Potassium t-butoxide alone can promote the biaryl coupling of electron-deficient nitrogen heterocycles and haloarenes

Article abstract of DOI:10.1021/ol8019764

(Chemical Equation Presented) The biaryl coupling of electron-deficient nitrogen heterocycles and haloarenes can be promoted by potassium t-butoxide alone, without the addition of any exogenous transition metal species. Electron-deficient nitrogen heterocycles such as pyridine, pyridazine, pyrimidine, pyrazine, and quinoxaline are arylated with haloarenes. Control experiments support a radical-based mechanism. Taking these findings into account, radical processes may be partially involved in the reported transition-metal-catalyzed arylation reactions employing t-butoxide bases and haloarenes under elevated temperatures or under microwave irradiation.

Full text of DOI:10.1021/ol8019764

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4673-4676
Potassium t-Butoxide Alone Can
Promote the Biaryl Coupling of
Electron-Deficient Nitrogen Heterocycles
and Haloarenes
Shuichi Yanagisawa,† Kirika Ueda,† Tadashi Taniguchi,‡ and Kenichiro Itami*,†,§
Department of Chemistry, Graduate School of Science, Nagoya UniVersity,
Nagoya 464-8602, Japan, and PRESTO, Japan Science and Technology Agency (JST)
itami@chem.nagoya-u.ac.jp
Received August 24, 2008
ABSTRACT
The biaryl coupling of electron-deficient nitrogen heterocycles and haloarenes can be promoted by potassium t-butoxide alone, without the
addition of any exogenous transition metal species. Electron-deficient nitrogen heterocycles such as pyridine, pyridazine, pyrimidine, pyrazine,
and quinoxaline are arylated with haloarenes. Control experiments support a radical-based mechanism. Taking these findings into account,
radical processes may be partially involved in the reported transition-metal-catalyzed arylation reactions employing t-butoxide bases and
haloarenes under elevated temperatures or under microwave irradiation.
The transition-metal-catalyzed arylation reactions of nucleo-
philic organic compounds with haloarenes are commonplace
in modern organic synthesis.1 Representative examples
include the palladium-catalyzed arylation of organometallic
reagents, amines, alcohols, and carbonyl compounds with
haloarenes.2 More recently, the C-H bond arylation of
arenes with haloarenes has become a rapidly growing area
of extensive research.3 These arylation reactions occasionally
employ strong bases such as t-butoxides and often proceed
at high temperatures. Herein, we describe a surprising result
from our laboratories, which demonstrates that the biaryl
coupling of electron-deficient nitrogen heterocycles and
haloarenes can be promoted by potassium t-butoxide alone,
without the addition of any exogenous transition metal
species (Scheme 1). Although the reaction is still in its
† Nagoya University.
‡ Shimadzu Corporation, Analytical Applications Department.
§ PRESTO, Japan Science and Technology Agency (JST).
(1) (a) Transition Metals for Organic Synthesis; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 2004. (b) Tsuji, J. Transition Metal Reagents
and Catalysts; John Wiley & Sons: Chichester, 2000.
(2) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd edition; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Cross-
Coupling Reactions. Top. Curr. Chem.; Miyaura, N., Ed.; Springer: Berlin,
2002; Vol. 219.
Scheme 1.
KOtBu-Promoted Biaryl Coupling of
Electron-Deficient Nitrogen Heterocycles and Haloarenes
(3) For recent reviews on biaryl synthesis through C-H bond arylation
of aromatic compounds, see: (a) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. ReV. 2007, 107, 174. (b) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrichimica Acta 2007, 40, 35. (c) Seregin, I. V.; Gevorgyan, V. Chem.
Soc. ReV. 2007, 36, 1173. (d) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200.
infancy from a practical point of view, the discovered new
reactivity of t-butoxides should raise concerns to the synthetic
community. Considering the occasional employment of
10.1021/ol8019764 CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

