2
094
S. Laval et al. / Tetrahedron Letters 51 (2010) 2092–2094
ide 1g was more difficult under the reduction conditions described
above for 1a. The starting material remained almost totally intact
and only traces (3%) of the corresponding aldehyde 2g were de-
tected by GC–MS. Surprisingly, after two additional amounts of
5. LiAlH(OEt)
959, 81, 502–503. J. Am. Chem. Soc. 1964, 86, 1089–1095; lithium
diisobutylpiperidinohydroaluminate and (Li, Na, K) diisobutyl-t-
3 2 2
and LiAlH (OEt) (a) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc.
1
butoxyaluminum hydride: (b) Woo, S. M.; Kim, M. E.; An, D. K. Bull. Korean
Chem. Soc. 2006, 27, 121–122; Choi, S. J.; Lee, K. J.; Lee, G. B.; An, D. K. Bull.
Korean Chem. Soc. 2008, 29, 1407–1409; aminoaluminum hydride: (c) Muraky,
M.; Mukaiyama, T. Chem. Lett. 1975, 875–878; Cha, J. S.; Lee, J. C.; Lee, H. S.; Lee,
S. E. Tetrahedron Lett. 1991, 32, 6903–6904; Cha, J. S.; Kim, J. M.; Jeoung, M. K.
Bull. Korean Chem. Soc. 1994, 15, 708–709.
4
the TMDS/Ti(OiPr) system and 48 h extra stirring time, the desired
aldehyde 2g was not detected by GC–MS analysis of the crude. The
only detected products were the starting material (55%), the alco-
hol issued from the over-reduction of the aldehyde 3% and 20% of
the tertiary amine. Consequently the TMDS/Ti(OiPr) system is
4
unsuccessful for the reduction of an aromatic primary amide to
aldehyde.
At present, no detailed mechanistic studies have been under-
taken yet. However, considering the mechanistic highlights pub-
lished recently by Petit et al. for the reduction of phosphine
6
.
.
Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 23, 3707–3738. and
references herein.
(a) Brown, H. C.; Bigley, D. B.; Arora, S. K.; Yoon, N. M. J. Am. Chem. Soc. 1970, 92,
7161–7167; (b) Godjoian, G.; Singaram, B. Tetrahedron Lett. 1997, 38, 1717–
7
1720.
8
9
.
.
Tsay, S.-C.; Robl, J. A.; Hwu, J. R. J. Chem. Soc., Perkin Trans. 1 1990, 757–759.
Kamochi, Y.; Kudo, T. Tetrahedron 1992, 48, 4301–4312.
10. Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007,
29, 3408–3419.
1
1
1. Larson, G. L.; Fry, J. L.. Ionic and Organometallic-Catalyzed Organosilane
Reductions. In Organic Reactions; John Wiley & Sons Inc., 2008; Vol. 71.
Chapter 1.
4
oxides to phosphines using the TMDS/Ti(OiPr) reducing system,
we assume the presence of Ti(III) species in the reaction medium.
That suggests a mechanism via a single electron transfer (SET)
rather than a titanium hydride-like complex.1 In view of our pre-
liminary results we assume that the mechanism of the reduction is
substrate dependent. In fact, we presume that Ti(III) species react
with the amide substrate to form a hemi-aminal in first instance.
Then this hemi-aminal (stabilized by coordination with Ti or Si)
or the imine (resulting from hemi-aminal rearrangement) is hydro-
lyzed to the corresponding aldehyde. Mechanistic studies are still
underway in the laboratory.
12. Bower, S.; Kreutzer, K.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1996, 35,
4c
1515–1516.
13. Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1993, 58, 3221.
1
4. (a) Berthod, M.; Favre-Reguillon, A.; Mohamad, J.; Mignani, G.; Docherty, G.;
Lemaire, M. Synlett 2007, 10, 1545–1548; (b) Mignani, G.; Berthod, M.; Lemaire,
M. WO patent (2005) N2005/110948.; (c) Petit, C.; Favre-Reguillon, A.; Albela,
B.; Bonneviot, L.; Mignani, G.; Lemaire, M. Organometallics 2009, 28, 6379–
6382.
15. Laval, S.; Dayoub, W.; Favre-Reguillon, A.; Berthod, M.; Demonchaux, P.;
Mignani, G.; Lemaire, M. Tetrahedron Lett. 2009, 50, 7005–7007.
