Using a two-step hydride transfer to achieve 1,4-reduction in the catalytic hydrogenation of an Acyl pyridinium cation

Article abstract of DOI:10.1021/jo801928t

(Chemical Equation Presented) The stoichiometric reduction of N-carbophenoxypyridinium tetraphenylborate (6) by CpRu(P-P)H (Cp = η⁵-cyclopentadienyl; P-P = dppe, 1,2-bis(diphenylphosphino) ethane, or dppf, 1,1′-bis(diphenylphosphino)ferrocene), and Cp*Ru(P-P)H (Cp* = η⁵-pentamethylcyclopentadienyl; P-P = dppe) gives mixtures of 1,2- and 1,4-dihydropyridines. The stoichiometric reduction of 6 by Cp*Ru(dppf)H (5) gives only the 1,4-dihydropyridine, and 5 catalyzes the exclusive formation of the 1,4-dihydropyridine from 6, H ₂, and 2,2,6,6-tetramethylpiperidine. In the stoichiometric reductions, the ratio of 1,4 to 1,2 product increases as the Ru hydrides become better one-electron reductants, suggesting that the 1,4 product arises from a two-step (e^-/H^?) hydride transfer. Calculations at the UB3LYP/6-311++G(3df,3pd)//UB3LYP/6-31G* level support this hypothesis, indicating that the spin density in the N-carbophenoxypyridinium radical (13) resides primarily at C4, while the positive charge in 6 resides primarily at C2 and C6. The isomeric dihydropyridines thus result from the operation of different mechanisms: the 1,2 product from a single-step H^- transfer and the 1,4 product from a two-step (e^-/H^?) transfer.

Full text of DOI:10.1021/jo801928t

Using a Two-Step Hydride Transfer To Achieve 1,4-Reduction in
the Catalytic Hydrogenation of an Acyl Pyridinium Cation
Anthony P. Shaw, Bradford L. Ryland, Mary J. Franklin, Jack R. Norton,*
Judy Y.-C. Chen, and Michelle Lynn Hall
Department of Chemistry, Columbia UniVersity, New York, New York 10027
jrn11@columbia.edu
ReceiVed August 30, 2008
The stoichiometric reduction of N-carbophenoxypyridinium tetraphenylborate (6) by CpRu(P-P)H (Cp
5
)
η -cyclopentadienyl; P-P ) dppe, 1,2-bis(diphenylphosphino)ethane, or dppf, 1,1′-bis(diphenylphos-
5
phino)ferrocene), and Cp*Ru(P-P)H (Cp* ) η -pentamethylcyclopentadienyl; P-P ) dppe) gives
mixtures of 1,2- and 1,4-dihydropyridines. The stoichiometric reduction of 6 by Cp*Ru(dppf)H (5) gives
only the 1,4-dihydropyridine, and 5 catalyzes the exclusive formation of the 1,4-dihydropyridine from 6,
H
2
, and 2,2,6,6-tetramethylpiperidine. In the stoichiometric reductions, the ratio of 1,4 to 1,2 product
increases as the Ru hydrides become better one-electron reductants, suggesting that the 1,4 product arises
-
•
from a two-step (e /H ) hydride transfer. Calculations at the UB3LYP/6-311++G(3df,3pd)//UB3LYP/
-31G* level support this hypothesis, indicating that the spin density in the N-carbophenoxypyridinium
6
radical (13) resides primarily at C4, while the positive charge in 6 resides primarily at C2 and C6. The
isomeric dihydropyridines thus result from the operation of different mechanisms: the 1,2 product from
-
-
•
a single-step H transfer and the 1,4 product from a two-step (e /H ) transfer.
Introduction
dropyridine system” and found that both N-(alkylcarbonyl)- and
N-(alkoxycarbonyl)-1,4-dihydropyridines can be prepared by a
In 1972, Stout, Takaya, and Meyers reported a synthesis of
,4-dihydropyridines via the addition of an azide to a 2,3-
completely regioselective (but stoichiometric) reduction with
1
t
5
Li( BuO)3AlH/CuBr (eq 2).
diazabicycloheptene to form an aziridine (followed by hydroly-
1
,2
sis, oxidation, and N2 extrusion). Dihydropyridines may also
be prepared by the reduction of pyridinium salts. However, in
a 1982 review with Stout entitled Recent AdVances in the
Chemistry of Dihydropyridines, Meyers noted that “the forma-
tion of dihydropyridines by the reduction of pyridines and
pyridinium salts is complicated by the fact that mixtures of 1,2-
3
and 1,4-dihydropyridines result”. For example, Fowler obtained
both N-carbomethoxy-1,2-dihydropyridine and N-carbomethoxy-
1
,4-dihydropyridine by treating a mixture of pyridine and sodium
4
borohydride with methyl chloroformate (eq 1). Comins con-
cluded in 1984 that “a 1-acyl substituent stabilizes the dihy-
(
1) Meyers, A. I.; Stout, D. M.; Takaya, T. J. Chem. Soc., Chem. Commun.
972, 1260–1261.
2) Stout, D. M.; Takaya, T.; Meyers, A. I. J. Org. Chem. 1975, 40, 563–
69.
1
In general, a 1,4-dihydropyridine is more stable thermody-
(
6-9
namically than its 1,2 isomer.
