Zirconium-mediated conversion of amides to nitriles: A surprising additive effect

Article abstract of DOI:10.1002/anie.200461064

Chloride coordination is the key: Dimethylzirconocene reacts with amides to form methylzirconium amide complexes. On heating, in the presence of a chloride source, these compounds are converted into N-acylimidozirconocene complexes that react intramolecularly to form the corresponding nitrile compounds (see scheme; Cp = C₅H₅). Mechanistic studies reveal that chloride coordination to zirconium is required for this transformation to occur.

Full text of DOI:10.1002/anie.200461064

Angewandte
Chemie
Reaction Mechanisms
Zirconium-Mediated Conversion of Amides to
Nitriles: A Surprising Additive Effect**
Rebecca T. Ruck and Robert G. Bergman*
ꢀ
The cyano (C N) functional group is useful for the introduc-
tion of nitrogen into organic molecules for the activation of
À
adjacent C H bonds and for efficient conversion into other
functional groups, such as amines and ketones.[1] The dehy-
dration of primary amides to nitriles has long relied upon the
Scheme 1.
use of strong dehydrating agents, such as P2O5 or SOCl2.[3]
[2]
Such transformations often require high temperatures and
lead to multiple by-products depending on the functional
groups present in the starting amide. The lone early-transi-
tion-metal-mediated process reported for this dehydration
involves the use of TiCl4 and base at 08C;[4] however, this
method has largely been ignored in synthetic applications.
Herein, we present a functionally simple method for prepar-
ing nitriles from primary amides that appears to proceed
through the corresponding N-acylimidozirconocene complex.
A detailed mechanistic study has been carried out that
elucidates a remarkable additive effect on this reaction.
Isotopic labeling and kinetic studies reveal an unprecedented
reaction pathway in imidozirconium chemistry.
We recently reported that N-sulfonyl, sulfinyl, and
phosphinyl imines insert into the metal–carbon-ring bond of
azazirconacyclobutene 1 to generate new six-membered-ring
zirconacycles 3 (see Scheme 1).[5] Upon heating, these com-
plexes undergo retro-[4+2] cycloadditions to generate a,b-
unsaturated imines and inactive imidozirconocene com-
plexes.[5] N-Benzoyl benzaldimine (2)[6] was also a competent
substrate in this chemistry, but only the a,b-unsaturated imine
product 4 (and not the new imidozirconium species) was
detected by 1H NMR spectroscopy. Instead, we identified the
quantitative formation of benzonitrile (6), presumably
formed by deoxygenation of the N-benzoylimidozirconocene
complex 5 (Scheme 1; Cp = C5H5).
We subsequently prepared an alternative zirconium
precursor to the imido compound 5 from the reaction
between the lithium salt of benzamide and [Cp2Zr(CH3)Cl][7]
(Method 1, Scheme 2). Heating this compound to 1508C in
benzene or THF (reactions carried out in sealed tubes, for full
experimental details see the Supporting Information) led to
Scheme 2.
methane elimination and afforded benzonitrile in quantita-
tive yield from the zirconium starting material, providing a
two-step synthetic sequence for the clean and quantitative,
albeit slow, conversion of primary amides to nitriles. Based on
earlier precedent,[8] we treated benzamide with
[Cp2Zr(CH3)2] (8) at 658C to generate the expected methyl-
zirconium amide 7 (Scheme 2, Method 2).[9] However, in
contrast to our observations in Method 1, prolonged heating
of 7 prepared by Method 2 at temperatures as high as 1658C
failed to provide the expected nitrile and left 7 intact.
X-ray diffraction studies conducted on crystals of com-
pound 7 prepared by Method 1 revealed that it was an 18-
electron complex with the carbonyl oxygen atom coordinated
À
À
to the zirconium center (Figure 1). The Zr N and Zr O bond
lengths were identical at 2.30 Š. Surprisingly, a chloride anion
was located in the crystal lattice. This finding led us to suspect
that residual LiCl by-product from the preparation of 7 by
Method 1 may facilitate the desired nitrile formation, thereby
accounting for the observed reactivity difference between 7
prepared by Methods 1 and 2. Indeed, heating compound 7
prepared by Method 2 in the presence of 0.2–2 equivalents of
LiCl led to quantitative formation of benzonitrile (Scheme 2)
and we were now able to carry out the reaction at 1058C in the
presence of added LiCl. The reaction is catalytic in LiCl, but
0.5 equivalents were used for synthetic purposes.
