Asymmetric sulfur ylide reactions with boranes: Scope and limitations, mechanism and understanding

Article abstract of DOI:10.1021/ja074110i

The reactions of aryl-stabilized sulfur ylides with organoboranes has been studied under a variety of conditions. At 5 or -78°C, the reaction with Et₃B gave a mixture of the first and second homologation products, but at -100°C, only the first homologation product was obtained even with just 1.1 equiv of Et₃B. Under these optimized conditions, the chiral sulfur ylides (derived from camphor sulfonic acid) with different aryl groups were reacted with Et₃B to give the corresponding alcohols (95-98% yield, 96-98% ee) and amines (74-77% yield, >98% ee). The origin of the high enantioselectivity is discussed. The use of nonsymmetrical 9-BBN derivatives was also explored. It was found that whereas primary alkyl substituents gave mixtures of products derived from competing migration of the boron substituent and the boracycle, all other groups resulted in either exclusive migration of the boron substituent (Ph, hexenyl, i-Pr) or exclusive migration of the boracycle (hexynyl, cyclopropyl). The factors responsible for the outcome of the reactions involving a hindered (i-Pr) and an unhindered (propynyl) substituent were studied by DFT calculations. This revealed that, in the case of an unhindered substituent, the conformation of the ate complex is the dominant factor whereas, in the case of a hindered substituent, the barriers to interconversion between the conformers of the ate complex and subsequent migration control the outcome of the reaction.

Full text of DOI:10.1021/ja074110i

Published on Web 11/07/2007
Asymmetric Sulfur Ylide Reactions with Boranes: Scope and
Limitations, Mechanism and Understanding
Guang Y. Fang, Olov A. Wallner, Nadia Di Blasio, Xavier Ginesta,
Jeremy N. Harvey, and Varinder K. Aggarwal*
Contribution from the School of Chemistry, UniVersity of Bristol, Cantock’s Close,
Bristol, BS8 1TS, UK
Received June 6, 2007; E-mail: V.Aggarwal@bristol.ac.uk
Abstract: The reactions of aryl-stabilized sulfur ylides with organoboranes has been studied under a variety
of conditions. At 5 or -78 °C, the reaction with Et3B gave a mixture of the first and second homologation
products, but at -100 °C, only the first homologation product was obtained even with just 1.1 equiv of
Et3B. Under these optimized conditions, the chiral sulfur ylides (derived from camphor sulfonic acid) with
different aryl groups were reacted with Et3B to give the corresponding alcohols (95-98% yield, 96-98%
ee) and amines (74-77% yield, >98% ee). The origin of the high enantioselectivity is discussed. The use
of nonsymmetrical 9-BBN derivatives was also explored. It was found that whereas primary alkyl substituents
gave mixtures of products derived from competing migration of the boron substituent and the boracycle, all
other groups resulted in either exclusive migration of the boron substituent (Ph, hexenyl, i-Pr) or exclusive
migration of the boracycle (hexynyl, cyclopropyl). The factors responsible for the outcome of the reactions
involving a hindered (i-Pr) and an unhindered (propynyl) substituent were studied by DFT calculations.
This revealed that, in the case of an unhindered substituent, the conformation of the ate complex is the
dominant factor whereas, in the case of a hindered substituent, the barriers to interconversion between
the conformers of the ate complex and subsequent migration control the outcome of the reaction.
Scheme 1. Matteson’s Asymmetric Synthesis of Chiral
Organoboronates
Introduction
Organoboranes are versatile synthetic intermediates because
they can be transformed into a broad range of functional groups,1
often with complete retention of configuration of the original
C-B bond.2 Their usefulness in organic synthesis was further
enhanced by the simple and straightforward route to chiral
boranes introduced by H. C. Brown.3 Indeed, the hydroboration
of alkenes using (-)-diisopinocamphenylborane in 1961 pro-
vided the first nonenzymatic asymmetric synthesis of any kind
that resulted in truly practical levels of enantioselection.4 Rh-
catalyzed hydroboration was developed much later, and through
the use of chiral ligands, it provided a catalytic asymmetric route
to organoboranes.5 In the early 1980s, Matteson reported a
conceptually different method for the preparation of organobo-
ronic esters with very high enantioselectivity: the reaction of
LiCHCl2 with a chiral boronic ester followed by the addition
of a Grignard reagent (Scheme 1).6 The reaction involves a series
of 1,2-metalate rearrangements7 that all occur with high levels
of selectivity. This chemistry has been applied ingeniously in
synthesis.8
The elegant work by Matteson involves substrate control: the
stereochemistry of the diol attached to the boronic acid controls
the stereochemistry of the 1,2-metalate rearrangement. Although
it is possible to change the stereochemistry of the product by
interchanging the groups attached to Mg and the boronic ester,
this is sometimes limited by the availability of reagents.
Alternatively, the stereochemistry of the diol attached to the
boronate ester can be inverted (by exchange) to prepare the
opposite stereoisomer, but this involves a three step sequence.
We reasoned that an alternative approach involving reagent
control might be more versatile as either stereoisomer of the
product could be made by using either enantiomer of the reagent.
(1) (a) Matteson, D. S. Stereodirected Synthesis with Organoboranes;
Springer: New York, 1995. (b) Brown, H. C. Boranes in Organic
Chemistry; Cornell University Press: Ithaca, NY, 1972. (c) Brown, H. C.
