Stereochemistry of imine reduction by a hydroxycyclopentadienyl ruthenium hydride

Article abstract of DOI:10.1021/ja056402u

The stereochemistry of hydrogen transfer from [2,5-Ph₂-3,4- Tol₂(η⁵-C₄COD)]Ru(CO)₂D to N-aryl imines to give amine complexes was shown to be mostly trans stereospecific. Stereospecific hydrogen transfer is proposed to generate an amine and a coordinatively unsaturated ruthenium intermediate in close proximity. Coordination of the amine is proposed to occur faster than lone pair inversion of the amine. In contrast, hydrogen transfer to N-alkyl imines is stereorandom. It is proposed that stereochemistry is lost in part due to the reversibility of the hydrogen transfer being faster than amine coordination.

Full text of DOI:10.1021/ja056402u

Published on Web 01/27/2006
Stereochemistry of Imine Reduction by a
Hydroxycyclopentadienyl Ruthenium Hydride
Charles P. Casey,* Galina A. Bikzhanova, and Ilia A. Guzei
Contribution from the Department of Chemistry, UniVersity of Wisconsin,
Madison, Wisconsin 53706
Received September 17, 2005; E-mail: casey@chem.wisc.edu
Abstract: The stereochemistry of hydrogen transfer from [2,5-Ph2-3,4-Tol2(η5-C4COD)]Ru(CO)2D to N-aryl
imines to give amine complexes was shown to be mostly trans stereospecific. Stereospecific hydrogen
transfer is proposed to generate an amine and a coordinatively unsaturated ruthenium intermediate in
close proximity. Coordination of the amine is proposed to occur faster than lone pair inversion of the amine.
In contrast, hydrogen transfer to N-alkyl imines is stereorandom. It is proposed that stereochemistry is lost
in part due to the reversibility of the hydrogen transfer being faster than amine coordination.
Scheme 2
Introduction
Shvo discovered that the diruthenium bridging hydride
complex {[2,3,4,5-Ph4(η5-C4CO)]2H}Ru2(CO)4(µ-H) (1-S) is an
efficient catalyst for the hydrogenation of aldehydes and
ketones1 and for transfer hydrogenation of ketones using
alcohols as the reducing agent.2 In the reduction of ketones to
alcohols, the mononuclear hydroxycyclopentadienyl ruthenium
hydride [2,3,4,5-Ph4(η5-C4COH)]Ru(CO)2H (2-S) was proposed
to be the active reducing agent and was shown to reduce
aldehydes and ketones (Scheme 1).1b,1c
Scheme 1
More recently, the mechanistic aspects of imine reduction
leading to ruthenium amine complexes3,4 have been investi-
gated.5,6 We reported detailed mechanistic studies of the
reduction of a series of imines having different electronic
properties.5 Reduction of N-aryl imines displayed large isotope
effects consistent with rate-limiting concerted hydrogen transfer,
reactivity that mirrors that of aldehyde and ketone reduction.
However, reduction of more electron-rich N-alkyl imines showed
inverse kinetic isotope effects, imine isomerization, and deu-
terium scrambling (Scheme 3).5 These phenomena were ex-
Based on detailed mechanistic studies on the related tolyl
complex [2,5-Ph2-3,4-Tol2(η5-C4COH)]Ru(CO)2H (2), including
observation of primary deuterium isotope effects for transfer
of both OH and RuH, we proposed a mechanism involving
concerted transfer of proton and hydride to aldehyde outside
the coordination sphere of the metal (Scheme 2).3
Scheme 3
(1) (a) Shvo, Y.; Czarkie, D.; Rahamim, Y. J. Am. Chem. Soc. 1986, 108,
7400. (b) Menashe, N.; Shvo, Y. Organometallics 1991, 10, 3885. (c)
Menashe, N.; Salant, E.; Shvo, Y. J. Organomet. Chem. 1996, 514, 97.
(2) (a) Almeida, M. L. S.; Beller, M.; Wang, G.-Z.; Ba¨ckvall, J.-E. Chem.
Eur. J. 1996, 2, 1533. (b) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall,
J.-E. Angew. Chem., Int. Ed. Engl. 1997, 36, 1211. (c) Persson, B. A.;
Larsson, A. L. E.; Le Ray, M.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 1999,
121, 1645. (d) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J.-E. J. Org. Chem.
1999, 64, 5237. (e) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J.-E. Org.
