One-step facile synthesis of deuterium labeled aldehydes from tertiary amides using Cp2Zr(D)Cl

Article abstract of DOI:10.1016/j.tetlet.2004.02.030

The synthesis of deuterium labeled aldehydes was accomplished in an expedient and facile manner through the reduction of amides using commercially available Cp₂Zr(D)Cl. The reactions proceeded rapidly (ca. 15min) and in high yields (70-99%).

Full text of DOI:10.1016/j.tetlet.2004.02.030

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Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2787–2789
One-step facile synthesis of deuterium labeled aldehydes from
tertiary amides using Cp2Zr(D)Cl
Jared T. Spletstoser, Jonathan M. White and Gunda I. Georg*
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, University of Kansas, Lawrence, KS 66045-7582, USA
Received 21 January 2004; revised 3 February 2004; accepted 6 February 2004
Abstract—The synthesis of deuterium labeled aldehydes was accomplished in an expedient and facile manner through the reduction
of amides using commercially available Cp2Zr(D)Cl. The reactions proceeded rapidly (ca. 15 min) and in high yields (70–99%).
Ó 2004Elsevier Ltd. All rights reserved.
Deuterium labeled aldehydes and their derivatives are
frequently found in a variety of biochemical and
chemical applications.1–3 Specifically, deuterioaldehydes
have been used to show that the enzymatic reduction of
acetaldehyde by yeast alcohol dehydrogenase is stereo-
specific.3 Furthermore, deuterioaldehydes were used to
determine deuterium isotope effects in imine formation
reactions to probe transition-state structures.2 Although
several methods are available for the synthesis of deu-
terioaldehydes, most involve multi-step procedures,
costly reagents, or extended reaction times.4–12 Some
representative examples of deuterioaldehyde prepara-
tion methods include: Rosenmund reduction of acid
chlorides (moderate yields with low deuterium incor-
poration),4 lithium aluminum deuteride reduction fol-
lowed by oxidation (two steps, moderate yields, and
substrate specific),5 aldehyde conversion to the dithiane
followed by n-butyllithium H–D exchange (three-steps
and requires strong basic conditions),7 reduction of
dihydro-1,3-oxazines (four steps and is specific for a, b-
unsaturated and aliphatic aldehydes).10 Methods have
been developed to overcome these limitations, but are
often highly substrate dependent.11 Most of the methods
reported to date for the synthesis of deuterioaldehydes
requires either heat4;7–9 or the use or generation of
strong bases,7;8;10;12 usually at low temperatures. Thus,
the need to develop an efficient and general method for
the synthesis of deuterium labeled aldehydes that oper-
ates under mild conditions remains.
Previous findings in our laboratory have shown that the
Schwartz reagent provides an efficient method to reduce
a
variety of tertiary amides, including N,O-di-
methylhydroxamates13 (Weinreb amides) to the corre-
sponding aldehydes.14 This reaction has been shown to
proceed on a variety of substrates and has also revealed
an extraordinary selectivity profile. Furthermore, this
reduction operates under very mild conditions and with
fast reaction times (at room temperature, typically in
under 15 min). We therefore sought to further expand
the use of this chemistry for the preparation of deute-
rium labeled aldehydes (Fig. 1). Fortunately, deuterium
labeled Schwartz reagent is commercially available
(Cp2Zr(D)Cl). Thus, the application of Cp2Zr(D)Cl was
explored and the results are detailed herein.
As shown in Table 1, a variety of amides was efficiently
reduced by Cp2Zr(D)Cl in good overall yield. Further,
the reactions proceeded very rapidly––comparable to
the results seen with Cp2Zr(H)Cl. The reaction is selec-
tive for tertiary amides and is unaffected by electronic
substituents (comparing entry 1 and 2, electron donating
and electron withdrawing compounds, respectively).
Compatibility is observed for aromatic, aliphatic, and
heteroaromatic systems. Further, the tertiary amide is
selectively reduced in the presence of the nitrile (entry 3),
as well as the secondary tert-butoxycarbonyl (BOC)
protected amide (entry 6). As is known with the hydrido
O
O
Cp2Zr(D)Cl
R'
R
N
R"
R
D
THF
Keywords: Schwartz reagent; Zirconium; Amide; Reduction; Deute-
rium labeled aldehyde; Cp2Zr(D)Cl.
Figure 1. General reduction of tertiary amides to deuterium labeled
aldehydes.
* Corresponding author. Tel.: +1-7858644498; fax: +1-7858645326;
e-mail: georgeku.edu
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.030

