Pyrimidine as an Aryl C-H Activating Group

Article abstract of DOI:10.1021/acs.orglett.8b01300

The Pd-catalyzed regioselective C-H activation/arylation, /iodination, and/acetoxylation reactions of 4-arylpyrimidines using aryl iodides, N-iodosuccinimide, and (diacetoxyiodo)benzene respectively as coupling partners are described. Suzuki-Miyaura coupl

Full text of DOI:10.1021/acs.orglett.8b01300

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pyrimidine as an Aryl C−H Activating Group
Sahaj Gupta,† Jennifer A. Melanson,† Louis Vaillancourt,‡,§ William A. Nugent,‡,# Gerald J. Tanoury,*,‡
Gabriele Schatte,† and Victor Snieckus*,†
†Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, Ontario K7L 3N6, Canada
‡Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States
S
* Supporting Information
ABSTRACT: The Pd-catalyzed regioselective C−H activa-
tion/arylation, /iodination, and/acetoxylation reactions of 4-
arylpyrimidines using aryl iodides, N-iodosuccinimide, and
(diacetoxyiodo)benzene respectively as coupling partners are
described. Suzuki−Miyaura coupling and Sonogashira reac-
tions of the resulting aryl iodides are demonstrated. The
scalability of the C−H activation/functionalization starting
with readily accessible 4-aryl pyrimidines is also reported.
Scheme 1. Aromatic C−H Activation Reaction
n the past two decades, transition metal catalyzed reactions
have become a dominant theme in organic synthesis.1 As part
I
of the cross-coupling reaction landscape, which was initially
established for C−C bond formation using C−halogen2 and C−
M partners (M = B,3 Zn,4 Mg,5 Sn,6 Si7) under transition metal
catalysis, there has been an expansion to include a large number
of C−H partners.1c The seminal results of Murai paved the way
for the C−H activation reactions that lead to C−C bond
formation, many of which we now rely on as routine chemical
transformations.8 More recently, this area has evolved into a
robust and active area for synthetic chemists9 and expanded into
C−O,10 C−N,11 and C−S12 bond activation processes. Among
the multitude of opportunities presented by the C−H activation
concept, the use of the directing group (DG) effect of a pyridine
moiety for diverse functionalization has received voluminous
attention (Scheme 1b).1c However, few reports are available for
other heterocycles such as pyrazoles,1c,13 pyrrolidin-2-ones,14
quinolines,15 and isoquinolines.16 To the best of our knowledge,
pyrimidine-directed C−H activation reactions have been mainly
limited to C−H bonds of 2-aryl pyrimidines (Scheme 1c).17 In
1997, Murai and co-workers demonstrated one example of the
Ru(III)-catalyzed C−H propynylation of 4-phenylpyrimidine
using CO and ethylene gases under high pressure and
temperature (20 atm at 160 °C).18c Subsequently, Nakamura
also employed 4-phenylpyrimidine in the Fe(III)-catalyzed
arylation reaction with excess PhMgBr furnishing a monophenyl
imidines are the next most commonly reported heterocycles in
medicinal chemistry.19 Additionally, biaryl and aryl-heteroaryl
skeletons are found in many key compounds in material and life
sciences.20 As a whole, the results presented herein provide new
methodology for the functionalization of an important class of
bioactive and medicinally vital heterocycles.19,20
To initiate the study, we set forth to optimize our initial
observation of the reaction of pyrimidine 1a, prepared by a
Suzuki−Miyaura cross-coupling tactic (see Supporting Informa-
tion (SI)), with 4-iodoanisole 2a following selected conditions
that are commonly used in the C−H activation of heteroaromatic
product in 18% yield.18b Pozgan et al. used a highly reactive
̌
Ru(II) carboxylate catalyst system generated in situ from
[RuCl2(p-cymene)]2 and 1-phenyl-1-cyclopentanecarboxylic
acid to achieve predominantly diarylation of 4-phenylpyrimidine
by employing various bromo- and chloro-arenes as coupling
partners.18a
Herein we report the first Pd-catalyzed C−H activation/
arylation reactions illustrating the 4-pyrimidinyl N-DG effect,
which afford predominantly monoarylated products (Scheme
