Palladium-Catalyzed Synthesis of (Hetero)Aryl Alkyl Sulfones from (Hetero)Aryl Boronic Acids, Unactivated Alkyl Halides, and Potassium Metabisulfite

Article abstract of DOI:10.1002/anie.201505918

A palladium-catalyzed one-step synthesis of (hetero)aryl alkyl sulfones from (hetero)arylboronic acids, potassium metabisulfite, and unactivated or activated alkylhalides is described. This transformation is of broad scope, occurs under mild conditions, and employs readily available reactants. A stoichiometric experiment has led to the isolation of a catalytically active dimeric palladium sulfinate complex, which was characterized by X-ray diffraction analysis.

Full text of DOI:10.1002/anie.201505918

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International Edition: DOI: 10.1002/anie.201505918
German Edition: DOI: 10.1002/ange.201505918
Alkylsulfonylation
Palladium-Catalyzed Synthesis of (Hetero)Aryl Alkyl Sulfones from
(Hetero)Aryl Boronic Acids, Unactivated Alkyl Halides, and
Potassium Metabisulfite
Andre Shavnya,* Kevin D. Hesp, Vincent Mascitti, and Aaron C. Smith
Abstract: A palladium-catalyzed one-step synthesis of (heter-
o)aryl alkyl sulfones from (hetero)arylboronic acids, potas-
sium metabisulfite, and unactivated or activated alkylhalides is
described. This transformation is of broad scope, occurs under
mild conditions, and employs readily available reactants. A
stoichiometric experiment has led to the isolation of a catalyti-
cally active dimeric palladium sulfinate complex, which was
characterized by X-ray diffraction analysis.
can readily undergo transmetalation with arylboronic acids[10]
and that sulfur dioxide can insert into the resulting carbon–
palladium bond to form palladium sulfinate complexes.[11] In
more recent investigations, these putative Pd species have
been shown to liberate free sulfinate salts, which are then
quenched with alkyl electrophiles in a net one-pot, two-step
process (Scheme 1). Only a single example has been reported
T
he sulfone functional group is frequently encountered in
many compounds of pharmaceutical,[1] agrochemical,[2] and
materials science[3] importance (Figure 1). Despite its ubiq-
uity in these areas, common methods for the preparation of
sulfones typically require either sulfide oxidation[4] or the
alkylation/arylation of sulfinate salts.[5] Given that oxidative
methods are often incompatible with sensitive functional
groups found in complex organic substrates, and that sulfinate
salts have very limited commercial availability,[6] there has
been an intense effort to identify mild and general alterna-
tives for sulfone synthesis starting from readily available
substrate feedstocks.[7]
Scheme 1. Aryl alkyl sulfone synthesis from readily available reactants.
where the alkyl electrophile was present from the start of the
reaction and, notably, this study relied on the use of an
activated electrophile (benzyl bromide).[8b] Despite these
advances, the development of a general and streamlined
procedure that introduces a range of activated and unacti-
vated alkyl electrophiles at the beginning of the reaction in
a one-step procedure has thus far been elusive. Herein, we
report a practical palladium-catalyzed three-component reac-
tion of (hetero)arylboronic acids, (un)activated alkyl halides,
and potassium metabisulfite to access a breadth of (hetero)-
aryl alkyl sulfones in a single step (Scheme 1). Furthermore,
we describe a stoichiometric experiment employing an
isolated palladium sulfinate intermediate to probe the
reaction mechanism.
We initially examined conditions for the one-pot synthesis
of sulfones using activated alkyl electrophiles and boronic
acids (Scheme 2). Our initial experiments consisted of heating
a mixture of 4-tolylboronic acid, an excess of the alkyl
electrophile, and potassium metabisulfite[12] in DME in the
presence of tetrabutylammonium bromide (TBAB) and
a catalytic amount of palladium acetate. For benzyl bromide
and a-bromoacetate substrates, this afforded the desired
alkyl-aryl sulfones in 85% (2a) and 92% (2b) yields,
respectively. However, our attempts to extend these con-
ditions to the corresponding less reactive activated chloride
Figure 1. Representative commercial products incorporating a sulfone
motif.
