A novel approach for rhodium(iii)-catalyzed C-H functionalization of 2,2′-bipyridine derivatives with alkynes: A significant substituent effect

Article abstract of DOI:10.1039/d0cc01077d

We described a novel approach for the C-H functionalization of 2,2′-bipyridine derivatives with alkynes. DFT calculations and experimental data showed a significant substituent effect at the 6-position of 2,2′-bipyridine, which weakened the adjacent N-Rh bond and provided the possibility of subsequent rollover cyclometalation, C-H activation, and functionalization.

Full text of DOI:10.1039/d0cc01077d

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Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC01077D
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A novel approach on rhodium(III)-catalyzed C-H functionalization
of 2,2’-bipyridine derivatives with alkynes: significant substituent
effect
Received 00th January 20xx,
Accepted 00th January 20xx
Shaonan Wu,a Zhuo Wang,a Yinwei Bao,a Chen Chen,a* Kun Liua* and Bolin Zhua*
DOI: 10.1039/x0xx00000x
We described a novel approach on C-H functionalization of 2,2’- take advantage of a dramatic NHC effects. It is believed that
bipyridine derivatives with alkynes. DFT calculations and strong trans-effect of N-heterocyclic carbenes weakens a Rh−N
experimental data showed the significant substituent effect at 6- bond, which is trans to the Rh−NHC bond, thereby facilitates
position of 2,2’-bipyridine, which weakened the adjacent N-Rh rollover cyclometalation and C−H functionalization (Scheme
bond and provided the possibility for subsequent rollover 1b). In 2018, the group of Cheng14 described a Pd(II)-catalyzed
cyclometalation, C-H activation, and functionalization.
rollover C-H arylation of 2,2’-bipyridine-6-carboxamides with
aryl iodides, which exhibited excellent C3’ selectivity. Because
the amide anion moiety exerts a strong trans-effect to weaken
the Pd(II)−N bond (trans to the amide anion), it allows for the
rollover cyclometalation and the subsequent arylation by aryl
iodides. Later on, rhodium(III)-catalyzed C3 selective C−H
acylmethylation of 2,2’-bipyridine-6-carboxamides with
sulfoxonium ylides was developed by the same group in 2019
(Scheme 1c).15
N,N-bidentate chelating compounds have attracted
considerable interest in recent decades because of their wide
applications in photochemistry,1 biochemistry,2 medicinal
chemistry3 and coordination chemistry.4 In light of their
importance, the development of new methodologies for the
synthesis of diversiform functionalized N,N-bidentate chelating
compounds has been a growing research focus in organic
chemistry.
(a) Miura's work:
Transition-metal-catalyzed direct C−H bond functionalization
was recognized as a powerful tool to construct C−C and C–X
bonds.5 However, directed C−H bond functionalization of N,N-
bidentate chelating compounds turns out to be challenging
due to their N atoms have strong chelating ability to transition
metals and tend to form stable metal complexes. In recent
years, a series of rollover cyclometalation examples6 have
been developed using stoichiometric Ir,7 Pt,8 Pd,9 Au10 and
Ni,11 which demonstrate the capacity of these complexes to
undergo the rollover cyclometalation. But catalytic
functionalization on these ligating molecules was extremely
difficult and still remains an unmet challenge.12-16 In 2009,
Miura and co-workers12 realized a Rh(I)-catalyzed direct C−H
dialkenylation of 2,2’-bipyridines with terminal silylacetylenes.
However, only two examples were shown, and excessively high
reaction temperature limited its application (Scheme 1a).
Later, Chang group13 represented a breakthrough in this area.