Fowler measured in 1972 a
5
(
3) Stout, D. M.; Meyers, A. I. Chem. ReV. 1982, 82, 223–243.
substantial positive ∆G°, 2.3 kcal/mol, for eq 3 at 91.6° in
9
668 J. Org. Chem. 2008, 73, 9668–9674
10.1021/jo801928t CCC: $40.75  2008 American Chemical Society
Published on Web 11/06/2008

Catalytic Hydrogenation of an Acyl Pyridinium Cation
1
0
DMSO, and Eisner and Sadeghi reported in 1978 the Rh-
1
1
catalyzed isomerization of 1a to 1b. The reduction of a
pyridinium cation to a 1,2-dihydropyridine is thus usually the
result of kinetic control.
We have previously shown that half-sandwich ruthenium
hydride complexes catalyze the hydrogenation of the CdN
1
2
bonds in iminium cations (eq 4) and the rings in aziridinium
1
3
cations (eq 5). In the present work, we have investigated the
reactivity of the Ru hydride complexes 2-5 toward the acyl
1
4
pyridinium cation 6 and the ability of 5 to catalyze the
hydrogenation of 6. The water-soluble Ru catalyst 7 and the
Rh catalyst 8 have been shown to catalyze the 1,4 hydrogenation
+
+
15-17
of NAD models as well as NADP .
Results and Discussion
Stoichiometric and Catalytic Reactions. All four Ru-H
-
complexes quantitatively transfer H to 6, giving the 1,2- and
1
,4-dihydropyridines 9a and 9b (Table 1). The resulting 16-
electron Ru cations are trapped by excess CH3CN in entries
-4 or solvent CD3CN in entries 5-8. These stoichiometric
reactions proceed readily at room temperature, although entries
1
6
and 8 require heating to dissolve the sparingly soluble 3 and
5
. The trend in the product distribution among the different
hydride complexes is the same in CD2Cl2 and CD3CN. In both
26
While investigating the hydrogenation of aziridinium cations,
solvents, 5 (Hembre’s hydride, Cp*Ru(dppf)H) is remarkably
selective, giving only the 1,4-dihydropyridine.
we observed the formation of the radical cation 5• in eq 6,
+
13
suggesting electron transfer. Multistep mechanisms beginning
The product ratios in Table 1 are different for each hydride,
remain constant after each reaction, and are obviously the
result of kinetic control. Thermodynamic control (recall
-
with e transfer have often been suggested as an alternative to
-
the single-step transfer of hydride, particularly for H transfers
18
11
from NAD(P)H and its analogues. Scheme 1 shows a possible
the reported slow isomerization of 1a to 1b ) would give
•
19,20
multistep pathway, involving an H transfer (HAT)
after
the 1,4 product 9b. Only the formation of 9b (and none of
9a) was observed when the reaction in entry 4 was monitored
21,22
the initial single-electron transfer (SET);
the possibility that
the “H ” step involves the separate transfer of H and e has
We have therefore considered the
possibility of e transfer during the reaction of the Ru hydrides
•
+
-
1
by H NMR at 228 K.
2
2-25
also been considered.
The iminium and aziridinium cations in eqs 4 and 5 are
-
-
+
hydrogenated by an ionic mechanism, where H and H are
1
2,13
2
-5 with the pyridinium cation 6 and have examined the
transferred in separate steps.
In eqs 4 and 5, the tertiary
+
electrochemical oxidation of 2-5 and the electrochemical
reduction of 6.
amine product removes H from an H2 complex, regenerates
the hydride complex, and makes the reaction catalytic in Ru,
with H2 as the ultimate reductant. If we attempt to make the
(
(
14) King, J. A.; Bryant, G. L. J. Org. Chem. 1992, 57, 5136–5139.
15) Wagenknecht, P. S.; Penney, J. M.; Hembre, R. T. Organometallics
2
003, 22, 1180–1182.
(
16) Lo, H. C.; Fish, R. H. Angew. Chem., Int. Ed. 2002, 41, 478–481.
17) Hollmann, F.; Schmid, A.; Steckhan, E. Angew. Chem., Int. Ed. 2001,
(
(
(
(
(
(
4) Fowler, F. W. J. Org. Chem. 1972, 37, 1321–1323.
40, 169–171.
5) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1984, 49, 3392–3394.
6) Damji, S. W. H.; Fyfe, C. A. J. Org. Chem. 1979, 44, 1757–1761.
7) Keay, J. G. AdV. Heterocycl. Chem. 1986, 39, 1–77.
(18) Bunting, J. W. Bioorg. Chem. 1991, 19, 456–491.
(19) Mayer, J. M.; Hrovat, D. A.; Thomas, J. L.; Borden, W. T. J. Am. Chem.
Soc. 2002, 124, 11142–11147.
(20) Hydrogen atom transfer (HAT) reactions are a subclass of a more general
classification, proton-coupled electron transfer (PCET) reactions: Mayer, J. M.
Annu. ReV. Phys. Chem. 2004, 55, 363–390.
(21) Cheng, J. P.; Lu, Y. J. Phys. Org. Chem. 1997, 10, 577–584.
(22) Lee, I. S. H.; Kil, H. J.; Ji, Y. R. J. Phys. Org. Chem. 2007, 20, 484–
490.
(23) Fukuzumi, S.; Ohkubo, K.; Tokuda, Y.; Suenobu, T. J. Am. Chem. Soc.
2000, 122, 4286–4294.
