Direct heteroarylation of tautomerizable heterocycles into unsymmetrical and symmetrical biheterocycles via Pd/Cu-catalyzed phosphonium coupling

Article abstract of DOI:10.1021/ol300455e

The direct cross-coupling of tautomerizable heterocycles with various unfunctionalized heteroarenes has been achieved through PyBroP-mediated and Pd/Cu-catalyzed sequential C-OH/C-H activation. The methodology allows a facile entry into novel diazine-azol

Full text of DOI:10.1021/ol300455e

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1854–1857
Direct Heteroarylation of Tautomerizable
Heterocycles into Unsymmetrical
and Symmetrical Biheterocycles via
Pd/Cu-Catalyzed Phosphonium Coupling
Abhishek Sharma, Dipak Vachhani, and Erik Van der Eycken*
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of
Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001, Leuven,
Belgium
erik.vandereycken@chem.kuleuven.be
Received February 23, 2012
ABSTRACT
The direct cross-coupling of tautomerizable heterocycles with various unfunctionalized heteroarenes has been achieved through PyBroP-
mediated and Pd/Cu-catalyzed sequential CꢀOH/CꢀH activation. The methodology allows a facile entry into novel diazine-azole biheterocyclic
frameworks. Moreover, an unprecedented Pd-catalyzed phosphonium homocoupling of tautomerizable heterocycles was also developed to afford
a direct synthetic route to symmetrical 1,2-, 1,3-, and 1,4-bidiazine units.
The heterobiaryl framework is an important constituent
of various biologically active compounds and functional
materials.1 The synthesis of such biaryl units via transition
metal catalyzed direct CꢀH arylation of heteroarenes has
received increased attention due to several inherent
benefits.2 Thus, considerable progress has been achieved
in the formation of “heteroarylꢀaryl” units2,3 via CꢀH
arylation using various aryl halides and pseudohalides
including CꢀO electrophiles.3iꢀm,4 In contrast, similar
strategies for the construction of “heteroarylꢀheteroaryl”
scaffolds5 such as diazine-azoles or bidiazines remain far
less explored.
(1) For reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4442. (b) Carey, J. S.; Laffan, D.;
Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337.
(2) For leading reviews on CꢀH arylation, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (c) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (d)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
On the other hand, tautomerizable heterocycles are
widely distributed in naturally occurring compounds and
(3) For selected examples, see: (a) Do, H.-Q.; Khan, R. M. K.;
Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185. (b) Berman, A. M.;
Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2010, 75, 7863. (c)
Ohnmacht, S. A.; Culshaw, A. J.; Greaney, M. F. Org. Lett. 2010, 12,
224. (d) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826. (e) Huang, J.; Chan, J.; Chen, Y.; Borths,
C. J.; Baucom, K. D.; Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc.
2010, 132, 3674. (f) Cornella, J.; Lu, P.; Larrosa, I. Org. Lett. 2009, 11,
5506. (g) Kawano, T.; Yoshizumi, T.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2009, 11, 3072. (h) Wagner, A. M.; Sanford, M. S. Org. Lett.
2011, 13, 288. (i) Molander, G. A.; Beaumard, F. Org. Lett. 2010, 12,
4022. (j) Ackermann, L.; Althammer, A. S.; Fenner, S. Angew. Chem.,
Int. Ed. 2009, 48, 201. (k) Ackermann, L.; Mulzer, M. Org. Lett. 2008,
10, 5043. (l) Ackermann, L.; Fenner, S. Chem. Commun. 2011, 47, 430.
(m) Fan, S.; Yang, J.; Zhang, X. Org. Lett. 2011, 13, 4374.
(4) Li, B. J.; Yu, D. G.; Sun, C. L.; Shi, Z. J. Chem.;Eur. J. 2011, 17,
1728.
(5) (a) Steel, P. J. Adv. Heterocycl. Chem. 1996, 67, 1–117 and
references therein. (b) Zhao, D.; You, J.; Hu, C. Chem.;Eur. J. 2011,
17, 5466. (c) Hughes, R. A.; Moody, C. J. Angew. Chem., Int. Ed. 2007,
46, 7930. For selected examples, see: (d) Duric, S.; Tzschucke, C. C. Org.
Lett. 2011, 13, 2310. (e) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F.
Org. Lett. 2008, 10, 2717. (f) Shibahara, F.; Yamaguchi, E.; Murai, T.
Chem. Commun. 2010, 46, 2471. (g) Truong, J.; Alvarado, L.; Tran, D.;
Daugulis, O. Org. Lett. 2010, 12, 1200. (h) Zhu, M.; Fujita, K.;
Yamaguchi, R. Chem. Commun. 2011, 47, 12876. (i) Baghbanzadeh,
M.; Pilger, C.; Kappe, C. O. J. Org. Chem. 2010, 76, 8138.
(6) The Merck Index, An Encyclopedia of Chemicals, Drugs and
Biologicals, 13th ed.; Merck & Co., Inc.: Whitehouse Station, NJ, 2001.
r
10.1021/ol300455e
Published on Web 03/14/2012
2012 American Chemical Society

