Use of alkyl 2,4,6-triisopropylbenzoates in the asymmetric homologation of challenging boronic esters

Article abstract of DOI:10.1039/c1cc14469c

(-)-Sparteine induced lithiation of primary 2,4,6-triisopropylbenzoates and subsequent homologation of boronic esters is reported. A comparative study with lithiated N,N-diisopropylcarbamates has demonstrated the superiority of the hindered benzoate. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc14469c

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Chemical Communications
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Volume 47 | Number 47 | 21 December 2011 | Pages 12561–12716
ISSN 1359-7345
COMMUNICATION
Varinder K. Aggarwal et al.
Use of alkyl 2,4,6-triisopropylbenzoates in the asymmetric homologation
of challenging boronic esters
1359-7345(2011)47:47;1-5

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COMMUNICATION
Use of alkyl 2,4,6-triisopropylbenzoates in the asymmetric homologation
of challenging boronic estersw
Robin Larouche-Gauthier, Catherine J. Fletcher, Irantzu Couto and Varinder K. Aggarwal*
Received 22nd July 2011, Accepted 17th August 2011
DOI: 10.1039/c1cc14469c
(À)-Sparteine induced lithiation of primary 2,4,6-triisopropyl-
benzoates and subsequent homologation of boronic esters is
reported. A comparative study with lithiated N,N-diisopropyl-
carbamates has demonstrated the superiority of the hindered
benzoate.
boronic esters required Lewis acids to promote the
1,2-metallate rearrangement and yields were low. We have
therefore explored alternative leaving groups and now report
that using hindered benzoates, in place of carbamates, results
in substantially faster 1,2-metallate rearrangement, allowing
even the most reluctant of migrating groups to engage in the
process.
The enantioselective homologation of boronic esters has
established itself as highly useful methodology in asymmetric
synthesis. Matteson, a pioneer in the field, reported the
homologation of chiral boronic esters with LiCHCl2 followed
by the addition of a Grignard reagent, a process governed by
substrate control.1 An alternative approach is to use reagent
control in the homologation of boron compounds which
requires access to chiral carbanions bearing suitable leaving
groups (carbenoids). In this context, sulfur ylides2 and
a-chloro Grignard/organolithium reagents3 have been used
successfully for the homologation of boron compounds. The
former carbenoid gave good enantioselectivities for boranes
but was unreactive towards boronic esters, limiting their
applicability. a-Chloro Grignard reagents were found to react
well with boronic esters, but were limited in scope and some
degree of racemisation occurred during the homologation
process.
Recently, we reported that Hoppe’s lithiated carbamates4
could be used for the homologation of both boranes and
boronic esters with very high stereoselectivities (Scheme 1).5
In this process, s-BuLi/(À)-sparteine induced asymmetric
deprotonation of a primary carbamate 1 to give lithiated
carbamate 2, which reacted with a boron electrophile 3 to
give an ate complex 4, which finally underwent 1,2-metallate
rearrangement to give the homologated boron compound 5.
This could be oxidised to the alcohol 6 or utilized in further
homologations. Products of opposite enantioselectivity could
be easily obtained by replacing (À)-sparteine with O’Brien’s
(+)-sparteine surrogate.6 However, in exploring synthetic
applications of this methodology, we have encountered certain
boronic esters which were very slow to migrate. For example,
we found that the synthetically important Me and (CH2)2COOtBu
Based on the problems highlighted above, we sought a
carbenoid with a better leaving group than a carbamate and
so considered the use of 2,4,6-triisopropylbenzoates. Beak had
reported the a-lithiation of 2,4,6-triisopropylbenzoates
mediated by s-BuLi and TMEDA, demonstrating that
deprotonation was possible with a strong base.7 Hammerschmidt
demonstrated that these lithiated species, generated by tin-
lithium exchange from the corresponding stannanes, were
configurationally stable at low temperature (À78 1C).8 How-
ever, no example of asymmetric lithiation of a primary
2,4,6-triisopropylbenzoate had been reported, which was
therefore our first task.