Lett. 2000, 2, 1037. (f) Laxmi, Y. R. S.; Ba¨ckvall, J.-E. Chem. Commun.
2000, 611.
(3) Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R. K.; Kavana, M. J.
Am. Chem. Soc. 2001, 123, 1090.
9
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J. AM. CHEM. SOC. 2006, 128, 2286-2293
10.1021/ja056402u CCC: $33.50 © 2006 American Chemical Society

Stereochemistry of Imine Reduction
A R T I C L E S
Scheme 4
Scheme 5
Scheme 6
plained by a change in the rate-limiting step from hydrogen
transfer to amine coordination.
We also have studied the reduction of imines in the presence
of free amines to distinguish between mechanisms involving
coordination of nitrogen before reduction (concurrent with Cp
ring slippage)7 and mechanisms involving generation of amines
and coordinatively unsaturated ruthenium intermediates.8 Re-
duction of an amine-substituted imine resulted in the formation
of complexes of both the newly generated amine and the pre-
existing amine in a 1:1 ratio (Scheme 4). This combination of
products requires transfer of hydrogen from 2 to amine-
substituted imine to generate a diamine and coordinatively
unsaturated ruthenium intermediate which can be trapped by
either amine within the solvent cage.
In contrast, reduction of an imine in the presence of an
external amine resulted in only the complex formed from
complexation of the newly generated amine (Scheme 5). This
indicates that even though there may be competition between
amines inside the solvent cage, amine diffusion from the solvent
cage is much slower than amine coordination to the metal center.
Since trapping of amines by coordination to the ruthenium
center is even faster than diffusion from the solvent cage, we
thought that amine coordination to ruthenium might be even
faster than nitrogen inversion and provide the opportunity for
determination of the stereochemistry of imine reduction by 2.
Here we report deuterium labeling experiments that establish
the predominant trans stereochemistry of the reduction of N-aryl
imines by 2.
ruthenium occurs before diffusion apart. Since the newly
generated amine is so rapidly trapped by coordination and since
the amine complex has configurational stability, we set out to
determine the stereochemistry of imine reduction by 2.
Prior to our most recent trapping experiment studies that ruled
out a ring slippage mechanism,8 we were looking for experi-
ments that might distinguish between ring slip mechanisms
involving prior coordination of the imine and mechanisms
involving transfer of hydrogen without prior imine coordination.
We thought that determination of the stereochemistry of imine
reduction would provide information to help differentiate
between these mechanisms. Cp ring slip and substrate coordina-
tion prior to the reduction step, as proposed by Ba¨ckvall, would
be expected to lead to trans addition of deuterium (Scheme 6).
Hydrogen transfer outside the coordination sphere might lead
to either cis or trans addition of deuterium depending on the
orientation assumed by the newly generated nitrogen lone pair
(Scheme 7).
Results
Amine nitrogen inversion is extremely rapid (∆Gq ∼ 7.5 kcal
mol-1) and has until now precluded determination of the
stereochemistry of reduction of imines by any reagent or
catalytic system.9,10 In the reduction of imines by 2, the amine
is generated within a solvent cage and complexation to
Before examination of the stereochemistry of reduction of
imines by 2-RuDOD, we prepared the unlabeled amine
complexes to study their spectral properties (Scheme 8).
(4) Abed, M.; Goldberg, I.; Stein, Z.; Shvo, Y. Organometallics 1988, 7, 2054.
(5) Casey, C. P.; Johnson, J. B. J. Am. Chem. Soc. 2005, 127, 1883.
(6) 1-S is an effective catalyst for the reduction of imines via hydrogen transfer
from alcohols. Samec, J. S. M.; Ba¨ckvall, J.-E. Chem. Eur. J. 2002, 8,
2955.
(7) Csjernyik, G.; EÄ ll, A. H.; Fadini, L.; Pugin, B.; Ba¨ckvall, J.-E. J. Org.
(9) Rauk, A.; Allen, L. C.; Mislow, K. Angew. Chem., Int. Ed. Engl. 1970, 9,
Chem. 2002, 67, 1657.
(8) Casey, C. P.; Bikzhanova, G. A.; Guzei, I. A. J. Am. Chem. Soc. 2005
127, 14062.
400.
(10) Bushweller, C. H.; O’Neil, J. W.; Bilofsky, H. S. Tetrahedron 1972, 28,
2697.
