Experimental and computational studies on the mechanism of N-heterocycle C-H activation by Rh(I)

Article abstract of DOI:10.1021/ja0576684

Evidence is presented for a proposed mechanism of C-H activation of 3-methyl-3,4-dihydroquinazoline (1) by (PCy₃)₂RhCl. One intermediate (3), a coordination complex of 1 with (PCy₃) ₂RhCl, was identified along t

Full text of DOI:10.1021/ja0576684

Published on Web 01/25/2006
Experimental and Computational Studies on the Mechanism
of N-Heterocycle C-H Activation by Rh(I)
Sean H. Wiedemann,† Jared C. Lewis, Jonathan A. Ellman,* and
Robert G. Bergman*
Contribution from the Department of Chemistry, UniVersity of California, and DiVision of
Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720
Received November 10, 2005; E-mail: rbergman@berkeley.edu
Abstract: Evidence is presented for a proposed mechanism of C-H activation of 3-methyl-3,4-dihydro-
quinazoline (1) by (PCy3)2RhCl. One intermediate (3), a coordination complex of 1 with (PCy3)2RhCl, was
identified along the path to the Rh-N-heterocyclic carbene product of this reaction (2). Isotopic labeling
and reaction-rate studies were used to demonstrate that C-H activation takes place intramolecularly on
the reaction coordinate between 3 and 2. Computational studies corroborate the proposed mechanism
and suggest that the rate-limiting step is oxidative addition of the C-H bond to the metal center. The
consequences of this mechanism for coupling reactions of N-heterocycles that occur via Rh-catalyzed
C-H bond activation are discussed.
Introduction
potential benefit in understanding the mechanistic pathways
unique to this substrate class. The first example of a direct
Our group1 and others2 have been interested in the use of
directing groups to promote and control regioselectivity in
catalytic C-H additions to olefins. Murai and co-workers’
method for Ru-catalyzed ortho-alkylation of acetophenones was
the first general application of directed C-H activation toward
C-C bond formation.3 Mechanistic studies carried out on that
system showed that the keto group functions by coordinating
to the catalyst and establishing a geometry that facilitates
cyclometalation.4,5 Using mechanistic insight, the scope of
competent directing groups was expanded to include many other
functional groups that can act as Ru0 ligands.6
catalytic coupling between a heterocycle and an olefin was
reported by Jordan and co-workers in 1989.7 Using a zir-
conocene catalyst, the C6-H bond of 2-picoline was added to
propene in high yield. Despite a thorough investigation of that
reaction’s mechanism, its substrate scope could not be signifi-
cantly enlarged.8 In 1992, Moore and co-workers reported
heterocycle/olefin coupling with the incorporation of CO.9 The
development of this reaction by other investigators led to limited
gains in terms of scope and utility; direct mechanistic informa-
tion remains scarce because metal-carbonyl clusters are prob-
able intermediates.10
Contemporaneously with these investigations, it was revealed
that a single atom, the ring heteroatom of an N-heterocycle,
can perform the same function as a pendant directing group,
promoting selective functionalization of an adjacent C-H bond.
Because predictable methods for heterocycle elaboration are
critical to the synthesis of pharmaceuticals, there is great
Olefin/heterocycle coupling has made a resurgence recently
with the advent of potent electrophilic catalysts. Coupling
reactions targeting electronically activated C-H bonds of indole,
for example, have been demonstrated for Ru,11 Pt,12 and an
organo-catalyst.13 Still, the direct coupling of diverse and cheap
R-olefins to minimally activated heterocycles remains a tantaliz-
ingly underdeveloped transformation.14
† Present address: Graduate School of Pharmaceutical Sciences, Uni-
versity of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
(1) Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. In Handbook of C-H
Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005; Vol. 1,
p 187.
(2) (a) Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Eur. J. Inorg. Chem. 1999,
1047. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(c) Kakiuchi, F.; Murai, S. In ActiVation of UnreactiVe Bonds in Organic
Synthesis; Murai, S., Ed.; Freund Pub. House: London, 1999; Vol. 3, p
47.
(3) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529.
(7) Jordan, R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778.
(8) Jordan, R. F.; Taylor, D. F.; Baenziger, N. C. Organometallics 1990, 9,
1546.
(9) Moore, E. J.; Pretzer, W. R.; O’Connell, T. J.; Harris, J.; Labounty, L.;
Chou, L.; Grimmer, S. S. J. Am. Chem. Soc. 1992, 114, 5888.
(10) (a) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc.
1996, 118, 493. (b) Fukuyama, T.; Chatani, N.; Tatsumi, J.; Kakiuchi, F.;
Murai, S. J. Am. Chem. Soc. 1998, 120, 11522. (c) Chatani, N.; Fukuyama,
T.; Tatamidani, H.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2000, 65, 4039.
(d) Szewczyk, J. W.; Zuckerman, R. L.; Bergman, R. G.; Ellman, J. A.
Angew. Chem., Int. Ed. 2001, 40, 216.
(4) For a discussion of a cyclometalation mechanism involving direct oxidative
addition, see: Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1995, 68, 62.
(5) For a discussion of a cyclometalation mechanism involving conjugate
addition of Ru0, followed by R-elimination, see: (a) Matsubara, T.; Koga,
N.; Musaev, D. G.; Morokuma, K. J. Am. Chem. Soc. 1998, 120, 12692.
(b) Matsubara, T.; Koga, N.; Musaev, D. G.; Morokuma, K. Organome-
tallics 2000, 19, 2318.
(11) (a) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581. (b)
Pittard, K. A.; Lee, J. P.; Cundari, T. R.; Gunnoe, T. B.; Petersen, J. L.
Organometallics 2004, 23, 5514.
(12) (a) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 3700. (b) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 10250. (c) Liu, C.; Han, X. Q.; Wang, X.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2004, 126, 10493.
(13) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370.
(b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172.
(6) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
9
2452
J. AM. CHEM. SOC. 2006, 128, 2452-2462
10.1021/ja0576684 CCC: $33.50 © 2006 American Chemical Society

N-Heterocycle C−H Activation by Rh(I)/PCy3
A R T I C L E S
Scheme 1. The Proposed Mechanism for Rhodium-Catalyzed
Benzimidazole/Alkene Coupling
In 2001, we described a Rh(I)/phosphine catalyst system
capable of promoting the C-H coupling of N-heterocycles to
olefins.15 Initially, azoles and benzazoles were shown to be
efficiently activated.15a The substrate specificity of this reaction
was illuminated by a mechanistic study of one benzimidazole
derivative.15b Remarkably, in the principal catalyst resting state,
the benzimidazole substrate has undergone rearrangement, the
resulting product binding to rhodium as an N-heterocyclic
carbene (NHC) ligand.
With a Rh-NHC complex as the starting point, rate studies
and DFT calculations were carried out and used as the basis
for a proposed mechanism of Rh-catalyzed heterocycle/alkene
coupling (Scheme 1). Subsequent reaction development focused
on heterocycles capable of forming and stabilizing an NHC
tautomer, and the substrate scope of Rh-catalyzed olefin
coupling was expanded to include azolines16 and, more recently,
dihydroquinazolines17 (eq 1).
Figure 1. X-ray crystal structure (ORTEP diagram) of 2.
stoichiometric amounts of the catalyst mixture used in olefin
coupling reactions, [(coe)2RhCl]2/PCy3 (coe ) cis-cyclooctene,
Cy ) cyclohexyl), to give carbene complex 2 (eq 2).18 These
conditions were previously used to synthesize an analogous
NHC-complex from N-methylbenzimidazole.19 As in that case,
the structure of 2 was elucidated by single-crystal X-ray analysis
(Figure 1).
The irreversible conversion of 1 to 2 occurs between 45 and
75 °C, well below the temperature required for olefin coupling
(150 °C). At temperatures below 35 °C, carbene formation is
sluggish and an orange precipitate forms over 1-3 d. Based on
1H and 31P NMR analysis, this precipitate (3) was found to be
a new Rh-complex of 1. Further in situ NMR study of carbene
formation reactions revealed the presence of 3 at a variety of
temperatures. Importantly, throughout all reactions, the mass
balance of added 1 could be accounted for as either free 1,
carbene 2, or complex 3.
