Synthesis of dihydropyridines and pyridines from imines and alkynes via C-H activation

Article abstract of DOI:10.1021/ja7104784

A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence has been developed for the synthesis of highly substituted pyridine derivatives from alkynes and α,β-unsaturated N-benzyl aldimines and ketimines that proceeds through dihydropyridine intermediates. A new class of ligands for C-H activation was developed, providing broader scope for the alkenylation step than could be achieved with previously reported ligands. Substantial information was obtained about the mechanism of the reaction. This included the isolation of a C-H activated complex and its structure determination by X-ray analysis; in addition, kinetic simulations using the Copasi software were employed to determine rate constants for this transformation, implicating facile C-H oxidative addition and slow reductive elimination steps.

Full text of DOI:10.1021/ja7104784

Published on Web 02/27/2008
Synthesis of Dihydropyridines and Pyridines from Imines and
Alkynes via C-H Activation
Denise A. Colby, Robert G. Bergman,* and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, and DiVision of Chemical Sciences,
Lawrence Berkeley National Laboratory, Berkeley, California, 94720
Received November 20, 2007; E-mail: bergman@cchem.berkeley.edu; jellman@uclink.berkeley.edu
Abstract: A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence has been
developed for the synthesis of highly substituted pyridine derivatives from alkynes and R,â-unsaturated
N-benzyl aldimines and ketimines that proceeds through dihydropyridine intermediates. A new class of
ligands for C-H activation was developed, providing broader scope for the alkenylation step than could be
achieved with previously reported ligands. Substantial information was obtained about the mechanism of
the reaction. This included the isolation of a C-H activated complex and its structure determination by
X-ray analysis; in addition, kinetic simulations using the Copasi software were employed to determine rate
constants for this transformation, implicating facile C-H oxidative addition and slow reductive elimination
steps.
pyridines.4 Iminoannulation is also a mild method for the
Introduction
synthesis of pyridines from â-bromo-R,â-unsaturated imines and
alkynes, though this route requires the prefunctionalization of
the imine moiety.3b
The synthesis of N-heterocycles is an important area of
research because of their prevalence in natural products and
drugs.1 Of the N-heterocycles, pyridines are the most extensively
used in pharmaceutical research,2 and much effort has been
devoted to their synthesis. Despite these efforts, the selective
preparation of nonsymmetrically substituted pyridines continues
to be a significant challenge in synthesis.3 Traditional methods
for pyridine synthesis involve the condensation of amines with
carbonyl compounds, but high yields of single products can often
only be obtained for symmetrically substituted systems.1 Cy-
cloaddition reactions can also provide rapid access to substituted
pyridines; however, there are significant constraints on the steric
andelectronicnatureaswellasthelocationofthesubstituents.3a,i-k
Recently, a few elegant methods have appeared in the literature
for the synthesis of selectively substituted pyridine derivatives.
In particular, the triflic anhydride-mediated pyridine synthesis
from N-vinyl amides and alkene or alkyne inputs provides a
convenient route into the synthesis of highly substituted
Results and Discussion
Dihydropyridine Synthesis. We now report a new one-pot
C-H alkenylation/electrocyclization/aromatization sequence that
provides access to highly substituted pyridines from R,â-
unsaturated imines and alkynes.5,6 In contrast to other methods
for pyridine synthesis, rhodium-catalyzed C-H activation does
not require the use of activated precursors and is tolerant of a
variety of functional groups. As part of this work, a new class
of ligands for C-H activation has been developed to achieve
broad scope in the C-H alkenylation step.
We began our investigation into this reaction by utilizing
catalyst and reaction parameters optimized for the alkylation
of R,â-unsaturated imines with alkenes.7 Specifically, using the
electron-donating (dicyclohexylphosphinyl)ferrocene ligand in
a 2:1 ligand to rhodium ratio provided the aza-triene product 2,
which subsequently underwent in situ electrocyclization to yield
dihydropyridine (DHP) 3 (eq 1).8 While this catalyst system
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell: Oxford,
UK, 2000.