Organic Synthesis Via Boranes; Wiley-Interscience: New York, 1975. (d)
Weill-Raynal, J. Synthesis 1976, 633. (e) Pelter, A.; Smith, K.; Brown. H.
C. Borane Reagents; Academic Press: New York, 1988. (f) Bubnov, Y.
In Science of Synthesis; Kaufmann, D. E., Matteson, D. S., Eds.; Georg
Thieme Verlag: Stuttgart, 2004; Vol. 6, pp 945-1072.
(2) Brown, H. C.; Singaram, B. Pure Appl. Chem. 1987, 59, 879.
(3) Brown, H. C.; Singaram, B. Acc. Chem. Res. 1988, 21, 287.
(4) (a) Brown, H. C.; Zewifel, G. J. Am. Chem. Soc. 1961, 83, 486. (b) Zewifel,
G.; Brown, H. C. J. Am. Chem. Soc. 1964, 86, 4393.
(5) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. Tetrahedron: Asymmetry 1991, 2,
601. (b) Zhang, J.; Lou, B.; Guo, G.; Dai, L. J. Org. Chem. 1991, 56,
1670. (c) Brown, J. M. Mod. Rhodium-Catalyzed Org. React. 2005, 33.
For a recent review see: Crudden, C. M.; Edwards, D. Eur. J. Org. Chem.
2003, 4695.
(6) (a) Matteson, D. S.; Ray, R. J. Am. Chem. Soc. 1980, 102, 7590. (b)
Matteson, D. S.; Ray, R.; Rocks, R. R.; Tsai, D. J. S. Organometallics
1983, 2, 1536. For a review see: (c) Matteson, D. S. Chem. ReV. 1989,
89, 1535. (d) Matteson, D. S. Tetrahedron 1989, 45, 1859. (e) Matteson,
D. S. Tetrahedron 1998, 54, 10555.
(7) Kociensky, P.; Barber, C. Pure Appl. Chem. 1990, 62, 1933.
(8) Maurer, K. W.; Armstrong, R. W. J. Org. Chem. 1996, 61, 3106.
9
14632
J. AM. CHEM. SOC. 2007, 129, 14632-14639
10.1021/ja074110i CCC: $37.00 © 2007 American Chemical Society

Asymmetric Sulfur Ylide Reactions
A R T I C L E S
Scheme 2. Reactions of Chiral Ylide 1a and Symmetric Boranes at 5 °C
Table 1. Optimization of the Reaction Conditions for the
Homologation Reaction
To effect homologation of boranes, the “reagent” required the
following properties: (i) it had to be nucleophilic to react with
the borane, (ii) it had to possess a good leaving group at the
same nucleophilic carbon to effect a 1,2-metalate rearrangement,
and (iii) it had to have the potential to be chiral. Ylides possessed
all of these requirements, and of the S-,9 N-,10 and P-ylides,11
sulfur ylides possessed the best leaving group for the 1,2-
metalate rearrangement.12,13 Furthermore, we had successfully
prepared a class of chiral sulfides that furnished very high
enantioselectivity in sulfur ylide mediated epoxidation.14 In our
preliminary communication,15 we reported that chiral sulfur
ylides reacted with organoboranes, furnishing homologated
products with high enantioselectivity (>95% ee) and that either
enantiomer could be obtained from either enantiomer of the
sulfide (Scheme 2). However, there were two practical issues
that needed to be addressed. First, the homologation reaction
was accompanied by a second homologation product in ap-
proximately 10% yield, and second, only symmetrical boranes
had been employed (Et3B, Bu3B, Ph3B). If the borane substituent
was valuable, this would clearly be a waste. In this paper, we
address both of these issues and provide additional information
on the origins of selectivity that improves the foundations of
this potentially useful reaction.
entry
solvent
temp. (
°
C)
equiv of Et3B
yield (2a)
yield (3)
1a
2b
3b
dioxane
THF
THF-CH2Cl2
5
1.5
1.5
1.1
78%c
63%d
98%c
11%c
25%d,e
0
-78
-100
f
a LiHMDS was added slowly to the mixture of the sulfonium salt and
the borane. b Borane was added to the ylide solution, which was preformed
from the corresponding sulfonium salt and LiHMDS at -78 °C. c Isolated
yield. d Yield determined by 1H NMR with internal standard. e Some higher
homologation products were also observed. f CH2Cl2 was added to solubilize
the salt and to prevent freezing of the reaction mixture.
borane has similar steric hindrance to the original borane. This
polyhomologation reaction has been exploited by Shea in “living
polymerization” reactions17 and ingeniously used to make large
macrocyclic ketones.18 The success of our reaction in which
polymerization was mostly eliminated can be attributed to the
increased steric hindrance of the homologated borane, which
makes it less reactive toward the ylide than the original borane,
and so the rates of successive homologations are slowed down.
