Mild and selective hydrozirconation of amides to aldehydes using Cp 2Zr(H)Cl: Scope and mechanistic insight

Article abstract of DOI:10.1021/ja066362+

An investigation of the use of Cp₂Zr(H)Cl (Schwartz's reagent) to reduce a variety of amides to the corresponding aldehydes under very mild reaction conditions and in high yields is reported. A range of tertiary amides, including Weinreb's amides, can be converted directly to the corresponding aldehydes with remarkable chemoselectivity. Primary and secondary amides proved to be viable substrates for reduction as well, although the yields were somewhat diminished as compared to the corresponding tertiary amides. Results from NMR experiments suggested the presence of a stable, 18-electron zirconacycle intermediate that presumably affords the aldehyde upon water or silica gel workup. A series of competition experiments revealed a preference of the reagent for substrates in which the lone pair of the nitrogen is electron releasing and thus more delocalized across the amide bond by resonance. This trend accounts for the observed excellent selectivity for tertiary amides versus esters. Experiments regarding the solvent dependence of the reaction suggested a kinetic profile similar to that postulated for the hydrozirconation of alkenes and alkynes. Addition of p-anisidine to the reaction intermediate resulted in the formation of the corresponding imine mimicking the addition of water that forms the aldehyde.

Full text of DOI:10.1021/ja066362+

Published on Web 02/22/2007
Mild and Selective Hydrozirconation of Amides to Aldehydes
Using Cp2Zr(H)Cl: Scope and Mechanistic Insight
Jared T. Spletstoser, Jonathan M. White, Ashok Rao Tunoori, and Gunda I. Georg*
Contribution from the Department of Medicinal Chemistry, UniVersity of Kansas,
1251 Wescoe Hall DriVe, Lawrence, Kansas 66045-7582
Received September 12, 2006; E-mail: georg@ku.edu
Abstract: An investigation of the use of Cp2Zr(H)Cl (Schwartz’s reagent) to reduce a variety of amides to
the corresponding aldehydes under very mild reaction conditions and in high yields is reported. A range of
tertiary amides, including Weinreb’s amides, can be converted directly to the corresponding aldehydes
with remarkable chemoselectivity. Primary and secondary amides proved to be viable substrates for reduction
as well, although the yields were somewhat diminished as compared to the corresponding tertiary amides.
Results from NMR experiments suggested the presence of a stable, 18-electron zirconacycle intermediate
that presumably affords the aldehyde upon water or silica gel workup. A series of competition experiments
revealed a preference of the reagent for substrates in which the lone pair of the nitrogen is electron releasing
and thus more delocalized across the amide bond by resonance. This trend accounts for the observed
excellent selectivity for tertiary amides versus esters. Experiments regarding the solvent dependence of
the reaction suggested a kinetic profile similar to that postulated for the hydrozirconation of alkenes and
alkynes. Addition of p-anisidine to the reaction intermediate resulted in the formation of the corresponding
imine mimicking the addition of water that forms the aldehyde.
aldehydes.7 It was further observed that an increase in the size
of the substituents at the amide nitrogen provided a higher yield
Introduction
The amide group is a robust functionality that is fairly inert
to many oxidative and reductive conditions.1 While the simple
reduction of amides with metal hydride reagents has been known
since the late 1940s,2 many of these methods reduce this group
to the corresponding alcohol and amine, several of which
proceed in high yields under fairly mild conditions.3 However,
controlling the reduction of an amide to the aldehyde oxidation
state has proven more difficult, typically requiring substrate-
specific conditions to achieve reliable yields of the aldehyde
products.4,5
In general, the reduction of amides to aldehydes using
common commercially available metal hydrides provides the
aldehydes in poor to moderate yields with isolation of the
corresponding alcohols and amines as byproducts in many of
the cases.6 Early investigations demonstrated that the reaction
of tertiary amides with lithium aluminum hydride generally
furnished a mixture of the corresponding amine and the
alcohol.2,7 It was then found that a reverse order of addition of
the reagents (addition of the hydride to the amide) resulted in
the formation of a significant amount of the corresponding
of the aldehyde. Monosubstituted amides and N,N-dimethyl-
benzamide did not react under these conditions or gave low
yields of the aldehydes. Many other methods have been reported
since and include reductions with LiAlH(OEt)3 and LiAlH2-
(OEt)2,8,9 NaAlH2(OCH2CH2OMe)2,10 and other variously sub-
stituted aluminum hydride-based reagents,11 dissolving metals,12
L-Selectride and alkyl trifluoromethanesulphonate,13 substituted
borohydride reagents,14 a SmI2-acid system,15 and a procedure
based on a POCl3-mediated conversion to a Vilsmeier complex,
followed by treatment with zinc dust and then water.16 Of these
methods, the LiAlH(OEt)3 procedure has been the most suc-
cessful in terms of generality and yield for the reduction of a
variety of N,N-dimethyl and N,N-diethyl amides to the corre-
sponding aldehydes. However, large N-substituents hinder this
reaction as N,N-diisopropyl-n-butyric amide was unreactive
(8) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089-1095.
(9) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1959, 81, 502-503.
(10) Ramegowda, N. S.; Modi, M. N.; Koul, A. K.; Bora, J. M.; Narang, C. K.;
Mathur, N. K. Tetrahedron 1973, 29, 3985-3986.
(11) (a) Cha, J. S.; Lee, J. C.; Lee, H. S.; Lee, S. E.; Kim, J. M.; Kwon, O. O.;
Min, S. J. Tetrahedron Lett. 1991, 47, 6903-6904. (b) Muraki, M.;
Mukaiyama, T. Chem. Lett. 1975, 875-878. (c) Yoon, N. M.; Ahn, J. H.;
An, D. K.; Shon, Y. S. J. Org. Chem. 1993, 58, 1941-1944. (d) Zakharkin,
L. I.; Maslin, D. N.; Gavrilenko, V. V. Tetrahedron 1969, 25, 5555-5569.
(12) Bedenbaugh, A. O.; Payton, A. L.; Bedenbaugh, J. H. J. Org. Chem. 1979,
25, 4703-4705.
(1) The Amide Linkage: Structural Significance in Chemistry, Biochemistry,
and Materials Science; Greenberg, A., Breneman, C. M., Liebman, J. F.,
Eds.; John Wiley & Sons: New York, 2000.
(2) Nystrom, R. F.; Brown, W. G. J. Am. Chem. Soc. 1948, 70, 3738-3740.
(3) Larock, R. C. ComprehensiVe Organic Transformations: A Guide to
Functional Group Preparation; VCH: New York, 1989.
(13) Tsay, S.-C.; Robl, J. A.; Hwu, J. R. J. Chem. Soc., Perkin Trans. 1 1990,
757-759.
(4) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(5) Bower, S.; Kreutzer, K.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl.
1996, 35, 1515-1516.
(14) (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, 1717-1720.
(6) Hudlicky´, M. Reductions in Organic Chemistry; Ellis Horwood Limited:
Chichester, England, 1984; pp 164-171.
(15) Kamochi, Y.; Kudo, T. Tetrahedron 1992, 48, 4301-4312.
(16) Rahman, A.; Basha, A. J. Chem. Soc., Chem. Commun. 1976, 594-595.
(7) Mic´ovic´, V. M.; Mihailovic´, M. L. J. Org. Chem. 1953, 18, 1190-1200.
