Factors affecting migration of tertiary alkyl groups in reactions of alkylboronic esters with bromomethyllithium

Article abstract of DOI:10.1021/jo4000459

The reactions of bromomethyllithium with tert-alkylboronic esters could be of great potential for the formation of quaternary carbon centers but often give poor yields/conversions. Calculations and experimental evidence show that tert-alkyl groups migrate less effectively than other types of alkyl group in such reactions and that O-migration competes. Furthermore, slow/incomplete capture of the bromomethyl reagent by the boronic ester is a problem in more hindered systems, and an additional competing reaction, possibly Li-Br exchange on the bromomethylborate species, also leads to lower yields of migrated products. Based on this, experimental protocols have been devised in which the competing reactions are largely suppressed, leading to higher conversions to migrated product for several substrates.

Full text of DOI:10.1021/jo4000459

Article
pubs.acs.org/joc
Factors Affecting Migration of Tertiary Alkyl Groups in Reactions of
Alkylboronic Esters with Bromomethyllithium
Mark C. Elliott,* Keith Smith,* D. Heulyn Jones, Ajaz Hussain,§ and Basil A. Saleh
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, U.K.
S
* Supporting Information
ABSTRACT: The reactions of bromomethyllithium with tert-
alkylboronic esters could be of great potential for the
formation of quaternary carbon centers but often give poor
yields/conversions. Calculations and experimental evidence
show that tert-alkyl groups migrate less effectively than other
types of alkyl group in such reactions and that O-migration
competes. Furthermore, slow/incomplete capture of the
bromomethyl reagent by the boronic ester is a problem in more hindered systems, and an additional competing reaction,
possibly Li−Br exchange on the bromomethylborate species, also leads to lower yields of migrated products. Based on this,
experimental protocols have been devised in which the competing reactions are largely suppressed, leading to higher conversions
to migrated product for several substrates.
hindered alkylboronic esters giving only modest yields of
migrated products.8,9 In both of these studies, 11B NMR
spectroscopic evidence suggested that migration of oxygen was
a competing pathway, more so with ClCH2Li than with
BrCH2Li.
INTRODUCTION
■
The migration of alkyl groups from boron to carbon is an
important reaction for the formation of carbon−carbon bonds.1
Although there are examples of migrations of tert-alkyl groups,2
it is often found that tert-alkyl groups migrate less readily than
other types of alkyl groups;3 indeed thexyl is frequently used as
a nonmigrating group.4 This limitation restricts the applicability
of such reactions for tert-alkyl migration and, therefore, their
applicability to the construction of quaternary carbon centers.
Addition of halomethylithium5 reagents to alkylboronic esters
(Scheme 1 for BrCH2Li), first reported by Matteson,6 is a key
Clearly there is considerable scope for improvement of this
reaction. The poor results for tert-alkyl group migration could
be a result of a lower migratory aptitude or alternatively be the
result of other processes being more favored. Since
bromomethyllithium is highly unstable,5 it is also possible
that slow or incomplete capture of bromomethyllithium by the
alkylboronic ester is the cause of the poor results for more
hindered systems. Our goal in the present study was to gain a
clearer understanding of how factors that influence organo-
boron rearrangements1 would affect the outcome of these
reactions. A combined experimental and computational study
was therefore undertaken. Since it was likely that the nature of
the boronic ester would affect the outcome, the study was
planned to include a range of boronic esters of various alcohols,
diols, and thiols.
Scheme 1. Homologation of Alkylboronic Esters
COMPUTATIONAL STUDIES
■
Relative Migratory Aptitudes. A computational study published
in 2003 by Bottoni et al.10 suggested that, in the case of
chloromethylborates analogous to structures 5b−8b (Scheme 1), the
barrier to migration of a tertiary alkyl group was lower than that for
migration of other simple alkyl groups. In view of the experimental
evidence that higher conversions are obtained with BrCH2Li, we
focused on homologation reactions with this reagent in this study.
Minimum energy structures for the borates 5b−8b were identified
(Gaussian 03, B3LYP/6-31+G(d)), along with the transition states for
reaction in this area, since it allows introduction of a
functionalized one-carbon unit with considerable potential for
further elaboration. Brown and colleagues reported homo-
logation of a range of alkylboronic esters with halomethyl-
lithium reagents but found that the t-Bu group migrated less
well than other types of alkyl groups, at best a 66% (GC) yield
of 2,2-dimethylpropanol being reported after oxidative work-
up.7 Aggarwal has recently reported homologation of chiral
alkylboronic esters with halomethyllithium reagents and
showed that steric hindrance plays a key role, with more
Received: January 9, 2013
© XXXX American Chemical Society
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subsequent C-and O-migration. The activation energies for these two
processes are summarized in Table 1.
the B−CH2Br bond in the borates 8 (initially for series b at the PM3
semiempirical level, but then optimized (Gaussian 03, B3LYP/6-
31+G(d)) for all alkoxy groups (series a−e)), plausible structures were
identified for the transition states 17 for the addition of
bromomethyllithium to the boron center and earlier intermediates
16, in which bromomethyllithium was complexed to the alkylboronic
esters 4 by a Li−O interaction (Table 3). Formation of the
Table 1. ΔG‡ for C- and O-Migration in 5b−8b
R
Me
Et
i-Pr
t-Bu
C-migration (kJ mol−1
)
46.4
68.7
22.3
44.4
67.4
23.0
46.0
65.4
19.4
59.5
62.3
2.8
O-migration (kJ mol−1
)
Table 3. Free Energies (kJ mol−1) of Reactions for 4 → 16
and 16 → 8 and Activation Barriers for 16 → 8
difference (kJ mol−1
)
Our calculations suggest that the barrier to migration of the t-Bu
group in this system is considerably higher than that for other types of
alkyl group and, in particular, that O-migration is anticipated to be a
significant competing reaction in this case. Furthermore, since there
are two oxygen-bound groups, the effective activation barrier to O-
migration is lowered further, by RT ln 2 = 1.7 kJ mol−1 at 298 K, on
entropic grounds. These results are consistent with experimental
observations that lower yields of migrated products are obtained from
tertiary alkyl boron compounds and with 11B NMR data indicating that
oxygen migration could be a competing pathway.
Effect of Different Boron-Bound Ligands. Since we were
concerned particularly with the migration of tertiary alkyl groups, it
was of interest to determine whether the bias for C- over O-migration
could be modified by varying the ligands on boron. We therefore
undertook a series of calculations to compare the two possible
migration pathways, based on readily accessible tert-butylboronic esters
4a to 4e (Table 2). The lowest energy conformations for the
(R′O)2
series
letter ΔGr for 4 + BrCH2Li → 16 ΔG‡ for 16 → 8 ΔGr for 16 → 8
(a)
(b)
(c)
(d)
(e)
−30.0
−32.5
−49.0
−36.7
−41.3
35.5
28.0
39.4
31.4
34.5
−68.1
−30.5
−0.7
−20.5
−17.1
Table 2. ΔG‡ for C- and O-Migration of 8
intermediates 16 was calculated to be essentially barrierless, based
on a monomeric gas phase bromomethyllithium structure,12 but in
reality there would probably be a barrier, albeit small. Full
thermodynamic and structural parameters are provided in the
Supporting Information.
