Preparation of Quaternary Centers via Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Tertiary Sulfones

Article abstract of DOI:10.1021/jacs.7b10855

We describe the development of a nickel-catalyzed Suzuki-Miyaura cross-coupling of tertiary benzylic and allylic sulfones with arylboroxines. A variety of tertiary sulfones, which can easily be prepared via a deprotonation-alkylation route, were reacted to afford symmetric and unsymmetric quaternary products in good yields. We highlight the use of either BrettPhos or Doyle's phosphines as effective ligands for these challenging desulfonative coupling reactions. The utility of this methodology was demonstrated in the concise synthesis of a vitamin D receptor modulator analogue.

Full text of DOI:10.1021/jacs.7b10855

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Communication
Preparation of Quaternary Centers via Nickel-Catalyzed
Suzuki-Miyaura Cross-Coupling of Tertiary Sulfones
Zachary T. Ariki, Yuuki Maekawa, Masakazu Nambo, and Cathleen M. Crudden
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Dec 2017
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Preparation of Quaternary Centers via Nickel-Catalyzed Suzuki-
Miyaura Cross-Coupling of Tertiary Sulfones
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Zachary T. Ariki†, Yuuki Maekawa†, Masakazu Nambo‡*, and Cathleen M. Crudden† *
‡
†
Department of Chemistry, Queen’s University, Chernoff Hall, Kingston, Ontario, Canada
‡ Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, Japan
Supporting Information Placeholder
cross coupling of tertiary benzylic and allylic sulfones with aryl-
boron compounds catalyzed by Ni
ABSTRACT: We describe the development of a nickel-
catalyzed Suzuki-Miyaura cross-coupling of tertiary benzylic and
allylic sulfones with arylboroxines. A variety of tertiary sulfones,
which can easily be prepared via a deprotonation-alkylation route,
were reacted to afford symmetric and unsymmetric quaternary
products in good yields. We highlight the use of either BrettPhos
or the Doyle’s phosphines as effective ligands for these challeng-
ing desulfonative reactions. The utility of this methodology was
demonstrated in the concise synthesis of a vitamin D receptor
modulator analogue.
Scheme 1. Preparation of quaternary centres via metal-
catalyzed cross-coupling reactions of tertiary electrophiles.
Previous Work: Suzuki-Miyaura cross-coupling of tertiary electrophiles
NiBr2•DME
Alkyl Alkyl
Alkyl Alkyl
PyBOX
Fu et al.4a
Ar (9-BBN)
Ar B(neop)
Alkyl
Alkyl
Br
Ar
NiCl2•DME
CyJohnPhos
Me Et
Me Et
Watson et al.4b
Ar1
Ar
Ar1
OAc
up to >99% es
The Suzuki-Miyaura cross-coupling reaction is a powerful
method for the formation of carbon-carbon bonds1 that has found
utility in the synthesis of bioactive compounds, materials, dyes,
and natural products.2 While there are many effective examples of
the cross coupling of secondary electrophiles to furnish tertiary
products,3 there are only limited examples of Suzuki-Miyaura
cross-couplings of tertiary electrophiles.4 Since slow oxidative
addition and facile β-hydride elimination reactions are difficulties
associated with tertiary electrophiles, it is unsurprising that this is
a challenging reaction. The quaternary center motif is, however,
prevalent in bioactive compounds and natural products5 and thus
other valuable methods have been developed to access this func-
tional group.5,6,7,8 For allylic substrates, these methods include
substitution reactions of secondary allylic electrophiles9 and
Morken's cross-coupling of allylic boronate esters.10 Suzuki-
Miyaura cross-coupling methodologies to prepare quaternary
centers employing tertiary electrophiles are limited to only two
reports by Fu4a and Watson4b (Scheme 1).
