Enantiospecific sp2 -sp3 coupling of secondary and tertiary boronic esters

Article abstract of DOI:10.1038/nchem.1971

The cross-coupling of boronic acids and related derivatives with sp ² electrophiles (the Suzuki-Miyaura reaction) is one of the most powerful C-C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures.

Full text of DOI:10.1038/nchem.1971

ARTICLES
PUBLISHED ONLINE: 8 JUNE 2014 | DOI: 10.1038/NCHEM.1971
Enantiospecific sp2–sp3 coupling of secondary
and tertiary boronic esters
Amadeu Bonet, Marcin Odachowski, Daniele Leonori, Stephanie Essafi and Varinder K. Aggarwal
*
The cross-coupling of boronic acids and related derivatives with sp2 electrophiles (the Suzuki–Miyaura reaction) is one of
the most powerful C–C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals
and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited
when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic
esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve
using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled
to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are
easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where
there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with
three-dimensional architectures.
he Suzuki–Miyaura cross-coupling reaction is one of the most
widely used reactions in synthesis1,2. Indeed, it is the reaction
used most widely in the preparation of drug candidates and is
a
B(pin)
R1
• Easy to make
• Many other
Ar–Li available
• Readily available
• Stable
• High enantiopurity
+
Li
•
T
O
R
also commonly used in the synthesis of agrochemicals and conduct-
ing materials. The impact of this single reaction across many areas of
society has been immense. However, although extraordinarily useful
for sp2–sp2 coupling, this reaction actually shows rather limited
scope, particularly in relation to the nature of the aliphatic boron
reagents that can be employed. Primary organoboron reagents
work well, but apart from a few specific and isolated examples,
(chiral) secondary3–11 and tertiary boronic esters do not, which
limits the application of this reaction to flat molecules12. This limit-
ation is because of unwanted side reactions that begin to compete
with the much slower transmetallation and reductive elimination
steps associated with the more-hindered organometallic intermedi-
ates13,14. Such inherent problems have demanded alternative strat-
egies15, the most successful being Fu and co-workers’ Ni-catalysed
enantioselective cross-couplings of chiral (racemic) alkyl halides
with achiral organometallic reagents16–18 and of achiral alkyl halides
with chiral (racemic) organometallic reagents19, the stereospecific
cross-coupling of chiral secondary organostannanes20–22 and the
E
E
E
E
B(pin)
B(pin)
O
O
(A) Aromatic
electrophilic
substitution
R
R1
(B) Aliphatic
electrophilic
substitution
R
R1
R
R1
I
II
1,2-Shift
Nu–
Stereospecific
transition-
metal-free
coupling
B(pin)
R1
R1
Elimination
E
O
O
R
R
I2 or
NCS
b
c
n-BuLi, THF, –78 °C
B(Cy)3
Cy
O
O
O
then B(Cy)3
95%
stereospecific cross-coupling of chiral secondary benzyl ethers23,24
.
Our alternative strategy centred on utilizing the readily accessi-
ble, stereodefined secondary boronic esters. We reasoned that the
addition of an electron-rich aryl lithium reagent (for example,
2-lithiofuran) to the boronic ester would give an intermediate
boronate complex I that, on reaction with a suitable electrophile,
would generate cation II (Fig. 1a, Path A). The cation was expected
to trigger a 1,2-migration and, after elimination, would give the
aryl-coupled product stereospecifically. Although related reactions
NBS
n-BuLi, THF, –78 °C to r.t.
B(pin)
B(pin)
O
O
2a
O
–78 °C, 1 h
then
Ph
(R)-1a
e.r. 98:2
Ph
Ph
91% yield
e.r. 98:2
100% e.s.
of electron-rich aromatics with achiral boranes were reported over Figure 1 | Proposed method for stereospecific coupling of boronic esters
40 years ago (for example, Fig. 1b)25–34, this chemistry was not with an illustration of previous literature and key results. a, Proposed
developed further. Presumably, the combined difficulties associated pathway for the stereospecific, transition-metal-free coupling of chiral
with handling air-sensitive boranes, creating stereodefined boranes
and, in particular, issues as to which group would migrate in non-
secondary boronic esters with 2-lithiofuran. b, Previous coupling with
symmetrical boranes25,27,29. This reaction is believed to follow the
symmetrical boranes, thwarted its development. The intermediate mechanism shown in a. c, Optimized conditions discovered for
boronate complex I could also react with electrophiles at the stereospecific coupling. Cy, cyclohexyl; E, electrophile; e.r., enantiomeric ratio;
sp3 carbon35–38 (Fig. 1a, Path B) and so conditions/reagents would NBS, N-bromosuccinimide; NCS, N-chlorosuccinimide; Nu, nucleophile;
need to be tuned carefully to promote the desired reaction
pin, pinacolato; r.t., room temperature.
