Rhodium(III)-Catalyzed C-H activation of phenylazoles toward C-N bond cleavage of diazabicyclic olefins: A facile access to mono- and biscycloapentenyl-functionalized aza-heteroaromatics

Article abstract of DOI:10.1055/s-0033-1340221

A [RhCl₂Cp]₂-catalyzed stereoselective C-N bond cleavage of diazabicyclic olefins via C-H activation of phenylazoles in the presence of an acetate source is described. The developed method provides an easy access to biologically significant mono- and biscyclopentenyl- and alkylidenecyclopentenyl-functionalized aza heteroaromatics. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340221

LETTER
▌275
lRetther odium(III)-Catalyzed C–H Activation of Phenylazoles toward C–N Bond
Cleavage of Diazabicyclic Olefins: A Facile Access to Mono- and Biscyclo-
pentenyl-Functionalized Aza-Heteroaromatics
Cyclopentenyl-Functionalized Aza-Heteroaromatics
Praveen Prakash,a P. S. Aparna,a,b E. Jijy,a P. V. Santhini,a,b Sunil Varughese,c K. V. Radhakrishnan*a,b
a
Organic Chemistry Section, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum 695019, India
Fax +91(471)2491712; E-mail: radhu2005@gmail.com
b
Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India
c
Inorganic Chemistry Section, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum 695019, India
Received: 29.09.2013; Accepted after revision: 14.10.2013
8
9
ence of [RhCl2Cp*]2 and [Ru(p-cymene)Cl2]2 catalysts.
Later, Dixneuf et al. reported the Ru-catalyzed dehydro-
genative alkenylation of N-arylpyrazoles10 and 2-
phenyloxazolines11 in air.
Abstract: A [RhCl2Cp*]2-catalyzed stereoselective C–N bond
cleavage of diazabicyclic olefins via C–H activation of phenyl-
azoles in the presence of an acetate source is described. The devel-
oped method provides an easy access to biologically significant
mono- and biscyclopentenyl- and alkylidenecyclopentenyl-func-
tionalized aza heteroaromatics.
Diazabicyclic alkenes are potentially reactive diaza ana-
logues of norbornene, utilized well for the synthesis of bi-
ologically active heterocycles and carbocycles.12–17 In
continuation of our ongoing research on transition-metal-
catalyzed synthetic transformations of strained systems,18
we explored the C–H bond activation of phenylazoles to-
ward the stereoselective ring opening of heterobicyclic
olefins. Herein, we report a facile strategy to access mo-
no- and biscyclopentenyl- and alkylidenecyclopentenyl-
functionalized aza heteroaromatics via C–H activation of
phenyl azoles.
Key words: rhodium, C–H activation, bicyclic olefin, cyclopen-
tene, aza heteroaromatic
Aza heteroaromatics are valuable scaffolds of many im-
portant natural products and synthetic drugs.1 Among
them, imidazole,2 benzimidazole,3 and pyrazole4 nuclei
are found to be pharmacologically active and find wide
applications as antifungal, antibacterial, antitubercular,
and anticancer agents, among others. On the other hand,
cyclopentenes are a biologically relevant class of carbocy-
cles and exhibit various biological functions.5 The incor-
poration of functionalized cyclopentenes with aza
heteroaromatics is an important synthetic strategy to ac-
cess a diverse class of pharmaceutically important com-
We commenced our investigations with the treatment of
bicyclic olefin 1a and 2-phenylimidazole (2a) in the pres-
ence of [RhCl2Cp*]2 (2.5 mol%) and Cu(OAc)2·H2O (1.5
equiv) in DMF at 80 °C for 12 hours (Scheme 1). The re-
action afforded mono- and biscyclopentenyl-functional-
ized 2-phenylimidazole 3aa19,20 and 4aa19.21 in 23% and
8% yields, respectively. The structure of products was es-
tablished by usual spectroscopic techniques.
pounds.
