Mechanistic study of indolizine heterocycle Formation by ruthenium(II)-assisted three-component cross-coupling/cyclization

Article abstract of DOI:10.1021/om400372w

In the presence of the acid HBF₄, 3-alkenyl-2-phosphonium indolizines 3a-c can be produced respectively by adding PhC≡CCOCH ₃ (2a), CH₃OCOC≡CCOOCH₃ (2b), and CH ₃CH₂C≡CCOCH₃ (2c) to a mixture of ruthenium complex RuCl₂(PPh₃)₃ and the propargyl alcohol (2-Py)CH(OH)C≡CH (1). We carefully investigated the mechanism of this reaction by means of structurally characterizing two key intermediates, ruthenium vinyl (4) and ruthenium carbene (5), and by deuterium-labeling experiments. A plausible mechanism is proposed, which involves addition of a proton to an alkyne carbon and the insertion of an alkyne into the Cα bond of an alkenylcarbene group, followed by an α-H elimination and reductive elimination.

Full text of DOI:10.1021/om400372w

Article
pubs.acs.org/Organometallics
Mechanistic Study of Indolizine Heterocycle Formation by
Ruthenium(II)-Assisted Three-Component Cross-Coupling/
Cyclization
Chunhong Zhang, Hong Zhang, Laiying Zhang, Ting Bin Wen, Xumin He,* and Haiping Xia*
State Key Laboratory for Physical Chemistry of Solid Surfaces, and Department of Chemistry, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, 361005, People’s Republic of China
S
* Supporting Information
ABSTRACT: In the presence of the acid HBF4, 3-alkenyl-2-phosphonium
indolizines 3a−c can be produced respectively by adding PhCCCOCH3
(2a), CH3OCOCCCOOCH3 (2b), and CH3CH2CCCOCH3 (2c) to a
mixture of ruthenium complex RuCl2(PPh3)3 and the propargyl alcohol (2-
Py)CH(OH)CCH (1). We carefully investigated the mechanism of this
reaction by means of structurally characterizing two key intermediates,
ruthenium vinyl (4) and ruthenium carbene (5), and by deuterium-labeling
experiments. A plausible mechanism is proposed, which involves addition of
a proton to an alkyne carbon and the insertion of an alkyne into the Cα
bond of an alkenylcarbene group, followed by an α-H elimination and
reductive elimination.
It is interesting that ruthenium-based catalysts are used
extensively for promoting the synthesis of organic compounds;
however, a ruthenium catalyst involved in the synthesis of
indolizine is rare, and we are aware of just one example used in
a catalyst screening.6b In the following we report a mechanistic
study on the ruthenium-assisted formation of indolizines by a
three-component cross-coupling/cyclization that, in the future,
might assist in the development of ruthenium-catalyzed
processes for the synthesis of the indolizine hetereocycle. The
key feature of this mechanism proceeds through a thermally
stable but reactive ruthenium carbene intermediate, which is
similar to intermidiate A in Scheme 1.
INTRODUCTION
■
In recent years, the pharmacological potential of indolizines and
related derivatives has become well recognized.1 A number of
biologically important natural products contain the indolizine
framework.2 As a result, a variety of methods for their synthesis
have emerged.1a,3 One of these strategies is the transition-
metal-catalyzed cycloisomerization of easily available non-
conjugated propargylpyridines or other organic molecules
into indolizines.4 Transition-metal-catalyzed cycloisomeriza-
tions typically proceed through metal−carbene intermediates.5
For example, Gevorgyan and his co-workers reported the Rh-
catalyzed transannulation of pyridotriazoles with alkynes to
afford indolizines.6 As shown in Scheme 1, the mechanism for
the formation of indolizine was proposed, including one Rh-
carbene intermediate, A.6 To the best of our knowledge, this
kind of metal-carbene intermediate has never been isolated.
RESULTS AND DISCUSSION
■
Efficient One-Pot Synthesis of 3-Alkenyl-2-phospho-
nium Indolizine Salts 3a−c. We found that RuCl2(PPh3)3
can assist the synthesis of 3-alkenyl-substituted indolizines by
coupling and cyclizing propargyl alcohols with alkynes. For
example, in the presence of HBF4, RuCl2(PPh3)3 reacted with
the easily accessible (2-Py)CH(OH)CCH (1) and commer-
cially available alkyne PhCCCOCH3 (2a), and the 3-alkenyl-
2-phosphonium indolizines salt 3a (R1 = Ph, R2 = CH3) could
be isolated, albeit in low yields of 10%, as shown in Scheme 2.
