Catalytic Enantioselective Synthesis of Atropisomeric Biaryls: A Cation-Directed Nucleophilic Aromatic Substitution Reaction

Article abstract of DOI:10.1002/anie.201408205

A catalytic enantioselective nucleophilic aromatic substitution reaction which yields axially chiral biaryl derivatives in excellent yields with e.r. values of up to 97:3 has been developed. This process uses a chiral counterion to direct the addition of thiophenolate to a prochiral dichloropyrimidine by a tandem desymmetrization/kinetic resolution mechanism. The products can be derivatized to a range of atropisomeric structures without any reduction in enantioenrichment, thus offering access to unexplored chiral biaryl architectures.

Full text of DOI:10.1002/anie.201408205

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Angewandte
Communications
DOI: 10.1002/anie.201408205
Asymmetric Catalysis
Hot Paper
Catalytic Enantioselective Synthesis of Atropisomeric Biaryls:
A Cation-Directed Nucleophilic Aromatic Substitution Reaction**
Roly J. Armstrong and Martin D. Smith*
Abstract: A catalytic enantioselective nucleophilic aromatic
substitution reaction which yields axially chiral biaryl deriva-
tives in excellent yields with e.r. values of up to 97:3 has been
developed. This process uses a chiral counterion to direct the
addition of thiophenolate to a prochiral dichloropyrimidine by
a tandem desymmetrization/kinetic resolution mechanism. The
products can be derivatized to a range of atropisomeric
structures without any reduction in enantioenrichment, thus
offering access to unexplored chiral biaryl architectures.
T
he nucleophilic aromatic substitution reaction is a bench-
mark transformation within the field of synthetic organic
chemistry, representing a powerful method for the construc-
tion of functionalized aromatic systems.[1] Despite the signifi-
cant synthetic utility of this reaction, few methods have been
reported which enable the absolute stereochemical outcome
of the transformation to be controlled[2,3] and to the best of
our knowledge, few catalytic asymmetric variants have been
disclosed. The groups of Jørgensen[4] and Maruoka[5] have
elegantly demonstrated that trisubstituted enolates can be
employed as nucleophiles in aromatic substitution reactions
with electron-deficient aryl fluorides. Within both of these
studies, the formation of the resulting quaternary stereogenic
center is controlled by a chiral phase-transfer catalyst. Zhu
and co-workers have carried out an asymmetric intramolec-
Figure 1. Previous work and strategy. EWG=electron-withdrawing
group.
groups.[11,12] It was envisaged that under asymmetric phase-
transfer conditions, the tight ion pair formed in a nonpolar
organic solvent between a deprotonated nucleophile and
a chiral cation may allow such an event to be controlled
(Figure 1).[13] For such an approach to prove successful, we
rationalized that the electrophile should possess 1) a plane of
symmetry containing the biaryl axis, and 2) an arene which is
sufficiently electron-poor to undergo a nucleophilic aromatic
substitution under mild reaction conditions. With these
considerations in mind, we decided to investigate a sterically
encumbered dichloropyrimidine electrophile 1 (Scheme 1),[14]
which was synthesized in four steps from commercially
available starting materials.[15] There is significant hindrance
about the biaryl axis in this substrate, and hence we believed
that substitution of one of the enantiotopic chlorine atoms
would yield chiral material. Pleasingly, treatment of 1 with
thiophenol in the presence of KOH and tetra-n-butylammo-
nium bromide afforded racemic 2 at room temperature.[16]
Furthermore, this reaction proved to be selective for
single versus double addition, affording 2 and 3 in a 17:1 ratio.
ular cycloetherification reaction catalyzed by
a chiral
Brønsted base.[6] The product, an enantioenriched cyclo-
phane, is rendered chiral by virtue of restricted rotation of
a linker about a plane of chirality (Figure 1). Our aim was to
build on these methods and develop a synthesis of atropiso-
meric biaryls, axially chiral compounds whose chirality
originates from restricted rotation about a s bond.[7,8] Given
the central role occupied by atropisomeric materials within
the fields of asymmetric catalysis and synthesis,[9] enantiose-
lective methods for the construction of such compounds are of
great value.[10] We reasoned that a chiral catalyst could effect
a desymmetrizing nucleophilic aromatic substitution through
discrimination in the displacement of enantiotopic leaving
[*] R. J. Armstrong, Prof. Dr. M. D. Smith
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: martin.smith@chem.ox.ac.uk
Homepage: http://msmith.chem.ox.ac.uk/
[**] The European Research Council has provided financial support
(FP7/2007-2013)/ERC grant agreement no. 259056. We gratefully
acknowledge the Diamond Light Source for an award of instrument
time on I19 (MT7768). We are very grateful to Dr. Peter Knipe for
assistance with X-ray crystallography.