To reduce the extent of the second homologation further we
needed to consume all of ylide before any homologated borane
had been generated, that is, we needed to “stop” the reaction at
the stage of the ate complex. Since both the ylide and borane
are highly reactive, ate-complex formation should be rapid and
this should be followed by slow migration of one of the groups
on boron. Indeed, density functional theory (DFT) calculations
on a range of ylides (Me2SCH2, Me2SCHPh) with a range of
boranes (Me3B, Me2BPh) have all shown that ate complex
formation is highly exothermic with low enthalpic barrier to its
formation.12,19 This is followed by rate-limiting migration of
one of the substituents on boron. Thus, by working at low
temperature, one can expect the ylide to be completely converted
into the ate complex, thereby preventing higher homologations
since the ylide would never be present with the first homolo-
gation product. However, even at -78 °C, the reaction still
resulted in 25% of the second homologation product 3,
indicating that, even at this temperature (Table 1), we had not
been able to arrest the progress of the ate complex. Gratifyingly,
reducing the temperature further still (-100 °C, N2/ether)
Results and Discussion
Elimination of the Second Homologation Product. As
alluded to in the introduction, reaction of a sulfonium benzylide
1a with 1.5 equiv of a trialkyl/triaryl borane furnished the
monohomologated product in 70-87% yield together with
significant amounts of the second homologation product (Table
1, entry 1). Of course, unsubstituted sulfur ylides (Me2SCH2 or
Me2S(O)CH2) are well known to undergo polyhomologation
with boranes16 because, after monohomologation, the new
(9) (a) Tufariello, J. J.; Wojtkowski, P.; Lee, L. T. C. Chem. Commun. 1967,
505. (b) Tufariello, J. J.; Lee, L. T. C.; Wojtkowski, P. J. Am. Chem. Soc.
1967, 89, 6804. (c) Tufariello, J. J.; Lee, L. T. C. J. Am. Chem. Soc. 1966,
88, 4757.
(10) Musker, W. K.; Stevens, R. R. Tetrahedron Lett. 1967, 8, 995.
(11) Ko¨ster, R.; Rickborn, B. J. Am. Chem. Soc. 1967, 89, 2782.
(12) Aggarwal, V. K.; Harvey, J. N.; Robiette, R. Angew. Chem., Int. Ed. 2005,
44, 5468.
(13) In a very elegant study, Blakemore has described the use of R-chloro-
organolithiums to effect the same type of reaction with boronic esters:
Blakemore, P. R.; Marsden, S. P.; Vater, H. D. Org. Lett. 2006, 8, 773.
Blakemore, P. R.; Burge, M. S. J. Am. Chem. Soc. 2007, 129, 3068.
(14) (a) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.; Palmer,
M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson, R.; Studley, J.
R.; Vasse, J. L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125, 10926. (b)
Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 611. (c) Aggarwal,
V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.;
Studley J. R. Angew. Chem., Int. Ed. 2001, 41, 1430-1433. (d) Aggarwal,
V. K.; Fang, G. Y.; Kokotos, C. G.; Richardson, J.; Unthank, M. G.
Tetrahedron 2006, 62, 11297.
(17) (a) Shea, K. J. Chem.-Eur. J. 2000, 6, 1113. (b) Busch, B. B.; Paz, M.
M.; Shea, K. J.; Staiger, C. L.; Stoddard, J. M.; Walker, Y. R.; Zhou, X.-
Z.; Zhu, H. J. Am. Chem. Soc. 2002, 124, 3636.
(18) (a) Shea, K. J.; Lee, S. Y.; Busch, B. B. J. Org. Chem. 1998, 63, 5746. (b)
Wagner, C. E.; Kim, J.-S.; Shea, K. J. J. Am. Chem. Soc. 2003, 125, 12179.
(19) Robiette, R.; Fang, G. Y.; Harvey, J. N.; Aggarwal, V. K. Chem. Commun.
2006, 7, 741.
(15) Aggarwal, V. K.; Fang, G. Y.; Schmidt, A. T. J. Am. Chem. Soc. 2005,
127, 1642.
(16) Shea, K. J.; Walker, J. W.; Zhu, H. D.; Paz, M.; Greaves, J. J. Am. Chem.
Soc. 1997, 119, 9049.
9
J. AM. CHEM. SOC. VOL. 129, NO. 47, 2007 14633

A R T I C L E S
Fang et al.
Table 2. Reactions of Et3B with Chiral Sulfonium Ylides 1 under
Optimized Conditions
The high selectivity made us consider the possibility of exploit-
ing this reaction in synthesis. However, when we used 2 equiv
of the ylide, we were still unable to increase the yield of the
second homologation product to practical levels (Scheme 3).
Scheme 3. Use of 2 equiv of Sulfur Ylide: Attempts to Maximize
the Second Homologation Product
entry
Ar
X
compound
yield (%)a
ee(%)b
1
C6H5
OH
NH2
OH
NH2
OH
NH2
2a
5a
2b
5b
2c
5c
98
78
95
74
97
77
98
98
97
>99
96
2
3
4-CH3-C6H4
4-Cl-C6H4
>99
a Isolated yield. b Enantiomeric excesses were determined by HPLC, and
ee of amines were determined as their acetamides.
resulted in clean monohomologation without observing any of
the second homologation products. The procedure involved
preformation of the ylide in CH2Cl2-THF (2:1, v/v) at
-78 °C, cooling to -100 °C with subsequent slow addition of
the borane solution (1 N in THF), followed by warming the
reaction to trigger the migration. Dichloromethane was necessary
to solubilize the sulfonium salt and to prevent freezing of the
reaction mixture at -100 °C. Using this modified procedure,
we were also able to reduce the amount of the organoborane to
1.1 equiv without detriment to the yield (Table 1, entry 3).
