Pd-Catalyzed Desulfonative Cross-Coupling of Benzylic Sulfone Derivatives with 1,3-Oxazoles

Article abstract of DOI:10.1021/acs.orglett.7b01510

The Pd-catalyzed desulfonative cross-coupling reaction of benzylic sulfone derivatives with 1,3-oxazoles via a deprotonative pathway has been developed. Broad substrate scope for both sulfone and 1,3-oxazole partners is observed, affording a variety of 1,3-oxazole-containing triarylmethanes. Sulfone partners that are primary benzylic, secondary benzylic, and benzhydryl are all effective. Using this method, the straightforward synthesis of multiply arylated structures has been demonstrated.

Full text of DOI:10.1021/acs.orglett.7b01510

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Desulfonative Cross-Coupling of Benzylic Sulfone
Derivatives with 1,3-Oxazoles
Jacky C.-H. Yim,† Masakazu Nambo,*,† and Cathleen M. Crudden*,†,‡
†Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya 464-8601, Japan
‡Department of Chemistry, Queen’s University, Chernoff Hall, Kingston, Ontario K7L 3N6, Canada
S
* Supporting Information
ABSTRACT: The Pd-catalyzed desulfonative cross-coupling
reaction of benzylic sulfone derivatives with 1,3-oxazoles via a
deprotonative pathway has been developed. Broad substrate
scope for both sulfone and 1,3-oxazole partners is observed,
affording a variety of 1,3-oxazole-containing triarylmethanes.
Sulfone partners that are primary benzylic, secondary benzylic,
and benzhydryl are all effective. Using this method, the straightforward synthesis of multiply arylated structures has been
demonstrated.
of 1,3-oxazoles to access the corresponding triarylmethanes in
ultiply arylated methanes, including triarylmethanes,
Mhave considerable promise as functional organic good yields. As 1,3-oxazole-containing triarylmethanes have
materials and biologically active agents.1 In addition to
interesting biological applications, such as anti-inflammatory
agents,7 analgesics,8 and prostacyclin agonists,9 the develop-
ment of new straightforward and modular synthetic methods to
access these important molecules in a facile manner is
important for the discovery of novel compounds.
conventional synthetic methods using Lewis acid catalysts,2
transition-metal-catalyzed cross-coupling methods have been
shown to improve chemo- and regioselectivity and broaden the
scope of substrates, providing access to a wide variety of new,
multiply arylated structures.1a,b,3
Our group has developed an arylation strategy employing
organosulfones as starting materials in transition-metal-
catalyzed C−SO2 activation reactions that produce various
multiply arylated methanes.10 Recent advances include
enhancing the reactivity of the C−SO2 bond by the
introduction of electron-withdrawing substituents, such as
3,5-bis(trifluoromethyl)phenyl and trifluoromethyl on the
sulfone.10b Our work thus far has focused on Suzuki−Miyaura
cross-coupling reactions or Lewis acid catalyzed arylations with
these unique electrophiles. We envisioned that the scope of this
reaction would be enhanced if weakly acidic heteroaromatics
could be employed as coupling partners in a deprotonative
cross-coupling reaction manifold.3c,d,j Herein, we describe the
Pd-catalyzed desulfonative cross-coupling employing 1,3-
oxazoles and their derivatives as the nucelophiles (Figure 1).
Using this method, a variety of 1,3-benzoxazoles and oxazoles
react smoothly to afford 1,3-oxazole-containing triarylmethanes
in good yields. The sulfone substrates are readily prepared
through α C−H functionalization reactions. Overall, this
sequence results in the concise synthesis of multiply arylated
structures bearing the 1,3-oxazole fragment.
Despite remarkable progress in synthetic methods, cross-
coupling reactions for the preparation of triarylmethanes
bearing azoles have remained relatively unexplored (Figure
1). Some early examples include the Pd-catalyzed reaction
between aryl halides and 2-methyl-1,3-benzoxazole (as
described by Li)4a or the monoarylation of 2-benzyl-1,3-
benzoxazole (as described by Yorimitsu and Oshima).4b More
recently, the Wang group5 and the Miura group6 have
separately reported transition-metal-catalyzed diarylmethylation
We began our work with benzyl 3,5-bis(trifluoromethyl)-
phenyl sulfone 1a and benzoxazole (2a) as key substrates. In
early experiments,11 we found that bidentate phosphine ligands
gave the desired cross-coupling product 3aa along with 1,1,2,2-
tetraphenylethane (4) as a byproduct.6,12 Among the various
Figure 1. Synthesis of 1,3-oxazole-containing triarylmethanes via Pd-
catalyzed cross-coupling reactions.