The calculations suggested that the free energies of activation for
bromomethylation were higher for the dimethoxy case (transition state
17a) and for the more hindered cyclic cases (17c and 17e) than they
were for the less hindered cyclic cases (17b and 17d). Also, the free
energies of reaction for bromomethylation of the more hindered
compounds were much less favorable than those for the less hindered
examples. Decomposition of bromomethyllithium would be expected
to be particularly competitive in these cases, leading to lower yields of
derived products.
Summary of Computational Findings. The calculations
suggested that the reaction of bromomethyllithium with tert-
butylboronic esters 4 could be yield-limited in two different ways.
(R′O)2 series
ΔG‡ for C
ΔG‡ for O
difference/
letter
migration/kJ mol−1
migration/kJ mol−1
kJ mol−1
1. With hindered alkylboronic esters (e.g., 4c or 4e) addition of
bromomethyllithium to the ester would be less favorable, such
that nonproductive decomposition of the bromomethyllithium
could compete.
2. Potentially, O-migration competes with C-migration in the next
step, with the predicted relative proportion of C-migration
increasing for more hindered tert-butylboronic esters.
(a)
(b)
(c)
(d)
(e)
76.9
59.5
48.1
58.4
54.3
79.7
62.3
55.6
57.4
62.5
2.8
2.8
7.6
−1.0
8.2
bromomethylborates 8 were located, as were transition states 13 and
14 for C- (t-Bu) and O-migration, respectively. In the case of the six-
membered ring borates, 8d and 8e, two conformers of the transition
states for C- and O-migration were located in each case. Data for all
conformers are presented in the Supporting Information.11 The more
hindered pinacol and 2,2-dimethyl-1,3-propanediol systems showed a
significantly lower barrier to C-migration than to O-migration.
Therefore, higher selectivity for C-migration should be achievable
with borates 8c and 8e than with the other cases.
RESULTS AND DISCUSSION
■
Thexyl was chosen as a representative tertiary alkyl group, since
thexylborane is easy to prepare and to derivatize. A range of
thexylborane derivatives was prepared, including the simple
dimethoxy compound, 18a; several cyclic boronic esters with
different ring sizes and different levels of steric hindrance; an
electron-withdrawn dialkoxy compound, 18f; and two com-
pounds incorporating sulfur instead of oxygen (Figure 1).
These were homologated according to Method A (see
Experimental Section), involving use of a small excess each of
dibromomethane and n-butyllithium. The ratio of thexylme-
thanol/thexanol produced is shown in parentheses in Figure 1.
Formation of the Initial Halomethylborate. Both Aggarwal8
and Brown7 have suggested that incomplete capture of the carbenoid
is partly responsible for the lower yields of products with more
hindered alkylboronic esters. Therefore, we calculated the relative
energy barriers for the complexation step. By systematic lengthening of
B
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7. bromine−lithium exchange between n-BuLi (or bromo-
methyllithium) and the bromomethylborate 21b, leading
to the lithiated species 27b.
In order to try to distinguish between some of these aspects,
a series of experiments was undertaken with 18b.
Incomplete Rearrangement of Borate 21b. When the
reaction was quenched oxidatively at low temperature, the
proportion of migration product was much reduced (thex-
ylmethanol/thexanol 17:83), indicating that little rearrange-
ment took place at −78 °C, so the migration step was clearly
rate-limiting. Maintaining the reaction temperature at −78 °C
for 30 min−4 h and then either rapid or slow (1 h) warming to
room temperature followed by further stirring gave ratios in the
range 74:26 to 80:20. Therefore, it seems unlikely that
incomplete rearrangement was responsible for the unmigrated
thexyl derivative.
Direct Addition of n-BuLi to 18b. There was no evidence
from 11B NMR spectroscopy for formation of butylborate 22b,
while GC of the product after oxidation showed levels of 1-
butanol consistent only with butoxide impurities in the n-BuLi
used. Use of larger excesses of CH2Br2 also did not improve the
ratio of thexylmethanol/thexanol, and less nucleophilic lithium
reagents (sec-BuLi, t-BuLi, and lithium 4,4′-di-tert-butylbiphen-
yl) all gave lower yields of migration products from their
reactions with 18b and CH2Br2. These experiments strongly
argue against the formation of 22b as a significant cause of the
20% of substrate not converted into thexylmethanol.
Figure 1. Thexylboron compounds used (and ratio of thexylmetha-
nol/thexanol produced).
The compounds containing sulfur (19, 20) gave no
thexylmethanol at all, while the electron withdrawn boronic
ester (18f) offered no advantages. In view of these observations,
no further work was conducted with compounds 18f, 19, and
20. There was essentially no difference between the results for
the unhindered five- and six-membered cyclic boronic esters
(18b, 18d) and the dimethyl thexylboronic ester (18a).
However, the more hindered boronic esters (18c, 18e) gave
consistently less of the migrated product than their less
substituted counterparts.
While ca. 80% of the desired product was observed in three
cases, it was of interest to determine what factors were limiting
the yield to this level. Several possible explanations (Scheme 2)
were considered to account for the 20% of thexanol produced
in the reaction of 18b:
Incomplete Capture of BrCH2Li by 18b. If the problem
was incomplete capture of the bromomethyllithium by 18b
(point 3 above), as a result of either a slow reaction between
the two species or the formation of an equilibrium mixture in
which a significant proportion of free 18b was still present, use
of excess reagent should improve the yield at least to some
extent, but by use of boronic ester (1 equiv), dibromomethane
(5 equiv), and n-BuLi (2 equiv) a similar yield of
thexylmethanol was obtained as by use of the standard reactant
proportions. Furthermore, carrying out the standard procedure
as in Method A, but recooling the mixture to −78 °C after
warming to room temperature, and then adding further
dibromomethane (1.2 equiv) and n-BuLi (1.1 equiv) before
warming again and carrying out the usual oxidative workup,
gave a 26:51:23 ratio of thexylethanol/thexylmethanol/
thexanol. If the nonmigrated product from Method A were a
result of incomplete capture of the carbenoid, it would then
react on the second addition. Since a similar amount of
nonmigrated product was obtained in this case, even though
further reaction of the major product to give thexylethanol had
taken place, it is clear that the side products were no longer able
to react with bromomethyllithium in the desired way.
Therefore, incomplete capture of bromomethyllithium does
not appear to be a significant factor, at least for this unhindered
boronic ester (18b).