In order to address the deficiency in cross-coupling approaches
to quaternary centers, we employed our recently developed sul-
fone electrophiles along with typical boron-based coupling part-
ners (Scheme 1).11 Previously, our group has reported the synthe-
sis of multiply-arylated methanes via α-arylation followed by
Suzuki-Miyaura cross-couplings with methyl sulfone deriva-
tives.11 If these sulfones could be prepared rapidly via deprotona-
tive functionalizations it would be a useful method to access com-
plex molecules in few steps. However, cross-coupling had not
been demonstrated on sulfones bearing alkyl groups on the ben-
zylic carbon, and the preparation of quaternary centres was simi-
larly unknown. With benzylic functionalization facilitated due to
the inherent acidity of hydrogens α to the sulfonyl group,12 the
challenge entailed the use of these species in cross-coupling
chemistry to generate quaternary centres. Herein, we describe
This Work: Suzuiki-Miyaura cross-coupling of tertiary sulfones as electrophiles
R1 R2
Ni catalysis
R1 R2
SO2Ph
(Ar2BO)3
Ar1
Ar1
Ar2
bench stability
rapid preparation
diverse quaternary products
(Scheme 1). A variety of functionalized methane derivatives were
easily obtained from readily available building blocks.
We began our investigation into the desulfonative cross-
coupling reaction of dimethyl(naphthyl)methyl phenyl sulfone 1a
with 4-methoxyphenylboronic acid. For our first attempts, bis(1,5-
cyclooctadiene)nickel (Ni(cod)2) was selected as the catalyst and
the electron-rich and bulky Buchwald biaryl phosphine, RuPhos13
(L1), as ligand (Chart 1). Using NaOEt as the base at 85 °C in
toluene, we were delighted to obtain the desired quaternary cross-
coupled product 2aa in 40% yield (Table 1, entry 1). A significant
improvement was observed when the corresponding boroxine 3a
was used in place of the boronic acid, giving 2aa in 86% yield
(entry 2). Examination of other biaryl(dialkyl)phosphine ligands
led us to identify BrettPhos (L2) as a superior ligand giving the
quaternary product 2aa in 91% yield (entry 3).
Recently, Doyle reported a novel class of dialkyl aryl phos-
phine ligands designed for nickel-catalyzed reactions.14 We were
delighted to find that one of these ligands, L3 (Chart 1) gave the
desired product in near quantitative yield (entry 4). Thus either
this ligand, or Brettphos were employed for further optimization.
Ethereal solvents did not promote the reaction (entry 6) and fur-
ther studies showed that the arylboroxine loading could be re-
duced to 0.7 equivalents relative to the sulfone (entries 3, 5-8).
Lowering or raising the reaction temperature to 60 °C or 120 °C,
respectively, diminished the yield of quaternary product (entries 9
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and 10). The use of electron-donating N-heterocyclic carbene
(3h,3i, 3j). The Doyle ligand L3 proved advantageous when steri-
cally hindered arylboroxines (3j, 3k, 3l) were used, providing
significantly improved yields. Additionally, BrettPhos L2 did not
promote the cross couplings of 4-trifluoromethoxyphenylboroxine
(3f), (4-methoxylcarbonyl)phenylboroxine (3m), or 4-
chlorophenylboroxine (3o) and no quaternary products were de-
tected. However, when L3 was employed as the ligand, the corre-
sponding products were obtained in modest to good yields. 4-
Vinylphenylboroxine (3n) reacted in low yield likely due to the
formation of by-products by reaction at the vinyl moiety.15 Unfor-
tunately, electron-deficient heteroarylboroxines such as 3-
pyridylboroxine (3p), 3-thiophenylboroxine (3q), and 2-
furylboroxine (3r) were not effective cross-coupling
parnters.4b,14,16
ligands such as L4 and L5 afforded reduced amounts of 2aa (en-
tries 11 and 12). Finally, control reactions confirmed the require-
ment of both the nickel catalyst and ligand (entries 13 and 14).
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Table 1. Optimization of the Suzuki-Miyaura cross-coupling
reaction of 1a with 3a.a
10 mol % Ni(cod)2,
12 mol % ligand
Ar2B(OH)2 or (Ar2BO)3 (3a)
Me Me
SO2Ph
Me Me
NaOEt
PhMe
9
OMe
85 °C, 16 h
(Ar = 4-MeOC6H4)
1a
2aa
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Entry
Arylboron
(equiv)
Ligand
NaOEt
(equiv)
Yieldb
Table 2. Scope of Suzuki-Miyaura cross-coupling reaction of 1a
with arylboroxines 3.a
10 mol % Ni(cod)2
1
2
ArB(OH)2 (2.0)
(ArBO)3 (3a) (1.0)
3a (0.7)
RuPhos (L1)
1.5
40%
86%
91%
98%d
88%d
32%
55%
71%
80%
80%
<5%
62%d
n.d.