Scheme 1. Racemic phase-transfer-catalyzed nucleophilic aromatic sub-
stitution reaction. Reaction conditions: 1 (1.0 equiv), PhSH
(1.1 equiv), nBu4NBr (10 mol%), 50% KOH (aq., w/w, 5.0 equiv),
PhMe ([1]=0.1 moldmÀ3).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408205.
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Analytical HPLC, using a chiral stationary phase, indicated
that 2 was indeed atropisomeric, with no interconversion
between enantiomers observed at room temperature on the
HPLC timescale (Scheme 1).[17] With these initial results in
hand, we turned our attention to the asymmetric nucleophilic
aromatic substitution reaction. Gratifyingly, upon treatment
of 1 with a biphasic mixture of thiophenol, N-benzylcincho-
nidinium chloride 4, and aqueous potassium carbonate in
toluene we obtained 2 in a moderate, but promising 58:42 e.r.
(Table 1, entry 1). We next probed the efficacy of the catalysts
5 and 6, derived from cinchonine and quinidine, respectively,
but little impact on the degree of enantioinduction was
observed (entries 2 and 3). We were therefore delighted to
find that employing N-benzylquininium chloride 7 led to
a significant improvement in enantioselectivity, affording the
product 2 in 87:13 e.r. (entry 4). It is noteworthy that in these
four examples (entries 1–4), the major enantiomer possesses
the same absolute configuration, irrespective of which
pseudoenantiomer of the catalyst is employed.
Variation of the steric and electronic nature of the N-
pendant group of the catalyst had a significant impact upon
selectivity, reversing the absolute configuration of the major
enantiomeric product (relative to that for entries 1–4 in
Table 1), along with significantly reduced enantioselectivities
(entries 5–9). A range of aqueous carbonate bases proved
equally effective at promoting the reaction, although aqueous
hydroxide and solid bases generated 2 with inferior stereo-
selectivity (entries 10–14). The use of carbon tetrachloride,
which has previously been demonstrated to be an effective
solvent for asymmetric phase-transfer-catalyzed reactions of
thiol nucleophiles, led to a further increase in enantioselec-
tivity to 95:5 e.r. (entry 15).[18] We found that increasing the
number of equivalents of thiophenol from 1.0 to 1.1 also led to
increased enantioenrichment, affording
(entry 16).
3 in 97:3 e.r.
With conditions for a highly enantioselective asymmetric
nucleophilic aromatic substitution reaction established, we set
out to examine the generality of the process by varying the
electrophile (Table 2). Substitution of the naphthyl group in
the 4-position was well tolerated in the case of a methyl group,
affording 13 in 96:4 e.r., and subsequently the absolute
configuration of 13 was established by X-ray crystallogra-
phy.[19] When a bromine substituent was incorporated into the
Table 1: Optimization: asymmetric nucleophilic aromatic substitution
reaction.[a]
Table 2: Asymmetric nucleophilic aromatic substitution reaction.[a]
Entry
Catalyst
Base
e.r.[b]
1
2
3
4
5
6
7
8
4
5
6
7
8
9
10
11
12
7
7
7
7
7
7
7
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Cs2CO3
KOH
58:42
61:39
55:45
87:13
39:61
46:54
43:57
43:57
45:55
85:15
86:14
68:32
36:64
66:34
95:5
9
10
11
12
13[c]
14[c]
15[d]
16[d,e]
K2CO3
KOH
K2CO3
K2CO3
97:3
[a] Conditions: 1 (0.073 mmol), PhSH (1.0 equiv), catalyst (10 mol%),
base (33% aq., w/w, 5.0 equiv), PhMe ([1]=0.1 moldmÀ3), RT, 24 h.
[b] Determined by HPLC using a chiral stationary phase. [c] Solid base
(1.0 equiv) was used. [d] CCl4 was used as the reaction solvent. [e] Used
1.1 equiv of PhSH; reaction time 48 h.
[a] Reaction conditions: PhSH (1.1 equiv), 7 (10 mol%), 50% K2CO3
(aq., w/w, 5.0 equiv), CCl4 ([electrophile]=0.1 moldmÀ3), 48 h. Yields
refer to isolated materials. The e.r. value was determined by HPLC using
a chiral stationary phase. r.s.m.=recovered starting material.
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same position, the selectivity was somewhat diminished, and
the product 14 was isolated in 87:13 e.r.
