Benzylic arylation of 2-methyl-5-membered heterocycles using TMP-bases

Article abstract of DOI:10.1021/ol300517q

A new general Pd-catalyzed arylation of various 2-methyl-5-membered heterocycles is reported. This novel method requires Li-, Mg-, or Zn-TMP bases and allows selective metalation of the benzylic position. Subsequent Negishi cross-coupling provides the cor

Full text of DOI:10.1021/ol300517q

ORGANIC
LETTERS
2012
Vol. 14, No. 8
1951–1953
Benzylic Arylation of 2-Methyl-5-
membered Heterocycles Using
TMP-Bases
ꢀ
Stephanie Duez, Andreas K. Steib, and Paul Knochel*
€
Department Chemie, Ludwig-Maximilians-Universitat Munchen,
€
Butenandtstrasse 5-13, 81377 Mu€nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received February 29, 2012
ABSTRACT
A new general Pd-catalyzed arylation of various 2-methyl-5-membered heterocycles is reported. This novel method requires LiÀ, MgÀ, or
ZnÀTMP bases and allows selective metalation of the benzylic position. Subsequent Negishi cross-coupling provides the corresponding arylated
heterocycles.
The benzylic arylation of pyridines and related N-hetero-
cycles is of great synthetic interest due to the importance of
these heterocycles for pharmaceutical applications.1 Such
arylation reactions on the methylpyridine scaffold often
require the preparation of suitable precursors, such as 2-(2-
pyridyl)ethanol,2 N-oxides,3 or N-iminopyridinium ylides.4
Recently, we have shown that a direct benzylic arylation on
picolines, lutidines, and methy-substituted quinolines pro-
ceeds readily in the presence of TMPZnCl LiCl (1) (TMP=
3
2,2,6,6-tetramethylpiperidyl) and an appropriate Lewis acid
such as Sc(OTf)3.5 However, the arylation of methyl-
substituted 5-membered heterocycles remains by far an
unsolved problem.6 The arylation of 1,2-dimethylimidazole
(2) occurs usually at position 5, and no “benzylic” CÀH
activation followed by cross-couplings has been reported.7,8
Only alkylation reactions on the methyl group have been
(1) (a) Nicolaou, K. C.; Scarpelli, R.; Bollbuck, B.; Werschkun, B.;
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Miller, K.; Caggiano, N.; ONeill, A. J.; Cuny, G. D.; Hoemann, M. Z.;
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Kapdi, A. R. Org. Lett. 2011, 13, 3082. (c) Fleming, P.; O’Shea, D. F.
J. Am. Chem. Soc. 2011, 133, 1698. (d) Lei, A.; Liu, W.; Liu, C.; Chen, M.
Dalton Trans. 2010, 39, 10352. (e) Ackermann, L. Modern Arylation
Methods; Wiley-VCH: Weinheim, 2009. (f) Ackermann, L.; Vincente, R.;
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Org. Lett. 2007, 9, 1449. (d) Bellina, F.; Cauteruccio, S.; Mannina, L.;
Rossi, R.; Viel, S. J. Org. Chem. 2005, 70, 3997. (e) Bellina, F.;
Cauteruccio, S.; Di Fiore, A.; Rossi, R. Eur. J. Org. Chem. 2008, 5436.
(f) Bellina, F.; Cauteruccio, S.; Di Fiore, A.; Marchetti, C.; Rossi, R.
Tetrahedron 2008, 64, 6060. (g) Toure, B. B.; Lane, B. S.; Sames, D. Org.
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r
10.1021/ol300517q
2012 American Chemical Society
Published on Web 04/10/2012

