Cp?Co(III)-catalyzed direct functionalization of aromatic C-H bonds with α-diazomalonates

Article abstract of DOI:10.1016/j.tetlet.2015.05.025

Abstract Cp^?Co(III)-catalyzed intermolecular C(sp²)-C(sp³) assembly of (hetero)arenes with α-diazomalonates using a direct C-H functionalization logic was developed. A series of (hetero)arenes underwent alkylation efficiently under the assistance of pyrazolyl and pyrimidyl directing groups under relatively mild and operationally simple reaction conditions. Good functional group tolerance, satisfactory yields, and excellent regioselectivity were found.

Full text of DOI:10.1016/j.tetlet.2015.05.025

Tetrahedron Letters 56 (2015) 4093–4095
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cp⁄Co(III)-catalyzed direct functionalization of aromatic C–H bonds
with a-diazomalonates
⇑
Xu-Ge Liu, Shang-Shi Zhang, Jia-Qiang Wu, Qingjiang Li, Honggen Wang
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Cp⁄Co(III)-catalyzed intermolecular C(sp2)–C(sp3) assembly of (hetero)arenes with
a-diazomalonates
Article history:
Received 10 April 2015
Revised 5 May 2015
Accepted 7 May 2015
Available online 14 May 2015
using a direct C–H functionalization logic was developed. A series of (hetero)arenes underwent alkylation
efficiently under the assistance of pyrazolyl and pyrimidyl directing groups under relatively mild and
operationally simple reaction conditions. Good functional group tolerance, satisfactory yields, and
excellent regioselectivity were found.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Cobalt
C–H activation
Carbenes
C–C coupling
The development of efficient and greener methods to the assem-
bly of C–C bonds is the central topic in the discipline of organic
chemistry.1 In recent years, transition-metal catalyzed direct C–H
functionalization offers a powerful and straightforward strategy
for C–C bonds formation.2 To this purpose, noble metal-based cata-
lysts (such as Pd, Rh, Ru, and Ir) have been extensively investigated
and therefore, have achieved significant advances.2 Nevertheless,
the exploration of cheap and earth-abundant first-row transition
metals as catalysts is still of great interest. In this context, it has been
demonstrated that iron3, nickel4, cobalt5 and manganese6 are effec-
tive in C–H activation reactions, though limitations such as low reac-
tivity, drastic reaction conditions, and limited reaction types still
exist. Pioneered by Kanai7, and later advanced by the groups of
Ackermann8, Ellman9, Glorius10, and Chang11, Cp⁄Co(III) was found
to be an efficient catalyst for C–H functionalizations, which shows
similar, and in certain cases complementary reactivity to its coun-
terparts Cp⁄Rh(III) and Cp⁄Ir(III) species. Furthermore, the reactions
initiated by Cp⁄Co(III) could take place under relatively mild reac-
tion conditions compared to other first-row cheap metals.
and Cp⁄Ir(III)14-catalyzed C–H coupling reactions with diazo com-
pounds. During the preparation of this manuscript, Glorius and
Zhao realized the first example of Cp⁄Co(III)-catalyzed C–H alkyla-
tion with diazo compounds.10b An in situ cyclization enables the
straightforward access toward several extended pi-systems.
Herein, we report our development of an efficient Cp⁄Co(III)-
catalyzed intermolecular C–H coupling with diazomalonates for
the assembly of C(sp2)–C(sp3) bond. The reaction occurs under
rather simple reaction conditions, and is operationally simple.
At the outset of our studies, N-phenylpyrazole (1a) was chosen
as a model substrate (Table 1). The reaction of 1a with 1.2 equiv
of dimethyl diazomalonate 2a in the presence of 5 mol %
Cp⁄Co(CO)I2 and 10 mol % AgSbF6 in toluene at 100 °C delivered
the desired alkylation product 3aa in 5% yield (entry 1). A survey
of different solvents led us to identify that reaction proceeded
smoothly in DCE, effecting the alkylation in a good yield of 80%
(entries 2–5). Control experiments showed that cobalt is essential
for this transformation, as its omission gave no trace amount of
3aa (entry 6). In addition, the employment of Ag salt to remove
the iodide to generate cationic Cp⁄Co(III) species was also impor-
tant (entries 7 and 8). Gratifyingly, the catalyst loading could be
decreased to as low as 1 mol %, wherein a good yield of 70% could
be maintained (entries 9 and 10). The attempt to lower the temper-
ature failed (entries 11 and 12). Only 20% yield was obtained when
the reaction was conducted at 50 °C.