The yield could be further improved to around 80% (NMR) if
we first incubated RuCl2(PPh3)3 together with 1, PPh3, and
HBF4 for 12 h before the addition of the alkyne 2a. With
different alkyne starting materials, two related indolizines, 3b
(R1 = COOCH3, R2 = OCH3) and 3c (R1 = CH2CH3, R2 =
Scheme 1. Proposed Rh-Carbene Intermediate in the Rh-
Catalyzed Cycloisomerization
Received: April 28, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/om400372w | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Scheme 2. Synthesis of Indolizine-2-phosphonium Salts 3a−
c
Scheme 3. Trapping of Intermediates 4 and 5
CH3), could be also synthesized in the same fashion. A crystal
structure of 3a is shown in Figure 1 and confirms the formation
of indolizine 3a, whereas the indolizines 3b and 3c were
identified by NMR and HRMS.
Figure 1. X-ray molecular structure for the cation of complex 3a
drawn with 50% probability. The hydrogen atoms in PPh3 moieties are
omitted for clarity. Selected bond lengths [Å] and angles [deg]:
N(1)−C(1) 1.368(6), C(1)−C(2) 1.391(6), C(2)−C(3) 1.411(6),
C(3)−C(4) 1.365(7), C(4)−C(5) 1.431(7), C(5)−C(6) 1.330(8),
C(6)−C(7) 1.428(8), C(7)−C(8) 1.348(8), C(8)−N(1) 1.388(6),
C(1)−C(10) 1.490(6), C(10)−C(9) 1.317(7), C(2)−P(1) 1.772(5);
N(1)−C(1)−C(2) 105.8(4), C(1)−C(2)−C(3) 108.8(4), C(2)−
C(3)−C(4) 107.9(4), C(3)−C(4)−N(1) 106.7(4), C(4)−N(1)−
C(1) 110.8(4).
Figure 2. X-ray molecular structure for the cation of complex 4 drawn
with 50% probability. The hydrogen atoms in PPh3 moieties are
omitted for clarity. Selected bond lengths [Å] and angles [deg]:
Ru(1)−C(1) 1.986(4), C(1)−C(2) 1.354(6), C(2)−C(3) 1.533(6),
C(3)−O(1) 1.462(5), O(1)−Ru(1) 2.227(3), Ru(1)−P(2)
2.2780(13), Ru(1)−C1(3) 2.5145(12), Ru(1)−P(1) 2.3291(13),
Ru(1)−N(1) 2.120(4); Ru(1)−C(1)−C(2) 114.5(4), C(1)−C(2)−
C(3) 113.9(4), C(2)−C(3)−O(1) 106.5(4), C(3)−O(1)−Ru(1)
97.9(2), O(1)−Ru(1)−C(1) 77.77(16).
Identification of the Intermediate [Ru(CHC(PPh3)C-
(OH)(2-Py))Cl(PPh3)2]Cl (4). In order to elucidate this
RuCl2(PPh3)3-assisted transformation, we attempted to isolate
potential intermediates by reacting RuCl2(PPh3)3 with 1 in
CH2Cl2 for 7 h and obtained a yellow precipitate, which we
referred to as complex 4 (Scheme 3).
X-ray crystallographic analysis of complex 4 revealed a
ruthenium vinyl structure (Figure 2). The coordination
geometry around the ruthenium atom can be rationalized as
a distorted octahedron with one phosphorus atom of PPh3
ligands and the nitrogen atom of the pyridine occupying trans
positions (P(1)−Ru(1)−N(1) = 166.94(11)°), while one
chloride atom and another PPh3 ligand are cis to each other
(Cl(3)−Ru(1)−P(2) = 82.26(10)°). The Ru(1)−C(1) bond
length is 1.986(4) Å, and distance of C(1)C(2) bonds in the
metallacycle of 4 is 1.354(6) Å. These bond distances are
similar to those of reported ruthenium vinyl complexes (1.984
and 1.346 Å).7 The NMR spectra of 4 also exhibited the
characteristic chemical shifts of a Ru-vinyl complex: a low-field
resonance at 11.3 ppm in the 1H NMR corresponds to a proton
atom bound to ruthenium (RuCH) due to the effect of the
metal atom and phosphonium group on C2. This value is in the
range of our reported Os-vinyl compound (OsCH is 12.2
ppm).8 In its 13C NMR, typical downfield signal at 241.6 ppm
could be assigned to a carbon atom that is directly bound to the
metal (RuCH). The doublet signal at 105.8 ppm was assigned
to CPPh3 due to the phosphorus-containing ligand. The 31P
NMR spectrum of 4 consists of a singlet and two doublets: 7.9
ppm corresponds to CPPh3; the doublets at 41.0 and 61.1 ppm
correspond to two PPh3 groups that are coordinated to
ruthenium. The 26.7 Hz coupling constant between the two
PPh3 groups suggested that they are coordinated cis to each
other.
