Catalyst-Switchable Regiocontrol in the Direct Arylation of Remote C-H Groups in Pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1002/anie.201502150

The regiodivergent palladium-catalyzed C-H arylation of pyrazolo[1,5-a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. A phosphine-containing palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas a phosphine-free catalyst targets the most electron-rich position (C3).

Full text of DOI:10.1002/anie.201502150

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502150
German Edition: DOI: 10.1002/ange.201502150
À
C H Activation
Catalyst-Switchable Regiocontrol in the Direct Arylation of Remote
À
C H Groups in Pyrazolo[1,5-a]pyrimidines**
Robin B. Bedford,* Steven J. Durrant, and Michelle Montgomery
À
Abstract: The regiodivergent palladium-catalyzed C H ary-
lation of pyrazolo[1,5-a]pyrimidine has been achieved,
wherein the switch in regioselectivity between positions C3
and C7 is under complete catalyst control. A phosphine-
containing palladium catalyst promotes the direct arylation at
the most acidic position (C7), whereas a phosphine-free
catalyst targets the most electron-rich position (C3).
Figure 1. Catalyst-driven site selectivity in the arylation of pyrazolo[1,5-
a]pyrimidine (1).
À
À
T
he direct C H arylation of heterocyclic substrates
(Scheme 1) is a powerful synthetic tool for the construction
C H groups, and whether catalyst “tuning” could be
employed to drive this selectivity.[7]
We report herein the catalyst-controlled switching in
regioselectivity between the remote positions C3 and C7 of
pyrazolo[1,5-a]pyrimidine (1; Figure 1). We chose this motif[8]
because it forms the core of a range of biologically active
compounds. Specifically, aryl-substituted pyrazolo[1,5-a]pyr-
imidines show antitumor[9] and anti-inflammatory proper-
ties,[10] have been examined as hepatitis C virus inhibitors and
estrogen receptor ligands,[11,12] and are found in the approved
sedative agents zaleplon and indiplon as well as in the
anxiolytic agent ocinaplon.
À
Scheme 1. The direct C H arylation of heterocycles.
of functionalized heterocycles. It maintains the expediency
associated with simple cross-coupling reactions, but with
greater step economy and lower waste production.[1] In
À
heterocycles with multiple C H groups, it would be highly
À
advantageous to be able to choose which C H group is
functionalized, ideally with complete selectivity and with the
ability to “switch” regioselectivity at will.[2] Seminal examples
of this approach include the vinylation or arylation of pyrroles
and indoles at either C2 or C3, where the outcome is driven by
a change in substrate derivatization,[3,4] solvent,[5] or oxidant.[6]
In these cases, the site selectivity is typically controlled by
prohibiting or encouraging migration between positions C3
and C2. By contrast, we were interested to find out whether
site selectivity could be engendered in the arylation of remote
[*] Prof.Dr. R. B. Bedford, M. Montgomery
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: r.bedford@bristol.ac.uk
We began our study with the optimization of the coupling
of compound 1 with bromobenzene in the presence of
a variety of palladium sources, with and without phosphines,
changing solvents, bases, additives, and conditions. The results
from this survey are summarized in the Supporting Informa-
tion, and Scheme 2 highlights the optimized conditions.
The use of the monodentate phosphine ligand SPhos
proved crucial to achieving site selectivity at C7, giving the
desired product 2a in good yield.[13] NMR and UHPLC/ES-
MS analyses of the crude reaction mixture showed a trace
amount (4%) of the 3,7-diphenylated product (4a) but none
of the 3-arylated species 3a, thus indicating that arylation at
C3 can only occur (to a very limited extent) after arylation at
C7.[14] Conveniently, the reaction works just as well under air
as under an inert atmosphere. The relatively high air stability
of SPhos is obviously a pivotal factor here.[15]
Dr. S. J. Durrant
Vertex Pharmaceuticals Ltd. (Europe)
86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire, OX14
4RW (UK)
[**] We thank the EPSRC the Bristol Chemical Synthesis Centre for
Doctoral Training (M.M.) and Vertex Pharmaceuticals for funding.
We thank Dr. Nathalie Fey for very helpful discussions regarding the
computational analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502150.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Angew. Chem. Int. Ed. 2015, 54, 8787 –8790
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8787

.
Angewandte
Communications
Scheme 2. Results of optimization of reaction conditions. Yields deter-
mined by 1H NMR spectroscopy (1,3,5-(MeO)3C6H3 used as internal
standard).
