Reactions of Zirconocene-1-Aza-1,3-diene Complexes with Acyl Cyanides: Substrate-Dependent Synthesis of Acyl- or Non-Acyl-Substituted Pyrroles

Article abstract of DOI:10.1021/acs.organomet.5b00801

Insertion of acyl cyanides into azazirconacyclopentenes derived from 1,3-azadienes has been described, which affords acyl- or non-acyl-substituted pyrroles upon acidic quenching. These reactions are initialized through C=O insertion into the azazirconacycle to afford seven-membered oxaazazirconacycles. In the cases of 1,4- or 1,2,4-substituted azadienes, addition of a second molecule of acyl cyanide followed by cyclization upon acidic quenching leads to acyl-substituted pyrroles. In the cases of 1,3,4-substituted azadienes, the addition of a second molecule of acyl cyanide cannot proceed due to the steric hindrance caused by the R³ group on the zirconium intermediate. Acidic quenching of the resulting zirconium intermediate affords non-acyl-substituted pyrroles.

Full text of DOI:10.1021/acs.organomet.5b00801

Article
pubs.acs.org/Organometallics
Reactions of Zirconocene−1-Aza-1,3-diene Complexes with Acyl
Cyanides: Substrate-Dependent Synthesis of Acyl- or Non-Acyl-
Substituted Pyrroles
Meijun Xiong, Shasha Yu, Xin Xie, Shi Li, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: Insertion of acyl cyanides into azazirconacyclopen-
tenes derived from 1,3-azadienes has been described, which affords
acyl- or non-acyl-substituted pyrroles upon acidic quenching. These
reactions are initialized through CO insertion into the
azazirconacycle to afford seven-membered oxaazazirconacycles. In
the cases of 1,4- or 1,2,4-substituted azadienes, addition of a second
molecule of acyl cyanide followed by cyclization upon acidic quenching leads to acyl-substituted pyrroles. In the cases of 1,3,4-
substituted azadienes, the addition of a second molecule of acyl cyanide cannot proceed due to the steric hindrance caused by the
R3 group on the zirconium intermediate. Acidic quenching of the resulting zirconium intermediate affords non-acyl-substituted
pyrroles.
and CN moieties in acyl cyanides enhances the electro-
INTRODUCTION
■
philicity of both groups.5 During our study on the reactions of
Zirconocene−1-aza-1,3-diene complexes, which can be de-
zirconacycles with acyl cyanides, we found that their CO and
CN bonds could both react with zirconacycles selectively.6
For example, the CO moiety of acyl cyanides was found to
insert preferentially into the Zr−C(sp3) bond of zirconacyclo-
pentenes or zirconacyclopentanes6a or react selectively with a
seven-membered zirconacyclocumulene,6b and the CN
moiety of acyl cyanides was found to react with zirconium−
butadiyne complexes preferentially at the initial step.6c These
results promoted us to explore the reactivity of zirconocene−1-
aza-1,3-diene complexes toward acyl cyanides. In this paper, we
report the direct reaction of zirconocene−1-aza-1,3-dienes with
acyl cyanides, which provides an efficient route to either acyl- or
non-acyl-substituted pyrroles upon acidic quenching, depend-
ing also on the substitution patterns of the azadienes (Scheme
1).
scribed as σ2,π-2-azazirconacyclo-3-pentenes, are attractive
intermediates for further transformation reactions, since they
can undergo various insertion reactions formally through their
highly polarized Zr−C bonds with unsaturated compounds.1,2
They are known to react with tert-butyl isocyanide,1a
ketones,1b,d,i special imines,1f and PhBCl2;1h nevertheless, the
synthetic utility of these azadiene complexes has far less been
explored. Recently, we have reported a direct insertion of
nitriles into zirconocene−1-aza-1,3-diene complexes, which
provided an efficient, regioselective, and controllable synthesis
of N-H and/or N-substituted pyrroles upon acidic aqueous
workup.3,4 The reaction outcome was dependent on the
substitution patterns of the azadiene substrates (Scheme 1). On
the other hand, acyl cyanides are one of the most important
classes of functionalized nitriles, and the proximity of the CO
RESULTS AND DISCUSSION
■
Scheme 1. Zirconium-Mediated Synthesis of Substituted
Pyrroles from 1-Aza-1,3-dienes
At the beginning, the zirconium-mediated reaction of 1,4-
diphenyl-substituted azadiene 1a with benzoyl cyanide 3a was
examined (Table 1, entry 1). Treatment of azazirconacyclo-
pentene 2a1a,i,3 (R1, R4 = Ph, R2 = H), prepared by the reaction
of 1a with 1.3 equiv of Negishi reagent,7 with 3 equiv of
benzoyl cyanide (3a) in THF at 50 °C for 3 h resulted in the