t-butoxide bases and haloarenes in arylation reactions,1-3
gauging the ability of these reagents to promote reactions in
the absence of presumed metal catalysts is obviously critical.
Table 2. Phenylation of Pyrazine with Halobenzenea
Biaryls are ubiquitous in natural products and pharma-
ceuticals and are frequently used in organic materials or as
ligands for metals.4 Consequently, the development of new
methods for making these privileged structures has been a
topic of great importance in chemical synthesis. As a part
of our program aimed at establishing a new catalytic biaryl
coupling through C-H bond functionalization,3 we recently
reported that RhCl(CO){P[OCH(CF3)2]3}2 can catalyze the
C-H bond arylation of arenes with iodoarenes.5 Since this
rhodium catalysis is best with electron-rich arenes, the
development of a protocol applicable for electron-deficient
arenes such as pyridine has been our next goal.6
With the hypothesis that a “radical-type” transition metal
mediated reaction might be optimal to achieve such a
process,7 we examined Fujita’s iridium-based protocol, which
has been assumed to be a radical process,8 for the coupling
of pyridine and iodobenzene. In fact, the C-H bond
phenylation of pyridine with iodobenzene can be affected
in the presence of [Cp*IrHCl]2 and KOtBu (C5H5N/C6H5I/
Ir/KOtBu ) 40:1:0.05:3.3 molar ratio) at 80 °C for 30 min
under microwave irradiation to give phenylpyridine in 30%
yield as a mixture of regioisomers (Table 1, entry 1). As
entry
X
promoter
conditions
50 °C, 5 min
yield (%)
1
I
I
I
I
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
LiOtBu
KOMe
KOH
98
79
54
35
26
2b
3c
120 °C, 13 h
80 °C, 0.5 h (in DMAc)
80 °C, 0.5 h (in DMAc)
23 °C, 72 h (in DMAc)
80 °C, 0.5 h
80 °C, 0.5 h
80 °C, 0.5 h
50 °C, 5 min
50 °C, 5 min
50 °C, 5 min
50 °C, 5 min
c d
,
4
5b c
6
I
,
Br
Cl
F
I
I
I
54
7
8
9
10
11
12
<1
<1
<1
<1
<1
<1
I
a Conditions: pyrazine (20 mmol), halobenzene (0.50 mmol), promoter
(0.75 mmol), under microwave irradiation. b Reaction was conducted without
microwave irradiation. c 0.5 mL of N,N-dimethylacetamide (DMAc) was
used as solvent. d 5.0 mmol of pyrazine was employed.
min under microwave irradiation, C-H bond phenylation
takes place to afford 2-phenylpyrazine in 98% yield (Table
2, entry 1).9 The reaction also takes place under conventional
heating but requires higher temperatures and longer reaction
times to achieve full conversion (79% at 120 °C, 13 h, entry
2). N,N-Dimethylacetamide (DMAc) can also be used as a
solvent for this reaction (54% at 80 °C, 0.5 h, entry 3).
Interestingly, the use of DMAc as a solvent allows the
reaction to proceed at lower substrate loading (entry 4) or at
room temperature (entry 5), albeit less efficiently. The
reaction also takes place with bromobenzene at 80 °C (54%),
but chlorobenzene and fluorobenzene are virtually unreactive
Table 1. Discovery of KOtBu-Promoted Biaryl Couplinga
entry
Ir complex
yield (%)b
1
2
3
4
5
6
7
8
[Cp*IrHCl]2
[Cp*IrCl2]2
[IrCl(cod)]2
Ir(acac)(cod)
IrH(CO)(PPh3)3
IrCl(CO)(PPh3)2
(NH4)3IrCl6
none
30
32
17
18
29
41
26
39
(4) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359.
(5) (a) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am. Chem.
Soc. 2006, 128, 11748. (b) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K.
Tetrahedron 2008, 64, 6073.
(6) In the metal-catalyzed direct C-H bond arylation chemistry, electron-
deficient nitrogen heterocycles are still challenging substrates. (a) Mukho-
padhyay, S.; Rothenberg, G.; Gitis, D.; Baidossi, M.; Ponde, D. E.; Sasson,
Y. J. Chem. Soc., Perkin Trans. 2 2000, 1809. (b) Campeau, L.-C.;
Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020. (c) Leclerc,
J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781.
a Conditions: pyridine (16 mmol), iodobenzene (0.40 mmol), Ir complex
(0.02 mmol), KOtBu (1.32 mmol), 80 °C, 30 min, under microwave
irradiation. b As a mixture of regioisomers.
(7) (a) Mo¨hlau, R.; Berger, R. Chem. Ber. 1893, 26, 1994. (b) Gomberg,
M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339. (c) Hey, D. H.;
Walker, E. W. J. Chem. Soc. 1948, 2213. (d) Fields, E. K.; Meyerson, S.
J. Org. Chem. 1969, 34, 62. (e) Minisci, F.; Porta, O. AdV. Heterocycl.
Chem. 1974, 16, 123. (f) Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.;
Serravalle, M.; Giordano, C. J. Org. Chem. 1986, 51, 4411. (g) Studer, A.;
Bossart, M.; Vasella, T. Org. Lett. 2000, 2, 985. (h) Orito, K.; Uchiito, S.;
Satoh, Y.; Tatsuzawa, T.; Harada, R.; Tokuda, M. Org. Lett. 2000, 2, 307.
(i) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Org. Biomol. Chem. 2003,
1, 4047. (j) Nu´n˜ez, A.; Sa´nchez, A.; Burgos, C.; Alvarez-Builla, J.
Tetrahedron 2004, 60, 6217. (k) Curran, D. P.; Keller, A. I. J. Am. Chem.
Soc. 2006, 128, 13706.
shown in Table 1, a variety of iridium sources were ap-
parently able to catalyze this reaction in moderate yield.
Struck by the similarity of reactions employing dramatically
distinct iridium sources (entries 1-7), we carried out the
coupling reaction in the absence of iridium and remarkably
found that the coupling reaction proceeded to the same extent
with KOtBu as the sole reagent (Table 1, entry 8).
With these unexpected results in hand, we further exam-
ined the reaction conditions (Table 2). For simplicity,
pyrazine was chosen as a substrate for this study. When a
mixture of pyrazine (20 mmol), iodobenzene (0.50 mmol),
and KOtBu (0.75 mmol) is stirred in the dark at 50 °C for 5
(8) Fujita, K.; Nonogawa, M.; Yamaguchi, R. Chem. Commun. 2004,
1926.
(9) Although we hold the temperature at 50 °C, this is the bulk
temperature of the reaction mixture. As well documented, we assume that
the reaction is taking place at high-temperature “hotspots” that are generated
by microwave irradiation. For reviews on the use of microwave in organic
´
synthesis, see: (a) de la Hoz, A.; D´ıaz-Oritiz, A.; Moreno, A. Chem. Soc.
ReV. 2005, 34, 164. (b) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43,
6250.
4674
Org. Lett., Vol. 10, No. 20, 2008