[*] Dr. R. T. Ruck, Prof. R. G. Bergman
Department of Chemistry
University of California, Berkeley
Berkeley, CA 94720 (USA)
Fax: (+1)510-642-2156
E-mail: bergman@cchem.berkeley.edu
[**] This work was supported by the NationalInstitutes of Heatlh (GM-
25459) and by an NIH post-doctoral fellowship to R.T.R. We thank
Dr. Fred Hollander and Dr. Allen Oliver of the UC Berkeley CHEXRAY
facility for the X-ray crystal structure determination.
Supporting information (full experimental details) for this article is
available on the WWW under http://www.angewandte.org or from
the author.
Angew. Chem. Int. Ed. 2004, 43, 5375 –5377
DOI: 10.1002/anie.200461064
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Communications
catalyzing this chemistry was required. The possibility that
traditional Lewis bases could effect this chemistry was ruled
out since these reactions were conducted in neat THF, known
to be an excellent ligand for zirconium. Other lithium salts,[10]
some soluble in THF, were screened in the decomposition
reaction of complex 7. However, all these Li+ additives
performed poorly relative to LiCl, requiring increased
temperatures and/or reaction times. A series of tetraalkylam-
monium salts were also screened as additives; we were
pleased to find that the soluble salt tetra-n-hexylammonium
chloride (hex4NCl) catalyzed the formation of benzonitrile
from 7 with t1/2 ꢁ 20 min (versus t1/2 ꢁ 80 min with LiCl). These
results suggest that interaction of chloride (rather than
lithium) with zirconium compound 7 facilitates the genera-
tion of the imidozirconocene complex 5. Consistent with this
assessment is the observation that sodium isopropoxide and
potassium tert-butoxide also catalyzed nitrile formation,
albeit at diminished rates, probably because of the partial
insolubility of the alkoxide additives. Further, based on the
results of Scheme 1, conversion of the imidozirconocene 5
into benzonitrile does not require the presence of an added
anion source.
Figure 1. ORTEP diagram of methylzirconium benzamide complex 7
(thermal ellipsoids set at 50% probability). Also shown are the chlo-
ride ion and two benzene molecules found in the lattice. A line draw-
ing is provided for clarity.
A variety of primary amides were competent substrates
for this transformation, affording the corresponding nitrile
compounds in excellent yields (Table 1). Intermediate meth-
ylzirconium amide complexes were detected by 1H NMR
spectroscopic monitoring of the transformation. In addition to
the parent benzamide (entry 1), electron-rich (entries 2 and
3) and electron-poor (entries 4 and 5) aryl amides underwent
this reaction efficiently. The reaction
With this soluble additive in hand, we could investigate
the mechanism of the overall reaction and the surprising
effect of added chloride ion. A crossover experiment was
conducted, in which 2.2 equivalents of [Cp2Zr(CH3)2] were
treated with one equivalent each of p-toluamide and 15N-
labelled benzamide in the presence of hex4NCl [Eq. (1)]. No
crossover was observed in this reaction: only unlabeled p-
tolerated the increased steric hin-
drance of o-toluamide (entry 6). Pri-
mary alkyl amides with and without a-
protons were also competent sub-
strates, with hexanoamide (entry 7)
and trimethylacetamide (entry 8)
each providing the corresponding nitrile in excellent yield.
To study the mechanism of this transformation and
elucidate the role of LiCl, a soluble additive capable of
tolunitrile and 15N-labeled benzonitrile were detected by
15N NMR spectroscopy and GC/MS.[11]
Kinetic studies were undertaken to determine the rate law
for the reaction of complex 7 with hex4NCl. Disappearance of
1
7 at a given [hex4NCl] was monitored by H NMR spectros-
Table 1:
copy. These data revealed a first-order dependence on [7] and
provided the first-order rate constant, k, from the equation,
ln[7] = Àkt.[12] Plotting values of k determined at different
concentrations of hex4NCl provided a linear correlation
between the two variables and a first-order dependence on
[hex4NCl] (Figure 2). The rate law for the decomposition of 7
was thus determined to be: d[7]/dt = Àk[hex4NCl][7]. Rates
determined over the temperature range of 105–1508C gave
activation parameters DH° = 18 Æ 2 kcalmolÀ1 and DS° =
À16 Æ 5 calmolÀ1 KÀ1, consistent with a bimolecular rate-
determining step.