They reported a Rh(NHC) catalytic system for C−H alkenylation
and alkylation of 2,2’-bipyridines or 2,2’-biquinolines, which
RhI
N
N
N
Si(iPr)3
+
Si(iPr)3
(iPr)3Si
o-xylene, 160 oC, N2
N
(b) Chang's work:
NHC
Rollover
Cyclometalation
NHC
R
RhIII
N
N
N
N
H
H
R
RhIII
RhIII
R
C-H Activation
NHC
N
N
N
L
N
L
Action Twice
trans-effect
(c) Cheng's work:
O
O
O
O
R
R
R
N
R
N
N
H
H
O
N
PdII
ArI
N
N
RhIII
N
N
H
N
N
N
PdII
R'
O
O
S
Ar
L
N
R'
trans-effect
C3' selective
C3 selective
(d) This work:
R'
R'
R'
R'
R
N
H
H
R
R'
R'
R'
R'
R
RhIII
N
N
N
remove
R
R'
R'
N
N
RhIII
N
N
Scheme 1. Strategies on C−H functionalization of 2,2’-bipyridine derivatives
Being distinct to the strategies mentioned above, herein we
reported novel approach on rhodium(III)-catalyzed C−H
functionalization of 2,2’-bipyridine derivatives with alkynes. In this
case, the substituents on the 6-position of 2,2’-bipyridine play the
important role for the rollover cyclometalation process.8a,8b Notably,
a
a. Tianjin Key Laboratory of Structure and Performance for Functional Molecules,
College of Chemistry, Tianjin Normal University, Tianjin 300387, P. R. China. E-
mail: hxxycc@tjnu.edu.cn, hxxyliuk@tjnu.edu.cn, hxxyzbl@tjnu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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the substituents can be easily removed under mild conditions
(Scheme 1d).
R'
View Article Online
DOI: 10.1039/D0CRC01077D
R
[Cp*RhCl2]2 (5 mol%)
AgOAc (2.5 equiv)
NaOAc (5.0 equiv)
'
R
R'
N
N
N
R'
+
To initiate our investigation, 6-bromo-2,2'-bipyridine 1a was
chosen as a model substrate with diphenylacetylene 2a under
rhodium catalysis. Satisfyingly, 5 mol% [Cp*RhCl2]2, 2.5 equiv
AgOAc and 5.0 equiv NaOAc in toluene at 110 °C under a
nitrogen atmosphere gave 35% of 3aa after 24 h (Table 1,
entry 1). And the molecular structure of 3aa was
unambiguously confirmed by X-ray crystallographic analysis
(Scheme 2).17a Subsequently, the influence of the solvent, base,
catalyst and temperature was studied. To improve the yield,
we screened other solvents such as 1,4-dioxane, MeCN and
DCE, among which DCE was proved to be the optimal solvent,
affording 3aa in 92% yield (Table 1, entries 2-4). The use of a
proper base was crucial for this transformation and NaOAc was
found to be optimal (Table 1, entries 5-7). In the absence of
NaOAc, only 45% yield of desired product 3aa was obtained
(Table 1, entry 8). When the loading of NaOAc was decreased
to 3.0 equiv, the yield of 3aa decreased to 76% (Table 1, entry
9). Other rhodium catalyst, such as Cp*Rh(MeCN)3(PF6)2, led to
a slight reduction of the yield (Table 1, entry 10). Decreasing
DCE, 110 oC, 24 h
R'
R'
2
N
1
3
Ph
Ph
R' = 4-Me-C6H4, 3ab, 85%
R' = 4-Et-C6H4, 3ac, 89%
R'
Ph
Ph
Br
R'
R'
Br
R' = 4-OMe-C6H4, 3ad, 90%
N
R' = 4-F-C6H4, 3ae, 52%
R' = 4-Cl-C6H4, 3af, 63%
R' = 4-Br-C6H4, 3ag, 55%
R' = 3-Cl-C6H4, 3ah, 75%c
R' = 3-Me-C6H4, 3ai, 43%c
R' = 2-Me-C6H4, 3aj, NDd
N
N
R'
N
3aa, 92%
S
S
Et
Br
Et
Et
Br
Br
Br
N
N
N
N
N
N
S
N
N
Et
S
3am, 79%
3an, 45%
3al, 66%
3ak, 88%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cl
Ph
Ph
F
N
N
N
N
N
Ph
o
Ph
Ph
the temperature to 85 C caused the yield to descend to 62%
N
(Table 1, entry 11). Thus, the optimized reaction conditions
were as follows: 1a (0.2 mmol), 2 (0.5 mmol), 5 mol%
[Cp*RhCl2]2, 2.5 equiv AgOAc and 5.0 equiv NaOAc in DCE (2.0
mL) at 110 °C under a nitrogen atmosphere for 24 h.