formation of several products according to TLC analysis after
the resulting mixture was quenched with 3 N HCl solution. A
major product could be isolated in 57% yield, which was
assigned to be tetrasubstituted 3-acylpyrrole 4a. The results
Received: September 21, 2015
© XXXX American Chemical Society
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3b−e bearing electron-donating (p-Me) or electron-with-
drawing (p-Cl, p-F or p-CF3) groups at the para position of
aryl substituents (entries 2−5). Heteroaryl-substituted acyl
cyanides such as 3f,g with 2-furyl and 2-thienyl functionalities
were also compatible with this reaction, furnishing the
corresponding pyrroles 4f,g in 40% and 48% yields, respectively
(entries 6 and 7). Next, the substituent effect of the R1 group
on the nitrogen of the azadienes 1 was examined. When the
reactions of N-(p-methoxyphenyl)-, N-(3,4,5-trimethoxyphen-
yl)-, and N-(p-chlorophenyl)-substituted azadienes 1b−d were
employed, the corresponding pyrroles 4h−j were obtained in
49−69% yields (entries 8−10). It was also found that the
reaction of 1e bearing a bulky N-(1-naphthyl) group proceeded
well to give 4k in 65% yield (entry 11). Regarding the R4
substituents on alkene terminus of azadienes 1, both electron-
donating (p-Me, p-MeO) and electron-withdrawing (p-Br, p-F)
groups on aryl rings were tolerated well to afford 4l−o in 47−
67% yields (entries 12−15), indicating that the electronic
nature of R4 had little influence on the product yields. Pyrrole
4p, with three different substituents on the pyrrole ring, could
be easily constructed by this method (entry 16). It was noted
that the methods for the regioselective synthesis of multi-
substituted pyrroles with different substituents from the easily
accessible starting materials under mild reaction conditions are
limited.8 In addition, azadiene 1j bearing one more substituent
(Me group) at the C-2 position could also smoothly react with
benzoyl cyanide to give the fully substituted pyrrole 4q in 46%
yield (entry 17). The structures of 3-acylpyrroles were
unambiguously confirmed by X-ray crystallographic analysis
of product 4p.9
Table 1. Zirconium-Mediated Synthesis of 3-Acylpyrroles
from 1,4- or 1,2,4-Substituted Azadienes
Interestingly, when 1,3,4-trisubstituted azadiene 1k was
employed as the substrate, tetrasubstituted pyrrole 5a without
acyl substitution was formed in 73% yield (Table 2, entry 1).
The results indicated that only one molecule of acyl cyanide
was incorporated into the product. In this case, the use of 2.0
equiv of acyl cyanide was enough to achieve the best product
yields. We also briefly investigated the substrate scope of this
type of reaction. When p-Me- and p-Cl-substituted aroyl
cyanides and 2-thienyl acyl cyanide were used as the coupling
partners to react with 1k, the corresponding pyrroles 5b−5d
were obtained in 62−72% yields (entries 2−4). For N-aryl
substituents of azadienes, the p-OMe or p-Cl groups on aryl
rings were well accommodated, leading to 5e,f in 47% and 55%
yields, respectively (entries 5 and 6). C-3-Hexyl-substituted
azadiene 1n afforded 5g in a lower yield of 30% (entry 7).
Azadiene 1o bearing a phenyl group at the C-3 position was
also well suited for this reaction, furnishing 5h in 70% yield
(entry 8). It was noted that the pyrrole products 5 are the same
as those obtained through the zirconium-mediated reactions of
1,3,4-trisubstituted azadienes with nitriles.3 Pyrroles constitute
important classes of natural products,10 synthetic pharmaceut-
icals,11 and functional materials.12 Especially, multiply sub-
stituted pyrroles have been shown to display important
biological activities such as antibacterial,13a antiviral,13b and
antiinflammatory13c activity. Our method provides a mild and
efficient route to these compounds.
a
b
Isolated yields. The reaction was carried out at 80 °C for 3 h after 3a
was added.
indicated that two molecules of benzoyl cyanide reacted with
zirconacycle 2 during the process. We envisioned that the
choice of an appropriate quenching reagent might be crucial for
achieving a clean transformation. After many trials, we found
that the desired pyrrole 4a could be obtained in a satisfactory
yield of 68% after the reaction mixture was quenched by 5.0
equiv of TsOH·H2O and stirred at room temperature for 1 h
(Table 1, entry 1). Decreasing the amount of PhCOCN to 2
equiv afforded 4a in a lower yield of 53%. Reducing the amount
of the quenching reagent of TsOH·H2O to 2.5 equiv also gave a
lower yield of 4a (14%).