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK. e-mail: v.aggarwal@bristol.ac.uk
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1971
ARTICLES
O
(Fig. 1a, Path A). In this paper we describe our success in promoting
this pathway, and thus achieving a practical stereospecific coupling of
secondary and tertiary boronic esters with electron-rich aromatics.
O
Li
R2
R3–B(pin)
OCb
(pin)B R3
R1 R2
i-Pr2N
(pin)B
R3
R1
R1
R2
+
Results
Boronate
complex
We began our studies with the addition of 2-lithiofuran to boronic
ester (R)-1a (prepared by our lithiation–borylation methodology39)
and explored a range of electrophiles (see the Supplementary
Information). Of the electrophiles tested, N-bromosuccinimide
(NBS) was found to be the optimum; it reacted rapidly at low temp-
erature and furnished the product with complete stereospecificity
(100% enantiospecificity (e.s.)) (Fig. 1c).
Secondary, R2 = H
1a (e.r. 98:2) :1 R1 = PhCH2CH2
1b (e.r. 96:4) : R1 = Me
1c (e.r. 97:3) : R1 = PhCH2CH2
1d (e.r. 96:4) : R1 = CH2CH2CO2-t-Bu
R
R
3 = Me
3 = CH2CH2-p-OMe-Ph
R3 = i-Pr
R
3 = PhCH2CH2
1e (e.r. 93:7) :
R
1 = Ph
R3 = Me
A range of enantioenriched secondary39 and tertiary boronic
esters40–42 was then prepared by the lithiation–borylation method-
ology or by hydroboration (Fig. 2; see the Supplementary
Information for details) and subsequently tested under these opti-
mized reaction conditions (Table 1).
B(pin)
(pin)B
(pin)B
N
Boc
In general, secondary dialkyl- and secondary benzylic-
substituted boronic esters 1a and 1c–1e reacted well to give the
products 2a and 2c–2e with complete enantiospecificity (Table 1).
This initial screening showed that the process tolerated increased
steric hindrance on the boronic ester (1c) and was compatible
with ester functionalities (1d). The utility of this chemistry was
evaluated further in the stereospecific arylation of terpene-based
secondary boronic esters 1f and 1g (derived from (þ)-carene and
(þ)-pinene, respectively). In both cases, the desired products 2f
and 2g were obtained in high yields and with complete diastereo-
specificity. (R)-2-borylpyrrolidine43 (1h) also coupled effectively
with 2-lithiofuran in good yield and complete enantiospecificity,
which extended the range of functional groups compatible with
the new protocol (2h). Direct hydroboration of b-cholesterol44
(see the Supplementary Information) gave the cyclic boronic ester
1i, which underwent the desired arylation process (2i) without the
need for protection of the hydroxyl group.
1h
(e.r. 95:5)
1f
1g
H
H
H
H
1i: R = H
1j: R = TBS
RO
H
B(pin)
Tertiary
1k (e.r. 99:1) :1
1l (e.r. 99:1) :1 R1 = Ph
1m (e.r. 99:1) :
1 = Ph
1n (e.r. 99:1) : R1 = Ph
R
1 = PhCH2CH2
R
R
R
2 = Me
R
R
R
3 = Et
2 = Me
2 = Me
3 = Et
R
3 = i-Bu
R3 = p-Br-Ph
R2 = Me
Figure 2 | Range of secondary and tertiary boronic esters tested in
this study. Although most of the boronic esters were prepared by
lithiation–borylation reactions of carbamates, as described in the scheme,
some were prepared by hydroboration (1f, 1g, 1i and 1j) and one
by deprotonation and borylation (1h). Boc, tert-butoxycarbonyl;
TBS, tert-butyldimethylsilyl.
The carene-coupling reaction (Table 1, 2f) was carried out on a
gram scale and with all the steps conducted at 0 8C, in similarly
high yield and complete diastereospecificity. The larger-scale,
higher-temperature and transition-metal-free conditions demonstrate
the potential of the methodology to industrial application.
