Pd(ii)-Catalyzed arylation of unactivated methylene C(sp3)-H bonds with aryl halides using a removable auxiliary

Article abstract of DOI:10.1039/c4cc03615h

A Pd(ii)-catalyzed arylation of methylene C(sp³)-H bonds in aliphatic amides directed by our newly developed PIP directing group with aryl iodides/bromides has been achieved. Arylation occurs efficiently with a broad range of aryl halides and amides. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03615h

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Pd(II)-Catalyzed arylation of unactivated
methylene C(sp3)–H bonds with aryl halides
Cite this:DOI: 10.1039/c4cc03615h
using a removable auxiliary†
Received 13th May 2014,
Accepted 9th June 2014
Qi Zhang,‡a Xue-Song Yin,‡a Sheng Zhao,a Sheng-Long Fanga and
Bing-Feng Shi*ab
DOI: 10.1039/c4cc03615h
www.rsc.org/chemcomm
A Pd(II)-catalyzed arylation of methylene C(sp3)–H bonds in aliphatic and cost-effective arylating reagents, such as aryl bromides, is
amides directed by our newly developed PIP directing group with highly desirable.
aryl iodides/bromides has been achieved. Arylation occurs efficiently
with a broad range of aryl halides and amides.
Despite the well-established arylation of C(sp3)–H bonds
with ArI in the Pd(II)/Pd(IV) catalytic cycle,4–7 the use of aryl
bromides as arylating reagents was mainly limited to the Pd(0)/
In recent years, transition-metal-catalyzed C–H arylation has Pd(II) catalytic cycle initiated by the oxidative addition of ArBr to
emerged as an attractive alternative to traditional cross-coupling palladium(0).10 Recently, the You group has reported the first
reactions due to the minimization of stoichiometric metallic nickel-catalyzed arylation of C(sp3)–H with aryl bromides
waste and the avoidance of multi-step sequences to prepare the assisted by 8-aminoquinoline DG.11 However, this reaction
starting materials.1 Compared to the significant progress made protocol was limited to the arylation of methyl C(sp3)–H bonds
with the arylation of C(sp2)–H bonds of arenes and heteroarenes, adjacent to quaternary centers. We have recently developed a
general strategies for the arylation of unactivated C(sp3)–H bonds, removable bidentate DG derived from 2-(pyridine-2-yl)iso-
especially methylene C(sp3)–H bonds, remain relatively rare.2 propylamine (PIP-amine), which exhibited superior reactivity
An isolated example of methylene C(sp3)–H arylation of 2-ethyl- in the activation of unactivated methylene C(sp3)–H bonds.9,12
pyridine with aryl iodides was first reported by Daugulis in Compared to Daugulis’ 8-aminoquinoline DG, the nitrogen atom on
2005.3 Shortly after, the seminal work by the same group this DG is more electron-rich and sterically bulky. We hypothesized
described a removable bidentate directing group (DG) derived that this may not only facilitate the C–H activation but also promote
from 8-aminoquinoline for effective arylation with a broad the oxidative addition of the less reactive aryl bromides to the Pd(II)
substrate scope.4 In 2006, Corey reported the b-arylation of intermediates. Herein we report an efficient Pd(II)-catalyzed arylation
phthalimide protected a-amino acids with aryl iodides assisted by of secondary C(sp3)–H bonds with aryl bromides and/or iodides
the same DG.5 Recently, Yu reported a ligand-enabled arylation of directed by our newly developed PIP DG. The reaction could tolerate
the methylene C(sp3)–H bond using a weakly coordinating per- a broad range of aryl halides and aliphatic amides, providing an
fluorinated arylamide DG (CONHArF).6a Very recently, Yu et al. efficient protocol for the synthesis of b-arylated aliphatic carboxylic
have extended this elegant strategy to the b-arylation of a-amino acids and their derivatives.13
acids with aryl iodides.6b Besides, Shi has reported the arylation
Inorganic bases and silver(I) salts have been widely used as
of methylene C(sp3)–H bonds with diarylhyperiodonium salts halide scavengers in the direct arylation of C–H bonds in a
using 8-aminoquinoline DG.8 However, the above-mentioned Pd(II)/Pd(IV) catalytic cycle.4–7 Moreover, carboxylate counter-
arylation reactions mainly depended on the use of aryl iodides4–7 or anions also play a key role in the C–H activation reactions.14
diarylhyperiodonium salts.8 Thus, extending arylation reactions of Therefore, initial experiments were performed in t-amyl alcohol
methylene C(sp3)–H bonds to other unreactive, yet readily available with K2CO3 (2.5 equiv.) as the halide scavenger and (BnO)2PO2H
(0.2 equiv.) as the ligand, which has been found to facilitate the
C(sp3)–H alkylation reactions.12b To our delight, the desired
product 3a was obtained in 39% yield (Table 1, entry 1). Further
investigation revealed that 3a was produced in 53% yield when
PivOH was used as the ligand (entry 3).4b,d Other inorganic
bases and silver salts gave reduced yields (entries 4–8). t-BuOH
was found to be the ideal solvent for the reaction providing
arylated product 3a in 75% yield (entries 9–11 and see ESI†).
a Department of Chemistry, Zhejiang University, Hangzhou 310027, China.