9
J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006 2287

A R T I C L E S
Scheme 7
Casey et al.
Scheme 8
resonance of 4c at δ 2.39 gave rise to two clear signal
enhancements at δ 1.65 (NHX, 9% nOe) and 3.57 (HA, 4% nOe)
(Figure 2). Irradiation of the HB resonance at δ 3.77 of 4c
resulted in two significant enhancements at δ 1.65 (NHX,
5% nOe) and 3.57 (HA, 16% nOe). The nOe between the
methyl group and HA but not HB establishes conformation I
for 4c.
In a NOESY 1D NMR experiment on 4d, irradiation of the
o-methyl resonance at δ 2.78 gave rise to two clear signal
enhancements at δ 4.15 (HA, 5% nOe) and 6.62 (m-H of mesityl,
4% nOe). Irradiation of the HB resonance at δ 3.85 of 4d
resulted in two significant enhancements at δ 4.15 (HA, 16%
nOe) and 4.78 (NHX, 4% nOe). These nOe results require
conformation I for 4d (Figure 2).
Stereochemistry of hydrogenation of aryl aldimines can be
determined by 1H NMR spectroscopy since ruthenium benzyl-
amine complexes 4a-4d have diastereotopic benzyl hydrogens.
The benzyl hydrogen with large geminal and large vicinal
couplings is defined as HA, and the benzyl hydrogen with large
1
geminal and small vicinal couplings is defined as HB. The H
NMR resonance of HA, which is anti to a proton HX on nitrogen,
is an apparent triplet due to similar couplings to HB and HX.
The resonance of HB, which is gauche to HX, appears at lower
frequency than HA as a doublet of doublets with a larger
coupling to HA and smaller one to HX. To determine which of
the benzylic protons is HA and which is HB, we need to know
the major rotamer about the N-benzyl bond (Figure 1).
Figure 2. NOESY 1D NMR spectroscopy data for 4c and 4d.
In summary, NOESY 1D NMR spectroscopy on 4c and 4d,
the X-ray structure of 4a, and DFT calculations all support the
assignment of conformation I with phenyl and Ru anti for amine
complexes 4a-4d. With the conformation of 4a-4d firmly
established, it is possible to determine the stereochemistry of
reduction of imines by 2-RuDOD. trans-Addition of deuterium
would generate a ruthenium amine complex with deuterium in
place of HB and the benzyl hydrogen resonance of HA would
Figure 1. Three rotamers about the N-benzyl bond of ruthenium amine
complexes.
1
appear as a broad singlet in the H NMR spectrum. Similarly,
cis-addition of deuterium would result in the appearance of only
the HB benzyl hydrogen resonance.
Rotamer III, which has Ph gauche to both Ru and R, would
be expected to have similar coupling constants to HX and was
excluded based on the observation of very different JAX (13
Hz) and JBX (2 Hz). The X-ray crystal structure of 4a (Figure
1S, Supporting Information) has conformation I with Ru anti
to Ph. DFT calculations on a simplified analogue of 4a,
(C5H4O)(CO)2RuNHMe(CH2Ph), at the B3LYP/LANL2DZ
level of theory also showed that conformation I was 2.3 kcal
mol-1 more stable than II with Ru gauche to Ph.11
trans-Stereochemistry of Reduction of p-Ph-C6H4Nd
CHTol by 2-RuDOD. When p-Ph-C6H4NdCHTol was added
to a toluene-d8 solution of 2-RuDOD at -60 °C, broad singlets
corresponding to 0.87 HA (δ 4.27) and 0.13 HB (δ 4.08) of 4b
1
appeared in the H NMR spectrum within 2 min at -60 °C
(Scheme 9).12 Complete disappearance of the tolyl methyl
resonances at δ 1.85 of 2-RuDOD and appearance of new
resonances for inequivalent tolyl methyl groups of 4b at δ 1.77
1
Conformations I and II were experimentally distinguished
by NOESY 1D NMR spectroscopy. Irradiation of the N-Me
and 1.80 were also observed in the H NMR spectrum. The
(12) Integrations were measured relative to the tolyl methyl group resonances,
were within 5% of 1.00, and normalized to 1.00.
(11) See Supporting Information for details of DFT calculations.
