Mild and general method for the α-Arylation of heteroaromatic ketones

Article abstract of DOI:10.1021/ol1000318

Chemical equation Presented The development of a general and mild method for Pd-catalyzed α-arylatlon of a variety of ketones bearing multiple heteroatoms Is described. The ligand to metal ratio and the position of the heteroatoms with respect to the carbonyl moiety significantly impact the efficiency of these transformations. In addition, these conditions were successfully applied to the α-arylation of cyclic imines. A detailed Investigation of the scope of this methodology, including the effect of the ligand to metal ratio, Is discussed.

Full text of DOI:10.1021/ol1000318

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1032-1035
Mild and General Method for the
r-Arylation of Heteroaromatic Ketones
Lopa V. Desai,* Danan T. Ren, and Thorsten Rosner
Bristol-Myers Squibb, 1 Squibb DriVe, New Brunswick, New Jersey 08903
lopa.desai@bms.com
Received January 6, 2010
ABSTRACT
The development of a general and mild method for Pd-catalyzed r-arylation of a variety of ketones bearing multiple heteroatoms is described.
The ligand to metal ratio and the position of the heteroatoms with respect to the carbonyl moiety significantly impact the efficiency of these
transformations. In addition, these conditions were successfully applied to the r-arylation of cyclic imines. A detailed investigation of the
scope of this methodology, including the effect of the ligand to metal ratio, is discussed.
The R-aryl carbonyl functionality is an important component
of many pharmaceuticals and bioactive molecules.1 Hence,
significant efforts have been devoted to the construction of this
motif using transition metal catalysis. In particular, the pal-
ladium-catalyzed R-arylation reaction is an attractive method
for the rapid construction of C-C bonds R to a carbonyl
moiety.2 Miura,3 Buchwald,4 Hartwig,5 and others2 have shown
that this transformation is effective for the coupling of various
aryl halides with esters, amides, unfunctionalized ketones, and
aldehydes. Both electron-deficient and electron-rich aryl halides
have been successfully employed, rendering the R-arylation
reaction versatile and synthetically valuable. Furthermore, a
recent report by Buchwald and co-workers expanded the scope
toward arylation of heteroaromatic ketones.6 Despite these
advances, to the best of our knowledge, there have been no
reported examples for R-arylation of multi-heteroaromatic
ketones. This constitutes a limitation due to the ubiquitous
presence of heteroaryl moieties in pharmaceuticals and agro-
chemicals. In addition, the strong bases typically employed for
the arylation of simple methyl aryl ketones limits the functional
group compatibility of these reactions. Hence, a general and
mild method for the monoarylation of a wide array of methyl
heteroaromatic ketones is desirable. Herein, we report the
palladium-catalyzed R-arylation of substrates containing mul-
tiple heteroatoms using a mild base. Careful optimization of
the ligand to metal ratio was critical in the development of these
transformations.
Fluorinated arenes are widely prevalent in pharmaceuticals
due to their enhanced metabolic stability, bioavailability, binding
efficacy, selectivity, and solubility.7 However, surveying the
literature reveals that the use of fluorinated arenes, for example,
2-fluorobromobenzene (A), in R-arylation reactions is rare.8 In
addition, ꢀ-arylated pyrazine motifs are often found in biologi-
cally active molecules.9 Therefore, our initial studies focused
on R-arylation of 2-acetylpyrazine 1 with A (Table 1).
(1) (a) Hendrikson, J. B.; Bogard, T. L.; Fisch, M. E.; Grossert, S.;
Yoshimura, N. J. Am. Chem. Soc. 1974, 96, 7781. (b) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (c) Edmondson, S.;
Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc. 1999,
121, 2147. (d) Yokoshima, S.; Keda, T.; Kobayashi, S.; Sato, A.; Kuboyama,
T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
(2) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (b)
Bellina, F.; Rossi, R. Chem. ReV. 2009, DOI: 10.1021/cr9000836.
(3) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1740. (b) Miura, M.; Nomura, M. Top. Curr. Chem.
2002, 219, 211. (c) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron Lett. 2002, 43, 101. (d) Miura, M.; Satoh, T. Palladium in
Organic Synthesis; Springer: Berlin/Heidelberg, 2005; Vol. 14. (e) Terao,
Y.; Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2002,
43, 101.
(4) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360. (c) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7996. (d) Marty´n, R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2007, 46, 7236.
(6) Biscoe, M. R.; Buchwald, S. L. Org. Lett. 2009, 11, 1773.
(7) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881, and
references therein.
(8) Ehrentraut, A.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2002, 344,
209. The only reported example of arylation of 1-chloro-2-fluorobenzene
with acetophenone used nBuPAd2 as the ligand, 1 mol% of Pd(OAc)2, and
K3PO4 as the base in dioxane at 100 °C. The monoarylated product is formed
in 57% yield, as a 2.5:1 mixture of mono and diarylated products.
(5) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,
12382. (b) Hama, T.; Liu, X.; Culkin, D.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176. (c) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126,
5182. (d) Vo, G. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 2127.
10.1021/ol1000318  2010 American Chemical Society
Published on Web 02/10/2010