After the synthetic protocol was established, the reaction
scope was next investigated. The representative results are
shown Table 1. First, the scope of acyl cyanides 3 was explored
by using azadiene 1a as a reaction partner. It was found that the
desired 3-acylpyrroles 4b−e were formed in moderate yields
through the reactions with the corresponding acyl cyanides
It was noteworthy that when the reaction mixture of
zirconacycle 2 derived from 1,4-substituted azadienes was
quenched with saturated aqueous NaHCO3 solution, a different
product was formed. For example, enaminone 6c was isolated
in 61% yield upon quenching the reaction mixture of
zirconacycle 2c and benzoyl cyanide with saturated aqueous
NaHCO3 solution (Scheme 2). The results indicated that the
B
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before quenching, since acyl cyanides decompose rapidly in
saturated aqueous NaHCO3 solution.
Table 2. Zirconium-Mediated Synthesis of Non-Acyl-
Substituted Pyrroles from 1,3,4-Trisubstituted Azadienes
On the basis of the above observation, we tentatively propose
the following reaction mechanism for the formation of pyrroles
(Scheme 3). In comparison with our previous work concerning
zirconium-promoted reactions of azadienes with nitriles, in this
reaction, insertion of the CO bond14 rather than the CN
bond of acyl cyanide into the Zr−C(sp3) bond of
azazirconacyclopentene 2 occurs to provide the seven-
membered oxaazazirconacycle 7. 7 might also be formed
through the reaction of alkenyl zirconaaziridine 8 with acyl
cyanide via a syn-SE2′ process.15 β-Cyanide elimination6a of 7
affords the ring-opened zirconium species 10. In the case of R3
= H, the enamine moiety in 10 attacks the second molecule of
acyl cyanide to give the imine intermediate 11, which
tautomerizes to enamine 6 in the presence of acid or base.
Cyclization of 6 under acidic conditions leads to 3-acylpyrrole
4. However, other possible reaction pathways for the formation
of 11 cannot yet be excluded. For example, nucleophilic attack
of 7 through its enamine moiety to acyl cyanide followed by β-
cyanide elimination might also give intermediate 11. In the case
of R3 ≠ H, the zirconium intermediate 10 cannot react with the
second molecule of acyl cyanide due to the steric hindrance
caused by the R3 group. Thus, upon quenching and cyclization
of the resulting intermediate 13 under the acidic conditions, the
non-acyl-substituted pyrrole 5 is formed.
CONCLUSION
■
In summary, insertion of acyl cyanides into azazirconacyclo-
pentenes derived from 1,3-azadienes has been described, which
affords acyl- or non-acyl-substituted pyrroles upon acidic
quenching. These reactions are initialized through CO
insertion into the azazirconacycle to afford seven-membered
oxaazazirconacycles. In the cases of 1,4- or 1,2,4-substituted
azadienes, addition of a second molecule of acyl cyanide
followed by cyclization upon acidic quenching leads to acyl-
substituted pyrroles. In the cases of 1,3,4-substituted azadienes,
the addition of a second molecule of acyl cyanide cannot
proceed due to the steric hindrance caused by the R3 group on
the zirconium intermediate. Acidic quenching of the resulting
zirconium intermediate affords non-acyl-substituted pyrroles.
Further studies on the reaction mechanism and the new
reactivity of zirconocene-1-aza-1,3-diene complexes toward
other electrophiles are in progress in our laboratory.
a
Isolated yields.