Scheme 2. Possible Reactions of 18b with n-BuLi/CH2Br2
1. slow (and/or incomplete) rearrangement of the
bromomethylborate 21b;
2. direct addition of n-BuLi to the boronic ester, forming
22b, which would then prevent the desired migration as
well as reduce the amount of bromomethyllithium
available;
3. incomplete capture of bromomethyllithium by the
boronic ester, leading to decomposition of uncaptured
bromomethyllithium and leaving unreacted boronic
ester;
4. further reaction of the product 23b with BrCH2Li,
leading to the (2-thexylethyl)boron compound 24b and
reducing the amount of BrCH2Li available, so that
unreacted 18b would remain;
Formation of Compounds 24b/25b. Of the other
processes considered as possibly responsible for limiting the
yield of migrated product to 80%, two (points 4 and 5) should
lead to the production of additional alcohols (2-thexylethanol
for further reaction of product 23b with BrCH2Li to give 24b
or 1-pentanol for nucleophilic substitution of bromide from
21b to give 25b). However, neither of these alcohols was
identifiable in the standard product mixture. Therefore, these
processes are unlikely to be significant reasons for the
suppression of yield.
5. nucleophilic substitution of the bromide in 21b by n-
BuLi to give the pentyl derivative 25b;
6. O-migration (to give 26b) competing with C-migration;
C
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Competing C/O-Migration and Li−Br Exchange on
21b. A typical reaction of n-BuLi/CH2Br2 with 18b followed
by rapid aqueous workup but without oxidation showed two
expectations based on the computational study), but the
formation of 27e by Br−Li exchange had also been suppressed.
In the case of the pinacol boronic ester 18c, NMR data
suggested that the side reactions were also less prominent than
in the case of the ethylene glycol boronic ester 18b, but the
suppression of these reactions was not as complete as for the
2,2-dimethyl-1,3-propanediol boronic ester 18e.
1
coupled multiplets at 3.57 and 4.02 ppm in the H NMR
spectrum, tentatively attributed to the ethylenedioxy bridge of
the oxygen migration product 26b. This compound was
estimated to account for no more than 2% of the crude
product mixture. An identical experiment was carried out using
ClCH2Br. This gave a broadly similar result, although the
amount of O-migration product 26b was increased in line with
previous reports.7,8 However, the amount (approximately 5%)
again did not account for a substantial proportion of the
resultant thexanol (56:44 mixture of thexylmethanol:thexanol
formed).
Optimization of Reaction Conditions. We speculated
that incomplete formation of the bromomethylborates in the
hindered cases might be responsible for the lower yields.
Therefore, we investigated a range of reaction stoichiometries
and addition regimes in order to try to optimize the reactions.
The standard procedure (1.0 equiv of substrate, 1.2 equiv of
CH2Br2, 1.1 equiv of n-BuLi were added dropwise, and the
mixture was stirred for 30 min at −78 °C; Method A) was used
as a reference point. Increasing the amount of CH2Br2 (up to 5
equiv) and n-BuLi (up to 3 equiv) gave a small decrease in
migration for 18b and only a modest increase in migration for
18c. However, sequential addition of three portions of CH2Br2
(1.2 equiv) and n-BuLi (1.1 equiv) in an alternating sequence
(Method B) gave significantly improved yields for the more
hindered boronic esters (Table 4, entries 3−6). With the 2,2-
dimethyl-1,3-propanediol boronic ester 18e, an analogous
method involving five sequential additions of CH2Br2 and n-
BuLi gave the highest proportion of migrated compound yet
obtained (89:11; Table 4, entry 7). These observations
confirmed that unreacted boronic ester remained after
completion of the standard reaction (Method A) with the
hindered cases, 18c and 18e, which supported the view that
complexation of bromomethyllithium with such boronic esters
was incomplete. The fact that yields of alkyl migration product
could be increased to close to quantitative by sequential
addition of CH2Br2 and n-BuLi showed that the side reactions
that limited the yield for the ethylene glycol derivative to 80%
could be suppressed by using the more hindered boronic esters.
With even more hindered tert-alkylboronic esters, the
increases in yield were proportionately more significant. With
triethylmethylboronic ester 28, a good conversion to the
migration product (72:28 ratio of Et3CCH2OH/Et3COH) was
achieved by use of Method B, compared with a 26:74 ratio
using Method A. Even with trioctylmethylboronic esters 29
and 30 (which would have contained around 17% of 2-
octylbis(1-octyl)methylboronic ester because the hydrobora-
tion of 1-octene is not totally regioselective13), around 20% of
the homologated product was produced in each case by use of
Method A (entries 10 and 12). While the application of
Method B to 18b had given a lower conversion to the
homologated product (entry 2), with the more hindered alkyl
group in compound 29, Method B gave an increase to a 40:60
ratio of Oct3CCH2OH/Oct3COH, marginally better than by
application of Method B to the 2,2-dimethylpropane-1,3-diol
ester 30 (37:63) (entries 11 and 13), so that the optimal
method depends on a balance of steric properties, including
those of the tert-alkyl group as well as the esterifying diol. While
modest, this yield is still synthetically useful for a compound
bearing such a high level of steric hindrance. However, the
tricyclopentylmethylboronic esters 31 and 32 gave no
homologation under any of the conditions investigated. It
would appear that the extreme steric hindrance inherent in the
tricyclopentylmethyl group has found the limitation to the
method.
11B NMR spectroscopy of the CH2Br2 reaction after washing
showed major peaks at 31.8 and 33.3 ppm (typical for
compounds of the type RB(OR)2) and small peaks at 51.1 and
55.2 ppm (typical for R2BOR). These observations support the
formation of 26b by oxygen migration, with hydrolysis products
perhaps giving rise to one of the signals in each pair (this could
mean that the amount of O-migration product reported has
been underestimated somewhat). However, the amount of the
product again seemed sufficient to account for only a fraction of
the 20% of thexanol obtained on oxidation.
Furthermore, the 11B NMR spectrum of the original reaction
mixture prior to washing showed a small but significant peak at
around 6 ppm and a very small peak around 9 ppm alongside
the expected peak for 23b at 33.5 ppm and two more small
peaks at 51.2 and 55.5 ppm. The 6 ppm peak was not due to a
simple adduct of the alkylboronic ester with n-BuLi; the borate
22b derived by addition of n-BuLi to 18b gave a very sharp
peak at −15.8 ppm. The 6 ppm peak could be due to the Br−Li
exchange product 27b. Following a quick water wash, the peaks
at 6 and 9 ppm disappeared and there was a noticeable increase
in the size of the peak at 55 ppm. If 27b is responsible for the
peaks at 6/9 ppm, use of an excess of n-butyllithium should
result in an increase in their intensity. Consistent with this
expectation, such an experiment gave substantial increases in
the peaks at 6 and 9 ppm and a corresponding decrease in the
peak at 33 ppm, which was no longer bigger than the peak at 54
ppm. After a rapid water wash, only peaks at 30.9, 33.3, and
54.4 ppm remained, with the peak at 54.4 ppm (corresponding
to a borinic species of the type R2BOR) being considerably the
largest. Furthermore, formation of the O-migrated product 26b
1
was completely suppressed (according to H NMR spectros-
copy), so the peak at 54 ppm was not due to 26b. After
oxidation, this reaction gave a 34:66 mixture of thexylmetha-
nol/thexanol. The significant suppression of migration, increase
in the 11B NMR peak at 6 ppm, and diminution of the 11B
NMR peak at 33 ppm seem consistent with the formation of
additional 27b by reaction of 21b with the excess n-BuLi.
