Highly diastereoselective and enantiospecific allylation of ketones and imines using borinic esters: Contiguous quaternary stereogenic centers

Article abstract of DOI:10.1002/anie.201407127

3,3-Disubstituted allylic boronic esters are not sufficiently reactive to react with ketones and imines. However they can be converted into the corresponding borinic esters by the sequential addition of nBuLi and TFAA. These reactive intermediates possess

Full text of DOI:10.1002/anie.201407127

Angewandte
Chemie
DOI: 10.1002/anie.201407127
Synthetic Methods Very Important Paper
Highly Diastereoselective and Enantiospecific Allylation of Ketones
and Imines Using Borinic Esters: Contiguous Quaternary Stereogenic
Centers**
Jack L.-Y. Chen and Varinder K. Aggarwal*
Abstract: 3,3-Disubstituted allylic boronic esters are not
sufficiently reactive to react with ketones and imines. However,
they can be converted into the corresponding borinic esters by
the sequential addition of nBuLi and TFAA. These reactive
intermediates possess the perfect balance between reactivity
and configurational stability. Their enhanced reactivity allows
the highly selective allylation of both ketones and ketimines,
and facile access to adjacent quaternary stereocenters with full
stereocontrol. The versatility of the methodology is demon-
strated in the construction of all possible stereoisomers of
a quaternary-quaternary motif and by the allylation of the
heterocycles, dihydroisoquinoline and indole.
T
he asymmetric allylboration reaction is one of the most
reliable and useful methods for the synthesis of homoallylic
alcohols.[1] Whilst extraordinarily useful for aldehydes, reac-
tions with less reactive ketones[2] and imines are much more
limited, because of the low reactivity of allylic boronic esters.
Indeed, Hoffmann[3] reported the crotylation of a pinacol
boronic ester with acetophenone and it required high pressure
(8 kbar) and extended reaction times (3 days) to achieve full
conversion (Scheme 1a). Nevertheless, several new protocols
have been developed and have begun to address such systems,
for example, using allylic boronic acids or 1,3-propanediol
boronic esters together with binol.[4] However, there are no
successful asymmetric examples of the reactions of such poor
electrophiles combined with even less reactive 3,3-disubsti-
tuted allylic boron reagents. Such a combination would lead
to adjacent quaternary-quaternary stereocenters,[5,6] an espe-
cially difficult motif to create with control of relative and
absolute stereochemistry. There are sporadic reports of
diastereoselective allylation of ketones using 3,3-disubsti-
tuted allylic boronic acids,[4n,o] but no asymmetric examples
have been reported.[7] Likewise, with 3,3-disubstituted allylic
boranes,[8] allylations have been achieved with ketones but no
examples possessing non-identical groups on the 3-position
have been reported. This shows that 3,3-disubstituted allylic
boranes are sufficently reactive to engage with ketones but
their synthesis with non-identical groups in the 3-position is
Scheme 1. a) Reaction conditions required for allylboration of ketones
with a-substituted boronic esters. b) Proposed allylboration of ketones
and imines with a-substituted borinic esters to form contiguous
quaternary centers. TFAA=trifluoroacetic anhydride.
an issue, perhaps because of their tendency to isomerize
through borotropic shifts.
As indicated above, 3,3-disubstituted allylic boronic esters
are not sufficiently reactive to react with ketones. Between
these two extremes of reactivity and stability lie allylic borinic
esters. We have discovered a convenient way of generating
this unusual class of reagents (by the addition of nBuLi to
pinacol boronic esters followed by TFAA) and demonstrated
that they show much higher E selectivity in reactions with
aldehydes when compared to the same reactions using pinacol
boronic esters.[9] We now show that the enhanced reactivity of
these in situ generated borinic esters can be exploited in the
allylation of challenging ketones and imines, even when using
the least reactive 3,3-disubstituted reagents, with very high
diastereoselectivity and complete enantiospecificity for the
unprecedented creation of adjacent quaternary-quaternary
stereogenic centers.
We began our studies with the synthesis of enantioen-
riched a-substituted-3,3-disubstituted allylic boronic esters
using our lithiation-borylation methodology.[10] This involves
deprotonation of a carbamate or hindered benzoate using
sBuLi with (+)- or (ꢀ)-sparteine followed by addition of
a vinylboronic ester. The resulting boronate complex under-
goes a 1,2-metallate rearrangement upon heating, thus giving
the allylic boronic ester. Whilst this worked well for the
preparation of allylic boronic esters 1a and 1b (see Table 1),
other aryl-containing substrates (1c–f) initially proved to be