(24) Ohno, A.; Shio, T.; Yamamoto, H.; Oka, S. J. Am. Chem. Soc. 1981,
103, 2045–2048.
(25) Yuasa, J.; Yamada, S.; Fukuzumi, S. J. Am. Chem. Soc. 2006, 128,
14938–14948.
(26) Hembre, R. T.; McQueen, J. S.; Day, V. W. J. Am. Chem. Soc. 1996,
118, 798–803.
8) 1,2-Dihydropyridines are significantly stabilized by a methoxy substituent
at the 2 position, and in such cases are often more stable than their 1,4
counterparts: Doddi, G.; Ercolani, G.; Mencarelli, P. J. Org. Chem. 1992, 57,
431–4434.
4
(
9) Another counterexample is reported in: Feith, B.; Weber, H. M.; Maas,
G. Chem. Ber. 1986, 119, 3276–3296.
(
(
10) Fowler, F. W. J. Am. Chem. Soc. 1972, 94, 5926–5927.
11) Eisner, U.; Sadeghi, M. M. Tetrahedron Lett. 1978, 299–302, The
isomerization of 1a was said to be “incomplete” after 5 days, but the 1,4 isomer
1
b remained unchanged under the same conditions.
12) Guan, H.; Iimura, M.; Magee, M. P.; Norton, J. R.; Zhu, G. J. Am.
Chem. Soc. 2005, 127, 7805–7814.
13) Guan, H.; Saddoughi, S. A.; Shaw, A. P.; Norton, J. R. Organometallics
005, 24, 6358–6364.
(
(
2
J. Org. Chem. Vol. 73, No. 24, 2008 9669

Shaw et al.
a
TABLE 1. Product Distributions of the Stoichiometric Reduction
TABLE 2. Catalytic Reactions in CH2Cl2
a
of 6 with Ruthenium Hydrides
b
T, °C
% conversion
entry
complex
solvent
9a
9b
rt
10
0
28
58
38
b
1
2
3
4
2
3
4
5
2
3
4
5
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD3CN
CD3CN
CD3CN
CD3CN
52
30
4
48
70
96
100
77
85
b
b
a
b
General reaction conditions: 0.50 mmol of 6, 0.60 mmol of TMP,
b
1
c
2 2 2
0.01 mmol of 5, 10 mL of CH Cl , 80 psi H , 24 h. Determined by H
5
23
15
2
d
NMR integration.
6
c
7
98
100
d
8
SCHEME 3
a
General reaction conditions: 0.02 mmol of 6, 0.02 mmol of hydride
1
complex, 700 µL of solvent, product ratio determined by H NMR
integration.
temperature. 75 °C, 2 h.
b
c
0.08 mmol of CH3CN, room temperature. Room
d
SCHEME 1
SCHEME 4
SCHEME 2
room temperature gives 10a, which rapidly isomerizes to 10b
Scheme 3). At lower temperatures, the isomerization (a first-
(
1
order reaction) can be followed by H NMR. At 0 °C, k )
-
3
-1
1
9
1
.32(2) × 10
s
in CD2Cl2, giving 10a a half-life of about
min at this temperature. Belkova has recently reported k )
-
3
-1
.53 × 10
s
for the isomerization of protonated 4
29
reduction of the pyridinium cation 6 in Table 1 catalytic, the
dihydropyridine products 9a and 9b are not sufficiently basic
to deprotonate the H2 complex (10a), so a non-nucleophilic base
must be added (Scheme 2). TMP (2,2,6,6-tetramethylpiperidine)
fulfills this requirement and makes the reaction catalytic; DBN
+
+
(
Cp*Ru(dppe)(H2) f trans-Cp*Ru(dppe)(H)2 ) at 260 K.
One would expect lower temperatures to decrease the rate of
catalyst deactivation, slowing the unwanted (intramolecular)
isomerization of 10a f 10b relative to the needed (intermo-
lecular) proton transfer from the H2 ligand of 10a (note the
q
2
9
(
1,5-diazabicyclo[4.3.0]non-5-ene) and NEt3 react with 6.
relatively large ∆H for isomerization reported by Belkova).
Isomerization of the cationic dihydrogen complex
Unfortunately, 6 is not very soluble in CH2Cl2 below room
temperature; a reaction at 0 °C in CH2Cl2 gave only a modest
improvement in conversion over the room temperature reaction
+
27
Cp*Ru(dppf)(H2) 10a to the trans-dihydride complex (10b)
competes with the catalytic cycle, as TMP is not basic enough
to deprotonate 10b. Such isomeric dihydrogen and dihydride
(
Table 2). An intermediate temperature of 10 °C gave a
1
complexes are readily distinguished by the T1 (min) of their H
significant improvement in the conversion of 6 to 9b in CH2Cl2.
The solubility of 6 is much greater in THF than in CH2Cl2.
Using THF at 10 °C gave 86% conversion to 9b (eq 7); aqueous
workup and flash chromatography gave pure 9b in 75% yield
2
8
NMR hydride resonances; the dihydrogen resonance of 10a
has a typically short T1 (min) of 11.5 ms (218.5 K, 300 MHz),
while that of the dihydride resonance of 10b is much longer,
0
.151 s (195.2 K, 300 MHz).