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2288 J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006

Stereochemistry of Imine Reduction
A R T I C L E S
Scheme 9
Scheme 10
Scheme 11
formation of a 7:1 ratio of trans hydrogenation product (trans-
4b) : cis hydrogenation product (cis-4b) shows that reduction
occurs mainly by trans addition of hydrogen.
tolyl methyl groups of 4a at δ 1.78 and 1.82 were also observed
in the H NMR spectrum. The observation of a 2:1 ratio of
1
trans-4a:cis-4a shows that imine reduction occurs by predomi-
nant trans addition. Upon warming to room temperature, the
mixture of trans-4a and cis-4a equilibrated to a 1:1 ratio.
Stereorandom Products from Reduction of 2,4,6-Me3-
C6H2NdCHPh. To determine the effect of steric crowding at
nitrogen on the stereochemistry of reduction, the reaction of
N-benzylidene-2,4,6-trimethylaniline by 2-RuDOD in toluene-
d8 was studied. No reduction was seen at -60 °C, but reduction
proceeded slowly at -10 °C. Two broad singlets corresponding
In a similar experiment, a 5:1 ratio of HA:HB was observed.
Differences may be the result of some product isomerization
upon inadvertent warming of samples when NMR tubes are
inserted into the pre-cooled spectrometer. No isomerization of
trans-4b was seen at -60 °C and only slow isomerization was
seen at -40 °C. Upon warming to room temperature, the
mixtures of trans-4b and cis-4b equilibrated to a 1:1 ratio
probably due to the inversion at the nitrogen. This equilibration
presumably occurs through complete transfer of the proton from
nitrogen to oxygen, inversion at the nitrogen center,13 rotation
around the ruthenium nitrogen bond, and proton transfer back
on nitrogen (Scheme 10).
trans-Stereochemistry of Reduction of PhNdCHPh by
2-RuDOD. When N-benzylideneaniline was added to a toluene-
d8 solution of 2-RuDOD at -60 °C, broad singlets correspond-
ing to 0.66 HA (δ 4.16) and 0.34 HB (δ 4.01) appeared in the
1H NMR spectrum within 2 min at -60 °C (Scheme 11).12
Complete disappearance of the tolyl methyl resonances at δ 1.85
of 2-RuDOD and appearance of new resonances for inequivalent
1
to 0.53 HA (δ 3.97) and 0.47 HB (δ 3.74) appeared in the H
NMR spectrum at -10 °C (Scheme 12).12 Complete disappear-
ance of the tolyl methyl resonances at δ 1.85 of 2-RuDOD and
appearance of new resonances for inequivalent tolyl methyl
1
groups of 4d at δ 1.70 and 1.76 were also observed in the H
NMR spectrum. The 1:1 ratio of trans-4d:cis-4d is likely the
result of fast equilibration of trans and cis reduction products
at -10 °C. Consequently, no information is obtained about the
initial stereochemistry of reduction in this experiment.
Low trans-Stereospecificity in Reduction of MeNdCHPh
by 2-RuDOD. Since alkylamines are more basic and also have
higher inversion barriers than arylamines,9,14 we thought that
reduction of N-alkyl imines by 2-RuDOD might proceed with
higher stereospecificity. We reasoned that the initially generated
alkylamine would invert more slowly and complex more rapidly
to ruthenium and thus retain whatever its initial stereochemistry.
When N-benzylidenemethylamine was added to a toluene-d8
solution of 2-RuDOD at -60 °C, broad singlets corresponding
(13) While the nitrogen center in metal amides is flat for electron-deficient metal
species, amide ligands bound to 18e metal centers are often pyramidal.
TpRu(CO)(PPh3)(NHPh) has a pyramidal nitrogen center with the sum of
the angles around nitrogen of 346.5°.a Cp(NO)(PPh3)ReNHPh is also
pyramidal with the sum of the angles around nitrogen of 345.5°.b,c (a)
Jayaprakash, K. N.; Gunnoe, T. B.; Boyle, P. D. Inorg. Chem. 2001, 40,
6481. (b) Dewey, M. A.; Arif, A. M.; Gladysz, J. A. J. Chem. Soc., Chem.
Commun. 1991, 712. (c) Dewey, M. A.; Knight, D. A.; Arif, A. M.; Gladysz,
J. A. Chem. Ber. 1992, 125, 815.
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A R T I C L E S
Casey et al.