3da, 24%
3ba, 80%
R'
3ca, 20%
X-Ray of 3ef
Ph
Ph
OMe
Ph
R'
R'
OMe
R' = C6H5, 3ea, 88%
N
N
N
R' = 4-Me-C6H4, 3eb, 45%
R' = 4-F-C6H4, 3ee, 77%
R' = 4-Cl-C6H4, 3ef, 66%
R' = 4-Br-C6H4, 3eg, 78%
R' = 2-thienyl, 3em, 50%
Ph
N
Ph
Ph
N
R'
Table 1. Optimization of reaction conditionsa
N
Ph
Br
[Cp*RhCl2]2 (5 mol%)
AgOAc (2.5 equiv)
base (5.0 equiv)
3eo, 52%
3fa, 0%
Ph
Ph
Br
Ph
Ph
N
N
N
N
Scheme 2. Scope of the rhodium(III)-catalyzed C−H functionalization of 2,2’-bipyridine
derivatives with alkynesa,b a Reaction conditions: the reactions were carried out with 1
(0.2 mmol), 2 (0.5 mmol), [Cp*RhCl2]2 (0.01 mmol), AgOAc (0.5 mmol) and NaOAc (1.0
mmol) in DCE (2.0 mL) at 110 oC under a nitrogen atmosphere for 24 h. b Isolated yield.
c Cp*Rh(MeCN)3(PF6)2 as catalyst. d ND = not detected.
+
solvent, 110 oC, 24 h
Ph
1a
2a
3aa
(1.0 equiv)
(2.5 equiv)
Entry
Base
Solvent
T (oC)
Yieldb (%)
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
85 oC
35%
40%
78%
92%
81%
86%
67%
45%
76%
89%
62%
reacted effectively, providing the corresponding products 3ab-
3ad in satisfactory yields (85%-90%). Furthermore,
diphenylacetylene bearing electron-withdrawing substituents
at the para-positions of the aromatic ring were tolerated,
which included fluoro, chloro and bromo, the desired products
3ae-3ag were obtained in 52%-63% yields. Gratifyingly,
substrates bearing the chloro or methyl group at the meta-
position of phenyl ring were found compatible with this
reaction, the target products 3ah and 3ai were obtained in 75%
and 43% yields, respectively. It's worth noting that halide
substituents were compatible with this transformation,
providing an opportunity for further elaboration. To our
1
2
NaOAc
NaOAc
NaOAc
NaOAc
Cs2CO3
K2CO3
Et3N
Toluene
1,4-Dioxane
MeCN
DCE
3
4
5
DCE
6
DCE
7
DCE
8
-------
DCE
9c
10d
11
NaOAc
NaOAc
NaOAc
DCE
DCE
DCE
a
All reactions were performed with 0.2 mmol of 1a, 0.5 mmol of 2a, 0.01 mmol of
[Cp*RhCl2]2 and 1.0 mmol of base in 2.0 mL of the indicated solvent under a nitrogen
b
c
d
atmosphere for 24 h. Isolated yield. 3.0 equiv of NaOAc Cp*Rh(MeCN)3(PF6)2 as disappointment, ortho-substituted diarylalkyne 2j was found
catalyst.
to be incompatible, probably due to steric congestion.
Diarylacetylene bearing dimethyl-substituted (2k) reacted
In order to demonstrate the applicability of our protocol, we
turned our attention to exploring a variety of other substrates
beyond the 6-bromo-2,2'-bipyridine and diphenylacetylene
under the optimized reaction conditions (Scheme 2). First, we
investigated the reaction of different internal alkynes 2 with 6-
bromo-2,2'-bipyridine 1a. Diarylalkynes 2b-2d bearing
electron-donating groups at the para-position of the aryl ring
smoothly to give the corresponding product 3ak in 88% yield.