By contrast, the use of palladium acetate alone, in the
absence of a phosphine co-ligand, led to selective arylation at
C3, giving 3a in good yield. The arylation at C3 is marginally
less selective, giving small amounts of 2a and 4a.[14]
Figure 2. Products of the C7 arylation of compound 1 (0.25 mmol)
with aryl bromides under reaction conditions A (Scheme 2).
The addition of a salt such as lithium chloride proved
essential for maintaining a good yield in the SPhos-containing
reaction, with only 40% of 2a obtained in its absence, while in
the phosphine-free case omitting the salt led to a pronounced
decrease in selectivity with significant amounts of 2a (10%)
and the diarylated product 4a (12%) obtained in addition to
the desired product 3a (50%).[16]
With the optimized conditions to hand, we next examined
the range of aryl bromides that could be exploited in the C7-
selective reaction (Figure 2).[17] Electron-donating, electron-
withdrawing, and sterically demanding substrates were all
tolerated under the reaction conditions and the products (2a–
l) were isolated in moderate to excellent yields. Gratifyingly,
ester and nitro functionalities were tolerated under the
reaction conditions (2 f and i). Aryl chlorides do not
participate in the reaction, thus allowing them to be
incorporated into the product (2g) and therefore offering
an opportunity for subsequent functionalization. In addition,
heteroaryl bromides are compatible with the reaction con-
ditions, enabling the preparation of compounds 2m–p in one
step, in moderate to good yields, from commercial starting
materials.
Figure 3 summarizes the C3-selective arylation reactions
with a range of aryl bromides under phosphine-free con-
ditions.[17] Again, electron-donating, electron-withdrawing,
sterically demanding, and heteroaryl bromides were all
tolerated under the reaction conditions, giving isolated 3-
arylpyrazolo[1,5-a]pyrimidines (3a–q) in moderate to excel-
lent yields. In addition, 3-bromobenzonitrile, which did not
react in the C7 arylation, was tolerated under the reaction
conditions to afford 3k in good yield.
Figure 3. Products of the C3 arylation of compound 1 (0.25 mmol)
with aryl bromides under reaction conditions B (Scheme 2).
Selected products of the C3- or C7-arylation reactions can
subsequently be arylated in the alternative position in
reasonable yields (Scheme 3).
Finally we turned our attention to gleaning preliminary
mechanistic insights. It is clear from previous reports that the
8788
www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 8787 –8790

Angewandte
Chemie
a base-assisted deprotonation mechanism for C7 arylation on
addition of SPhos.[21] In base-assisted deprotonation, the C H
À
bond cleavage is slow with respect to the coordination of the
aryl function to the metal center, however, the rate-determin-
À
ing step in the catalytic manifold may not be the C H bond
cleavage. Indeed, a competition experiment between 1 and
[7-D]-1 (Scheme 5) shows only a modest kinetic isotope effect
À
(KIE), inconsistent with C H bond cleavage being the rate-
determining step in the cycle.[22]
Scheme 3. Sequential arylation reactions, for conditions see Scheme 2.
Scheme 4. Deuteration of 1 to [7-D]-1, conversion determined by
Scheme 5. Competitive arylation of deuterated and nondeuterated
substrates. KIE determined by 1H NMR spectroscopy (1,3,5-tri-
methoxybenzene used as internal standard).
1H NMR spectroscopy.
natural site of electrophilic substitution is the C3 position,[18]
while a simple deuteration experiment (Scheme 4) confirmed
that the most acidic site is the C7 position. These empirical
observations are supported by density functional theory
(DFT) calculations.[19] On the one hand, these showed that
the HOMO orbital has significant electron density at the C3
position, and that this position has by far the highest
“electrophile affinity” (Ea) value (Figure 4a),[20] on the
other hand, they highlight the significantly greater acidity of
With regard to the type of palladium species responsible
for the C7 arylation, the requirement for SPhos makes it
likely that the active component is a homogeneous complex.
Indeed, a 31P{1H} NMR spectrum of a catalytic reaction
mixture of 1 reacting with PhBr (conditions A, Scheme 2)
recorded after 1.5 h (corresponding to ꢀ 30% conversion to
2a) showed the presence of two main species (in addition to
free SPhos),[23] neither of which require the presence of either
1 or PhBr to form.[24] The structures and possible involvement
or otherwise of these species in the catalytic cycle is the
subject of ongoing investigations.
À
the C7 H group as determined by comparing the calculated
relative energies for the removal of each of the protons by
acetate (Figure 4b).