In order to overcome these limitations, our laboratories[8]
and others[9] have recently developed transition-metal-cata-
lyzed procedures for the preparation of aryl alkyl sulfones
starting from readily available (hetero)aryl halide and
boronic acid substrates. It is well-established that PdII species
[*] A. Shavnya, Dr. K. D. Hesp, Dr. V. Mascitti, Dr. A. C. Smith
Pfizer, Inc., Worldwide Medicinal Chemistry
Groton, CT 06340 (USA)
E-mail: andre.shavnya@pfizer.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505981.
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palladium-catalyzed synthesis of sulfone 2d from 4-tolylbor-
onic acid and phenethyl bromide (2 equiv) in the presence of
10 mol% Pd(OAc)2, 10 mol% ligand, tetrabutylammonium
bromide (1.1 equiv), and K2S2O5 (2.2 equiv) in DME at 858C
for 22 h (Table 1, entries 2–10).[13] A constant observation
over the course of these studies was that electron-rich,
sterically encumbered ligands featuring P(tBu)2 substitution
consistently supported efficient catalysis for this transforma-
tion (Table 1, entries 7,8). Having identified tBuXPhos (L6)
as the optimal ligand, we screened the other reaction
parameters (palladium source, solvent, additives) in search
of improved reaction yields. Notably, the source of palladium
and solvent had a dramatic impact on the reaction outcome,
whereby the use of [Pd(MeCN)2Cl2] and DMF was shown to
provide superior yields of 2d (Table 1, entry 13). Whereas
most other PdII sources provided modest yields of 2d, the use
of Pd0 sources, such as [Pd2dba3], resulted in no observable
sulfone product. The effect of TBAB on the reaction was
tested by preparing sulfone 2d in the absence of this additive
(Table 1, entry 14). The observed decrease in yield from 74%
to 52% prompted us to further use TBAB in reaction scope
exploration. The heterogeneous nature of the reaction
mixture has thus far precluded further investigation into the
beneficial effect of TBAB; however, it is reasonable to
postulate that its presence contributes to increasing the
solubility of the inorganic salt employed. Whereas partial
catalytic activity was also observed in the absence of L6
(Table 1, entry 15), the notable increase in yield of 2d with the
ligand present warranted its use in further defining the
substrate scope of this reaction. Interestingly, replacement of
K2S2O5 with DABSO[5l,14] (an alternative surrogate of SO2)
produced sulfone 2d in only 16% yield (Table 1, entry 16).
Sulfur dioxide and K2SO3 also proved to be ineffective.
Having defined an effective catalyst system and reaction
conditions for the synthesis of aryl alkyl sulfone 2d from
readily available precursors, we sought to explore the scope of
suitable (hetero)aromatic boronic acid substrates (Scheme 3).
When reacted with n-propyl bromide, both electron-rich and
-neutral aromatic boronic acids gave the corresponding n-
propylsulfones in good yields (2c, 2e,f; 45–86%). Halo-
substituted substrates were equally competent under standard
conditions (2g–2i), which may provide further opportunities
for subsequent derivatization by metal-mediated couplings.
Hydroxy and acetamide functional groups were well tolerated
under the reaction conditions and no side-products arising
from alkylation of these groups were isolated (2j, 2k). Ortho-
substituted boronic acids were also compatible substrates for
this reaction, providing the products 2l and 2m in 62% and
54% yields, respectively. The compatibility of this reaction
with boronic acids featuring protic functional groups and
ortho-substitution, in addition to capitalizing on another set of
widely available monomers, makes it complementary to our
previously reported method using heteroaryl halides.[8a,15]
Given the value of substituted heterocycles in the pharma-
ceutical industry, where control of the lipophilicity of drug
candidates is of prime importance, we were pleased to
observe that the method was compatible with substituted
pyridines (2n, 2o), quinolines (2p, 2q), indazole (2r), and
thiophene (2s). Of note, alternative boron coupling partners
Scheme 2. Initial results of aryl akyl sulfone synthesis from boronic
acids.