(2) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem.
2006, 4, 2337-2347.
(3) For recent reviews on pyridine syntheses, see the following and references
therein: (a) Varela, J.; Saa, C. Chem. ReV. 2003, 103, 3787-3801. (b)
Zeni, G.; Larock, R. L. Chem. ReV. 2006, 106, 4644-4680. For recent
examples of transition-metal facilitated pyridine syntheses, see: (c) Trost,
B. M.; Gutierrez, A. C. Org. Lett. 2007, 9, 1473-1476. (d) Movassaghi,
M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592-4593. (e) McCormick,
M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127,
5030-5031. (f) Yamamoto, Y.; Kinpara, K.; Ogawa, R.; Nishiyama, H.;
Itoh, K. Chem. Eur. J. 2006, 12, 5618-5631. (g) Tanaka, R.; Yuza, A.;
Watai, Y.; Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem.
Soc. 2005, 127, 7774-7780. (h) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang,
H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora M. J. Am. Chem.
Soc. 2002, 124, 5059-5067. For pyridine syntheses from Diels Alder inputs,
see: (i) Boger, D. L. Chem. ReV. 1986, 86, 781-793. (j) Fletchter, M. D.;
Hurst, T. E.; Miles, T. J.; Moody, C. J. Tetrahedron 2006, 62, 5454-
5463. (k) Saito, A.; Hironaga, M.; Oda, S.; Harzawa, Y. Tetrahedron Lett.
2007, 48, 6852-6855.
(4) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007, 129,
10096-10097.
(5) For an example of pyridine synthesis from oxime and alkyne inputs via
C-H activation, see: Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H.
Org. Lett. 2008, 10, 325-328.
(6) For previous studies on chelation-assisted alkenylation proceeding via C-H
activation, see the following: (a) Lim, S.-G.; Lee, J. H.; Moon, C. W.;
Hong, J.-B.; Jun, C.-H. Org. Lett. 2003, 5, 2759-2761. (b) Lim, Y.-G.;
Lee, K.-H.; Koo, B. T.; Kang, J.-B. Tetrahedron Lett. 2001, 42, 7609-
7612. (c) Kakiuchi, F.; Uetsuhara, T.; Tanaka, Y.; Chatani, N.; Murai, S.
J. Mol. Cat. A 2002, 183-183, 511-514.
(7) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128,
5604-5605.
(8) Similar reactivity was reported by Odom in the â-alkylation of the N-phenyl
imine of 1-acetylcyclohexene, which was prepared in situ by Ti - mediated
hydroamination of cyclohexenylacetylene. See: Cao, C.; Li, Y.; Shi, Y.;
Odom, A. L. Chem. Commun. 2004, 2002-2003.
9
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J. AM. CHEM. SOC. 2008, 130, 3645-3651
3645

A R T I C L E S
Colby et al.
1; 6a-c). Using a 2:1 ratio of ligand to rhodium, the diethyl-
(DMAPh)phosphine ligand 6b (Table 1, entry 5) provided a
more efficient catalyst than either the dicyclohexyl (6a) or
dimethyl (6c) derivatives (Table 1, entries 4 and 6).
We next anticipated that decreasing the ligand loading might
improve the reaction efficiency by reducing competitive phos-
phine binding to the six-coordinate Rh species prior to alkyne
binding. Indeed, decreasing the ratio of ligand to rhodium from
2:1 to 1:1 (Table 1, entries 7 and 8) decreased the reaction time
and considerably improved the yield for 6b (entry 8). To further
investigate the effect of the electronic properties of the ligand,
the corresponding diaryl alkyl phosphines 7a-c were prepared
and screened (Table 1, entries 9-11). While these ligands did
produce active catalyst systems, the yields were inferior to those
obtained with ligand 6b, which was used in all subsequent
experiments.