Identification of the Intermediate [RuCHC(PPh3)CH(2-
Py)Cl2PPh3]BF4 (5). Treatment of ruthenium vinyl 4 with
HBF4 afforded the Ru-carbene 5 by protonation of the hydroxyl
group followed by dehydration. Ru-carbene 5 could be directly
produced also by treatment of RuCl2(PPh3)3, 1, and HBF4 all
together in chloroform. The solid-state structure of 5 was
established by X-ray diffraction. As shown in Figure 3, the
geometry of the ruthenium center can be viewed as a square-
B
dx.doi.org/10.1021/om400372w | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
3a, 3b, and 3c quantitatively. These results suggest that the Ru-
carbene is the key intermediate for the formation of indolizine.
Ru-carbenes have been proposed as key intermediates and
efficient catalysts in many reactions, and many scientists
therefore have been trying to isolate related Ru-carbenes.7
However, the isolation of carbenes from reaction systems is
extremely difficult because metal carbenes are often highly
reactive and sensitive to air. To the best of our knowledge, Ru-
carbene intermediate 5 is the very first carbene that is isolated
from reaction systems that lead to indolizine heterocycles. It is
also worth noting that complex 5 has excellent thermal
stabilities despite the unsaturated Ru coordination center. Solid
samples of 5 remain nearly unchanged at 120 °C under air for 5
h. Such remarkable thermal stabilities may be related to the
bulky PPh3 ligand and quaternary phosphonium salt.13 The
high thermal stability of the Ru-carbene does not effect its
reactivity, which may be related to the unsaturated ruthenium
coordination center.
Figure 3. Molecular structure for the cation of 5 (ellipsoids at the 50%
probability level). Counteranion and hydrogen atoms in PPh3 are
omitted for clarity. Selected bond lengths [Å] and angles [deg]:
Ru(1)−C(1) 1.834(3), C(1)−C(2) 1.458(4), C(2)−C(3) 1.336(5),
C(3)−C(4) 1.449(5), N(1)−C(4) 1.360(4), Ru(1)−N(1) 2.117(3).
N(1)−Ru(1)−C(1) 92.62(12), Ru(1)−C(1)−C(2) 125.8(2), C(1)−
C(2)−C(3) 127.5(3), C(2)−C(3)−C(4) 127.6(3), C(3)−C(4)−
N(1) 119.5(3), C(4)−N(1)−Ru(1) 126.9(2), Cl(1)−Ru(1)−Cl(2)
148.08(3), Cl(1)−Ru(1)−C(1) 107.96(10), Cl(2)−Ru(1)−C(1)
103.81(10).
Scheme 4. Preparation of Indolizines from Ru-Carbene 5
based pyramid as Grubbs’ first-generation catalyst,9 in which
the five coordination sites are occupied by C(1), N(1), two
chloride atoms, and one phosphorus atom of the phosphine
ligand. Complex 5 contains an essentially planar six-membered
ring, as reflected by the deviation of rms = 0.009 Å from the
plane of the best fit of the Ru(1), C(1), C(2), C(3), C(4), and
N(1) chain. The value through the C(4), N(1), C(6), C(7),
C(8), and C(9) chain (pyridine plane) is 0.0366 Å. The
dihedral angle between the plane through C(1), C(2), C(3),
C(4), and C(5) and the pyridine plane is 1.9°, which proves
that the two cycles are nearly planar. As expected, there is a
clear alternation of the bond lengths around the six-membered
ring of Ru(1)/C(1)/C(2)/C(3)/C(4)/N(1). The Ru(1)
C(1) bond length (1.834(3) Å) is similar to that in Ru
CHPhCl2(PCy3)2 (1.838(3) Å).10 The bond lengths of C(1)−
C(2) and C(2)−C(3) are 1.458(4) and 1.336(5) Å, consistent
with the value of C−C single bonds and CC double bonds,
respectively. All these parameters strongly support a 1,3-
butadiene moiety in complex 5.
The solid-state structure of 5 is fully supported by NMR
spectroscopy. In the 1H NMR spectrum, the α-H proton signal
is found at 17.1 (dd, apprant t, J(PH) = 12.5 Hz) ppm. Similar
proton patterns have been observed for the analogous
vinylcarbene complexes Cl2(PPh3)2Ru(CH−CHCPh2)9
and ruthenabenzenes [Ru(CHC(PPh3)CHC(PPh3)CH)-
Cl2(PPh3)2]Cl.11 In its 31P NMR spectrum, two singlets at
40.3 and 22.0 ppm correspond to RuPPh3 and CPPh3,
respectively. In the 13C NMR spectrum, the metal-bound
carbon atom α-C shows typical downfield signals at 258.3 ppm,
which is in the same range as those found for a variety of
known ruthenium carbene complexes,12 and the β-C connected
to PPh3 displays a signal at 116.3 (J(PC) = 87.4 Hz) ppm.