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J. T. Spletstoser et al. / Tetrahedron Letters 45 (2004) 2787–2789
Table 1. Reaction scope
was concentrated and directly purified via silica gel
column chromatography to provide the aldehyde
(123 mg, 0.9 mmol) in 90% yield (see Table 1 for specific
yields).
Entry Product
Yield
(%)
Reaction
time (min)
Starting
amide
O
1
2
90
70
10
15
–NEt2
–NEt2
D
D
Spectral data of aldehydes from entries 1, 2,16 and 812
were in accordance with their reported values. The
MeO
O2N
1
O
remaining products were fully characterized by H and
13C NMR, IR, and MS. Deuterium incorporation was
1
P95% as determined by H NMR for all products.
In summary, an efficient and high-yielding method for
the preparation of deuterium labeled aldehydes has been
developed. This method has the advantage of being
nonsubstrate specific and works on a variety of tertiary
amides, including Weinreb amides, and proceeds with
no observed over-reduction of the aldehyde.
O
D
3
4
85
93
10
5
–NEt2
CN
O
D
–N(OMe)Me
Cl
Cl
O
References and notes
5
6
D
92
91
10
5
–N(OMe)Me
–N(OMe)Me
N
1. (a) Ogino, T.; Watanabe, T.; Matsuura, M.; Watanabe,
C.; Ozaki, H. J. Org. Chem. 1998, 63, 2627–2633; (b)
Rucker, J.; Cha, Y.; Jonsson, T.; Grant, K. L.; Klinman,
J. P. Biochemistry 1992, 31, 11489–11499; (c) Baldwin,
J. E.; Barden, T. C.; Pugh, R. L.; Widdison, W. C. J. Org.
Chem. 1987, 52, 3303–3307; (d) Choi, H.-S.; Kuczkowski,
R. L. J. Org. Chem. 1985, 50, 901–902; (e) Polla, E.;
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Chem. Soc. 1966, 88, 3595–3599; (h) Thomas, A. F.
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O
D
BocHN
MeO
D
7
92
5
–NEt2
O
OMe
O
8
9
89
80
10
20
–N(OMe)Me
–NEt2
D
O
O
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Chem. 1990, 55, 1300–1303.
MeO
D
8
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reagent, the tertiary amides are reduced in the presence
of esters as well.14 This feat is not possible with DIBAL-
D and has not been reported to occur with any other
reagent to the best of our knowledge. These are mean-
ingful points, as alternative methods cannot achieve the
same selectivities. For example, lithium aluminum deu-
teride (LAD) is one method that can be used for the
preparation of deuterium labeled aldehydes. Unfortu-
nately, the use of LAD with compounds containing the
aforementioned functional groups is not possible. The
same is true for DIBAL-D, another reagent used to
generate deuterium labeled aldehydes. In all cases, no
over-reduction to the corresponding alcohol was
observed.
A typical procedure is as follows: Cp2Zr(D)Cl15 (380 mg,
1.5 mmol) was suspended in THF (2 mL) under argon at
ambient temperature to which N,N-diethyl-4-meth-
oxybenzamide (210 mg, 1.0 mmol) in THF (1 mL) was
added in one-portion. The reaction mixture was stirred
and monitored by TLC. Typical reactions were com-
pleted in 15 min––see Table 1 for specific reaction peri-
ods. Upon reaction completion (10 min), the mixture
10. (a) Meyers, A. I.; Nabeya, A.; Adickes, H. W.; Politzer,
I. R. J. Am. Chem. Soc. 1969, 91, 763–764; (b) Meyers,
A. I.; Nabeya, A.; Adickes, H. W.; Fitzpatrick, J. M.;
Malone, G. R.; Politzer, I. R. J. Am. Chem. Soc. 1969, 91,
764–765.
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Kuebrich, J. P. J. Org. Chem. 1972, 37, 1272–1273.
12. Yamashita, M.; Miyoshi, K.; Nakazono, Y.; Suemitsu, R.
Bull. Chem. Soc. Jpn. 1982, 55, 1663–1664.

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J. T. Spletstoser et al. / Tetrahedron Letters 45 (2004) 2787–2789
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13. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815–3818.
14. White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem.
Soc. 2000, 122, 11995–11996.
15. In most cases as little as 1.1–1.2 equiv of the hydride can
be used. This is especially required in the presence of
sensitive functionalities as in entry 9.
16. Stahl, I. Chem. Ber. 1985, 118, 3166–3177.