Table 1. Screening R-Arylation of 2-Acetylpyrazine (1)
Entry
L:M
Ketone:ArBr
Solution yieldb
1
2
3
4
5
6
1:1
1:1
1.5:1
2:1
0.5:1
0.5:1
1:1
2:1
2:1
2:1
2:1
2:1
40%
69%
21%
22%
76%
92%a
a In-process yield obtained with 4 mol % of Pd(OAc)2 and 2 mol % of
Xantphos. Aryl bromide A as the limiting reagent. b Solution yield
determined using an HPLC calibration, see SI for further information.
Figure 1. Ligand to metal ratio studies for substrates 1-5.
Extensive screening using Pd(OAc)2 as the metal precursor
and K3PO4 as the base demonstrated Xantphos to be the most
competent ligand in implementing the R-arylation, albeit
affording the product 1A in only 40% solution yield (entry 1).
Increasing the concentration of 1 relative to A (entry 2)
enhanced the yield of the desired product.10 We reasoned that
the presence of multiple heteroatoms might be impacting the
effective ligand to metal ratio by binding to the metal. In order
to test this hypothesis, we conducted a systematic screening of
the ligand to metal ratio (L:M) required for this transformation
(entries 3-5) and were gratified to observe increased yields
when the L:M was reduced to 0.5 (entry 5). The highest in-
process yield (92%) of 1A was obtained with an increased
catalyst loading of 4 mol % of Pd(OAc)2, 2 mol % of Xantphos,
and 2.8 equiv of K3PO4 in 4:1:1 1,4-dioxane/THF/toluene at
100 °C for 18 h (entry 6). Interestingly, under these conditions,
none of the diarylated product was observed. The results in
Table 1 suggest that under our conditions the reactivity of multi-
heteroaromatic ketones greatly depends on the ligand to metal
ratio. In order to determine the generality of this effect, we
studied the impact of varying ligand and metal stoichiometries
on the R-arylation reaction of various heteroaromatic ketones
(acetylpyridine 2, acetylpyrazine 1, 5-acetyl pyrimidine 3, and
4-acetylpyrimidine 4).
multiple heteroatoms (1, 3, and 4). The application of these
studies toward obtaining optimum yields for the arylation
of substrates 1-7 is summarized in Table 2.
Table 2. Screening R-Arylation for Heteroaromatic Ketones
As depicted in Figure 1, an interesting correlation was
observed between the L:M and the number and position of
heteroatoms in the substrate. The optimal L:M range (2.5-2)
for 2,11 containing only one heteroatom, is analogous to that
of acetophenone 5. This is in sharp contrast to the 1:1 L:M
reported for Xantphos for R-arylation reactions in the
literature.4b On the other hand, a lower L:M is required to
obtain good yields for the arylation of substrates containing
(9) (a) Yao, Z.; Zhou, H. Method for synthesis of Sinomenine deriVatiVe
with C ring connected with pyrazine and its application in immunomodu-
lator. Faming Zhuanli Shenqing Gongkai Shuomingshu CN 1687065,
October 26, 2005. (b) Buhr, C. A.; Baik, T.-G.; Ma, S.; Tesfai, Z.; Wang,
L.; Co, E. W.; Epshteyn, S.; Kennedy, A. R.; Chen, B.; Dubenko, L.; Anand,
N. K.; Tsang, T. H.; Nuss, J. M.; Peto, C. J.; Rice, K. D.; Ibrahim, M. A.;
Schnepp, K. L.; Shi, X.; Leahy, J. W.; Chen, J.; Dalrymple, L. E.; Forsyth,
T. P.; Huynh, T. P.; Mann, G.; Mann, L. W.; Takeuchi, C. S. Preparation
of substituted pyrazines as protein kinase modulators. WO 2003093297,
November 13, 2003.
a Isolated yields and average of two runs.
As shown in Table 2, the position of the heteroatom in
the substrate appears to dictate the optimal L:M.12 For
Org. Lett., Vol. 12, No. 5, 2010
1033