Formation of 3-Alkenyl-2-phosphonium Indolizine
Salt 3 from Ru-Carbene 5. Ru-carbene 5 turns out to be
very active toward alkynes such as PhCCCOCH3 (2a),
CH3OCOCCCOOCH3 (2b), and CH3CH2CCCOCH3
(2c). Under acid conditions (HBF4 or CF3COOH), addition of
2a, 2b, and 2c to a CH2Cl2 solution of complex 5 at room
temperature leads to 3-alkenyl-2-phosphonium indolizine salts
Deuterium-Labeling Experiement. In order to gain more
insight into the mechanism for the formation of 3, we
performed a deuterium-labeling experiment by means of
isotopically homogeneous CF3COOD. Accordingly, treatment
of 5 and 2a with CF3COOD all together in CH2Cl2 afforded
the compound 3a′, in which a deuterium is incorporated in a
defined position next to the phenyl group (Scheme 5). This
result reveals that this proton derives mechanistically from the
acid rather than from the Ru-carbene 5.
On the basis of the structures of the Ru-vinyl 4 and Ru-
carbene 5 intermediates and the result of the deuterium-
labeling experiment, we here propose a possible mechanism of
the formation of indolizines (Scheme 6). According to this
Scheme 5. Deuterium-Labeling Experiment for Synthesizing
3a′
C
dx.doi.org/10.1021/om400372w | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Scheme 6. Possible Mechanism for the Formation of Indolizines
Preparation of Indolizine 3a. Method 1: To a solution of
RuCl2(PPh3)3 (535 mg, 0.560 mmol), PPh3 (438 mg, 1.68 mmol), (2-
Py)CH(OH)CCH (89.1 mg, 0.670 mmol), and HBF4 (0.20 mL, 1.5
mmol) in 1:1 CHCl3/CH2Cl2 (20 mL) was added PhCCCOCH3
(0.16 mL, 1.5 mmol). After stirring for 24 h at room temperature, the
solution was then concentrated to about 2 mL. The resulting solution
was then purified by chromatography over neutral alumina eluting with
CH2Cl2/CH3COCH3 (10:1), affording 3a as a yellow solid (31 mg,
10%). Method 2: To a suspension of compound 5 (450 mg, 0.50
mmol) and HBF4 (0.20 mL, 1.5 mmol) in CH2Cl2 (10 mL) was added
PhCCCOCH3 (0.16 mL, 1.5 mmol). After stirring for 4 h at room
temperature, the solution was concentrated to ca. 2 mL. The resulting
solution was purified by chromatography over neutral alumina eluting
with CH2Cl2/CH3COCH3 (10:1), affording 3a as a yellow solid (253
mg, 83%). Mp: 209−211 °C. 1H NMR (400 MHz, CD2Cl2): δ 7.74 (t,
J = 7.4 Hz, 3 H), 7.59 (s, 1 H, CH3COCCH), 7.55−7.40 (m, 14 H),
7.23 (t, J = 7.4 Hz, 1 H), 7.12 (t, J = 7.6 Hz, 2 H), 6.89 (dd, J = 6.6, 8.8
Hz, 1 H), 6.72 (d, J(PH) = 5.1 Hz, 1 H, C(PPh3)CH), 6.62 (d, J = 7.3
Hz, 2 H), 6.60 (t, J = 7.1 Hz, 1 H), 2.08 (s, 3 H, CH3). 31P NMR (161
MHz, CD2Cl2): δ 14.5 (s, CPPh3). 13C NMR (100 MHz, CD2Cl2): δ
198.3 (s, CO), 149.6 (s, COCCH), 135.2 (d, J(PC) = 2.5 Hz), 135.0,
134.3(d, J(PC) = 10.9 Hz), 132.5, 131.7, 130.4, 130.0 (d, J(PC) = 12.9
Hz), 129.2, 127.0, 126.7, 122.5, 121.3, 120.2, 119.4, 118.4, 114.6
mechanism, RuCl2(PPh3)3 reacts with 1 affording the
ruthenium vinyl complex 4. In the presence of HBF4, vinyl
complex 4 is then transformed into ruthenium carbene complex
5 by dehydroxylation.14 Subsequently, ruthenium coordinates
to the alkyne of the alkynone to form the π-alkyne intermediate
B, which then rearranges to C by a net proton of acid adding to
an alkyne carbon. Similar roles played by acid have already been
postulated for the reaction of C5(CH3)5(CO)2Re(η2-CH3C
CCH3) with HBF4.14,15 Next, insertion of the alkyne into the
Cα bond of the alkenylcarbene group gives D. Compound E
then forms by α-H elimination of D.16 Finally, through a 6π-
electrocyclization and subsequent reductive elimination, the
product indolizine 3 is furnished.