1d). Furthermore, we demonstrate the first corresponding
iodination and acetoxylation reactions. After pyridines, pyr-
Received: April 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01300
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
systems21 (Table 1; for the complete study, see SI). The use of
catalytic Pd(OAc)2 in acetic acid, either in combination with or in
Scheme 2. Substrate Scope for C−H Activation/Arylation
Reaction of Pyrimidines 1a−s
Table 1. Pyrimidine 1a C−H Activation/Arylation Reaction:
Optimization of Conditions
ab
,
entry
catalyst
Pd(OAc)2
oxidant
time
3a, % yield
d
c
1
−
5 d
5 d
5 d
5 d
5 d
2 h
2 h
2 h
15 h
−
d
2
Pd(OAc)2
K2S2O8
−
−
d
c
3
Pd(OAc)2
Oxone
d
4
Pd(OAc)2
Cu(OAc)2
AgOAc
25
46
52
44
43
46
d
5
Pd(OAc)2
e
6
Pd(OAc)2
AgOCOCF3
AgOCOCF3
AgOCOCF3
AgOCOCF3
e
7
Pd(MeCN)2(BF4)2
Pd(TFA)2
e
8
fg
9 ,
Pd(OAc)2
a
b
Yields of isolated compounds. 1a was recovered (15−40% yield) in
c
a number of cases (see SI). 10−18% conversion of 1a to 3a by GC-
MS analysis. Heated at 130 °C in AcOH. Microwave irradiation at
170 °C in EtCOOH. Heated at 170 °C in EtCOOH. 2.5 equiv of 2a
were used.
d
e
f
g
the absence of oxidant, led to decomposition or low conversion
(entries 1−3). Employing Cu(OAc)2 as an oxidant22 led to the
isolation of the diazatetraaryl derivative 3a in low yield (entry 4).
Adapting Daugulis’ conditions,21a which use AgOAc, to the
aforementioned reaction afforded reasonable conversion and
modest yield of the expected product (entry 5). Further
modification of the palladium catalyst employed (entries 7 and
8), the silver salt additive (see SI), the equivalents of 2a (entry 9),
and a change in solvent to propionic acid provided our optimized
reaction conditions (entries 6 and 9).
a
b
Yield of isolated product. Corresponding pyrimidine 1 was
c
d
recovered in 10−38% yields. 2.5 equiv of 2a−c were used. 1.5
e
f
equiv of 2a−c were used. 5.0 equiv of 2a were used. Diarylated
g
product 3i′ was also isolated in 22−39% yield (see SI). No reaction.
Based on the optimization results, the substrate scope for the
C−H activation reaction was investigated (Scheme 2). Treating
6-unsubstituted systems 1b, 1d, and 1e with electron-rich 4-
iodoanisole 2a afforded products 3f, 3h, and 3g, respectively, in
modest yields. Likewise, substrates bearing electron-withdrawing
character (i.e., 4-iodoacetophenone 2b) gave a similar result
forming 3b in 38% yield. The use of excess 2a (2.5−5.0 equiv)
with 1f under the prescribed reaction conditions led to the
formation of diarylated product 3i′ (see SI). To minimize
formation of product 3i′, decreased amounts of reagent 2 (1.5
equiv) were used when employing substrates 1f−k under the
reaction conditions. With the focus turned toward 6-substituted
pyrimidines, the 6-phenyl 1a and 6-t-Bu (1f−j) derivatives were
then investigated. There was no discernible trend observed when
considering electron-withdrawing group (EWG) or electron-
donating group (EDG) effects on the iodoaryl partner 2a−c in
the formation of product 3i, 3m, and 3n. Thus, the 4-OMe, 4-
COMe, and 4-CF3 iodo benzenes 2a, 2b, and 2c in C−H
activation/coupling reactions with the 6-phenyl 1a and 6-t-Bu
1f−j pyrimidines afforded a yield range (37−58%) similar to that
of corresponding products 3a and 3i−o. Thus, the 6-substituted
pyrimidines undergo more efficient coupling compared to 6-
unsubstituted substrates 1b−e, which afforded 3b−h in lower
yields (25−39%, Scheme 2). This may be attributed to the
interference of the remote nitrogen group by causing non-
productive coordination to the metal atom.18b The failure of 1m
to provide the desired product (3r) under the prescribed reaction
conditions indicates that these conditions are not favorable for
use with substrates bearing substituents at the ortho position due
to steric hindrance. Heteroatom containing substituents (SMe,
NHBn, pyridinyl, thienyl, and indolyl) are not tolerated under
the reaction conditions, presumably due to potential non-
productive coordination to the Pd-catalyst which prevents the
delivery of the arylated products 3s−w.