Transition-metal-catalyzed
direct
C–H
functionalization has become an attractive synthetic
method to access complex scaffolds in an atom-economic
way.6 Aryl-substituted azoles have previously been uti-
lized as effective coupling partners in C–H activation re-
actions with different substrates.7 Satoh and Miura
developed promising dehydrogenative olefination reac-
tions of arylpyrazoles and related compounds in the pres-
We have chosen rhodium(III)-catalyzed C–H activation
of 2-phenylimidazole (2a) with bicyclic olefin 1a as the
model reaction to screen for optimal catalytic conditions.
To improve the yield, the reaction was carried out in dif-
ferent solvents. The results revealed acetonitrile as the
E
N
NHE
H
N
H
N
[Cp*RhCl2]2
N
NH
+
N
N
+
Cu(OAc)2⋅H2O
DMF, 80 °C
E
N
N
NHE
E
N
NHE
N
E
E
4aa (8%)
1a
E = CO2Et
2a
3aa (23%)
Scheme 1 C–N bond cleavage of bicyclic olefin 1a with 2a
SYNLETT 2014, 25, 0275–0279
Advanced online publication: 06.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340221; Art ID: ST-2013-B0923-L
© Georg Thieme Verlag Stuttgart · New York

276
P. Prakash et al.
LETTER
most effective reaction medium. Use of other solvents °C for 12 hours was found to be the optimal catalytic con-
such as 1,4-dioxane, o-xylene, and DCE was less effective ditions for the ring opening via C–H activation (see Sup-
and resulted in lower yields of the products. Without alter- porting Information).
ing other reaction parameters, we increased the equiva-
lents of 1a to 1.5 equivalents and observed the formation
of products in higher yield. When the equivalents of 1a
were further increased to 1.75 equivalents, the reaction re-
sulted in excellent yield and provided 3aa and 4aa in 48%
and 39% yields, respectively. Employment of excess 2a
was not favorable for the transformation. Other acetate
sources such as NaOAc and CsOAc did not enhance the
catalytic efficiency, and the reaction did not work in the
presence of Ag2CO3 as an additive. Finally, 1a (1.75
equiv) and 2a (1 equiv) in the presence of [RhCl2Cp*]2
(2.5 mol%) and Cu(OAc)2·H2O (1.5 equiv) in MeCN at 80
To evaluate the C–H activation of 2-phenylimidazole to-
ward the C–N bond cleavage of bicyclic olefins, the scope
of various olefins was examined under optimal condi-
tions. Diazabicyclic alkenes 1a–d smoothly underwent
ring opening with 2a and gave the corresponding mono-
and biscyclopentenyl-functionalized products in good
yields. Similarly, 4-methyl-2-phenylimidazole (2b) react-
ed efficiently with 1a,b and furnished aza-heteroaromatic
derivatives in good yields (Figure 1).
In the next stage, we elaborated the scope of the reaction
by employing 2-phenylbenzimidazoles as an aza-hetero-
aromatic partner. The reaction of 2-phenylbenzimidazole
CO2Et
CO2i-Pr
N
N
NHCO2Et
NHCO2Et
NHCO2i-Pr
NHCO2i-Pr
H
N
H
N
H
N
H
N
N
N
N
N
+
+
NHCO2Et
NHCO2i-Pr
N
N
N
N
CO2Et
CO2Et
4aa (39%)
CO2i-Pr
3ba (42%)
CO2i-Pr
4ba (24%)
3aa (48%)
CO2t-Bu
CO2Bn
N
N
NHCO2t-Bu
NHCO2Bn
H
N
H
H
H
N
N
N
N
N
N
N
+
+
NHCO2t-Bu
NHCO2t-Bu
NHCO2Bn
NHCO2Bn
N
N
N
N
CO2t-Bu
3ca (43%)
CO2t-Bu
4ca (28%)
CO2Bn
3da (41%)