Table 1. A Brief Survey of Catalyst Conditions
Under optimized conditions for catalysis, the scope of this
transformation with other imines and alkynes was found to be
quite good.11 Aldimine 1 and â-substituted aldimines 4, 8, and
9 each gave good DHP yields (Table 2, entries 1, 5-7, columns
5 and 6). Additionally, ketimines 10 and 11 reacted rapidly with
3-hexyne to give the desired DHP products (entries 9 and 15,
columns 5 and 6). Alkyne scope was also good, with nonsym-
metric alkynes giving DHP products in most cases as single
regioisomers when one substituent on the alkyne is R-branched.
In the simplest case, 4-methyl-2-pentyne reacted with 1 and 9
to give single regioisomers of DHP products (entries 2 and 8,
columns 5 and 6), although this alkyne coupled with â-substi-
tuted imine 8 with poor regiocontrol (data not shown). The more
sterically hindered TMS-substituted alkynes consistently ex-
hibited good regioselectivity with the TMS substituent proximal
to the DHP nitrogen for all imines evaluated (entries 3, 4, 10-
12, columns 5 and 6). In some cases, the electronic character
of the alkyne was found to override steric control to give major
DHP products with the bulkier substituents distal to the nitrogen
(entries 13 and 14, columns 5 and 6). When terminal alkynes
were employed, alkyne dimerization was competitive with C-H
alkenylation, leading to complex product mixtures.
mol%
time
(h)
yielda
(%)
entry
imine
ligand
L
1
2
3
4
5
6
7
8
9
1
4
4
4
4
4
4
4
4
4
4
FcPCy2
FcPCy2
5
6a
6b
6c
10
10
10
10
10
10
5
5
5
5
5
2
24
8
24
24
24
8
6
24
8
quant.
trace
84
20
36
0
82
88
42
5
6b
7a
7b
7c
10
11
55
73
8
a All yields were determined by NMR integration relative to 2,6-
dimethoxytoluene as an internal standard.
Figure 1. Ligands for C-H activation.
Oxidation to Pyridines. With a method to prepare highly
substituted DHPs in hand, we next sought to develop an efficient
method for their conversion to the corresponding highly
substituted pyridines. We envisioned that this could be ac-
complished by oxidation of the DHPs to N-benzylpyridinium
intermediates followed by debenzylation.12
did prove successful with aldimine 1, only trace product was
seen using aldimines bearing a â-substituent, e.g., 4 (Table 1,
entry 2), even at elevated temperatures. Ligand optimization
was therefore performed. An extensive screen of commercially
available phosphine ligands did not produce an ideal catalyst
system, and we began to consider new ligand design. To
ascertain the influence of steric effects, (diethylphosphinyl)-
ferrocene (Figure 1, 5) was prepared and showed improved
reactivity with â-substituted imine 4, providing the DHP product
in 84% yield in 8 h (Table 1, entry 3). In several examples of
imine-directed alkylations and alkenylations, electron-donating
ligands have exhibited improved reactivity.9 We were therefore
intrigued by a novel class of ligands with a 4-(N,N-dimethy-
lamino)phenyl substituent (DMAPh) that recently were reported
for use in Suzuki-Miyaura couplings.10 A series of analogous
aniline-substituted phosphine ligands with dialkyl substituents
possessing various steric properties were thus prepared (Figure
Using purified DHP 3, a variety of oxidants were probed for
this transformation. DDQ,13 while effectively oxidizing the DHP,
formed only small amounts of the pyridinium salt along with
extensive decomposition (Table 3, entry 3). Manganese oxidants
14
15
such as MnO2 and Mn(OAc)3/H5IO6 were also ineffective,
with MnO2 providing only trace pyridinium with much DHP 3
remaining and Mn(OAc)3 primarily decomposing the reagents
(11) Many of the DHP products are not stable to chromatographic purification,
and therefore only NMR yields are reported.