The application of carbenoid in C–H bond functionalization
under the catalysis of transition metals has been realized as a
powerful approach for C–C bonds formation.12 Classically, these
reactions proceeded via a carbene formation and thereafter C–H
insertion mechanism. Recently, it was demonstrated that an
alternative mechanism involving C–H activation, metal-carbene
formation, and migration insertion was operative in Cp⁄Rh(III)13
With the optimized conditions in hand, the scope of the reac-
tion was investigated. A variety of substituted N-phenylpyrazoles
were synthesized and subjected to the reaction (Table 2). It was
found that the commonly encountered functional groups such as
⇑
Corresponding author.
E-mail address: wanghg3@mail.sysu.edu.cn (H. Wang).
http://dx.doi.org/10.1016/j.tetlet.2015.05.025
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4094
X.-G. Liu et al. / Tetrahedron Letters 56 (2015) 4093–4095
Table 1
Table 3
Reaction optimizationa
Cp⁄Co(III)-catalyzed coupling of N-pyrimidinylindoles with 2-diazomalonatesa
COOR
R
Cp*Co(CO)I2 (5 mol %)
AgSbF6 (10 mol %)
R
Cp*Co(CO)I2
AgSbF6
N
N
ROOC
COOR
N
COOR
N
MeOOC
COOMe
N
N
COOMe
COOMe
+
+
N
DCE, 100 oC, 20-48 h
N2
H
N
N
N2
N
4
2
5
1a
2a
3aa
T (°C) Yieldb (%)
MeO
Br
COOMe
COOMe
COOR
COOR
COOMe
COOMe
Entry Cp⁄Co(III) (mol %) AgSbF6 (mol %) Solvent
N
N
N
1
2
3
4
5
6
7
8
5
5
5
5
5
0
5
0
10
10
10
10
10
10
0
0
5
2
10
10
Toluene 100
5
N
N
N
N
N
N
DMF
EtOH
CH3CN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
100
100
100
100
100
100
100
100
100
25
Trace
Trace
0
80
0
0
0
74
72
0
5aa
, R = Me, 85%, 20 h
5ab, R = Et, 77%, 24 h
5ac, R = iPr, 71%, 24 h
5ba, 75%, 24 h
5ca, 65%, 24 h
COOMe
CHO
OBn
COOMe
COOMe
COOMe
COOMe
COOMe
N
N
9
2.5
1
5
N
COOMe
10
11
12
N
N
N
N
N
N
5
50
20
5da, 69%, 24 h
COOMe
5ea, 76%, 24 h
COOMe
5fa, 61%, 24 h
a
Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), Cp⁄Co(CO)I2, AgSbF6, sol-
COOMe
vent (2.0 mL), 12 h.
b
Isolated yield.
N
COOMe
N
N
COOMe
COOMe
O2N
Cl
MeO
Table 2
N
N
N
N
Cp⁄Co(III)-catalyzed coupling of N-arylpyrazoles with diazo compoundsa
N
N
5ga
5ha
5ia
, 49%, 48 h
, 45%, 48 h
COOMe
,32%, 48 h
COOMe
COOMe
R2
N
R2
N
MeOOC
Cp*Co(CO)I2 (5 mol %)
AgSbF6 (10 mol %)
DCE, 100 oC, 11-48 h
COOMe
COOMe
N
EWG1
EWG2
N
COOMe
COOMe
+
N2
N
N
N
H
N
R1
R1
N
N
N
N
N
1
2a
3
5ja
, 24%, 48 h
5ka
5la
, 40%, 48 h
, 33%, 48 h
N
N
Reaction conditions: 4 (0.3 mmol), 2 (0.36 mmol), Cp⁄Co(CO)I2 (5 mol %),
N
a
N
N
N
COOMe
COOMe
N
COOMe
COOMe
N
COOMe
COOMe
COOMe
COOMe
AgSbF6 (10 mol %), DCE (2.0 mL), 100 °C. Yields of isolated products.