9
3408
J. AM. CHEM. SOC. 2007, 129, 3408-3419
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Hydrozirconation of Amides to Aldehydes
A R T I C L E S
under the reported conditions.8 Furthermore, very little informa-
tion is available for this reaction with respect to functional group
tolerance and selectivity. Brown has reported that the reduction
of N,N-dimethyl-4-nitrobenzamide with LiAlH(OEt)3 afforded
75% of the desired aldehyde while observing partial reduction
of the nitro group. This suggests that chemoselectivity could
be problematic in amide reductions with this reagent in the
presence of more electrophilic functionalities. Cha has reported
the synthesis of aldehydes from primary and tertiary amides
using lithium tris(dialkylamino)aluminum hydrides17 and dipyr-
rolidinoaluminum hydrides.18 These reactions furnished good
yields of aldehydes but showed significant reactivity with
accompanying nitro substituents. Borohydrides have been much
less studied in this regard; however, Sia2BH (diisoamylborane)
has been successful in the reduction of N,N-dimethyl and
-diethyl amides.14 Unfortunately, there was no investigation into
functional group compatibility with this reagent.
without a dependence on the nature of the nitrogen substituents.
We have found that Cp2Zr(H)Cl (1) is effective in this regard.
First reported by Wailes and Weigold, Schwartz’s reagent,
Cp2Zr(H)Cl, is a 16-electron, d0 complex with the zirconium at
the (+4) oxidation state.28 The one remaining coordination site
renders the molecule Lewis-acidic, while the absence of a
valence-shell filled nonbonding orbital leaves it relatively non-
nucleophilic. This empty orbital allows for complexation of the
metal to a wide variety of functionalities that contain available
nonbonding electron pairs, π-bonds/electrons, or in some cases
σ-bonds/electrons.29
Pioneering studies by Schwartz and collaborators have made
the hydrozirconation of alkenyl and alkynyl substrates one of
the most widely used zirconium-mediated reactions because
hydrogen can be added stereo- and regioselectively across
π-bonds.30 The resulting hydrozirconated products can then react
with a variety of electrophiles including protons, halides, and
certain carbon moieties or undergo transmetalation reactions.31,32
Hydrozirconation of heteroatomic functionalities is also known
and includes the reduction of nitriles,33 esters, ketones,34
thioketones,35 aldehydes,36 imines, nitro groups, phosphine
oxides and sulfides,37 and secondary amides.38
More recently, there have been investigations into specialized
amide derivatives to cleanly afford the aldehyde products.
Generally, those in which the nitrogen lone pair competes for
localization within the amide bond tend to give higher yields
of the corresponding aldehydes. Specifically, N-acylcarbazoles,19
N-acylimidazoles,20 1-acylaziridines,21,22 1-acyl-3,5-dimeth-
ylpyrazoles,23 N-methylanilides,24 morpholine amides,25 3-acyl-
thiazolidine-2-thiones,26 and an N-[2-(dimethylamino)ethyl]-N-
methyl amide27 reacted with aluminum hydride reagents to give
higher aldehyde yields. Of course, the most notable specialized
amide is the N,O-dimethylamide (Weinreb amide).4 It is
presumed that the presence of the oxygen atom allows for
selective association with the metal, forming a stable five-
membered chelate preventing further reduction. Hydrolysis then
affords the aldehyde cleanly and in good yields.
We have previously communicated a novel procedure for the
reduction of tertiary amides to aldehydes using Cp2Zr(H/D)Cl
that operates under mild conditions.39,40 These reactions are
generally high yielding and remarkably tolerant of many
functionalities. Herein, we report an extended scope of this
chemistry and the results of our studies aimed at elucidating
the reaction mechanism.
(28) (a) Wailes, P. C.; Weigold, H.; Bell, A. P. J. Organomet. Chem. 1971, 27,
373-378. (b) Wailes, P. C.; Weigold, H. J. Organomet. Chem. 1970, 24,
405-411.
(29) Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-
VCH: Weinheim, 2002.
(30) (a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115-8116.
(b) Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. Engl. 1976, 15,
333-340.
(31) For a review up to ca. 1995, see: Wipf, P.; Jahn, W. Tetrahedron 1996,
52, 12853-12910.
Buchwald has reported a procedure that utilizes a presumed
titanium hydride-like species that can efficiently reduce a variety
of differentially N-substituted amides to the corresponding
aldehyde.14b This method was successful on a variety of
substrates including the usually problematic N,N-diisopropyl-
derived amides and those containing sensitive functionalities
such as olefins, alkynes, nitriles, and epoxides. However, this
particular transformation has been shown to proceed through
an enamine intermediate and therefore is limited to R-enolizable
amide substrates.
(32) For a review from ca. 1995-2001, see: Lipshutz, B. H.; Pfeiffer, S. S.;
Noson, K.; Tomioka, T. In Titanium and Zirconium in Organic Synthesis;
Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; pp 110-148.
(33) Labinger, J. A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: New York, 1991; Vol. 8, pp 667-702.
(34) Cesarotti, E.; Chiesa, A.; Maffi, S.; Ugo, R. Inorg. Chim. Acta 1982, 64,
L207-L208.
(35) Laycock, D. E.; Alper, H. J. Org. Chem. 1981, 26, 289-293.
(36) Majoral, J. P.; Zablocka, M.; Igau, A.; Cenac, N. Chem. Ber. 1996, 129,
879-886.
Thus, there still remains a need for a mild method for the
reduction of carboxamides to aldehydes that is generally free
of alcohol and amine contaminants, is chemoselective, and
works on a variety of alkyl and aromatic amide substrates
(37) Zablocka, M.; Delest, B.; Igau, A.; Skowronska, A.; Majoral, J. M.
Tetrahedron Lett. 1997, 38, 5997-6000.
(38) (a) Schedler, D. J. A.; Godfrey, A. G.; Ganem, B. Tetrahedron Lett. 1993,
34, 5035-5038. (b) Schedler, D. J. A.; Li, J.; Ganem, B. J. Org. Chem.
1996, 61, 4115-4119.
(17) Cha, J. S. Bull. Korean Chem. Soc. 1992, 13, 670-676.
(18) Cha, J. S.; Kwon, O. O.; Kim, J. M.; Lee, J. C. Bull. Korean Chem. Soc.
1994, 15, 644-649.
(39) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2000, 122,
11995-11996.
(40) Spletstoser, J. T.; White, J. M.; Georg, G. I. Tetrahedron Lett. 2004, 45,
2787-2789.
(19) Wittig, G.; Hornberger, P. Ann. Chim. (Paris) 1952, 577, 11-15.
(20) Staab, H. A.; Bra¨unling, H. Ann. Chim. (Paris) 1962, 654, 119-130.
(21) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1961, 83, 2016-2017.
(22) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1961, 83, 4549-4552.
(23) Ried, W.; Ko¨nigstein, F. J. Angew. Chem. 1958, 70, 165.
(24) (a) Weygand, R.; Eberhardt, G. Angew. Chem. 1952, 64, 458. (b) Weygand,
R.; Eberhardt, G.; Linden, H.; Scha¨fer, F.; Eigen, I. Angew. Chem. 1953,
65, 525-531. (c) Weygand, R.; Linden, H. Angew. Chem. 1954, 66, 174-
175. (d) Weygand, R.; Mitgau, R. Chem. Ber. 1955, 88, 301-308. (e)
Weygand, R.; Bestmann, H. J. Chem. Ber. 1959, 92, 528-529.