(12) The Diels-Alder reaction of aza-dienes with activated alkynes provides 1,4-
DHP products, which can be converted to the corresponding pyridines.
However, the scope of this transformation is limited to highly activated
alkynes. (See refs 3i,j.)
(9) (a) Thalji, R. L.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Org.
Chem. 2005, 70, 6775-6781. (b) O’Malley, S. J.; Tan, K. L.; Watzke, A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496-13497.
(10) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan,
J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider, P.
J. Org. Lett. 2006, 8, 1787-1789.
(13) Wallace, D. J.; Gibb, A. D.; Cottrell, I. F.; Kennedy, D. J.; Brands, K. M.
J.; Dolling, U. H. Synthesis 2001, 12, 1784-1789.
(14) Eynde, J. J. V.; Delfosse, F.; Mayence, A.; van Haverbeke, Y. Tetrahedron
1995, 23, 6511-6516.
(15) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A. B. Org. Lett. 2004,
6, 3517-3520.
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3646 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

Synthesis of Dihydropyridines and Pyridines
A R T I C L E S
Table 2. One Pot Synthesis of Pyridines from R,â-Unsaturated Imines and Alkynes
a Determined by NMR integration relative to 2,6-dimethoxytoluene as an internal standard. b Isolated overall yields based on starting R,â-unsaturated
imine. c For this specific substrate, purified DHP was used for pyridine synthesis, and the yield provided is the overall yield for the three steps. d The minor
regioisomer with the Ph-substituent in the 2-position was isolated in 26% yield.
(entries 1 and 2). Trityl chloride was a very effective oxidant,
producing the pyridinium salt cleanly and efficiently. We
envisioned that debenzylation might occur in situ by nucleophilic
displacement, but this transformation was not realized (entry
4). Ideal conditions were ultimately found using 10% Pd/C and
air as the oxidant in acetic acid.16 Under these conditions, the
pyridinium salt was formed cleanly. Previous reports indicated
that the addition of phenol could facilitate the debenzylation in
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3647

A R T I C L E S
Colby et al.
Table 3. Oxidant Screen for the Conversion of DHP 3 to Pyridine
13
Using the less acidic solvent methanol at 50 °C did oxidize
14 with little dealkylation; however, the reaction was substan-
tially slowed in this solvent and did not go to completion,
resulting in low conversion (Table 4, entry 2). Next, 2,2,2-
trifluoroethanol (TFE) was used as a solvent, and the temper-
ature was lowered to 23 °C. Under these conditions, 15 and 16
were obtained in a 1:1 ratio with an overall yield of 54% (entry
3). Dropping the temperature to 0 °C decreased the dealkylation
pathway even further, giving 15 and 16 in a 4:1 ratio without
effecting the overall yield (entry 4). It was noted that 14 was
not soluble in TFE at room temperature or below. To improve
the solubility of the DHP, cosolvents were next investigated
and the concentration was decreased. In a 2:1 solution of TFE:
toluene at 0 °C, the overall selectivity increased only slightly
(entry 5); however, by increasing the amount of cosolvent to a
1:1 mixture, a significant increase in selectivity was seen and
pyridines 15 and 16 were obtained in a 9:1 ratio (entry 6).
It was additionally noted that while TFE and toluene were
miscible at room temperature, at 0 °C the solvents were no
longer miscible and a fine suspension formed with vigorous
stirring. Further increases in the relative amount of the co-
solvent attenuated this problem, and using a 1:3 ratio of TFE:
toluene provided 15 exclusively in 60% yield (entry 7). The
use of toluene is particularly advantageous because it enables
a one-pot synthesis of pyridines from R,â-unsaturated imines
and alkynes via a C-H activation /electrocyclization /aroma-
tization sequence with no intermediary isolation or solvent
removal.