E-mail: bfshi@zju.edu.cn
b State Key Laboratory of Bioorganic & Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
† Electronic supplementary information (ESI) available: Experimental details and
characterization data for new compounds. See DOI: 10.1039/c4cc03615h
‡ These authors contributed equally to this work.
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Table 1 Optimization of the reaction conditionsa
The yield decreased to 41% when Pd(TFA)2 was used as the
catalyst (entry 12).
With the optimized conditions in hand, we explored the
scope of the aryl bromide coupling partners (Table 2). The
reaction conditions were compatible with a wide range of aryl
bromides with different functional groups, such as alkyl, fluoro,
methoxy, trifluoromethyl, cyano, methoxycarbonyl, nitro, acetyl-
amino and chloro. It is worth noting that aryl bromides bearing
strong electron-withdrawing groups, such as nitro, methoxy-
carbonyl and cyano, were also tolerated under the optimized
reaction conditions, affording the desired products in moderate
yields (3k–3n, 43–64% yields). Notably, aryl bromides bearing
free hydroxyl groups were also survived, albeit affording the
products in reduced yields (3q and 3rb). Moreover, disubstituted
aryl bromides bearing synthetically useful functional groups
were also good arylating reagents and gave the desired products
in reasonable yields (3r–3u).
Entry
Base
Additive (equiv.)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
AgF
KHCO3
K3PO4
CsCO3
NaHCO3
K2CO3
K2CO3
K2CO3
K2CO3
(BnO)2PO2H (0.2)
MesCOOH (0.2)
PivOH (0.2)
—
PivOH (0.2)
PivOH (0.2)
PivOH (0.2)
PivOH (0.2)
PivOH (0.2)
PivOH (0.2)
PivOH (0.2)
PivOH (0.2)
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
DCM
39
41
53
Trace
17
43
23
Trace
36
9
10
11
12d
Toluene
t-BuOH
t-Amyl-OH
25
75c
41
a
Reaction conditions: 1a (0.15 mmol), Pd(OAc)2 (10 mol%), base and
The present reaction was next applied to various aliphatic
amides (Table 3). A variety of functional groups, such as chloro,
additive in 1.5 mL solvent at 120 1C for 36 h. b 1H NMR yield using CH2Br2
c
d
as the internal standard. Isolated yield. Pd(TFA)2 (10 mmol%) was used.
Table 3 Pd(II)-Catalyzed arylation of methylene C(sp3)–H bonds with aryl
halidesa
Table 2 Pd(II)-Catalyzed arylation of methylene C(sp3)–H bonds with ArBra,b
a
b
c
Isolated yield. Conditions A. Conditions B: 1 (0.2 mmol), Pd(OAc)2
Reaction conditions: 1a (0.15 mmol), Pd(OAc)2 (10 mol%), K2CO3 (10 mol%), AgOAc (1.5 equiv.) and ArI (1.5 equiv.) in 2 mL t-BuOH at
a
d
e
(2.5 equiv.) and PivOH (0.2 equiv.) in 1.5 mL t-BuOH at 120 1C for 100 1C for 24 h. Work-up by treating with 0.5 mL Et3N for 5 h. 60 1C,
b
f
24 h. Isolated yield.
3 equiv. ArI. Conditions B, AgF (1.5 equiv.).
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M. S. Sanford, Chem. Rev., 2010, 110, 1147; (h) F. Bellina and R. Rossi,
Chem. Rev., 2010, 110, 1082; (i) L. Ackermann, R. Vicente and A. R.
Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; ( j) O. Daugulis, H.-Q. Do
and D. Shabashov, Acc. Chem. Res., 2009, 42, 1074; (k) X. Chen,
K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009,
48, 5094; (l) B.-J. Li, S.-D. Yang and Z.-J. Shi, Synlett, 2008, 949;
(m) F. Kakiuchi and T. Kochi, Synthesis, 2008, 3013; (n) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (o) I. V. Seregin
and V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173.
indolyl and Phth-protected amine, were tolerated under the
reaction conditions. Arylation of cyclobutanecarboxamide gave
the diarylated product 3ac in 38% yield. To our delight, some
specific carboxamides and aryl bromides, which were ineffec-
tive for arylation under Conditions A, were compatible with the
reaction conditions established by Daugulis (Conditions B)4
using ArI as the arylating reagents (3ad–3ao). Thus, aryl iodides
with strong electron-withdrawing groups, and heteroaryl iodides,
proceed smoothly under Conditions B to give the desired
products in good yields (3ai–3ao, 51–90%). Interestingly, bromo
was tolerated under Conditions B (3ah, 86%). It is also worth
noting that heteroaryl iodides such as 2-iodothiophene and
4-iodopyridine were also tolerated under the arylation condi-
tions, affording the desired products in good yields (3an, 89%
and 3ao, 51%, respectively).
2 For selected reviews on C(sp3)–H activation, see: (a) O. Baudoin,
Chem. Soc. Rev., 2011, 40, 4902; (b) J. F. Hartwig, Chem. Soc. Rev.,
2011, 40, 1992; (c) H. Li, B.-J. Li and Z.-J. Shi, Catal. Sci. Technol.,
2011, 1, 191; (d) M. Wasa, K. M. Engle and J.-Q. Yu, Isr. J. Chem.,
2010, 50, 605; (e) K. Godula and D. Sames, Science, 2006, 312, 67.
3 D. Shabashov and O. Daugulis, Org. Lett., 2005, 7, 3657.
4 (a) V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am. Chem. Soc.,
2005, 127, 13154; (b) D. Shabashov and O. Daugulis, J. Am. Chem.
Soc., 2010, 132, 3965; (c) L. D. Tran and O. Daugulis, Angew. Chem.,
Int. Ed., 2012, 51, 5188; (d) E. T. Nadres, G. I. F. Santos, D. Shabashov
and O. Daugulis, J. Org. Chem., 2013, 78, 9689.
5 B. V. S. Reddy, L. R. Reddy and E. J. Corey, Org. Lett., 2006, 8, 3391.
6 (a) M. Wasa, K. S. L. Chan, X.-G. Zhang, J. He, M. Miura and J.-Q. Yu,
J. Am. Chem. Soc., 2012, 134, 18570; (b) J. He, S. Li, Y. Deng, H. Fu,
B. N. Laforteza, J. E. Spangler, A. Homs and J.-Q. Yu, Science, 2014,
343, 1216.
7 (a) W. R. Gutekunst and P. S. Baran, J. Org. Chem., 2014, 79, 2430;
(b) C. P. Ting and T. J. Maimone, Angew. Chem., Int. Ed., 2014,
53, 3115; (c) W. R. Gutekunst and P. S. Baran, J. Am. Chem. Soc.,
2011, 133, 19076; (d) Y. Feng, Y. Wang, B. Landgraf, S. Liu and
G. Chen, Org. Lett., 2010, 12, 3414; (e) Y. Feng and G. Chen, Angew.
Chem., Int. Ed., 2010, 49, 958.
Finally, the PIP directing group was removed under acidic
conditions (eqn (1)). The corresponding carboxylic acid 6 was
obtained in 66% yield. Most importantly, the 2-(pyridine-2-yl)-
isopropylamine (PIP-amine) is readily prepared from the reac-
tion of 2-cyanopyridine with MeMgBr on a large scale following
an improved procedure (eqn (2), see ESI†).15
8 F. Pan, P.-X. Shen, L.-S. Zhang, X. Wang and Z.-J. Shi, Org. Lett.,
2013, 15, 4758.
(1)
9 For selected examples of transition-metal-catalyzed C–H activation
directed by bidentate auxiliary, see: (a) X. Wu, Y. Zhao and H. Ge,
J. Am. Chem. Soc., 2014, 136, 1789; (b) Y. Aihara and N. Chatani,
J. Am. Chem. Soc., 2014, 136, 898; (c) L.-S. Zhang, G.-H. Chen,
X. Wang, Q.-Y. Guo, X.-S. Zhang, F. Pan, K. Chen and Z.-J. Shi,
Angew. Chem., Int. Ed., 2014, 53, 3899; (d) Z. Wang, J.-Z. Ni,
Y. Kuninobu and M. Kanai, Angew. Chem., Int. Ed., 2014, 53, 3496;
(e) W.-W. Sun, P. Cao, R.-Q. Mei, Y. Li, Y.-L. Ma and B. Wu, Org. Lett.,
2014, 16, 480; ( f ) R. Shang, L. Ilies, A. Matsumoto and E. Nakamura,
J. Am. Chem. Soc., 2013, 135, 6030; (g) Y. Ma, W. Li and B. Yu, Acta
Chim. Sin., 2013, 71, 541; (h) M. Fan and D. Ma, Angew. Chem., Int.
