Desulfonylative Arylation of Redox-Active Alkyl Sulfones with Aryl Bromides

Article abstract of DOI:10.1021/acs.orglett.9b01987

We describe the development of the first reductive cross-electrophile coupling between alkyl sulfones and aryl bromides. The use of alkyl sulfones offers strategic advantages over other alkyl electrophiles as they can be incorporated into molecules in unique ways and permit α-functionalization prior to coupling. The conditions developed here enable incorporation of a wide array of aromatic rings onto (fluoro)alkyl scaffolds with broad functional group tolerance and generality, making this a practical method for late-stage diversification.

Full text of DOI:10.1021/acs.orglett.9b01987

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Desulfonylative Arylation of Redox-Active Alkyl Sulfones with Aryl
Bromides
Jonathan M. E. Hughes* and Patrick S. Fier*
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: We describe the development of the first
reductive cross-electrophile coupling between alkyl sulfones
and aryl bromides. The use of alkyl sulfones offers strategic
advantages over other alkyl electrophiles as they can be
incorporated into molecules in unique ways and permit α-
functionalization prior to coupling. The conditions developed
here enable incorporation of a wide array of aromatic rings onto
(fluoro)alkyl scaffolds with broad functional group tolerance
and generality, making this a practical method for late-stage
diversification.
n drug discovery and development, the percentage of sp3-
hybridized carbons in drug candidates is positively
While seminal methods for cross-electrophile coupling
employed alkyl halides as sp3-coupling partners,4,6 the scope
has since expanded to include alkyl acetates,7 carbonates,8
sulfonates,9 epoxides,10 aziridines,11 activated esters,12 ox-
alates,13 pyridinium salts,14 iminiums,15 and others (Figure
1A).4,16 Such flexibility is valuable during synthetic planning,
and further expansion to include alternative alkyl electrophiles
is desirable. In this regard, we aimed to develop reductive
coupling chemistry with alkyl sulfones due to their unique
strategic advantages over other alkyl electrophiles.17 In
particular, alkyl sulfones can be deprotonated and function-
alized at the α-position and can be prepared via cycloaddition
or conjugate addition reactions. These diversifying bond
formations can enable rapid exploration of chemical space,
which is a vital aspect of drug discovery.
I
correlated to success in the clinic.1 This has been attributed
to factors such as improved biological and physicochemical
properties as well as reduced promiscuity relative to less
saturated analogues.1,2 Consequently, numerous synthetic
methods have been developed that enable the cross-coupling
of aliphatic motifs to facilitate access to sp3-rich molecules.3
Ni-catalyzed reductive cross-electrophile couplings have been
particularly useful in this regard and have undergone extensive
development in recent years (Figure 1A).4,5 One attractive
Our proposal to use alkyl sulfones as electrophiles in
reductive cross-coupling was inspired by a recent report from
the Baran laboratory describing Ni-catalyzed Negishi-type
cross-coupling (Figure 1B, left),17h a method that we recently
applied toward structure activity relationship (SAR) explora-
tion on scaffold 1. Notably, the use of an alkyl sulfone
electrophile was advantageous here for several reasons,
including the ability to perform α-functionalization prior to
coupling and its greater stability compared to other alkyl
electrophiles. While this method was enabling, the use of
preformed organometallic reagents prevented direct incorpo-
ration of aryl groups with acidic hydrogens (e.g., 3) and
required several additional synthetic operations. To avoid
protecting group manipulations and be able to use readily
available aryl halides, we hypothesized that direct cross-
electrophile coupling between sulfone 1 and aryl bromide 3
could be possible under reducing conditions. Although
Figure 1. (A) General scheme for reductive cross-electrophile
coupling. (B) Negishi-coupling of alkyl sulfone 1 with phenylzinc
chloride and cross-electrophile coupling of 1 with aryl bromide 3.
feature of these transformations is that they circumvent the
need to preform nucleophilic reaction partners, resulting in
simple reaction setups and broad functional group tolerance.
As a result, cross-electrophile couplings have seen rapid uptake
by synthetic chemists in recent years.
Received: June 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
sulfones have not been previously used as electrophiles in
reductive cross-coupling, phenyl tetrazole sulfones (e.g., 1) are
known to be redox active and capable of engaging in single
electron transfer reactions.17h We herein describe the discovery
and development of the first reductive cross-electrophile
coupling reaction between alkyl sulfones and aryl bromides.