1
to 0.59 HA (δ 2.95) and 0.41 HB (δ 3.75) of 4c appeared in the
1H NMR spectrum within 2 min at -60 °C (Scheme 13).12
Complete disappearance of the tolyl methyl resonances at δ 1.85
of 2-RuDOD and appearance of new resonances for inequivalent
tolyl methyl groups of 4c at δ 1.78 and 1.80 were also observed
to 0.48 HA (δ 3.94) and 0.52 HB (δ 4.43) appeared in the H
NMR spectrum within 2 min at -60 °C (Scheme 14).12
Complete disappearance of the tolyl methyl groups at δ 1.85
of 2-RuDOD and appearance of new resonances for inequivalent
tolyl methyl groups of 5 at δ 1.73 and 1.76 were also observed
in the 1H NMR spectrum. Possible events leading to formation
of approximately equal amounts of trans-5:cis-5 will be
considered in the Discussion section.
Raising the temperature above 0 °C led to decomposition of
5 generating N-benzyl-tert-butylamine and ruthenium cyclo-
pentadienone dimer 3 identified by H NMR spectroscopy as
1
in the H NMR spectrum. The observation of a 1.4:1 ratio of
trans-4c:cis-4c shows that imine reduction occurs with a slight
preference for trans addition. Upon warming to room temper-
ature, the mixture of trans-4c and cis-4c equilibrated to a 1:1
ratio. The lower stereospecificity of N-alkyl imine reduction
compared with N-aryl imine reduction was contrary to our
expectations.
1
well as other decomposition products.
The reaction of Me3CNdCHPh (0.120 M) with 2-RuDOD
(0.018 M) at -60 °C in toluene was also monitored by 2H NMR
spectroscopy. No deuterium incorporation into residual excess
Scheme 12
2
imine Me3CNdCHPh was seen in the H NMR spectrum at
-60 °C. The deuterium resonances of the benzyl group were
broad and could not be resolved at -60 °C. Upon warming of
the mixture to room temperature, three deuterium resonances
for 5 (δ 2.39 ND, 4.34 CHDPh, and 3.94 CDHPh) and the
CHDPh resonance of N-benzyl-tert-butylamine (δ 3.54) were
observed. However, all deuterium resonances were too broad
for accurate integration.
2H NMR spectroscopy was employed to further investigate
the reduction of MeNdCHPh by 2-RuDOD. The reaction of
MeNdCHPh (0.120 M) with 2-RuDOD (0.018 M) was run at
2
-60 °C in toluene and the product 4c was examined by H
Discussion
NMR spectroscopy at room temperature. In addition to ap-
proximately equal amounts of deuterium in the two benzyl
positions of 4c (δ 3.18, CHDAPh, 37% of total D; and δ 3.80,
CDBHPh, 43% of D), deuterium was also observed in the
N-methyl group of 4c (δ 1.80, 11% of D). In addition, deuterium
was seen in the residual excess imine MeNdCHPh (δ 7.77,
NdCD, 9% of D).
The stereochemistry of imine reduction by any reagent or
catalyst system has never been reported since rapid nitrogen
inversion scrambles the stereochemistry of the amine product.
In this study, the rapid trapping of the newly generated amine
by complexation to ruthenium enabled the determination of the
stereochemistry of imine reduction by 2-RuDOD.
trans-Stereospecificity of Reduction of N-Aryl Imines. The
reduction of p-Ph-C6H4NdCHTol by 2-RuDOD in toluene
produced ruthenium amine complex 4b with a 5 to 7:1
preference for trans addition of hydrogen; similarly, PhNdCHPh
was reduced with a 2:1 preference for trans addition. Previously,
we had observed normal deuterium kinetic isotope effects for
both RuD and OD in the reaction of N-aryl imines with
2-RuDOD and interpreted this in terms of simultaneous transfer
of OH to the imine nitrogen and transfer of RuH to the imine
carbon to give intermediate B (Scheme 7). Intermediate B, which
has a vacant site at ruthenium and an amine hydrogen bonded
to the dienone carbonyl oxygen, collapses to a ruthenium amine
complex faster than amine escapes from the solvent cage
(Schemes 4 and 5).