Entry Amide
Nitrile[a]
Yield [%][b]
1
2
3
4
5
benzamide
p-methoxybenzamide
p-toluamide
p-bromobenzamide
p-trifluoromethyl-benza- p-trifluoromethyl-benzo- 93
benzonitrile
p-methoxybenzonitrile
p-tolunitrile
100
97
91
p-bromobenzonitrile
92 (83)[c]
mide
nitrile
6
7
8
o-toluamide
hexanoamide
trimethylacetamide
o-tolunitrile
hexanenitrile
trimethylacetonitrile
98
Having established the rate law, we conducted a kinetic
92
À
96[d]
isotope effect (KIE) study using compound 7 and its N D
analogue. The deuterated analogue (7-D) was prepared by
treatment of [Cp2Zr(CH3)2] with [D2]benzamide. Comparison
of the decomposition rates for 7 and 7-D enabled the
measurement of a deuterium isotope effect of kH/kD = 1.07.
This KIE very close to unity stands in stark contrast to the
[a] 1H NMR spectra of all the nitrile products were correlated with
authentic material. [b] Yield after 15 h relative to an internal standard by
1H NMR spectroscopy; all starting amide had been consumed. [c] Value
in parentheses is the yield of isolated product after chromatography.
[d] Reaction required 48 h to proceed to completion.
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Chemie
[3] J. A. Krynitsy, H. W. Carhart, Org. Synth. Coll. Vol. IV
1963, 436.
[4] W. Lehnert, Tetrahedron Lett. 1971, 1501.
[5] R. T. Ruck, R. G. Bergman, Organometallics 2004, 23,
2231.
[6] R. Kupfer, S. Meier, E.-U. Wꢀrthwein, Synthesis 1984, 688.
[7] [Cp2Zr(CH3)Cl] was prepared via a conproportionation
reaction of [Cp2Zr(CH3)2] and [Cp2ZrCl2] in toluene at
1358C.
[8] P. J. Walsh, F. J. Hollander, R. G. Bergman, Organometal-
lics 1993, 12, 3705.
[9] Dimethylzirconocene may be purchased from Strem. In
this case, it was prepared from [Cp2ZrCl2]: S. Couturier, B.
Gautheron, J. Organomet. Chem. 1978, 157, C61.
[10] LiOTf, LiBr, LiBPh4 and LiBARF20 (BARF20=[B(C6F3)4]À)
were screened as additives.
[11] A control experiment was conducted, in which 15N-labeled
benzonitrile and 15N-labeled tolunitrile were shown to have
distinct resonance signals in the 15N NMR spectrum.
[12] All reactions were conducted in the presence of catalytic
concentrations of hex4NCl.
[13] The reaction used in KIE studies is shown in Equation (2).
The reaction rate was shown to be independent of [alkyne]
under the conditions employed.
Figure 2. a) Graph for determining the order in [7] at two concentrations of
hex4NCl. b) Graph for determining the order in [hex4NCl].
[14] Hydrogen bonding to the NH proton was ruled out as a possible
mechanism because chloride can be used to accelerate the
following reaction [Eq. (3)].
value of kH/kD = 3.6 determined for formation of a common
N-arylimidozirconocene complex from the methylzirconium
amide precursor.[13] The collective data presented herein are
most consistent with a mechanism in which rate-determining
chloride-association takes place with displacement of the
carbonyl oxygen atom from zirconium.[14] The resulting
intermediate, in a fast step, undergoes methane elimination
to generate the N-acylimidozirconium species, which goes on
to form the product nitrile. Presumably, chloride-assisted
oxygen de-chelation is required for the complex to adopt the
conformation necessary for reductive elimination.
In summary, we have developed a new method for the
dimethylzirconocene-mediated conversion of primary amides
to the corresponding nitriles in excellent yields. This trans-
formation proceeds via the N-acylimidozirconocene complex,
formation of which is dependent upon an unprecedented
chloride-anion additive effect. Full experimental details can
be found in the Supporting Information. A related paper
describing catalytic imine insertions into azazirconacyclobu-
tenes also appears in this issue.[15]
[15] R. T. Ruck, R. L. Zuckerman, S. W. Krska, R. G. Bergman,
Angew. Chem. 2004, 116; Angew. Chem. Int. Ed. 2004, 43
Received: June 24, 2004
Keywords: additive effects · amides · kinetics · nitriles ·
.
zirconium
[1] S. R. Sandler, W. Karo in Organic Functional Group Prepara-
tions, Academic Press, San Diego, 1983, chap. 17.
[2] D. B. Reisner, E. C. Coring, Org. Synth. Coll. Vol. IV 1963, 144.
Angew. Chem. Int. Ed. 2004, 43, 5375 –5377
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