(25) Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2000,
41, 37-40.
(41) The commercially available reagent is stable for several months if the bottle
is purged with argon following each use, the cap wrapped with parafilm,
and stored in a desiccator at room temperature. The reagent should exist
as a white powder, and discoloration to an off-white or pinkish hue is usually
indicative of impure reagent. Lipshutz has noted that the reagent can last
ca. 3 months with careful handling; see ref 5. After this time, the reagent
loses its efficiency even in the absence of appearance changes. We have
noticed a similar trend. In addition to its commercial availability, Cp2Zr-
(H)Cl may also be synthesized from the dichloride in high purity following
the procedure of Buchwald et al. (see: Buchwald, S. L.; LaMaire, S. J.;
Nielsen, R. B.; Watson, B. T.; King, S. M. Tetrahedron Lett. 1987, 28,
3895-3898. Buchwald, S. L.; LaMaire, S. J.; Nielson, R. B.; Watson,
B. T.; King, S. M. Org. Synth. 1993, 71, 77-82). The reagent can be
assayed using 1H NMR following the procedure of Schwartz et al. (Gell,
K. I.; Posin, B.; Schwartz, J.; Williams, G. M. J. Am. Chem. Soc. 1982,
104, 1846-1855) and Buchwald et al. (see Org. Synth. reference above).
(26) (a) Nagao, Y.; Kawabata, K.; Seno, K.; Fujita, E. J. Chem. Soc., Perkin
Trans. 1 1980, 2470-2473. (b) Izawa, T.; Mukaiyama, T. Chem. Lett. 1977,
1443-1446. (c) Izawa, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1979,
52, 555-558.
(27) Comins, D. L.; Brown, J. D. J. Org. Chem. 1986, 51, 3566-3572.
9
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A R T I C L E S
Spletstoser et al.
Table 1. Reduction of N,N-Dialkyl Amides39
Results and Discussion
Extended Scope and Utility. The mild reduction of tertiary
amides to aldehydes was efficiently carried out on both aromatic
and alkyl substrates with the Schwartz reagent41 as shown in
eq 1.42 A variety of substrates that vary in electronic and steric
properties were investigated for the reduction and are shown in
Table 1.
Aromatic, heteroaromatic, and aliphatic amides were ef-
ficiently reduced to the corresponding aldehyde in good to
excellent yields (Table 1). Entry 1 highlights the ability of
heteroaromatic compounds to participate in the reduction without
a noticeable effect on the reaction rate or yield due to a potential
interaction between zirconium and the pyridine nitrogen.
Substitution of the aromatic substrates with electron-donating
or -withdrawing groups did not significantly alter the reaction
course (entries 2-7). Exceptional chemoselectivity was observed
with fast reaction rates. Nitrile and nitro functionalities were
maintained, although they can be reduced with other hydride
reagents (entries 2 and 3) including LiAlH(OEt)3.8 Remarkably,
the tertiary amide was selectively reduced in the presence of
an ester group (entries 5 and 10). This selectivity was observed
on both aromatic and aliphatic substrates, and they are the only
known general examples of such selectivity to the best of our
knowledge.43 Tertiary amides are reduced exclusively in the
presence of carbamate groups as is shown in entry 6. Aliphatic
amides are viable substrates for this reaction (entries 7-10),
highlighting the generality of this reduction.
A variety of Weinreb amides were also examined (Table 2).
For comparative reasons, many of the same substrates were used
as in Table 1. In most cases, similar yields, reaction times, and
selectivities were observed. Entry 7 shows that aromatic ketones
are reduced in addition to the amide functionality, when 2 equiv
of 1 is used. The cinnamic amide 32 (entry 10) afforded the
aldehyde in good yield with the olefin remaining intact, but
12% of the corresponding alcohol was obtained.
This protocol was also effective when applied to primary and
secondary amides. Reaction times remained the same, but the
yields were significantly reduced. It is worthwhile to note that
only 1 equiv of the reagent was employed for aldehyde
formation from aliphatic and aromatic amides. Ganem has
reported a procedure that requires 2 equiv of Cp2Zr(H)Cl for
the reduction of aliphatic secondary amides to the corresponding
imines following a nonaqueous workup.38 Thus, this method
gives an interesting alternative to the Ganem procedure on the
same substrates. Again, functional group selectivity was main-
tained as shown in Table 3.
to tertiary amides (Table 4). Cinnamic amides (entries 1 and 2)
were selectively reduced without observed reduction of the
double bond. Entry 1 afforded a 1:1 mixture of the aldehyde
and alcohol each in 19% yield with no recovery of the starting
amide. The problematic reduction of N,N-diethylcinnamamides
has been previously reported with LiAlH4 in which only 29%
of the cinnamyl alcohol was obtained.7 Interestingly, the
Weinreb amide derivative 32 (Table 2, entry 10) yielded 87%
of the aldehyde and 12% of the alcohol. The increase in yield
for entry 2 (Table 4) suggests that the Weinreb amide may
impart certain properties that increase intermediate stabilities
or reactant selectivities, possibly by the same mechanism as
proposed by Weinreb.4 In entry 3, the amide was reduced in
the presence of the terminal olefin, affording 63% of the
corresponding aldehyde. On the contrary, the terminal alkyne
furnished the alkynyl and alkenyl aldehydes in 13% and 9%
Alkenes and alkynes are excellent substrates for hydrozir-
conation and were investigated for their selectivity as compared
(42) Hudlicky´, M. Reductions in Organic Chemistry, 2nd ed.; American
Chemical Society: Washington, DC, 1996.
(43) A representative procedure for the hydrozirconation of tertiary amides is
as follows: Cp2Zr(H)Cl (0.29 mmol) is suspended in THF (3 mL) under
argon at room temperature in a flame-dried round bottom flask. To this
suspension is added the substrate (0.24 mmol) in THF (2 mL) also at room
temperature. The mixture is stirred until the reaction turns clear usually
within 15-30 min. Workup by the addition of silica gel (ca. 3 g) and
removal of the solvent in vacuo, followed by elution through a short path
silica gel column, affords the aldehyde.
9
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Hydrozirconation of Amides to Aldehydes
A R T I C L E S
Table 3. Reduction of Primary and Secondary Amides
Table 2. Reduction of Weinreb Amides
Table 4. Reduction of Alkenyl and Alkynyl Amides
a Two equivalents of 1 was required. b The corresponding alcohol was
also obtained (12%).
yield, respectively (entry 4). The conjugated internal alkyne
(entry 5) afforded exclusively the corresponding aldehyde but
in poor yields and mass balances. This selectivity is not
unexpected as hydrozirconation of internal alkynes is typically
kinetically disfavored when compared to terminal alkynes.33
a A mixture of aldehyde and alcohol (1:1) was obtained in 19% yield
each. b The corresponding alcohol (12%) was also obtained.
dichlorobenzamide (Table 5, entry 4) was subjected to hydrozir-
conation, only 17% of the aldehyde (with 63% of the starting
material recovered) could be obtained even after prolonged
reaction times and with the addition of excess reagent (3 equiv).
This could be due to the presence of di-ortho substituents, the
increased electron deficiency of this substrate, or both. Increased
steric demand is most likely the major cause of inefficiency
because the analogous Weinreb-derived 3,4-dichlorobenzamide
reacts completely with the zirconium deuteride reagent, affording
the desired aldehyde in 93% yield after only 5 min (Table 7,
entry 5).40 Overall, it appears that steric bulk is better tolerated
on the amine side of the amide than on the carbonyl side.