example, ketones 1, 3, and 4 differing only in the relative
positions of the two nitrogens, require L:M ranging between
0.5-1, 1.0-1.5, and 0.5, respectively, to obtain the optimum
yield of the arylated product. In addition, the bidentate
chelation of the substrate to the metal appears to impact both
the L:M and the efficiency of these transformations. This is
exemplified by the arylation of substrates bearing a nitrogen
atom ortho to the carbonyl moiety. For example, substrates
1 and 4 require lower L:M relative to other ketones while
2-acetylpyridine and 2-acetylpyrimidine exhibit extremely
poor reactivity. The difference in reactivity between 1 (and
4) and 2-acetylpyridine (and 2-acetylpyrimidine) suggests
that the presence of multiple heteroatoms facilitates the
arylation of substrates capable of bidendate chelation to the
metal. In all, these studies suggest that a complex interplay
of the number, position, and chelating ability of heteroatoms
dictates the optimal L:M required for the arylation of multi-
heteroaromatic ketones.
Table 4. Scope of Aryl Halides
With these results in hand, we next studied the versatility
of these mild conditions for the arylation of other ketones.
A variety of heteroaromatic substrates were successfully
R-arylated with A (Table 3). Besides methyl ketones,
Table 3. Substrate Scope for R-Arylation
a Isolated yields and average of two runs. b Ratio of monoarylated:
diarylated product.
arylation of ethyl ketone 8, having increased substitution at
the R-carbon, is also feasible. Substrates such as acetylth-
iophene 9 and acetylfuran 11 were compatible under our
conditions. Regardless of the heteroatom, the optimal L:M
range for ketones containing a single heteroatom such as 9
and 11 was 2.0-2.5, consistent with the trend observed in
Figure 1. In addition, these reaction conditions were compat-
ible with electron-rich arenes (entry 7, Table 3) and benzylic
(10) Refs 4 and 5 illustrate that excess ketone is generally used for
R-arylation reactions.
(11) Along with Xantphos, high yield of the arylated product 2A was
obtained with cataCXiumPOMeCy as ligand (L:M 2:1) and K3PO4 as base
in toluene at 100 °C. To the best of our knowledge, this is the first report
of using cataCXiumPOMeCy as a ligand for an R-arylation reaction, making
it a valuable alternative.
a Isolated yields and average of two runs.
1034
Org. Lett., Vol. 12, No. 5, 2010