The C−H activation−arylation results (vide supra) prompted
investigation of other forms of C−H activation/functionalization
of the aryl pyrimidines. Iodination23 and acetoxylation24
reactions were chosen on the basis of the further functionaliza-
tion potential of derived products. After considerable trials on
pyrimidine 1f under various iodination conditions (see Table,
S2), use of NIS and catalytic Pd(OAc)2 in 1,4-dioxane at 100 °C
proved optimal. Under these conditions, the scope of the
reaction was further probed (Scheme 3). The t-Bu pyrimidines
1f−j, designed to hinder catalyst complexation at the alternate N-
1 site, afforded the corresponding products 4a−e and 4g,h in
reasonable synthetic yields. No significant variation in yields was
observed as a function of electron-donating 1o (R = 4-OMe) or
-withdrawing 1h (R = 4-F) groups. Although no reaction was
observed for 1m (R = 2-Me), presumably due to steric effects, the
2-thiomethyl derivative 4g was obtained without incident, and
the 6-CF3 (4i) and 6-phenyl (4j) derivatives were prepared in
modest yields.
B
DOI: 10.1021/acs.orglett.8b01300
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
calculations on the conformer energetics of 3a′, see SI. Further,
Sonogashira coupling of 4a led smoothly to the formation of
product 7, which may possibly be used as an intermediate for the
synthesis of fused helicene compounds.27
Scheme 3. Scope of the C−H Activation/Iodination Reaction:
a b
,
Synthesis of Pyrimidines 4a−j
Optimized conditions (HOAc/Ac2O or dioxane) for the
palladium-catalyzed acetoxylation reaction were established
using 1f as the substrate (see SI), and the reaction was
generalized for a variety of substrates (Scheme 5). The presence
Scheme 5. Scope of the C−H Activation/Acetoxylation
Reaction: Synthesis of Pyrimidines 9a−j
a
b
c
Yield of isolated product. Reaction time in parentheses. No
reaction.
Using our iodinated products, we were able to explore
additional reactivity (Scheme 4). Thus, anhydrous Suzuki−
Scheme 4. Suzuki−Miyaura Reaction and Sonogashira
Reaction of Iodopyrimidines 4a and 4j′
a
b
Yield of isolated product. No reaction.
of electron-donating (1o) or -withdrawing (1h) groups has no
significant influence on the outcome, and the corresponding
products 9c and 9d were obtained in similar yields. A steric effect
was evident in the case of 1m (R3 = 2-Me), affording product 9f
in 45% yield. Unfortunately, 1j (R2 = H) and 1n (R2 = SMe)
failed to give corresponding products 9i and 9j for reasons not
currently understood.
With the aim of demonstrating scalability, we undertook 1 g
(4.4 mmol) scale C−H arylation, iodination, and acetoxylation
reactions of substrate 1f to obtain 3x (44%), 4a (63%), and 9a
(76%), respectively (Scheme 6). These yields are comparable to
those obtained on the 0.66−0.88 mmol scale.
Miyaura cross-coupling of mono- and di-iodo derivatives 4a and
4j′ with commercially available 4-methoxyphenyl boronic acid
525 furnished high yields of products 3i and 3a′, respectively.
Aryl-substituted pyrimidines 8 (R = 4-Ar), with close
resemblance to our substrate 3a′, are known to exhibit
electroluminescent properties.26 The structure of 3a′ was
determined using single crystal X-ray diffraction analysis (Figure
1). The analysis revealed that the asymmetric unit contains two
Scheme 6. Scale-up Reactions of Pyrimidine 1f
Figure 1. X-ray crystal structure (ORTEP diagram) of 3a′. Hydrogen
atoms are omitted for clarity. The thermal ellipsoids are shown at the
50% probability level.
In conclusion, our present report establishes a new and general
methodology for the direct ortho-arylation of 4-aryl pyrimidines
with aryl iodides, which is mediated by a pyrimidinyl nitrogen
directed C−H activation reaction. In addition, it provides new
reactions for ortho-iodination and acetoxylation that are
promoted by the same DG effect. In addition, the derived
systems have been shown to be useful in further Suzuki−Miyaura
and Sonogashira processes. The ready availability of the 4-aryl
pyrimidine starting materials contributes to facilitating scale-up
processes. The use and application of the reported methodology
in the synthesis of bioactive and material science related
molecules may be anticipated.
molecules of 3a′. The molecules differ in the orientation of the
OMe group attached to the phenyl rings labeled as [C23, C24,
C25, C26, C27, C28] (molecule A) and [C63, C64, C65, C66,
C67, C68] (molecule B). A π−π interaction is observed between
pairs consisting of two molecules of A related by symmetry
(inversion and translation) and involves one of the aromatic rings
attached to the pyrimidine ring (see SI). The distance of
separation between the ring centroids is 3.769(11) Å. For DFT
C
DOI: 10.1021/acs.orglett.8b01300
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
8081. See also Cluster of papers, prefaced by: (c) Tobisu, M.; Chatani,
N.; Snieckus, V. Synlett 2017, 28, 2559.