Cp2Zr(H)Cl is known to be sensitive to congestion at or near
the reaction center of the substrate in olefin hydrozirconation,
and thus we sought to examine the associated issues for amide
reductions.33 Table 5 (entries 1-3) shows that steric encum-
brance is tolerated on the amine portion of the carboxamide,
although the yields are somewhat reduced when compared to
the diethyl amide case (Table 1, entry 4). Diisopropyl amide
47 reacts in 10 min providing 72% of the aldehyde, whereas
its reaction with LiAlH4 or LiAlH(OEt)3 is extremely slow
giving nearly all unreacted material after 1 h.8,22 When 2,6-
9
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A R T I C L E S
Spletstoser et al.
Table 6. Reduction of Amides Containing Chiral Auxiliaries
Table 5. Effects of Steric Bulk on the Reduction Reaction
a 63% yield of starting material recovered.
In addition to the reduction of a variety of amides discussed
above, the Schwartz reagent was investigated for its ability to
remove amide-based chiral auxiliaries. Initial attempts using the
norephedrine-derived oxazolidinone developed by Evans44
proved successful on a model system (Table 6, entry 1), but
provided only moderate yields when extended to other substrates
(Table 6, entries 2-4). This is likely due to competitive
reduction of the two carbonyls of the imide substrate with the
more electron-rich endo carbonyl being preferentially reduced.
As carbonyl conjugation is removed (Table 6, entries 2-4), the
aldehyde yield decreases likely due to reduction of the endo
carbonyl competing with the exo carbonyl group. It is also
conceivable that enolization of the aliphatic imide substrates
may account for the decreased yields for entries 2-4. The
oxazolidinone auxiliary could not be recovered, presumably due
to complexation of the norephedrine amino-alcohol with the
zirconium byproduct (see the mechanistic discussion below).
Myers’ pseudoephedrine derived auxiliary45 was examined
due to its true tertiary amide nature versus the oxazolidinone-
based systems. When a model system was subjected to the
hydrozirconation conditions, a complete loss of starting material
was observed without accompanying aldehyde formation (Table
6, entry 5). We believed this was due to deprotonation of the
alcohol group on the auxiliary by the reagent.33 However, the
addition of 2 or more equiv was not able to elicit product
formation. When the alcohol was protected as the tert-
butyldimethylsilyl ether, the desired aldehyde was isolated in a
90% yield as expected (Table 6, entry 6). This finding is notable
as the pseudoephedrine auxiliary has recently been shown to
impart asymmetric induction via alkylation using either an
O-benzylated “protected” auxiliary or a polymer-bound auxiliary
(via a similar oxygen-polymer bond) with comparable enan-
tioselectivity.46 Attempted hydrozirconation of R-methyl deriva-
a Complete loss of starting material without observation of aldehyde.
tive 60 (Table 6, entry 7) did not result in product formation.
Additionally, hydrozirconation of chiral compound 61 failed
(Table 6, entry 8). Thus, it appears that R substitution, in these
particular cases, confers a large enough steric environment to
block hydrozirconation under these conditions. The discrepan-
cies in yield between entries 6 and 7 (Table 6) strongly suggest
that the inability of substrates 50, 60, and 61 to react is due to
a steric interaction rather than an electronic bias. In support of
this, it is important to note that the 4-nitrocarboxamides
(compounds 6 and 24) and 3,4-dichlorobenzamide 67 react well.
Attempted hydrozirconation of various amide-based chiral
auxiliaries has been reported since our initial communication
and has been met with varying success.47 Mickel et al. were
unsuccessful in the removal of an oxazolidinone-based chiral
auxiliary containing an R-stereocenter with the Schwartz reagent
in their process synthesis of (+)-discodermolide.47 Yamada et
al. have reported the successful removal of 2,2-dimethyloxazol-
(44) Evans, D. A. In Topics in Stereochemistry; Nelson, J. V., Taber, T., Eds.;
John Wiley & Sons: New York, 1982; Vol. 13, pp 1-115.
(45) (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511. (b) Myers,
A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995, 117, 8488-8489.
(46) (a) Hutchison, P. C.; Heightman, T. D.; Procter, D. J. J. Org. Chem. 2004,
69, 790-801. (b) Hutchison, P. C.; Heightman, T. D.; Procter, D. J. Org.
Lett. 2002, 4, 4583-4585.
(47) (a) Mickel, S. J.; et al. Org. Process Res. DeV. 2004, 8, 107-112.
(b) Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124, 8184-8185.
9
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Hydrozirconation of Amides to Aldehydes
A R T I C L E S
Scheme 1
Table 7. Amide Reduction Using Cp2Zr(D)Cl40
Scheme 2
idine chiral auxiliaries using this methodology in the synthesis
of 1,4-dihydropyridines, affording the corresponding aldehyde.47
Apparently, the ability to remove such auxiliaries is substrate-
specific under these conditions.
In a recent communication, Rawal et al. have reported the
cleavage of R-substituted N,N-dimethyl amides utilizing a 3-fold
excess of 1 in methylene chloride that afforded the correspond-
ing aldehydes in good yields (Scheme 1).48 Thus, it appears
that certain R-substituted chiral aldehydes can be viable
substrates for hydrozirconation under the appropriate conditions.
The use of the commercially available Cp2Zr(D)Cl was
investigated for the ability to prepare deuterium-labeled alde-
hydes. This proved to be an efficient reaction for the preparation
of deuterio-aldehydes, which are often difficult to synthesize
through other methods.40 Many of the existing methods involve
expensive or difficult to synthesize reagents, multistep proce-
dures, or harsh reaction conditions en route to the specific
labeling of the 1-aldehydic position.49 In addition to these
concerns, many of these procedures are substrate-specific with
unknown or low chemoselectivity.
As is evident in Table 7, these labeled aldehydes were
synthesized with results comparable to those of the hydrido
reagent. Again, both aromatic and aliphatic substrates react well,
affording the desired deuterio-aldehydes in good yields. As
expected, the chemoselectivity profile is retained in this reaction
variant. In all cases, deuterium incorporation was g95% as
measured by H NMR spectroscopy. The ability to selectively
label the aldehydic proton with a high deuterium incorporation
in short reaction times with high yields from easily obtainable
starting materials makes this method superior to existing
procedures.
1
(48) This information was published while this manuscript was under review:
McGilvra, J. D.; Unni, A. K.; Modi, K.; Rawal, V. H. Angew. Chem., Int.
Ed. 2006, 118, 6276-6279.
(49) (a) Axenrod, T. A.; Loew, L.; Pregosin, P. S. J. Org. Chem. 1968, 33,
1274. (b) Bennett, D. J.; Kirby, G. W.; Moss, V. A. J. Chem. Soc., Chem.