Other diarylalkynes, such as di(2-naphthyl)acetylenes (2l) and
di(2-thienyl)acetylenes (2m) could also be employed for this
transformation, 3al and 3am were obtained in 66% and 79%
yields, respectively. Fortunately, dialkylalkyne 2n also worked
well to furnish the desired product 3an in 45% yield. To our
delight, substituent at 6-position of 2,2'-bipyridine was not
2 | J. Name., 2012, 00, 1-3
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limited to bromo. Substrates bearing other substituents at 6-
position, such as chloro, fluoro, methyl and methoxyl, can also
realize this transformation, albeit in lower yield (3ba-3ea, 20%-
88%). Moreover, various internal alkynes smoothly reacted
with 1e, and afforded the corresponding products 3eb-3em in
moderate to good yields. The structure of 3ef was confirmed
by single crystal X-ray diffraction.17b When unsymmetrical
alkynes 2o was employed, 3eo was exclusively obtained in 52%
yield. The structure of 3eo was unambiguously achieved on
the basis of NOE NMR experiments. No corresponding C−H
functionalized product was observed when 2,2'-bipyridine was
used as substrate, which demonstrated the significant
substituent effect of our protocol.
View Article Online
DOI: 10.1039/D0CC01077D
a) Synthesis of intermediates 4-A-Br, 4-C-Br and 4-D-Br:
Br
Br
Cl
N
N
N
N
[Cp*RhCl2]2
Rh Cp*
Cl
MeOH, RT, 1 h
(CCDC 1970824)
1a
4-A-Br (99%)
Br
Br
N
Cl
N
N
AgOAc (3.0 equiv)
DCE, 84 oC, 3 h
Cp*
Cl
Rh
Rh Cp*
Cl
N
A
(CCDC 1973309)
4-C-Br (68%)
Br
Br
N
Ph
Ph
Ph
(1.0 equiv)
Ph
N
Cp*
Cl
Rh
N
On the basis of the experimental results and previous
NaBArF4 (1.2 equiv)
DCM, RT, 0.5 h
Rh
N
Cl
Cp*
18
report,12-15,
a plausible reaction pathway is proposed
(Scheme 3). First, the coordination of 1a with Cp*Rh(III) forms
Rh(III) complexes 4-A-Br, followed by N-Rh cleavage (4-B-Br)
and rollover cyclometalation to give complex 4-C-Br.
Subsequently, diphenylacetylene 2a coordinates with the
rhodium, which undergoes 1,2-insertion to form intermediate
4-D-Br. Next, dissociate the N-Rh bond with the assistant of
excess amount of Ag+, followed by C−H activation leads to a
new five-membered rhodium complex 4-E-Br. This rhodacycle
intermediate can coordinate with 2a and insert once again to
give a seven-membered rhodacycle 4-F-Br or 4-F’-Br. Finally,
reductive elimination of 4-F-Br or 4-F’-Br delivers the target
product 3aa and Rh(I) species, which could be oxidized to the
Rh(III) catalyst by AgOAc to complete the catalytic cycle.
B
(CCDC 1973311)
4-D-Br (66%)
b) Control experiments with the representative intermediate:
4-A-Br (10 mol%)
AgOAc (2.5 equiv)
NaOAc (5.0 equiv)
DCE, 110 oC, 24 h
1a
+
+
2a
3aa (61%)
3aa (64%)
3aa (87%)
(0.2 mmol)
(0.5 mmol)
4-C-Br (10 mol%)
AgOAc (2.5 equiv)
NaOAc (5.0 equiv)
DCE, 110 oC, 24 h
1a
2a
(0.2 mmol)
(0.5 mmol)
4-D-Br (10 mol%)
AgOAc (2.5 equiv)
NaOAc (5.0 equiv)
DCE, 110 oC, 24 h
1a
+
2a
(0.2 mmol)
(0.5 mmol)
Scheme 4. Synthesis of pre-rollover and post-rollover intermediates and control
experiments.