L1
2.25
2.2
12 mol % ligand
0.7 equiv (Ar2BO)3 (3)
Me Me
SO2Ph
Me Me
3
BrettPhos (L2)
Ar2
2.2 equiv NaOEt
PhMe
85 °C, 16 h
4c
5
3a (0.7)
Doyle (L3)
2.2
1a
2
3a (1.0)
L2
2.25
2.25
0.75
1.1
Me Me
2-Naph
Me Me
2-Naph
Me Me
2-Naph
6e
7
3a (1.0)
L2
3a (0.3)
L2
OMe
CF3
2aa
L2: 88%, 77%b
L3: 98%c
2ab
L2:88%
2ac
L2:73%
8
3a (0.3)
L2
9f
3a (0.7)
L2
2.2
Me Me
Me Me
NMe2
2-Naph
Me Me
2-Naph
10g
11
12
13h
14
3a (0.7)
L2
SIPr⋅HCl (L4)
SICy⋅HCl (L5)
L2
2.2
2-Naph
F
OCF3
3a (0.7)
4.1
2ad
L2: 98%
2ae
L2:70%
2af
L2: 0%
L3: 48%c
3a (0.7)
4.1
Me Me
Me Me
2-Naph
Me Me
3a (0.7)
2.2
Me
2-Naph
2-Naph
3a (0.7)
--
2.2
trace
Ph
2ag
L2:80%
2ah
L2:83%
2ai
L2:98%
Me
a Conditions: 1a (0.1 mmol), ArB(OH)2 or (ArBO)3 (3a) (0.7–2.0
equiv), Ni(cod)2 (10 mol %), ligand (12 mol %), NaOEt (1.1-4.1
equiv), PhMe (0.2 M). b Determined by GC-MS integration; dodec-
ane was used as an internal standard. c Reaction conducted at 0.05
mmol scale. d Isolated yield. e THF was used in place of PhMe.
Reaction conducted at 60 °C. g Reaction conducted at 120 °C. h Re-
action conducted without Ni(cod)2. n.d. = not detected.
Me
OMe
Me Me
2-Naph
Me Me
Me Me
2-Naph
2-Naph
f
2aj
2ak
2al
L2: 45%
L3: 86%b
L2: 60%
L3: 77%c
L2: 26%
L3: 89%c
Me Me
Me Me
2-Naph
Me Me
2-Naph
i-Pr
i-Pr
iPr
2-Naph
N
N
OMe
Cl
i-Pr i-Pr
CO2Me
Cl
2am
2an
L2:25%
2ao
iPr
iPr
L2: 0%
L3: 85%c
L2: 0%
L3: 21%c
P(Cy)2 MeO
OiPr iPr
P(Cy)2
iPr
SIPr•HCl
L4
iPr
iPrO
a Conditions: 1a (0.1 mmol), 3 (0.7 equiv), Ni(cod)2 (10 mol %),
ligand (12 mol %), NaOEt (2.2 equiv), PhMe (0.2 M). b Reaction
conducted at 3.22 mmol (1.0 g) scale. cReaction conducted at 0.05
mmol scale.
(Cy)2P
N
N
iPr
iPr
iPr
Cl
RuPhos
L1
BrettPhos
L2
Doyle
L3
SICy•HCl
L5
Chart 1. Ligands employed in screening study.