Furthermore, 27b would give rise to t-Hx(Me)BOH on
hydrolysis and this could be responsible for the enlarged
peak at around 54 ppm in the 11B NMR spectrum.
Similar experiments were undertaken using the 2,2-dimethyl-
1,3-propanediol boronic ester 18e. With 1.2 equiv of
dibromomethane and 2.2 equiv of n-butyllithium, a 69:31
mixture of thexylmethanol/thexanol was obtained after
oxidation, i.e. the same result as with 1.1 equiv of n-BuLi, so
that in this case an excess of organolithium reagent did not
suppress the desired migration. The 11B NMR spectrum prior
to an aqueous wash did not show peaks at 55, 9, or 6 ppm so
that oxygen migration had been suppressed (in line with
Aggarwal has developed an elegant approach to generation of
stereodefined tertiary alkylboron compounds, but attempts to
D
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Table 4. Effect of Stoichiometry and Order of Addition on
the Homologation Reactions
Scheme 3. Optimization of Migration Reactions in Systems
Related to Those Reported by Aggarwal8
overall proportions
substrate/CH2Br2/n-BuLi
RCH2OH/
ROH
a
entry substrate
method
1
18b
18b
18c
18c
18e
18e
18e
28
1:1.2:1.1
1:3.6:3.3
1:1.2:1.1
1:3.6:3.3
1:1.2:1.1
1:3.6:3.3
1:6.0:5.5
1:1.2:1.1
1:3.6:3.3
1:1.2:1.1
1:3.6:3.3
1:1.2:1.1
1:3.6:3.3
1:1.2:1.1
1:3.6:3.3
1:3.6:3.3
A
B
A
B
A
B
80:20
70:30
34:66
59:41
70:30
85:15
89:11
26:74
72:28
20:80
40:60
18:82
37:63
0:100
0:100
0:100
problem with the most hindered boronic esters and leads to
low yields because of competitive destruction of the
bromomethyllithium by nonproductive processes); (ii) com-
petition between migration of the tert-alkyl group and one of
the oxygen groups (which has previously been discussed by
others but accounts for only a small amount of the loss of yield
of the tert-alkylmethanol in the case of 2-thexyl-1,3,2-
dioxaborolane (18b)); and (iii) another reaction of the initial
complex 21b that we speculate may be Br−Li exchange, but in
any case leads to a species that does not rearrange in the
desired way. With more hindered tert-alkyl groups, boronic
esters derived from less hindered diols give better results.
However, with less hindered tert-alkyl groups, boronic esters
derived from more hindered diols in conjunction with the use
of a procedure (Method B) involving stepwise treatment three
times with bromomethyllithium can be advantageous. With
extremely hindered tert-alkyl groups, best results can be
obtained from the combination of an unhindered diol and
Method B. By use of these approaches we have shown that the
reaction can provide higher yields for cases that have previously
given only modest yields and have extended the level of steric
hindrance of the tert-alkyl groups that can be accommodated by
the reaction. Even with these improvements, however, the most
hindered of tert-alkyl groups, such as the tricyclopentylmethyl
group, fail to participate in the reaction. The homologation
should now be applicable to a wider range of tertiary alkyl
substrates. With this improved understanding of the factors
affecting efficient bromomethylation/tert-alkyl migration in
boronic ester systems, it should now be possible to apply this
reaction to all but the most hindered boronic ester substrates.
2
3
4
5
6
b
7
B
8
A
B
A
B
A
B
A
B
B
9
28
10
11
12
13
14
15
16
29
29
30
30
31
31
32
a
Method A: 1 equiv of substrate, 1.2 equiv of CH2Br2, −78 °C, 1.1
equiv of n-BuLi, 30 min, then warm and oxidize. Method B: 1 equiv of
substrate, 1.2 equiv of CH2Br2, −78 °C, 1.1 equiv of n-BuLi added
over 30 min, 1.2 equiv of CH2Br2, 1.1 equiv of n-BuLi added over 30
min, 1.2 equiv of CH2Br2, 1.1 equiv of n-BuLi added over 30 min, then
b
warm, and oxidize. This experiment used a variation on Method B in
which 5 additions of CH2Br2 and n-BuLi were carried out.
convert such compounds into the corresponding tertiary
alkylmethanols often gave only low yields (30% of 34 from
33 and 37% from the less bulky 2,2-dimethyl-1,3-propanediol
ester 35, for example, Scheme 3).8 Application of Method B to
substrate 35 gave a 64:36 ratio of compounds 34:37 (compared
to 50:50; 38% isolated yield using Method A). However, since
the migrating group is particularly bulky, application of Method
A to the less hindered diol derivative 36 proved superior, with a
product ratio of 85:15 for 34:37 (73% isolated yield) being
achieved. These results demonstrate the benefits of a greater
understanding of the reaction for development of successful
synthetic procedures and illustrate the potential for the
formation of quaternary stereocenters.14
EXPERIMENTAL SECTION
General Experimental Details. Melting point determinations
■
were performed by the open capillary method and are reported
1
uncorrected. H and 13C NMR chemical shifts δ are reported in parts
per million (ppm) relative to TMS, and coupling constants J are
reported to the nearest 0.1 Hz. C, CH, CH2, or CH3 13C signals are
assigned from DEPT-90 and -135 spectra. In a number of cases,
carbon atoms attached to boron gave very broad peaks in 13C NMR
spectra, and these could not always be distinguished. Hydrogen atoms
attached to these carbons were not always observed in 1H NMR
spectra. Low- and high-resolution mass spectra were recorded on a
time-of-flight mass spectrometer using electron impact (EI). High
resolution mass spectra were recorded only for new compounds. IR
spectra were recorded on an FT−IR spectrometer as a thin film (liquid
samples) or applied as a solution in chloroform with the chloroform
CONCLUSION
■
Following a thorough study by computational and experimental
techniques it has been possible to identify three problems that
inhibit success in generating tert-alkylmethanols in good yields
by reactions of tert-alkylboronic esters with bromomethyl-
lithium: (i) slow formation of the borate (e.g., 8, 21) from the
boronic ester and bromomethyllithium (which is a particular
E
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The Journal of Organic Chemistry
Article
allowed to evaporate (solid samples). Column chromatography was
carried out using 60A (35−70 μm) silica.