The structure of 3 was assigned to be a trans-2:1 PCy3/1
coordination complex of Rh(I)Cl based on peak integration in
1H NMR spectra and peak splitting in 31P NMR spectra. Single-
crystal X-ray analysis of 3 was not possible because, regardless
of solvent system, 3 crystallized with too much interstitial
solvent to survive even gentle handling. NMR studies of
isotopically labeled materials, on the other hand, did provide
details about the solution structure of 3. Using a convergent
three-step procedure, 15N1-1 was prepared from 15N-benzamide
and used to synthesize 15N1-3 (Scheme 2). The magnitude of
15N-31P coupling observed in the 31P spectrum of 15N1-3 was
consistent with a Rh(I) complex bearing 15N-heteroarene and
phosphine ligands in a cis orientation (3.0 Hz).20 Given this
Yet, portions of the proposed mechanism were still not fully
understood. In fact, the most remarkable step, the formation of
a Rh-NHC complex from heterocycle and Rh(I) via H-
migration, is without literature precedent. Being a unique C-H
bond activation process and a mild method for the preparation
of NHC ligands, we felt that a deeper understanding of this
fundamental transformation could lead to new opportunities for
reaction discovery. The results of experimental and computa-
tional studies of Rh(I)-mediated heterocycle C-H activation
reactions are described in this report. On the basis of these
studies, a detailed mechanism for C-H activation is presented
and evaluated in the context of catalysis.
Results
Structural Studies. Following some initial work, 3-methyl-
3,4-dihydroquinazoline (1) was chosen from among the het-
erocycles active toward Rh-catalyzed C-H functionalization as
our platform for mechanistic study. It reacted cleanly with
(14) Some oxidative protocols for the heterocycle/olefin couple have appeared
recently: (a) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004,
126, 6556. (b) Yi, C. S.; Yun, S. Y.; Guzei, I. A. Organometallics 2004,
23, 5392. (c) Beccalli, E. M.; Broggini, G. Tetrahedron Lett. 2003, 44,
1919. (d) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578.
(15) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001,
123, 2685. (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2002, 124, 13964. (c) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2002, 124, 3202. (d) Tan, K. L.; Vasudevan, A.; Bergman,
R. G.; Ellman, J. A.; Souers, A. J. Org. Lett. 2003, 5, 2131. (e) Tan, K. L.;
Park, S.; Ellman, J. A.; Bergman, R. G. J. Org. Chem. 2004, 69, 7329.
(16) Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 1685.
(17) Wiedemann, S. H.; Ellman, J. A.; Bergman, R. G. J. Org. Chem. In press.
(18) For a previous synthesis of a 1-derived M-NHC complex, see: Basato,
M.; Benetollo, F.; Facchin, G.; Michelin, R. A.; Mozzon, M.; Pugliese, S.;
Sgarbossa, P.; Sbovata, S. M.; Tassan, A. J. Organomet. Chem. 2004, 689,
454.
(19) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org. Lett.
2004, 6, 35.
(20) Carlton, L.; De Sousa, G. Polyhedron 1993, 12, 1377.
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J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006 2453

A R T I C L E S
Wiedemann et al.
Scheme 2. Synthesis of Isotopically Labeled Rh-Complexes
Scheme 3. Possible Mechanisms for Carbene Formation via C-H
Activation
of the others (δ ) 10 vs 6.9 ppm), supporting the structure of
3 depicted in Figure 2.24
strong evidence that 1 binds to rhodium through N1, rather than
N3, we proposed the structure of 3 depicted in Scheme 2.
To confirm that the heterocycle was indeed σ-bound to
rhodium, we synthesized and formed the Rh(I)-complex of
15N1,13C2-1 (Scheme 2). The 13C chemical shift change of the
amidine carbon upon complexation was found to be small and
upfield (∆δ ) +5.1 ppm). Gladysz and others have shown that
small chemical shift changes are expected for σ-complexes of
carbonyls to electron-rich late metals, whereas large downfield
shift changes (∆δ ) -90 to 140 ppm) are observed for the
corresponding π-complexes.21
With confirmation of σ-bonding in 3 in hand, DFT calcula-
tions were performed on a model system (using PMe3 in place
of PCy3, 5) to obtain more detailed structural information. After
energy minimization, 5 adopted a calculated geometry that can
be described as an intersection of two orthogonal molecular
planes, where one plane is made up of the dihydroquinazoline
framework and the other is defined by the Rh-square plane
(Figure 2).22 In this conformation, the C8-H atom of bound 1
Reactivity Studies. Before proceeding further, it became
necessary to ascertain the role of 3 in the formation of 2. Two
C-H activation reactions were monitored concurrently at 60
°C: one starting from isolated 3, and the other starting from 1
and [(coe)2RhCl]2/2PCy3. In both of these reactions, an observ-
able equilibrium between 1 and 3 was rapidly established. From
this maximum point, the concentration of 3 dropped continu-
ously to zero as 1 was consumed to form 2. Thus, either 3 is a
reactive intermediate lying on the path to 2 (Scheme 3, path
A), or the equilibrium between 1 and 3 is a kinetic “dead end”,
with C-H activation arising from a separate bimolecular
pathway (Scheme 3, path B).
This sort of uncertainty is typically resolved by comparing
the rate that product is formed by the reaction of starting
materials to the rate that product is formed by subjecting the
isolated intermediate to the same reaction conditions. Unfortu-
nately, that exact experiment is not possible in the present case,
because it relies on k1/k-1 equilibration being sufficiently slow.
At the temperatures required to dissolve 3 for NMR reaction
analysis (>45 °C), there is rapid equilibration between 1 and
3. Once equilibrium is established, path A and path B become
kinetically indistinguishable; by applying the equilibrium ap-
proximation, the rate expression for either path can be rewritten
so that it differs from the rate expression for the other path only
in the way that kobs is defined (eq 3).
d[2]/dt (path A) ) k2[3]
d[2]/dt (path B) ) k2′[1][(PCy3)2RhCl]
Keq ) [3]/([1][(PCy3)2RhCl])
(3a)
(3b)
(3c)
Figure 2. Calculated structure for 5 showing the Rh-H “pre-agostic”
interaction.
d[2]/dt (path B) ) (k2′/Keq)[3] ) kobs[3] ) k2[3] )
resides 2.7 Å above the square-planar rhodium center. At that
distance, the M-H close contact falls into the upper range of
“pre-agostic” interactions.23 If the true geometry of 3 in solution
were analogous to the calculated geometry of 5 in the gas phase,
d[2]/dt (path A) (3d)
Eventually, the two reaction paths were discriminated by
monitoring a reaction between 1, [(coe)2RhCl]2, and PCy3 at a
temperature low enough for 1 and 3 to slowly approach
equilibrium, yet high enough for the rate of formation of 2 (d[2]/
dt) to be accurately measured. Accordingly, at 37 °C the
concentrations of 1, 2, and 3 were measured continuously as a
1
then the resulting pre-agostic interaction would cause the H
NMR resonance for C8-H to be strongly shifted downfield.
Indeed, upon complexation of 1 to (PCy3)2RhCl, a single Ar-H
resonance attributable to C8-H was observed 3 ppm downfield
1
function of time using in situ H NMR analysis (Figure 3). If
(21) (a) Mendez, N. Q.; Seyler, J. W.; Arif, A. M.; Gladysz, J. A. J. Am. Chem.
Soc. 1993, 115, 2323. (b) Stark, G. A.; Gladysz, J. A. Inorg. Chem. 1996,
35, 5509.
(24) Pre-agostic interactions have been identified as intermediates preceding
C-H oxidative addition. The question of whether the C8-H bond of 3
can undergo metal-insertion is beyond the scope of this report. For a
discussion of this rare type of interaction in a related system, see: Lewis,
J. C.; Wu, J.; Bergman, R. G.; Ellman, J. A. Organometallics 2005, 24,
5737.
(22) While we have chosen to depict the metal center of 3 as square planar, we
cannot rule out the presence of one weakly bound inner-sphere solvent
ligand.
(23) Yao, W. B.; Eisenstein, O.; Crabtree, R. H. Inorg. Chim. Acta 1997, 254,
105.
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N-Heterocycle C−H Activation by Rh(I)/PCy3
A R T I C L E S
Scheme 4. Proposed Mechanism for Isotopic Scrambling of
C2-D-3
Figure 3. Plot of concentration versus time for the species present during
the reaction of 1 with Rh(I)/PCy3 at 36.7 °C. The solid curves depict kinetics
Such a mechanism would lead to a first-order dependence of
d[2]/dt on the concentration of 3. The simulated reaction profiles
generated for path A by kinetics modeling software (Figure 3,
smooth curves) presuppose first-order dependence on 3 and
precisely fit observed data. While this does constitute evidence
in favor of an intramolecular mechanism, goodness of fit is
generally regarded as a weak measure of reaction order. We
posed two crucial questions, therefore, to clarify the role of
bimolecular processes in the seemingly intramolecular conver-
sion of 3 to 2 via path A: (1) Is the H removed from C2 the
same atom as that added to N1? (2) If so, does that H exchange
with any others as it is transferred? A deuterium tracer
experiment was performed to shed light on these questions.