used successfully to perform cross-coupling reactions with
various aryl bromides of type 5 affording 2-benzylated
imidazoles (6) in 71À91% yield (Table 1). For example,
the magnesiation of 1,2-dimethylimidazole (2) with
Table 1. Pd-Catalyzed Benzylic Arylation of 1,2-Dimethylimi-
dazole (2) Leading to Products of Type 6
TMPMgCl LiCl (3: 1.5 equiv) in THF is complete within
3
3 h at 25 °C.13 After transmetalation with ZnCl2 (1.5 equiv,
25 °C, 15 min), the zincated imidazole derivative (4) is
treated with ethyl 4-bromobenzoate (5a: 0.8 equiv) in the
presence of 2% Pd(dba)2 (dba = dibenzylideneacetone)
and 4% SPhos14 to provide the desired arylated 1,2-
dimethylimidazole (6a) at 50 °C within 2 h in 85% yield
without the formation of a 5-arylatedimidazolederivative7
(Table 1, entry 1). Similarly, cyano- and trifluoromethyl-
substituted aryl bromides (5b,c) can be successfully con-
verted leading to the imidazole derivatives (6b,c, 71À77%,
entries 2 and 3). Also, electron-rich aryl bromides bearing
alkoxy, pivaloxy, methyl, or amino substituents undergo
the cross-coupling in excellent yields (71À91% yields,
entries 4À8) showing the broad scope of this arylation.
Efforts were made to extend this method to even less
acidic methyl-substituted 5-membered heterocycles. We
found that 2-methylbenzothiophene (7) was readily meta-
lated with TMPLi15 (8: 1.15 equiv, À78 °C, 15 min) in
THF.16 After transmetalation with ZnCl2, the resulting
heterocyclic benzylic reagent (9) was smoothly arylated
with various aryl bromides using 2% Pd(OAc)2 and 4%
SPhos14 (50 °C, 2 h) leading to the benzothiophenes
(10aÀh) in 68À98% yield (Table 2, entries 1À8). Interest-
ingly, the 2,3-dimethylbenzothiophene (7b) undergoes an
exclusive lithiation at position 2 providing after cross-
coupling the 2-benzylated product (10i) in 87% yield
(entry 9). A further extension to the 2-methylbenzofuran
scaffold was successful using similar conditions. The lithia-
tion of 2-methylbenzofuran (11) was complete within 1 h
at À78 °C. After transmetalation with ZnCl2 and cross-
coupling with various aryl bromides, methyl-substituted
benzofurans (13aÀd) were obtained in 52À75% yield
(Table 3). In the case of cyano-substituted aryl bromides
(5b and 5j), we have found that the addition of 10%
Sc(OTf)317 improves the cross-coupling yield.5,18
a Isolated yield of analytically pure product.
performed successfully after deprotonation with n-BuLi.9 In
addition, the benzylic metalation and subsequent arylation
of 2-methylbenzothiophenes10 and 2-methylbenzofurans10b
has not yet been described. Recently, we have developed a
range of TMP bases which allow the metalation of various
unsaturated molecules under mild conditions.11 Herein, we
wish to report that such a direct benzylic arylation can be
performed on a variety of different methyl-substituted
5-membered heterocycles, including 2-methylimidazoles, -
benzothiophenes, and -benzofurans and related 5-membered
heterocycles.
The generality of our approach is demonstrated by per-
forming the arylation of other related 5-membered hetero-
cycles such as the 2-methylindole derivative 1419 and the
Thus, by using the magnesium base TMPMgCl LiCl12
(3) and subsequent transmetalation with ZnCl2, we were
able to zincate 1,2-dimethylimidazole (2) selectively at the
2-methyl position. The resulting zincated reagent 4 was
3
2-methylbenzimidazole 15.20 In these cases, TMPZnCl LiCl
3
(1) proved to be a suitable base, and a complete zincation
could be obtained within 1 h at 25 °C. Thus, cross-coupling of
2-methylindole (14) with 4-bromoanisole 5d gave the indole
(8) Song, G.; Su, Y.; Gong, X.; Han, K.; Li, X. Org. Lett. 2011, 13,
1968.
(9) (a) Field, L. D.; Messerle, B. A.; Vuong, K. Q.; Turner, P. Dalton
Trans. 2009, 18, 3599. (b) Oxenford, S. J.; Wright, J. M.; O’Brien, P.;
Panday, N.; Shipton, M. R. Tetrahedron Lett. 2005, 46, 8315. (c) Sagae,
T.; Ogawa, S.; Furukawa, N. Bull. Chem. Soc. Jpn. 1991, 64, 3179.
(10) For benzylic functionalization of 2-methylbenzofuran, see: (a)
Setoh, M.; Kouno, M.; Miyanohana, Y.; Kori M. (Takeda Pharmaceu-
tical Co. Ltd.) US 2010/41891, 2010. (b) Ellingboe, J. W.; Alessi, T. R.;
Dolak, T. M.; Nguyen, T. T.; Tomer, J. D.; Guzzo, F.; Bagli, J. F.; McCaleb,
M. L. J. Med. Chem. 1992, 35, 1176. (c) Alvarez, M.; Bosch, J.; Feliz, M.
J. Heterocycl Chem. 1978, 15, 1089.
(13) The direct zincation with TMPZnCl LiCl (1) is too sluggish at
3
25 °C.
(14) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem. 2004, 116, 1907. Angew. Chem., Int. Ed. 2004, 43,
1871. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685. (c) Altman, R. A.; Buchwald, S. L.
Nat. Protocols 2007, 2, 3115. (d) Martin, R.; Buchwald, S. L. Acc. Chem.
Res. 2008, 41, 1461.
(11) Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P.
Angew. Chem. 2011, 123, 9968. Angew. Chem., Int. Ed. 2011, 50, 9794.
(12) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.
2006, 118, 3024. Angew. Chem., Int. Ed. 2006, 45, 2958. (b) Mulvey,
R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem. 2007, 119,
3876. Angew. Chem., Int. Ed. 2007, 46, 3802.
(15) (a) Mulvey, R. E. Acc. Chem. Res. 2009, 42, 743. (b) Whisler,
M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem. 2004, 116,
2256. Angew. Chem., Int. Ed. 2004, 43, 2206.
(16) Metalation with TMPMgCl LiCl (3) can only proceed at ele-
3
vated temperatures and the yield of the subsequent cross-coupling
proved to be less high, compared to initial metalation with TMPLi (8).
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Org. Lett., Vol. 14, No. 8, 2012