offer a convenient source of various heterocyclic building
blocks.6 Recently, these have also emerged as an attractive
class of substrates for Pd-catalyzed cross-couplings via in
situ CꢀOH activation using phosphonium salts.7 Inpartic-
ular, the pioneering work of Kang et al. allowed the direct
arylation of tautomerizable heterocycles using boronic
acids as coupling partners (Scheme 1).7a However, it would
be highly beneficial if unfunctionalized heteroarenes2
could be utilized as a latent source of heterocyclic
coupling partners for tautomerizable heterocycles. Such
a combination of two complementary CꢀC bond forming
approaches2,7 would give a direct access to a wide range
of biologically important biheterocyclic scaffolds. In the
course of our continued interest in the development of
catalytic approaches for the synthesis of novel biaryl
frameworks,7e,8 we became interested in exploring the
utility of tautomerizable heterocycles for the synthesis
of varied heteroarylꢀheteroaryl units. Herein, we report
the Pd-catalyzed direct heteroarylation of tautomerizable
heterocycles into diazine-azoles and bidiazines respectively
via PyBroP-mediated cross-coupling with azoles or phos-
phonium homocoupling (Scheme 1).
Table 1. Optimization of the Cross-Coupling between 2-Methyl-
1H-pyridazine-3,6-dione and 2-Phenyl-1,3,4-oxadiazolea
yieldb
entry solvent
base
Pd/ligand
additive
(%)
1
Dioxane K2CO3
Pd(OAc)2/
PPh3
ꢀ
traces
2
DMA
DME
DMF
DMA
DMA
DMA
DMA
DMA
DMA
DMA
K2CO3
K2CO3
K2CO3
Pd(OAc)2/
PPh3
ꢀ
20
3
Pd(OAc)2/
PPh3
ꢀ
traces
10
4
Pd(OAc)2/
PPh3
ꢀ
5
Cs2CO3 Pd(OAc)2/
PPh3
ꢀ
15
6
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Pd(OAc)2/
PPh3
CuIc
51 (30)d
65
Scheme 1. Strategies for Arylation/Heteroarylation of Tauto-
merizable Heterocycles Using Phosphonium Coupling
7
Pd(OAc)2/
PPh3
CuI
8
Pd(OAc)2/
PPh3
Pivalic
acidc
CuI
21
9
Pd(OAc)2/
XPhos
traces
55
10
11
Pd(OAc)2/
Xantphos
CuI
CuI
Pd(OAc)2
/
77(nd,g,h
72i)
e
PPh3
f
12
13
DMA
DMA
K2CO3
K2CO3
Pd(PPh3)4
CuI
CuI
66
f
Pd(PPh3)2Cl2
62
a General conditions: 1a (0.27 mmol), PyBroP (1.2 equiv), Pri2NEt
(3 equiv), in 1,4-dioxane (1.5 mL), MW, 100 °C, 30 min; then Pd(OAc)2
(5 mol %), PPh3 (10 mol %), base (3 equiv), additive (50 mol %), 2a
(1.5 equiv), DMA (1.5 mL), MW, 120 °C, 40 min. b Yield of pure isolated
product (single run). c 30 mol %. d Yield using Et3N in place of Pri2NEt.
e Pd(OAc)2 (7 mol %)/PPh3 (14 mol %). f (7 mol %). g Not detected.
h Reaction without Pd catalyst. i Reaction under conventional heating
at 120 °C, 16 h
Initially, the direct heteroarylation was explored using
2-methyl-1H-pyridazine-3,6-dione (1a) and 2-phenyl-
1,3,4-oxadiazole (2a) as substrates (Table 1). Thus, a
mixture of 1a (0.3 mmol), PyBroP (1.2 equiv), and Pri2NEt
(3 equiv) in 1,4-dioxane7 was irradiated with microwaves
(MW) at 100 °C for 30 min to form the phosphonium salt.
Thereafter, Pd(OAc)2 (5 mol %), PPh3 (10 mol %), K2CO3
(3 equiv), and 2a (1.5 equiv) were added, and the resulting
mixture was further irradiated at 120 °C for 40 min
(Table 1, entry 1).
coupling of the heterocycle-phosphonium salt with hetero-
arenes might not be feasible using dioxane as the sole
solvent. Therefore, after the initial formation of the phos-
phonium salt, DMA was also added to the reaction
mixture while keeping the rest of the conditions unchanged
(Table 1, entry 2). This modification provided the desired
biheterocyclic product 3a in 20% yield. A further optimi-
zation of this cross-coupling reaction (Table 1) indicated
that other solvents such as DME (Table 1, entry 3) and
DMF (entry 4) or another base (Cs2CO3, Table 1, entry 5)
were not beneficial. Interestingly, the use of CuI
(Table 1, entries 6ꢀ7) as an additive led to a significant
improvement of the yield (65%, Table 1, entry 7), while
addition of pivalic acid3d proved unsuitable under our
conditions (21% yield, entry 8). The various other
However, these conditions afforded the desired product
only in traces. This led us to hypothesize that the direct
(7) (a) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008,
130, 11300. (b) Kang, F.-A.; Sui, Z.; Murray, W. V. Eur. J. Org. Chem.
2009, 461. (c) Kang, F.-A.; Lanter, J. C.; Cai, C.; Sui, Z.; Murray, W. V.
Chem. Commun. 2010, 46, 1347. (d) Shi, C.; Aldrich, C. C. Org. Lett.
2010, 12, 2286. (e) Mehta, V. P.; Modha, S. G.; Van der Eycken, E.
J. Org. Chem. 2010, 75, 976. (f) Li, S.-M.; Huang, J.; Chena, G.-J.; Han,
F.-S. Chem. Commun. 2011, 47, 12840.
(8) (a) Beryozkina, T.; Appukkuttan, P.; Mont, N.; Van der Eycken,
E. Org. Lett. 2006, 8, 487. (b) Appukkuttan, P.; Dehaen, W.; Van der
Eycken, E. Chem.;Eur. J. 2007, 13, 6452.
Org. Lett., Vol. 14, No. 7, 2012
1855