Received: May 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bidentate phosphines, 1,3-bis(diphenylphosphino)propane
(dppp) was identified as the optimal ligand for this reaction
(Table 1, entry 1). Other common bidentate phosphines gave
Table 2. Pd-Catalyzed α-Arylation and Methylation of
Arylmethyl Sulfones 6 with Haloarenes 7−9 and
a
Iodomethane (ArF = 3,5-(CF3)2C6H3)
Table 1. Optimization of Pd-Catalyzed Cross-Coupling of
Diphenylmethyl Sulfone 1a with 1,3-Benzoxazole 2a (ArF =
a
3,5-(CF3)2C6H3)
b
entry
Ar
RX
1
yield (%)
1
2
3
4
5
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
p-FC6H4 (6b)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
PhI (7a)
1a
1a
1a
1b
1c
1d
1e
1f
92 (92)
(90)
(85)
87
PhBr (8a)
PhCl (9a)
p-MeOC6H4I (7b)
p-(Et2NCO)C6H4Br (8c)
p-FC6H4I (7d)
88
c
b
6
75
yield (3aa/4)
c
entry
Pd precursor
ligand
dppp
base (equiv)
(%)
7
1-bromonaphthalene (8e)
3-iodothiophene (7f)
3-iodopyridine (7g)
MeI (10h)
61
c
8
c
31
1
2
3
4
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
[PdCl(allyl)]2
LiO-t-Bu (3)
LiO-t-Bu (3)
LiO-t-Bu (3)
74/10
9
1g
1h
39
dppe
dppb
16/15
48/16
62/8
10
72
a
dcypp−2HBF4 LiO-t-Bu (3)
dppp
Conditions: 6 (1 equiv), 7−10 (1.5 equiv), Pd(OAc)2 (10 mol %),
c
P(t-Bu)3·HBF4 (30 mol %), Cs2CO3 (2 equiv), CPME (0.33 M), 120
°C, 24 h. Isolated yields. GC yields (decane as an internal standard)
are shown in parentheses. Reaction was conducted at 145 °C.
5
LiO-t-Bu (6)
LiO-t-Bu (6)
NaO-t-Bu (6)
KO-t-Bu (6)
LiO-t-Bu (6)
83/4
b
c
d
6
Pd2dba3·CHCl3 dppp
Pd2dba3·CHCl3 dppp
Pd2dba3·CHCl3 dppp
Pd2dba3·CHCl3 dppp
90(89) /7
38/8
c
c
7
c
8
36/29
c,e
9
46/54
a
Conditions: 1a (1 equiv), 2a (2 equiv), Pd precursor (5 mol %),
also be introduced, albeit in lower yields (Table 2, entries 8 and
9). The use of p-fluoroiodobenzene afforded the corresponding
sulfone 1d in good yield (Table 2, entry 6). With these
conditions, we were also able to introduce alkyl substituents.
For example, iodomethane was reacted to give the methylation
product (1h) without overalkylation (Table 2, entry 10). With
this more reactive electrophile, direct alkylation could be
accomplished without Pd catalyst; however, higher yields were
obtained under the catalytic manifold.
With a series of sulfones in hand, we investigated their
reactivity in the desulfonative cross coupling with several
benzoxazoles (Figure 2). Derivatives bearing 5-methyl (2b), 5-
methoxy (2c), and 5-(N,N-dimethylaminocarbonyl) (2d)
substituents were effective for this reaction, affording the
desired products (3ab, 3ac, and 3ad) in good to excellent
yields. Variations in the sulfone, such as the inclusion of
electron-donating (1b) or electron-withdrawing (1c, 1d)
substituents, were well tolerated. Sterically hindered sulfone
1e also gave the corresponding triarylmethane 3ea in good
yield. Unsymmetric diarylmethyl sulfones bearing heteroaryl
groups (1f, 1g) were also effective substrates.
With more stable 1,3-oxazoles, such as 5-aryl-1,3-oxazoles
(11a−i), high yields of the corresponding triarylmethanes
12aa−ai could be obtained with 2 equiv of the nucleophile
(Figure 3). 1,3-Oxazoles bearing both electron-rich (11b and
11d) and electron-deficient (11c) aryl groups at 5-position gave
the corresponding products (12ab, 12ac, and 12ad) in good
yields. 5-Heteroaryl substituents, such as 2-furyl and 2-thienyl,
were also well tolerated (12ae and 12af). On the other hand, 5-
(3-pyridyl)-1,3-oxazole (11g) showed low reactivity (55%
isolated yield), but by replacing the solvent 1,4-dioxane with
CPME, the yield of product 12ag was improved to 72%.