C2-D-1 reacted with the usual Rh(I)/PCy3 mixture to produce
N1-D-2 with 88% isotopic incorporation at the N1 position (eq
4). Some minor deuterium loss can be explained by invoking
transient Rh-D intermediates. If such intermediates underwent
reversible cyclometalation, a well-known process for Rh(I)/PCy3
complexes,26 deuterium exchange into phosphine cyclohexyl
groups could occur (Scheme 4). Because rhodium hydride
intermediates were indeed located computationally (vida infra)
and a reaction pathway involving the dissociation of PCy3 was
recognized experimentally (vida infra), this mechanism seems
reasonable. Moreover, the extent of deuterium loss is small and
thus does not jeopardize the conclusion that the C2-H of 1 is
the primary source of N1-H in 2.27
simulations of the data (path A: k1 ) (1.0 ( 0.2) × 10-2 M-1 s-1, k-1
)
(2.0 ( 0.2) × 10-4 s-1, kd ) (1.10 ( 0.05) × 10-5 s-1).
Figure 4. Plot of [2] versus time from Figure 3, enlarged to show fits for
two possible reaction pathways depicted in Scheme 3 (path A: k2 ) (1.809
( 0.003) × 10-5 s-1).
path A were operative, d[2]/dt would be expected to increase
over time as [3] increases, resulting in an upward curving graph
of [2] versus time. In contrast, path B predicts that as [1] and
[(PCy3)2RhCl] are depleted to form 3, d[2]/dt should decrease,
resulting in a downward curving graph of [2] versus time. The
observed plot of [2] versus time showed slight upward curvature
at early conversion, when the approach to equilibrium was most
rapid, providing support for path A over path B (Figure 4). To
further confirm this qualitative result, the observed concentration
versus time profiles were fitted to the mechanistic pathways
illustrated in Scheme 3 with the aid of the Gepasi kinetics
modeling program.25 The simulated [2] versus time profile
generated from path A matched experimental data far better than
the profile derived from path B (Figure 4).
In an effort to answer the question of whether H-transfer from
C2 to N1 occurs directly or with intermolecular exchange, a
double-labeling crossover experiment was carried out using
equal amounts of C2-D-1 and 15N1-1 (Table 1). The amount of
(25) (a) Mendes, P. Comput. Appl. Biosci. 1993, 9, 563. (b) Mendes, P. Trends
Biochem. Sci. 1997, 22, 361. (c) Mendes, P.; Kell, D. B. Bioinformatics
1998, 14, 869.
(26) Cyclometalation into the alkyl groups of (PCy3)2RhCl has been implicated
in the decomposition of this complex: Hietkamp, S.; Stufkens, D. J.; Vrieze,
K. J. Organomet. Chem. 1978, 152, 347.
Given that 3 is an intermediate on the pathway to 2, and has
the same stoichiometry as 2, the simplest plausible mechanism
for C-H activation would seem to be intramolecular H-transfer.
9
J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006 2455

A R T I C L E S
Wiedemann et al.
Table 1. Double Labeling Crossover Experiment Data
Scheme 5. Equilibria Governing [(PCy3)2RhCl]
than 85% for 1:1 reactions between 1 and Rh(I)/PCy3.32 Thus,
to compute k2 given the three quantities measurable by 1H NMR
analysis ([1], [3], [2]), kinetics simulation software was used.
By allowing the software to freely vary [(PCy3)2RhCl] and the
rate constants defined in path A of Scheme 3, good fits to
empirical data were achieved (relative errors for k2 < 1%).33
% yield
% crossover
observedb
a
time (h:min)
2dir
2cross
2dirD
+
2crossD
total
0:00
1:30
4:30
8:20
21:10
27:20
0
10
24
34
41
41
0
1
1
3
5
6
0
6
14
19
26
27
0
16
39
56
72
75
NA
5
4
5
7
d[2]/dt ) k2[3] ) Keqk2[1][(PCy3)2RhCl]
(5)
To obtain activation parameters for C-H activation, a series
of reactions, starting from isolated 3, were monitored continu-
ously by in situ 1H NMR analysis over a range of temperatures
(45-75 °C). In addition to values for k2, kinetics simulations
provided values for Keq. From these values, a Van’t Hoff plot
was constructed and fitted to a linear function (Figure S-1c).
Probably as a result of the aforementioned uncertainty in
[(PCy3)2RhCl], there was considerable scatter of data about the
best-fit Van’t Hoff line (r2 ) 0.82). Nevertheless, the slope and
intercept of the fitting function did correspond to thermodynamic
parameters that are consistent with reversible binding of a neutral
ligand (∆H° ) -5.9 ( 0.8 kcal/mol and ∆S° ) -10 ( 2 cal/
mol‚K).
Initially, when data collected for k2 were transformed into
an Eyring plot, deviation from linear behavior was once again
observed. This imprecision was puzzling to us because the
parameters governing k2, [2] and [3], are accurately measurable.
In an effort to trace the source of what seemed to be systematic
error, we hypothesized that C-H activation might proceed
through a rate-limiting transition structure with only one bound
PCy3. In such a sequence, rapid, post-rate-limiting recoordination
of free PCy3 would complete the conversion to 2 (eq 6). This
mechanism predicts an inverse dependence of d[2]/dt on [free
PCy3]. Systematic error would thus occur if small but differing
amounts of free PCy3 were introduced, for example, from
different batches of reaction starting material (3).
8
a 2dirD and 2crossD are not independently observable by 1H NMR analysis.
b Observed % crossover ) % 2cross/% total. Because 2crossD is not
independently observable, the true extent of isotopic scrambling may be
greater than the observed value.
observable crossover product (14N1-H-2, 2cross) produced in this
experiment was no greater than the amount expected to arise
from minor deuterium loss via the pathway discussed above.
Furthermore, the fact that percent crossover stayed nearly
constant at first, and then slowly rose over long reaction times,
suggests that some of the observed crossover product may have
arisen from isotopic scrambling between NHC products after
they were formed. Hence, we conclude that the conversion of
3 to 2 results from intramolecular H-transfer,28 and we rule out
mechanisms involving the exchange of hydrides between metal
centers or the reductive elimination and recapture of hydrides
as HCl.29
Rate Studies. Assuming that C-H activation takes place via
intramolecular H-transfer, according to the mechanism presented
in path A of Scheme 3, an overall rate law can be derived for
the conversion of 1 to 2 (eq 5). By applying this expression,
d[2]/dt and the concentrations of 1 and (PCy3)2RhCl can be used
to calculate k2, which provides information about the C-H
activation step in isolation. Unfortunately, it is difficult to
ascertain the concentration of (PCy3)2RhCl necessary for this
calculation because (1) (PCy3)2RhCl lacks diagnostic resonances
for quantification by 1H NMR, (2) it exists in equilibrium with
its dimer and other complexes (Scheme 5),30 and (3) it undergoes
decomposition over the course of the carbene formation
reaction.31 In addition to causing uncertainty in the concentration
of “active Rh”, the tendency of (PCy3)2RhCl toward decomposi-
tion readily explains the observed reaction yields of not greater
In agreement with our hypothesis, we found that a small
amount of added PCy3 (13 mM ) 0.5 equiv vs [Rh]t) generally
did lead to a 2-2.5-fold reduction in the rate of carbene
formation. However, for [free PCy3] > 13 mM, the rate of
carbene formation was found to be independent of [PCy3]
(Figure 5). Taken together, these data reveal the existence of
two competing reaction pathways between 3 and 2: one that is
dissociative in phosphine and one that is not.
(27) The 1H NMR signals of PCy3 are too poorly resolved to permit the
measurement of any minor deuterium incorporation there. Also, N1-D-2 is
not soluble enough for the same measurement to be made by 2H NMR.
(28) Another scenario that is consistent with the observed data is a large extent
of crossover in conjunction with a large kinetic isotope effect. This
interpretation is invalidated by the small measured kinetic isotope effect
(vide infra).
(29) Other evidence that free HCl is uninvolved in C-H activation is provided
by our observation that the rate of formation of 2 is insensitive to added
acid (HCl) or base (K2CO3).
(32) Incomplete conversion of 1 was also observed for reactions employing
related trialkylphosphines (PiPr3, PtBu2Me). Higher conversions can be
obtained by using excess (PR3)2RhCl.
(33) The omission of more complicated [Rh] equilibria was not found to affect
data fitting.
(30) (a) Van Gaal, H. L. M.; Van Den Bekerom, F. L. A. J. Organomet. Chem.
1977, 134, 237. (b) Van Gaal, H. L. M.; Moers, F. G.; Steggerda, J. J. J.
Organomet. Chem. 1974, 65, C43.
(31) For a description of the decomposition of (PCy3)2RhCl, see ref 30a.
