonation occurs (as confirmed by evolution of CO2
detected by limewater test) releasing the aldehyde product.
To probe the scope of the triethylamine-promoted reduction
of cyclic malonates, a range of 5-monoalkyl Meldrum’s acid
derivatives were prepared and subjected to the reaction condi-
tions (Table 1).9
Pleasingly, good substrate scope was observed, with both
aromatic and aliphatic substituents being tolerated. Of particular
note is the selective reduction of cyclic malonate 3f containing
an alkene (entry 6) and the synthesis of chiral amino aldehyde
2g (entry 7) derived from N-Boc-L-proline. The use of tandem
or domino chemical transformations in a one-pot, multiple-step
organic synthesis can increase efficiency by avoiding repeated
isolation and purification processes.10 We were intrigued by the
possibility of utilizing the aldehyde functionality generated by
the reduction of cyclic malonates in further transformations. In
this context, we set out to develop a one-pot reductive amination
procedure to form γ-substituted propylamines directly from
5-monoalkyl Meldrum’s acid derivatives 3.11 The triethylamine-
promoted hydrosilylation of 3 followed by treatment with
methanol reveals the aldehyde functionality in situ. The imine
formed on addition of the relevant amine (Scheme 6, 6a-g)
(7) (a) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407–408.
(b) Iwasaki, F.; Onomura, O.; Mishima, K.; Maki, T.; Matsumura, Y. Tetrahedron
Lett. 1999, 40, 7507–7511. (c) Iwasaki, F.; Onomura, O.; Mishima, K.;
Kanematsu, T.; Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525–
2527. (d) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett.
2006, 8, 999–1001. (e) Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org.
Lett. 2006, 8, 3045–3048. (f) Malkov, A. V.; Stoncius, S.; MacDougall, K. N.;
Mariani, A.; McGeoch, G. D.; Kocovsky, P. Tetrahedron 2006, 62, 264–284.
(g) Sugiura, M.; Sata, N.; Kotani, S.; Nakajima, M. Chem. Commun. 2008, 4309–
4311.
(8) In the conversion of 3b to 2b with PhSiH3 (3 equiv) at room temperature
a range of Lewis bases (0.5 equiv) were tested. After 2 h the reactions were
quenched with water and the 1H NMR conversions were as follows: triethylamine
(49%), 4-(N,N-dimethylamino)pyridine (49%), N-methylmorpholine N-oxide
(45%), N,N-diiosopropylethylamine (40%), 1,8-diazabicyclo[5.4.0]undec-7-ene
(30%), N,N-dimethylformamide (0%), dimethyl sulfoxide (0%), and triph-
enylphosphine (0%).
(9) For the synthesis of 5-monoalkyl Meldrum’s acid derivatives, see: (a)
Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G.
Tetrahedron Lett. 2001, 42, 5203–5205. (b) Maggi, R.; Bigi, F.; Carloni, S.;
Mazzacani, A.; Sartori, G. Green Chem. 2001, 3, 173–174. (c) Frost, C. G.;
Penrose, S. D.; Lambshead, K.; Raithby, P. R.; Warren, J. E.; Gleave, R. Org.
Lett. 2007, 9, 2119–2122.
(10) For recent accounts of tandem or domino organic reactions, see: (a)
Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2006. (b) Chapman, C. J.; Frost, C. G.
Synthesis 2007, 1–21. (c) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem.,
Int. Ed. 2007, 46, 1570–1581. (d) Walji, A. M.; MacMillan, D. W. C. Synlett
2007, 1477–1489.
(11) Tripathi, R. P.; Verma, S. S.; Pandey, J.; Tiwari, V. K. Curr. Org. Chem.
2008, 12, 1093–1115.
3600 J. Org. Chem. Vol. 74, No. 9, 2009