Applying the modified procedure to our chiral sulfonium salt
was also successful, and so we briefly explored its scope.
Reactions of a series of sulfonium salts with Et3B were carried
out, and the homologated boranes were converted into the
corresponding alcohols and amines (Table 2).
The yields of the alcohols obtained were exceptionally high
(almost quantitative), whereas the amines were obtained in
slightly reduced yields, which may be a reflection of the fact
that only two of the groups in 4 migrate effectively in amination
reactions with H2NOSO3H.20 The lack of the second homolo-
gation product considerably assisted purification of the amines,
which in the previous procedure were invariably obtained as
mixtures of the mono- and bis- homologation adducts. A further
advantage of the new procedure was the significant increase in
enantioselectivity: the amines were obtained in greater than 98%
e.e. and the alcohols with slightly lower selectivity. Since the
homologated borane 4 is a common intermediate in the
formation of both the alcohol and the amine, it must be formed
in at least 98% ee, which means there is some erosion during
the oxidation process to the alcohol. This could originate from
a very small amount of homolysis of the benzylic-boron bond
followed by recombination or oxidation of the benzylic radical.21
Nevertheless, this competing process is extremely minor as the
ee’s were still >96%. The origin of the high enantioselectivity
is discussed later.
It seemed that without very low-temperature we could not
avoid the second homologation, but then when we tried to
maximize it, there was some stubborn resistance to increasing
its extent. A possible explanation for these observations is that
there were actually no problems in forming the second ate
complex, just issues over which groups migrated. Migration of
the benzyl substituent (pathway a) would lead to the second
homologation product, whereas ethyl migration (pathway b)
would lead to a borane, which upon oxidation would give the
mono homologation product (Scheme 3).22 Because of these
issues, we decided to terminate further work on the multiple
homologation of the borane.
Origin of Enantioselectivity. Since addition of the ylide to
the borane is expected to be nonreversible, the high selectivity
can be accounted for by using the same (established) model to
account for enantioselectivity in epoxidation. Thus, ylide 1a can
adopt either conformers A or B, but B suffers significant
nonbonded interactions (Scheme 4). Indeed, the energy differ-
ence between the two conformers has been calculated to be 4.37
kcal mol-1 23
Reaction of the borane on the less hindered Re
.
face of the ylide followed by stereospecific migration of the
ethyl group (with inversion of configuration at the ylidic carbon)
then leads to the enantiomer observed.24
Scheme 4. Origin of the Enantioselectivity in the Borane Ylide
Reaction
The second homologation product was originally obtained
in 10% yield as a single diastereoisomer and single enantiomer.
As the selectivity issues for both the epoxidation and borane
homologation reactions focus on the ylide (conformation and
face selectivity) and not on the electrophile, one would expect
(20) Brown, H. C.; Kim, K. W.; Srebnik, M.; Singram, B. Tetrahedron 1987,
43, 4071.
(21) Davies, A. G.; Hook, S. C. W.; Roberts, B. P. J. Organomet. Chem. 1970,
22 (3), C37.
9
14634 J. AM. CHEM. SOC. VOL. 129, NO. 47, 2007

Asymmetric Sulfur Ylide Reactions
A R T I C L E S
similar levels of selectivity for both classes of reactions. This
revealed that there is substantially greater pyramidalization in
the TS of the former reaction (Figure 1). The greater degree of
pyramidalization in the TS of the ylide-borane reaction
compared to the epoxidation reaction results in the ylide
substituents being pushed further toward the sulfonium scaffold
in the ylide-borane reaction, which in turn means that the
reaction will be more sensitive to the steric environment around
the ylidic carbon, thus supporting our conjecture that kA is
significantly less that kB.
is indeed observed for sulfonium salt 1a (Scheme 5).25
Scheme 5. Comparison of Borane Homologation with Epoxidation
Using Ylide 1a
Scheme 7. Origin of the Enantioselectivity in the Borane-Ylide
Reactions
Here the enantioselectivities are already very high, and as
such, it is difficult to assess any differences between them.
However, when we compared two other salts 1e26 and 1f,27 the
enantioselectivities for the two processes were markedly dif-
ferent (Scheme 6). Even though the borane reactions were
carried out at much lower temperature than the epoxidations,
we were surprised to find that the enantioselectivities were
considerably poorer.
Scheme 6. Comparison of Borane Homologation with Epoxidation
Using Ylides 1e and 1f
This model highlights a fundamental problem in the design
of chiral sulfides for the ylide-borane reaction: to achieve high
enantioselectivity, one face of the ylide should be effectively
blocked. However, effective blocking of one face of the ylide
by substituents on the sulfonium scaffold will also reduce the
reactivity of the same ylide conformer since, during reaction
with the borane, the groups attached to the ylide carbon are
pushed toward the same substituents attached to the sulfonium
scaffold. If these two effects balance out, no enantioselectivity
will be observed. The very high enantioselectivities observed
with the camphor-derived sulfonium salt 1a are thus all the more
remarkable and must originate from the fortuitous position of
bicyclic camphor moiety, which effectively blocks one face of
the ylide without having a big impact on the relative rates of
reaction of the two conformers.