(
with respect to the initial 6). To the best of our knowledge,
An attempt to catalyze the hydrogenation of 6 with 5 at room
this is the first catalytic hydrogenation of an N-acylpyridinium
cation that gives a 1,4 product exclusively.
temperature in CH2Cl2 gave only 28% conversion to 9b (Table
1
2
). The H NMR analysis of a reaction aliquot showed the
presence of 10b, confirming that the isomerization reaction (10a
f 10b) is responsible for stopping catalysis.
Because the 10a f 10b isomerization shuts down the catalytic
cycle, it is important to know its rate. The protonation of 5 at
(
27) Hembre, R. T.; McQueen, J. S. Angew. Chem., Int. Ed. Engl. 1997, 36,
6
5–67.
(
(29) Belkova, N. V.; Dub, P. A.; Baya, M.; Houghton, J. Inorg. Chim. Acta
2007, 360, 149–162.
28) Luo, X. L.; Crabtree, R. H. Inorg. Chem. 1990, 29, 2788–2791.
9
670 J. Org. Chem. Vol. 73, No. 24, 2008

Catalytic Hydrogenation of an Acyl Pyridinium Cation
TABLE 3. Cyclic Voltammetry
a
compd
potential
process
b
CpRu(dppe)H (2)
CpRu(dppf)H (3)
Cp*Ru(dppe)H (4)
Cp*Ru(dppf)H (5)
6
-0.16
Ru(III/II)
Ru(III/II)
Ru(III/II)
Ru(III/II)
reduction
reduction
c
-0.31
d
-0.51
-0.63
d
e
-0.87
e
1
1
-1.42
a
+
b
Potentials in volts (V) in CH2Cl2 vs Fc/Fc . Epa, irreversible, 50
c
mV/s. Epa, quasireversible, Ia/Ic ) 1.25, Epa - Epc ) 0.09, 50 mV/s.
E1/2, reversible, 50 mV/s. Epc, irreversible, 200 mV/s.
d
e
-
Probing the Mechanism of H Transfer. The reactivities
of the hydride ligands in the Ru complexes 2-5 are influenced
by the nature of the chelating bisphosphine and by the extent
of substitution on the Cp ring. For example, 2 readily transfers
FIGURE 1. X-band EPR spectrum of 5• at 77 K (from the reaction
+
of 5 with 6 in CH
2
Cl
2
at 223 K).
-
H to the iminium cation in eq 4, while the hydride ligand of
1
2
•+
2+
4
is basic enough to deprotonate that cation. The dppf ligand
2Ru-H f Ru-H + Ru-H
(9)
2
6
makes 3 and 5 unusually good one-electron reducing agents,
2+
+
+
Ru-H + Ru-H f Ru(H ) + Ru
(10)
but it does not make them better hydride donors: complexes 2,
2
3
, and 4 (but not 5) react with the iminium cation 11 (eq 8).
EPR evidence for the formation of 5•+ was obtained by
mixing CH2Cl2 solutions of 5 and 6 at 223 K. The reaction
mixture, initially orange, became green after 10 min. The X-band
EPR, recorded at 77 K after quenching the reaction in liquid
nitrogen, clearly showed the presence of 5• (Figure 1).
+
32
Apparently at this temperature, the second step (HAT) in
Scheme 4 is slow relative to the first step (SET), permitting the
•+
accumulation of some 5 .
Computational Results. A two-step mechanism for the
reaction of 5 with 6 involves not only 5 but also the radical
The difference in reactivity between 5 with 6 and 5 with 11
-
led us to suspect a two-step mechanism for H transfer from 5
•+
-
•
to 6, with e transfer preceding H transfer. Hembre found that
1
3 as a short-lived intermediate (Scheme 4). Further evidence
2
6,27
5
is easily oxidized by ferrocenium or trityl cation.
Although the potentials of 2,
for this mechanism is available from various quantum mechan-
ical calculations. Mulliken population analysis provides a
3
0,31
29
26
4, and 5 have been
33
reported, they were obtained in THF. We therefore performed
cyclic voltammetry on 2-5 (and 6 and 11 for comparison) in
CH2Cl2 (Table 3).
means of assessing radical character as well as charge at any
atomic center. In the case of radical character, the atomic spin
density (S) is given by the difference in R and ꢀ electron density
Under our conditions, the cyclic voltammogram of 2 is
sufficiently irreversible (see the Supporting Information) to leave
some doubt about its thermodynamic potential relative to that
of 3. However, the order of the reVersible potentials of 4 and 5
implies that the thermodynamic potential of 3 must be more
negative than that of 2 and that the order of the reduction
potentials of the hydride complexes, from least to most negative,
is 2, 3, 4, and 5. This order correlates with the increase in 9b/
(
DR and Dꢀ) at the atomic center of interest. By definition,
R-electrons are assigned positive spin and ꢀ-electrons are
assigned negative spin, such that the atomic spin density at a
particular atomic center is given by eq 11. One unpaired electron
on an atomic center is ideally given by S ) 1, while a closed
shell atom is ideally given by S ) 0. However, atomic spin
densities are often noninteger and deviate from these ideal
numbers.
9
a as we go from 2 to 5 in Table 1.