Table 2. Benzylic Cross-Coupling of 2-Methylbenzo-
[b]thiophene (7)
Table 3. Benzylic Arylation of 2-Methylbenzofuran (11)
a Isolated yield of analytically pure product. b 10% Sc(OTf)3 was
added. c 2% Pd(dba)2 and 4% SPhos was used. d 2% Pd(dba)2 and 2%
Xantphos was used.
Scheme 1. Benzylic Cross-Coupling of Indole (14) and Benzo-
[d]imidazole (15)
a Isolated yield of analytically pure product.
16 in 57% yield (Scheme 1). To the best of our knowledge,
this example represents the first benzylic cross-coupling on a
2-methylindole.
heterocycles with aryl bromides using standard Pd cata-
lysts. Extension of this method to other 5-membered
heterocycles is currently underway.
In addition, 2-methylbenzimidazole (15) can be arylated
successfully after zincation with TMPZnCl LiCl (1) with
3
Acknowledgment. The research leading to these results
has received funding from the European Research Council
under the European Community’s Seventh Framework
Programme (FP7/2007-2013), ERC grant agreement no.
227763. We thank BASF AG, W. C. Heraeus GmbH,
Chemetall GmbH, and Solvias AGforthe generousgiftsof
chemicals.
4-bromoanisole (5d) to yield the benzoimidazole derivative
17 in 68% yield (Scheme 1).
In conclusion, we have found a new convenient method
for the direct arylation of various 2-methyl 5-membered
(17) (a) Ogawa, C.; Gu, Y.; Boudou, M.; Kobayashi, S. Acid
Catalysis in Modern Organic Synthesis; Wiley-VCH: Weinheim, 2008;
Vol. 2, p 589. (b) Kobayashi, S. Lewis Acids in Organic Synthesis; Wiley:
Weinheim, 2000; Vol. 2, p 883. (c) Kobayashi, S.; Hachiya, I.; Araki, M.;
Ishitani, H. Tetrahedron Lett. 1993, 34, 3755.
(18) (a) For a review, see:Stephan, D. W.; Erker, G. Angew. Chem.
2010, 122, 50. Angew. Chem., Int. Ed. 2010, 49, 46. (b) Jaric, M.; Haag,
B. A.; Unsinn, A.; Karaghiosoff, K.; Knochel, P. Angew. Chem. 2010,
122, 5582. Angew. Chem., Int. Ed. 2010, 49, 5451.
Supporting Information Available. Experimental pro-
cedures and characterization data of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) For preparation of 14, see:Macor, J. E.; Ryan, K.; Newman,
M. E. J. Org. Chem. 1989, 54, 4785.
(20) For the preparation of the benzimidazole 15, see the Supporting
Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
1953