(4:1 hexane/diethyl ether) to give pure thexylmethanol as a colorless
liquid; δH (400 MHz; CDCl3) 3.3 (2 H, s), 1.55 (1 H, septet, J 6.9),
1.54−1.47 (1 H, br), 0.80 (6 H, d, J 6.9), and 0.75 (6 H, s); δC (125
MHz; CDCl3) 70.6 (CH2), 37.2 (C), 32.5 (CH), 20.9 (CH3), and 17.2
(CH3); νmax. (neat) 3367 and 2957 cm−1; m/z (EI) 85 ([M −
CH2OH]+, 100%), 73 (78), 69 (37), and 55 (72).
General Procedure for Preparation of Thexylboronic Esters
and Related Compounds. A dry 50 mL round bottomed flask
equipped with a magnetic stirrer bar and septum was assembled when
hot and flushed with nitrogen for 10 min. Borane dimethyl sulfide
complex (0.48 mL, 5.0 mmol) was added, and the flask was cooled
using an ice bath. 2,3-Dimethyl-2-butene (0.59 mL, 5.4 mmol) was
added dropwise with stirring over 5 min. The mixture was left to stir at
0 °C for 90 min. The appropriate alcohol (10 mmol) or diol/dithiol (5
mmol) was added dropwise with safe venting of the evolved hydrogen
gas. The cooling bath was removed, and the mixture was left to stir for
an additional 1 h. Excess dimethyl sulfide was removed under a fast
stream of nitrogen to give the desired thexylborane derivative.
Thexyldimethoxyborane15 (18a), 2-thexyl-1,3,2-dioxaborolane16
(18b), 2-thexyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane16 (18c), 2-
thexyl-1,3,2-dioxaborinane17 (18d), and 2-thexyl-1,3,2-dithiaborola-
ne2c (20) are known compounds.
Thexyl Group Migration Using LiDBB. A 250 mL two-necked flask
equipped with a stirrer bar was assembled while hot and flushed with
nitrogen. 4,4′-di-tert-Butylbiphenyl (7.99 g, 30.0 mmol) was added to
the flask when it was around 50 °C, the flask was flushed with nitrogen
for a further 5 min, and dry THF (60 mL) was introduced via syringe.
Lithium wire (0.174 g, 25.0 mmol, with 0.5−1% sodium) was cut into
small pieces and pressed to increase surface area. The flask was cooled
to 0 °C, and the lithium was introduced quickly via the side arm with
vigorous stirring under a fast stream of nitrogen. The solution took the
dark green/purple color of the radical anion within 2−5 min. The
reaction was stirred vigorously for 5 h, by which time the Li was fully
consumed. The solution was cooled to −78 °C and transferred
dropwise over 45 min via cannula to a freshly prepared solution of 2-
thexyl-1,3,2-dioxaborolane (18b) (0.78 g, 5.0 mmol) and dibromo-
methane (0.42 mL, 6.0 mmol) in dry THF (15 mL), also cooled to
−78 °C. Additional THF (10 mL) was used to dissolve and transfer
the thick residues at the bottom of the radical anion solution. The
reaction was stirred for an additional 30 min at −78 °C, then the
cooling bath was removed, and the solution was allowed to warm up
over 1 h. The reaction mixture was oxidized as in Method A. The ratio
of thexylmethanol to thexanol was determined to be 55:45 by GC
analysis (Zebron ZB-5 column; 70−260 °C at 6 °C/min; hexadecane
as internal standard).
2-Thexyl-5,5-dimethyl-1,3,2-dioxaborinane (18e). Using 2,2-di-
methyl-1,3-propanediol (0.55 g, 5.25 mmol); colorless liquid (Found
(TOF-EI): [M − H]+, 197.1708. C11H22BO2 requires 197.1713); δH
(400 MHz; CDCl3) 3.55 (4 H, s), 1.58 (1 H, septet, J 6.8), 0.91 (6 H,
s), and 0.81−0.76 (12 H, m); δC (125 MHz; CDCl3) 71.8 (2 × CH2),
34.3 (CH), 31.4 (C), 21.9 (CH3), 21.3 (CH3) and 18.4 (CH3); δB (96
MHz; CDCl3) 30.1; νmax. (neat) 2952, 2873, and 1476 cm−1; m/z (EI)
197 ([M − H]+, 6%), 183 (100%), 155.1 (100), 141 (43), 125 (15),
113 (90), 97 (97), 84 (89), 67 (100), and 55 (68).
Thexylbis(2,2,2-trichloroethoxy)borane (18f). Using 2,2,2-trichlor-
oethanol (0.96 mL, 10.0 mmol); air-sensitive colorless liquid; δH (250
MHz; CDCl3) 4.56 (4 H, s), 1.80 (1 H, septet, J 6.8), 0.99 (6 H, s),
and 0.90 (6 H, d, J 6.8); δC (125 MHz; CDCl3) 97.4 (C), 76.0 (CH2),
33.8 (CH), 21.1 (CH3), and 18.0 (CH3); δB (96 MHz; CDCl3) 29.8.
The air sensitivity of this compound precluded the determination of
HRMS data.
2-Thexyl-1,3,2-oxathiaborolane (19). Using 2-mercaptoethanol
(0.35 mL, 5.0 mmol); slightly impure colorless liquid (Found
(TOF-EI): M+, 172.1097. C8H17BOS requires 172.1093); δH (500
MHz; CDCl3) 4.37 (2 H, t, J 7.4), 2.99 (2 H, t, J 7.4), 1.65 (1 H,
septet, J 6.9), 0.92 (6 H, s), and 0.85 (6 H, d, J 6.9); δC (125 MHz;
CDCl3) 72.5 (CH2), 35.4 (CH), 30.0 (CH2), 22.2 (CH3), and 18.5
(CH3); δB (96 MHz; CDCl3) 53.2; νmax. (neat) 2956, 1567, 1393,
1180, 1131 cm−1; m/z (EI) 172 (M+, 8%), 153 (5), 130 (22), 113
(14), 85 (24), 84 (100), and 61 (78).
Lithium Butyl(thexyl)(ethylenedioxy)borate (22b). THF (15 mL)
was added to 2-thexyl-1,3,2-dioxaborolane (18b), and the mixture was
cooled to −78 °C. n-BuLi (2.2 mL of a 2.5 M solution in hexanes, 5.5
mmol) was added dropwise over 10 min, and the cooling bath was
removed. The mixture was concentrated under a fast stream of
nitrogen, and the 11B NMR spectrum was recorded; δB (96 MHz;
CDCl3) −15.8.