1
6. It is noticed that reductions of amide 1a in MCH or toluene give similar results.
Solvents are chosen in way to render the starting material soluble in the
reaction medium; otherwise the reduction does not occur. MCH and toluene
are suitable for tertiary amides whereas secondary and primary ones require
THF.
3
. Conclusion
17. Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1995, 60, 7884–7890.
In summary we reported here a mild procedure for the reduc-
18. 1,1,3,3-Tetramethyldisiloxane 97% and N,N-diethyl-m-toluamide 98% were
purchased from ACROS; titanium (IV) isopropoxide 95% and N,N-
diethyldodecanamide 98% from ALFA AESAR; 2-(trifluoromethyl)-benzamide
tion of amides to aldehydes that proceeds at room temperature
and employs readily available and air-stable reagents. The reaction
is general for aromatic and aliphatic tertiary amides and also
shows good preliminary results with a secondary aromatic one.
However preliminary essays with a primary aromatic amide did
not give the expected results. Nevertheless, the ease of this method
constitutes an alternative to existing methods. The tolerance and
97% from Maybridge.
19. N,N-Diethyl-4-chlorobenzamide,
N,N-diethyl-1-naphtyl-benzamide,
N,N-
diethyl-2,2-diphenylacetamide and N-benzyl-benzamide were synthesized
from the corresponding acid. Typical procedure for the synthesis of N,N-diethyl-
4
-chlorobenzamide 1b: To a suspension of 4-chlorobenzoic acid (8.0 g,
51.3 mmol, 1.0 equiv) in dichloromethane (35 mL) were added at rt. Oxalyle
chloride (5.4 mL, 61.7 mmol, 1.2 equiv) and dimethylformamide (one drop).
[
caution: exothermic reaction]. The crude mixture was stirred until gas
4
selectivity of the TMDS/Ti(OiPr) reducing system as well as the
mechanistic pathway will be studied in due course.
evolution stopped. Then it was concentrated in vacuo, washed with
dichloromethane and concentrated again, twice. The 4-chloro-benzoyl
chloride was isolated as a yellow oil in quantitative yield. The latter was
then transferred into a round-bottom flask, diluted in toluene (40 mL) and the
crude heated to 50 °C. Then N,N-diethylamine (12 mL, 116.0 mmol, 2.3 equiv)
was added dropwise and the mixture was stirred at 50 °C overnight. The
temperature was cooled to rt, the organic layer was washed with 3 Â 20 mL
Acknowledgment
We thank the ‘Fond Unique Interministériel’ for the financial
support of this work.
HCl 1 m, dried with MgSO
4
and concentrated in vacuo. The N,N-diethyl-4-
chloro-benzamide was isolated as an orange oil in 90% yield.
20. General procedure for the reduction of amides: N,N-diethyl-toluamide 1a: To a
References and notes
nitrogen purged screw-caped vial containing 1a (1.0 mL, 5.2 mmol, 1.0 equiv)
in 2.8 mL of methylcyclohexane were added TMDS (920
lL, 5.2 mmol,
1
.0 equiv) and Ti(OiPr) (1.5 mL, 5.2 mmol, 1.0 equiv) at rt. The mixture was
4
1
.
Greenberg, A., Breneman, C. M., Liebman, J. F., Eds.The Amide Linkage:
Structural Significance in Chemistry, Biochemistry, and Materials Science;
John Wiley & Sons: New York, 2000.
stirred at rt until analysis by TLC showed the complete consumption of the
starting material (ca. 15 h). The mixture was then diluted with
methylcyclohexane (20 mL) and acidified using 1 M HCl (11.0 mL, 2.1 equiv.).
2
.
Krebs, A.; Kaletta, B.; Nickel, W. U.; Rueger, W.; Tikwe, L. Tetrahedron 1986, 42,
The organic layer was washed with 1 M HCl (3 Â 10 mL), then dried (MgSO
and concentrated in vacuo. Flash column chromatography on silica gel
cyclohexane/ethyl acetate; 8:2) afforded the aldehyde 2a with 70% yield.
4
)
1
693–1702.
3
4
.
.
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(
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Halterman, R. L.; Ramsey, T. M.; Chen, Z. J. Org. Chem. 1994, 59, 2642–2644; (c)
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1
16, 11667–11670.