under these conditions (entries 6-8). Other potential promot-
ers related to KOtBu were also examined (entries 9-12).
The use of NaOtBu or LiOtBu instead of KOtBu does not
give the product under these conditions (50 °C, 5 min).
However, it should be noted that, at temperatures above 80
°C, NaOtBu also promotes the biaryl coupling. In addition
to the nature of the metal cation (K), the t-butoxide moiety
is also crucial, as KOMe and KOH exhibited nearly no
reactivity.
Other than iodoarenes, iodoalkenes such as ꢀ-iodostyrene
also react with pyrazine (entry 5). A range of electron-
deficient nitrogen heterocycles other than pyrazine undergo
arylation with iodoarenes. For example, pyridine, pyridazine,
pyrimidine, and quinoxaline react with iodobenzene to afford
the coupling products in good yields, albeit with poor
regioselectivity with respect to the heteroarene (entries 6-9).
Considering that trace transition metals present in sodium
carbonate have been shown to catalyze coupling reactions such
as the Suzuki-Miyaura reaction when performed under forcing
conditions,11 all reagents were purified extensively before use,
including sublimation for KOtBu.12 All reaction glassware and
equipment were thoroughly cleaned prior to use. Finally, the
quantitative elemental analysis of KOtBu was conducted by
ICP-AES (inductively coupled plasma-atomic emission spec-
trometry).13 Though very low in concentration, the most
abundant exogenous elements found to be present in the
KOtBu used in this study are Si (0.92 ppm), Al (0.38 ppm),
and Ca (0.048 ppm). These elements are unlikely to be
promoters for the present coupling since there is no correla-
tion between the yield of coupling product and the concen-
tration of these elements in the promoters listed in Table
2.13 More importantly, the concentration of all transition
metals in the KOtBu employed in our study is less than 0.50
ppm. In particular, Pd, Rh, and Ru, which one might suspect
as potential catalysts for such biaryl couplings,3 were not
found in concentrations above the detection limits (Pd: <0.06
ppm, Rh: <0.20 ppm, Ru: <0.30 ppm). Although the
possibility of transition metal mediation in this reaction
cannot be completely excluded, such a catalyst, if any, must
be effective at low parts per billion concentrations.11
Although the precise mechanism of this reaction remains
to be determined, our current hypotheses favor either
homolytic aromatic substitution14 or SRN1 reaction,15 both
of which involve the generation of an aryl radical from
iodoarene as a key step. While other possibilities such as
SNAr and aryl cation16 mechanisms cannot be rigorously
excluded at this stage, the radical nature of the present
reaction is supported by control experiments performed in
the presence of radical scavengers. For example, the addition
of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), galvi-
noxyl, or acrylonitrile to the reaction of pyrazine, iodoben-
zene, and KOtBu completely shuts down the otherwise
efficient biaryl coupling (Scheme 2).
Next the scope of the reaction with respect to the iodoarene
and nitrogen heterocycle was examined. Representative
results are summarized in Table 3. Various iodoarenes react
Table 3. Substrate Scope of KOtBu-Promoted Biaryl Couplinga
a Molar ratio: 1/2/KOtBu ) 40:1.0:1.5. b Isolated yield. c Molar ratio:
1/2/KOtBu ) 40:1.0:2.0. Conditions: 80 °C, 30 min. d Isomer ratio: 2-/3-/
4- ) 36:21:43. e Isomer ratio: 3-/4- ) 24:76. f Isomer ratio: 2-/4-/5- )
23:52:25. g Isomer ratio: 2-/5- ) 64:36.
Scheme 2
.
KOtBu-Promoted Coupling with Radical Scavengers
with pyrazine to give the corresponding nitrogen-containing
biaryls in good yields (entries 1-4). These reactions take
place exclusively at the C-I bond of iodoarenes, and
regioisomers with respect to the iodoarene are not detected.10
(10) These results imply that our reaction does not proceed through aryne
intermediates, although such a mechanism cannot be rigorously excluded
at this stage. (a) Bates, R. B.; Janda, K. D. J. Org. Chem. 1982, 47, 4374.
(b) Beller, M.; Breindl, C.; Riermeier, T. H.; Eichberger, M.; Trauthwein,
H. Angew. Chem., Int. Ed. 1998, 37, 3389.
Org. Lett., Vol. 10, No. 20, 2008
4675