From their irreversible potentials in Table 3 it appears that 6
S ) D -Dꢀ
(11)
R
is more easily reduced than 11 and that an SET mechanism for
For the radical 13, different resonance structures place the
unpaired electron on C2, C4, or C6. Mulliken population
analysis at the UB3LYP/6-311++G(3df,3pd)//UB3LYP/6-31G*
level shows that the radical resides primarily para to nitrogen,
at C4. In contrast, the positive charge in the pyridinium cation
-
H transfer is much more plausible with 6 than with 11. The
E1/2 of 5 is close to the Epc of 6 but not to the Epc of 11,
-
suggesting that an e transfer mechanism is available for the
reaction of 5 with 6 (which occurs) but not for the reaction of
with 11 (which does not occur).
5
6
resides primarily at C2 and C6 (Figure 2). Our results vary
Indirect evidence for an initial electron transfer in the reaction
little across basis sets and regardless of whether implicit
solvation is included. Our results are consistent with calculations
performed as early as 1970 in which H u¨ ckel theory and SCF
quantum calculations were used to show that the electron density
of the 7-(π-electron) pyridine anion resides primarily at the 4
1
of 5 with 6 (Scheme 4) was obtained by H NMR. At 228 K,
the hydride signal of 5 was broadened, and after 1 h a significant
amount of 10a was present (see the Supporting Information).
The broadening arose from self-exchange with Ru-H• (5 ).
+
•+ 13
The 10a came from disproportionation (eq 9) and proton transfer
34
position. Semiempirical methods AM1 and MNDO have also
(
eq 10), a sequence known to result in the formation of
•+
31
dihydrogen complexes from Ru-H .
(
32) The EPR spectrum of this complex has been reported: Sixt, T.; Fiedler,
J.; Kaim, W. Inorg. Chem. Commun. 2000, 3, 80–82.
(33) Mulliken, R. S. J. Chem. Phys. 1955, 23, 1833–1840.
(34) Kuthan, J.; Ferles, M.; Volke, J.; Koshmina, N. V. Tetrahedron 1970,
26, 4361–4366.
(
(
30) Jia, G.; Morris, R. H. J. Am. Chem. Soc. 1991, 113, 875–883.
31) Smith, K. T.; Rømming, C.; Tilset, M. J. Am. Chem. Soc. 1993, 115,
8
681–8689.
J. Org. Chem. Vol. 73, No. 24, 2008 9671

Shaw et al.
Indeed, the importance of single-step or multistep mechanisms
in determining the regiochemistry of nucleophilic attack on
pyridinium cations is implied by much previous literature. In
his 1995 review of the RegioselectiVity of the Reactions of
Pyridinium and Quinolinium Salts with Various Nucleophiles,
Poddubnyi cited various calculations as predicting “the highest
FIGURE 2. Calculated atomic spin densities (13) and charges (6) at
the UB3LYP/6-311++G(3df,3pd)//UB3LYP/6-31G* level.
-
spin density for the γ position” of the radicals formed by e
transfer, and concluded that an “SET mechanism...gives rise to
γ-selectivity...whereas the polar...mechanism...is characteristic
of R-selective addition”.
SCHEME 5
3
5
Experimental Section
General Procedures. All air-sensitive compounds were prepared
and handled under an N /Ar atmosphere using standard Schlenk
2
and inert-atmosphere box techniques.
N-Carbophenoxypyridinium tetraphenylborate (6) was prepared
1
4
by the method of King and recrystallized from CH
2
Cl
2
-Et
2
O.
been used to show that the kinetic regioselectivity for nucleo-
philic attack on the pyridinium ring is governed by the electron
40
N-Benzylidenepyrrolidinium tetrafluoroborate (11), Cp*Ru(dppf)H
26
41
29
(
(
5), CpRu(dppf)H (3), Cp*Ru(dppe)H (4), and CpRu(dppe)H
8
density at each carbon.
42
2) were prepared by the literature methods. CD
were degassed and stored over 3 Å molecular sieves. CH
2
Cl
2
and CD
Cl
3
CN
was
Single- and Multistep Mechanisms. The first explanation
2
2
of the regioselectivity of nucleophilic attack on pyridinium
deoxygenated and dried by two successive columns (Q-5, activated
alumina). THF was distilled from sodium/benzophenone under an
8
,35
cations
was offered by Kosower in 1956. He noted the
-
formation of charge-transfer complexes between I and pyri-
dinium cations and suggested that nucleophiles which could
form such complexes added to the 4 position while other
nucleophiles preferred the 2/6 position. Later, Klopman
suggested that the regioselectivity was the result of the hard/
soft character of the nucleophile, with the total charge density
N
2
atmosphere.
3
6
General Electrochemical Procedure. Cyclic voltammetry was
performed with a BAS CV-50W potentiostat. The supporting
electrolyte for all solutions except the reference electrode was 0.10
3
7
M [Bu
platinum disk working electrode, a platinum wire auxiliary elec-
trode, and a silver wire reference electrode (0.01 M AgNO + 0.10
M [Bu N]PF in CH CN). The reference electrode was separated
4 6 2 2
N]PF in CH Cl . The cell consisted of a 1.6 mm diameter
3
(
charge control) directing hard nucleophiles to the 2/6 position
4
6
3
while the coefficient of C4 in the LUMO (frontier orbital
from the sample solutions with a porous Vycor tip (Bioanalytical
3
8
control) directed soft nucleophiles to the 4 position. Doddi,
+
Systems, MF-2042). Fc/Fc was used as an external reference and
8
Ercolani, and Mencarelli have noted the frequent misuse of
was found to be +0.22 V with respect to our reference electrode.