Table 1: Reaction optimization with unactivated electrophiles.[a]
entry
[Pd]
Ligand
Yield[b]
1
Pd(OAc)2
–
0
8
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd2dba3]
[Pd(MeCN)2Cl2]
[Pd(MeCN)2Cl2]
[Pd(MeCN)2Cl2]
[Pd(MeCN)2Cl2]
L1
L2
L3
L4
L5
L6
L7
L8
L9
L6
L6
L6
L6
–
22
25
22
0
37
6
15
22
56
0
74
52
61
16
10
11[c]
12[c]
13[c]
14[c,d]
15[c]
16[c,e]
L6
[a] Reaction conditions: 4-TolB(OH)2 (0.52 mmol), Ph(CH2)2Br
(2 equiv), K2S2O5 (2.2 equiv), TBAB (1.1 equiv), [Pd] (10 mol%), ligand
(10 mol%), DME (0.3m), 858C, 22 h. [b] Yield of isolated sulfone 2d
product (%). [c] DMF used in place of DME. [d] TBAB omitted from
reaction. [e] DABSO used in place of K2S2O5.
substrates resulted in significantly diminished yields of
isolated sulfone. More importantly, employing these condi-
tions for unactivated n-propyl halides resulted in no con-
version to the desired aryl alkyl sulfone 2c and led to
unproductive protodeboronation. To develop a more effec-
tive and general method, we focused our efforts on the
identification of conditions amenable to the use of unacti-
vated alkyl electrophiles (Table 1).
We initiated our optimization studies by evaluating
a series of structurally diverse ligands to support the
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obtained for benzyl chloride (2v; 89%), a-chloroacetate (2w;
94%), and substituted allyl chloride (2x; 33%) substrates.
The utility of this transformation is further demonstrated by
the one-step synthesis of unnatural amino acid derivatives 2y
and 2z, which feature pendant aryl sulfone groups.[16]
Drawing inspiration from previous studies concerning the
synthesis of discrete palladium sulfinate complexes,[11f,17] we
became interested in investigating the mechanism of this
reaction through the use of stoichiometric experimentation.
To isolate putative palladium sulfinate intermediates under
catalytically relevant conditions, the reaction of 4-tolylbor-
onic acid, K2S2O5, and stoichiometric [Pd(MeCN)2Cl2] was
executed in the absence of an alkyl electrophile, TBAB, and
tBuXPhos. Treatment of the crude product with an aqueous
solution of PPh4Cl led to the isolation of anionic Pd complex 3
as an orange solid [Eq. (1)].[18] The assignment of 3 as a C2-
symmetric dimer has been confirmed by single crystal X-ray
diffraction analysis (Figure 2).[19] NMR and IR spectroscopic
data, as well as elemental analysis are also in support of
structure 3. The stoichiometric preparation of complex 3 from
p-tolyl boronic acid likely proceeds via initial transmetalation
with the PdII species.[10] Subsequent insertion of SO2 (liber-
ated from in situ disproportionation of K2S2O5) into the
resulting carbon–palladium bond then affords the palladium
sulfinate linkage in complex 3.[11]
Scheme 3. Substrate scope in boronic acids. Reaction conditions:
ArB(OH)2 (0.52 mmol), nPrBr (2 equiv), K2S2O5 (2.2 equiv), TBAB
(1.1 equiv), [Pd(MeCN)2Cl2] (10 mol%), tBuXPhos (10 mol%), DMF
(1.5 mL), 858C, 22 h. All examples are shown with yields of isolated
sulfone 2 product.
such as potassium 4-tolyltrifluoroborate, pinacol 4-toluene-
boronate, and neopentylglycol 4-tolueneboronate were found
to be incompatible substrates under these optimized condi-
tions, producing 2c in less than 10% yields.
The scope of alkylating agents is illustrated in Scheme 4.
Unactivated primary alkyl bromides, iodides, and tosylates
are all competent reagents for the synthesis of sulfone 2e (56–
86% yields). Furthermore, the use of more hindered electro-
philes, such as cyclopropylmethyl bromide and isopropyl
iodide, provided the desired sulfone products in synthetically
useful yields (2t and 2u, 70% and 45%, respectively). Using
the optimized conditions, useful to excellent yields were also
+
Figure 2. X-ray crystal structure of 3; two PPh4 counterions are
omitted for clarity. Ellipsoids set at 50% probability.