Next, we sought to examine the scope of the tertiary benzylic
sulfone electrophiles (Table 3). These compounds were readily
prepared by deprotonative alkylation of benzyl sulfones (details in
Supporting Information). With respect to the aryl substituent,
electron-rich (2ba) and sterically hindered (2ca, 2da) π-extended
aromatics were well tolerated. 6-Quinolinyl sulfone 1e also un-
derwent cross-coupling albeit in modest yield (2ea). Unfortunate-
ly, when the naphthyl group was substituted with a phenyl group,
no cross- coupled product (2la) was detected using either L2 or
L3, consistent with a likely requirement for a π-benzyl nickel
intermediate.4b,17 In terms of the alkyl substituents, primary alkyl
Having identified two ligands, L2 and L3, capable of promot-
ing the desulfonative cross-coupling reaction under the optimized
conditions (entries 3 and 4), we then examined the scope of aryl-
boroxines (Table 2). Electron-rich (3a, 3e), neutral (3b, 3d, 3g),
and electron-deficient (3c) arylboroxines afforded the correspond-
ing quaternary products in good yields. To demonstrate the effec-
tiveness of the reaction on a larger scale, 1 g of 1a was cross-
coupled to afford 2aa in 77% yield. For this reaction, the com-
mercially available ligand Brettphos was employed. Conjugated
and π-extended aryl boroxines also cross-coupled efficiently
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chains of increasing steric hindrance (2fa, 2ga, 2ha) were well
tolerated to afford interesting unsymmteric methane derivatives.
And a synthetically useful allyl group could be introduced into
product (2ja) in moderate yield.
Table 3. Scope of tertiary benzylic (1) and allylic sulfones 3.a
1
2
3
4
5
6
7
8
10 mol % Ni(cod)2
12 mol % ligand
R1 R2
R1 R2
(Ar2BO)3
SO2Ph
Ar1
Ar2
Ar1
2.2 equiv NaOEt
PhMe
85 °C, 16 h
3
(0.7 equiv)
2, 5
1, 4
9
Benzylic sulfones
Allylic sulfones
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Me
Me Me
Me Me
Me Me
Me Me
Me Me
Ph
Me Me
Ph
OMe
OMe
OMe MeO
OMe
OMe
5aa
L2:87%
5ak
L3:80%b
2aa
L2:88%
2ba
L2:90%
2ca
L2:80%
2da
L3:57%b
Me
Me
Ph
Me Me
Me
Me Me
Me Me
Me
Me
Me
Ph
S
Me
N
OMe
OMe
CF3
OMe
OMe
OMe
5ac
2ea
L3:30%b
2fa
L2:92%
2ga
L3:53%b
2ha
L3:89%b
5ba
L2: 0%
L3: 66%b
L2: 19%
L3: 81%b
Me Me
Me
Me Ph
Me Me
O
OMe
OMe
OMe
OMe
5ca
OMe
2ia
L3:47%b
2ja
L3:51%b
2ka
L3:86%b
2la
L2, L3: 0%
L2: 63%
L3: 72%b
a Conditions: sulfone 1 or 4 (0.1 mmol), 3 (0.7 equiv), Ni(cod)2 (10 mol %), ligand (12 mol %), NaOEt (2.2 equiv), PhMe (0.2 M). b Reac-
tion conducted at 0.05 mmol scale
A sulfone bearing a cyclic alkyl group (1j) was also cross-
coupled in good yield. As well, a diarylalkylmethyl sulfone 1k
was cross-coupled to afford the corresponding triarylalkyl me-
thane 4ka in good yield. Analogously to the cross-coupling of
arylboroxines, the cross-coupling of sterically hindered sulfones
was most effective with L3.
Scheme 2. Synthesis of vitamin-D receptor modulator.a
Et Et
SO2Ph
a. EtI, NaHMDS
SO2Ph
(37%)
MeO2C
MeO2C
6
7
In addition to these results employing π-extended tertiary sul-
fones, we were intrigued to find that tertiary allylic sulfones could
also be cross-coupled to afford the corresponding quaternary al-
lylic products. With respect to the arylboroxine, electron rich (3a),
electron-poor (3c), and bulky (3k) substrates underwent cross-
coupling in good yields. With the use of the ligand L3, we were
excited to find that heteroaromatic moieties were well tolerated,
giving quaternary products 5ba and 5ca. For these substrates,
interestingly, no isomerization of the alkene was observed and the
linear cross-coupled product was exclusively obtained. We as-
sume that by coupling at the linear position, conjugation with the
aromatic system is maintained. Indeed, when the cross coupling
reaction of allyl phenyl sulfone was conducted under the standard
reaction conditions, the linear and branched products were ob-
tained in nearly 1:1 ratios (see Supporting Information).