Primary 2,4,6-triisopropylbenzoates were easily obtained
from their corresponding alcohols by direct acylation with
2,4,6-triisopropylbenzoyl chloride (TIBCl)9 (Scheme 2). We
explored the asymmetric lithiation of primary 2,4,6-triisopropyl-
benzoates by reacting 7a with s-BuLi and (À)-sparteine in
Et2O at À78 1C followed by Bu3SnCl and were pleased to
isolate stannane (S)-8 in high yield and 96 : 4 e.r. This indi-
cated that the benzoate behaved similarly to the corresponding
carbamate 1a in promoting asymmetric deprotonation, albeit
with slightly lower e.r.10 Furthermore, treatment of the
stannane (S)-8 with n-BuLi followed by i-PrBpin (9a) gave,
School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
BS8 1TS, UK. E-mail: v.aggarwal@bristol.ac.uk;
Fax: +44 (0)117 929 8611; Tel: +44 (0)117 954 6315
w Electronic supplementary information (ESI) available: Full experi-
mental details and characterisation. See DOI: 10.1039/c1cc14469c
Scheme 1 Homologation of boron compounds with lithiated primary
N,N-diisopropylcarbamates, Cb = ÀC(O)NiPr2.
c
12592 Chem. Commun., 2011, 47, 12592–12594
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Table 1 Comparison of benzoates and carbamates in the homologa-
tion of boronic esters
Entry R1
R2
Conditionsa Yieldb (%) e.r.c
1
2
3
4
5
6
7
8
Cb
Cb
Me 9b
Me 9b
A
B
C
A
B
C
A
B
o10
50
76
73
70
84
71
n.d.
86
0
n.d.
95 : 5
96 : 4
99 : 1
99 : 1
96 : 4
98 : 2
n.d.
96 : 4
n.d.
93 : 7
96 : 4
n.d.
n.d.
97 : 3
n.d.
99 : 1
96 : 4
TIB Me 9b
Cb
Cb
TIB Et 9c
Cb
Cb
TIB cPr 9d
Cb
Cb
TIB (CH2)2COOtBu 9e
Cb
Cb
Et 9c
Et 9c
Scheme 2 Preparation of 2,4,6-triisopropylbenzoates and homologa-
tion of boronic esters.
cPr 9d
cPr 9d
9
C
A
after oxidation, secondary alcohol 10a in 79% yield with
complete stereochemical integrity.11
10
11
12
13
14
15
16
17
18
(CH2)2COOtBu 9e
(CH2)2COOtBu 9e Bd
35
63
0
A
A
B
A
A
B
The rate of 1,2-migration for boron-ate complexes derived
from lithiated 2,4,6-triisopropylbenzoate and lithiated N,N-
diisopropylcarbamate were qualitatively evaluated (Scheme 3).
Stannanes 8 and 11 were treated with n-BuLi at À78 1C to
generate the lithiated species which were subsequently trapped
with EtBpin (9c) and allowed to warm to RT. The reaction
was monitored by 11B NMR as it was possible to follow the
conversion of the boron-ate complexes 12 and 13 (d B5–7 ppm)
into the homologated boronic ester 14 (d = 34 ppm). After 1 h
at room temperature, 20% conversion was observed for ate
complex 12 whereas no sign of migration was observed for the
related carbamate 13. After 24 h, 70% conversion was
observed for 12 whereas only marginal conversion was
observed for 13. More conveniently, complete conversion of
the benzoate-derived boron-ate complex 12 could be achieved
after only 2 h at 35 1C, whereas under the same conditions
only 15% conversion of the carbamate-derived ate complex 13
had occurred. These results demonstrate the significant
increase in the rate of 1,2-migration of the 2,4,6-triisopropyl-
benzoate compared to the N,N-diisopropylcarbamate.
(CH2)2CN 9f
(CH2)2CN 9f
0
TIB (CH2)2CN 9f
Cb
Cb
46
o10
88
79
Ph 9g
Ph 9g
TIB Ph 9g
C
a
Conditions A: 16 h reflux. Conditions B: MgBr2ÁEt2O (2 equiv.),
b
16 h, reflux. Conditions C: 2 h, reflux. Isolated yield. Determined
d
by chiral HPLC. 5 days, reflux. n.d. = Not determined. cPr =
cyclopropyl.
c
complex was reacted for 16 h at 35 1C (conditions A), or under
the more forcing conditions of 16 h at 35 1C in the presence of
MgBr2,12 (conditions B). The benzoate ester-derived boron-ate
complex was reacted for 2 h at 35 1C (conditions C).
In this study we largely focussed on boronic esters that did
not migrate easily and began with MeBpin (9b). As is evident
from entry 1, the Me group is a very slow migrating group
indeed and hardly migrated at all after 16 h at 35 1C when the
carbamate group was employed. The addition of MgBr2
improved the yield to 50% (entry 2) but the reaction employing
the benzoate produced the desired alcohol in 76% yield after
only 2 h under reflux (conditions C) (entry 3).