(11) (a) Wang, Q.; Su, Y.; Li, L.; Huang, H. Chem. Soc. Rev. 2016, 45,
1257. (b) Ouyang, K.; Hao, W.; Zhang, W. X.; Xi, Z. Chem. Rev. 2015,
115, 12045.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01300.
■
S
(12) (a) Pan, F.; Shi, Z. J. ACS Catal. 2014, 4, 280. (b) Wang, L.; He,
W.; Yu, Z. Chem. Soc. Rev. 2013, 42, 599.
Full experimental details (PDF)
NMR and HRMS spectra (PDF)
(13) For selected references on pyrazole-directed C−H activation, see:
(a) Teskey, C. J.; Sohel, S. M. A.; Bunting, D. L.; Modha, S. G.; Greaney,
M. F. Angew. Chem., Int. Ed. 2017, 56, 5263. (b) Li, Y. G.; Wang, Z. Y.;
Zou, Y. L.; So, C. M.; Kwong, F. Y.; Qin, H. L.; Kantchev, E. A. B. Synlett
2017, 28, 499. (c) Doherty, S.; Knight, J. G.; Addyman, C. R.; Smyth, C.
H.; Ward, N. A. B.; Harrington, R. W. Organometallics 2011, 30, 6010.
(14) For selected references on pyrolidin-2-one-directed C−H
activation, see: (a) Yeung, C. S.; Dong, V. M. Synlett 2011, 2011, 974.
(b) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci. 2010, 1,
331.
Accession Codes
CCDC 1822991 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(15) For selected references on quinoline-directed C−H activation,
see: (a) Wang, H.; Yu, S.; Qi, Z.; Li, X. Org. Lett. 2015, 17, 2812.
(b) Zhang, Y.; Feng, J.; Li, C. J. J. Am. Chem. Soc. 2008, 130, 2900.
(16) For selected references on isoquinoline-directed C−H activation
see: (a) Su, L.; Guo, D. D.; Li, B.; Guo, S. H.; Pan, G. F.; Gao, Y. R.;
Wang, Y. Q. ChemCatChem 2017, 9, 2001. (b) Zhang, P.; Hong, L.; Li,
G.; Wang, R. Adv. Synth. Catal. 2015, 357, 345.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: snieckus@chem.queensu.ca.
*E-mail: jerry_tanoury@vrtx.com.
ORCID
(17) (a) Nareddy, P.; Jordan, F.; Szostak, M. Org. Lett. 2018, 20, 341.
(b) Zhu, X.; Su, J. H.; Du, C.; Wang, Z. L.; Ren, C. J.; Niu, J. L.; Song, M.
P. Org. Lett. 2017, 19, 596. (c) Du, C.; Li, P. X.; Zhu, X.; Suo, J. F.; Niu, J.
L.; Song, M. P. Angew. Chem., Int. Ed. 2016, 55, 13571. (d) Wu, Q.; Du,
C.; Huang, Y.; Liu, X.; Long, Z.; Song, F.; You, J. Chem. Sci. 2015, 6, 288.
(e) Lu, M. Z.; Lu, P.; Xu, Y. H.; Loh, T. P. Org. Lett. 2014, 16, 2614.
(f) Punji, B.; Song, W.; Shevchenko, G. A.; Ackermann, L. Chem. - Eur. J.
2013, 19, 10605. (g) Yoshikai, N.; Matsumoto, A.; Norinder, J.;
Nakamura, E. Synlett 2010, 2010, 313. (h) Cheng, K.; Zhang, Y.; Zhao,
J.; Xie, C. Synlett 2008, 2008, 1325. (i) Hull, K. L.; Sanford, M. S. J. Am.
Chem. Soc. 2007, 129, 11904. (j) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am.
Chem. Soc. 2010, 132, 3648.