To assess the feasibility of using alkyl sulfones as substrates
in cross-electrophile couplings, we studied the reaction
between sulfone 5 and bromobenzene 6 (Scheme 1). A
Scheme 2. Aryl Bromide Scope
Scheme 1. Initial Hit from High Throughput Screening and
Final Reaction Conditions for the Cross-Coupling of Alkyl
Sulfone 5 and Bromobenzene 6
preliminary screen of 48 different reaction conditions (12
ligands, 2 solvents, and 2 reductants) using microscale high-
throughput experimentation revealed that arylated product 7
could be formed in ca. 10% yield at 80 °C in DMPU in the
presence of NiCl2·dme/9a (10 mol %) and Zn (3 equiv) (see
Supporting Information for details).18 From this initial hit,
further development led to the identification of DMI as being a
particularly effective solvent for the reaction. Finally, a
thorough screening of Ni sources and electronically differ-
entiated ligands 9a−e (R = H, Me, OMe, NMe2, CF3) revealed
that the combination of NiBr2 and 9a enabled the formation of
arylated product 7 in 65% yield (Scheme 1).
a
Isolated yields shown for reactions conducted with 0.5 mmol of 5.
b
In every reaction, the mass balance of limiting reagent 5 is sulfinate 8
c
(Scheme 1). Ten equiv of 4-bromoanisole was used.
smoothly to form pyridine-, pyrimidine-, indole-, quinoline-,
and benzoxazole-containing products in synthetically useful
yields (10l−p). Of particular significance, functional groups
with acidic hydrogens such as primary amides (10j),
unprotected indoles (10l), and alcohols (10k) were well-
tolerated in the reaction.
During reaction development, we identified sulfinate 8 as the
major side product, which accounts for nearly all of the mass
balance of 5.19 In attempts to reduce the formation of 8 during
the reaction, we investigated the effects of several additives
(bases, metal salts, TMSCl, etc.) on product distribution.
However, none of these additives resulted in increased yields of
cross-coupled product 7. Control experiments revealed that the
reaction does not proceed in the absence of Ni, 9a, or Zn.
Finally, the reaction was found to be largely insensitive toward
both water and air, which simplifies material handling and
reaction setup (see Supporting Information for details).
With reaction conditions in place, we explored the scope of
this reductive cross-coupling reaction and found that a variety
of electronically differentiated aryl bromides were competent
coupling partners with sulfone 5 (Scheme 2). Several common
functional groups were tolerated in the reaction, including
esters (10d), ketones (10e), aldehydes (10f), sulfonamides
(10g), sulfones (10h), nitriles (10i), and amides (10j). The
synthesis of compound 10h highlights the method’s ability to
chemoselectively differentiate between redox-active phenyl
tetrazole sulfones and standard aryl sulfones. Moreover, aryl
chlorides remain intact under the reaction conditions, thereby
offering the potential to deliver products with a synthetic
handle for further derivatization (10p). While para- and meta-
substitution were both tolerated in this reaction, ortho-
substituted aryl bromides were unreactive (see Supporting
Information for details). The cross-coupling of several
pharmaceutically relevant heteroaryl bromides also proceeded
In addition to compound 5, several other sulfones reacted
under the standard conditions with similar levels of efficiency
(Scheme 3). For example, primary (12a−c), secondary (12d
and e), benzylic (12c), and α-heteroatom-containing (12b)
sulfones all underwent cross-coupling to give arylated products
in moderate to good yields. Notably, a fluorinated sulfone
could also be employed in the reaction to deliver 12f in 21%
yield.20 This example highlights the unique ability of alkyl
sulfones to serve as handles for two-point diversification when
a
Scheme 3. Alkyl Sulfone Scope
a
Isolated yields shown for reactions conducted with 0.5 mmol of 11
b
unless otherwise stated. Assay yield determined by HPLC analysis
versus an authentic standard. Five equiv of ethyl 4-bromobenzoate
was used. DMPU was used in place of DMI.
c
d
B
DOI: 10.1021/acs.orglett.9b01987
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
employed as electrophiles for cross-coupling reactions.