Commun. 1967, 218-219. (c) Craig, J. C.; Kray, L. R. J. Org. Chem. 1968,
33, 871-872. (d) Degani, I.; Fochi, R. Synthesis 1976, 759-761. Franzen,
V. V. Liebigs Ann. Chem. 1956, 600, 109-114. (e) 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. (f) Meyers, A. I.; Nabeya, A.;
Adickes, H. W.; Politzer, I. R. J. Am. Chem. Soc. 1969, 91, 763-764. (g)
Olofson, R. A.; Zimmerman, D. M. J. Am. Chem. Soc. 1967, 89, 5057-
5059. (h) Schlosser, M. Chem. Ber. 1964, 97, 3219-3233. (i) Schowen,
R. L.; Burgstahler, A. W.; Walker, D. E.; Kuebrich, J. P. J. Org. Chem.
1972, 37, 1272-1273. (j) Scott, C. A.; Smith, D. G.; Smith, D. J. H. Synth.
Commun. 1976, 6, 135-139. (k) Seebach, D.; Erickson, B. W.; Singh, G.
J. Org. Chem. 1966, 31, 4303-4304. (l) Thompson, A. F.; Cromwell,
N. H. J. Am. Chem. Soc. 1939, 61, 1374-1376. (m) Yamashita, M.;
Miyoshi, K.; Nakazono, Y.; Suemitsu, R. Bull. Chem. Soc. Jpn. 1982, 55,
1663-1664.
Mechanistic Investigation. During the course of establishing
the reaction scope, the presence of a seemingly stable intermedi-
ate became evident, in that over-reduction of the aldehyde to
the alcohol was not observed in most cases, even when an excess
of the zirconium hydride was employed. Aldehydes and ketones
are known substrates for hydrozirconation,34,36 and any aldehyde
formed before the workup is expected to be reduced to the
corresponding alcohol.
This observation led to the hypothesis of two intermediates.
Hydrozirconation of the amide could result in an iminium ion
species after hydride delivery and zirconium oxide expulsion
9
J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007 3413

A R T I C L E S
Spletstoser et al.
(path a, intermediate II, Scheme 2) or by incorporation of the
zirconium reagent to form an sp3-hybridized, 18-electron
complex (path b, intermediate III, Scheme 2). Hydrolysis of
either of these intermediates by the addition of water would
then afford the aldehyde products. It is also feasible that the
conversion of III to IV could occur by amine expulsion in which
the amide oxygen in the carbonyl of the product aldehyde is
retained. The proposed zirconacycle (III) should be stable as
compounds related to intermediate III have been previously
reported.50 Although iminium ions are generally highly reactive
toward reducing agents, Buchwald has proposed them as
intermediates in his reported reduction of amides.5 Thus, the
iminium species II was initially considered a possible interme-
diate for this reaction.39
it seems that the residual amine component from the amide is
bound to the zirconium byproducts.
Iminium ions react quite readily with a variety of nucleo-
philes, and the cyanide anion is well documented for its ability
to derivatize such species.52 However, the addition of several
cyanide anion sources failed to afford any of the aminonitrile
after silica gel workup. Although these functional groups are
reportedly stable to such chromatography,53 it was premature
to rule out an iminium ion intermediate for various reasons:
(1) cyanide retro-addition could occur, (2) the resulting amine
product could be sequestered by the zirconium byproduct (as
noted above), or (3) the nature of the counterion could change
the reactivity of the iminium ion.54 It is worthwhile to note that
the presence of the cyanohydrin from nitrile addition to the
aldehyde was never observed.
Extension of the reaction to generate deuterium-labeled
aldehydes using the commercially available Cp2Zr(D)Cl con-
firmed the obvious assumption that the hydride is transferred
to the carbonyl carbon and is incorporated into the aldehyde.
This gives direct evidence as to the hydride source and answers
a preliminary question concerning the reaction mechanism.
Another question to the mechanistic details regarded the
source of the aldehyde carbonyl oxygen. Did the addition of
water (from silica gel employed in the workup)42 result in the
hydrolysis of a reaction intermediate to form the aldehyde, or
was the amide carbonyl oxygen retained in the product?
Toward this end, the addition of 18O-labeled water (1:1
mixture of H2O16 and H2O18) to the reaction of 4-methoxy-
N,N-diethylbenzamide (8) and 1 (eq 2) after 15 min demon-
strated incorporation of the labeled oxygen into the aldehyde
as observed by 13C NMR and MS [carbonyl peaks at δ 191.25
and 191.22 in a 1:1 ratio, and a 1:1 ratio for the pairs m/z 165,
163 (M+), and 164, 162 (M+ - 1)]. Control experiments with
benzaldehyde and 18O-labeled water showed no isotopic incor-
poration after 5 min, 1 h, and 24 h. An additional control
experiment with a catalytic amount of the Lewis acidic Cp2-
ZrCl2 was performed (1 is made from the dichloride, and trace
amounts may be present in the reaction mixture). Therefore, 8
and 1.1 equiv of 18O-labeled water in the presence of 10 mol
% of Cp2ZrCl2 showed no isotopic enrichment after 5 min, and
a small peak was discernible after 1 h as detected by 13C NMR
(24:1 of 16O:18O). However, a 1.6:1 ratio of 16O:18O-labeled
carbonyl peaks was apparent after 24 h. Although this second
control experiment confirms that organozirconium species can
catalyze the oxygen exchange of water with p-anisaldehyde,
we believe it unlikely that such a process is accounting for the
observed 18O incorporation (1:1 ratio within 15 min) illustrated
in eq 2 on the reaction time scale. This implies that the oxygen
atom of the amide is sequestered by the zirconium reagent. This
suggestion is supported by zirconium’s widely known oxophi-
licity and the strength of the zirconium-oxygen bond.51
Indirect evidence for complex III was gained from IR data
as the differences in hybridization of the proposed intermediates
would be distinct. The intermediate was prepared in an inert
atmosphere from N,N-diethylbenzamide (77) and 1, and the
corresponding spectrum was obtained as a solution in THF using
an air-free IR cell. The resulting spectrum did not show a peak
definitively corresponding to an iminium ion.55 After the solution
was exposed to water, a new peak formed at 1699 cm-1
.
Notably, there was no concomitant loss of an existing peak from
the carbonyl region of the spectrum. If path a predominates, it
would be expected that the addition of water would cause the
loss of a peak corresponding to an iminium ion stretch and
replace it with an aldehyde signal. The formation of a carbonyl
stretch without concomitant loss of another signal from the same
region supports intermediate III.
More direct evidence for intermediate III came from NMR
spectroscopy. The intermediate was prepared in an NMR tube
under anhydrous conditions with the addition of Cp2Zr(H)Cl
to N,N-diethylbenzamide (77, in slight excess) in THF-d8. The
resulting spectra are overlaid in Figure 1. Spectrum a is the
N,N-diethylbenzamide substrate, and spectrum b shows the
intermediate after the addition of 1. As is evident, the initially
rotameric diethyl peaks of the starting amide become defined
multiplets and shift upfield ((). This would be expected in the
sp3-hybridized intermediate as shielding of the diethyl peaks
by the cyclopentadienyl groups should occur. An iminium ion
could show diastereotopicity of the ethyl peaks, but the chemical
shifts would be expected downfield due to, formally, a quat-
ernization of the nitrogen atom. Diastereotopicity of the alkyl
amino portion suggests a closed cycle where the nitrogen
coordinates to the zirconium atom resulting in a formal 18-
electron intermediate. The formation of a new signal at 5.83
ppm (+) is clearly observed.
(50) For selected examples, see: (a) Gately, D. A.; Norton, J. R.; Goodson,
P. A. J. Am. Chem. Soc. 1995, 117, 986-996. (b) Plo¨ssl, K.; Norton, J. R.;
Davidson, J. G.; Barefield, E. K. Organometallics 1992, 11, 534-539.