CONCLUSION
■
We here presented a mechanistic study on a ruthenium-assisted
reaction for the synthesis of indolizines. By successfully
isolating and characterizing two important intermediates and
an additional deuterium-labeling experiment, we were able to
propose a reasonable mechanism for the formation of the
indolizine salt products. A key component of this mechanism is
a thermally stable but reactive ruthenium carbene intermediate.
These insights might pave the way to the development of a
ruthenium-catalyzed indolizine synthesis.
2
(PPh3, Ph and others carbon atoms), 106.2 (d, J(PC) = 10.9 Hz,
1
C(PPh3)CH), 99.0 (d, J(PC) = 112.1 Hz, C(PPh3)), 26.2 (s, CH3).
HRMS (ESI): m/z calcd for [C36H29ClORuP]+, 522.1981; found
522.1975.
Preparation of [Ru(CHC(PPh3)C(OH)(2-Py)Cl(PPh3)2]Cl (4).
RuCl2(PPh3)3 (535 mg, 0.560 mmol), (2-Py)CH(OH)CCH (89.1
mg, 0.670 mmol), and PPh3 (663 mg, 2.53 mmol) were dissolved in 15
mL of CH2Cl2. A yellow precipitate formed after stirring at room
temperature for 7 h. The product was collected by filtration, washed
with CH2Cl2 (2 × 3 mL), and dried as a yellow solid (458 mg, 75%).
EXPERIMENTAL SECTION
■
General Information. All syntheses were carried out in a dry
nitrogen atmosphere using standard Schlenk techniques, unless
otherwise stated. Solvents were distilled from sodium/benzophenone
(diethyl ether) or calcium hydride (CH2Cl2, CHCl3) under N2 prior to
use. The starting material (2-Py)CH(OH)CCH (1)5d was
synthesized according to a literature procedure. Other reagents were
used as received from commercial sources without further purification.
Column chromatography was performed on alumina gel (200−300
mesh) in air. NMR spectra were performed on a Bruker AVIII-500
(1H, 500.1 MHz; 13C, 125.8 MHz; 31P, 202.5 MHz), AVIII-400 (1H,
400.13 MHz; 13C, 100.63 MHz; 31P, 161.96 MHz), and AVIII-300
(1H, 300.1 MHz; 13C, 75.48 MHz; 31P, 121.5 MHz) spectrometer at
room temperature. 1H and 13C NMR chemical shifts (δ) are relative to
tetramethylsilane, and 31P NMR chemical shifts are relative to 85%
H3PO4. The absolute values of the coupling constants are given in
hertz (Hz). Multiplicities are abbreviated as singlet (s), doublet (d),
triplet (t), multiplet (m), and broad (br). High-resolution mass spectra
(HRMS) experiments were recorded on a Bruker En Apex Ultra 7.0T
FT-MS.
1
Mp = 178−185 °C (dec). H NMR (300 MHz, CD2Cl2): δ 11.32 (d,
J(PH) = 18.0 Hz, 1 H, RuCH), 7.84−6.56 (m, 50 H, other aromatic
carbon atoms and OH), 5.96 (d, J(PH) = 4.0 Hz, 1 H,
RuCHC(PPh3)CH). 31P NMR (121 MHz, CD2Cl2): δ 7.9 (s,
CPPh3), 41.0 ppm (d, J(PP) = 26.7 Hz, RuPPh3), 61.1 (d, J(PP) =
26.7 Hz, RuPPh3). 13C NMR plus DEPT 135 and 1H−13C HSQC (75
MHz, CD2Cl2): δ 241.6 (br, RuCH), 156.3 (s, CHN), 156.0 (s,
C(PPh3)CHC), 136.6−119.7 (m, other aromatic carbon atoms), 105.8
(d, J(PC) = 81.9 Hz, C(PPh3)), 80.57 ppm (d, J(PC) = 29.4 Hz,
C ( P P h 3 ) C H ( O H ) ) . H R M S ( E S I ) : m / z c a l c d f o r
[C62H52ClNORuP3]+, 1056.1989; found 1056.1984.
Preparation of [Ru(CHC(PPh3)CH(2-Py))Cl2PPh3]BF4 (5). To a
suspension of compound 4 (1.1 g, 1.0 mmol) and NH4Cl (0.16 g, 3.0
mmol) in CHCl3 (15 mL) was added HBF4/Et2O (0.41 mL, 3.0
mmol). After 6 h, the resulting green solution was concentrated to ca.