These differences in selectivity between the epoxidations
(which gave higher ee’s) and borane reactions are best accounted
for by assuming that the rates of reaction of the two ylide
conformers are substantially different (Curtin Hammett) in the
borane reactions.28 In the borane reactions, the major conformer
must react more slowly (kA < kB), which would account for
the lower ee’s compared to the epoxidation reactions. This can
be rationalized by considering the TS’s of the reactions of the
two conformers (Scheme 7). In the case of the major conformer,
the phenyl group of the ylide substituent is pushed toward the
large camphor moiety, whereas in the case of the minor
conformer the hydrogen of the ylide substituent is pushed toward
the camphor moiety. These factors could reasonably result in
kA < kB. Indeed, DFT calculation of the ylide-borane reaction
(see later for details) and the ylide-aldehyde reaction have
Figure 1. Comparison of degree of pyramidalization of the ylidic carbon
in the transition states of the ylide-borane and ylide-aldehyde reactions.
(22) For a discussion on the use of borinic and boronic esters in this type of
homologation, see the Supporting Information.
(23) Aggarwal, V. K.; Charmant, J.; Dudin, L.; Porcelloni, M.; Richardson, J.
Proc. Natl. Acad. Sci. U.S.A. 2004, 5467.
(26) Badine, D. M.; Hebach, C.; Aggarwal, V. K. Chem. Asian, J. 2006, 1,
438.
(27) Hansch, M.; Aggarwal, V. K. In preparation.
(24) Aggarwal, V. K.; Richardson, J. Chem. Commun. 2003, 2644.
(25) Aggarwal, V. K.; Bae, I.; Lee, H.-Y.; Williams, D. T. Angew. Chem., Int.
Ed. 2003, 42, 3274.
(28) A related model has been extended by Goodman, to account for the
selectivity observed in epoxidations using C2 symmetric chiral thiolanes:
Silva, M. A.; Bellenie, B. R.; Goodman, J. M. Org. Lett. 2004, 7, 2559.
9
J. AM. CHEM. SOC. VOL. 129, NO. 47, 2007 14635

A R T I C L E S
Fang et al.
Use of Nonsymmetrical Boranes: 9-BBN Derivatives.
Having established conditions for clean monohomologation of
boranes with high enantioselectivity, we sought nonsymmetrical
boranes in which only one group would migrate. To achieve
this, we were drawn to 9-BBN derivatives as Brown had shown
that in reactions of R-haloesters, R-haloketones, and R-haloni-
triles selective transfer of the boron substituent rather than
migration of the ring occurred.29 However, a broader search of
the literature revealed that in fact these were the only cases in
which selective transfer of the boron substituent occurred; in
most cases, ring migration occurred preferentially!30 Because
none of the alternative “nonmigrating” groups reported in the
literature were universally selective, we elected to test a range
of 9-BBN derivatives in their reactions with the sulfonium
benzylide 1b (Table 3).
benzaldehyde gave the corresponding homoallylic alcohol 2j
in 96% yield with very high anti selectivity and high Z
selectivity (Scheme 8). This showed that the borane 7i, resulting
from alkenyl migration, was formed in high yield. This useful
reaction has been developed and exploited further.34
Scheme 8. Highly Selective Homologation and Allylation Reaction
Sequence
The isopropyl and hexynyl 9-BBN derivatives, which afforded
2h and 6, respectively in a highly selective manner in the
reaction with 1b, were reacted with the chiral sulfonium salt
1a, and in each case, alcohols were isolated with very high
enantioselectivity (entries 9 and 10). The origin of the enanti-
oselectivity of the products are the same as discussed above,
but additional comment is warranted for the formation of diol
6. Interestingly, the two conformations 8a and 8b of the ate
complex formed in the reaction of 1a with 7h result in migration
of different carbons (Scheme 9), however, they ultimately lead
to the same enantiomer (and diastereomer). Indeed, diol 6 was
always formed as the same single diastereoisomer in all cases,
and its stereochemistry has been proven by X-ray analysis.
Table 3. Reactions of Sulfonium Ylide with 9-BBN Derivatives
entry
sulfonium salt
B-R-9-BBN
yield of 6
yield of 2
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1b
1b
1a
1a
Hexyl (7a)
Allyl (7b)
Benzyl (7c)
i-Pr (7d)
Cyclopropyl (7e)
Ph (7f)
1-Hexenyl (7g)
1-Hexynyl (7h)
i-Pr (7d)
56%
51%
51%
trace
89%
trace
trace
92%
-
41% (2e)
39% (2f)
35% (2g)
77% (2h)
trace
94%a
21%b (2i)
trace
Scheme 9. Rationalization of the Enantioselectivity of the
Reaction of 1a and hexynyl-B-9-BBN
97%c (2h)
-
10
1-Hexynyl (7h)
90%d
a Yield of diphenylmethane. b Yield of 1-phenylhept-1-en-3-ol (2i). c 99%
ee. d 97% ee.
Although little selectivity was observed for primary alkyl,
allyl, and benzyl substituents (entries 1-3), essentially complete
selectivity was observed for migration of the secondary alkyl
group (i-Pr) (entry 4). In sharp contrast, the cyclopropyl group
did not migrate at all; only migration of the ring substituent
occurred (entry 5). Phenyl and alkenyl substituents migrated
preferentially presumably because of assistance from the π
system (entries 6 and 7).19,31 In sharp contrast, the alkynyl group
remained rooted to boron and the ring substituent migrated
instead (entry 8).
