Versatile C(sp2)?C(sp3) Ligand Couplings of Sulfoxides for the Enantioselective Synthesis of Diarylalkanes

Article abstract of DOI:10.1002/anie.201602264

The reaction of chiral (hetero)aryl benzyl sulfoxides with Grignard reagents affords enantiomerically pure diarylalkanes in up to 98 % yield and greater than 99.5 % enantiomeric excess. This ligand coupling reaction is tolerant to multiple substitution patterns and provides access to diverse areas of chemical space in three operationally simple steps from commercially available reagents. This strategy provides orthogonal access to electron-deficient heteroaromatic compounds, which are traditionally synthesized by transition metal catalyzed cross-couplings, and circumvents common issues associated with proto-demetalation and β-hydride elimination.

Full text of DOI:10.1002/anie.201602264

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201602264
German Edition: DOI: 10.1002/ange.201602264
Cross-Coupling
2
3
À
Versatile C(sp ) C(sp ) Ligand Couplings of Sulfoxides for the
Enantioselective Synthesis of Diarylalkanes
ˇ
ˇ
William M. Dean, Mindaugas Siauciulis, Thomas E. Storr, William Lewis, and
Robert A. Stockman*
Abstract: The reaction of chiral (hetero)aryl benzyl sulfoxides
with Grignard reagents affords enantiomerically pure diaryl-
alkanes in up to 98% yield and greater than 99.5% enantio-
meric excess. This ligand coupling reaction is tolerant to
multiple substitution patterns and provides access to diverse
areas of chemical space in three operationally simple steps
from commercially available reagents. This strategy provides
orthogonal access to electron-deficient heteroaromatic com-
pounds, which are traditionally synthesized by transition metal
catalyzed cross-couplings, and circumvents common issues
associated with proto-demetalation and b-hydride elimination.
cross-coupling of chiral secondary and tertiary C(sp3) units is
taxing because of the loss of stereochemical integrity[5] as well
as issues associated with b-hydride elimination.[6] Whilst both
complications have been overcome independently, to the best
of our knowledge they have never been resolved simulta-
neously.
Research into transition-metal-free carbon–carbon bond-
forming reactions promoted by main-group elements has
emerged at the forefront of synthetic technologies in recent
years, driven by significant advances in the development of
boron and iodine reagents.[7] However, analogous reactions of
other p-block elements, such as sulfur, remain overlooked by
comparison despite promising initial results published in the
field over half a century ago.[8]
The ability of sulfur(IV) auxiliaries and reagents to impart
chiral information in the formation diastereomerically
enriched compounds is well known.[9] Furthermore, reactions
such as the Pummerer rearrangement[10] and magnesium
sulfoxide exchange[11] have received significant attention of
late. The ligand coupling reaction of sulfoxides has, by
comparison, been remarkably underexploited. Pioneering
work by Oae and co-workers proposed that attack of
a Grignard reagent at a sulfinyl center forms a metastable
disphenoidal s-sulfurane intermediate (4; Scheme 1).[12] The
sulfurane 4 may decompose through a reductive extrusion of
two ligands, from an axial and equatorial position, to form the
cross-coupled product 5 and the magnesium sulfenate 6.[12i]
Syntheses of both enantiomerically pure and racemic diaryl-
alkanes have been become a topic of intense research because
of the presence of these moieties in a multitude of biologically
active molecules,[1] with the diarylmethane motif being
described as a privileged structure.[2] In particular, 2-benzyl-
pyridines such as the farnesyltransferase inhibitor, lonafarnib
(1), and the antihistamines pheniramine (2a), chlorphen-
amine (2b; Piritonꢀ) and bromphenamine (2c), are of great
interest (Figure 1).
Figure 1. Selected drug targets containing di(hetero)arylalkanes.
Scheme 1. Proposed mechanistic pathway.
2
3
À
While the use of transition metal catalyzed C(sp ) C(sp )
reactions in the synthesis of diarylmethanes has become
common place,[3] such methodologies suffer from several
competing processes. First, the coupling of electron-deficient
heteroaromatics is widely known to be troublesome because
of protodemetallation.[4] Furthermore, the stereocontrolled
Despite initial mechanistic investigations into the ligand
coupling reactions of sulfoxides, few accounts on the synthetic
utility of this reaction have been described. Herein, we report
the results of our investigation into the scope and application
of the ligand coupling reaction (Scheme 2).