CO2Et
CN
O
OH
acetyl (3ba), cyano (3ca), hydroxymethyl (3da), ester (3ea), and
chloro (3fa) were tolerated in this transformation, giving the
desired products in moderate-to-good yields. These functionalities
offer ample opportunities for further functionalizations. With
meta-chloro substituted N-phenylpyrazole, only reaction taking
place at the less hindered position was found (3fa). Of note, thio-
phene 1g underwent efficiently, with alkylation occurring selec-
3ba, 63%, 48 h
3ca, 53%, 48 h
3da, 44%, 20 h
3ea, 72%, 48 h
O
N
N
N
N
COOMe
N
COOMe
COOMe
N
N
COOMe
N
COOMe
COOMe
COOMe
COOMe
S
Cl
3fa, 52%, 48 h
3ga, 60%, 11 h
3ha, 45%, 48 h
3ia, 11%,48 h
tively at the
a position (3ga). 1-(Naphthalen-1-yl)-1H-pyrazole
was also a suitable substrate, giving 3ha in 45% yield. The sub-
stituent effect on the pyrazole ring was also examined. When an
electron-withdrawing acetyl group was introduced, a low yield of
only 11% was obtained (3ia), probably due to an attenuated coor-
dination ability of the resulting pyrazole ring. With electron-re-
leasing methyl group substituted, the yields were also decreased,
indicative of a bad compatibility of steric hindrance on the direct-
ing group (3ja and 3ka). Of note, no dialkylation was observed in
these reactions. It was found that diethyl diazomalonate 2b and
diisopropyldiazomelonate 2c were also efficient coupling partners
for this transformation (3ab and 3ac). To our disappointment,
however, the use of diazo compounds 2d–2h, gave no correspond-
ing products. And attempt to expand the scope to other substrates
failed (substrates 6–11), with none of which giving any desired
products.
N
N
N
N
N
COOEt
COOEt
N
COOiPr
COOiPr
N
COOMe
N
COOMe
COOMe
COOMe
3ja,
3ka,
3ab
3ac
40%, 48 h
25%, 48 h
, 75%, 24 h
, 76%, 24 h
O
unsuccessful coupling partners
N2
N2
N2
N
N
Ph
EtOOC
N2
COOEt
COOEt
EtOOC
PO(OEt)2
O
O
O
O
N2
2d
2e
2f
2g
2h
unsuccessful substrates
OH
O
O
HN
N
N
N
N
NHOMe
To further expand the scope, we explored the direct alkylation
reaction of indoles. Indoles are important skeletons in numerous
functional molecules. As shown in Table 3, it was found that using
the same protocol described above, the indoles underwent func-
tionalization efficiently under the assistance of a pyrimidyl direct-
ing group.15 Thus, different functional groups, such as methoxyl
6
7
8
9
10
11
a
Reaction conditions:
AgSbF6 (10 mol %), DCE (2.0 mL), 100 °C. Yields of isolated products.
1
(0.3 mmol), 2a (0.36 mmol), Cp⁄Co(CO)I2 (5 mol %),

X.-G. Liu et al. / Tetrahedron Letters 56 (2015) 4093–4095
4095
1147–1169; (e) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624–655; (f) Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740–4761; (g) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev.
2012, 112, 5879–5918; (h) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588–
5598; (i) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369–375; (j)
Ackermann, L. Acc. Chem. Res. 2014, 47, 281–295; (k) Xie, F.; Qi, Z.; Yu, S.; Li, X. J.
Am. Chem. Soc. 2014, 136, 4780–4787; (l) Nagata, T.; Hirano, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2014, 79, 8960–8967.
Cp*Co(CO)I2
+
N
AgSbF6
N
COOMe
COOMe
H
N
N
Cp*Co2+
protonation
C-H activation
3. For selected examples, see: (a) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75,
6061–6067; (a) Shang, R.; Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem. Soc.
2014, 136, 14349–14352; (b) Ilies, T.; Matsubara, T.; Ichikawa, S.; Asako, S.;
Nakamura, E. J. Am. Chem. Soc. 2014, 136, 13126–13129; (c) Matsubara, T.;
Asako, S.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2014, 136, 646–649; (d)
Kuzmina, O. M.; Steib, A. K.; Flubacher, D.; Knochel, P. Org. Lett. 2012, 14, 4818–
4821; (e) Cong, X.; Zeng, X. Org. Lett. 2014, 16, 3716–3719; (f) Cai, Y.; Zhu, S.-F.;
Wang, G.-P.; Zhou, Q.-L. Adv. Synth. Catal. 2011, 353, 2939–2944.