9
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N-Heterocycle C−H Activation by Rh(I)/PCy3
A R T I C L E S
mechanistic data were augmented with DFT calculations.36
Aided by ample structural information about 3 and 2, a model
system, using 3-methyl-3,4-dihydropyrimidine in place of 1 and
PMe3 in place of PCy3, was constructed. After energy minimi-
zation, all bond distances common to both isolated carbene
complex 2 and model carbene complex I differed by no more
than 5%, thus ensuring the applicability of the chosen basis set
and level of theory (B3LYP, LACVP**++). Starting complex
A, the structure of which is consistent with all spectroscopic
observables for 3,37 was connected to I via two possible
nondissociative, intramolecular H-transfer reaction coordinates
differing from one another in the manner by which they effect
spatial interchange of the reacting Rh and H atoms (Figure 7).
Both pathways initially pass through transition state B, which
involves migration of the Rh-center toward the C2-H bond
and into the energy-minimized C-H σ-complex C. C-H
σ-complexes have generally been proposed and identified along
reaction coordinates for C-H activation38 and have been
specifically located along calculated pathways for the C-H
oxidative addition of azoliums to (PMe3)2RhCl and IrH3-
(PMe3)2.36 Consistent with these reports, we were readily able
to locate a transition state for C-H oxidative addition (D)
originating from the C-H σ-bound intermediate C. Contrary
to our expectations, the resultant minimized anti-hydride
complex (E) could not be connected to carbene I. Intramolecular
H-transfer from Rh to N3 is prohibited due to the anti orientation
of N and H atoms about C2-Rh bond of E. Nor could a
transition state be located that connects C directly to a different
hydride complex with a more favorable N-C-Rh-H dihedral
angle (G), presumably due to improper orientation of the Rh-
center with respect to the C2-H bond. Nevertheless, we were
able to determine a productive reaction coordinate from anti-
hydride complex E by recognizing that a 180° C-Rh bond
rotation would bring N3 and the hydride into alignment for
intramolecular H-transfer. A corresponding rotation transition
state (F, 20 kcal/mol above E) and the desired syn-hydride (G)
were successfully minimized. Finally, the transition state for
H-transfer between Rh and N3 was located along the path from
G to the final product, I. To our knowledge, this result
constitutes the first instance of NHC formation by â-hydride
insertion.
Figure 5. Graph of k2 versus [free PCy3] (at 62.7 °C). The curve depicts
a linear least-squares fit k2 ) a[PCy3] + b (a ) 4.7 × 10-5, b ) 4.4 ×
10-4). The filled point is provided for reference only (see Supporting
Information for details) and is not included in the linear fit.
Figure 6. Eyring plot of 2 formation (k2) in the presence of 13 mM excess
PCy3 between 42.2 and 72.9 °C. The curve depicts a linear least-squares
fit to ln(k2/T) ) a[1/T] + b (a ) (-1.31 ( 0.01) × 104, b ) 18.6 ( 0.4).
Between the two operative pathways, the dissociative one is
the more difficult to study due to its extreme sensitivity to free
PCy3. We elected to study the nondissociative pathway instead.
In subsequent studies, the dissociative pathway was effectively
suppressed by the addition of a small amount of excess PCy3
(13 mM) to all reaction solutions.34 The deuterium kinetic
isotope effect on k2 was measured under these conditions. The
observed kH/kD (1.8 ( 0.1) is consistent with cleavage of the
C2-H bond during or prior to the rate-determining step. When
the Eyring plot of k2 was redrawn using data acquired from
reactions employing excess PCy3, a very precise linear fit was
obtained (r2 ) 0.9995) (Figure 6). The resulting activation
parameters (∆Hq ) 26.0 ( 0.3 kcal/mol and ∆Sq ) -10.3 (
0.8 cal/mol‚K) reveal the dramatic extent to which metal-
mediation facilitates heterocycle to NHC tautomerization.35
A second path to I was identified diverging from the
“rotation” pathway at the C-H σ-complex C. Instead of
ascending to the high-energy transition state for C-H oxidative
addition, C was shown to undergo a low-energy Rh-migration
to a second C-H σ-complex (K) via transition state J. During
the migration, the Rh-center moves about the C2-H bond to a
position closer N3 than N1. A transition state for oxidative
addition (L) was located from C-H σ-complex K. Just as the
geometry of K is inverse of C, the geometries of the resulting
hydrides were also found to be inverse. Transition state L
provides syn-hydride G directly. The remainder of the reaction
(36) For detailed computational studies of the oxidative addition of 1,3-
dimethylimidazolium to (PR3)xRhCl36a and IrH3(PMe3)2,36b see: (a) Hawkes,
K. J.; McGuinness, D. S.; Cavell, K. J.; Yates, B. F. Dalton Trans. 2004,
2505. (b) Appelhans, L. N.; Zuccaccia, D.; Kovacevic, A.; Chianese, A.
R.; Miecznikowski, J. R.; Macchioni, A.; Clot, E.; Eisenstein, O.; Crabtree,
R. H. J. Am. Chem. Soc. 2005, 127, 16299.
(37) For the sake of simplicity, no inner-sphere solvent molecules were included
in our models. In a related system, reaction coordinates calculated with
inner sphere solvent did not differ significantly from coordinates lacking
solvation (ref 36a).
(38) Crabtree, R. H.; Holt, E. M.; Lavin, M.; Morehouse, S. M. Inorg. Chem.
1985, 24, 1986.
Computational Studies. In an effort to gain further insight
into the microscopic steps of C-H activation, our experimental
(34) Added PCy3 does not affect the position of the preequilibrium because
(PCy3)2RhCl has been shown not to coordinate additional PCy3 to give
(PCy3)3RhCl (ref 30b).
(35) For treatments of uncatalyzed and proton-catalyzed 1,2-hydrogen shifts at
imidazol-2-yl carbenes, see: (a) Amyes, T. L.; Diver, S. T.; Richard, J. P.;
Rivas, F. M.; Toth, K. J. Am. Chem. Soc. 2004, 126, 4366. (b) Bourissou,
D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. ReV. 2000, 100, 39.
9
J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006 2457

A R T I C L E S
Wiedemann et al.
Figure 7. Calculated reaction coordinates for C-H activation (zero-point calculations, 298 K).
Table 2. Comparison of Measured and Computed Activation
Parameters
coordinate for the “migration” pathway is identical to that
described above for the “rotation” pathway.
mechanism
∆
Gq (kcal/mol)a
∆
Hq (kcal/mol)
∆ ‚K)
Sq (cal/mol
These mechanisms provide two possible microscopic reaction
coordinates for the Rh-mediated intramolecular H-transfer
leading from coordination complex A to NHC complex I. By
either pathway, the computed reaction is exergonic by 4.3 kcal/
mol at 298 K. This value corresponds to an equilibrium constant
favoring product by >103:1, in agreement with the observation
that 1 reacts irreversibly with (PCy3)2RhCl to give 3. Also, as
in the observed reaction of 1, neither the “migration” nor the
“rotation” mechanisms predict observable intermediates other
than the N1-σ-bound complex (A).39 Both calculated pathways
are nondissociative in phosphine and involve rate-limiting C-H
activation steps, consistent with the significant primary kinetic
isotope effect measured for the nondissociative pathway of
2-formation. The activation parameters calculated for both
mechanistic variants compare well with experimental values
(Table 2).40
calculated “migration”
calculated “rotation”
experimentalb
28.3
30.0
29.1 ( 0.4
24.0
26.0
26.0 ( 0.3
-14.5
-13.2
-10.3 ( 0.8
a At 298.15 K. b Derived from Eyring plot (Figure 6).
the real system, possibly prohibitively so. The “migration”
pathway avoids obvious steric interactions with PR3 because
the heterocycle and the Rh-square plane stay relatively perpen-
dicular throughout the reaction coordinate. In light of this
divergence, the extreme preference for bulky phosphines that
we have consistently observed in Rh(I)/PR3-catalyzed hetero-
cycle coupling reactions can now potentially be understood in
terms of the limitations that such phosphines place on accessible
(deleterious) reaction pathways.
Discussion
In the model system, the “rotation” and “migration” mech-
anisms seem nearly interchangeable (the highest overall barriers
differ by an insignificant amount, <2 kcal/mol at 298 K). In
the real system, however, when the PMe3 ligands are replaced
by considerably more bulky PCy3 ligands, the same is not likely
to be true. As a result of nonbonded interactions between the
phosphine and heterocycle ligands, we expect the transition state
for C2-Rh bond rotation (F) to be especially high in energy in
By combining kinetic, structural, and computational data, it
is possible to draw a plausible general mechanism for the C-H
activation of N-heterocycles by Rh(I)/PCy3 (Scheme 6). The
reaction is initiated by the association of a heterocycle to
(PCy3)2RhCl as a dative ligand through an sp2 hybridized
nitrogen. The adjacent C-H bond is then cleaved by rate-
limiting intramolecular oxidative addition to give a transient
rhodium hydride. A final, rapid H-transfer step restores rhodium
to the +1 oxidation state, and the transformation from hetero-
cycle to NHC is complete. Less information is available about
a competing PCy3-dissociative pathway. Because the experiment
verifying the intermediacy of 3 was run under conditions in
which both pathways make substantial contributions to d[2]/dt,
the PCy3-dissociative pathway can be said to proceed via
intermediate 3. Given such a ground state, the stoichiometry of
(39) While the “migration” pathway does pass through a relatively low energy
rhodium-hydride intermediate (E), based on its relative free energy with
respect to A (∆G° ) 5.2 kcal/mol), it is not predicted to be observable.