Table 1 | Scope of the secondary and tertiary boronic esters tested in the coupling reaction with furan.
n-BuLi, THF, –78 °C to r.t., 1 h
R3
R1
NBS, –78 °C, 1 h
R2
B(pin)
R3
R2
O
O
O
then (pin)B R3 , –78 °C
R1 R2
R1
O
O
O
O
O
O
CO2-t-Bu
Ph
Ph
Ph
Ph
2a
91%
2c
92%
2d
2e
2f
2g
90%
e.r. 96:4
100% e.s.
93%
e.r. 93:7
100% e.s.
68%
77%
82%
e.r. 98:2
e.r. 97:3
100% e.s.
100% e.s.
(gram scale, T = 0°C)
Br
H
O
O
O
O
O
Ph
Ph
N
Boc
Ph
H
O
Ph
2k
89%
e.r. >99:1
100% e.s.
H
H
2h
74%
e.r. 93:7
96% e.s.
2l
83%
2m
76%
e.r. >99:1
100% e.s.
2n
53%
e.r. 98:2
99% e.s.
HO
2i
78%
H
e.r. >99:1
100% e.s.
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1971
ARTICLES
Table 2 | Stereospecific coupling of electron-rich aromatics with secondary and tertiary boronic esters.
Ar
Ar R3
R1
R2
Lithiation (see SI)
(pin)B R3
NBS
(pin)B R3
Ar–H/Br
–78 °C
then
, –78 °C
R1
R2
R1
R2
t-BuO2C
CO2-t-Bu
MeO
OMe
S
N
Ph
O
O
Ph
Ph
4a
Ph
7a†
83%
Ph
3d
85%
5d
66%
6a
86%
*
92%
e.r. 96:4
100% e.s.
e.r. 98:2
100% e.s.
e.r. 96:4
100% e.s.
e.r. 98:2
100% e.s.
e.r. 98:2
100% e.s.
MeO
Me2N
H
Ph
Ph
Ph
H
MeO
8a*
65%
e.r. 98:2
100% e.s.
9a†
72%
e.r. 98:2
100% e.s.
10a†
89%
e.r. 98:2
11b†
83%
e.r. 96:4
100% e.s.
H
H
RO
H
100% e.s.
Ar
OMe
OMe
N
Ar =
MeO
MeO
MeO
OMe
NMe2
Ph
Ph
7l†
Ph
Ph
6j
7i‡
R = H
91%
8j
*
*
7k‡
78%
10k†
75%
11k†
66%
R = TBS
75%
R = TBS
68%
63%
e.r. 99:1
100% e.s.
e.r. >99:1
100% e.s.
e.r. 99:1
100% e.s.
e.r. 98:2
100% e.s.
*NIS was used instead of NBS. †The solvent was switched to MeOH before NBS addition. ‡NBS was added in MeOH. SI, Supplementary Information.
We were keen to determine whether our method could be aromatic 3,5-dimethoxyphenyllithium and the secondary boronic
extended to the much more challenging coupling of enantioenriched ester 1a resulted in an 87:13 mixture of the arylated product 7a
tertiary boronic esters to make quaternary stereogenic centres, a and bromide 12 (resulting from NBS attack at the sp3 carbon)
process that is highly desirable but not achievable by current (Fig. 3, (i)). However, in MeOH the arylated product 7a was
methods. We therefore tested the enantioenriched benzylic40,41 and formed exclusively. 3-Dimethylaminophenyllithium behaved simi-
non-benzylic42 tertiary boronic esters 1k–1n in our process larly, although, as with other highly electron-rich aromatics, NIS
(Table 2) and found that the desired products 2k–2n were was found to be superior to NBS. The dimethylamino group is an
obtained in good yields and complete stereospecificity, which especially useful handle as it can be replaced readily by hydrogen45
demonstrates the power of the new methodology. As these or used in subsequent Ni-catalysed cross-coupling46. The use of
boronic esters were prepared readily in an essentially enantiopure MeOH in place of THF proved even more critical in the case of
form, the furyl-coupled products were also obtained in a similarly the weakly electron-rich aromatics, including 3-methoxyphenyl-
enantiopure form.