5,5-Dimethyl-2-(3-ethylpent-2-yl)-1,3,2-dioxaborinane (28). An
oven-dried flask equipped with a stirrer bar and septum was flushed
with nitrogen for 10 min. Triethylborane solution (15 mL, 1.0 M in
THF, 15 mmol) was added, and the flask was placed in an ice bath.
Once cooled, α,α-dichloromethyl methyl ether (1.5 mL, 15 mmol) was
added dropwise via syringe, followed by the dropwise addition via
cannula of a freshly prepared solution of lithium triethylcarboxide19
(15 mmol) in dry THF (10 mL) over 15 min. The cooling bath was
removed, and the mixture was stirred for a further 1 h. A solution of
2,2-dimethyl-1,3-propanediol (1.87 g, 18 mmol) in dry THF (5 mL)
was added dropwise, and the solution stirred overnight at room
temperature. The volatiles were evaporated under reduced pressure,
and the crude product was purified by column chromatography on
silica (petroleum ether, followed by 95:5 petroleum ether/ethyl
acetate) to give the title compound (1.43 g, 45%) as a colorless liquid
(Found (TOF-EI): M+, 212.1954. C12H25BO2 requires 212.1948); δH
(400 MHz; CDCl3) 3.58 (4 H, s), 1.32 (6 H, q, J 7.5), 0.95 (6 H, s),
and 0.75 (9 H, t, J 7.5); δC (125 MHz; CDCl3) 71.8 (CH2), 31.4 (C),
25.6 (CH2), 22.1 (CH3), and 9.2 (CH3); δB (96 MHz; CDCl3) 30.3;
νmax. (neat) 2957, 2875, 1476, 1244, and 1157 cm−1; m/z (EI) 212
(M+, 2%), 183 (100), 182 (76), 141 (38), 98 (64), 97 (25), 87 (48),
83 (59), 69 (33), 57 (22), 55 (39).
2-(9-Octylheptadecan-9-yl)-1,3,2-dioxaborolane (29). An oven-
dried flask equipped with a stirrer bar and septum was flushed with
nitrogen for 10 min. Once immersed in an ice bath, a borane dimethyl
sulfide complex (10.5 M, 0.86 mL, 10 mmol) was added via syringe,
followed by the dropwise addition of 1-octene (4.7 mL, 30 mmol).
The cooling bath was removed, and the solution was stirred for 3 h.
The solution was cooled to 0 °C, and α,α-dichloromethyl methyl ether
(1.0 mL, 11 mmol) was added dropwise via syringe, followed by the
dropwise addition via cannula of a freshly prepared solution of lithium
triethylcarboxide19 (10 mmol) in dry THF (10 mL) over 15 min. The
cooling bath was removed, and the mixture left to stir for a further 1 h.
Ethylene glycol (0.56 mL, 10 mmol) was added dropwise, and the
General Procedure for Tertiary Alkyl Group Migration by
Method A. Dry THF (15 mL) was added to the boronic ester
substrate (5.0 mmol). Dibromomethane (0.42 mL, 6.0 mmol) was
added, and the solution was cooled using a dry ice−acetone bath. n-
Butyllithium (2.2 mL of a 2.5 M solution in hexanes, 5.5 mmol) was
added dropwise over 25−30 min with vigorous stirring. The mixture
was left to stir for an additional 30 min, and the cooling bath was
removed. The mixture was left to warm up for 1 h, before being cooled
to 0 °C. A solution of sodium hydroxide (1.2 g, 30 mmol) in water (10
mL) was added dropwise, followed by excess aqueous hydrogen
peroxide (30% by weight, 6 mL). Once the initial exothermic reaction
had subsided, the cooling bath was removed and the mixture was
stirred overnight. The aqueous layer was saturated with potassium
carbonate, and the mixture was extracted with diethyl ether (3 × 25
mL). The organic extract was washed with brine (2 × 20 mL) and
distilled water (2 × 20 mL), dried over magnesium sulfate, and filtered.
The solvent was evaporated carefully under reduced pressure to
around 120% of the maximum theoretical yield to give a mixture of
migrated and nonmigrated products, the ratio of which was
1
determined by H NMR spectroscopy (see Supporting Information).
General Procedure for Tertiary Alkyl Group Migration by
Triple Addition (Method B). The procedure was identical to that
described in Method A, except that the addition of the dibromo-
methane and n-BuLi was repeated 3 times with no warming between
additions.
Thexylmethanol (2,2,3-Trimethyl-1-butanol).18 A sample of the
migrated product was purified by column chromatography on silica
F
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The Journal of Organic Chemistry
Article
solution left to stir overnight at room temperature. The volatiles were
evaporated under reduced pressure, hexane (30 mL) was added, and
the mixture was filtered. The resulting clear hexane solution was
washed with methanol (2 × 15 mL). The hexane layer was
concentrated under reduced pressure to give the title compound
(2.04 g, 48%) as a colorless viscous oil (Found (TOF-EI): M+,
422.4297. C27H55BO2 requires 422.4295); δH (400 MHz; CDCl3) 4.15
(4 H, s), 1.37−1.05 (42 H, m), and 0.87 (9 H, t, J 6.6); δC (125 MHz;
CDCl3) 65.3 (CH2), 34.6 (CH2), 31.9 (CH2), 30.6 (CH2), 29.6
(CH2), 29.4 (CH2), 24.8 (CH2), 22.7 (CH2), and 14.1 (CH3); δB (96
MHz; CDCl3) 33.9; νmax. (neat) 2924, 2853, 1466, 1389, and 1348
cm−1; m/z (EI) 422 (M+, 2%), 350 (5), 323 (22), 309 (100), 267 (7),
253 (14), 239 (18), 211 (17), 197 (38), 182 (11), 168 (15), 153 (17),
and 139 (8).
5,5-Dimethyl-2-(9-octylheptadecan-9-yl)-1,3,2-dioxaborinane
(30). The above procedure was repeated on a 15 mmol scale, but with
a solution of 2,2-dimethyl-1,3-propanediol (1.87 g, 1.2 equiv, 18.0
mmol) in dry THF (5 mL) replacing ethylene glycol, to give the title
compound (3.98 g, 57%) as a colorless oil (Found (TOF-EI): [M −
H]+, 463.4685. C30H60BO2 requires 463.4686); δH (400 MHz; CDCl3)
3.57 (4 H, s), 1.35−1.05 (42 H, m), 0.94 (6 H, s), and 0.88 (9 H, t, J
6.8); δC (100 MHz; CDCl3) 71.8 (CH2), 34.3 (CH2), 32.0 (CH2),
31.4 (C), 30.7 (CH2), 29.7 (CH2), 29.4 (CH2), 24.8 (CH2), 22.7
(CH2), 22.1 (CH3), and 14.1 (CH3); δB (160.5 MHz; CDCl3) 28.6;
νmax. (neat) 2923, 2952, 1476, 1467, and 1246 cm−1; m/z (EI) 463
([M − H]+, 2%), 393 (10), 351 (98), 255 (98), 155 (100), and 71
(94).