We then explored the asymmetric homologation of a series
of boronic esters with the lithiated alkyl 2,4,6-triisopropyl-
benzoate 7a and compared it with the N,N-diisopropyl-
carbamate analogue 1a (Table 1). The carbamate-derived boron-ate
For groups on boron with good migratory aptitude (Et and
cPr, entries 4–9), we found only moderate improvement in
yields when the benzoate ester was employed compared to the
carbamate. Nonetheless, the shorter reaction times for the homo-
logations involving the benzoate are noteworthy (2 h vs. 16 h).
Boronic esters bearing b-electron withdrawing groups [ester
(9e) or nitrile (9f)] turned out to be very slow migrating groups
(entries 10–15). Even under the most forcing conditions using
MgBr2ÁEt2O these groups hardly migrated when carbamate
leaving groups were employed (entries 11,14). Even after
5 days under reflux in the presence of MgBr2ÁEt2O, the ester
9e had only migrated to a limited extent and gave the desired
alcohol 10d in only 35% yield (entry 11). In contrast, using the
lithiated benzoate the alcohol 10d was produced in 63%
after 16 h at 35 1C (without any Lewis acid) and in 96 : 4 e.r.
(entry 12). A similar trend was observed in the homologation
of cyano substituted boronic ester 9f, which only worked with
the lithiated benzoate (entry 15).
Scheme 3 Comparative rates of 1,2-migration for 2,4,6-triisopropyl-
benzoate vs. N,N-diisopropylcarbamate.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12592–12594 12593

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R.L.-G. thanks the FQRNT (Que
´
bec) for a postdoctoral
fellowship. C.J.F. thanks the EPSRC and GSK for funding.
I.C. thanks the Spanish Ministry for a grant. We thank
Inochem-Frontier Scientific for the generous donation of
boronic acids and boronic esters.
Notes and references
1 (a) D. S. Matteson and D. Majumder, J. Am. Chem. Soc., 1980,
102, 7588; (b) D. S. Matteson and D. Ray, J. Am. Chem. Soc.,
1980, 102, 7590. For reviews on the use of boronic esters in
asymmetric syntheses, see: (c) D. S. Matteson, Tetrahedron, 1989,
45, 1859; (d) D. S. Matteson, Tetrahedron, 1998, 54, 10555.
2 (a) V. K. Aggarwal, G. Y. Fang and A. T. Schmidt, J. Am. Chem.
Soc., 2005, 127, 1642; (b) G. Y. Fang and V. K. Aggarwal, Angew.
Chem., Int. Ed., 2007, 46, 359; (c) D. Howells, R. Robiette,
G. Y. Fang, L. S. Knowles, M. D. Woodrow, J. N. Harvey and
V. K. Aggarwal, Org. Biomol. Chem., 2008, 6, 1185.
3 (a) P. R. Blakemore and M. S. Burge, J. Am. Chem. Soc., 2007,
129, 3068; (b) P. R. Blakemore, S. P. Marsden and H. D. Vater,
Org. Lett., 2006, 8, 773; (c) C. R. Emerson, L. N. Zakharov and
P. R. Blakemore, Org. Lett., 2011, 13, 1318.
4 (a) D. Hoppe, F. Hintze and P. Tebben, Angew. Chem., Int. Ed.
Engl., 1990, 29, 1422. For reviews on a-lithiation of carbamates,
see: (b) D. Hoppe and F. Hintze, Angew. Chem., Int. Ed. Engl.,
1997, 36, 2282; (c) A. Basu and S. Thayumanavan, Angew. Chem.,
Int. Ed., 2002, 41, 716; (d) D. Hoppe, F. Marr and
Scheme 4 Effect of alkyl substituent’s bulk on stereoselectivity.
Boronic esters bearing aryl groups also emerged as slow
migrating groups (entry 16). Heating at reflux for 16 h in the
presence of Lewis acid was required with the lithiated
carbamate, to obtain the alcohol 9g (entry 17). Once again,
the benzoate showed remarkable reactivity, allowing the
production of the desired alcohol in similar yield and selectivity
after only 2 h under reflux without any Lewis acid assistance
(entry 18).
The factors that affect the rate of migration of boron
substituents are complex and include steric, conformational
and electronic effects.13 In the examples of the slow migrating
groups, we believe that the following issues may be operative.
In the case of the small Me substituent, the short C–B bond
length in the boron-ate complex will make it a stronger bond
and so the barrier to migration will be greater.14 Substituents
bearing electron withdrawing groups will be less nucleophilic
and so will migrate less rapidly. Although Ph is usually a good
migrating group, it had been found to be poor when sulfonium
ions were leaving groups but this was due to conformational
effects.15 Such effects are absent here and as such it is not easy
to account for its poor migrating ability.