Ed., 2013, 52, 12152; (i) K. Chen, F. Hu, S.-Q. Zhang and B.-F. Shi,
Chem. Sci., 2013, 4, 3906; ( j) D. S. Roman and A. B. Charette, Org.
(2)
In conclusion, we have developed a Pd(II)-catalyzed direct
arylation of methylene C(sp3)–H bonds with aryl bromides and/or
aryl iodides. Good structural versatility in both aryl halides and
aliphatic amides and high functional group tolerance were
achieved, providing an efficient protocol for the synthesis of
b-arylated carboxylic acid derivatives. Unlike the arylation reac-
tions proceeded in a palladium–phosphine ligand catalytic
system, this reaction protocol was believed to go through a
Pd(II)/Pd(IV) catalytic cycle. Further studies to elucidate the
mechanistic details are currently underway.
´
´
Lett., 2013, 15, 4394; (k) N. Rodrıguez, J. A. Romero-Revilla, M. A.
´
´˜
Fernandez-Ibanez and J. C. Carretero, Chem. Sci., 2013, 4, 175;
(l) N. Hasegawa, V. Charra, S. Inoue, Y. Fukumoto and N. Chatani,
J. Am. Chem. Soc., 2011, 133, 8070; (m) G. He and G. Chen, Angew.
Chem., Int. Ed., 2011, 50, 5192; (n) W. A. Nack, G. He, S.-Y. Zhang,
C. Lu and G. Chen, Org. Lett., 2013, 15, 3440.
10 For selected examples of Pd(0)-catalyzed C(sp3)–H arylation with
ArBr, see: (a) G. Dyker, Angew. Chem., Int. Ed. Engl., 1992, 31, 1023;
´
(b) O. Baudoin, A. Herrbach and F. Gueritte, Angew. Chem., Int. Ed.,
Financial support from the National Science Foundation of
China (21272206), the Fundamental Research Funds for the
Central Universities (2014QNA3008), Zhejiang Provincial NSFC
(Z12B02000), Qianjiang Project (2013R10033) and Specialized
Research Fund for the Doctoral Program of Higher Education
(20110101110005) is gratefully acknowledged.
2003, 42, 5736; (c) L.-C. Campeau, D. J. Schipper and K. Fagnou,
´
J. Am. Chem. Soc., 2008, 130, 3266; (d) J. J. Mousseau, A. Larivee and
A. B. Charette, Org. Lett., 2008, 10, 1641; (e) S. Aspin, A.-S. Goutierre,
P. Larini, R. Jazzar and O. Baudoin, Angew. Chem., Int. Ed., 2012,
51, 10808, and references therein.
11 M. Li, J. Dong, X. Huang, K. Li, Q. Wu, F. Song and J. You, Chem.
Commun., 2014, 50, 3944.
12 (a) F.-J. Chen, S. Zhao, F. Hu, K. Chen, Q. Zhang, S.-Q. Zhang and B.-F.
Shi, Chem. Sci., 2013, 4, 4187; (b) Q. Zhang, K. Chen, W. Rao, Y. Zhang,
F.-J. Chen and B.-F. Shi, Angew. Chem., Int. Ed., 2013, 52, 13588.
13 During the preparation of this manuscript, Zeng and co-workers
reported a Pd-catalyzed arylation of C(sp3)–H bonds using the
8-aminoquinoline directing group, see: Y. Wei, H. Tang, X. Cong,
B. Rao, C. Wu and X. Zeng, Org. Lett., 2014, 16, 2248.
Notes and references
1 For selected reviews on transition-metal-catalyzed C–H arylation,
see: (a) G. Rouquet and N. Chatani, Angew. Chem., Int. Ed., 2013,
52, 11726; (b) F. Shibahara and T. Murai, Asian J. Org. Chem., 2013,
2, 624; (c) P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev., 14 For selected reviews, see: (a) K. M. Engle and J.-Q. Yu, J. Org. Chem.,
2012, 112, 5879; (d) J. Yamaguchi, A. D. Yamaguchi and K. Itami,
Angew. Chem., Int. Ed., 2012, 51, 8960; (e) S.-Y. Zhang, F.-M. Zhang
2013, 78, 8927; (b) L. Ackermann, Chem. Rev., 2011, 111, 1315, and
references therein.
and Y.-Q. Tu, Chem. Soc. Rev., 2011, 40, 1937; ( f ) C. Liu, H. Zhang, 15 K. M. Yager, E. A. Plaza, D. V. Kumar and I. C. Kim, US Pat.,
W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780; (g) T. W. Lyons and
20080207573 A1, 2008.
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