Applying this method to the crude reaction mixture from the
formation of 14, we were pleased to find that 15 was formed in
good yield over the three steps (please refer to Table 2, entry
2, columns 9 and 10). This one-pot method is quite general,
delivering good to high overall yields of pyridine products for
the three-step sequence (Table 2, columns 9 and 10). Increasing
substitution on the DHP did require prolonged reaction times
and increased temperature (e.g., entry 9), but all substrates were
cleanly oxidized to the pyridine products. Interestingly, TMS-
substituted DHPs did not provide silylated pyridines, but instead,
in situ desilylation occurred to generate pyridine products
without substitution at the ortho-position (entries 3, 4, 10-12,
columns 9 and 10). In this manner, the silyl substituents can
serve as blocking groups to enable bulky substituents to be
located distal to the nitrogen. The presence of carboxy substit-
uents is also well tolerated, leaving a site for further transforma-
tions (entry 13, columns 9 and 10).
T
entry
oxidant
solvent
(°
C)
result
1
2
3
4
5
MnO2
Mn(OAc)3/H3IO5
DDQ
CH2Cl2
AcOH
EtOAc
CH2Cl2
AcOH
23
23
23
23
50
trace 12
trace 12
trace 12
12
Ph3CCl
Pd/C, aira
13, 70%
a Followed by 1 atm H2 for 1 h at 23 °C.
Table 4. Optimization of the Oxidation of DHP 14 to Pyridine 15
temp
C)
time
(h)
total
entry
solvent (M)
(
°
15:16
yield (%)
1
2
3
4
5
AcOH (0.2)
MeOH (0.2)
TFEa (0.2)
TFEa (0.2)
TFE:Me-Phb
2:1 (0.1)
50
50
23
0
5
12
3
5
5
16 only
10:1
1:1
4:1
4:1
trace
<20
54
51
>50
0
6
7
TFE:Me-Phb
1:1 (0.1)
0
0
5
8
9:1
>50
TFE:Me-Ph
15 only
60
1:3 (0.1)
a 14 was not soluble in the solvent at this temperature. b TFE was not
fully miscible in the cosolvent at this temperature.
situ.17 While we did not find this additive to be effective in
removing the benzyl group (data not shown), simply subjecting
the reaction to an atmosphere of hydrogen following the
oxidation did provide the deprotected pyridine via hydrogenoly-
sis in a one-pot procedure with no additives, simplifying the
overall transformation (entry 5).
While the DHPs can be isolated and purified in some cases,
significant decomposition during chromatography is often seen,
and in many cases, for example with the silyl-substituted DHPs,
the compounds are too unstable to isolate. We were therefore
hopeful that conversion to the pyridines could be carried out
using crude DHP reaction mixtures, alleviating the problem of
intermediate isolation. This idea was validated when the crude
reaction mixture from the formation of DHP 3 provided pyridine
13 in 66% yield.
Applying this procedure to other DHPs, e.g., 14, we
unfortunately found that it was not general. Instead of isolating
the expected pyridine 15, the major pyridine product 16 had
lost the isopropyl substituent and was formed in very low yield
(Table 4, entry 1). This oxidative dealkylation is a known
decomposition pathway in the oxidation of 1,4- and 1,2-DHPs.18
The oxidants used with DHP 3 were reexamined with DHP 14
but did not show any improvement. A screen of temperatures
and solvents was then undertaken.
Isolation of a Potential Intermediate and Discussion of
Mechanism. In considering whether the reaction was proceeding
via a C-H activation mechanism, we were hopeful that a C-H
activated species could be detected directly. In a stochiometric
reaction of 1 (1 equiv), [RhCl(coe)2]2 (0.5 equiv), and FcPCy2
(2 equiv) at room temperature, a new complex 17 formed
immediately upon combination of the reagents (eq 2). Complex
17 was identified based on the presence in its 1H NMR spectrum
of an apparent quartet shifted strongly upfield to -14.15 ppm,
which corresponds to the doublet of triplets expected for a [Rh]-
H species with two equivalent coordinated phosphine ligands.