(51) Ferreri, C.; Palumbo, G.; Caputo, R. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 1, pp
139-172.
(52) For a recent example of iminium ion trapping with cyanide, see: Myers,
A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon, S. J. Am. Chem.
Soc. 1999, 121, 8401-8402.
(53) The authors report the flash chromatography purification of various
R-aminonitriles: Heydari, A.; Fatemi, P.; Alizadeh, A.-A. Tetrahedron Lett.
1998, 39, 3049-3050.
In all cases, the amine component of the amide is unrecover-
able from the reaction mixture. In the particular case of lactams
(both â-lactams and caprolactams were investigated), a complete
loss of starting material was noted with no discernible amounts
of the aldehyde observed by thin-layer chromatography. Thus,
(54) For an example of different iminium counterions affording different reaction
products, see: Ofial, A. R.; Mayr, H. Angew. Chem., Int. Ed. Engl. 1997,
36, 143-145.
(55) Imine salt stretching vibrations (-CdN-) are found approximately at ν
1680 cm-1
: Conley, R. T. Infrared Spectroscopy, 2nd ed.; Allyn and
Bacon: Boston, 1972.
9
3414 J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007

Hydrozirconation of Amides to Aldehydes
A R T I C L E S
Figure 1. 1H NMR spectra of reaction intermediate III: (() denotes -CH2- and -CH3 peaks, (*) residual THF signals, (+) methine proton, ()) minor
product.
Figure 2. Expansion of Cp region for intermediate III: (() denotes diastereotopic Cp resonances.
zirconium oxide from nitrogen lone pair donation. The zirco-
nium oxide dimer has been well characterized and shows
distinctly a singlet corresponding to the cyclopentadienyl
ligands.56
A peak in the 13C NMR was observed at 97 ppm that
correlates to the sp3 carbon based on DEPT data. The chemical
1
shifts of the H (5.83 ppm) and 13C (97 ppm) peaks are very
close to known N,O acetal shifts,57 while the +NdCH(Ph) proton
of N,N-dimethylbenzylideneammonium salts has been reported
1
to be between 8.64 and 10.25 ppm in the H NMR spectrum
and 172.9 and 173.9 ppm in the 13C spectrum depending upon
the counterion.58 Recently, Suginome and Murakami reported
the proton and carbon chemical shifts for an N,N-diethylben-
zylideammonium borate salt that displays a spectral profile
different from the intermediate characterized from the hydrozir-
conation of tertiary amides, unequivocally eliminating the
iminium ion as a potential intermediate (Figure 3).59 The most
striking difference lies in the upfield chemical shift of the
Figure 3. Comparison of 1H chemical shifts of iminium ion59 and
intermediate III.
Most importantly, an expansion of the cyclopentadienyl
region for intermediate III in Figure 2 shows diastereotopic
splitting of the Cp groups with each integrating for five protons.
This is only consistent with an sp3-hybridized intermediate.
Iminium ion formation would require the elimination of the
(56) Reid, A. F.; Shannon, J. S.; Swan, J. M.; Wailes, P. C. Aust. J. Chem.
1965, 18, 173-181.
(57) The authors report the -NCHO- proton at 5.64 ppm for an indole-derived
cyclic N,O-acetal: Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482-5487.
(58) For NMR data of iminium salts, see: (a) Mayr, H.; Ofial, A. R.; Wu¨rthwein,
E. U.; Aust, N. C. J. Am. Chem. Soc. 1997, 119, 12727-12733. (b) Mere´nyi,
R. In Iminium Salts in Organic Chemistry; Bo¨hme, H., Viehe, H. G., Eds.;
Interscience: New York, 1976; Vol. 9, part 1, pp 23-105.
9
J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007 3415

A R T I C L E S
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Table 8. Competition Experiments between Amides with Different
Electronic Properties
Figure 4. Possible products of hydrozirconation of Weinreb amides.
methine proton in intermediate III as compared to the iminium
ion reported by Sufinome and Murakami. The downfield shift
of the methyl and methylene peaks in the ionic compound and
their upfield shifts in intermediate III (as also compared to the
starting amide) corroborate our hypothesis of zirconium com-
plexation over iminium ion formation.
1
a Determined by H NMR spectroscopy, average of two runs.
The reaction of 77 with Cp2Zr(D)Cl resulted in a complete
loss of the methine peak in the 1H and 13C spectra. This signal
should exist as a triplet in the 13C spectrum due to splitting of
the carbon from the deuterium atom but was not evident. It was
anticipated that the carbon may not be observable due to the
lack of an Overhauser effect and signal splitting. We therefore
subjected N,N-diethylbenzamide 13C-enriched at the carbonyl
carbon to Cp2Zr(D)Cl and observed a triplet at 97 ppm. Last,
the 2H NMR spectrum of the deuterated intermediate showed a
peak at 5.83 ppm, confirming the origin and identity of the pre-
aldehydic proton. This data collectively give solid support to
compound III as the intermediate in this reaction.
As shown in Table 2, methoxymethyl (Weinreb) amides are
excellent substrates for the reaction. NMR spectroscopy of the
reaction of 1 and N-methyl-N-methoxy benzamide showed the
presence of a single set of methyl groups upfield from the
original amide peaks. The Weinreb-derived intermediate can
possibly exist as one of two constitutional isomers depending
upon which substrate heteroatom is bound to zirconium (V vs
VI/VII, Figure 4). Should Zr-N coordination predominate, it
is then possible for the existence of two diastereomers arising
from the nitrogen substituents occupying two chemically distinct
positions. 2D-NOESY experiments did not show a correlation
between the N,O-acetal methine peak and any other protons in
the molecule. This lack of an NOE interaction suggests that
structure V may be the identity of the Weinreb-derived
intermediate. This is not unexpected as the stability of the five-
membered ring is expected to be greater than that of the four-
membered ring.
Attempted crystallization of the intermediate derived from
77 at ambient temperatures resulted in the unexpected formation
of the µ-oxo zirconium dimer (80) after 24-48 h, which was
fully characterized by X-ray crystallography (eq 3).62 Temper-
ature reduction to -35 °C again resulted in the µ-oxo zirconium
species albeit after several weeks. This confirms that intermedi-
ate III is only transiently stable and it appears to degrade to
the zirconium dimer over time. The intermediate exists as a
pale-yellow oil when the solvent is removed in vacuo, which
has been previously noted for the organozirconium products of
the hydrozirconation of alkenes and alkynes.33 This property
obviously limits their characterization to solution NMR spec-
troscopy.33 The addition of halogens to the substrate (79) or
variation of the substituents on nitrogen (78) did not seem to
confer solidity or crystallinity to the intermediate.
1
Careful examination of the H NMR spectra revealed the
existence of another compound in the reaction mixture (), Figure
1). This minor compound is similar in all respects to the major
product with the most pronounced change in the chemical shift
for the methine proton at 5.07 ppm, a 0.76 ppm shift upfield
from the major peak. Both signals were visible in the 2H
spectrum, suggesting they are derived from the zirconium
reagent.