CO2Bn
4da (31%)
CO2Et
CO2i-Pr
N
N
NHCO2Et
NHCO2i-Pr
H
N
H
N
H
N
H
N
N
N
N
N
Me
Me
Me
Me
+
+
NHCO2Et
NHCO2Et
NHCO2i-Pr
NHCO2i-Pr
N
N
N
N
CO2Et
3ab (trace)
CO2Et
4ab (64%)
CO2i-Pr
3bb (trace)
CO2i-Pr
4bb (72%)
Figure 1 Scope of various bicyclic olefins 1 and 2-phenylimidazoles 2
CO2Et
N
NHCO2Et
H
N
N
N
NH
[Cp*RhCl2]2
CO2Et
CO2Et
N
+
Cu(OAc)2⋅H2O
MeCN, 80 °C
N
NHCO2Et
N
CO2Et
1a
5a
6aa (75%)
Scheme 2 C–H activation of 2-phenylbenzimidazole with 1a
Synlett 2014, 25, 275–279
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cyclopentenyl-Functionalized Aza-Heteroaromatics
277
CO2Et
CO2i-Pr
CO2t-Bu
CO2Bn
N
N
N
N
NHCO2Et
NHCO2i-Pr
NHCO2t-Bu
NHCO2Bn
H
N
H
N
H
N
H
N
N
N
N
N
NHCO2Et
NHCO2i-Pr
NHCO2t-Bu
NHCO2Bn
N
N
N
N
CO2Et
CO2i-Pr
CO2t-Bu
CO2Bn
6aa (75%)
6ba (79%)
6ca (92%)
6da (84%)
Cl
Cl
Cl
Cl
H
N
H
N
H
N
H
N
N
N
N
N
NHCO2Et
NHCO2i-Pr
CO2i-Pr
NHCO2t-Bu
CO2t-Bu
NHCO2Bn
CO2Bn
N
N
N
N
CO2Et
6ab (94%)a
6bb (80%)a
6cb (85%)a
6db (81%)a
Figure 2 Scope of various bicyclic olefins 1 and 2-phenylbenzimidazoles 5. a Bicyclic olefin 1 (1 equiv).
(5a) with diazabicyclic alkene 1a proceeded efficiently We were also interested to examine the efficacy of 1-phe-
and led to the exclusive formation of biscyclopentenyl- nylpyrazoles toward the C–N bond cleavage of diazabicy-
functionalized phenylbenzimidazole 6aa in 75% yield clic olefins via C–H activation. As expected, the reaction
(Scheme 2).
of 1a and 1-phenylpyrazole (7a) under the same catalytic
conditions led to the formation of the desired cyclopente-
nyl derivative of 1-phenylpyrazole 8aa in 73% yield
(Scheme 3). The C–H activation of 7a was attempted with
a variety of bicyclic olefins 1b–d, and the reactions pro-
ceeded smoothly to furnish the monocyclopentenyl-func-
tionalized phenylpyrazoles in good yields (Figure 4).
After accomplishing promising results for the rhodi-
um(III)-catalyzed C–H activation of 2-phenylbenzimid-
azole (5a) with bicyclic olefin 1a, we investigated the
scope of other bicyclic olefins. Satisfyingly, a range of al-
kenes 1b–d could be successfully employed in the ring-
opening reaction to produce the corresponding biscyclo-
pentenyl derivatives in good yields (Figure 2). The reac-
tion of 2-(2-chlorophenyl)benzo[d]imidazole (5b) with 1a
afforded monocyclopentenyl-functionalized aza hetero-
aromatic 6ab in good yield. Various olefins 1b–d were
tolerated well and provided the corresponding cyclopen-
tenyl derivatives in good yields. Furthermore, the stereo-
chemistry of highly functionalized aza heteroaromatic
was unambiguously confirmed by single-crystal X-ray
analysis of compound 6cb (Figure 3, CCDC 952086).22
The stereochemistry of the biscyclopentenyl derivatives
was established by comparison with our previous report.23
N
N
[Cp*RhCl2]2
N
N
N
+
CO2Et
CO2Et
N
Cu(OAc)2⋅H2O
MeCN, 80 °C
NHCO2Et
N
CO2Et
8aa (73%)
1a
7a
Scheme 3 C–H Activation of 1-phenylpyrazole (7a) with 1a
The same strategy was found to be compatible with pen-
tafulvene-derived bicyclic olefin 1e. The reaction afford-
ed the corresponding alkylidinecyclopentenyl derivative
in 40% yield (Scheme 4).