In the 31P NMR spectrum, a doublet at 128.42 ppm with a
coupling constant of 113 Hz (1J; Rh-H) is seen. These data
(16) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4, 3955-
3957.
(17) Bennasar, M.-L.; Zulaica, E.; Roca, T.; Alonso, Y.; Monerris, M.
Tetrahedron Lett. 2003, 44, 4711-4714.
(18) (a) Zhu, X.-Q.; Zhao, B.-J.; Cheng, J.-P. J. Org. Chem. 2000, 65, 8158-
8163. (b) For a review on the chemistry of dihydropyridines see: Lavilla,
R. J. Chem. Soc., Perkin Trans. 1 2002, 1141-1156.
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Synthesis of Dihydropyridines and Pyridines
A R T I C L E S
are consistent with other Rh-H complexes with similar ligand
environments.19
Orange, block-like crystals of 17 were obtained by vapor
diffusion of pentane into a toluene solution at room temperature.
X-ray diffraction studies provided the structure shown in Figure
2. The geometry of 17 is distorted octahedral, with a P-Rh-P
angle of 157.69(4)°, which is common for hydride complexes
bearing bulky phosphine ligands.19 The angle of the metalla-
cyclic N-Rh-C bond is 78.4(2)°, and this distortion from 90°
causes the remaining bond angles in the square plane to be
slightly more obtuse than would be true for an ideal octahedral
complex. The Rh-H bond length is 1.36(4) Å.
Figure 2. X-ray crystal structure (ORTEP diagram) of 17 with thermal
ellipsoids drawn at the 50% probability level. Hydrogen atoms distant from
the metal center have been omitted for clarity.
Scheme 1. Proposed Mechanistic Pathway
Isolated 17 is only sparingly soluble in most solvents, but
redissolving it in both toluene-d8 and THF-d8 resulted in a 2:1
equilibrium mixture of 17 and free imine 1. The 31P NMR
spectrum accordingly shows a mixture of complex 17, RhCl-
(FcPCy2)2, and free FcPCy2.20 Because of the lability of 17 in
solution, its involvement in the catalytic cycle cannot be readily
ascertained. However, when used catalytically (5 mol %) in the
reaction between 1 and 3-hexyne, DHP 3 is obtained quanti-
tatively. Additionally, in a stoichiometric reaction between 17
and 3-hexyne, DHP 3 is formed rapidly and in quantitative yield.
While attempts were made to identify the analogous catalytic
intermediate using the more active aniline-substituted phosphine
ligand 6b, no peaks indicative of a [Rh]-H complex were seen
by 1H or 31P NMR spectroscopy. However, it is reasonable that
a facile and readily reversible C-H activation occurs with this
ligand, and that the equilibrium lies in favor of the non-C-H
activated substrate. Because ligand 6b was more active under
catalytic conditions, it was used in further kinetic experiments.
A plausible mechanistic pathway is shown in Scheme 1.21
Coordination of the imine to the catalyst through the imine
nitrogen followed by oxidative addition of the C-H bond gives
intermediate 18. Association of the alkyne followed by migratory
insertion of the Rh-H bond provides intermediate 19.22
Subsequent reductive elimination provides the azatriene inter-
mediate 2. Electrocyclization of 2 produces the dihydropyridine
product, 3. Reversible E/Z isomerization of 2 produces 20,
which cannot cyclize. Under typical reaction conditions, 2 and
20 are not generally observable by NMR. Reducing the reaction
temperature to room temperature slows the rate of electrocy-
clization such that the growth and decay of 2 can be traced.