The starting material 2 was found to be enantioenriched
(60:40 e.r.), and the major enantiomer was R configured, as
obtained previously (Scheme 2a). This observation strongly
suggests that a desymmetrization kinetic resolution effect is
responsible for the enhanced enantioselectivity observed with
excess thiol (Scheme 2b),[22] and is consistent with the seminal
It was also possible to introduce a substituent onto the
pyrimidine ring. A substrate with a 2-methyl group partici-
pated in the desired reaction, forming 15 in high yield with
excellent enantioselectivity (Table 2). We also found that the
leaving group could be varied from chlorine to bromine,
affording 16 in 88% yield and 92:8 e.r. Substrates with a single
ortho-substituted aromatic ring are also interesting synthetic
targets, provided that the barrier to rotation about the aryl–
aryl bond is sufficiently high to avoid racemization of the
product. We synthesized a series of compounds with increas-
ingly bulky ortho groups and were pleased to find that under
our previously optimized reaction conditions 17, 18, 19, 20,
and 21 were all formed in high yields with good to excellent
enantioselectivities. The steric nature of the electrophile
appears to have some impact upon reactivity. The extremely
hindered ortho-isopropyl-substituted example 22 only
reached 26% conversion after 48 hours, albeit still with
good enantioselectivity. This trend continues, with more
hindered 2,6-disubstituted electrophiles as exemplified by
23, which proved unreactive under the reaction conditions.
All compounds in Table 2 display a remarkably high barrier to
rotation about the aryl–aryl bond. For instance, 19 racemizes
in solution with a t1/2 > 0.6 years. A solid sample of 19
exhibited showed no racemization after several months at
room temperature.[20]
Scheme 2. Kinetic resolution. [a] Reaction conditions: rac-2 (1.0 equiv),
PhSH (1.1 equiv), 7 (10 mol%), 50% K2CO3 (aq., w/w, 5.0 equiv), CCl4
([rac-2]=0.1 moldmÀ3), RT, 6 d. Conversion and e.r. determined by
HPLC using a chiral stationary phase.
During reaction optimization, we had noted that employ-
ing a slight excess of thiophenol led to increased levels of
enantioselectivity. We investigated this effect further by
subjecting 1 to various loadings of thiol (Table 3). A clear
trend was observed: an increased excess of thiophenol led to 2
in improved enantioselectivity along with a corresponding
increase in the amount of double addition product 3.
work of Hayashi et al., who observed a similar phenomenon
in the transition-metal-catalyzed enantioselective desymmet-
rization of pro-stereogenic biaryls.[12]
To further expand the synthetic utility of the reaction, we
wished to demonstrate that the products of the reaction (as
exemplified by 2) can be selectively manipulated (Scheme 3).
The aryl sulfide in 2 could be oxidized with meta-chloroper-
benzoic acid to the corresponding sulfone 24 in 99% yield
with no erosion of enantiomeric purity. The products of the
nucleophilic aromatic substitution reaction (13–22) contain
an activated aryl chloride, which serves as a useful handle for
further functionalization. A range of S, N, and O nucleophiles
were able to undergo nucleophilic aromatic substitution at
this position, leading to the corresponding products 25, 26,
and 27, with no change in enantiomeric ratio.[23] We were also
able to carry out a Suzuki–Miyaura cross-coupling reaction
with phenylboronic acid to afford the product 28 in 96%
yield, again with no loss of stereochemical integrity. We found
that organolithium reagents add selectively to the 2-position
of the pyrimidine. Treatment with nBuLi followed by in situ
oxidation with DDQ, afforded 29 in excellent yield, with no
reduction in enantioenrichment.
We were interested in the origin of this effect, speculating
that the excess nucleophile remaining after the first addition
may preferentially scavenge the minor enantiomer of the
product ent-2 from the system in a kinetic resolution.[21] To
test this hypothesis, we subjected rac-2 to the optimized
asymmetric conditions and observed 17% conversion to 3.
Table 3: Increased thiol loading in asymmetric nucleophilic aromatic
substitution reaction.[a]
Entry
PhSH
2
2
3
(equiv)
Yield [%]
e.r.
Yield [%]
1
2
3
4
1.0
1.1
1.3
1.5
98[b]
93
90
95:5
97:3
98:2
98:2
–
6
8
7
From a mechanistic perspective, we believe that the
asymmetric nucleophilic aromatic substitution reaction
occurs by an interfacial process, as described by Ma˛kosza
and Bialecka.[24] Deprotonation of the thiol at the interface
followed by ion exchange with the catalyst generates a lip-
ophilic ion pair which moves into the organic phase to react
with the dichloropyrimidine. The nucleophilic substitution
93
[a] Reaction conditions: 1 (0.18 mmol), PhSH, 7 (10 mol%), 50% K2CO3
(aq., w/w, 5.0 equiv), CCl4 ([1]=0.1 moldmÀ3), 48 h. Yields refer to
isolated material. The e.r. value was determined by HPLC using a chiral
stationary phase. [b] 94% conversion of starting material.