NHCO2Et
N
N
N
[Cp*RhCl2]2
+
CO2Et
N
Cu(OAc)2⋅H2O
MeCN, 80 °C
CO2Et
CO2Et
N
N
N
1e
7a
9 (40%)
Scheme 4 C–H activation of 1-phenylpyrazole 7a with 1e
Based on the results and previous reports on C–H activa-
tion reactions, we propose a plausible mechanism as illus-
Figure 3 Single-crystal X-ray structure of 6cb (CCDC 952086)
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 275–279

278
P. Prakash et al.
LETTER
N
N
N
N
N
N
N
N
NHCO2Et
NHCO2i-Pr
NHCO2t-Bu
NHCO2Bn
N
N
N
N
CO2Et
CO2i-Pr
CO2t-Bu
CO2Bn
8aa (73%)a
8ba (68%)a
8ca (66%)a
8da (58%)a
Figure 4 Scope of various bicyclic olefins 1 with 7a. a Bicyclic olefin 1 (1 equiv).
trated in Scheme 5. Coordination of the nitrogen atom of studies to broaden the scope of the reaction and explora-
2a to the active rhodium species and subsequent cyclorho- tion of synthetic applications are ongoing in our laborato-
dation with the release of acetic acid leads to the forma- ry.
tion of a five-membered metallacycle A. Insertion of
bicyclic alkene 1 into the Rh–C bond of metallacycle A
generates intermediate B. In next step, the addition of an
Acknowledgment
P.P., A.P.S., J.E., and P.V.S. thank CSIR and UGC for a research
fellowship. Financial assistance from Department of Science and
Technology (DST No: SR/S1/OC-78/2009, INT/FINLAND/P-
01/1) and Council of Scientific and Industrial Research, New Delhi
(12th FYP project, ORIGIN-CSC-0108) are greatly acknowledged.
The authors also thank Ms. Saumini Mathew, Mr. P. Saran, Ms. S.
Viji, and Ms. S. Aathira of CSIR-NIIST for recording NMR and
mass spectra.
acetate ion to rhodium accompanied by C–N bond
cleavage24 of bicyclic olefin along the endo face results in
the formation of C. Demetalation of intermediate C fur-
nishes the product 3 and regenerates the active rhodium
species for the next catalytic cycle. The ring opening of
the second molecule of bicyclic olefin proceeds by the
similar mechanism to produce biscyclopentenyl deriva-
tives 4.25
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
HN
N
3
References and Notes
RhIIIX3
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2
– AcOH
HN
OAc
RhIIIX2
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N
N
RhIIIX2
A
N
E
NHE
C
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E
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B
Scheme 5 Proposed catalytic cycle
In conclusion, we have disclosed a rhodium(III)-catalyzed
stereoselective C–N bond cleavage of diazabicyclic ole-
fins through C–H bond activation of phenylazoles. The
acetate ion assisted ring opening of strained alkenes offers
an efficient approach for the preparation of biologically
relevant mono- and biscyclopentenyl- and alkylidenecy-
clopentenyl-functionalized aza heteroaromatics. Further
Synlett 2014, 25, 275–279
© Georg Thieme Verlag Stuttgart · New York

LETTER
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Cyclopentenyl-Functionalized Aza-Heteroaromatics
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(19) Typical Experimental Procedure for 3aa and 4aa
A mixture of bicyclic olefin 2a (0.2083 mmol, 1.75 equiv),
2-phenylimidazole (0.1191 mmol, 1.0 equiv), [RhCl2Cp*]2
(0.0029 mmol, 2.5 mol%), and Cu(OAc)2·H2O (0.1338
mmol, 1.5 equiv) were weighed in a Schlenk tube and
degassed for 10 min. Anhydrous MeCN (2 mL) was added,
and the reaction mixture was purged with argon and allowed
to stir at 80 °C for 12 h. The solvent was evaporated in
vacuo, and the residue was purified with column
chromatography (silica gel, 100–200 mesh) using an
EtOAc–hexane mixture. Mono- and biscyclopentenyl-
functionalized aza heteroaromatics were obtained in 48%
and 39% yields, respectively.