Substitution of benzylic halides or 2-pyridyl chloride by
a range of thiols and oxidation provided a range of sulfoxides
(3a–y; see Scheme 3) for examination.[13] A simple optimiza-
tion of reaction conditions was performed to enhance the
steric and electronic effects of the Grignard reagent used to
promote the ligand coupling reaction. Two optimal protocols
were identified which use readily available Grignard reagents,
either methylmagnesium bromide or tert-butylmagnesium
ˇ
ˇ
[*] W. M. Dean, M. Siauciulis, Dr. T. E. Storr, Dr. W. Lewis,
Prof. R. A. Stockman
School of Chemistry, University of Nottingham
University Park, Nottingham, NG7 2RD (UK)
E-mail: robert.stockman@nottingham.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602264.
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Scheme 2. Summary of ligand coupling reactions developed.
THF=tetrahydrofuran.
chloride, as the promoter.[13] The results from the subjection
of the sulfoxide substrates 3a–y to the Grignard reagents in
THF are presented in Scheme 3. In general, substitution
around the aromatic ring is well tolerated for unactivated
(5a–e), electron-deficient (5 f–m), and electron-rich function-
alities (5n,o). It is important to note that sterically encum-
bered groups, such as mesityl sulfoxide 5b, were also tolerated
well. Pleasingly, methylene units bearing heteroaromatics
were also found amenable to the reaction conditions, thus
producing the corresponding di(hetero)arylmethanes 5p–t in
moderate to excellent yields.
A general trend was observed where tBuMgCl provided
best yields with electron-rich substrates, while MeMgBr was
most efficient for electron-deficient substrates. This trend can
be attributed to the relative electronic and steric biases of the
equatorial and axial positions of 4 (Scheme 4). Grignard
Scheme 4. Electronic and steric biases on the s-sulfuranes 4.
reagents are known to attack a sulfoxide (3) opposite to the
sulfinyl oxygen atom, thus yielding the sulfurane 4a, where
the newly incorporated ligand is in an axial position.
Reversible pseudorotation processes (denoted as y) isomer-
ize 4a into the sulfurane 4b, the required conformation to
undergo ligand coupling. The sulfurane 4b is more stable with
electron-deficient benzylic ligands, which undergo reductive
extrusion readily. Electron-rich benzylic ligands are less
stable in the axial position, thus leading to lower yields of
these ligand coupling products when MeMgBr is used,
because of competing magnesium-sulfoxide exchange reac-
tions. The use of tBuMgCl introduces a steric bias on the
conformation of the sulfuranes 4, since the tert-butyl ligand is
more easily accommodated in an equatorial position than in
a confined axial position. This lowers the energy of the
required conformation 4b relative to its isomer 4a. Thus
higher yields are observed in the ligand coupling reactions of
electron-rich benzylic ligands when tBuMgCl is used.
We have also examined the use of electron-deficient
(hetero)aromatic rings in ligand coupling reactions. Benzimi-
dazole was found to be a viable coupling partner, thus
providing 5u in a 36% yield (Scheme 3). With electron-
deficient arylsulfoxides bearing trifluoromethyl and nitrile
groups the formation of the desired diarylmethane was also
observed (5v–y). Interestingly, only the ortho- and para-
trifluoromethyl substrates were effective in the ligand cou-
pling reaction (5v–x). In the case of 5y, benzyl Grignard gave
the best yields, as in this case two benzyl ligands are on the
sulfur atom and either can migrate. Formation of the nitrile
5y provides significant scope for further functionalization
following ligand coupling reaction.
To exemplify the potential for more complex substitution
at the benzylic position, we embarked on a synthesis of the
antihistamine pheniramine (2a; Scheme 5). Synthesis of the
required sulfoxide 7 was efficiently achieved in three steps
from commercially available alcohol 6. Treatment of 7 with
methylmagnesium bromide followed by an acidic workup
afforded pheniramine (2a) in 42% yield.
Scheme 3. Ligand coupling reactions of benzyl sulfoxides 3a–y.
[a] R’=tBu, X=Cl; [b] R’=Me, X=Br; [c] R’=Bn, X=Cl.