Furthermore, the isomerization pathway to 20 is not reversible
at this temperature; thus, a buildup of 20 is seen throughout
the course of the reaction. Under these conditions, four of the
species shown in Scheme 1 (1, 2, 3, and 20) could be identified
and their concentrations monitored by NMR spectroscopy. A
plot of the concentrations of these species over time during a
typical reaction course is given in Figure 3, plot A. The
disappearance of 1 obeys pseudo-first-order kinetics, producing
a linear plot when ln([1]) is plotted versus time. Plot A in Figure
3 shows the appearance of intermediate 2 preceding the
formation of DHP 3. Intermediate 2 builds up to a maximum
concentration of 0.02 M before decaying.
(19) (a) Albinati, A.; Arz, C.; Pregosin, P. S. J. Organomet. Chem. 1987, 335,
379-394. (b) Hara, T.; Yamagata, T.; Mashima, K.; Kataoka, Y. Orga-
nometallics 2007, 26, 110-118.
(20) See supporting information for further spectroscopic discussion and evidence
for the identity and purity of isolated 17.
(21) For mechanistic studies on other chelation-assisted C-H alkylations, see:
(a) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem. Eur. J. 2002, 8, 2423-
2328. (b) Kakiuchi, F.; Ohtaki, H.; Sonoda, M.; Chatani, N.; Murai, S.
Chem. Lett. 2001, 918-919. (c) Lenges, C. P.; Brookhart, M. J. Am. Chem.
Soc. 1999, 121, 6616-6623.
To extract information regarding the rate constants of this
reaction, the system was modeled computationally using the
kinetic modeling program Copasi.23 Because the proposed
(22) Alternatively, carbometalation of the alkyne could occur generating a seven-
membered aza-metallacycle. In addition to the instability of the seven-
membered intermediate, carbometalation should place the more sterically
hindered substituent distal to the nitrogen, which is opposite to the
regioselectivity observed in our case (Table 2 entries 2-4, 8, 10-12).
(23) Copasi, version 4.2 was employed for these simulations. See Hoops, S.;
Sahle, S.; Gauges, R.; Lee, C.; Pahle, J.; Simus, N.; Singhal, M.; Xu, L.;
Mendes, P.; Kummer, U. Bioinformatics 2006, 22, 3067-3074. For further
information or to download Copasi, see http://www.copasi.org/tiki-index.
php.
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A R T I C L E S
Colby et al.
Figure 3. Experimental and simulated timecourses for the reaction of 1 with 5 equiv of 3-hexyne using 2.5 mol % [RhCl(coe)2]2 and 5 mol % 6b at 25 (
0.5 °C. A: experimental timecourse for Scheme 1. For plots B-D, the experimental and simulated data for Scheme 2 are overlaid, with experimental data
designated using dashed lines and the corresponding simulated data using solid lines. Starting concentrations of 1: B, 0.10 M; C, 0.025 M; D, 0.50 M. The
error in the values for the experimental data was <10%. See the Supporting Information for further details. Simulated data were obtained using the appropriate
starting concentrations of reactants A, B, and D, and using the following rate constants: k1 ) 250 M-1 h-1; k2 ) 50 M-1 h-1; k3 ) 8 h-1; k4 ) 0.6 h-1; k5
) 0.03 h-1
.
Scheme 2. Simplified System for Modeling in Copasi and the
Values Obtained for k1-k5
1
catalytic intermediates could not be detected by either H or
31P NMR spectroscopy, a simplified system was used in
simulations. The modeled cycle is shown in Scheme 2.24 In
addition to removing all of the ligand exchange steps from the
mechanistic cycle, the reactions were all made irreversible for
the simulation. Without the ability to detect and quantify
catalytic intermediates, the simulated data obtained for the
reverse reactions were highly underdetermined.