lithium, 1-naphthyllithium and 3,5-dimethylphenyllithium, for
The scope of the aromatic component was also investigated which we observed a complete switch from C(sp3)-bromination to
with secondary and tertiary boronic esters (Table 2). In addition the desired arylation (Fig. 3). In all cases, coupled products were
to the 2-substituted furan, the 3-substituted furan 3d worked obtained in high yield and complete enantiospecificity (Table 2,
just as well. The reaction was also extended to other electron- 7a–10a and 11b). The two representative enantioenriched benzylic
rich heteroaromatics. Thiophene, benzofuran and N-methyl- and non-benzylic tertiary boronic esters 1k and 1l were also tested
indole all led to the coupled products 4a, 5d and 6a, respectively, with several representative aryl lithiums that span a range of aro-
in high yield and complete enantiospecificity, although in the case matics: 3,5-dimethoxyphenyllithium, 3,5-dimethylphenyllithium
of N-methyl indole, N-iodosuccinimide (NIS) was found to be and 1-lithionaphthalene. Under optimized conditions, the tertiary
superior to NBS, as the latter reagent caused bromination of the boronic esters coupled in good-to-high yield and complete enantio-
indole ring.
We also found that the coupling could be applied to a broad
specificity in all cases (Table 2, 7k, 7l, 10k and 11k).
However, not all aromatics worked. They needed to be suffi-
range of electron-rich benzene derivatives, although further modifi- ciently electron rich (phenyllithium and 3-methylphenyllithium
cation of the reaction conditions was required. Under standard con- were unsuccessful) and have a donor substituent meta to the boro-
ditions (in THF), the coupling between the highly electron-rich nate complex, otherwise competing electrophilic attack at the sp3
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1971
ARTICLES
R1
R1
(i)
Nu
Br
Br
R
R1
A
[Br+]
R1
B(pin)
A: SEAr
Fast
1,2-Shift
Elimination
R
B(pin)
R
Ph
Ph
R
Ph
B(pin)
B
Ph
R
R1
Solvent
A:B1*
Br
B: SE2inv
Slow
[Br+]
MeO
MeO
MeO
MeO
THF
87:13
99:1
Ph
12
MeOH
MeO
MeO
H
H
THF
1:99
99:1
(ii)
MeO
Br
MeOH
MeO
A: SEAr
Slow
Me
Me
Me
Me
THF
1:99
99:1
B(pin)
MeOH
Ph
[Br+]
B(pin)
B
A
Me
Me
H
H
THF
1:99
MeOH
28:72
Ph
B: SE2inv
Fast
Br
[Br+]
H
H
H
H
THF
1:99
1:99
Ph
MeOH
12
Figure 3 | Possible reaction pathways for the reactions of aryl–boronate complexes with electrophiles, illustrated with [Br1]. This highlights the major
difference in the reaction pathway according to the substitution of the aromatic ring: meta donor groups favour (i), whereas para donor groups favour (ii).
A further solvent effect was found in the cases of the meta donor groups in that (i) was favoured in polar protic media (MeOH). *Ratio determined by gas
chromatography mass spectrometry and 1H NMR spectroscopy analysis of the crude reaction mixture. SEAr, aromatic electrophilic substitution.
carbon centre occurred (2- and 4-methoxyphenyllithium were not effects of both the boronate and the donor groups must reinforce
effective, whereas 3-methoxyphenyllithium was (9a))38. In the each other to favour Path A over the competing Path B. When the
case of the least electron-rich aromatic, 3-methylphenyllithium, a donor substituent is in either the ortho or para position, Path A is
28:72 mixture of products comprising the desired coupled retarded because now the two donor substituents do not reinforce
product and 2-bromo-4-phenylbutane 12 was obtained, showing each other, and Path B is enhanced, which leads to reaction via
the lower limit of the aromatic group that can be employed (see Path B (Fig. 3, (ii)).
Discussion for this aspect of the mechanism).
The dramatic effect of solvent on the success of the coupling
The development of a methodology that enables the chemical reaction is especially striking in the case of weakly donating aro-
modification of complex natural products is extremely challenging, matic boronate complexes: in THF, SE2inv dominated (Path B),
but it can be highly rewarding as it can lead to molecules with but in MeOH, arylation dominated (Path A). This solvent effect is
improved properties47. By the introduction of boron to a natural believed to result from increased rates of electrophilic aromatic sub-
product through the routine procedure of hydroboration and the stitution processes (which have cationic intermediates) in more-
methodology described herein, it is now possible to introduce a polar media50.
library of aromatic substituents at an olefinic site in a regio- and
The dramatic effect of even weak donor substituents in the meta
stereocontrolled manner, as illustrated with the steroid 1j. Thus, position on the success of the coupling reaction is also striking. With
coupling of 1j with indole and several benzene derivatives gave no donor groups (that is Ph, just H in the meta position), Path B
the cholesterol analogues 6j, 7i and 8j (Table 2) with full control dominated over Path A (.98:2), with just one Me group a 72:28
of the regio- and stereochemistry.
ratio of products derived from Paths B and A were obtained, but
with two Me groups (meta-dimethyl) Path A dominated over
Path B (99:1) (Fig. 3).