This is consistent with the lack of observed 1H NMR resonances in the
hydride region.
(40) The large, negative experimental and calculated entropies of activation are
similar in magnitude to that calculated for a related oxidative addition
proceeding from the C-H σ-complex between 1,3-dimethylimidazolium
and (PH3)2RhCl (-10.4 cal/mol‚K, ref 36a).
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2458 J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006

N-Heterocycle C−H Activation by Rh(I)/PCy3
A R T I C L E S
Scheme 6. Proposed Mechanism of C-H Activation of 1
via a catalyst-substrate precomplex. Despite the differences
between the Rh- and Ni-based mechanisms, both seem to benefit
from a well of stability along the energy surface of the catalytic
cycle provided by an M-NHC intermediate. Taken together,
these studies strongly contradict the notion that NHC’s tend to
act only as dative ligands toward transition metals.
Because the Rh(I)-catalyzed functionalization reactions of
dihydroquinazolines, such as 1, occur under conditions and with
selectivity patterns similar to those of the reactions of other
N-heterocycles, the mechanism for C-H activation of 1 is likely
general for Rh-NHC-mediated C-H processes. Strong predic-
tions can thus be made about the substrate scope for Rh-
catalyzed coupling reactions. Earlier work by our group showed
that all competent substrates have in common the ability to form
and stabilize an NHC tautomer. If our newly outlined mecha-
nism is a general one, then it reveals the further requirement
that the site of dative coordination (the sp2-hybridized nitrogen)
and the scissile C-H bond be cis to one another about a CdN
double bond. Only then can facile intramolecular oxidative
addition take place. All competent substrates recognized so far
are cyclic and therefore meet this requirement. Potential acyclic
substrates, such as formamidines or formimidates, on the other
hand, are unlikely to exhibit the necessary geometry for
activation, because they exist predominantly in the S-trans form.
Indeed, in our hands, acyclic substrates have never produced
coupling products. Nor have substrates requiring a hydride shift
of farther than two atoms produced functionalized products to
date.
The proposed reaction mechanism of Scheme 6 does provide
some guidance concerning the expansion of substrate scope.
Heterocycles capable of forming pyrazolyl45 or “abnormal”-
type46 carbenes should, in principle, be compatible with this
mechanism. More enticingly, our investigations reveal that the
other atom (besides the sp2-nitrogen) bonded to the carbene
carbon does not directly interact with catalyst during C-H
activation. While this atom may be important to the electronic
structure of active substrates, our previous work has already
shown that, in addition to N, the atoms S and O are tolerated at
this position.15d Given recent reports by Bertrand and co-workers
of stable amino-alkyl NHC’s,47 catalytic functionalization might
now also be expected to proceed with C adjacent to the carbene
position.48 If successful, such a coupling reaction between cyclic
imines and alkenes would constitute a rare example of catalytic
hydroiminoacylation.49
the rate-limiting transition structure is likely to be as depicted
in Scheme 6. However, because the dissociative reaction could
not be studied in isolation, the validity of the depicted bonding
cannot be verified at this time.
This mechanism of Scheme 6 bears similarities to related
directed C-H activation reactions. As in the Murai system, the
directing group functions to bring the reactive metal fragment
into proximity with the scissile C-H bond via pre-coordina-
tion.41 There are substantial differences, however, between that
system, which relies on a pendant directing group, and a
heterocycle C-H activation system, like the one discussed here.
Pendant directing groups can stay coordinated to a metal
fragment during C-H oxidative addition. Often described as
taking place by cyclometalation, these reaction steps are
promoted by the formation of stable five- or six-membered
chelate rings. Calculated models of our system, in contrast, show
that the directing heteroatom (N1) must detach from the metal
fragment prior to C-H cleavage.42 Thus, catalytic functional-
ization of N-heterocycles by Rh(I)/PR3 can be said to operate
via a complex-induced proximity effect. Only by proceeding
through an N-bound intermediate can the reactants gain access
to an energetically accessible transition state for C-H activation.
Cavell and co-workers have recently reported a Ni0-catalyzed
C-H coupling of olefins to the 2-position of imidazolium salts
(eq 7).43 Similar to the Rh(I) C-H activation, this reaction
probably proceeds through a well-characterized metal-NHC
intermediate.44 However, the proposed mechanism is most
similar to that of other group 10 metal-catalyzed cross coupling
reactions that operate within the M0/M2+ redox couple. No
experimental evidence was found for directed C-H activation
(45) Kocher, C.; Herrmann, W. A. J. Organomet. Chem. 1997, 532, 261.
(46) (a) Grundemann, S.; Kovacevic, A.; Albrecht, M.; Faller, J. W.; Crabtree,
R. H. J. Am. Chem. Soc. 2002, 124, 10473. (b) Lebel, H.; Janes, M. K.;
Charette, A. B.; Nolan, S. P. J. Am. Chem. Soc. 2004, 126, 5046. (c)
Reference 36b.
(47) (a) Lavallo, V.; Mafhouz, J.; Canac, Y.; Donnadieu, B.; Schoeller, W. W.;
Bertrand, G. J. Am. Chem. Soc. 2004, 126, 8670. (b) Lavallo, V.; Canac,
Y.; Prasang, C.; Donnadieu, B.; Bertrand, G. Angew. Chem., Int. Ed. 2005,
44, 5705.
(48) We have once observed functionalization at such a site in the case of the
purine (ref 15b).
(41) An instance of ortho-directed transition metal-mediated C-H activation
that is not chelation-assisted has been recently reported: Zhang, X. W.;
Kanzelberger, M.; Emge, T. J.; Goldman, A. S. J. Am. Chem. Soc. 2004,
126, 13192.
(42) Maintaining N-coordination during C-H oxidative addition of an N-
heterocycle would lead to a strained three-membered chelate ring. This
type of coordination is known exclusively for early metals. See ref 8 and
references therein.
(43) Clement, N. D.; Cavell, K. J. Angew. Chem., Int. Ed. 2004, 43, 3845.
(44) Clement, N. D.; Cavell, K. J.; Jones, C.; Elsevier, C. J. Angew. Chem., Int.
Ed. 2004, 43, 1277.
(49) Efficient, versatile Rh-catalyzed hydroiminoacylation is possible when the
imine N-substituent is a metal-coordinating group (2-pyridyl). See: Jun,
C. H.; Lee, J. H. Pure Appl. Chem. 2004, 76, 577.
9
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A R T I C L E S
Wiedemann et al.
on silica (5:4:0.5:0.5 EtOAc/acetone/MeOH/Et3N) afforded a white
powder that was redissolved in THF, filtered to remove traces of silica,
and concentrated under vacuum. The white crystals obtained from this
procedure (380 mg, 38%) exhibited spectroscopic properties consistent
with literature data.54 1H NMR (500 MHz, C6D6): δ 7.49 (d, 1H, J )
8.0 Hz, Ar-H), 7.07 (t, 1H, J ) 7.5 Hz), 6.90 (t, 1H, J ) 7.5 Hz,
Ar-H), 6.58 (s, 1H, C2-H), 6.56 (d, 1H, J ) 7.5 Hz, Ar-H), 3.74 (s,
2H, CH2), 1.80 (s, 3H, CH3). MS (EI); m/z (%): 145 [M+ - H] (100),
147 [M+ + (D-M+ - H)] (47.3).