The low yield in the reaction of 1b with hexenyl-B-9-BBN
(entry 7) was due to competitive protodeborination during
oxidation.32 It has been reported that benzylic boranes with
further anion stabilizing groups attached are especially prone
to such a process.33 In contrast, quenching the borane with
(29) (a) Knights, E. F.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 5280. (b)
Knights, E. F.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 5281. (c) Knights,
E. F.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 5283.
(30) For a brief discussion of the factors involved in migration of borate
complexes see: Aggarwal, V. K.; Fang, G. Y.; Ginesta, X.; Howells, D.
M.; Zaja, M. Pure Applied Chem. 2006, 78, 215.
(31) (a) Nakamura, K.; Osamura, Y. Tetrahedron Lett. 1990, 31, 251. (b)
Nakamura, K.; Osamura, Y. J. Am. Chem. Soc. 1993, 115, 9112. (c)
Winstein, S.; Lindegren, C. R.; Marshall, H.; Ingraham, L. L. J. Am. Chem.
Soc. 1953, 75, 147. (d) Wistuba, E.; Ruchardt, C. Tetrahedron Lett. 1981,
22, 4069. (e) Brown, H. C.; Kim, C. J. J. Am. Chem. Soc. 1968, 90, 2082.
(f) Winstein, S.; Morse, B. K.; Grunwald, E.; Schreiber, K. C.; Corse, J. J.
Am. Chem. Soc. 1952, 74, 1113.
Rationale for the Observed Selectivity in Migrating
Groups. The results in Table 3 show that aryl and vinyl groups
show a strong preference for B-substituent migration over ring
migration, presumably because they have greater migratory
(32) Bubnov, Y. N.; Mikhailov, B. M.; Tsyban, A. V. J. Organomet. Chem.
1978, 154, 113.
(33) Kabalka, G. W.; Maddox, J. T.; Bogas, E. J. Org. Chem. 1994, 59, 5530.
(34) Fang, G. Y.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2007, 46, 359.
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14636 J. AM. CHEM. SOC. VOL. 129, NO. 47, 2007

Asymmetric Sulfur Ylide Reactions
A R T I C L E S
power.19,31 The remaining groups (primary/secondary alkyl,
cyclopropyl, and alkynyl) show different degrees of substituent
vs ring migration, and it is believed that this is largely controlled
by conformation of the ate complex. The three possible
staggered conformers 9a-c of the different ate complexes are
shown in Scheme 10.
Scheme 10. Staggered Conformations of Ate Complexes
Figure 2. Sterical interactions in the ate complexes 10 and 11.
It is clear that conformer distribution (9a:9b) dictates which
group will migrate. To favor migration of the boron substituent,
conformer 9a has to be strongly favored over conformer 9b.
We can now easily understand why H. C. Brown’s homologa-
tions with chloro-esters/nitriles/ketones worked so well: the
small chloro substituent was easily accommodated over the ring
resulting in migration of the boron substituent. Thus, small
leaving groups are key to enhancing the extent of migration of
the boron substituent in 9-BBN derivatives.
Computational Study of 9-BBN Derivatives. The above
experimental results (Table 3) show that there is an inherent
preference for bulky groups or groups with high migratory
aptitude to undergo the 1,2-migration in the intermediate 9-BBN
ate complexes. Moreover, we have recently shown19 that the
selectivity of the 1,2-migration in the reaction of dimethylphe-
nylborane with PhCHSMe2 is dependent upon several factors:
(i) differential conformational stability of rotamers of the ate
complexes, (ii) electronic effects of the nonmigrating boron
substituents, (iii) migratory power of the different substituents,
(iv) steric bulk of the migrating group, and (v) electronic effects
of the ylide substituent. We were interested to find out which
of these effects was responsible for controlling the selectivity
in the reactions of sulfur ylides with 9-BBN derivatives. We
therefore decided to investigate the potential energy of two
different reactions: (i) sulfur ylide 12 with isopropyl-B-9-BBN
(7d), for which the isopropyl group migrates exclusively and
(ii) sulfur ylide 12 with 1-hexyne-B-9-BBN (7h) where the side-
chain migration product 6 was obtained. The calculations were
performed at the MP2/6-311+G**//B3LYP/6-31G* level of
theory as this has been shown to be a good method for similar
systems.19 DFT calculations were carried out using the Jaguar
6.0 pseudo spectral program package,35 and for the MP2 single-
point calculations, the Gaussian 03 program package36 was
employed. Due to computational limitations, the 1-hexyne group
of 7h was approximated with 1-propyne (7j). Harmonic
frequencies have been calculated at the level of optimization
for all structures to characterize the calculated stationary points.
Because of the requirement that the migrating group has to
align antiperiplanar to the leaving group, conformer 9a will lead
to migration of the B-substituent whereas 9b and 9c will lead
to migration of the ring. Since 9b and 9c lead to the same
product and 9b is favored over 9c because of steric repulsion
between the phenyl group and the boracycle, we will restrict
discussion to conformers 9a and 9b. The conformer distribution
(9a:9b) will depend on the competing steric interactions of what
was the ylide component with the boracyclic ring and the ylide
component with the boron substituent. Thus, for small boron
substituents (hexynyl), conformer 9b will be strongly favored,
resulting in ring migration. As the boron substituent increases
in size from primary alkyl to secondary alkyl, increasing
amounts of migration of the boron substituent was observed.