To demonstrate the utility of present cross-coupling reaction, we
selected the vitamin D receptor modulator 10 as a synthetic target
(Scheme 2).18 Tertiary benzylic sulfone 7 was prepared via the
double-alkylation of benzyl sulfone 6 using NaHMDS and io-
doethane. Subjecting the tertiary benzylic sulfone to our opti-
mized cross-coupling conditions gave the quaternary product 8 in
good yield. Subsequent deprotection was promoted by BBr3.
Since treating compound 9 with 2-tert-butyl oxirane directly af-
forded two products resulting from alkylation at the carboxylate
and phenolate, 9 was protected as the methyl ester prior to alkyla-
tion. Subsequent deprotection afforded the desired product 10 in
good yield in 6 total steps from the primary benzylic sulfone indi-
cating that our method can be used to prepare such biologically-
active molecules having quaternary centres in a modular manner.
b. (Ar2BO)3 (3s)
Ni(cod)2, L3
Et Et
Me
OR
(65%)
RO2C
8, R = Me
9, R = H
c. BBr3
(83%)
d. H2SO4, MeOH
Et Et
O
e.
f. KOH
(71%, 3 steps)
Cs2CO3
t-Bu
Me
O
t-Bu
OH
HO2C
10
Vitamin-D receptor
modulator
a
Reaction conditions: (a) EtI, NaHMDS, THF, 0 °C; (b) 4-
Methoxy-3-methylphenyl-boroxine (3s), Ni(cod)2, L3, NaOEt,
PhMe, 85 °C; (c) BBr3, CH2Cl2, -78 °C; (d) H2SO4, MeOH; (e) 2-
tert-butyl oxirane, Cs2CO3; (f) KOH, THF.
In conclusion, we have developed a Suzuki-Miyaura cross-
coupling of tertiary benzylic and allylic sulfones as new electro-
philes to yield structurally diverse quaternary products. Tertiary
sulfones can be prepared by a simple alkylation procedure render-
ing the modular synthesis of diaryl-dialkyl methane products in
short steps. With the prevalence of the quaternary benzylic centre
motif in bioactive molecules and natural products, we demonstrat-
ed the utility of the cross-coupling methodology in the synthesis
of a bioactive molecule. Importantly, our strategy for the present
sequential functionalization of sulfones can provide a new syn-
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ASSOCIATED CONTENT
Supporting Information
Synthetic and spectral data
AUTHOR INFORMATION
Corresponding Author
E-mail: mnambo@itbm.nagoya-u.ac.jp
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E-mail: cruddenc@chem.queensu.ca
(10) Potter, B.; Edelstein, E. K.; Morken, J. P. Org. Lett. 2016, 18,
3286.
ACKNOWLEDGMENT
(11) (a) Nambo, M.; Crudden, C. M. Angew. Chem. Int. Ed. 2014, 53,
742–746. (b) Nambo, M., Crudden, C.M. ACS Catal. 2015, 5, 4734-4742.
(c) Nambo, M.; Ariki, Z. T.; Canseco-Gonzalez, D.; Beattie, D. D.; Crud-
den, C. M. Org. Lett. 2016, 18, 2339–2342. (d) Nambo, M.; Keske, E. C.;
Rygus, J. P. G.; Yim, J. C.-H.; Crudden, C. M.; ACS Catal. 2017, 7, 1108–
1112. (e) Yim, J. C.-H.; Nambo, M.; Crudden, C. M. Org. Lett. 2017, 19,
3715–2342.
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Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006–7014.
(13) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028–13032.
C.M.C. acknowledges the Natural Sciences and Engineering Re-
search Council of Canada (NSERC) and the Canada Foundation
for Innovation (CFI) for funding of the work from her lab de-
scribed in this article. Z.T.A. thanks Queen’s University for fund-
ing. JSPS and NU are acknowledged for funding of this research
through The World Premier International Research Center Initia-
tive (WPI) program.
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R1 R2
SO2Ph
R1 R2
(Ar2BO)3
Ar1
Ar1
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Ni catalysis
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tertiary sulfones
as new electrophiles
diverse quaternary products
rapid synthesis of bio-molecules
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