hydrogens (entry 7, Table 2 and entries 3-5 and 7, Table
3). Notably, the selective arylation of methyl ketone versus
the amide in substrate 12 exemplifies the chemoselectivity
for these reactions (entry 5, Table 3).
We were also interested in studying the arylation of imines
such as 13 and 14, which would allow access to motifs
prevalent in many biologically active molecules.13 Impor-
tantly, our conditions were mild, selective, and general
enough to successfully R-arylate these challenging hetero-
cyclic substrates (entries 6 and 7, Table 3).
Surveying the imine arylation literature reveals that only
NaOtBu, LiOtBu, and a few examples with Cs2CO3 have
been reported to promote R-arylation of imines, albeit in low
selectivity for mono- versus diarylation.14 Hence, the success
of our mild basic conditions for affording monoarylated
products 13A and 14A in high selectivity is an important
addition to the previously reported imine arylations. We are
currently expanding the boundaries of this process.
An important feature of these R-arylation reactions is that the
required L:M is dictated by only the ketone coupling partner.
As illustrated in Figure 1, the range of L:M preference was
1-1.5 for 5-acetylpyrimidine 3 and 0.5-1 for 2-acetylpyrazine
1. Unexpectedly, the R-arylation of 3 or 2 with J proceeded
similarly at L:M ranging from 0.5 to 2.0. These preliminary
results indicate that heteroaryl halides do not significantly impact
the ligand to metal ratio.17
In summary, we have reported R-arylation reactions of
an unexplored class of multi-heteroaromatic ketones, namely,
pyrazines, pyrimidines, and quinoxaline. The reactivity of
these substrates was dictated by the ligand to metal ratio. In
addition, we have developed a mild, chemoselective, and
general method to effectively R-arylate a variety of substrates
such as imines, acetylthiophenes, acetylfurans, and acetylpy-
ridines. We are currently conducting mechanistic studies to
elucidate the intriguing effect of the ligand to metal ratio on
the reactivity of these substrates.
The scope of the ketone arylation reaction with respect to
the aryl halide was investigated next. As shown in Table 4,
electron-rich (G), electron-deficient (B-E), and heteroaryl
halides (I,J) were effective substrates. In general, better selectiv-
ity for monoarylation versus diarylation was observed for
electron-deficient or heteroaryl halides.15 Interestingly, while
diarylation was not observed with 1-bromo-2-fluorobenzene,8
27% diarylated product is formed with 1-bromo-4-fluoroben-
zene. This difference in selectivity can be attributed to the more
electron-deficient character of 1-bromo-2-fluorobenzene over
1-bromo-4-fluorobenzene. Such electronic effects with ortho-
and para-fluorinated arenes have been previously documented.16
Notably, aryl chlorides such as D and F are also effective
coupling partners for the R-arylation reaction (entries 3 and 5,
Table 4). However, given the option, preferential oxidative
addition into the C-Br bond is observed (entry 7, Table 4).
Acknowledgment. The authors wish to acknowledge
David Leahy, Antonio Ramirez, Phil Baran, and Dave
Kronenthal for reviewing the paper and helpful discussions.
The authors also want to acknowledge Charles Pathirana,
Michael Peddicord, Frank Rinaldi, and Merrill Davies for
analytical support.
Supporting Information Available: Experimental details
and spectroscopic and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL1000318
(15) Ref 5a discusses that the selectivity between mono- and diarylation
is base-dependent. Arylations of electron-rich or electron-neutral aryl
bromides were more selective for monoarylation with KHMDS as the base,
while electron-deficient aryl bromides were more selective with NaOtBU
as the base.
(16) Rosenthal, J.; Schuster, D. I. J. Chem. Educ. 2003, 80, 679.
(17) (a) The effect of heteroaryl halides on reductive elimination in the
context of amination chemistry has been studied. However, the impact of
ligand to metal ratio was not explored. Hooper, M. W.; Hartwig, J. F.
Organometallics 2003, 22, 3394–3403. (b) Guram, A. S.; Wang, X.; Bunel,
E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J. J. Org. Chem. 2007,
72, 5104–5112.
(12) The effect of the position of the heteroatom on reactivity in the
context of Suzuki reactions has been studied. Kondolff, I.; Doucet, H.;
Santelli, M. J. Heterocycl. Chem. 2008, 45, 109.
(13) Lugnier, C.; Dore, J. C.; Viel, C. Eur. J. Med. Chem. 1994, 29,
723.
(14) (a) Barluenga, J.; Jimenez-Aquino, A.; Valdes, C.; Aznar, F. Angew.
Chem., Int. Ed. 2007, 46, 1529. (b) Barluenga, J.; Jimenez-Aquino, A.;
Aznar, F.; Valdes, C. J. Am. Chem. Soc. 2009, 131, 4031.
Org. Lett., Vol. 12, No. 5, 2010
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