The exclusive migration of the i-Pr group in particular can be
rationalized by considering the interactions between the methyl
groups of the i-Pr group and the ylide component in the
conformers 10a and 10b (Figure 2). In conformer 10b, the i-Pr
substituent will align the hydrogen above the boracyclic ring,
and this would result in syn-pentane interactions with both the
sulfonium ion and the phenyl group. Conformer 10a has only
one syn-pentane interaction together with steric interactions
between the sulfonium ion and the ring, but evidently these
combined interactions are less troublesome than the steric
interactions in 10b.
Perhaps the most difficult example to rationalize is the
reaction of cyclopropyl-B-9-BBN with 1b, in which the cyclo-
propyl moiety behaves as though it is smaller than an un-
branched alkyl group. The low steric bulk of the cyclopropyl
group allows one of the ring carbons to protrude into space
above the boracycle ring, which leaves an H and a “small” CH2
eclipsing the phenyl group and ylide sulfonium ion (11b, Figure
2). These interactions are apparently less severe than the
interaction between the tetrahydrothiophene moiety and the
boracycle in 11a. The cyclopropyl group is thus behaving as a
very small group (similar to alkynyl) in this case.
The following computational study involved exploration of
the possible reaction paths for migration of the isopropyl and
1-propyne moiety as well as the boracycle to the ylidic carbon.
It was found that the potential energy surface of these processes
is rather complicated as it involves formation of several different
(35) Jaguar 6.0; Schro¨dinger, LLC.: Portland, OR, 2005.
(36) Frisch, M. J.; et al. Gaussian 03, revision B.04; Gaussian, Inc.: Pittsburgh,
PA, 2003.
9
J. AM. CHEM. SOC. VOL. 129, NO. 47, 2007 14637

A R T I C L E S
Fang et al.
addition pathway may also occur. The observation of only traces
of product derived from 16 means either that our calculations
underestimate the energy gap between TSs 13a and 13b (the
present values predict a ratio 16/17 of ca. 1/10 at 0 °C) or that
formation of 14a is indeed reversible as suggested above.
Figure 4. Calculated (MP2/6-311+G**//B3LYP/6-31G*) potential energy
surface for interconversion of the ate-complex rotamers 14a-c through B-C
Figure 3. Calculated potential energy surface of the reaction of 12 with
7h (MP2/6-311+G**//B3LYP/6-31G*). Energies are given in kcal mol-1
.
bond rotation. Energies are given in kcal mol-1
.
ate complexes, interconversion between the different ate com-
plexes, and subsequent 1,2-migration to afford the corresponding
products.
The computational results for the reaction of 12 with 7j
showed that in contrast to the isopropyl system, but as for the
less congested cases studied previously,19 ate complex formation
to yield 20a-c (Figure 5) via transition states 19a-c is
exothermic and also involves low activation energies. This
observation can be rationalized by the low steric bulk of the
1-propyne group, which allows the bulky tetrahydrosulfonium
and phenyl groups to occupy a sterically unhindered position
synclinal to the 1-propyne group. The most stable rotamer of
the ate complex (20a, -16.8 kcal mol-1) has the leaving
sulfonium group antiperiplanar to one of the R-carbons of the
boracycle. Furthermore, formation of the product from 20a
proceeds via the most stable transition state for 1,2-migration
(21a, ∆Eq ) -7.1 kcal mol-1). Migration from the other two
rotamers, 20b-c proceeds via higher-lying TSs 21b-c.
The reaction of 12 with 7h (Figure 3) is initiated by formation
of three different conformers of the ate complex (14a-c) which
form via TS 13a and 13b (we were unable to locate a
corresponding TS for the formation of 14c). Due to the
considerable steric bulk of the boracycle and isopropyl groups,
repulsive nonbonding interactions make formation of ate
complexes 14a-c endothermic. The subsequent 1,2-migration
in each of these conformers via TS 15a-c affords the products
16-17 in an exothermic reaction. Although the computational
results indicate a slight preference for formation of 14b via 13b,
the 1,2-migration via 15b has the highest activation energy of
the three possible pathways due to the sterically congested
transition state. The migration via 15a has an activation energy
that is almost the same as the activation energy for dissociation
via 13a to 12 and 7h, indicating that the formation of this
particular ate complex may be reversible.
The energetically most favored 1,2-migration occurs from
14c, in which the leaving group is antiperiplanar to the isopropyl
group, via 15c (∆Eq) 2.0 kcal mol-1) and leads to 17. The
low barrier in this case could be explained by the high
exothermicity of the rearrangement. Formation of 16 is 8.9 kcal
mol-1 less favorable due to steric interactions between the
phenyl and isopropyl groups and the boracycle. Ate complex
14c can be formed from 14b by B-C bond rotation via 18c
(Figure 4) with a very low activation energy (∆Eq ) 5.1 kcal
mol-1). The low barrier for rotation is a consequence of the
eclipsed conformation of 14b, which relatively easily allows
this transformation to occur. The transformations 14a f 14b
(18a) and 14a f 14c (18b) have much higher barriers for
rotation (∆Eq ) 16.8 and 14.1 kcal mol-1, respectively) since,
during the rotation, one of the sterically bulky sulfonium or
phenyl groups must be eclipsed with the large isopropyl group.37
These results suggest that product 17, which is obtained in the
reaction of 11 with 7h (Table 3), is formed via the pathway
(11 + 7h) f 13b f 14b f 18c f 14c f 15c f 17. Although
TS 13a leading to 14a is 1.3 kcal mol-1 higher than TS 13b,
this energy difference is relatively small; hence, this competing
Figure 5. Calculated potential energy surface of the reaction of 12 with
7j (MP2/6-311+G**//B3LYP/6-31G*). Energies are given in kcal mol-1
.