These observations suggest that the change in observed
Turning our attention to the active species in C3 arylation,
it seems likely that the reactions proceed through the
formation of heterogeneous palladium. In contrast with the
C7-arylation reaction, which showed a fairly short induction
period of around 20 min,[25] the C3-arylation reaction dis-
played a protracted induction phase of several hours, a time
that varied significantly between runs (Figure 5).[25,26] In these
cases, the timing of the onset of catalysis coincided with
a change in appearance from a yellow, homogeneous solution
to a black suspension.
À
regioselectivity is the direct result of a switch in the C H
activation mechanism from electrophilic palladation in the
case of C3 arylation under phosphine-free conditions, to
The induction phase was followed by a period of activity
before the onset of catalyst decomposition. Interestingly,
there appear to be two distinct periods of catalysis (Figure 5),
suggesting that there are at least two discrete catalytically
active species, one formed during the induction phase before
rapidly undergoing deactivation, and a second species that is
formed later accounting for the major proportion of coupled
product.[27] The extended induction period, the observation of
more than one active species, and the fact that catalysis
terminates before completion of the reaction all imply that
the formation of heterogeneous palladium is not by itself
sufficient for activity,[28] instead it is likely that catalysis is
restricted to smaller palladium clusters or nanoparticles that
change morphology over the course of the reaction before
undergoing decomposition by over-aggregation, which leads
to loss of activity.
Figure 4. Summary of DFT computational results. a) Left: calculated
(B3LYP-d2/6-311+ +G(d)) HOMO for 1 (isovalue Æ0.05 (electron/
bohr3)1/2), right: gas-phase electrophile affinity (Ea) values, determined
using Br+ as test electrophile (B3LYP/6-311+G(2d,2p)). b) Calculated
(B3LYP/6-311+ +G(2df,2p)//B3LYP/6-31G(d)) free energies for the
deprotonation of each of the CH groups of 1 by acetate.
Angew. Chem. Int. Ed. 2015, 54, 8787 –8790
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8789

.
Angewandte
Communications
[9] A. Kiessling, R. Wiesinger, B. Sperl, T. Berg, ChemMedChem
2007, 2, 627.
[10] C. Almansa, A. F. de Arriba, F. L. Cavalcanti, L. A. Gómez, A.
Miralles, M. Merlos, J. García-Rafanell, J. Forn, J. Med. Chem.
2001, 44, 350.
[11] J. Y. Hwang, M. P. Windisch, S. Jo, K. Kim, S. Kong, H. C. Kim, S.
Kim, H. Kim, M. E. Lee, Y. Kim, J. Choi, D. S. Park, E. Park, J.
Kwon, J. Nam, S. Ahn, J. Cechetto, J. Kim, M. Liuzzi, Z. No, J.
Lee, Bioorg. Med. Chem. Lett. 2012, 22, 7297.
[12] D. R. Compton, S. Sheng, K. E. Carlson, N. A. Rebacz, I. Y. Lee,
B. S. Katzenellenbogen, J. Katzenellenbogen, J. Med. Chem.
2004, 47, 5872.
[13] A reaction that was performed under the same conditions, but in
the absence of SPhos, gave both 2a (8%) and 3a (9%).
Replacing toluene with 1,4-dioxane under the optimized con-
ditions reduced the conversion to 2a to 36%, but did not affect
the selectivity.
[14] The selectivities shown in Scheme 2 are reflected in the
selectivities of the reactions outlined in Figures 2 and 3, see
the Supporting Information (Table S4) for full details.
[15] T. E. Barder, S. L. Buchwald, J. Am. Chem. Soc. 2007, 129, 5096.
[16] Repeating the C7 arylation with Li2CO3, LiOH, and NaCl in
place of LiCl gave 2a in 77, 28, and 48%, respectively. In the case
of C3 arylation, LiOH, Li2CO3, and NaCl gave essentially
identical performance to LiCl.
[17] See the Supporting Information for experimental details.
[18] For selected examples of electrophilic substitution at C3, see:
a) B. M. Lynch, M. A. Khan, S. C. Sharma, H. C. Tea, Can. J.
Chem. 1975, 53, 119; b) G. D. Cuny, P. B. Yu, J. K. Laha, X. Xing,
J. F. Liu, C. S. Lai, D. Y. Deng, C. Sachidanandan, K. D. Bloch,
R. T. Peterson, Bioorg. Med. Chem. Lett. 2008, 18, 4388; c) J.
Quiroga, J. Trilleras, B. Insuasty, R, Abonía, M. Nogueras, J.
Cobo, Tetrahedron Lett. 2008, 49, 2689.