Pd-catalysts/ligands (entries 9, 10, 12, and 13) did not
result in a substantial amelioration of the yield. However,
an increase in catalyst loading of Pd(OAc)2 up to 7 mol %
(entry 11) further enhanced the yield of 3a (77%).
Table 2. Pd-Catalyzed Direct Heteroarylation of Tautomerizable
HeterocycleswithHeteroarenes Using PhosphoniumCouplinga,b
With the optimized conditions (A) in hand (Table 1,
entry 11), the substrate scope with respect to both coupling
partners was explored (Table 2). Interestingly, the above
heteroarylation also proceeded well with other biologically
important9 heteroarene10 cores such as 1,3,4-thiadiazole
(entry 2) and benzoxazoles (entries 3ꢀ6). However, a slight
modification (condition B) employing Et3N (3 equiv)
instead of Pri2NEt was found to be beneficial in the case
of benzoxazoles. Similarly, the protocol was also applic-
able to various tautomerizable heterocycles, thereby, al-
lowing an unprecedented direct linkage of 1,3-, (entries
7ꢀ8), 1,4-, (entry 9) and 1,2-diazine units (entries 10ꢀ12)
with diverse azoles. Such diazine-azole biheterocyclic scaf-
folds are expected to possess important applications in
medicinal9,11 and materials chemistry.12
The above transformation plausibly proceeds through a
sequential CꢀOH7 and CꢀH activation pathway2,3g
(Scheme 2). The phosphonium salt I, obtained by activation
of the tautomerizable heterocycle with PyBroP, enters the Pd
catalytic cycle via oxidative addition of Pd(0) to give a
heterocycle-Pd(II)-complex II. Subsequently, the above Pd-
(II)-complex undergoes transmetalation with a Cu(I)-
heteroaryl species IV (formed concurrently via CꢀH bond
activation of heteroarene III) to give V which provides the
desired biheterocycle upon reductive elimination (Scheme 2).
Scheme 2. Plausible Mechanism of the Pd/Cu-Catalyzed Direct
Cross-Coupling of Tautomerizable Heterocycles with Hetero-
arenes
In the course of our above studies, some homocoupled
product (10ꢀ15%) of the tautomerizable heterocycle was
(9) (a) Koezen, J. E. M.; Timmerman, H.; Vollinga, R. C.; Kunzel, J.
F. V. D.; Groote, M. D.; Visser, S.; IJzerman, A. P. J. Med. Chem. 2001,
44, 749. (b) Rao, A. U.; Shao, N.; Aslanian, R. G.; Chan, T.-Y.;
Degrado, S. J.; Wang, L.; McKittrick, B.; Senior, M.; West, R. E.;
Williams, S. M.; Wu, R.-L.; Hwa, J.; Patel, B.; Zheng, S.; Sondey, C.;
Palani, A. ACS Med. Chem. Lett. 2012, 3, 198. (c) Yoshida, S.;
Shiokawa, S.; Kawano, K.; Ito, T.; Murakami, H.; Suzuki, H.; Sato,
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Cheng, H.; Hwang, I.; Cravatt, B. F.; Boger, D. L. Bioorg. Med. Chem.
Lett. 2005, 15, 1423.
a Condition A: Het1 (0.27 mmol), PyBroP (1.2 equiv), Pri2NEt
(3 equiv) in 1,4-dioxane (1.5 mL), MW, 100 °C, 30 min; then Pd(OAc)2
(7 mol %), PPh3 (14 mol %), K2CO3 (3 equiv), CuI (50 mol %), Het2
(1.5 equiv), DMA (1.5 mL), MW, 120 °C, 40 min. b Condition B: this is
the same as condition A, except that Pri2NEt is replaced by Et3N
(3 equiv) and 2 equiv of Het2 were used. c Yield of pure isolated product
(single run). d 5 equiv of Pri2NEt were used.
(10) The use of heteroarenes such as imidazoles, indoles, and ben-
zothiazoles was also explored; however, these did not undergo cross-
coupling under the above conditions.
(11) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
1856
Org. Lett., Vol. 14, No. 7, 2012