Cp*RhIII
Br
Ag+
RhI
N
N
Br
RhIII
1a
a) Bond length (in Å):
Cl
b) BDE (in kcal/mol):
N
3aa
via
RhIII
4-A-Br
N
4-B-Br
Ph
Ph
Ph
RhIII
Ph
Br
Br
Br
N
RhIII
Ph
Ph
Ph
N
N
or
RhIII
Ph
N
N
N
4-A-H
4-A-Br
R = Br
4-A-Br
R = F
4-A-H
R = Cl
4-F'-Br
4-F-Br
2a
4-C-Br
c) Reaction barrier:
G / kcal/mol
R = H
TS-Decomplexation-H
21.7
RhIII
Br
2a
Br
TS-Decomplexation-F
Ph
Ph
N
TS-Decomplexation-Br
N
19.4
Ph
4-E-Br
Ph
RhIII
15.3
TS-Decomplexation-Cl
N
N
13.7
11.8
4-D-Br
10.1
4-B-H
ligands on the rhodium complexes have been omitted for clarity
4-B-F
6.2
5.0
Scheme 3. Plausible catalytic cycle.
4-B-Cl
4-B-Br
0.0
0.0
0.0
0.0
4-A-H
4-A-F
4-A-Br
4-A-Cl
To further verify our aforementioned mechanism, a series of
pre-rollover and post-rollover complexes 4-A-Br, 4-C-Br and 4-D-Br
were synthesized by stoichiometric reactions of 1a, 2a and
[Cp*RhCl2]2. The crystal structures of 4-A-Br, 4-C-Br and 4-D-Br
were shown in Scheme 4a.17c-17e Subsequently, these intermediates
were subjected to their viable intermediacy test in the catalytic
reactions. Positive results in all the test reactions supported our
proposed mechanism (Scheme 4b).
Scheme 5. DFT calculations (in Gibbs free energies) on substituent effect of 6-
substituted 2,2’-bipyridine.
delight, calculations for the bond length, bond dissociation
energy, and lowest energy path for the rollover step are all in
accordance with our experimental results, which support our
postulate. As shown in Scheme 5, the bond length difference
of two Rh-N bonds on 4-A-H is 0.005 Å. In 4-A-Br, Rh-N bond
(with Br on pyridine) and Rh-N’ bond difference is 0.058 Å,
which is longer than 4-A-H (Scheme 5a). Furthermore, due to
To get insights into the reaction mechanism, we performed the
DFT calculations on Rh(III) intermediates 4-A and 4-B to elaborate
the mechanistic details of substituent effect in our protocol. To our
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J. Name., 2013, 00, 1-3 | 3
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Yuichiro, O.-K. Nobuko, S. Hideki and K. Kazuyuki,
the substituent effect, the bond dissociation energy of Rh-N
bond (with Br on pyridine) is lower than Rh-N’ bond (6.7
Kcal/mol vs 15.0 Kcal/mol), which gives an opportunity to
break Rh-N bond (Scheme 5b). Moreover, compared with 2,2'-
bipyridine, a much easier decomplexation process is displayed
in 6-substituted 2,2'-bipyridine (Scheme 5c). These results
clearly show that the significant substituent effect on 6-
position of 2,2’-bipyridine.
View Article Online
Organometallics, 2007, 26, 702.
DOI: 10.1039/D0CC01077D
5
For selected reviews on C−H functionalizations, see: a) Y.
Park, Y. Kim and S. Chang, Chem. Rev., 2017, 117, 9247; b) J.
He, M. Wasa, K. S. L. Chan, Q. Shao and J.-Q. Yu, Chem. Rev.,
2017, 117, 8754; c) M. Moselage, J. Li and L. Ackermann, ACS
Catal., 2016, 6, 498; d) W. Liu and L. Ackermann, ACS Catal.,
2016, 6, 3743; e) W. R. Gutekunsta and P. S. Baran, Chem.
Soc. Rev., 2011, 40, 1976; f) G. Song and X. Li, Acc. Chem.
Res., 2015, 48, 1007; For selected examples on C−H
functionalizations, see: g) T. Li, C. Liu, S. Wu, C. Chen and B.
Zhu, Org. Biomol. Chem., 2019, 17, 7679; h) R. Mi, G. Zheng,
Z. Qi and X. Li, Angew. Chem Int. Ed., 2019, 58, 17666; i) Z.
Wang, T. Li, J. Zhao, X. Shi, D. Jiao, H. Zheng, C. Chen and B.
Zhu, Org. Lett., 2018, 20, 6640; j) K. Ueura, T. Satoh and M.