Scheme 2. Quenching the Reaction Mixture by Saturated
NaHCO3 Solution and Formation of 3-Acylpyrrole 4i
EXPERIMENTAL SECTION
■
Typical Procedure for the Synthesis of 3-Acylpyrrole 4a. To
a solution of Cp2ZrCl2 (0.19 g, 0.65 mmol) in THF (5 mL) was added
dropwise n-BuLi (0.81 mL, 1.3 mmol, 1.6 M solution in hexane) at
−78 °C. After this mixture was stirred for 1 h at the same temperature,
(E)-N-((E)-3-phenylallylidene)aniline (1a; 103.6 mg, 0.5 mmol) was
added and the reaction mixture was warmed to room temperature and
stirred for 3 h. Benzoyl cyanide (196.7 mg, 1.5 mmol) was added, and
the reaction mixture was stirred at 50 °C for 3 h. Then 5.0 equiv of
TsOH·H2O (475.6 mg, 2.5 mmol) was added, and the resulting
mixture was stirred at room temperature for 1 h. Water was then
added, and the resulting mixture was extracted with ethyl acetate. The
organic layer was washed with saturated NaHCO3 solution. The
aqueous layer was neutralized by adding saturated NaHCO3 solution
and then extracted with ethyl acetate. The combined organic layers
were washed with water and brine and dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure, and the residue
was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate 20/1) to afford the product 4a in 68% yield (135.8
product distribution was strongly affected by quenching
reagents. 6c was contaminated with ca. 10% of a byproduct
and trace amounts of other species, which could not be
separated from each other by column chromatography. The
byproduct was suggested to be an imine (see intermediate 11 in
Scheme 3). To our delight, 6c could be obtained in pure form
by recrystallization. The X-ray crystallographic analysis of 6c
verified its structure.9 Compound 6c (with 10% of the
byproduct) could be converted into 3-acylpyrrole 4i in
excellent yield by treating with TsOH·H2O (Scheme 2). The
high yield of 4i also indicated that the byproduct contained in
6c was also transformed into the pyrrole product under the
reaction conditions. The results suggested that enaminone 6c
was the key reaction intermediate, and cyclization of 6c to
pyrroles occurred during the acidic quenching. The addition of
both of the acyl cyanides to azazirconacycles possibly occurs
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Scheme 3. Possible Reaction Mechanism
1
mg) as a light yellow solid. Mp: 169−171 °C. H NMR (400 MHz,
CDCl3, Me4Si): δ 6.93−6.95 (m, 2H), 7.05−7.43 (m, 17H), 7.87 (d, J
= 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3, Me4Si): δ 122.96,
125.37, 125.78, 126.02, 127.13, 127.36, 127.43, 127.77, 127.88, 128.91,
129.29, 129.99, 130.54, 130.65, 130.88, 131.51, 132.81, 134.31, 139.06,
139.67, 190.85. IR (film): 3053, 1643, 1597, 1498, 1476, 1444, 1388,
1327, 1306, 1216, 1068, 1024, 1012, 897, 780, 764, 693, 672 cm−1.
HRMS (ESI): calcd for C29H22NO [M + H]+ 400.1696, found
400.1690.
(m, 2H), 7.03−7.07 (m, 5H), 7.12−7.24 (m, 8H). 13C NMR (100
MHz, CDCl3, Me4Si): δ 11.00, 118.67, 121.38, 124.82, 125.58, 125.62,
126.04, 126.30, 127.72, 127.84, 128.72, 130.30, 130.39, 130.74, 132.19,
135.91, 140.29. IR (film): 3040, 2919, 1598, 1529, 1503, 1389, 1371,
807, 762, 748, 737, 697 cm−1. HRMS (ESI): calcd for C23H20N [M +
H]+ 310.1590, found 310.1587. The spectroscopic data are in
agreement with those previously reported.3
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00801.
■
Typical Procedure for the Synthesis of Non-Acyl-Substi-
tuted Pyrrole 5a. To a solution of Cp2ZrCl2 (0.19 g, 0.65 mmol) in
THF (5 mL) was added dropwise n-BuLi (0.81 mL, 1.3 mmol, 1.6 M
solution in hexane) at −78 °C. After this mixture was stirred for 1 h at
the same temperature, (E)-N-((E)-2-methyl-3-phenylallylidene)aniline
(1k; 110.7 mg, 0.5 mmol) was added and the reaction mixture was
warmed to room temperature and stirred for 3 h. Benzoyl cyanide 3a
(131.1 mg, 1.0 mmol) was added, and the reaction mixture was stirred
at 50 °C for 3 h. Then 5.0 equiv of TsOH·H2O (475.6 mg, 2.5 mmol)
was added and the resulting mixture was stirred at room temperature
for 1 h. Water was then added, and the resulting mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
NaHCO3 solution. The aqueous layer was neutralized by adding
saturated NaHCO3 solution and then extracted with ethyl acetate. The
combined organic layers were washed with water and brine and dried
over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the
residue was purified by column chromatography on silica gel
(petroleum ether/dichloromethane 10/1) to afford the product 5a
in 73% yield (113.4 mg) as a white solid. Mp: 161−163 °C. 1H NMR
(400 MHz, CDCl3, Me4Si): δ 2.16 (s, 3H), 6.82 (s, 1H), 6.91−6.93
S
Experimental details and NMR spectra of all new
products (PDF)
Crystallographic data of compounds 4p and 6c (CIF)
AUTHOR INFORMATION
Corresponding Author
*Y. Liu.: fax, (+86) 021-64166128; e-mail, yhliu@sioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(Grant Nos. 21125210 and 21421091), the Chinese Academy
■
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Yang, C.-Y.; Aguilar, A.; Liu, L.; Bai, L.; Cong, X.; Cai, Q.; Fang, X.;
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DOI: 10.1021/acs.organomet.5b00801
Organometallics XXXX, XXX, XXX−XXX