All samples were prepared under an N /Ar atmosphere and further
2
purged with Ar before measurement. Analyte concentrations were
Klopman’s analysis to explain results that have arisen from
thermodynamic control rather than from the kinetic control he
assumed.
0
.001 M. Cyclic voltammograms of the hydride complexes (2-5)
-
were recorded at 50 mV/s. Cyclic voltammograms of 6 and 11 were
The regioselectivities we obtain for the transfer of H from
recorded at 200 mV/s. All potentials are reported in volts (V) vs
Ru hydrides to 6 arise entirely from kinetic control. Our results
suggest that, at least with Ru hydrides, the 1,2 and 1,4 products
arise from the operation of different mechanisms. Mulliken
population analysis confirms that the positive charge in the
cation 6 resides predominantly at C2 and C6, whereas the spin
density in the radical 13 resides predominantly at C4. A single-
+
Fc/Fc .
General Hydrogenation Procedure. CAUTION! Always shield
pressurized Vessels! Under an inert atmosphere, 6 (0.26 g, 0.50
mmol)and5(7.9mg,0.01mmol)werecombinedinaFischer-Porter
bottle. THF or CH
(TMP, 0.10 mL, 0.6 mmol) were added, and the apparatus was
charged with H (80 psi). The reaction mixture was stirred rapidly
2 2
Cl (10 mL) and 2,2,6,6-tetramethylpiperidine
-
step H transfer is likely to be charge controlled and reduction
2
at C2/C6 will be electronically favored, although steric factors
for 24 h at room temperature. For lower temperature reactions, the
sealed apparatus was cooled in a salt-water bath at 0 or 10 °C for
2
5 min prior to charging with H . The temperature was maintained
for 24 h by placing the sealed apparatus, salt-water bath, magnetic
stir plate, and shielding inside an appropriately set refrigerator. A
-
may result in a mixture; the e transfer at the beginning of a
•
multistep mechanism will favor H transfer to C4 (Scheme 5).
As our Ru hydrides become better one-electron reductants, they
give greater percentages of the 1,4 reduction product, until 5
gives only the 1,4 product.
1
mL aliquot of the reaction mixture was evaporated and the residue
dissolved in CD Cl . The percent conversion was determined by
comparing the H NMR integrations of the product peaks with that
of 3.0 µL of added CH CN.
2
2
Other reductants that result exclusively in 1,4-dihydropy-
ridines are ones we expect to be particularly good at single-
1
3
7
electron transfer. Examples include sodium dithionite, the
Variable-Temperature NMR. Probe temperatures were cali-
brated with an ethylene glycol or methanol (99.97% MeOH +
copper hydride (probably polynuclear) formed from Li-
5
4
3,44
t
(
(
BuO)3AlH and CuBr, and the formyl complex [Ru(bpy)2-
0.03% HCl) chemical shift thermometer.
39
Cp*Ru(dppf)(H2)+ (10a). HBF ·OMe (0.01 mmol) and 400
µL of CD Cl were added to a screw-cap NMR tube with a Teflon-
2 2
+
CO)(CHO)] .
4
2
(
35) A general review on the regioselectivity with which nucleophiles attack
pyridinium cations is: Poddubnyi, I. S. Khim. Geterotsikl. Soedin. 1995, 774–
(40) Leonard, N. J.; Paukstelis, J. V. J. Org. Chem. 1963, 28, 3021–3024.
(41) Bruce, M. I.; Butler, I. R.; Cullen, W. R.; Koutsantonis, G. A.; Snow,
M. R.; Tiekink, E. R. T. Aust. J. Chem. 1988, 41, 963–969.
(42) Bruce, M. I.; Humphrey, M. G.; Swincer, A. G.; Wallis, R. C. Aust.
J. Chem. 1984, 37, 1747–1755.
(43) Van Geet, A. L. Anal. Chem. 1970, 42, 679–680.
(44) Raiford, D. S.; Fisk, C. L.; Becker, E. D. Anal. Chem. 1979, 51, 2050–
2051.
8
15, English translation: Chem. Heterocycl. Compd. 1995, 31, 682-714.
36) Kosower, E. M.; Klinedinst, P. E. J. Am. Chem. Soc. 1956, 78, 3493–
497.
(
3
(
(
(
37) Kosower, E. M. J. Am. Chem. Soc. 1956, 78, 3497–3501.
38) Klopman, G. J. Am. Chem. Soc. 1968, 90, 223–234.
39) Konno, H.; Sakamoto, K.; Ishitani, O. Angew. Chem., Int. Ed. 2000,
3
9, 4061–4063.
9
672 J. Org. Chem. Vol. 73, No. 24, 2008

Catalytic Hydrogenation of an Acyl Pyridinium Cation
coated septum insert. The NMR tube was cooled in an acetone/
Stoichiometric Hydride Transfer from Ruthenium Hydrides
to 6 in CD CN. The Ru hydride (0.02 mmol) and 6 (0.02 mmol)
were dissolved in 700 µL of CD CN at room temperature; the
product ratio was measured by H NMR integration. The hydride
complexes 3 and 5 are sparingly soluble in CD CN. For reactions
CO
2
bath while connected to an N
2
bubbler. Separately, 5 (0.01
3
mmol) was dissolved in 400 µL of CD
2
Cl and then added slowly
2
3
1
to the cold NMR tube with a syringe. The tube was quickly shaken
1
and inserted into a precooled NMR probe. H NMR (300 MHz,
3
1
4
2
95.2 K, CD
Cl
2 2
): δ -8.12 (s, br, Ru(H
2
), 2H), 1.21 (s, Cp*, 15H),
with 3 or 5, the NMR tube was heated in a 75 °C oil bath and
shaken to mix the contents every 20 min. Once most of the yellow
3 or 5 had dissolved (about 2 h), the tube was removed from the
bath and the product ratio determined by H NMR integration.