However, 5-(2-pyridyl)-1,3-oxazole (11h) gave a moderate
yield of 12ah (39%) even in CPME. When 4,5-diphenyl-1,3-
oxazole (11i) was used, the desired product 12ai was also
obtained in moderate yield with significant amounts of 4
detected.
b
ligand (10 mol %), base, 1,4-dioxane (0.33 M), 120 °C, 12 h. GC
yields were determined using decane as an internal standard. 4 equiv
of 2a were used. Isolated yield. Diphenylmethyl phenyl sulfone 5
was used instead of 1a.
c
d
e
decreased yields (Table 1, entries 2−4). Slight improvements in
yield could be obtained when 4 equiv of 2a and 6 equiv of base
were used (Table 1, entry 6), which is attributed to the
instability of 2a under reaction conditions. Since the gains in
yield are modest, a smaller excess (2 equiv) can be used and
still gives reasonable yields (compare entries 1 and 6, Table 1).
Similarly, we explored lower temperatures which might be
expected to improve the stability of 2a to the reaction
conditions, but in fact, lower yields were obtained (59% at 100
°C compared with 90% at 120 °C).
Intriguingly, base screening revealed that only LiO-t-Bu was
suitable for this reaction; other tert-butoxide bases (NaO-t-Bu,
KO-t-Bu) were less effective (Table 1, entries 7 and 8). This
result suggests that the counterion might affect the generation
of the azolylmetal species. Predictably, the reaction of the less
electrophilic diphenylmethyl phenyl sulfone (5) gave the
product in lower yield (Table 1, entry 9).
Having developed conditions for the cross coupling of simple
benzhydryl sulfone 1a, our next goal was to examine the scope
of sulfones tolerated (Table 2). We have previously prepared
simple unsymmetrical sulfones by the arylation of benzyl
sulfones (6) with Pd(OAc)2/P(t-Bu)3 as the catalyst system
and Cs2CO3 as a mild base.10b However, the scope of this
synthesis was not widely explored. We found that in addition to
previously reported iodobenzene both bromo and less reactive
chlorobenzene gave the phenylated product 1a in excellent
yields (Table 2, entries 1−3). Methoxy- and amide-substituted
arenes were well tolerated (Table 2, entries 4 and 5), and
sterically hindered 1-bromonaphthalene also provided the
desired product 1e (Table 2, entry 7). Heteroaromatic
substituents, such as the 3-thienyl and 3-pyridyl group, could
B
DOI: 10.1021/acs.orglett.7b01510
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Organic Letters
Letter
Scheme 1. Synthesis of Unsymmetric Triarylmethane 12eb
with Lower Catalyst Loading (ArF = 3,5-(CF3)2C6H3)
catalyst loading afforded unsymmetric triarylmethane 12eb in
73% yield.
Finally, we examined whether or not the transformation
would be successful with monoarylated sulfones, which are less
reactive than the benzhydryl derivatives described thus far. We
began by reacting benzyl sulfone 6a with 1,3-oxazole (11d)
under our standard conditions. However, the decreased
reactivity of 6a resulted in lower yields of product 13ad
(31%). Fortunately, we found that yield was improved to 56%
yield by simply changing the ratio of substrates (6a/11d = 2:1,
Scheme 2). This same strategy was effective for the reaction of
Scheme 2. Rapid Generation of Multiply Arylated Structures
Bearing 1,3-Oxazole from Arylmethyl Sulfone 6a
Figure 2. Pd-catalyzed desulfonative cross-coupling reaction of
diarylmethyl sulfones 1 with 1,3-benzoxazoles 2 (ArF = 3,5-
(CF3)2C6H3). Conditions: 1 (1 equiv), 2 (4 equiv), Pd2dba3·CHCl3
(5 mol %), dppp (10 mol %), LiO-t-Bu (6 equiv), 1,4-dioxane (0.33
M), 120 °C, 12 h.
a
Conditions: 1a (1 equiv), 11d (2 equiv), Pd2dba3·CHCl3 (5 mol %),
dppp (10 mol %), LiOt-Bu (3 equiv), 1,4-dioxane (0.33 M), 120 °C,
b
12 h. Conditions: 6a or 1h (2 equiv), 11d (1 equiv), Pd2dba3·CHCl3
(5 mol %), dppp (10 mol %), LiOt-Bu (3 equiv), CPME (0.33 M),
120 °C, 12 h.