Victor Snieckus: 0000-0002-6448-9832
Present Addresses
§NMX Research and Solutions Inc., 500 Cartier Blvd. W., Laval,
́
Quebec, H7 V 5B7, Canada.
#Department of Chemistry and Biochemistry, The Ohio State
University, Columbus, OH 43210, USA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(18) To date the pyrimidine directed C−H activation on aryl attached
̌
This project was funded by the Natural Sciences and Engineering
Research Council of Canada−Collaborative Research and
Development (NSERC−CRD).
to C4 has been demonstrated only in three instances: (a) Stefane, B.;
Fabris, J.; Pozgan, F. Eur. J. Org. Chem. 2011, 2011, 3474. (b) Norinder,
̌
J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc. 2008,
130, 5858. (c) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem.
1997, 62, 2604.
REFERENCES
■
(19) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(20) Seki, M. Org. Process Res. Dev. 2016, 20, 867.
(21) (a) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (b) Oi,
S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org. Lett.
2001, 3, 2579.
(1) (a) Metal-catalyzed cross-coupling reactions and more; de Meijere, A.,
Brase, S., Oestreich, M., Eds.; Wiley-VCH: Weinheim, 2014. (b) Gensch,
T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev.
2016, 45, 2900. (c) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.;
Zhang, Y. Org. Chem. Front. 2015, 2, 1107. (d) Zhang, F.; Spring, D. R.
Chem. Soc. Rev. 2014, 43, 6906.
(22) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2009, 48, 5094.
(2) (a) Seechurn, C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V.
Angew. Chem., Int. Ed. 2012, 51, 5062. (b) The Mizoroki−Heck reaction;
Oestreich, M., Ed.; Wiley-VCH: Weinheim, 2009. (c) Chinchilla, R.;
Najera, C. Chem. Rev. 2007, 107, 874.
(23) (a) Aiso, H.; Kochi, T.; Mutsutani, H.; Tanabe, T.; Nishiyama, S.;
Kakiuchi, F. J. Org. Chem. 2012, 77, 7718. (b) Huang, C.; Chernyak, N.;
Dudnik, A. S.; Gevorgyan, V. Adv. Synth. Catal. 2011, 353, 1285.
(c) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006,
8, 2523.
(24) (a) Lakshman, M. K.; Zajc, B. ARKIVOC 2018, 2018, 252 and
references therein. (b) Lu, W.; Xu, H.; Shen, Z. Org. Biomol. Chem. 2017,
15, 1261. (c) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem.
Soc. 2006, 128, 6790. (d) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7,
4149.
(3) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722.
(4) Negishi, E. I. Angew. Chem., Int. Ed. 2011, 50, 6738.
(5) Knappke, C. E. I.; von Wangelin, A. J. Chem. Soc. Rev. 2011, 40,
4948.
(6) Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
4704.
(7) Nakao, Y.; Hiyama, T. Chem. Soc. Rev. 2011, 40, 4893.
(8) (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (b)
Activation of unreactive bonds and organic synthesis; Murai, S., Ed.;
Springer: New York, 1999. (c) Homogeneous catalysis for the unreactive
bond activation; Zhang-Jie, S., Ed.; Wiley-VCH: Weinheim, 2014.
(d) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529.
(25) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett.
2003, 5, 1899.
(26) Schafer, T.; Bujard, P.; Rogers, J.; Bardon, K. PCT Int. Appl. WO
2004039786A1.
(27) (a) Mohamed, R. K.; Mondal, S.; Guerrera, J. V.; Eaton, T. M.;
Albrecht-Schmitt, T. E.; Shatruk, M.; Alabugin, I. V. Angew. Chem., Int.
Ed. 2016, 55, 12054. (b) Feng, X.; Wu, J.; Ai, M.; Pisula, W.; Zhi, L.;
(9) For a special issue on C−H activation, see: Crabtree, R. H.; Lei, A.
Chem. Rev. 2017, 117, 8481.
Rabe, J. P.; Mullen, K. Angew. Chem., Int. Ed. 2007, 46, 3033.
̈
(10) (a) Reviews: Tobisu, M.; Chatani, N. Acc. Chem. Res. 2015, 48,
1717. (b) Cornella, J.; Zarate, C.; Martin, R. Chem. Soc. Rev. 2014, 43,
D
DOI: 10.1021/acs.orglett.8b01300
Org. Lett. XXXX, XXX, XXX−XXX