2-(Tricyclopentylmethyl)-1,3,2-dioxaborolane (31). The proce-
dure was the same as that for the preparation of 29, except that
cyclopentene (2.75 mL, 30 mmol) replaced octene and that the
reaction was left to stir overnight after the ethylene glycol was added.
The crude mixture was concentrated under reduced pressure, and
methanol (40 mL) was added. The mixture was swirled vigorously
until the oily substance at the bottom of the flask began to precipitate.
The mixture was then cooled to 0 °C for 2 h, whereupon the title
compound (1.53 g, 53%) precipitated as a white solid, mp 89−93 °C
(Found (TOF-EI): M+ − cyclopentyl, 221.1714. C13H22BO2 requires
221.1713); δH (400 MHz; CDCl3) 4.11 (4 H, s), 2.05−1.95 (3 H, m)
and 1.72−1.36 (24 H, m); δC (125 MHz; CDCl3) 64.8 (CH2), 45.9
(CH), 30.0 (CH2), and 25.1 (CH2); δB (96 MHz; CDCl3) 33.8; νmax.
(neat) 3019, 2952, 2869, 1389, and 1215 cm−1; m/z (EI) 221 (M −
cyclopentyl, 100%), 179 (50), 165 (91), 153 (82), 139 (83), 125 (28),
109 (62), 95 (77), 81 (66), 67 (78), and 55 (29).
2-(Tricyclopentylmethyl)-1,3,2-dioxaborinane (32). The proce-
dure was the same as that for the preparation of 31, except that 1,3-
propanediol (1.25 g, 1.2 equiv, 12 mmol) replaced ethylene glycol, to
give the title compound (1.72 g, 57%) as a white solid, mp 77−79 °C
(Found (TOF-EI): M+, 304.2577. C19H33BO2 requires 304.2574); δH
(400 MHz; CDCl3) 3.94 (4 H, app. t, J 5.4), 1.99−1.84 (5 H, m), and
1.68−1.35 (24 H, m); δC (125 MHz; CDCl3) 61.0 (CH2), 46.4 (CH),
30.0 (CH2), 27.6 (CH2), and 25.3 (CH2); δB (96 MHz; CDCl3) 29.8;
νmax. (neat) 3019, 2951, 2868, 1480, 1413, 1267, and 1215 cm−1; m/z
(EI) 304 (M+, 3%), 303 (12), 235 (100), 221 (20), 193 (56), 179
(98), 167 (85), 153 (96), 139 (32), 109 (90), 95 (95), 81 (97), and 67
(70).
octylheptadecan-9-yl)-1,3,2-dioxaborolane (29) (1.62 g, 3.84 mmol).
1H NMR spectroscopy of the crude mixture after oxidation showed a
mixture containing around 40% of 2,2-dioctyldecan-1-ol. Determi-
nation of the product ratio is discussed in the Supporting Information.
( )-2-(3-Methyl-2-phenylbutan-2-yl)-1,3,2-dioxaborinane (36). A
dry 100 mL flask equipped with a magnetic stirrer bar and stopcock
was flushed with nitrogen for 10 min. ( )-1-Phenylethyl diisopro-
pylcarbamate (1.18 g, 4.74 mmol), prepared by the literature
procedure,21 and dry diethyl ether (20 mL) were added, and the
solution cooled to −78 °C using a dry ice acetone bath. sec-BuLi (1.3
M in 92:8 cyclohexane/hexane, 4.0 mL, 5.21 mmol) was added
dropwise over 10 min, and the solution stirred for a further 20 min. To
this was added a cold solution of 2-isopropyl-1,3,2-dioxaborinane22
(0.92 g, 7.2 mmol) in diethyl ether (10 mL) dropwise over 10 min
with vigorous stirring. The mixture was left to come to room
temperature slowly as the dry ice/acetone bath gradually warmed.
After stirring for 16 h, the mixture was cooled to 0 °C and saturated
ammonium chloride solution (20 mL) was added. The aqueous layer
was extracted with diethyl ether (3 × 15 mL), and the combined
organic extracts were washed with water (15 mL) and brine (15 mL)
and concentrated under reduced pressure. Methanol (20 mL) was
added, and the mixture was left in the freezer for 1 h, whereupon some
impurities precipitated out. After filtration of the impurities and
evaporation of the methanol, diethyl ether (20 mL) was added. The
supernatant layer was taken, and the diethyl ether evaporated under
reduced pressure to give the essentially pure title compound (0.85 g,
77%) as a light yellow oil (Found (TOF-EI): M+, 232.1634.
C14H21BO2 requires 232.1635); δH (400 MHz; CDCl3) 7.39−7.35
(2 H, m), 7.27 (2 H, app. t, J 7.7), 7.12 (1 H, tt, J 7.2, 1.2), 4.00−3.94
(4 H, m), 2.40 (1 H, app. septet, J 6.8), 1.90−1.83 (2 H, m), 1.16 (3
H, s), 0.98 (3 H, d, J 6.8), and 0.54 (3 H, d, J 6.8); δC (125 MHz;
CDCl3) 147.8 (C), 127.8 (CH), 127.2 (CH), 124.5 (CH), 61.8
(CH2), 33.8 (CH), 27.3 (CH2), 20.5 (CH3), 16.5 (CH3), and 13.4
(CH3); δB (96 MHz; CDCl3) 29.5; νmax. (neat) 2963, 1482, 1274, and
1159 cm−1; m/z (EI) 232 (M+, 69%), 189 (100), 117 (92), 105 (99),
84 (100).
( )-2,3-Dimethyl-2-phenylbutan-1-ol8 (34) by Homologation of
36. The reaction was carried out using Method A, to give the crude
1
product (85:15 ratio of migrated/nonmigrated product by H NMR
spectroscopy), which was purified by column chromatography on silica
(95:5 petroleum ether/ethyl acetate (100 mL), followed by 90:10
petroleum ether/ethyl acetate (200 mL)) to give the title compound
(0.44 g, 73%) as a colorless oil; δH (400 MHz; CDCl3) 7.39−7.32 (4
H, m), 7.22 (1 H, app. tt, J 6.8, 1.8), 3.90 (1 H, d, J 10.9), 3.61 (1 H, d,
J 10.9), 2.09 (1 H, app. septet, J 6.8), 1.28 (3 H, s), 1.16 (1 H, br),
0.98 (3 H, d, J 6.8), and 0.64 (3 H, d, J 6.8); δC (125 MHz; CDCl3)
145.1 (C), 128.4 (CH), 127.0 (CH), 126.1 (CH), 70.8 (CH2), 46.5
(C), 34.3 (CH), 18.0 (CH3), 17.4 (CH3), and 15.7 (CH3); νmax. (neat)
3399, 3089, 3058, 2971, 1600, 1498, 1467, 1444, and 1374 cm−1; m/z
(EI) 178 (M+, 10%), 147 (100), 135 (100), 117 (100), 106 (100), 91
(100), 84 (100), 77 (88), 65 (34), and 57 (75).