2 mL, and then diethyl ether (20 mL) was added to the solution. The
D
dx.doi.org/10.1021/om400372w | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 1. Crystal Data and Structure Refinement for 3a, 4, and 5
3a·CH2Cl2
4·3CH2Cl2
5·CH2Cl2
formula
C73H60B2Cl2F8N2O2P2
1303.69
C65H58Cl8NOP3Ru
1346.70
C45H38BCl4F4NP2Ru
984.38
Mr
color
yellow
yellow
green
temp, K
173(2)
173(2)
173(2)
radiation (Mo Kα), Å
cryst syst
space group
a, Å
0.71073
0.71073
0.71073
monoclinic
P21/c
monoclinic
P21/c
triclinic
P1
̅
22.8041(13)
14.1895(6)
19.9794(9)
90
12.9636(3)
20.3607(7)
23.0029(7)
90.00
11.3830(3)
12.8300(5)
15.3047(4
83.862(3)
80.728(2)
87.617(3)
2192.63(12)
2
b, Å
c, Å
α, deg
β, deg
93.628(5)
90
94.751(3)
90.00
γ, deg
V, Å3
6452.0(5)
4
6050.7(3)
4
Z
ρcalcd, g cm−3
θ range, deg
F(000)
1.342
1.478
1.491
3.00−25.00
2696
2.74−25.00
2752
2.74−25.00
996
cryst size, mm
reflns collected
indep reflns
data/restraints/params
GOF on F2
R1/wR2
0.4 × 0.3 × 0.2
31 452
0.3 × 0.2 × 0.2
30 962
0.25 × 0.15 × 0.1
22 325
11 331
10 659
7703
11 331/3/820
1.025
10 659/0/667
1.050
7703/0/523
0.953
R1 = 0.0918
wR2 = 0.2000
R1 = 0.1462
wR2 = 0.2286
1.584 and −1.007
R1 = 0.0573
wR2 = 0.1430
R1 = 0.0832
wR2 = 0.1505
2.141 and −1.461
R1 = 0.0408
wR2 = 0.1199
R1 = 0.0500
wR2 = 0.1306
1.185 and −0.841
[I ≥ 2σ(I)]
R1/wR2 (all data)
largest peak/hole [e Å−3
]
oily precipitate was collected by filtration, washed with CHCl3 (2 × 3
mL), and dried as a green solid (809 mg, 90%). Mp = 185−191 °C
chromatography over neutral alumina eluting with CH2Cl2/
CH3COCH3 (10:1), affording 3c as a yellow solid (255 mg, 91%).
1
1
1
1
Mp: 214−216 °C. H NMR plus H−13C HSQC and H−1H COSY
(400 MHz, CDCl3): δ 7.76 (t, J = 7.4 Hz, 3 H), 7.64−7.55 (m, 12 H),
7.49 (d, J = 7.2 Hz, 1 H), 7.43 (d, J = 9.5 Hz, 1 H), 6.92 (t, J = 7.3 Hz,
1 H, CH3CH2CH), 6.86 (dd, J = 9.1, 6.6 Hz, 1 H), 6.66 (t, J = 6.9 Hz,
1 H), 6.62 (d, J = 5.2 Hz, 1 H, C(PPh3)CH), 1.91 (s, 3 H, CH3CO),
1.75 (m, 2 H, CH3CH2), 0.85 (t, J = 5.2 Hz, 3 H, CH3CH2). 31P NMR
(162 MHz, CDCl3): δ 14.5 (s, CPPh3). 13C NMR plus DEPT 135 and
1H−13C HSQC (100 MHz, CDCl3): δ 197.7 (s, CH3CO), 157.4 (s,
(dec). H NMR (400 MHz, CD2Cl2): δ 17.1 (dd, apprant t, J(PH) =
12.5 Hz, 1 H, RuCH), 9.4 (d, J(HH) = 4.7, 1 H, NCH), 8.0−7.1 (m,
34 H, other aromatic carbon atoms). 31P NMR (162 MHz, CD2Cl2): δ
40.3 (s, RuPPh3), 22.0 ppm (s, CPPh3). 13C NMR (100 MHz,
CD2Cl2): δ 258.3 (m, RuCH), 151.2 (d, J(PC) = 18.2 Hz,
RuCHC(PPh3)CH), 150.9 (s, NCH), 138.6−125.2 (m, other aromatic
carbon atoms), 116.3 (d, J(PC) = 87.4 Hz, C(PPh3)). HRMS (ESI):
m/z calcd for [C44H36Cl2NRuP2]+, 812.0744; found 812.0739.
Preparation of Indolizine 3b. To a suspension of compound 5
(450 mg, 0.50 mmol) and HBF4/Et2O (0.20 mL, 1.5 mmol) in
CH2Cl2 (10 mL) was added CH3OCOCCCOOCH3 (0.19 mL, 1.5
mmol). The resulting solution was concentrated to ca. 2 mL after
stirring for 4 h at room temperature and then purified by
chromatography over neutral alumina eluting with CH2Cl2/
CH3COCH3 (10:1), affording 3b as a yellow solid (242 mg, 80%).