Conclusion
To better understand the C-H activation step governing the
Rh(I)-catalyzed coupling of N-heterocycles and olefins, sto-
ichiometric reactions between (PCy3)2RhCl and heterocycle 1
were studied. The product of these reactions, a Rh-NHC
complex analogous to those previously reported as catalytic
intermediates (2), was isolated and characterized. Furthermore,
a datively bound catalyst-substrate complex (3) was identified
as an intermediate in the formation of 2. The Rh-mediated 1,2-
hydrogen shift responsible for C-H cleavage and NHC forma-
tion was studied in detail using experimental and computational
methods. Based on these studies, a directed intramolecular
hydrogen transfer pathway proceeding via Rh-H intermediates
was implicated as the operative reaction mechanism. Similarities
between the reactivity patterns of dihydroquinazolines and other
N-heterocycles activated by (PCy3)2RhCl suggest that this
mechanism may be a common route to reactive M-NHC
intermediates. Insights gained from this mechanistic study are
being applied toward the ongoing development of Rh(I)-
catalyzed C-H functionalization reactions in our laboratories.
trans-(3-Methyl-1,2,3,4-tetrahydro-1H-quinazolin-2-ylidene)(P-
Cy3)2RhCl (2, 2cross from Crossover Experiment). In a N2 atmosphere
glovebox 1 (37 mg, 0.25 mmol), [(coe)2RhCl]2 (90 mg, 0.13 mmol)
and PCy3 (140 mg, 50 mmol) were combined in THF (5 mL) and sealed
into a glass-walled vessel equipped with a vacuum stopcock. The
reaction mixture was heated to 75 °C for 24 h and then returned to the
glovebox. After the reaction solvent was removed under vacuum, 2
was obtained as a yellow solid. This material could be further purified
by crystallization (slow diffusion of hexanes into THF at -30 °C under
N2) to give clear yellow blocks (153 mg, 72%). IR: 3422, 2913, 2845,
1
1603, 1514, 1472, 1445, 1403, 1058, 947, 732 cm-1. H NMR (300
MHz, d8-THF): δ 7.99 (s, 1H, N-H), 7.16 (t, 1H, J ) 7.6 Hz, Ar-
H), 7.02 (d, 1H, J ) 7.1 Hz, Ar-H), 6.92 (t, 1H, J ) 7.4 Hz, Ar-H),
6.67 (d, 1H, J ) 7.7 Hz, Ar-H), 4.29 (s, 2H, CH2), 4.10 (s, 3H, CH3),
2.3-0.9 (m, 66H, PCy3). 13C NMR (75 MHz, d8-THF): δ 134.4 (d,
JRh-C ) 1.6 Hz, C9), 129.5 (CAr), 127.0 (CAr), 123.5 (CAr), 118.6 (C10),
113.3 (CAr), 49.7 (CH2), 48.4 (CH3), 36.2 (t, JP-C ≈ JRh-C ) 8.2 Hz,
PCH), 32.2 (bs, 1C, PCy), 31.0 (s, 1C, PCy), 29.1 (t, 2C, JP-C ≈ JRh-C
) 4.8 Hz, PCHCH2), 28.0 (s, 1C, PCy) (missing C-2 signal revealed
by 13C-labeling). 13C NMR (100 MHz, C6D6) (only partial data given):
δ 32.0 (PCy), 30.8 (PCy), 28.9 (t, JP-C ≈ JRh-C ) 4.7 Hz, PCHCH2),
28.8 (t, JP-C ≈ JRh-C ) 4.9 Hz, PCHCH2), 27.7 (PCy). 31P NMR (200
MHz, d8-THF): δ 28.0 (d, JRh-P ) 152 Hz). Anal. Calcd for C45H76-
ClN2P2Rh: C, 63.93; H, 9.06; N, 3.31. Found: C, 64.02; H, 9.14; N,
3.59. See Supporting Information for X-ray crystal structure.
Experimental Section
General. Unless otherwise noted, all reagents were obtained from
commercial suppliers and degassed prior to use. Tetrahydrofuran (THF)
and hexanes were passed through a column of activated alumina (A1,
12 × 32, Purifry Co.) under nitrogen pressure and sparged with nitrogen
prior to use.50 The 1,4-dioxane was purchased anhydrous, stored over
3 Å activated molecular sieves, and degassed prior to use. Benzene-d6
was degassed by three freeze-pump-thaw cycles and stored over 3
Å activated molecular sieves. THF-d8 was vacuum transferred from
sodium/benzophenone ketyl prior to use. All compounds were stored
and handled in a N2-filled IT Braun inert atmosphere glovebox. All
reactions were carried out in oven-dried glassware. Thin-layer chro-
matography was performed on Merck 60 F254 250-µm silica gel plates.
The developed chromatograms were visualized by UV (254 nm) light.
Flash column chromatography was carried out using Merck 60 230-
400 mesh silica gel. All infrared (IR) spectra were recorded on a Thermo
Electron Avatar 370 spectrometer fitted with a single bounce ZnSe
ATR plate. Only partial IR data are listed. The 1H, 13C {1H}, 31P {1H},
2H {1H}, and 15N NMR spectra were obtained on Bruker AV-300,
AVQ-400, AVB-400, DRX-500, and AV-500 instruments and refer-
enced to residual solvent. When necessary, J coupling was deconvoluted
using 13C {1H, 15N} NMR experiments, and 13C assignments were made
on the basis of DEPT experiments. Elemental analyses were performed
at the University of California, Berkeley, elemental analysis facility.
The X-ray crystal structure was obtained at the UC Berkeley CHEXRAY.
[(coe)2RhCl]2 was prepared according to literature procedures and stored
at -30 °C under N2.51
trans-N1-(3-Methyl-3,4-dihydroquinazoline)(PCy3)2RhCl (3). In
a N2 atmosphere glovebox, 1 (73 mg, 0.50 mmol), [(coe)2RhCl]2 (180
mg, 0.25 mmol), and PCy3 (280 mg, 1.00 mmol) were dissolved in 10
mL of THF. The solution was allowed to stand for 5 d. The solid was
then separated by filtration, washed with pentane, and the remaining
solvent was removed under vacuum. The resulting orange powder (202
mg, 46%) was stored at -30 °C under N2. Under these conditions,
this compound is relatively stable with color change to pale green
1
(decomposition) occurring slowly (>1 month). H NMR (400 MHz,
d8-THF): δ 10.04 (d, 1H, J ) 8.4 Hz, C8-H), 7.61 (s, 1H, C2-H),
7.20 (t, 1H, J ) 7.6 Hz, Ar-H), 6.97 (t, 1H, J ) 7.4 Hz, Ar-H), 6.71
(d, 1H, J ) 7.2 Hz, Ar-H), 4.51 (s, 2H, CH2), 2.97 (s, 3H, CH3),
2.2-0.9 (m, 66H, PCy3). 31P NMR (160 MHz, d8-THF): δ 22.1 (d,
JRh-P ) 143 Hz). Inconsistent amounts of bound solvent prevented this
complex from giving reliable microanalysis data.
General Procedure for the Synthesis of Isotopically Labeled
3-Methyl-3,4-dihydroquinazolines. To an NMR tube were added
2-methylaminomethyl-phenylamine (100 mg, 0.73 mmol) and 0.5 mL
of formic acid. The tube was flame-sealed under vacuum and heated
for 1 h until 13C NMR analysis indicated that a complete reaction had
occurred. After cooling, the tube contents were diluted with 2 mL of
water, basified with of 0.5 mL of NH4OH, and extracted with CH2Cl2
(3 × 2 mL). The combined organic phases were washed with brine,
dried over MgSO4, and concentrated under vacuum to give a white
solid. Purification by crystallization (slow diffusion of hexanes into
THF at -30 °C under N2) gave white needles.
3-Methyl-3,4-dihydroquinazoline (1). Following a modified lit-
erature procedure,52 3,4-dihydroquinazoline53 (907 mg, 6.86 mmol) and
iodomethane (974 mg, 6.86 mmol) were sealed into a glass-walled
vessel equipped with a vacuum stopcock with MeOH (7 mL) and
allowed to stand at 25 °C for 4 d until crystallization of salts was
complete. The reaction suspension was then treated with 30 mL of 0.6
M NaOH and extracted with EtOAc (3 × 30 mL). The combined
organic phases were washed with brine, dried over MgSO4, and
concentrated onto a small amount of silica. Column chromatography
2-Methylaminomethyl-phenyl-15N-amine (4). The reaction was run
according to a modified general procedure for the amidation of aryl
bromides.55 In an N2 atmosphere glovebox, CuI (94 mg, 0.49 mmol)
(50) Alaimo, P. J.; Peters, D. W.; Arnold, J.; Bergman, R. G. J. Chem. Educ.
2001, 78, 64.
(51) Vanderent, A.; Onderdelinden, A. L. Inorg. Synth. 1990, 28, 90.
(52) Armarego, W. L. J. Chem. Soc. 1961, 2697.
(53) The 3,4-dihydroquinazoline was prepared according to a literature proce-
dure: Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2004, 6, 35.
(54) Tietz, H.; Rademacher, O.; Zahn, G. Eur. J. Org. Chem. 2000, 2105.
(55) Klapars, A.; Huang, X. H.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421.