Stoichiometric Hydride Transfer from Ruthenium Hydrides
.11 (s, dppf Cp, 2H), 4.22 (s, dppf Cp, 2H), 4.29 (s, dppf Cp,
H), 4.49 (s, dppf Cp, 2H), 7.30-7.70 (m, Ar, 20H). P { H} NMR
31
1
1
(
121.5 MHz, 195.2 K, CD
2
2
Cl ): δ 55.09. T measurements (300
1
MHz) of the dihydrogen resonance: T ) 12.6(2) ms, 195.2 K;
1
1
1.5(2) ms, 218.5 K; 12.8(2) ms, 238.9 K.
to 11 in CD
were dissolved in 700 µL of CD
(0.08 mmol) was added, and the H NMR spectrum was recorded.
2
Cl
2
. The Ru hydride (0.02 mmol) and 11 (0.02 mmol)
+
27
trans-Cp*Ru(dppf)(H)
2
(10b). The title dihydride complex
2
Cl at room temperature. CH CN
2
3
1
may be prepared by treating 5 with HBF
ature or by warming a solution of 10a to room temperature. H
NMR (300 MHz, 279.5 K, CD Cl ): δ -7.80 (t, Ru(H)
5.8 Hz, 2H), 1.24 (s, Cp*, 15H), 4.19 (s, dppf Cp, 4H), 4.21 (s,
dppf Cp, 4H), 7.58-7.66 (m, Ar, 12H), 7.85-7.96 (m, Ar, 8H).
4
·OMe
2
at room temper-
1
Complexes 2, 3, and 4 transferred hydride to 11, giving the tertiary
, JP-H
)
amine (12). In these cases, the CD
the residue extracted with Et O, the Et
the resulting residue dissolved in CDCl
2 2
Cl
2
solution was evaporated,
2
2
2
2
2
O solution evaporated, and
1
3
. The H NMR spectra
4
6
3
1
1
matched the reported spectrum of 12. The hydride complex 5
did not react with 11 in CD Cl
Low-Temperature Reaction of 5 with 6 ( H NMR). CH
mmol), 6 (0.02 mmol), and 550 µL of CD Cl were added to a
screw-cap NMR tube with a Teflon-coated septum insert. The NMR
tube was cooled in an acetone/CO bath while connected to a N
bubbler. Separately, 5 (0.02 mmol) was dissolved in 250 µL of
CD Cl and then added slowly to the cold NMR tube with a syringe.
P { H} NMR (121.5 MHz, 279.5 K, CD
measurements (300 MHz) of the dihydride resonance: T
s, 178.0 K; 0.151(2) s, 195.2 K; 0.223(5) s, 218.5 K; 0.253(5) s,
2
Cl
2
): δ 58.33. T
1
) 0.224(4)
2
2
.
1
1
3
CN (0.08
2
38.9 K; 0.323(5) s, 258.9 K; 0.439(7) s, 279.5 K.
2
2
2 2
Isomerization Kinetics. A solution of 10a (0.04 M in CD Cl )
was prepared as described above and inserted into an NMR probe
precooled to 0 °C. The reaction was followed by the integration of
the dihydrogen complex peak at δ 4.59 (s, dppf Cp, 2H) in
comparison with the integration of the residual solvent peak at δ
2
2
2
2
The tube was quickly shaken and inserted into a precooled NMR
1
probe. The reaction was monitored by 300 MHz H NMR at 228.0
5
.32. The average of three experiments gave a first-order rate
-3
-1
K for 1 h, during which time the only dihydropyridine product
formed was 9b.
constant of 1.32(2) × 10
s
for the disappearance of 10a.
N-Carbophenoxy-1,2-dihydropyridine (9a). Compound 9a as
4
5
Low-Temperature Reaction of 5 with 6 (EPR). An EPR tube
quartz, 3 mm) was charged with 6 (200 µL, 0.02 M in CH Cl ).
2 2
The tube was sealed with a septum and cooled in a hexanes/CO2
prepared by the literature method was contaminated with 6% of
the isomeric 1,4-dihydropyridine (9b). Two conformers of 9a (in
a 3/4 ratio) were observed at room temperature. H NMR (300 MHz,
(
1
bath at 223 K while connected to a N
µL, 0.02 M in CH Cl ) was slowly added to the cold EPR tube
with a syringe. The mixture, initially orange, became green after
0 min and was then quenched in liquid N . The X-band EPR
2
bubbler. Separately, 5 (200
2
98 K, CD
m, 1H), 5.62 (m, 1H), 5.90 (m, 1H), 6.65-6.95 (m, N-CH, 1H),
.15 (m, Ar, 2H), 7.26 (m, Ar, 1H), 7.41 (m, Ar, 2H). An averaged
spectrum was observed at 340 K: δ 4.46 (s, br, CH , 2H), 5.31 (m,
H), 5.64 (m, 1H), 5.92 (m, 1H), 6.83 (m, N-CH, 1H), 7.15 (m,
Ar, 2H), 7.26 (m, Ar, 1H), 7.41 (m, Ar, 2H).