The catalytic activity of this dimeric palladium species was
then evaluated by conducting the alkylsulfonylation reaction
of 4-tolyl boronic acid with K2S2O5 and n-propyl bromide in
the presence of
3 (5 mol%), TBAB, and tBuXPhos
(10 mol%).[20] When compared with the optimized conditions
presented in Table 1, complex 3 was found to be an equally
active catalyst for the synthesis of sulfone 2c [Eq. (2)].
Collectively, these results provide support for the possible
role of 3 as an intermediate in the catalytic cycle of this
transformation. Furthermore, the reaction of complex 3 with
piperidine in the presence of NCS led to formation of 1-
tosylpiperidine in 96% yield, which presents an opportunity
for the future development of Pd-catalyzed sulfonamide
synthesis.[13]
Scheme 4. Substrate scope in alkyl electrophiles. Reaction conditions:
ArB(OH)2 (0.52 mmol), electrophile (2 equiv), K2S2O5 (2.2 equiv),
TBAB (1.1 equiv), Pd(MeCN)2Cl2 (10 mol%), tBuXPhos (10 mol%),
DMF (1.5 mL), 858C, 22 h. All examples are shown with yields of
isolated sulfone 2 product. [a] ArB(OH)2:electrophile=1.2:1.
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A preliminary catalytic cycle that accounts for the
intermediacy of dimeric Pd complex 3, under phosphine-
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species would transmetalate with the boronic acid and
À
following SO2 insertion into the Pd C bond would afford
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Scheme 5. Preliminary catalytic cycle that accounts for the intermedi-
acy of 3.
In conclusion, we have developed a practical one-step
palladium-catalyzed synthesis of (hetero)aryl alkyl sulfones
from readily available (hetero)arylboronic acids, alkyl hal-
ides, and potassium metabisulfite. This represents the first
general approach to (hetero)aryl alkyl sulfone synthesis that
introduces the electrophile at the beginning of the reaction
and does not rely on two-step sulfinate salt synthesis–
alkylation methods. Furthermore, we have conducted stoi-
chiometric experiments that have provided preliminary
insight into the structure of catalytically active palladium–
sulfinate complexes. Given its mild experimental conditions
and broad scope, this method is well-suited for any applica-
tions where the rapid synthesis and evaluation of alkyl
sulfones is required.
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We thank Dr. Justin Stroh and Ronald Morris for high
resolution mass spectrometry determination and Ivan J.
Samardjiev and Brian Samas for help in crystallographic
studies.
Keywords: alkylation · boronic acids · homogeneous catalysis ·
palladium · sulfones
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Chemie
[12] K2S2O5 has been exemplified as a suitable surrogate for sulfur
dioxide, see: S. Ye, J. Wu, Chem. Commun. 2012, 48, 10037.
[13] See the Supporting Information for additional details.
[14] For the initial report of the DABCO·(SO2)2 complex, see: a) P. S.
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[15] Efforts to prepare sulfone products 2k, 2l, and 2m from aryl
bromides and n-propyl bromide using our previous conditions
(Ref. [8a]) provided significantly diminished yields (36%, 0%,
and 0%, respectively).
[16] Compounds of this class have recently attracted considerable
attention owing to their biological and pharmacological proper-
ties. For recent examples, see: a) C. Fortugno, G. Varchi, A.
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2014, 95, 151; b) S. Nakatani, K. Hidaka, E. Ami, K. Nakahara,
A. Sato, J.-T. Nguyen, Y. Hamada, Y. Hori, N. Ohnishi, A. Nagai,
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[18] Similar dimeric palladium arylsulfinate complexes have also
been previously synthesized from sodium arylsulfinates and
Na2PdCl4 (see Ref. [17a]).
[19] CCDC 1418844 contains the supplementary crystallographic
data for complex 3. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
[20] Attempts to prepare a discrete palladium sulfinate–tBuXPhos
complexes were thwarted by multiple side-products and decom-
position.
Received: June 27, 2015
Revised: August 15, 2015
Published online: September 18, 2015
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