Commercial and freshly prepared versions of 1 are usually
contaminated with small to moderate amounts of Cp2ZrH2 (or
Cp2ZrD2 for the deuterated Schwartz reagent).60 We hypoth-
esized that it was quite likely that the minor compound could
be the result of the reaction of this dihydride with 1 or 2 equiv
of the amide substrate. When 77 was reacted with the reagent
containing an increased amount of the dihydride,61 the relative
intensity of the minor peak was increased along with the
formation of three new peaks within close proximity to the
original signal (along with corresponding signals for new
-CH2- and -CH3 peaks upfield). Thus, it appeared that the
minor component was due to reaction of the substrate amide
with amounts of a hydride contaminant, most likely Cp2ZrH2.
Further evidence for the identity of this compound came when
a substoichiometric amount of 1 was added to 77 followed by
the addition of Cp2ZrH2. The resulting spectrum showed an
increase in the relative intensity and integration area for the
minor peak at 5.07 and those at 2.65. New peaks in the Cp
region near 6.4 also accompanied this change. Additionally, the
amount of this minor compound relative to the major methine
peak seems to differ depending on the source (or lot) of 1.
We next turned our attention to events that precede interme-
diate formation. Because of the heterogenicity of the reaction
and very short reaction times, kinetic studies were not a viable
(59) 1H and 13C spectra are available in the Supporting Information of:
Suginome, M.; Uehlin, L.; Murakami, M. J. Am. Chem. Soc. 2004, 126,
13196-13197.
(60) Buchwald, S. L.; LaMaire, S. J.; Nielsen, R. B.; Watson, B. T.; King,
S. M. Tetrahedron Lett. 1987, 28, 3895-3898.
(62) The crystal structure for compound 80 can be found in the Supporting
Information. It was first reported in: Clarke, J. F.; Drew, M. G. B. Acta
Crystallogr. 1974, B30, 2267-2269.
(61) Gell, K. I.; Posin, B.; Schwartz, J.; Williams, G. M. J. Am. Chem. Soc.
1982, 104, 1846-1855.
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3416 J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007

Hydrozirconation of Amides to Aldehydes
A R T I C L E S
Scheme 3
Table 9. Solvent Effects on Reaction
investigational tool. We thus utilized simple competition studies
to provide information pertaining to the initial pathway for
formation of the intermediate.
A 1:1 mixture of each probe was subjected to 0.5 equiv of 1,
expecting this saturation to show a kinetic preference for the
reaction (Table 8). Accordingly, N,N-diethylbenzamide sub-
strates substituted at the para-position of the aryl ring with the
methoxy and the nitro substituents showed no statistically
significant preference by the reagent for either substrate (entry
1). The IR stretching frequencies for these amides are very close
at 1625 and 1622 cm-1. Thus, it is apparent that the electronic
substitution on the carbonyl side of these amides imparts little
to no kinetic selectivity in this reaction.
a Aldehyde yield after a 30 min period. b Time of reagent dissolution in
minutes.
activate the substrate.65 This “lone-pair activation” is also
supported by the selective reduction of tertiary amides in the
presence of esters as well as the reduced yields observed for
primary and secondary amides, all of which have direct
differences in the electron densities of the carbonyl oxygen.
Based on these results, it is clear that an increase in the carbonyl
electron densities of the substrate favors hydrozirconation and
these results further imply that the degree of resonance in the
amide linkage affects its kinetic reduction potential. This appears
to be in contrast to the reduction of amides to aldehydes with
LiAlH4 or LiAlH(OEt)3.8,21,22 In these cases, it has been noted
that substrates in which the unshared electron pair of the amide
is involved in resonance with a heterocyclic ring (N-acylated
pyrroles, indoles, and carbazoles) or in which the amide
resonance develops strain (aziridine amides) give aldehydes in
higher yields than do N,N-alkyl-substituted amides.8
It has been proposed that migratory insertion of zirconium
hydride to alkenes and alkynes is not the rate-limiting step and
that events prior to hydrozirconation may provide the energy
maximum.66 Whether this holds true for hydrozirconation of
tertiary amides is unconfirmed. Because of the experimental
difficulty associated with the kinetics of heterogeneous reactions,
we offer a qualitative explanation based on precedent and basic
observations.
Brown et al. have shown that aziridine amides are resistant
to over-reduction to the amine with lithium aluminum hydride,
affording mostly the corresponding aldehyde even in the
presence of 100% excess of the reagent.21,22 This is attributed
to the developing strain by lone pair donation during formation
of the iminium ion. The decrease in lone pair donation
(resonance) is apparent in the amide itself as reflected by the
higher IR carbonyl stretching frequency (1635 versus 1625 cm-1
for 9, Table 2), and the pyramidalization of the nitrogen was
observed in the solid state for the related 4-bromo-N-benzoyl-
aziridine.63 Additionally, Brown has reported evidence for this
amide distortion in which N-benzoylaziridine was shown to be
∼200 000-fold more susceptible to hydrolysis than N,N-dim-
ethylbenzamide.64 We had anticipated that amides of this type
would serve as useful probes to determine how the degree of
lone pair donation would affect the kinetic selectivity for this
reaction. Thus, a competitive reaction between an N-benzoyldi-
ethylamide and an N-benzoylaziridine (Table 8, entry 3) resulted
in a 22:1 selectivity for the diethyl amide, showcasing a kinetic
selectivity for the resonance-stabilized amide.
It was anticipated that the aromaticity requirement for the
nitrogen lone pair for the dimethylpyrrazole probe in entry 4
would also bias the reagent against this substrate.23 This was
again based on the IR carbonyl stretch observed for this amide
probe (1683 cm-1). Accordingly, a 19:1 preference for the
diethyl derivative was again observed for these compounds
(entry 4).
As a control, the 4-methoxy (1625 cm-1) and 4-ethoxy (1625
cm-1) diethylamide probes were compared under the same
conditions, resulting in a 1:1.1 mixture of the aldehyde products
(entry 2). Thus, it is clear that the presence of the larger ethoxy
group has little to no effect on the kinetic selectivity for this
reaction.
Wipf and Jahn have reported a comparison of the solvent
dependence for the rate of hydrozirconation of 1-hexene.31 They
disclosed a correlation between the coordinating ability of the
solvent and the rate of hydrozirconation to which they ascribed
solvent dissolution as the rate-determining step. Furthermore,
it was observed that the reaction is first order in Cp2Zr(H)Cl in
oxetane and zeroth order in reagent when carried out in THF.
They conclude that in THF the rate-limiting step is dissolution
of the oligomeric reagent and for oxetane the rate of dissolution
is comparable to the rate of hydrozirconation.
Not surprisingly, the hydrozirconation of tertiary amides
displays a similar solvent dependency (Scheme 3 and Table 9).
Strongly coordinating solvents favor hydrozirconation, whereas
weakly or non-coordinating solvents slow the reaction. Reactions
These results collectively suggest that the reagent prefers
substrates that do not decrease nitrogen lone pair availability.
The participation for the nitrogen lone pair does not seem to be
required for hydrozirconation to occur, but seems to kinetically
(65) Compound 81 was treated independently with approximately 1.5 equiv of
Cp2Zr(H)Cl, and the aldehyde was obtained as a 2:1 mixture with the
starting material (as judged by 1H NMR) along with 30% of p-methoxy-
benzyl alcohol. This shows that 81 is a viable substrate for hydrozirconation.
The formation of the alcohol is most likely due to instability of the
intermediate to the reagent as the nitrogen lone pair should be less available
for coordination to zirconium.
(63) Shibaeva, R. P.; Atovmyan, L. O.; Kostyanovskii, R. G. Dokl. Bulg. Akad.