2
CH3CH2CH), 105.8 (d, J(PC) = 10.9 Hz, C(PPh3)CH), 99.8 (d,
1J(PC) = 112.1 Hz, C(PPh3)), 29.2 (s, CH3CO), 25.8 (s, CH3CH2),
12.1 (s, CH3CH2), 135.2−114.3 (other carbon atoms). HRMS (ESI):
m/z calcd for [C32H29NOP]+, 474.1981; found 474.1984.
Crystallographic Analysis. Crystals suitable for X-ray diffraction
were grown from CH2Cl2 solutions layered with diethyl ether for 3a, 4,
and 5. Data collections were performed on an Oxford Gemini S Ultra
or a Rigaku R-AXIS SPIDER IP CCD area detector using graphite-
monochromated Mo Kα radiation (λ = 0.71073 Å). Multiscan
absorption corrections (SADABS) were applied. All of the data were
corrected for absorption effects using the multiscan technique. The
structures were solved by direct methods, expanded by difference
Fourier syntheses, and refined by full matrix least-squares on F2 using
the Bruker SHELXTL (version 6.10) program package. Non-H atoms
were refined anisotropically unless otherwise stated. Hydrogen atoms
were introduced at their geometric positions and refined as riding
atoms unless otherwise stated. CCDC 941265 (3a), 941263 (4), and
941264 (5) contain the supplementary crystallographic data for this
paper. Further details on crystal data, data collection, and refinements
are summarized in Table 1.
1
Mp: 236−238 °C. H NMR (500 MHz, CDCl3): δ 7.85−7.52 ppm
(m, 17 H), 6.98 (t, J(HH) = 8.4 Hz, 1 H), 6.80 (s, 1 H,
CH3OCOCH), 6.76 (t, J(HH) = 6.9 Hz, 1 H), 6.74 (d, J(PH) = 4.3
Hz, 1 H, C(PPh3)CH), 3.89 (s, 3 H, CH3O), 3.85 (s, 3 H, CH3O). 31
P
NMR (202 MHz, CDCl3): δ 14.37(s, CPPh3). 13C NMR (125 MHz,
CDCl3): δ 163.8 (s, CH3OCO), 163.4 (s, CH3OCO), 136.3 (s,
CH3OCOCH), 135.4 (d, J(PC) = 2.36 Hz), 135.1 (d, J(PC) = 14.7
Hz), 134.4 (d, J(PC) = 10.5 Hz), 131.9, 130.2 (d, J(PC) = 12.8 Hz),
123.5 (d, J(PC) = 19.35 Hz), 122.5, 121.3, 120.1, 119.2, 118.5, 114.6
(other carbon atoms), 106.5 (d, J(PC) = 10.8 Hz, CPPh3CH), 100.6
(d, J(PC) = 112.5 Hz, CPPh3), 53.3 (s, CH3OCO), 52.6 (s,
CH3OCO). HRMS (ESI): m/z calcd for [C32H27NO4P]+, 520.1672;
found 520.1678.
Preparation of Indolizine 3c. To a suspension of compound 5
(450 mg, 0.50 mmol) and CF3COOH (0.12 mL, 1.5 mmol) in CH2Cl2
(10 mL) was added CH3CH2CCCOCH3 (0.15 mL, 1.5 mmol). The
solution was concentrated to ca. 2 mL after stirring at room
temperature for 4 h. The resulting solution was then purified by
E
dx.doi.org/10.1021/om400372w | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(12) (a) Chung, C. P.; Chen, C. C.; Lin, Y. C.; Liu, Y. H.; Wang, Y. J.
Am. Chem. Soc. 2009, 131, 18366. (b) Shaffer, E. A.; Chen, C. L.;
Beatty, A. M.; Valente, E. J.; Schanz, H. J. J. Organomet. Chem. 2007,
692, 5221. (c) Gandelman, M.; Naing, K. M.; Rybtchinski, B.;
Poverenov, E.; Ben-David, Y.; Ashkenazi, N.; Gauvin, R. M.; Milstein,
D. J. Am. Chem. Soc. 2005, 127, 15265. (d) Conrad, J. C.; Yap, G. P. A.;
Fogg, D. E. Organometallics 2003, 22, 1986. (e) Volland, M. A. O.;
Rominger, F.; Eisentrager, F.; Hofmann, P. J. Organomet. Chem. 2002,
641, 220.
ASSOCIATED CONTENT
* Supporting Information
CIF files giving crystallographic data of compounds 3a, 4, and
5. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: hpxia@xmu.edu.cn; hejin@xmu.edu.cn.
■
(13) Zhao, Q. Y.; Gong, L.; Xu, C. F.; Zhu, J.; He, X. M.; Xia, H. P.
Angew. Chem., Int. Ed. 2011, 50, 1354.
Notes
(14) (a) Casey, C. P.; Brady, J. T. Organometallics 1998, 17, 4620.