M. Bruggemann, Organolithiums in Enantioselective Synthesis, ed.
¨
D. M. Hodgson, Springer, Heidelberg, 2003, pp. 61-137.
5 (a) J. L. Stymiest, G. Dutheuil, A. Mahmood and V. K. Aggarwal,
Angew. Chem., Int. Ed., 2007, 46, 7491; (b) G. Dutheuil,
M. P. Webster, P. A. Worthington and V. K. Aggarwal, Angew.
Chem., Int. Ed., 2009, 48, 6317; (c) M. P. Webster, B. M. Partridge
and V. K. Aggarwal, Org. Synth., 2011, 88, 247; (d) G. Besong,
K. Jarowicki, P. J. Kocienski, E. Sliwinski and F. T. Boyle, Org.
Biomol. Chem., 2006, 4, 2193.
6 (a) M. J. Dearden, C. R. Firkin, J.-P. R. Hermet and P. O’Brien,
J. Am. Chem. Soc., 2002, 124, 11870; (b) A. J. Dixon,
M. J. McGrath and P. O’Brien, Org. Synth., 2006, 83, 141.
7 (a) P. Beak and B. G. McKinnie, J. Am. Chem. Soc., 1977,
99, 5213; (b) P. Beak, M. Baillargeon and L. G. Carter, J. Org.
Chem., 1978, 43, 4255; (c) P. Beak and L. G. Carter, J. Org. Chem.,
1981, 46, 2363.
We finally explored the scope of the primary alkyl substi-
tuent of the 2,4,6-triisopropylbenzoate in the homologation of
PhBpin (9g) (Scheme 4). Both the less hindered ethyl (7b) and
the more hindered isobutyl (7c) benzoate esters worked well
giving high yields and high enantioselectivities (95 : 5 and
97 : 3 e.r. respectively) in the lithiation-borylation reaction,
similar to the levels observed with the corresponding carba-
mates (97 : 3 and 98 : 2 e.r. respectively5a).
8 D. C. Kapeller and F. Hammerschmidt, J. Org. Chem., 2009,
74, 2380.
9 P. Beak and L. G. Carter, J. Org. Chem., 1981, 46, 2363.
10 The e.r. in the same reaction with the carbamate was 99.1.
11 Treatment of 7a with s-BuLi/ (À)-sparteine followed by iPrBpin
and subsequent oxidation gave alcohol 10a, the same isomer as
that obtained from the stannane S-8. Based on this and the fact
that both borylation and stanylation usually occur with retention
of stereochemistry we have assigned the stereochemistry of
stannane (S)-8 accordingly.
12 MgBr2 has to be freshly prepared from Mg and 1,2-dibromoethane
(carcinogen) in Et2O.
13 V. K. Aggarwal, G. Y. Fang, X. Ginesta, D. M. Howells and
M. Zaj, Pure Appl. Chem., 2006, 78, 215.
14 A. Bottoni, M. Lombardo, A. Neri and C. Trombini, J. Org.
Chem., 2003, 68, 3397.
15 R. Robiette, G. Y. Fang, J. N. Harvey and V. K. Aggarwal, Chem.
Commun., 2006, 741.
16 Homoallylic 2,4,6-triisopropylbenzoates have been employed in
the preparation of chiral allylboronic esters which were ultimately
used in a stereocontrolled synthesis of solandelactone: F. A. Robinson
and V. K. Aggarwal, manuscript in preparation.
In summary, we have found that a-lithiated alkyl 2,4,6-
triisopropylbenzoates can be easily generated using s-BuLi/
(À)-sparteine and subsequent addition to boronic esters leads
to boron-ate complexes which rapidly undergo 1,2-metallate
rearrangement to give homologated products. The significant
increase in rate of the 1,2-metallate rearrangement compared
to carbamates now enables the homologation of the most
challenging boronic esters including those that were essentially
unusable before. The increased scope now broadens the range
of chiral secondary boronic esters that can be prepared,16 and
these constitute important substrates in asymmetric synthesis
in general.17
17 (a) Boronic Acids-Preparation, Applications in Organic Synthesis
and Medicine, ed. D. G. Hall, Wiley-VCH, Weinheim, 2005;
(b) C. M. Crudden, B. W. Glasspoole and C. J. Lat, Chem.
Commun., 2009, 6704; (c) R. Larouche-Gauthier, T. G. Elford
and V. K. Aggarwal, manuscript in preparation.
We thank EPSRC and the European Research Council
(FP7/2007-2013, ERC grant no. 246785) for financial support.
VKA thanks the Royal Society for a Wolfson Research
Merit Award and EPSRC for a Senior Research Fellowship.
c
12594 Chem. Commun., 2011, 47, 12592–12594
This journal is The Royal Society of Chemistry 2011