3
CN): δ 4.36 (s, CH
2 2
, major), 4.56 (s, CH , minor), 5.29
(
7
2
2
1
2
2
spectrum was obtained at 77 K with a Bruker EMX EPR
spectrometer with a TE102 rectangular cavity.
1
5
N-Carbophenoxy-1,4-dihydropyridine (9b). The hydrogena-
tion of 0.50 mmol of 6 (see General Hydrogenation Procedure) in
Computational Methods
1
0 mL of THF at 10 °C for 24 h gave a yellow solution. An aliquot
1
Both the radical (13) and the pyridinium cation (6) were
subjected to conformational searching using Macromodel 6.0
(1 mL) was evaporated, and H NMR (in CD
Cl
2 2
3
+ 3.0 µL CH CN
4
7
internal standard) indicated 86% conversion to 9b. The remainder
4
8
and the OPLS 2001 force field. The lowest energy structures
were subsequently minimized at the DFT-UB3LYP/6-31G*
of the reaction solution was evaporated to give a yellow residue.
The residue was extracted with 4 × 5 mL of Et
solution was washed with 1 M NH
Cl (2 × 10 mL) and satd
NaHCO , and evaporated to give
(2 × 10 mL), dried over MgSO
a yellow solid. The solid was dissolved in an 8/2 mixture of
hexanes/Et O and loaded on a flash column (230-400 mesh silica,
4 cm × 1 cm diameter). The product was eluted with an 8/2
mixture of hexanes/Et O. Evaporation of the solvent gave the
2 2
O. The Et O
4
9-51
level
in both vacuum and implicit solvent (dichloromethane)
4
52
using Jaguar 7.0. Single-point calculations were also performed
at the UB3LYP/6-311++G(3df,3pd)//UB3LYP/6-31G* level.
Spin densities and atomic charges were determined by Mulliken
3
4
2
3
3
population analysis.
1
2
Acknowledgment. The experimental research was supported
by NSF Grant No. CHE-0749537. We thank Prof. N. Turro and
S. Jockusch for use of the EPR facility supported by NSF Grant
No. CHE-0717518. We are grateful to Novartis for providing
support for B.R. in the summer of 2007. We thank Prof. D.
product, a white crystalline solid, in 75% yield (corrected for the
1
aliquot removed, and with respect to 6). H NMR (300 MHz, 298
K, CD
-CH, 1H), 6.76 (d, R-CH, J ) 7.8 Hz, 1H), 6.91 (d, R-CH, J )
.7 Hz, 1H), 7.17 (m, Ar, 2H), 7.27 (m, Ar, 1H), 7.42 (m, Ar, 2H).
An averaged spectrum (due to fast rotation about the N-C(O) bond)
was observed at 340 K: δ 2.88 (m, CH , 2H), 5.06 (br, ꢀ-CH, 2H),
3
CN): δ 2.87 (m, CH
2
, 2H), 5.02 (br, ꢀ-CH, 1H), 5.07 (br,
ꢀ
8
1
Comins for authentic H NMR spectra of 9a and 9b and J.
2
Camara for useful discussions and chromatographic advice. We
thank Prof. M. Greenberg for useful discussions. The compu-
tational work (M. Hall) was supported by an NIH training
6
.84 (br, R-CH, 2H), 7.19 (m, Ar, 2H), 7.27 (m, Ar, 1H), 7.42 (m,
Ar, 2H). FAB MS (m-NBA): m/z for [M + 1]+ calcd 202.0868,
+
found 202.0867.
Stoichiometric Hydride Transfer from Ruthenium Hydrides
(46) Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Tetrahedron 2004,
60, 7899–7906.
to 6 in CD
were dissolved in 700 µL of CD
0.08 mmol) was added, and the product ratio was measured by
2
Cl
2
. The Ru hydride (0.02 mmol) and 6 (0.02 mmol)
(
(
47) MacroModel 6.0; Schr o¨ dinger, Inc.: Portland, OR.
48) Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. J. Am. Chem. Soc.
2
Cl at room temperature. CH CN
2
3
(
1
996, 118, 11225–11236.
1
H NMR integration.
(49) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789.
(50) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
51) Becke, A. D. J. Chem. Phys. 1993, 98, 1372–1377.
(
(
45) Sundberg, R. J.; Bloom, J. D. J. Org. Chem. 1981, 46, 4836–4842.
(52) Jaguar 7.0; Schr o¨ dinger, Inc.: Portland, OR.
J. Org. Chem. Vol. 73, No. 24, 2008 9673

Shaw et al.
program in molecular biophysics, Grant No. T32GM008281;
we are grateful to Prof. R. Friesner for guidance.
comments on) the low-temperature reaction of 5 with 6, kinetic
data for 10a f 10b, computational details for 6 and 13, and
cyclic voltammograms of 2, 3, 4, 5, 6, and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
Supporting Information Available: Lists of H NMR peaks
1
for 6 and 11, H NMR spectra of 9a and 9b (298 and 340 K)
1
and 10a (195.2 K), a H NMR spectrum from (and detailed
JO801928T
9
674 J. Org. Chem. Vol. 73, No. 24, 2008