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N-Heterocycle C−H Activation by Rh(I)/PCy3
A R T I C L E S
and N,N′-dimethyl-ethane-1,2-diamine (87 mg, 0.98 mmol) were
combined in 1,4-dioxane (5 mL), and this mixture was stirred until the
CuI completely dissolved. The resulting solution was added to a glass-
walled vessel equipped with a vacuum stopcock containing (2-bromo-
benzyl)-methyl-amine56 (983 mg, 4.91 mmol), 15N-benzamide (600 mg,
4.91 mmol), K2CO3 (1.36 g, 9.83 mmol), and a magnetic stirbar. The
reaction vessel was sealed and heated at 110 °C for 5.5 h until TLC
(5% Et3N in EtOAc) indicated complete consumption of the aryl
bromide. The crude reaction mixture was filtered through a pad of silica
eluting with CH2Cl2 containing 5% of a mixture of 10% NH4OH in
MeOH to give a yellow oil. This material was suspended in 5 mL of
water, and then 10 mL of concentrated HCl was added dropwise. The
resulting solution was washed (3 × 2 mL of Et2O) and then resealed
into the original reaction vessel and heated at 105 °C for 24 h. After
being cooled to 0 °C, the reaction solution was basified by dropwise
addition of NH4OH and extracted with Et2O (3 × 40 mL). The
combined ethereal phases were washed with brine, dried over MgSO4,
and concentrated under vacuum to give a yellow oil. After silica gel
chromatography (50% f 95% EtOAc in hexanes with 5% Et3N), 4
(324 mg, 48%) was obtained as a yellow oil. Its spectroscopic properties
were consistent with data reported for 2-methylaminomethyl-phenyl-
amine.57 1H NMR (500 MHz, C6D6): 7.11 (t, 1H, J ) 7.6 Hz, Ar-H),
6.96 (d, 1H, J ) 7.3 Hz, Ar-H), 6.73 (t, 1H, J ) 7.4 Hz, Ar-H), 6.43
(d, 1H, J ) 7.8 Hz, Ar-H), 4.43 (bd, 2H, JN-H ) 79.0 Hz, 15NH2),
3.47 (s, 2H, CH2), 2.01 (s, 3H, CH3), 0.29 (bs, 1H, NH). 13C NMR
(125 MHz, C6D6): 148.3 (d, JN-C ) 10.4 Hz, C-15N), 130.5, 129.0,
124.4 (d, JN-C ) 2.0 Hz), 117.8, 116.0 (d, JN-C ) 1.8 Hz), 56.1 (CH2),
36.1 (CH3). 15N {1H} NMR (40 MHz, C6D6): 55.8.
collected for 1, except that the 1H NMR signal at δ 6.6 ppm was absent,
1
as expected. IR: 2240 cm-1 (C-D). H NMR (400 MHz, C6D6): δ
7.51 (d, 1H, J ) 7.8 Hz, Ar-H), 7.08 (t, 1H, J ) 8.3 Hz, Ar-H), 6.89
(t, 1H, J ) 7.4 Hz, Ar-H), 6.56 (d, 1H, J ) 7.5 Hz, Ar-H), 3.74 (s,
2H, CH2), 1.79 (s, 3H, CH3). 13C NMR (125 MHz, DCO2D): δ 147.4
(t, JD-C ) 31 Hz, C2), 127.4, 126.9, 125.8, 124.8, 115.0, 114.9, 46.6,
39.8. 2H NMR (61 MHz, C6H6): δ 6.6. MS (ESI); m/z (%): 147 [1H-
M+ + H] (0.92), 148 [M+ + H] (100), 149 [D-M+ + H] (10.5).
2
Calcd: 99% H.
General Procedure for Observing Isotopically Labeled Rh-
Complexes. To an NMR tube was added a solution containing labeled-1
(3.8 mg, 25 µmol), [(coe)2RhCl]2 (9.0 mg, 13 µmol), and PCy3 (14.0
mg, 50 µmol) in d8-THF (0.5 mL). The tube was flame-sealed under
vacuum, and then heated between 45 and 75 °C for 1-24 h to observe
varying ratios of free 1, 3, and 2. The distinctive resonances corre-
sponding to the various complexes are reported as part of these mixtures.
From 15N1-1: trans-(3-Methyl-1,2,3,4-tetrahydro-1-15NH-quinazo-
lin-2-ylidene)(PCy3)2RhCl (15N1-2, 2dir from Crossover Experiment).
Its spectroscopic properties were consistent with data collected for 2.
1H NMR (400 MHz, d8-THF): δ 7.98 (d, 1H, JN-H ) 94.0 Hz, N-H).
This compound was not sufficiently soluble to obtain an 15N NMR
spectrum.
trans-N1-(3-Methyl-3,4-dihydro-1-15N-quinazoline)(PCy3)2RhCl
(15N1-3). Its spectroscopic properties were consistent with data collected
1
for 3. H NMR (400 MHz, d8-THF): δ 7.61 (d, 1H, JN-H ) 7.2 Hz,
C2-H). 31P NMR (160 MHz, d8-THF): δ 22.1 (d, JRh-P ) 143 Hz,
JN-P ) 3.0 Hz). This compound was not sufficiently soluble to obtain
an 15N NMR spectrum.
3-Methyl-3,4-dihydro-1-15N-quinazoline (15N1-1). The reaction was
performed as described in the general procedure using 4 (100 mg, 0.73
mmol). The white solid obtained after crystallization (55 mg, 51%)
exhibited spectroscopic properties consistent with data collected for 1.
1H NMR (400 MHz, CDCl3): δ 7.14 (t, 1H, J ) 7.6 Hz, Ar-H), 7.04
(d, 1H, J ) 7.9 Hz, Ar-H), 6.98 (t, 1H, J ) 7.4 Hz, Ar-H), 6.96 (d,
1H, JN-H ) 13.1 Hz, C2-H), 6.83 (d, 1H, J ) 7.5 Hz, Ar-H), 4.49
(s, 2H, CH2), 2.88 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 150.3
(d, JN-C ) 3.0 Hz, C2), 141.5, 128.3 (d, JN-C ) 3.0 Hz), 125.5, 124.6,
124.5 (d, JN-C ) 8.9 Hz, C9), 120.0, 48.9, 39.7. 15N NMR (40 MHz,
CDCl3): δ 203.4 (d, JH-N ) 13.2 Hz). MS (EI); m/z (%): 145 [14N-
M+ - H] (2.0), 146 [(14N-M+) + (15N-M+ - H)] (100), 147 [(15N-M+)
+ (15N,D-M+ - H)] (45.6). Calcd: 99% 15N by comparison to the
fragmentation pattern of 1.
From 15N1,13C2-1: trans-(3-Methyl-1,2,3,4-tetrahydro-1-15NH,2-
13C-quinazolin-2-ylidene)(PCy3)2RhCl (15N1,13C2-2). Its spectroscopic
properties were consistent with data collected for 15N1-2. 1H NMR (500
MHz, d8-THF): δ 7.99 (dd, 1H, JN-H ) 94.5 Hz, JC-H ) 3.9 Hz, N-H),
4.09 (d, 3H, JC-H ) 4.0 Hz, CH3). 13C NMR (125 MHz, d8-THF): δ
216.4 (dtd, JRh-C ) 54.4 Hz, JP-C ) 12.1 Hz, JN-C ) 2.0 Hz, C2).
trans-N1-(3-Methyl-3,4-dihydro-1-15N,2-13C-quinazoline)(PCy3)2-
RhCl (15N1,13C2-3). Its spectroscopic properties were consistent with
1
data collected for 15N1-3. H NMR (500 MHz, d8-THF): δ 7.60 (dd,
1H, JC-H ) 193 Hz, JN-H ) 7.4 Hz, C2-H), 2.97 (d, 3H, JC-H ) 4.1
Hz, CH3). 13C NMR (125 MHz, d8-THF): δ 155.2 (d, JN-C ) 10.5
Hz, C2).
From C2-D-1: trans-(3-Methyl-1,2,3,4-tetrahydro-1H,2-2H-quinazo-
lin-2-ylidene)-(PCy3)2RhCl (C2-D-2, 2dirD from Crossover Experi-
ment). Its spectroscopic properties were consistent with data collected
for 2, except that the 1H NMR signal at δ 8.0 ppm (N-H) was greatly
diminished, as expected. IR: 2543 cm-1 (N-D).
trans-N1-(3-Methyl-3,4-dihydro-2-2H-quinazoline)(PCy3)2RhCl (C2-
D-3). Its spectroscopic properties were consistent with data collected
for 3, except that the 1H NMR signal at δ 7.6 ppm (C2-H) was absent,
as expected.
3-Methyl-3,4-dihydro-1-15N,2-13C-quinazoline (15N1,13C2-1). The
reaction was performed as described in the general procedure using 4
(75 mg, 0.55 mmol) with 13C-formic acid (250 mg, 5.3 mmol). The
white solid obtained after crystallization (27 mg, 33%) exhibited
1
spectroscopic properties consistent with data collected for 15N1-1. H
NMR (400 MHz, C6D6): δ 7.49 (d, 1H, J ) 7.8 Hz, Ar-H), 7.08 (t,
1H, J ) 7.7 Hz, Ar-H), 6.90 (t, 1H, J ) 7.4 Hz, Ar-H), 6.59 (dd,
1H, JC-H ) 190 Hz, JN-H ) 13.4 Hz, C2-H), 6.57 (d, 1H, J ) 7.6
Hz, Ar-H), 3.75 (s, 2H, CH2), 1.81 (d, 3H, JC-H ) 4.0 Hz, CH3). 13
C
Procedure for Deuterium Tracer Experiment. In a N2 atmosphere
glovebox, C2-D-1 (3.8 mg, 26 µmol), [(coe)2RhCl]2 (8.9 mg, 12 µmol),
PCy3 (14.4 mg, 51 µmol), and 2,6-dimethoxytoluene (1.1 mg, 7 µmol)
were combined in d8-THF (0.5 mL). This mixture was flame-sealed
into a medium-walled NMR tube and then heated at 70 °C overnight.