(b) Wolf, J.; Werner, H. Organometallics 1987, 6, 1164.
(15) (a) Esteruelas, M. A.; Lahoz, F. J.; Lopez, J. A.; Oro, L. A.;
Schluenken, C.; Valero, C.; Werner, H. Organometallics 1992, 11,
2034. (b) Andriollo, A.; Esteruelas, M. A.; Meyer, U.; Oro, L. A.;
Sanchez-Delgado, R. A.; Sola, E.; Valero, C.; Werner, H. J. Am. Chem.
Soc. 1989, 111, 7431.
(16) (a) Conejero, S.; Paneque, M.; Poveda, M. L.; Santos, L. L.;
Carmona, E. Acc. Chem. Res. 2010, 43, 572. (b) Rankin, M. A.;
McDonald, R.; Ferguson, M. J.; Stradiotto, M. Angew. Chem., Int. Ed.
2005, 44, 3603.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (No.
2012CB821600), the National Natural Science Foundation of
China (Nos. 20925208, 21174115, 21272193), and the
program for Changjiang Scholars and Innovative Research
Team in University.
REFERENCES
■
(1) (a) Singh, G. S.; Mmatli, E. E. Eur. J. Med. Chem. 2011, 46, 5237.
(b) Vemula, V. R.; Vurukonda, S.; Bairi, C. K. Int. J. Pharm. Sci. Rev.
Res. 2011, 11, 159.
(2) (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 520. (b) Fan, H.;
Peng, J.; Hamann, M. T.; Hu, J. F. Chem. Rev. 2008, 108, 264.
́
(c) Facompre, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez, C.;
Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392.
(3) (a) Wen, J. J.; Zhu, Y.; Zhan, Z. P. Asian J. Org. Chem. 2012, 1,
108. (b) Basavaiah, D.; Rao, A. J. Tetrahedron Lett. 2003, 44, 4365.
́
(c) Sonnenschein, H.; Theil, F.; Kreher, T.; Koeckritz, A. Chem.
Commun. 1997, 6, 551. (d) Kim, I.; Won, H. K.; Choi, J.; Lee, G. H.
Tetrahedron 2007, 63, 12954. (e) Jung, Y.; Kim, I. Tetrahedron 2012,
68, 8198. (f) Furdui, B.; Dinica, R.; Demeunynck, M.; Druta, I. Rom. J.
Phys. 2008, 53, 369. (g) Furdui, B.; Dinica, R.; Druta, I. I.;
Demeunynck, M. Synthesis 2006, 16, 2640.
(4) (a) Hardin, N. A. R.; Sarpong, R. Green Chem. 2010, 12, 1556.
(b) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett.
2007, 9, 1169. (c) Hardin, A. R.; Sarpong, R. Org. Lett. 2007, 9, 4547.
(d) Chernyak, D.; Skontos, C.; Gevorgyan, V. Org. Lett. 2010, 12,
3242. (e) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in,
A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440. (f) Seregin, I.
V.; Schammel, A. W.; Gevorgyan, V. Tetrahedron 2008, 64, 6876.
(g) Xia, J. B.; Wang, X. Q.; You, S. L. J. Org. Chem. 2009, 74, 456.
(h) Xia, J. B.; You, S. L. Org. Lett. 2009, 11, 1187. (i) Chai, D. I.;
Lautens, M. J. Org. Chem. 2009, 74, 3054. (j) Alberico, D.; Scott, M.
E.; Lautens, M. Chem. Rev. 2007, 107, 174. (k) Thansandote, P.;
Lautens, M. Chem.Eur. J. 2009, 15, 5874.
(5) (a) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org. Lett.
2007, 9, 3433. (b) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc.
2006, 128, 12050. (c) Schwier, T.; Sromek, A. W.; Yap, D. M. L.;
Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868.
(d) Xia, Y.; Dudnik, A. S.; Li, Y.; Gevorgyan, V. Org. Lett. 2010, 12,
5538.
(6) (a) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2007, 46, 4757. (b) Chuprakov, S.; Gevorgyan, V. Org. Lett.
2007, 9, 4463.
(7) Lozano-Vila, A. M.; Monsaert, S.; Bajek, A.; Verpoort, F. Chem.
Rev. 2010, 110, 4865.
(8) Gong, L.; Lin, Y. M.; Wen, T. B.; Xia, H. P. Organometallics 2009,
28, 1101.
(9) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1992, 114, 3974.
(10) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1995, 34, 2039.
(11) Zhang, H.; Xia, H. P.; He, G. M.; Wen, T. B.; Gong, L.; Jia, G.
C. Angew. Chem., Int. Ed. 2006, 45, 2920.
F
dx.doi.org/10.1021/om400372w | Organometallics XXXX, XXX, XXX−XXX