1-phenylethyl sulfone 1h, which was easily prepared by α-
methylation of 6a, giving desired product 14hd in moderate
yield. As expected, 1,3-oxazole-containing triarylmethane 12ad
could be synthesized from 6a in two steps.
In summary, we have developed Pd-catalyzed desulfonative,
deprotonative cross-coupling reactions of benzylic sulfone
derivatives with 1,3-oxazoles to afford oxazole-containing
multiply arylated structures in a modular manner. These
structurally diverse derivatives can be synthesized by sequential
base-promoted α C−H functionalization followed by desulfo-
native cross-coupling starting from benzylic sulfones as the
reacting template. This sequence is highly tolerant of
functionality in the reacting partners, which will be important
for the discovery of new molecules with unique physical
properties and biological activities. This study illustrates the
potential of sulfones to act as versatile electrophiles in new
types of catalytic carbon−carbon-forming reactions. Further
Figure 3. Pd-catalyzed desulfonative cross-coupling of diphenylmethyl
sulfones 1a with 1,3-oxazoles 11 (ArF = 3,5-(CF3)2C6H3). Conditions:
1 (1 equiv), 2 (2 equiv), Pd2dba3·CHCl3 (5 mol %), dppp (10 mol %),
LiOt-Bu (3 equiv), 1,4-dioxane (0.33 M), 120 °C, 12 h. (a) Reaction
was conducted in CPME.
Using these optimized conditions, a gram-scale reaction was
carried out at 2% catalyst loading. As shown in Scheme 1, the
reaction of (1-naphthyl)phenylmethyl sulfone 1e with 5-(4-
methoxyphenyl)-1,3-oxazole 11b in the presence of 2 mol %
C
DOI: 10.1021/acs.orglett.7b01510
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(6) Tabuchi, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2014,
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studies toward expanding the scope of this reaction are
underway in our laboratory.
(7) Armand, L. J. F.; Edgard, F. E. J.; Gaston, V. M.; Maria, B. G. IL-5
inhibiting 6-azauracil derivatives. PCT Int. Appl. WO9902505A1, Jan
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ASSOCIATED CONTENT
* Supporting Information
■
S
(8) Hamanaka, N.; Takahashi, K.; Nagao, Y.; Torisu, K.; Tokumoto,
H.; Kondo, K. Bioorg. Med. Chem. Lett. 1995, 5, 1083−1086.
(9) Lee, L. F.; Masferrer, J. L.; Norman, B. H.; Talley, J. J. PCT Int.
Appl. WO1994027980A1, Dec 8, 1994.
(10) (a) Nambo, M.; Crudden, C. M. Angew. Chem., Int. Ed. 2014,
53, 742−746. (b) Nambo, M.; Keske, E. C.; Rygus, J. P. G.; Yim, J. C.
-H.; Crudden, C. M. ACS Catal. 2017, 7, 1108−1112. (c) Nambo, M.;
Ariki, Z. T.; Canseco-Gonzalez, D.; Beattie, D. D.; Crudden, C. M.
Org. Lett. 2016, 18, 2339−2342.
(11) For evaluation of other phosphine ligands and reaction
conditions, see Tables S1−S3 in the Supporting Information. See
Figure S1 in the Supporting Information for a tentative mechanistic
scheme.
(12) Byproduct 4 has also been observed by others when using
diarylmethyl electrophiles: Molander, G. A.; Elia, M. D. J. Org. Chem.
2006, 71, 9198−9202.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01510.
Detailed experimental procedures, characterization data,
1
and H, 13C, and 19F NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mnambo@itbm.nagoya-u.ac.jp.
*E-mail: cruddenc@chem.queensu.ca.
ORCID
Masakazu Nambo: 0000-0003-0153-3178
Cathleen M. Crudden: 0000-0003-2154-8107
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by KAKENHI from JSPS (26810056
to M.N.). J.C.-H.Y. is a recipient of a JSPS postdoctoral
fellowship for research in Japan (16F16749). JSPS and NU are
acknowledged for funding of this research through The World
Premier International Research Center Initiative (WPI)
program.
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DOI: 10.1021/acs.orglett.7b01510
Org. Lett. XXXX, XXX, XXX−XXX