After the mixture was cooled to room temperature, analysis of the
reaction mixture by 1H NMR indicated 80% yield of 3 with 88%
incorporation of deuterium at the N1-H position.
Procedure for Double Labeling Crossover Experiment (with C2-
D-1 and 15N1-1). In a N2 atmosphere glovebox, C2-D-1 (0.9 mg, 6
µmol), 15N1-1 (0.9 mg, 6 µmol), [(coe)2RhCl]2 (4.5 mg, 6 µmol), PCy3
(8.8 mg, 31 µmol), and 2,6-dimethoxytoluene (1.9 mg, 12 µmol) were
combined in d8-THF (0.5 mL). This mixture was flame-sealed into a
medium-walled NMR tube that was then heated at 45 °C for 1 d.
Periodically, the reaction tube was removed from its heating bath, cooled
to room temperature, and a one-pulse 1H NMR spectrum was acquired
NMR (100 MHz, THF) (only partial data given): δ 150.1 (d, JN-C
)
3.0 Hz, C2). MS (EI); m/z (%): 146 [singly labeled-M+ - H] (3.2),
147 [(singly labeled-M+) + (15N,13C-M+ - H)] (100), 148 [(15N,13C-
M+) + (15N,13C,D-M+ - H)] (44.8). Calcd: 96% 15N,13C by comparison
to the fragmentation pattern of 1.
3-Methyl-3,4-dihydro-2-2H-quinazoline (C2-D-1). The reaction was
performed as described in the general procedure using 2-methylami-
nomethyl-phenyl-14N-amine58 (125 mg, 0.92 mmol) with D2-formic acid
(500 mg, 10.4 mmol). The white solid obtained after crystallization
(48 mg, 35%) exhibited spectroscopic properties consistent with data
(56) Analytical data and a synthetic protocol have been reported for (2-bromo-
benzyl)-methyl-amine: Philippe, N.; Denivet, F.; Vasse, J.-L.; Santos, J.
S. O.; Levacher, V.; Dupas, G. Tetrahedron 2003, 59, 8049.
(57) Coyne, W. E.; Cusic, J. W. J. Med. Chem. 1968, 11, 1208.
(58) Prepared according to the procedure for 4.
9
J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006 2461

A R T I C L E S
Wiedemann et al.
prior to reheating to 45 °C. Based on these spectra, the relative
abundance of the various isotopomers of 2 was determined (Table 1).
General Procedures for Measurements of Reaction Rate. The
reactions were carried out in medium-walled NMR tubes flame-sealed
with a solid glass rod inside to minimize solvent reflux during heating.
Reaction progress was monitored by in situ NMR analysis in the
temperature-controlled probe of a Bruker DRX-500 MHz spectrometer.
Instrument temperature readings were verified by reference to an
ethylene glycol standard. Single pulse 1H NMR spectra were collected
at regular intervals of at least 5 times the longest measured T1. The
peak area of methyl and methylene resonances for the dihydroquinazo-
line moiety was measured relative to the internal standard (2,6-
dimethoxytoluene) methoxy group peak area to obtain absolute
concentrations. Initially, a reaction was run to complete conversion,
and the resulting concentration versus time data were satisfactorily fit
to our kinetic model (vida infra) (Figure S-1a). Subsequent reactions
were monitored to between 10% and 40% conversion (Figure S-1b).
Concentration versus time data were fitted using the Gepasi 3.0 software
package (mass action kinetics) to obtain rate constants corresponding
to Scheme 3, path A. The initial concentration of free (PCy3)2RhCl in
solution was set based on the weight of added reagents because it could
not be independently measured by NMR. While the actual concentration
of (PCy3)2RhCl is determined by complex equilibria (Scheme 5), for
the sake of data fitting, approximating [(PCy3)2RhCl] as the total
concentration of free Rh(I) proved to be an acceptable simplification.
A term for slow unimolecular decomposition of (PCy3)2RhCl (kd <
6.5 × 10-5 s-1) was included in all fits.
liquid N2, flame-sealed under vacuum, and kept frozen until use.
Reaction rates were otherwise measured as usual.
Computation Methodology. The B3LYP/LACVP**++//B3LYP/
LACVP** level of theory59 with “medium” grid density as implemented
in the Jaguar 4.0 quantum chemistry program package has been utilized
throughout this study.60 For N, C, Cl, P, and H, the 6-31G basis set of
Pople and co-workers was used.61 For rhodium, a Hay-Wadt small
core effective core potential replaces the 28 innermost core electrons.62
A single asterisk (*) indicates the addition of polarization functions to
atoms Li through Ar; a double asterisk indicates the addition of
polarization functions to atoms H through Ar. Similarly, a single plus
(+) indicates the addition of diffuse functions to atoms Li through Ar;
and double pluses indicate the addition of diffuse functions to atoms
H through Ar. The basis set on rhodium has double ú quality
[contraction scheme {331/311/31}]. A full geometry optimization and
analytical vibrational frequency calculation were performed for all
simplified models. Stationary points are characterized by exactly zero
imaginary vibrations; transition structures are characterized by exactly
one imaginary vibration. Gibbs free energies ∆G for 298.15 K and 1
atm are based on unscaled molecular vibrations.
Acknowledgment. We thank Dr. Fred Hollander at the UCB
X-ray diffraction facility for determination of the crystal
structure of 2. Dr. Jeff Pelton of the UCB structural biology
NMR facility is thanked for providing assistance for multi-
nuclear decoupling experiments. We acknowledge Dr. Katherine
Durkin of the Berkeley Molecular Graphics and Computation
Facility for her helpful advice on the use of Jaguar. This work
was supported by NIH grant GM069559 (to J.A.E.) and by the
Director and Office of Energy Research, Office of Basic Energy
Sciences, Chemical Sciences Division, U.S. Department of
Energy, under contract DE-AC02-05CH11231 (to R.G.B.).
General Methods for Preparing Reaction Solutions for Rate
Studies. Method A (in Situ Generation). In an N2 atmosphere
glovebox, 1 (1.8 mg, 13 µmol), [(coe)2RhCl]2 (4.5 mg, 6 µmol), PCy3
(8.8 mg, 31 µmol), and 2,6-dimethoxytoluene (1.9 mg, 12 µmol) were
combined in d8-THF (0.5 mL). The resulting dark red solution was
transferred to an NMR tube, frozen using liquid N2, flame-sealed under
vacuum, and kept frozen until use.
Supporting Information Available: Typical plots and nu-
merical rate data for the formation of 2, a Van’t Hoff plot for
the equilibrium between 1 and 3, tabulated energy values for
A-L, and X-ray crystallographic data for 2 in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Method B (Using Isolated Intermediate). In an N2 glovebox, 3
(11 mg, 13 µmol), PCy3 (1.8 mg, 6 µmol), and 2,6-dimethoxytoluene
(1.9 mg, 12 µmol) were transferred to an NMR tube using d8-THF
(0.5 mL). After being sealed under vacuum, the reaction tube was heated
with agitation using a warm water bath (45 °C) until the light orange
suspension became dark red and homogeneous. The reaction tube was
maintained at 45 °C until use.
JA0576684
Method for Measuring Deuterium Kinetic Isotope Effect. In an
N2 atmosphere glovebox, [(coe)2RhCl]2 (9.0 mg, 12 µmol), PCy3 (17.5
mg, 62 µmol), and 2,6-dimethoxytoluene (1.9 mg, 12 µmol) were
combined in d8-THF (1 mL). This solution was divided into two
portions, one of which was combined with 1 (1.8 mg, 13 µmol) while
the other was combined with C2-D-1 (1.8 mg, 13 µmol). The resulting
dark red solutions were transferred to separate NMR tubes, frozen using
(59) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Vosko, S. H.;
Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200. (c) Lee, C. T.; Yang,
W. T.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (d) Krishnan, R.; Binkley,
J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys. 1980, 72, 650.
(60) Jaguar 4.0, release 23; Schrodinger, Inc.: Portland, OR, 1998.
(61) Frisch, M. J.; Pople, J. A.; Binkley, J. S. J. Chem. Phys. 1984, 80, 3265.
(62) (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270-283. (b) Hay,
P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
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2462 J. AM. CHEM. SOC. VOL. 128, NO. 7, 2006