Nauk. 1968, 12, 669.
(64) SÄlebocka-Tilk, H.; Brown, R. S. J. Org. Chem. 1987, 52, 805-808.
(66) Doherty, N. M.; Bercaw, J. E. J. Am. Chem. Soc. 1985, 107, 2670-2682.
9
J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007 3417

A R T I C L E S
Scheme 4
Spletstoser et al.
1H NMR and HPLC analysis, displaying the apparent irrevers-
ibility of the reaction.
The formation of aldehydes from the reaction intermediate
by the addition of water raises the question if other nucleophiles
can effectively react with the intermediate. The addition of a
solution of p-anisidine in anhydrous THF to the reaction
intermediate resulted in imine formation (82, eq 4) upon analysis
of the crude reaction mixture after hexanes precipitation of the
zirconium oxide byproducts and filtration.70 This addition was
observed by NMR spectroscopy, and initially the amount of
imine product was small with large peaks corresponding to
unreacted p-anisidine and the intermediate zirconacycle pre-
dominating (see Supporting Information). However, over time
(ca. 40 min) the imine signals grew as the intermediate and
nucleophile signals decreased. The diastereotopic ethyl groups
on the amine slowly converged to defined multiplicities (a triplet
for the -CH3 and a quartet for the -CH2- groups) as expected
for freely rotating ethyl groups. These ethyl peaks retained their
upfield chemical shifts, suggesting that the amine component
stays bound to the zirconium. This is supported by the inability
to recover the amine portion of the carboxamide and the loss
of lactam substrates (vide supra). Furthermore, the diastereotopic
Cp signals resolved into a single Cp resonance as the zirconium
byproduct formed. This was accompanied by a yellowish
precipitation that was evident in the NMR tube. Some aldehyde
was apparent in the initial experiment, most likely from
adventitious water in the p-anisidine solution. The addition of
aniline afforded imine 82b in the same manner as for p-
anisidine, but the reaction rate was significantly slower.
This observation is significant as Ganem has reported the
conversion of secondary carboxamides to imines using the
Schwartz reagent that apparently follows a mechanistically
distinct pathway.38 This process could be considered comple-
mentary to Ganem’s method, allowing tertiary amides to be
cleanly converted to the corresponding imines. Thus, the tertiary
carboxamide can now be viewed as an accessible and chemically
robust precursor or “protecting group” for the more labile
aldehyde or imine derivatives, giving it advantages over the
generally more reactive ester functionality.
in THF tend to be complete in ca. 10-15 min for most
substrates, while non-coordinating solvents such as chloroform
afford no hydrozirconation products after extended reaction
periods.67 Moderately to weakly coordinating solvents such as
dioxane and toluene slow the rate of reaction and result in
reduced reaction yields after an arbitrary time point. Table 8
outlines the yields after a reaction time point and gives the time
of dissolution (tdiss) of the reagent for each solvent. For these
cases, tdiss can be viewed as a crude indicator of the rate of the
reaction as it has been generally noted that the time of reagent
dissolution marks the completion of the reaction.33 We have
noticed that the time it takes for the solution to clear corresponds
to a complete loss of starting material by TLC (for reactions
that run to completion in THF). Because Cp2Zr(H)Cl is an
insoluble polymer, it is believed that the reaction rate is limited
by the small amount of reagent in solution. Quite possibly, the
more strongly coordinating solvents (THF, oxetane, and pyri-
dine) are better able to dissociate these Zr-H polymers (e.g.,
k1THF > k1toluene, Scheme 3) and allow for reagent solvation as
proposed by Wipf for alkene hydrozirconation. The coordinating
solvent/ligand exchanges with the amide and hydrozirconation
ensue. Although speculative, this solvent dependence seems to
support reagent dissolution as the rate-determining step. With
pyridine, dissolution (tdiss) occurs almost instantly, resulting in
a straw-colored solution, but gives poor chemical yields. We
presume that pyridine is better able to dissolve the Schwartz
reagent but forms a highly stable 18-electron complex that is
resistant to exchange with the amide substrate.68 Tetrahydrofuran
and oxetane are optimal solvents, in that reagent dissolution is
favorable but does not bind too strongly. This is probably due
to the availability of the nonbonding electron pairs from
distortions of the tetrahedral geometry (of oxygen) caused by
constraint in a four- or five-membered ring. Dioxane has a more
tetrahedral geometry, likely impeding k1 and making reagent
dissolution impractically slow.
We anticipated that the migratory insertion event would be
irreversible for this reaction based on the high oxophilicity of
zirconium, the saturated coordination sphere of zirconium in
the intermediate, and the polarized M-H bond nature of early
transition metal hydrides.69 This would be in contrast to that of
olefin hydrozirconation where the actual insertion event has been
proposed to be reversible.31 To test this hypothesis, we subjected
a small excess of amide 2 to 1 (0.8 equiv) and allowed them to
react completely (Scheme 4). Upon consumption of 1, an
equimolar amount of amide 81 was added to the reaction
mixture. An irreversible hydrozirconation would result in
recovery of only aldehyde 9, while a reversible event should
give a mixture of the aldehydes over time. Thus, a 1.5 h
incubation afforded exclusively aldehyde 9 as determined by
In summary, we have reported an investigation of the
hydrozirconation of tertiary amides with the Schwartz reagent,
outlining the scope and limitations for the transformation. We
have demonstrated that hydrozirconation is the mildest and most
general method for the formation of aldehydes from amides with
the highest functional group tolerance reported to date. This
reaction proceeds with very short reaction times and gives
(67) This observation could also be due to H-Cl exchange between the reagent
and solvent.
(68) The addition of pyridine to 1 before the addition of substrate results in a
deep red color that changes upon the addition of substrate in pyridine.
(69) Fachinetti, G.; Floriani, C.; Roselli, A.; Pucci, S. J. Chem. Soc., Chem.
Commun. 1978, 269-270.
(70) The crude proton spectrum clearly shows the imine product with excess
p-anisidine. See the Supporting Information.
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3418 J. AM. CHEM. SOC. VOL. 129, NO. 11, 2007

Hydrozirconation of Amides to Aldehydes
A R T I C L E S
excellent to good yields of aldehyde with an unprecedented
chemoselectivity profile. Importantly, the reaction can be
performed using standard inert-atmosphere benchtop techniques
and employs a convenient workup procedure. Also presented
is the utility of the reagent to effectively reduce secondary and
primary amides albeit with reduced yields. We have character-
ized the intermediate for the reduction as well as provided
insight into the possible pathways for formation of the inter-
mediate and the aldehyde product. The high chemoselectivity
of this reaction and the robust nature of the amide functional
group could allow one to consider this usually inert moiety as
a protected form of the more reactive aldehyde and imine
oxidation states.
X-ray determination, and Dr. David Vander Velde and Sarah
Neuenswander for NMR assistance. J.T.S. is a recipient of an
American Foundation for Pharmaceutical Education predoctoral
fellowship and a Department of Defense predoctoral fellowship
(DAMD17-99-1-9243). J.M.W. would like to thank the National
Institutes of Health for a predoctoral training grant (GM-08545).
This work was supported by the NIH (CA-084173).
Supporting Information Available: General methods, ex-
perimental procedures, a complete listing of authors for ref 47a,
and spectral data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We would like to thank Profs. Jon Tunge
and Apurba Dutta for useful discussions, Dr. Doug Powell for
JA066362+
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