However, at this time, the scope of α-fluorosulfones is limited
due to the instability of the C−F bonds toward elimination
under the reaction conditions.21
Scheme 5. Selected Control Experiments
To highlight the utility of this method for late-stage
diversification of complex molecules, we prepared several
analogues from benzyl alcohol 13 (Scheme 4A). Common
Scheme 4. (A) Modular Synthesis of Diarylmethanes 16a−c
and (B) Synthesis of Aryl Indane 20 Using a Methyl
a,b
Linchpin/Reductive Cross-Coupling Strategy
bromide bond. Furthermore, alkane 27 was formed in 19%
yield when sulfone 5 was submitted to the standard reaction
conditions in the absence of an aryl bromide coupling partner,
providing further evidence in support of an initially generated
alkyl-Ni species (eq 4). Notably, negligible amounts of alkane
27 are generated in the absence of Ni, which further supported
this hypothesis (eq 5). On the basis of these experiments and
literature precedent,23 we propose a possible mechanism that
involves an initial single electron reduction of sulfone 11 with
Zn to generate radical anion 28 (Scheme 6).24 Radical anion
a
Conditions and reagents for Scheme 4A: 1. Ph3P (1.5 equiv), DIAD
(1.5 equiv), PTSH (1.5 equiv), THF, 0 °C → rt (88%); 2. (i)
mCPBA (6 equiv), 0 °C → rt; (ii) B2Pin2 (4 equiv), 0 °C → rt (91%);
3. optimized conditions from Scheme 1 with 5 equiv of 15a−c.
Scheme 6. Possible Mechanism for the Reductive Cross-
Coupling of Alkyl Sulfones and Aryl Bromides
b
Conditions and reagents for Scheme 4B: 1. NBS (2.2 equiv),
(PhCO2)2 (7 mol %), CCl4, 80 °C (90%); 2. NaH (2.2 equiv), 21
(1.1 equiv), rt (36% AY); 3. optimized conditions from Scheme 1
with 3 equiv of 15c (20%).
intermediate sulfone 14 was prepared in two steps from 13 in
80% overall yield. Subsequent reductive coupling with aryl
bromides 15a−c proceeded smoothly to deliver diaryl
methanes 16a−c in 34−66% isolated yield. Importantly, each
of these cross-couplings proceeded effectively in the presence
of acidic functional groups (benzylic/tertiary alcohols and/or
primary amide) without the need for protecting groups.
Furthermore, the synthesis of 2-aryl indane 20 was
accomplished via sequential annulation of dibromide 18 with
methyl sulfone 21 followed by reductive coupling of the
resulting sulfone 19 (Scheme 4B). This example highlights the
ability of sulfone 21 to serve as a methyl linchpin and offers
new opportunities for the installation of this versatile
functional handle. Notably, this strategy is unique to the use
of alkyl sulfones and has not been demonstrated with other
alkyl electrophiles within the context of reductive cross-
electrophile coupling.
Several experiments and observations provided insight into
the mechanism of this reaction (Scheme 5). First, conversion
of (cyclopropyl)methyl sulfone 22 into ethyl 4-(3-butenyl)-
benzoate (24) under the reaction conditions is consistent with
the formation of a radical-like intermediate (eq 1). Moreover,
control experiments confirmed that arylzinc halides are not
generated under the reaction conditions (eq 2), and preformed
arylzinc halides do not engage in cross-coupling under the
standard conditions (eq 3).22 The lack of conversion of
bromobenzene (6) in eq 2 suggests a reaction between Ni and
the alkyl component precedes oxidative addition into the aryl
28 can then undergo fragmentation to generate sulfinyl radical
30 and cyanamide 29 (consistently observed in crude reaction
mixtures by HPLC/LCMS analysis).25 Reaction of 30 with
Ni(0) might then generate alkyl-Ni(I) species 34 via loss of
SO2.26 Finally, reaction of 34 with aryl bromide 35 would lead
to the formation of cross-coupled product 37 and Ni(I) species
38 via the intermediacy of Ni(III) species 36. Reduction of 38
to Ni(0) would complete the catalytic cycle.27−29
In conclusion, we developed the first reductive cross-
electrophile coupling reaction between alkyl sulfones and aryl
bromides. This new method serves as a convenient approach
to forge C(sp3)-aryl bonds without the need for prefunction-
alization of the aryl halide coupling partner. Moreover, in
C
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Letter
Past Success to the Development of New Reactions for the Future.
Organometallics 2019, 38, 3−35.