Why should there be a preference for trans addition? Scheme
7 shows protonation of the imine nitrogen lone pair in the Cd
N plane and, as hydride is transferred from ruthenium to carbon,
a new lone pair is generated perpendicular to the CdN plane
in one of two orientations. If the amine substituents move toward
the sterically crowded dienone ligand, the lone pair goes anti
to the new C-H bond and a cis addition results. If the amine
substituents move away from the sterically crowded dienone
ligand, the lone pair goes syn to the new C-H bond and a trans
addition results. The observed trans stereochemistry of N-aryl
imine reduction is, therefore, attributed to steric effects pushing
the amine substituents away from the dienone. The observation
of stereospecificity requires that complexation of the stereospe-
cifically formed amine to ruthenium be much faster than
nitrogen inversion, which has a very low barrier (∼7.5 kcal
mol-1).9,10
Scheme 13
The incorporation of deuterium into MeNdCDPh requires
reversible imine reduction and the incorporation of deuterium
into a N-methyl group of amine complex 4c requires an
isomerization to CH2dNCHDPh and then reduction by 2-Ru-
DOD. Earlier, we reported evidence for reversible hydrogen
transfer from 2 to N-alkyl imines.5 The lack of stereospecificity
of N-alkyl imine reduction is related to this reversibility which
erodes any initial stereospecificity of the process. Further
explanation will be provided in the Discussion section.
Stereorandom Reduction Products from Me3CNdCHPh
and 2-RuDOD. To eliminate complications caused by imine
isomerization, we examined reduction of N-benzilidene-tert-
butylamine. When Me3CNdCHPh was added to a toluene-d8
solution of 2-RuDOD at -60 °C, broad singlets corresponding
(14) Nitrogen inversion is faster for arylamines than for alkylamines. The
magnitude of the energy barrier to inversion in amines is correlated by the
intergroup bond angle (R, C1-N-C2) and arylamines usually have larger
intergroup bond angles (R, C1-N-C2) and are easier to invert. Both the
wide angles and lower inversion barrier of arylamines are related to greater
resonance stabilization by interaction with the arene π-system as planarity
is approached. Koeppl, G. W.; Sagatys, D. S.; Krishnamurthy, G. S.; Miller,
S. I. J. Am. Chem. Soc. 1967, 89, 3396.
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Stereochemistry of Imine Reduction
A R T I C L E S
Scheme 14
Scheme 15
If trans hydrogenation predominates, then how do cis products
arise? There are three possible ways to form cis products: (1)
direct cis addition to the imine; (2) 100% trans addition followed
by some amine inversion prior to coordination; (3) partial
isomerization of trans addition products.
While a small amount of cis product might result from product
isomerization due to slight warming of samples upon transfer
to the pre-cooled NMR probe, we do not believe that this is a
major source of cis product. The arylamine complexes trans-4
and trans-5 are configurationally stable at -60 °C and slowly
isomerize over several hours above ca. -40 °C to 1:1 mixtures
of cis and trans isomers. This equilibration presumably occurs
through complete transfer of the proton from nitrogen to oxygen,
inversion at the nitrogen center, rotation around the ruthenium
nitrogen bond, and proton transfer back on nitrogen (Scheme
10).
Amine inversion prior to coordination also seems unlikely.
Nitrogen inversion in arylamines is faster than that in alky-
lamines. Coordination of the less basic arylamines to ruthenium
center would be expected to be slower than coordination of the
more basic alkylamines. If nitrogen inversion were responsible
for loss of stereospecificity, then reduction of N-aryl imines
would have been expected to be less stereospecific than
reduction of N-alkyl imines. Since the opposite is observed, it
is unlikely that nitrogen inversion before coordination is
responsible for loss of stereochemistry.
The most straightforward explanationsthat cis products result
from initial cis reductionsis, therefore, the one we favor.
Stereorandom Reduction of N-Alkyl Imines. Little or no
stereospecificity was seen in the reduction of N-alkyl imines
such by 2-RuDOD at -60 °C in tolutene-d8. This is a direct
consequence of a change in the rate-limiting step from hydrogen
transfer to amine coordination for the reduction of N-alkyl
imines compared with that of N-aryl imines.5 The reversibility
of hydrogen transfer to the imine provides additional pathways
for loss of stereochemistry. The more electron-rich N-alkyl
imines showed inverse kinetic isotope effects, imine isomer-
ization, and deuterium scrambling (Scheme 3).5 Electron donor
alkyl substituents on nitrogen are expected to speed up amine
dehydrogenation as well as amine coordination. We do not
understand why N-alkyl groups accelerate back hydrogen
transfer more than amine coordination.
No stereospecificity was seen in the reduction of Me3CNd
CHPh by 2-RuDOD. This is not inconsistent with some
preference for trans addition over cis addition as in the case of
arylamines coupled with reversibility of the hydrogen transfer.