Discussion
Our proposed mechanism for these reactions is presented in
In conclusion, we have discovered, for the first time, a general
Figs 1 and 3. The addition of an aryl lithium to a chiral boronic method for coupling electron-rich aromatic and heteroaromatic
ester generates a boronate complex. We have previously shown that compounds with enantioenriched secondary and tertiary boronic
these complexes are good nucleophiles and react with a range of esters. The reaction involves the initial formation of a boronate
electrophiles with inversion (SE2inv, for example, Fig. 3, Path B)38,48
.
complex followed by activation of the electron-rich aromatic
To promote nucleophilic reaction of the boronate complex at the moiety by an electrophile (NBS), which triggers a stereospecific
aromatic ring rather than at the sp3 centre (as required for an 1,2-migration and subsequent elimination/rearomatization. The
arylation process) we reasoned that aromatics that are more electron methodology, which uses simple, readily available reagents, no tran-
rich would be required; we initially selected furan. These boronate sition metals and user-friendly conditions, shows broad scope in
complexes reacted with NBS at the aromatic ring and, following both the boronic ester and the electron-rich aromatic, and shows
1,2-migration and elimination, gave the furyl-coupled product complete stereospecificity. Application to a number of more-
stereospecifically, as illustrated in Fig. 1.
complex and functionalized boronic esters also highlights the
In the case of differently substituted benzene derivatives, donor broad utility of the new methodology.
groups in the meta position relative to the boronate complex
lead to bromination at the para position, which triggers the
Methods
1,2-migration and subsequent elimination (Fig. 3, (i)). The boronate
Stereospecific synthesis of 2a was performed as follows: a solution of furan (1.2
moiety is also a strong donating group49 and, evidently, the directing equiv.) in THF (0.3 M) was cooled to 278 8C and treated with n-BuLi (1.2 equiv.,
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1971
ARTICLES
1.6 M in hexanes). The cooling bath was removed and the mixture was stirred
at room temperature for one hour. The mixture was cooled to 278 8C and
1a (1 equiv.) was added dropwise as a solution in THF (0.5 M). The mixture was
stirred at 278 8C for one hour, at which point 11B NMR spectroscopy showed
complete formation of the ‘ate’ complex (11B NMR (96 MHz, THF) dB ≈ 8 ppm).
A solution of NBS (1.2 equiv.) in THF (0.3 M) was added dropwise. After one
hour at 278 8C, Na2S2O3 (aqueous, saturated) was added and the reaction mixture
was allowed to warm to room temperature. The reaction mixture was diluted with
Et2O and water. The layers were separated and the aqueous layer was extracted with
Et2O. The combined organic layers were dried (MgSO4), filtered and concentrated
under vacuum. The crude material was adsorbed on silica and purified by flash
column chromatography on silica gel, eluting with n-hexane. For the complete
experimental details and the characterization of compounds, see the
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Supplementary Information.
Received 14 February 2014; accepted 30 April 2014;
published online 8 June 2014
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1971
ARTICLES
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Author contributions
D.L. and V.K.A. designed the project and wrote the manuscript. A.B. and M.O. contributed
intellectually and practically to the laboratory experiments, S.E. performed preliminary
computational studies and was involved in the mechanistic discussions.
Additional information
50. Reichardt, C. & Welton, T. E. Solvents and Solvent Effects in Organic Chemistry
4th edn (Wiley, 2010).
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be addressed
to V.K.A.
Acknowledgements
We thank the Engineering and Physical Sciences Research Council (EP/I038071/1) and the
European Research Council (FP7/2007-2013, ERC grant no. 246785) for financial support.
A.B. thanks the Marie Curie Fellowship program (EC FP7 No 329578). We thank H. Mayr, Competing financial interests
V. Rawal and J. N. Harvey for useful discussions.
The authors declare no competing financial interests.
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