Miura, J. Org. Chem., 2007, 72, 5362; k) T. Uto, M. Shimizu,
K. Ueura, H. Tsurugi, T. Satoh and M. Miura, J. Org. Chem.,
2008, 73, 298; l) B. Li, X. Li, B. Han, Z. Chen, X. Zhang, G. He
and G. Chen, J. Am. Chem. Soc., 2019, 141, 9401.
In order to highlight the synthetic utility of our approach,
further synthetic transformations of 3aa were conducted. The
bromo substituent of 3aa could be easily removed by the
NaBH4-TMEDA system under the catalysis of Pd(OAc)2,
affording the functionalized bipyridine 3fa in 90% yield, which
is extremely difficult to obtain from catalytic functionalization
of 2,2’-bipyridine directly (Scheme 6a).19 Moreover, further
functionalization of 3aa via Suzuki coupling was demonstrated,
and 5 was obtained in 42% yield (Scheme 6b).
6
7
B. Butschke and H. Schwarz, Chem. Sci., 2012, 3, 308.
P. Alam, G. Kaur, S. Chakraborty, A. R. Choudhury and I. R.
Laskar, Dalton Trans., 2015, 44, 6581.
Ph
Ph
Pd(OAc)2 (5 mol%)
PPh3 (20 mol%)
TMEDA (1.7 equiv)
Ph
Ph
Ph
Ph
Br
8
a) L. Maidich, G. Dettori, S. Stoccoro, M. A. Cinellu, J. P.
Rourke and A. Zucca, Organometallics 2015, 34, 817; b) L.
Maidich, M. A. Cinellu, F. Cocco, S. Stoccoro, M. Sedda, S.
Galli and A. Zucca, J. Organomet. Chem., 2016, 819, 76; c) F.
N. Hosseini, S. M. Nabavizadeh and M. M. Abu-Omar, Inorg.
Chem., 2017, 56, 14706; d) L. Maidich, G. Zuri, S. Stoccoro, M.
A. Cinellu and A. Zucca, Dalton Trans., 2014, 43, 14806.
G. L. Petretto, A. Zucca, S. Stoccoro, M. A. Cinellu and G.
Minghetti, J. Organomet. Chem., 2010, 695, 256.
N
N
N
N
(a)
NaBH4 (1.7 equiv)
THF, RT, 12 h
Ph
Ph
3aa
3fa (90%)
Ph
Ph
Ph
Ph
Ph
Br
Ph
Ph
Pd(PPh3)4 (3 mol%)
Na2CO3 (4.0 equiv)
N
9
N
N
+
(b)
toluene, H2O, EtOH (5:5:1)
80 oC, 18 h
Ph
N
B(OH)2
10 E. C. Tyo, A. W. Jr. Castleman, D. Schroeder, P. Milko, J.
Roithova, J. M. Ortega, M. A. Cinellu, F. Cocco and G.
Minghetti, J. Am. Chem. Soc., 2009, 131, 13009.
11 B. Butschke and H. Schwarz, Organometallics, 2010, 29,
6002.
12 T. Katagiri, T. Mukai, T. Satoh, K. Hirano and M. Miura, Chem.
Lett., 2009, 38, 118.
(1.1 equiv)
3aa (1.0 equiv)
5 (42%)
Scheme 6. Further transformations of 3aa.
In conclusion, we have developed a novel approach on C−H
functionalization of 2,2’-bipyridine derivatives, which showed
dramatic substituent effect of 6-substituent on 2,2’-bipyridine. 13 a) J. Kwak, Y. Ohk, Y. Jung and S. Chang, J. Am. Chem. Soc.,
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Moreover, the bromo substituent on 2,2’-bipyridine can be
easily removed under mild conditions. This method can be
considered as an alternative approach to synthesize
diversiform functionalized 2,2’-bipyridine derivatives.
We gratefully acknowledge National Natural Science Foundation
of China (21901184; 21572160) for generous financial support.
Conflicts of interest
There are no conflicts to declare.
1973311
(4-D-Br
)
contains
the
supplementary
crystallographic data for this paper. For other details, see the
Supporting Information.
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4 | J. Name., 2012, 00, 1-3
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