With many cycles through an only partially stereospecific
process, all stereochemical information will be lost. It is
significant that no Me3CNdCDPh was formed in the reduction.
This suggests that the reversible addition involves intermediate
C in which the imine is hydrogen-bonded to the CpOH group
and that C does not release imine into bulk solution (Scheme
15).15
No more than about 16% trans stereospecificity was seen in
the reduction of MeCNdCHPh by 2-RuDOD. Significantly,
deuterium was found in the N-methyl group of amine complex
4c (11%) and in residual imine MeNdCDPh (9%). The presence
of the N-methyl group provides additional opportunities for loss
of stereochemistry since reversible addition of hydrogen to the
imine can also lead to isomerized imine CH2dNCHDPh
(15) Another process that merits consideration is reversible dehydrogenation of
intermediate B to give an anti-imine. This process, on its own, cannot
account for loss of stereochemistry if only trans addition and elimination
occur.
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A R T I C L E S
Scheme 16
Casey et al.
cyclopentadienone dimer (3) (114 mg, 0.10 mmol) and the mixture
was stirred for 30 min, until all the material dissolved. Solvent was
evaporated under vacuum to afford 4b (120 mg, 71% yield) as a
yellowish green solid, mp 130-132 °C (dec). IR (CD2Cl2): 2016 (s),
(Scheme 16). The intervention of intermediate D in which CH2d
NCHDPh is hydrogen-bonded to the CpOH group is enough to
lose stereochemical information. The incorporation of deuterium
into the N-methyl group of 4c requires dissociation of CH2d
NCHDPh from D and then reaction of free with CH2dNCHDPh
with 2-RuDOD. The formation of MeNdCDPh requires
hydrogen transfer to imine with one stereochemistry, reverse
of the hydrogen transfer with the opposite stereochemistry,
and then dissociation of MeNdCDPh from E. We do not
understand why imine dissociation occurs from D and E but
not from C.
1
1957 (s) cm-1. H NMR (CD2Cl2, 500 MHz): δ 2.19 (s, tolyl CH3),
3
2.20 (s, tolyl CH3), 2.27 (s, tolyl CH3), 3.82 (br d, JBX ) 11.0 Hz,
NH), 3.90 (ABX, 2JAB ) 13.5 Hz, 3JAX ) 2.0 Hz, NCHAH), 4.51 (ABX,
3
2JAB ) 13.5 Hz, JBX ) 11.0 Hz, NCHHB), 6.91-7.51 (m, 29 H,
aromatic), 7.89 (d, 3J ) 8.5 Hz, 2 H, aromatic). 13C{1H} NMR (CD2-
Cl2, 125 MHz): δ 21.16, 21.23 (tolyl CH3); 63.08 (NCH2Tol), 83.45,
85.25 (C 3, 4 of Cp); 103.69, 103.94 (C 2, 5 of Cp); 120.11, 126.63,
126.95, 127.47, 127.53, 127.96, 128.20, 128.63, 128.79, 129.05, 129.36,
130.54, 131.07, 132.20, 132.31, 132.77, 133.14, 134.19, 137.67, 137.95,
138.07, 138.17, 140.25, 149.71 (aromatic),16 163.88 (C1 of Cp), 198.97,
201.26 (CO). HRMS (ESI) (M + H)+: Calcd for C53H43NO3102Ru,
844.2286; found, 844.2305.
Conclusion
Our observations of the trans reduction of N-aryl imines by
2-RuDOD constitute the first determination of the stereochem-
istry of an imine reduction. They also serve to highlight some
of the very fast reactions of intermediate B: coordination of
the aryl-alkyl-amine to Ru is faster than inversion at nitrogen.
The stereorandom reduction of N-alkyl imines by 2-RuDOD
also requires very fast reactions of intermediate B: reversible
dehydrogenation of the newly formed dialkylamine is faster than
amine coordination to ruthenium. Our earlier studies of suc-
cessful intramolecular trapping (but failed intermolecular trap-
ping) of B showed that breaking the amine hydrogen bond to
the dienone carbonyl oxygen of B and escape of the amine from
the solvent cage is slower than amine coordination to ruthenium.
The “slow” reactions of B including amine escape from the
solvent cage and amine inversion are only slow in comparison
with the even faster coordination of nitrogen to ruthenium and
reversible dehydrogenation of the amine.