2
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radical deoxygenation of 5ae and comparison of the
optical rotation of the product with literature values (see
the Supporting Information). The higher yields of the
diarylmethanes 5, produced by substrates with R-sulfinyl
centers, are attributed to steric differences between each
diastereomer. It may be possible to employ this insight to
produce optimal yields of diarylmethanes which are
functionalized at the benzylic center.
In summary, by using two generalized protocols we
have demonstrated the potential for ligand coupling
reactions as a complimentary approach to cross-coupling
Scheme 5. Synthesis of pheniramine (2a). Reaction conditions: a) MsCl,
NEt3, CH2Cl2, RT then 2-mercaptopyridine, RT; b) BH3·DMS, THF, 608C;
c) mCPBA, CH2Cl2, RT; d) MeMgBr (1.1 equiv), THF, RT. DMS=dimethyl-
sulfide, mCPBA=m-chloroperbenzoic acid, Ms=methanesulfonyl.
With the intramolecular ligand coupling explored, our
attention was turned to the possibility for the cross-
coupling of a substituted sulfoxide with a Grignard
reagent. Benzylmagnesium chloride was reacted with
sulfoxides furnished with ethyl 4-benzoate (3z) and
butadiene (both cis and trans, 3aa,ab; Scheme 6). In all
cases the cross-coupled products (5z–ab) were obtained,
albeit in low yield, with retention of alkene geometry in
the synthesis of 5aa and 5ab. We attribute the low yields
in the latter two cases to result from the lack of an
electron-withdrawing ligand on the sulfur, and thus
Grignard exchange becomes a more prevalent reaction
pathway.
To elucidate the retention of stereochemistry exhib-
ited by ligand coupling reactions, we set about the
synthesis of enantiomerically pure sulfoxides (3ac–ae;
Scheme 7). Erbium(III)-catalyzed alkylation of 2-mer-
captopyridine (9) with (R)-styrene oxide (8), followed by
protection and oxidation, provided the required sub-
strates 3ac–ae. The structure and absolute stereochemis-
try of 3ac’ was determined by X-ray crystallography
(Figure 2). Subjection to MeMgBr afforded the corre-
sponding 1,1-di(hetero)arylethanes 5ac–ae in moderate
Scheme 7. Synthesis of enantiomerically enriched diarylmethanes 5ac–ae.
Reaction conditions: a) Er(OTf)3, MeCN, RT; b) TBSCl, imidazole, CH2Cl2,
RT; c) NaH, BnBr, THF, RT; d) mCPBA, CH2Cl2, RT; e) MeMgBr (1.1 equiv),
THF, RT; f) MeMgBr (2.2 equiv), THF, RT. TBS=tert-butyldimethylsilyl,
Tf =trifluoromethanesulfonyl.
to very good yield and, importantly, excellent enantio-
meric excess. Stereoretention was confirmed by the
2
3
À
reactions in the formation of C(sp ) C(sp ) bonds. We have
studied 34 examples with electronic and steric diversity, thus
providing diarylmethanes in up to 98% chemical yield. This
work has been extended into cross-coupling reactions and
enantioretentive synthesis as well as being employed in the
synthesis of a drug molecule. Work within our group is
currently directed towards the further expansion of scope and
application of this reaction methodology.
Scheme 6. Cross-coupling reactions of the sulfoxides 3z–ab.
[a] reaction performed at 08C.
Acknowledgments
The authors acknowledge the EPSRC (EP/I038489) for
financial support.
Keywords: arenes · cross-coupling · magnesium ·
Figure 2. XRD structure of sulfoxide 3ac’ (CCDC 1457851). Thermal
ellipsoids shown at 50% probability.
reaction mechanisms · sulfur
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Received: March 4, 2016
Revised: April 29, 2016
Published online: && &&, &&&&
4
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Communications
Cross-Coupling
ˇ
ˇ
W. M. Dean, M. Siauciulis, T. E. Storr,
W. Lewis,
R. A. Stockman*
&&&& — &&&&
2
3
À
Versatile C(sp ) C(sp ) Ligand Couplings
of Sulfoxides for the Enantioselective
Synthesis of Diarylalkanes
On three: The reaction of chiral
three operationally simple steps from
(hetero)aryl benzyl sulfoxides with
Grignard reagents affords diarylalkanes
with greater than 99.5% enantiomeric
excess. The reaction is tolerant to multi-
ple substitution patterns and proceeds in
commercially available reagents. This
strategy provides orthogonal access to
electron-deficient heteroaromatic com-
pounds.
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