have been predominantly accessed via multiple steps or
functionalized substrates.15 Due to the above observa-
tions, the utility of this unprecedented homocoupling
reaction was evaluated using 4(3H)-pyrimidinone (1b) as
a model substrate. We found that the use of an increased
amount of Pri2NEt (5 equiv), Pd(OAc)2 (10 mol %), and
PPh3 (20 mol %) and replacement of DMA with DMF as
solvent at 140 °C led to a significant enhancement in yield
(72%) of the desired symmetrical 4,40-bipyrimidine (4a)
(Table 3, entry 1). Importantly, the above condition also
provided a novel access to the homodimers of other 1,4-
and 1,2-diazines (Table 3, entries 2ꢀ3).
Table 3. Pd-Catalyzed Homophosphonium Coupling of
Tautomerizable Heterocycles into Symmetrical Bidiazinesa
In conclusion, we have developed an elegant Pd-
catalyzed phosphonium coupling of tautomerizable hetero-
cycles with various unfunctionalized heteroarenes. The
protocol enables a direct and unprecedented linkage of
1,2-, 1,3-, as well as 1,4-diazines with azoles using readily
available substrates. Significantly, a direct approach for
the synthesis of symmetrical bidiazines was also achieved
via a novel Pd-catalyzed phosphonium homocoupling of
tautomerizable heterocycles.
Acknowledgment. The authors wish to thank the FWO
[Fund for Scientific Research - Flanders (Belgium)] and
the Research Fund of the University of Leuven (KU
Leuven) for financial support. A.S. is thankful to the
FWO for obtaining a visiting postdoctoral fellowship. D.
V. is grateful to EMECW13 (Erasmus Mundus External
Cooperation Window Lot 13 India) for obtaining a doc-
toral scholarship.
a General conditions: Het1 (0.36 mmol), PyBroP (1.2 equiv), Pri2NEt
(5 equiv) in 1,4-dioxane (1.5 mL), MW, 100 °C, 30 min; then Pd(OAc)2
(10 mol %), PPh3 (20 mol %), K2CO3 (2 equiv), DMF (1.5 mL), MW,
140 °C, 40 min. b Yield of pure isolated product (single run).
detected. To the best of our knowledge, such homodi-
merization of tautomerizable heterocycles has so far not
been reported in the case of palladium catalyzed phos-
phonium couplings.13 Interestingly, the resulting sym-
metrical biheterocycles have important applications in
photochemistry and as π-accepting ligands in coordina-
tion chemistry.14 Moreover, such homodimeric scaffolds
Supporting Information Available. Complete experi-
mental details and spectroscopic data of all synthesized
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) (a) Ioachim, E.; Medlycott, E. A.; Polson, M. I. J.; Hanan, G. S.
Eur. J. Org. Chem. 2005, 3775 and references cited therein. (b) Goswami,
S. A.; Maity, C.; Fun, H.-K.; Chantrapromma, S. Eur. J. Org. Chem.
2009, 1417.
(12) He, G. S.; Tan, L.-S.; Zheng, Q.; Prasad, P. N. Chem. Rev. 2008,
108, 1245.
(13) Ngwendson, J. N.; Atemnkeng, W. N.; Schultze, C. M.;
Banerjee, A. Org. Lett. 2006, 8, 4085.
(14) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
The authors declare no competing financial interest.
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