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Rf = 0.65 (hexane–EtOAc, 5:5). IR (neat): νmax = 3284, 3059,
2981, 2929, 2863, 1716, 1634, 1593, 1472, 1416, 1380,
1273, 1245, 1217, 1165, 1130, 1098, 1059, 950, 863, 809,
763, 664, 661, 557 cm–1. 1H NMR (500 MHz, CDCl3, TMS):
δ = 10.71–10.17 (m, 2 H), 7.41–7.33 (m, 1 H), 7.16–7.03 (m,
5 H), 5.81 (s, 1 H), 5.45 (s, 1 H), 5.04–4.86 (m, 2 H), 4.19–
4.17 (m, 2 H), 3.92–3.72 (m, 2 H), 2.59–2.56 (m, 2 H), 1.32–
1.23 (m, 3 H), 1.01–0.77 (m, 3 H). 13C NMR (125 MHz,
CDCl3): δ = 156.8, 156.6, 145.7, 141.8, 141.6, 133.9, 133.7,
129.6, 129.3, 129.1, 128.3, 126.6, 117.1, 69.4, 61.8, 61.7,
47.2, 34.4, 14.6, 14.2. ESI-HRMS: m/z calcd for C20H24N4O4
[M + Na]: 407.16952; found: 407.17032.
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(21) Spectral Data of Compound 4aa
Rf = 0.43 (hexane–EtOAc, 5:5); mp 163–165 °C. IR (neat):
ν
max = 3341, 2963, 2925, 2856, 1746, 1632, 1590, 1528,
1405, 1371, 1313, 1269, 1155, 1109, 1028, 757, 719, 665,
610, 557 cm–1. 1H NMR (500 MHz, CDCl3, TMS): δ = 10.78
(br s, 1 H), 7.42–7.37 (m, 1 H), 7.20–7.16 (m, 3 H), 7.00 (m,
1 H), 5.75 (s, 2 H), 5.44 (s, 2 H), 4.82–4.54 (m, 2 H), 4.11–
3.78 (m, 10 H), 2.62–2.47 (m, 4 H), 1.25–1.21 (m, 12 H). 13
NMR (125 MHz, CDCl3): δ = 156.7, 156.2, 155.8, 144.9,
143.9, 133.5, 132.7, 131.3, 130.0, 129.5, 128.5, 128.2,
C
125.7, 116.3, 71.1, 69.1, 62.1, 61.7, 49.1, 35.1, 29.7, 14.4,
14.3, 14.1. ESI-HRMS: m/z calcd for C31H40N6O8 [M + 1]:
625.29076; found: 625.29822.
(22) CCDC Number: 952086.
(23) Prakash, P.; Jijy, E.; Shimi, M.; Aparna, P. S.; Suresh, E.;
Radhakrishnan, K. V. RSC Adv. 2013, 3, 19933.
(24) For recent reports on β-oxygen elimination, see: (a) Wang,
H.; Schroder, N.; Glorius, F. Angew. Chem. Int. Ed. 2013,
52, 5386. (b) Wang, H.; Beiring, B.; Yu, D-G.; Collins, K.
D.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52, in press;
DOI: 10.1002/anie.201306754.
(25) When the present manuscript was ready for submission, a
similar report appeared in Chemical Science as accepted
manuscript. See: Cui, S.; Zhang, Y.; Qi, W. Chem. Sci. 2013,
in press; DOI: 10.1039/C3SC52524D.
(16) (a) Radhakrishnan, K. V.; Sajisha, V. S.; Anas, S.; Krishnan,
K. S. Synlett 2005, 2273. (b) Sajisha, V. S.; Radhakrishnan,
K. V. Adv. Synth. Catal. 2006, 348, 924. (c) John, J.; Sajisha,
V. S.; Mohanlal, S.; Radhakrishnan, K. V. Chem. Commun.
2006, 3510. (d) Anas, S.; John, J.; Sajisha, V. S.; John, J.;
Rajan, R.; Suresh, E.; Radhakrishnan, K. V. Org. Biomol.
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Synlett 2014, 25, 275–279

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