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1999, 5, 2584; d) S. Sen, V. R. Potti, R. Surakanti, Y. L. N.
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aromatic substitution employing superstoichiometric small-mol-
ecule chiral selectors, see: S. E. Snyder, A. B. Shvets, W. H.
Pirkle, Helv. Chim. Acta 2002, 85, 3605.
[4] a) M. Bella, S. Kobbelgaard, K. A. Jørgensen, J. Am. Chem. Soc.
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Org. Chem. 2006, 71, 4980.
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atropisomeric materials, see: a) J. Gustafson, D. Lim, S. J. Miller,
Science 2010, 328, 1251; b) K. T. Barrett, S. J. Miller, J. Am.
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[10] For reviews of atropselective syntheses of biaryls, see: a) G.
Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser, J.
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Linton, Chem. Soc. Rev. 2009, 38, 3193.
Scheme 3. Derivatization of substituted products. Reaction conditions:
a) mCPBA (5.0 equiv), CH2Cl2, RT, 16 h. b) p-thiocresol (1.3 equiv),
50% KOH (aq., w/w, 10 equiv), nBu4NBr (10 mol%), PhMe, RT, 16 h.
c) pyrrolidine (5.0 equiv), NEtiPr2 (5.0 equiv), DMF, RT, 3 h. d) MeOH
(5.0 equiv), CsOH.H2O(s) (2.0 equiv), nBu4NHSO4 (10 mol%), PhMe,
RT. 24 h. e) PhB(OH)2 (1.5 equiv), [Pd(PPh3)4] (10 mol%), K2CO3
(2.0 equiv), PhMe, 758C, 16 h. f) nBuLi (1.1 equiv), THF, À788C,
10 min, then H2O, DDQ (1.1 equiv), À788C to RT, 5 min. DMF=N,N-
dimethylformamide, mCPBA=m-chloroperbenzoic acid, THF=tetrahy-
drofuran.
event itself likely takes place by a two-step process involving
formation and subsequent collapse of a Meisenheimer com-
plex.[25] It is intriguing to consider whether the formation of
such a complex, which possesses both a stereogenic center
and axis, occurs diastereoselectively. We are currently inves-
tigating this possibility.
In conclusion, we have developed a selective and efficient
approach to the asymmetric synthesis of axially chiral biaryls
through a desymmetrizing nucleophilic aromatic substitution
process. We have identified that the enantioselectivity of this
process is reinforced by a kinetic resolution event which
transforms the minor enantiomer into an achiral species. The
resulting chiral biaryl products contain a second reactive aryl
halide which can be readily derivatized to afford a range of
new atropisomeric biaryl compounds.
[11] For other examples of desymmetrizing atropselective reactions,
see: a) L. M. Engelhardt, W.-P. Leung, C. L. Raston, G. Salem, P.
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[12] a) T. Hayashi, S. Niizuma, T. Kamikawa, N. Suzuki, Y. Uozumi, J.
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Received: August 13, 2014
Published online: September 24, 2014
[13] For selected reviews of asymmetric phase-transfer catalysis, see:
a) M. J. OꢄDonnell, Acc. Chem. Res. 2004, 37, 506; b) T. Ooi, K.
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Keywords: aromatic substitution · atropisomerism · chirality ·
kinetic resolution · phase-transfer catalysis
.
[14] For a discussion of the activating effect of aza-substitution on
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[17] In samples which the enantiomers interconvert on the timescale
of the HPLC, a raised plateau between the separate enantiomer
peaks is present; no such effect was observed for 2. For
a discussion of this effect, see: O. Trapp, Chirality 2006, 18, 489.
[18] Z.-B. Luo, X.-L. Hou, L.-X. Dai, Tetrahedron: Asymmetry 2007,
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[19] CCDC 1019025 (13) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre www.
ccdc.cam.ac.uk/data_request/cif. We tentatively speculate that
the absolute configuration of the major enantiomer of substrates
in Table 2 is the same as that for 13. This configuration is
consistent with the order of elution of the major enantiomer for
13 – 22 when using HPLC with a chiral stationary phase.
However, absolute configuration of 14 – 22 cannot be unequiv-
ocally demonstrated with the data we possess.
[20] The barrier to rotation for 19 is estimated to be 28 kcalmolÀ1; see
the Supporting Information for full details.
[21] For rationalization of this effect, see: S. L. Schreiber, T. S.
Schreiber, D. B. Smith, J. Am. Chem. Soc. 1987, 109, 1525.
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