Figure 5. C3-Arylation of 1 with PhBr (see the Supporting Information
for conditions) followed over time. Conversion to 3a determined by
1H NMR spectroscopy (1,3,5-trimethoxybenzene used as internal stan-
dard).
In conclusion, we have developed a switchable site-
selective direct arylation, wherein the switching is controlled
by a change in mechanism, facilitated by tuning the compo-
sition of the catalyst. Thus the site of the reaction of
pyrazolo[1,5-a]pyrimidine with aryl bromides can be switched
between the remote positions C3 and C7. Studies are ongoing
to both develop new reactions that proceed through switch-
À
able remote site-selective C H functionalization and to fully
elucidate the mechanisms that facilitate the switching.
À
Keywords: arylation · catalysis · C H activation · palladium ·
regiocontrol
[19] For full details and a discussion of the computational studies, see
the Supporting Information.
[20] For definition and discussions of electrophile affinity (Ea), see:
a) G. Koleva, B. Galabov, J. I. Wu, H. F. Schaefer III, P. v. R.
Schleyer, J. Am. Chem. Soc. 2009, 131, 14722; b) B. Galabov, G.
Koleva, H. F. Schaefer III, P. v. R. Schleyer, J. Org. Chem. 2010,
75, 2813.
[21] For a recent review on base-assisted deprotonation, see: Y.
Boutadla, D. L. Davis, S. A. Macgregor, A. I. Poblador-Baha-
monde, Dalton Trans. 2009, 5820.
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8787–8790
Angew. Chem. 2015, 127, 8911–8914
[1] For selected recent reviews, see: a) I. J. S. Fairlamb, Chem. Soc.
Rev. 2007, 36, 1036; b) L. Ackermann, R. Vicente, A. R. Kapdi,
Angew. Chem. Int. Ed. 2009, 48, 9792; Angew. Chem. 2009, 121,
9976; c) A. Sharma, D. Vacchani, E. Van der Eycken, Chem. Eur.
J. 2013, 19, 1158; d) K. Hirano, M. Miura, Synlett 2011, 294; e) R.
Rossi, F. Bellina, M. Lessi, C. Manzini, Adv. Synth. Catal. 2014,
356, 17.
À
[22] For a useful discussion on KIEs in C H functionalization, see:
E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51,
3066; Angew. Chem. 2012, 124, 3120.
À
[2] For a recent discussion on controlling site selectivity in C H
[23] The first of these (5) gave a singlet at 44.4 ppm (major
component). The second species (6) gave doublets at 48.6 and
functionalization processes, see: S. R. Neufeldt, M. S. Sanford,
Acc. Chem. Res. 2012, 45, 936.
[3] E. M. Beck, N. P. Grimster, R. Hatley, M. J. Gaunt, J. Am. Chem.
Soc. 2006, 128, 2528.
[4] R. J. Phipps, N. P. Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008,
130, 8172.
[5] N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt,
Angew. Chem. Int. Ed. 2005, 44, 3125; Angew. Chem. 2005, 117,
3185.
[6] D. R. Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007,
129, 12072.
[7] Catalyst tuning has been exploited in the control of selective C3
versus C2 arylation of thiophenes. See: K. Ueda, S. Yanagisawa,
J. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2010, 49, 8946;
Angew. Chem. 2010, 122, 9130.
2
À56.8 ppm with a Jpp = 389 Hz (minor component).
[24] Stirring Pd(OAc)2 with two equivalents of SPhos in toluene for
30 min gave a solution of 6, while the reaction between
Pd(OAc)2, SPhos (2 equiv), and Cs2CO3 (10 equiv) in toluene
gave 5.
[25] See the Supporting Information.
[26] In this case, individual reactions were analyzed at the specified
time.
[27] For a recent review on the mechanisms of nucleation and
nanoparticle growth, see: N. T. K. Thanh, N. Maclean, S.
Mahiddine, Chem. Rev. 2014, 114, 7610.
[28] In support of this, the use of palladium on carbon or commercial
palladium black gave no activity.
À
[8] To the best of our knowledge, the only prior example of C H
arylation of this motif is the C3 arylation of 5,7-dimethyl-2-
phenylpyrazolo[1,5-a]pyrimidine, in which the C7 position is
blocked. See: I. Bassoude, S. Berteina-Raboin, S. Massip, J.
Leger, C. Jarry, E. M. Essassi, G. Guillaumet, Eur. J. Org. Chem.
2012, 2572.
Received: March 6, 2015
Revised: April 8, 2015
Published online: June 10, 2015
8790 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 8787 –8790