4. Selected examples, see: (a) Song, W.; Lackner, S.; Ackermann, L. Angew. Chem.,
Int. Ed. 2014, 53, 2477–2480; (b) Leiendecker, M.; Hsiao, C.-C.; Guo, L.; Alandini,
M.; Rueping, M. Angew. Chem., Int. Ed. 2014, 53, 12912–12915; (c) Aihara, Y.;
Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308–5311; (d) Ano, Y.; Tobisu, M.;
Chatani, N. Org. Lett. 2012, 14, 354–357; (e) Yao, T.; Hirano, K.; Satoh, T.; Miura,
M. Angew. Chem., Int. Ed. 2012, 51, 775–779.
N
N
Co
N
N
Cp*
Co
MeOOC COOMe
A
Cp*
C
N
N
Cp*
MeOOC
COOMe
Co
MeOOC
migratory insertion
N2
carbene fomation
COOMe
N2
B
Scheme 1. Proposed mechanism.
5. For selected recent reviews on the co-catalyzed C–H bond functionalizations,
see: (a) Yoshikai, N. Synlett 2011, 1047–1051; (b) Gao, K.; Yoshikai, N. Acc.
Chem. Res. 2014, 47, 1208–1219; (c) Yoshikai, N. Bull. Chem. Soc. Jpn. 2014, 87,
843–857; (d) Su, B.; Cao, Z.-C.; Shi, Z.-J. Acc. Chem. Res. 2015, 48, 886–896; For
selected example on Co(II)-catalyzed C–H functionalization, see: (e) Wu, B.;
Yoshikai, N. Angew. Chem., Int. Ed. 2013, 52, 10496–10499; (f) Ding, Z.; Yoshikai,
N. Angew. Chem., Int. Ed. 2013, 52, 8574–8578; (g) Gao, K.; Yoshikai, N. J. Am.
Chem. Soc. 2013, 135, 9279–9282; (h) Gao, K.; Yamakawa, T.; Yoshikai, N.
Synthesis 2014, 46, 2024–2039; (i) Gao, K.; Paira, R.; Yoshikai, N. Adv. Synth.
Catal. 2014, 356, 1486–1490; (j) Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16,
4688–4690; (k) Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, 4684–4687; (l)
Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014, 53, 10209–10212; (m)
Grigorjeva, L.; Daugulis, O. Org. Lett. 2015, 17, 1204–1207; (n) Zhang, L.-B.; Hao,
X.-Q.; Zhang, S.-K.; Liu, Z.-J.; Zheng, X.-X.; Gong, J.-F.; Niu, J.-L.; Song, M.-P.
Angew. Chem., Int. Ed. 2015, 54, 272–275.
6. Selected examples on Mn-catalyzed C–H functionalizations, see: (a) He, R.;
Huang, Z.-T.; Zheng, Q.-Y.; Wang, C. Tetrahedron Lett. 2014, 55, 5705–5713; (b)
Zhou, B.; Ma, P.; Chen, H.; Wang, C. Chem. Commun. 2014, 14558–14561; (c)
Tsuji, H.; Yamagata, K.-I.; Fujimoto, T.; Nakamura, E. J. Am. Chem. Soc. 2008, 130,
7792–7793; (d) Gunay, A.; Theopold, K. H. Chem. Rev. 2010, 110, 1060–1081;
(e) Borovik, A. S. Chem. Soc. Rev. 2011, 40, 1870–1874; (f) Kuninobu, Y.; Nishi,
M.; Yudha, S. S.; Takai, K. Org. Lett. 2008, 10, 3009–3011.
7. (a) Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. Angew. Chem., Int. Ed.
2013, 52, 2207–2211; (b) Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M.
Chem. Eur. J. 2013, 19, 9142; (c) Sun, B.; Yoshino, T.; Matsunaga, S.; Kanai, K.
Adv. Synth. Catal. 2014, 356, 1491–1495; (d) Ikemoto, H.; Yoshino, T.; Sakata, K.;
Matsunaga, S.; Kanai, M. J. Am. Chem. Soc. 2014, 136, 5424–5431; (e) Sun, B.;
Yoshino, T.; Matsunaga, S.; Kanai, M. Chem. Commun. 2015, 4659–4661; (f)
Suzuki, Y.; Sun, B.; Yoshino, T.; Kanai, M.; Matsunaga, S. Tetrahedron 2015.
http://dx.doi.org/10.1016/j.tet.2015.02.032.
8. Li, J.; Ackermann, L. Angew. Chem., Int. Ed. 2015, 54, 3635–3638.
9. Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015, 137, 490–498.
10. (a) Yu, D.-G.; Gensch, T.; de Azambuja, T.; Vasquez-Cespeds, S.; Glorius, F. J. Am.
Chem. Soc. 2014, 136, 17722–17725; (b) Zhao, D.; Kim, J. H.; Stegemann, L.;
Strassert, C. A.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 4508–4511.