The potential energy surface for B-C bond rotation is
depicted in Figure 6 and indicates that the most stable ate
complex (20a) can be formed from the less stable ones (20b-
c) with fairly low activation energies. The rotation of 20c to
20a via 24b (-1.0 kcal mol-1) is unlikely to occur because of
the lower lying migration transition state (21c, Figure 5),
however, a more energetically favored path leads to 20b via
(37) Conversion of 14a to 14b or 14c also requires rotation of the isopropyl
group around the B-C bond. Given that 18a and 18b already lie much
higher in energy than other relevant transition states, TSs for these isopropyl
rotations were not located.
9
14638 J. AM. CHEM. SOC. VOL. 129, NO. 47, 2007

Asymmetric Sulfur Ylide Reactions
A R T I C L E S
-100 °C, clean monohomologation was observed presumably
because the ate complex did not evolve into the first homolo-
gation product at this low temperature, allowing all of the ylide
to be consumed. Use of the camphor derived sulfonium salt 1a
leads to intermediate boranes that have been converted ef-
ficiently into alcohols (95-98% yield, 96-98% ee) and amines
(74-77% yield, >98% ee). The high enantioselectivity origi-
nates from very high control of ylide conformation and face
selectivity, although this is somewhat compromised by the faster
rate of reaction of the minor ylide conformer.
The use of nonsymmetrical boranes for selective group
transfer was partially successful. Using a range of 9-BBN
derivatives, it was found that phenyl, hexenyl, and isopropyl
resulted in exclusive migration of the boron substituent whereas
hexynyl and cyclopropyl resulted in exclusive migration of the
boracycle, furnishing a diol. These processes could all be
rendered asymmetric, and high ee’s were achieved (96-99%).
Primary alkyl groups gave almost equal mixtures of migration
of the boron substituent and the boracycle. Calculations showed
that although conformation of the ate complex is the determining
factor responsible for the outcome of the reaction involving
alkynyl substituents, the situation with the isopropyl substituent
is more complex. In this case, a combination of factors including
the barriers to interconversion of the different ate complexes
and their respective barriers to migration, which is affected by
the exothermicity of the reaction, control the outcome of the
reaction leading to exclusive migration of the isopropyl sub-
stituent. The greater migratory power of phenyl and hexenyl is
an additional factor that is believed to contribute to the exclusive
migration of these groups. The ylide-borane reaction offers a
new route to chiral organoboranes that is conceptually related
to Matteson homologation but is governed by reagent rather
than substrate control. In certain cases, this will have significant
benefits in synthesis.
Figure 6. Calculated potential energy surface of the B-C bond rotation
of 20a-c (MP2/6-311+G**//B3LYP/6-31G*). Energies are given in kcal
mol-1
.
24c (-7.2 kcal mol-1). Before rotation around the C-B bond
can occur to form 20a from 20b, the tetrahydrothiophene ring
needs to rotate into a sterically less demanding position, and
the associated TS 24a is in fact the only barrier involved in
converting 20b to 20a. From 24a, the potential energy surface
appears to lead directly downhill to 20a.
These computational results show that some of the factors
presented earlier19 remain important for defining selectivity, but
some new features appear. First, it is clear that relative stability
of the different conformers of the ate complexes play an
important role in defining the final products observed [factor
(i)], for example, in the reaction of alkynyl borane 7j where
the high stability of adduct 20a drives formation of 23. This is
despite the high barrier (∆Eq ) 9.7 kcal mol-1) for ring
migration, which may be due to the electronic withdrawing
character of the spectator propynyl ligand [factor (ii)]. One
noticeable difference with respect to our previous work is that,
in all cases studied here, there is a potential energy barrier to
formation of the ate complex, and the latter is significantly less
stable compared to reactants. Both of these effects are clearly
due to the much greater steric bulk of the present systems. The
increased steric bulk also contributes to increased barriers for
interconversion of the conformers of the ate complexes, which
again has an impact on the selectivity of which group migrates.
Acknowledgment. We thank EPSRC for support of this work,
Stiftelsen Bengt Lundqvist Minne and The Foundation Blance-
flor Boncompagni-Ludovisi, ne´e Bildt for financial support to
O.A.W., and V.K.A. thanks the Royal Society for a Wolfson
Research Merit Award. We thank Dr. M. Hansch and Dr. M.
Badine for conducting the reactions shown in Scheme 6 and
Dr. J. P. H. Charmant for X-ray analysis.
Conclusion
Supporting Information Available: Synthesis and charac-
terization of compounds 2a-j, 5a-c, 6, and 7a-h, X-ray
structure of 6, and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org.
Aryl-stabilized sulfur ylides react with boranes (trialkyl/
triaryl) to give homologated products. When the reactions are
carried out at 5 or -78 °C, the first homologation adducts were
obtained in high yield accompanied by a small amount of
the second homologation product (up to 10%). However, at
JA074110I
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J. AM. CHEM. SOC. VOL. 129, NO. 47, 2007 14639