In summary, the arylation of electron-deficient nitrogen
heterocycles with iodoarenes promoted by potassium t-
butoxide has been described. Although further mechanistic
studies and a systematic optimization of the reaction condi-
tions are warranted for this reaction to reach its full synthetic
potential, the discovered new reactivity of t-butoxides should
raise concerns to the synthetic community. Given the
occasional use of t-butoxide bases and haloarenes in transi-
tion-metal-catalyzed arylation reactions (e.g., C-H bond
functionalization and amination),17,18 the ability of these
bases to promote coupling reactions is of significant impor-
tance. Taking our findings into account, radical processes
may be partially involved in the reported transition-metal-
catalyzed arylation reactions employing these t-butoxide
bases and haloarenes under elevated temperatures or under
microwave irradiation. Thus, great care is urged in the
analysis and interpretation of such reactions.
and Technology Agency (JST), and a Grant-in-Aid for
Scientific Research from MEXT and JSPS. S.Y. is a recipient
of the JSPS Predoctoral Fellowships for Young Scientists.
We thank Prof. Cathleen M. Crudden (Queen’s University,
Canada) and Dr. Jean Bouffard (Nagoya University) for
critical comments and discussion.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8019764
(16) (a) Dichiarante, V.; Fagnoni, M. Synlett 2008, 787. (b) Dichiarante,
V.; Fagnoni, M.; Albini, A. Angew. Chem., Int. Ed. 2007, 46, 6495.
(17) For the selected examples using t-butoxides and haloarenes in C-H
bond arylation reactions, see: (a) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2007, 129, 12404. (b) Proch, S.; Kempe, R. Angew. Chem., Int. Ed.
2007, 46, 3135. (c) Reference 8. (d) Kataoka, N.; Shelby, Q.; Stambuli,
J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553. (e) Bedford, R. B.;
Cazin, C. S. J. Chem. Commun. 2002, 2310. (f) Fox, J. M.; Huang, X.;
Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360. (g)
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473. (h) Wang,
D.; Wu, Z. Chem. Commun. 1999, 529. (i) Åhman, J.; Wolfe, J. P.;
Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 1918. (j) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1998, 63, 6546.
Acknowledgment. This paper is dedicated to Professor
Ryoji Noyori on the occasion of his 70th birthday. This work
was supported by the PRESTO program of Japan Science
(11) Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams, V. A.;
Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70, 161
(12) The reaction also takes place with commercial unsublimed KOtBu
similarly.
.
(18) t-Butoxides are typical bases in the arylation of amines and alcohols
using haloarenes. For a review, see: (a) Jiang, L.; Buchwald, S. L. Metal-
Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004; Chapter 13. For a report on the Pd-free
(KOtBu-promoted) reactions, see: (b) Shi, L.; Wang, M.; Fan, C.-A.; Zhang,
F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515.
(13) See Supporting Information for details.
(14) Studer, A.; Bossart, M. Radicals in Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, p 62
(15) Bunnett, J. F. Acc. Chem. Res. 1978, 11, 413
.
.
4676
Org. Lett., Vol. 10, No. 20, 2008