On the basis of the experimental data obtained for the reaction
in Scheme 2 at 25 ( 0.5 °C at three different reaction
concentrations, 0.025, 0.10, and 0.50 M,25 the Copasi software
was used to find rate constants k1-k5 (Scheme 2). Iterative
optimizations of k1-k3 and k4-k5 were performed at each
concentration until simulated plots for each matched the
observed plots (Figure 3, plots B-D). Errors were estimated
by incrementally modifying each optimized rate constant
independently until a reasonable fit was no longer obtained. As
is often the case with numerical integrations, the rate constants
generated by the simulation exhibited widely varying sensitivity
to changes. For example, the simulated value of k2 could be
varied over many orders of magnitude with deviations from the
experimental data occurring only when k2 was set below 50
mmol‚mL-1‚h-1. This implies that the migratory insertion step
(24) For recent examples of transition-metal mediated systems modeled using
an early version of the Copasi software Gepasi, see: (a) Watson, M. P.;
Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007, 129, 5031-
5044. (b) Ghosh, R.; Zhang, X.; Achord, P.; Emge, T. J.; Krogh-Jespersen,
K.; Goldman, A. S. J. Am. Chem. Soc. 2007, 129, 853-866. (c) Wiedemann,
S. H.; Lewis, J. C.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2006,
128, 2452-2462.
(25) Reaction concentrations are given with respect to imine 1. In all cases, 2.5
mol% [RhCl(coe)2]2, 5 mol% (DMAPh)PEt2, and 5 equiv of alkyne were
used.
is fast relative to the oxidative addition and reductive elimination
steps. To corroborate this finding, the concentration of the alkyne
was varied from 0.20 to 1.0 M in a 0.10 M (relative to 1)
reaction both experimentally and in the simulation. Experimen-
tally, the rates of intermediate and product formation were found
9
3650 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

Synthesis of Dihydropyridines and Pyridines
A R T I C L E S
to be independent of alkyne concentration, and the plots obtained
were nearly identical to the original plot at 0.50 M in alkyne.
Likewise, in the modeled experiment no change in the observed
rates was seen when the concentration of alkyne was varied.
On the basis of the obtained rate constants, the reductive
elimination step is rate limiting with a rate constant on the order
of 8 h-1. This is consistent with deuterium-labeling studies
performed on other C-H alkylation systems that showed that
C-H oxidative addition was rapid with reductive elimination
being the rate-limiting step.21 The rate constant for the elec-
identified that greatly expands the scope of the C-H alkeny-
lation reaction. The isolation and X-ray analysis of a C-H
activated complex sheds some light on the mechanism of this
transformation. Kinetic simulations were performed to find
possible rate constants for the transformation and implicate facile
oxidative addition with rate-limiting reductive elimination.
Acknowledgment. This work was supported by NIH Grant
GM069559 to J.A.E., an NSF predoctoral fellowship to
D.A.C., and the Director and Office of Energy Research, Office
of Basic Energy Sciences, Chemical Sciences Division, U.S.
Department of Energy, under Contract DE-AC03-76SF00098
to R.G.B. Thanks to Dr. Allen G. Oliver at the UCB X-ray
diffraction facility (CHEXRAY) for solving the structure of 17
and to Michael D. Pluth and Stuart E. Smith for helpful
discussions.
trocyclization is on the order of 0.6 h-1 26
.
Conclusion
A one-pot procedure has been developed for the synthesis of
highly substituted pyridines from R,â-unsaturated imines and
alkynes via a new C-H alkenylation/electrocyclization/aroma-
tization sequence. Additionally, a new class of ligands was
Supporting Information Available: Complete experimental
details and spectral data for all new compounds, and the X-ray
crystallographic information in CIF format for complex 17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) For another example where rate constants were determined for 6π
electrocyclizations of azatrienes, see: Maynard, D. F.; Okamura, W. H. J.
Org. Chem. 1995, 60, 1763-1771. For examples of DHP formation via
azatriene intermediates see the following and references therein: (a)
Sydorenko, N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006, 8, 2611-2614.
(b) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem.
2001, 66, 3099-3110.
JA7104784
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