11. (a) Patel, P.; Chang, S. ACS Catal. 2015, 5, 853–858; (b) Pawar, A. B.; Chang, S.
Org. Lett. 2015, 17, 660–663.
(5ba, 5ia), halogen (5ca, 5ha), benzyloxyl (5da), ester (5ea), nitro
(5ga), and even formyl (5fa), substituted at different positions
were well tolerated in this reaction. Interestingly, when b-methyl
indole was employed, the anticipated product was not detected.
Instead, the monoester 5ja, assumably derived from a subsequent
decarbalkoxylation, was isolated in 24% yield. Importantly, the
direct alkylation of pyroles was also feasible under the identical
reaction conditions (5ka and 5la).
A
reaction mechanism was proposed and is outlined in
Scheme 1. The active catalyst Cp⁄Co2+ is generated by the ligand
abstraction with AgSbF6. C–H activation takes place under the
assistance of the corresponding directing group, forming
a
cyclometallated intermediate A. A reacts with -diazomalonates
a
to diliver a metal carbene species B. Subsequently, a migratory
insertion furnishes intermediate C. Upon protonation, the final pro-
duct is produced and the catalyst is regenerated.
In conclusion, we developed a Cp⁄Co(III)-catalyzed C–H cou-
pling reaction with
a-diazomalonates for the direct alkylation of
(hetero)arenes under the assistance of pyrazoyl or pyrimidyl
directing group. The reaction proceeded under relatively mild
and operationally simple reaction conditions. Good functional
group tolerance, satisfactory yields, and excellent regioselectivity
were found.
Acknowledgments
12. For selected examples, see: (a) Chan, W.-W.; Yeung, S.-H.; Zhou, Z.; Chan, A. S.
C. Org. Lett. 2015, 12, 604–607; (b) Chan, W.-W.; Kwonga, T.-L.; Yu, W.-Y. Org.
Biomol. Chem. 2012, 10, 3749–3755; (c) Yu, Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu,
L.; Zhang, J. J. Am. Chem. Soc. 2014, 136, 6904–6907; (d) Gibe, R.; Kerr, M. A. J.
Org. Chem. 2002, 67, 6247–6249; (e) Ye, B.; Cramer, N. Angew. Chem., Int. Ed.
2014, 53, 7896–7899; (f) Ye, F.; Qu, S.; Zhou, L.; Peng, C.; Wang, C.; Cheng, J.;
Hossain, M. L.; Liu, Y.; Zhang, Y.; Wang, Z.-X.; Wang, J. J. Am. Chem. Soc. 2015,
137, 4435–4444.
We are grateful for the support of this work by a Start-up Grant
from Sun Yat-sen University and National Natural Science
Foundation of China (81402794 and 21472250).
Supplementary data
13. For selected examples, see: (a) Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y. J. Am.
Chem. Soc. 2012, 134, 13565–13568; (b) Dawande, S. G.; Kanchupalli, V.;
Kalepu, J.; Chennamsetti, H.; Lad, B. S.; Katukojvala, S. Angew. Chem., Int. Ed.
2014, 53, 4076–4080; (c) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2014, 53, 1364–1367; (d) Yu, X.; Yu, S.; Xiao, J.; Wan, B.;
Li, X. J. Org. Chem. 2013, 78, 5444–5452; (e) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J.
Am. Chem. Soc. 2013, 135, 5364–5367; (f) Shi, Z.; Koester, D. C.; Boultadakis-
Arapinis, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 12204–12207; (g) Jeong, J.;
Patel, P.; Hwang, H.; Chang, S. Org. Lett. 2014, 16, 4598–4601; (h) Yu, S.; Liu, S.;
Lan, Y.; Wan, B.; Li, X. J. Am. Chem. Soc. 2015, 137, 1623–1631.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
025.
References and notes
1. Corey, E. J.; Cheng, X. M. The Logic of Chemical Synthesis; John Wiley & Sons:
New York, 1989.
2. For selected reviews on transition metal-catalyzed C–H functionalization, see:
(a) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086;
(b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094–5115; (c) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc.
Rev. 2009, 38, 3242–3272; (d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
14. Xia, Y.; Liu, Z.; Feng, S.; Zhang, Y.; Wang, J. J. Org. Chem. 2015, 80, 223–236.
15. Glorius and Zhao also reported four examples on the alkylation of indoles and
one example on the dialkylation of pyrole under the conditions: Cp⁄Co(CO)I2
(2.5 mol %), AgSbF6 (5 mol %), KOAc (10 mol %), in TFE, 40 °C. See Ref. 10b for
detail.