[2,5-Ph2-3,4-Tol2(η4-C4CO)](CO)2RuNH(CMe3)(CH2Ph) (5). A
solution of N-benzylidene-tert-butylamine (3.7 µL, 0.02 mmol) in
toluene-d8 was added to a solution of 2 (11.4 mg, 0.02 mmol) in toluene-
d8 (0.5 mL) at -78 °C. The reaction mixture was slowly warmed to
-30 °C to yield complex 5. The complex 5 was spectrally characterized
at -30 °C. 1H NMR (CD2Cl2, 500 MHz, -30 °C): δ 0.77 (s, C(CH3)3),
2.12 (s, tolyl CH3), 2.22 (s, tolyl CH3), 2.68 (br s, NHX), 4.05 (ABX,
3
2
2JAB ) 14.7 Hz, JAX ) 11.0 Hz, NCHAH), 4.20 (ABX, JAB ) 14.7
Hz, JBX ) 2.0 Hz, NCHHB), 6.8-7.8 (m, 23 H, aromatics). 13C{1H}
3
NMR (CD2Cl2, 125 MHz, -30 °C): δ 21.1, 21.2 (tolyl CH3); 31.4
(NC(CH3)3), 47.6 (NC(CH3)3), 63.2 (NCH2Ph), 83.5, 84.1 (C 3, 4 of
Cp); 103.9, 104.2 (C 2, 5 of Cp); 126.6-135.0 (20 resonances,
aromatics), 155.5 (C1 of Cp), 201.8, 201.3 (CO).
Raising the temperature above ∼0 °C led to decomposition to
ruthenium cyclopentadienone dimer 3 (δ 1.82, tolyl CH3), N-benzyl-
tert-butylamine (δ 1.01, C(CH3)3), and other decomposition products.
Imine Hydrogenation Experiments. Imine hydrogenation experi-
ments will be illustrated with a specific example. A standard solution
of 3 (11.4 mg, 0.01 mmol, 0.022 M) in THF (0.45 mL) in a resealable
NMR tube was degassed by three successive freeze-pump-thaw cycles
and placed under 1 atm D2 (∼0.1 mmol) at -78 °C. The tube was
sealed at -78 °C and heated at 90 °C in a constant-temperature bath
for 8 h. The THF solvent was evaporated under vacuum to give
2-RuDOD, which was then dissolved in toluene-d8 (0.5 mL). A 50 µL
aliquot (0.02 mmol) of a standard solution of N-benzylideneaniline (36
Experimental Section
[2,5-Ph2-3,4-Tol2(η4-C4CO)](CO)2RuNH(C6H4-p-Ph)(CH2Tol) (4b).
Procedure A. A solution of N-(p-methylbenzylidene)-p-phenylaniline
(16.4 mg, 0.06 mmol) in toluene-d8 was added to a solution of 2 (34.2
mg, 0.06 mmol) in toluene-d8 (0.5 mL) at -78 °C. After slow warming
to room temperature, solvent was evaporated under vacuum to give a
green solid which was recrystallized from hexane at -10 °C to afford
4b (35 mg, 68% yield) as a yellowish green solid.
Procedure B. N-(p-Methylbenzyl)-p-phenylaniline (54.7 mg, 0.20
mmol) was added via syringe to a CD2Cl2 suspension of ruthenium
(16) If none of the aryl resonances were accidentally equivalent, then 28 peaks
would be expected; 24 were seen.
9
2292 J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006

Stereochemistry of Imine Reduction
A R T I C L E S
mg, 0.2 mmol, in 0.5 mL toluene-d8, 0.400 M) was added via a gastight
syringe to the solution of 2-RuDOD cooled to -78 °C. This sample
was inserted into an NMR spectrometer pre-cooled to -60 °C and
spectra were acquired.
Supporting Information Available: General experimental
information, preparation of (Mes)NdC(H)(Ph), (Mes)(H)N(CH2-
Ph), (p-Ph-C6H4)NdC(H)(Tol), and HN(CH2Tol)(C6H4-p-Ph),
preparations of 4a, 4c, and 4d, preparation of solutions of 2,
X-ray crystal structure of 4a, and density functional theory
(DFT) studies. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the Department
of Energy, Office of Basic Energy Sciences, and from NSF
(CHE-9629688) and NIH (I S10 RR04981-01) for the purchase
of NMR spectrometers is gratefully acknowledged.
JA056402U
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