( )-2,3-Dimethyl-2-phenylbutan-1-ol8 (34) and ( )-3-Methyl-2-
phenylbutan-2-ol23 (37) by Homologation of 35. A dry 100 mL
round bottomed flask equipped with a stopcock and magnetic stirrer
was flushed with nitrogen for 10 min. The tertiary alkylboronic ester
358 (0.73 g, 2.8 mmol), dry THF (15 mL), and dibromomethane
(0.24 mL, 0.59 g, 3.4 mmol) were added, and the solution was cooled
to −78 °C using a dry ice/acetone bath. n-BuLi in hexanes (2.1 mL,
1.5 M, 3.1 mmol) was added dropwise over 30 min with vigorous
stirring. The solution was stirred for 30 min, the cooling bath was
removed, and the mixture was stirred for 1 h more. The reaction
mixture was cooled to 0 °C, and 3 M aqueous NaOH solution (10
mL) was added dropwise. Once the initial vigorous reaction had
ceased, aqueous hydrogen peroxide solution (30% by weight, 6 mL)
was added dropwise, and the solution was heated to 50 °C for 2 h. The
aqueous layer was saturated with potassium carbonate, and the mixture
was extracted with diethyl ether (3 × 25 mL). The organic extract was
washed with brine (2 × 20 mL) and distilled water (2 × 20 mL), dried
over magnesium sulfate, and filtered. The volatiles were evaporated
Reaction of Boronic Ester 28 with Bromomethyllithium
According to Method B. Method B was applied to boronic ester 28
(0.38 g, 1.81 mmol). 1H NMR spectroscopy of the crude product after
oxidation showed a mixture of 2,2-diethylbutanol and 3-ethyl-3-
pentanol in a ratio of 72:28. A portion of the mixture was subjected to
column chromatography on silica (petroleum ether, followed by 98:2
petroleum ether/ethyl acetate) to give 2,2-diethyl-1-butanol20 as a
colorless liquid; δH (400 MHz; CDCl3) 3.36 (2 H, s), 1.35−1.25 (1 H,
br s), 1.23 (6 H, q, J 7.5), and 0.79 (9 H, t, J 7.5); δC (125 MHz;
CDCl3) 65.9 (CH2), 39.5 (C), 25.0 (CH2), and 7.4 (CH3); νmax.
(neat) 3365, 2965, 2927, 2880, 1465, 1379, and 1260 cm−1; m/z (EI)
99 (M+ − CH2OH, 63%), 98 (65), 86 (100), 74 (100), 69 (60), and
59 (100).
Reaction of Boronic Ester 29 with Bromomethyllithium
According to Method B. Method B was applied to 2-(9-
1
under vacuum to give the crude product (50:50 ratio of 34:37 by H
G
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The Journal of Organic Chemistry
Article
NMR spectroscopy), which was purified by column chromatography
on silica (95:5 petroleum ether/ethyl acetate (100 mL), followed by
90:10 petroleum ether/ethyl acetate (200 mL)) to give ( )-2,3-
dimethyl-2-phenylbutan-1-ol (34) (0.19 g, 38%) and ( )-3-methyl-2-
phenylbutan-2-ol (37) (0.11 g, 24%), both as colorless liquids. Data
for ( )-37 δH (400 MHz; CDCl3) 7.44 (2 H, dd, J 8.2, 1.3), 7.35 (2
H, app. t, J 7.6), 7.25 (1 H, tt, J 7.3, 1.3), 2.04 (1 H, app. septet, J 7.3),
1.86 (1 H, br s), 1.55 (3 H, s), 0.92 (3 H, d, J 6.8), and 0.84 (3 H, d, J
6.9); δC (125 MHz; CDCl3) 147.9 (C), 127.9 (CH), 126.4 (CH),
125.3 (CH), 76.8 (C), 38.6 (CH), 26.7 (CH3), 17.5 (CH3), and 17.2
(CH3); νmax. (neat) 3458, 2973, 1495, 1446, and 1373 cm−1; m/z (EI)
164 (M+, 4%), 147 (95), 131 (69), 122 (100), 105 (98), 91 (97), and
77 (96).
(c) Blakemore, P. R.; Burge, M. S. J. Am. Chem. Soc. 2007, 129, 3068−
3069.
(7) Soundararajan, R.; Li, G.; Brown, H. C. Tetrahedron Lett. 1994,
35, 8957−8960.
(8) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier,
R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, 50,
3760−3763.
(9) (a) Nave, S.; Sonawane, R. P.; Elford, T. G.; Aggarwal, V. K. J.
Am. Chem. Soc. 2010, 132, 17096−17098. (b) Bagutski, V.; Elford, T.
G.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, 50, 1080−1083.
(c) Roesner, S.; Casatejada, J. M.; Elford, T. G.; Sonawane, R. P.;
Aggarwal, V. K. Org. Lett. 2011, 13, 5740−5743. (d) Fletcher, C. J.;
Blair, D. J.; Wheelhouse, K. M. P.; Aggarwal, V. K. Tetrahedron 2012,
68, 7598−7604.
(10) Bottoni, A.; Lombardo, M.; Neri, A.; Trombini, C. J. Org. Chem.
2003, 68, 3397−3405. For earlier computational work on a related
reaction, see: Midland, M. M. J. Org. Chem. 1998, 63, 914−915.
(11) The barriers to chair inversion in the borates 8d and 8e have not
been calculated. However, the inversion barriers in 1,3-dioxanes are
similar to those in cyclohexane, so that barriers in the region of 40 kJ
mol−1 are anticipated: Anderson, J. E.; Brand, J. C. D. Trans. Faraday
Soc. 1966, 62, 39−45.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C, and 11B NMR spectra for all compounds.
Calculated thermodynamic and structural parameters for all
compounds discussed in the computational section of this
work. This material is available free of charge via the Internet at
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AUTHOR INFORMATION
Corresponding Author
*E-mail: elliottmc@cardiff.ac.uk; smithk13@cardiff.ac.uk.
■
Present Address
§Department of Chemistry, Government College University,
Faisalabad 38040, Pakistan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the EPSRC and Cardiff University (D.H.J.),
the Higher Education Funding Council of Pakistan (A.H.), and
́
the Iraqi Cultural Attache (B.A.S.) for financial support. We
would like to thank Professor Barry Carpenter and Dr. Jamie
Platts (Cardiff University) for much helpful advice on the
computational aspects of this study and Dr. Robert Jenkins, Mr.
Robin Hicks, and Mr. David Walker for technical assistance.
■
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75, 5008−5016.
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