(6) For a seminal report on the Ni-catalyzed reductive cross-
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Nickel-catalyzed reductive allylation of aryl bromides with allylic
combination with well-established chemistry to functionalize
alkyl sulfones, this method serves as a platform from which
rapid diversification can be accomplished. As such, we
anticipate that this method will have meaningful impacts
within drug discovery and synthetic chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01987.
Experimental procedures and characterization data for
new compounds (PDF)
acetates. Org. Biomol. Chem. 2013, 11, 3094−3097. (d) Correa, A.;
2
́
Leon, T.; Martin, R. Ni-Catalyzed Carboxylation of C(sp )- and
C(sp3)-O Bonds with CO2. J. Am. Chem. Soc. 2014, 136, 1062−1069.
(8) Dai, Y.; Wu, F.; Zang, Z.; You, H.; Gong, H. Ni-Catalyzed
Reductive Allylation of Unactivated Alkyl Halides with Allylic
Carbonates. Chem. - Eur. J. 2012, 18, 808−812.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jonathan.hughes@merck.com.
*E-mail: patrick.fier@merck.com.
ORCID
(9) (a) Liang, Z.; Xue, W.; Lin, K.; Gong, H. Nickel-Catalyzed
Reductive Methylation of Alkyl Halides and Acid Chlorides with
Methyl p-Tosylate. Org. Lett. 2014, 16, 5620−5623. (b) Liu, Y.;
Cornella, J.; Martin, R. Ni-Catalyzed Carboxylation of Unactivated
Primary Alkyl Bromides and Sulfonates with CO2. J. Am. Chem. Soc.
2014, 136, 11212−11215. (c) Ackerman, L. K. G.; Anka-Lufford, L.
L.; Naodovic, M.; Weix, D. J. Cobalt co-catalysis for cross-electrophile
coupling: diarylmethanes from benzyl mesylates and aryl halides.
Chem. Sci. 2015, 6, 1115−1119. (d) Molander, G. A.; Traister, K. M.;
O’Neill, B. T. Engaging Nonaromatic, Heterocyclic Tosylates in
Reductive Cross-Coupling with Aryl and Heteroaryl Bromides. J. Org.
Patrick S. Fier: 0000-0002-6102-815X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to L. C. Campeau, Ben Sherry, Andrew Neel,
and Tiffany Piou (all from Merck) for feedback on our
manuscript. We would like to thank J. J. Yin (Merck), Ji Qi
(Merck), and Shiping Ye (Pharmaron) for assistance with
preparing sulfone reagents and ligands.
́
Chem. 2015, 80, 2907−2911. (e) Smith, R. T.; Zhang, X.; Rincon, J.
A.; Agejas, J.; Mateos, C.; Barberis, M.; García-Cerrada, S.; de Frutos,
O.; MacMillan, D. W. C. Metallaphotoredox-Catalyzed Cross-
3
3
Electrophile Csp − Csp Coupling of Aliphatic Bromides. J. Am.
Chem. Soc. 2018, 140, 17433−14438.
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7085−7092.
(19) Assigned based on LCMS analysis of the crude reaction
mixture.
(20) While the standard cross-coupling conditions can be employed
to deliver cross-coupled product 12f, the use of DMPU in place of
DMI was found to give a slightly improved yield.
(21) See the Supporting Information for a list of substrates that did
not engage in cross-coupling under the current set of reaction
conditions.
(22) Under the conditions shown in eq 3, sulfone 5 is completely
converted to sulfinate 8.
(23) For mechanistic studies of cross-electrophile couplings, see ref
15 and (a) Everson, D. A.; Jones, B. A.; Weix, D. J. Replacing
Conventional Carbon Nucleophiles with Electrophiles: Nickel-
Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides. J.
Am. Chem. Soc. 2012, 134, 6146−6159. (b) Biswas, S.; Weix, D. J.
Mechanism and Selectivity in Nickel-Catalyzed Cross-Electrophile
Coupling of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2013,
135, 16192−16197.
(24) Control experiments showed that sulfone 5 is cleanly reduced
to sulfinate 8 in the presence of Zn. However, in the absence of Zn,
no reduction of 5 occurs with NiBr2/9a or Ni(COD)2/9a.
E
DOI: 10.1021/acs.orglett.9b01987
Org. Lett. XXXX, XXX, XXX−XXX