[*] Dr. J. L.-Y. Chen, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
[**] We thank the EPSRC and the European Research Council (FP7/2007-
2013, ERC grant no. 246785) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407127.
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Table 1: Allylation of ketones with a-substituted allyl, crotyl, and 3,3-
disubstituted allylic boronic esters.
problematic because of a slow 1,2-metallate rearrangement.
We were able to solve this problem by a combination of using
a hindered benzoate (which has been shown to be a better
leaving group than a carbamate)[11] and solvent exchange
from Et2O to CHCl3.[12] This enhanced methodology enabled
the synthesis of the trisubstituted allylic boronic esters 1c–f
with e.r. values in the range from 95:5 to 98:2 .
The enantioenriched a-substituted-3,3-disubstituted
allylic boronic esters 1a–f were subjected to our Lewis-
base-promoted allylation reaction with ketones. Thus, the
allylic pinacol boronic ester 1a was treated sequentially with
nBuLi and TFAA to generate the corresponding borinic ester
in situ. The ketone was subsequently added at low temper-
ature and it was found that the reaction went to completion
upon warming to room temperature overnight. This demon-
strated the considerably higher reactivity of the borinic ester
compared to the boronic ester.
We were delighted to find that essentially single diaste-
reoisomers of homoallylic alcohols were formed in good yield
and with complete stereospecificity when reacted with
acetophenone (Table 1, entries 1, 3, and 5–8). Control experi-
ments revealed that no reaction took place between the allylic
boronic esters 1a–f and acetophenone under ambient con-
ditions after one week, and underscores the much higher
reactivity of our allylic borinic esters. Furthermore, the even
less reactive dialkyl ketone and the a,b-unsaturated ketone
were also suitable coupling partners (entries 2 and 4).
Although the use of Lewis acids have been shown to promote
the allylboration of aldehydes,[13] we found that their appli-
cation (e.g. BF3·OEt2[4d]) with ketones was ineffective (see the
Supporting Information for details of control experiments
and alternative reaction conditions tested).
Entry
1
Li-B product
Yield[b]
Product
Yield[b]
87%
>99:1 d.r.[c]
98:2 e.r.
77%
98:2 e.r.
80%
2
3
>99:1 d.r.[c]
98:2 e.r.
83%
>99:1 d.r.[c]
98:2 e.r.
74%
98:2 e.r.
88%
4
5
97:3 d.r.[c]
98:2 e.r.
53%
74%
97:3 e.r.
>99:1 d.r.[c]
94:6 e.r.
69%
68%
96:4 e.r.
6
>99:1 d.r.[c]
96:4 e.r.
70%
62%
95:5 e.r.
7
>99:1 d.r.[c]
96:4 e.r.
Our a-substituted-3,3-disubstituted allylic borinic esters
showed considerably enhanced reactivity over conventional
boronic esters as we had desired. The high selectivity that was
observed was expected because of A1,3 strain associated with
the Z-substituent R3 (Scheme 1b). However, high selectivity
was also observed with less substituted allylic borinic esters
(R3 = H) provided a secondary alkyl a-substituent was
employed (Table 1, entries 9–13).
73%
74%
96:4 e.r.
8
>99:1 d.r.[c]
95:5 e.r.
85%
78%
98:2 e.r.
9
76:24 d.r.[c]
98:2 e.r.
To demonstrate the versatility of this methodology, we
wanted to access all four possible stereoisomers in a quater-
nary-quaternary motif (Figure 1). By using the lithiation-
borylation methodology with both E- and Z-boronic esters
(3a and 3b, respectively) and (+)-sparteine and (ꢀ)-sparteine
(both enantiomers of sparteine are commercially available;
see the Supporting Information for details), we were able to
access all four possible stereoisomers of the quaternary-
quaternary motif in ꢁ 99:1 d.r. and ꢁ 98:2 e.r., thus validating
the versatility of this methodology.
The allylation of imines is one of the most efficient and
direct ways of generating homoallylic amines.[1b,14] However,
the reaction with imines is more challenging than the
allylation of aldehydes because of their lower electrophilici-
ty.[14a] Whilst numerous advances[4r,15] have been made in the
allylation of aldimines and ketimines, few cases report the use
of 3,3-disubstituted allylic boron reagents.[15m,n]
73%
68%
98:2 e.r.
10
11
12
13
98:2 d.r.[c]
98:2 e.r.
80%
97:3 d.r.[c]
98:2 e.r.
71%
72%
98:2 e.r.
>99:1 d.r.[c]
97:3 e.r.
90%
>99:1 d.r.[c]
98:2 e.r.
[a] MgBr2·OEt2, reflux overnight or Et2O!CHCl3, reflux overnight.
[b] Yield of isolated product. [c] Determined by GC/HPLC/SFC analysis
of the crude reaction mixture using a chiral stationary phase. OCb=N,N-
diisopropyl carbamate, OTIB=2,4,6-triisopropylbenzoate, THF=tetra-
hydrofuran.
Reactions of our 3,3-disubstituted allylic boronic esters
under the control-reaction conditions (no additives) produced
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ketimine, which worked well and again gave very high
selectivity in the allylation process. This borinic ester medi-
ated allylboration provides a powerful new method for the
construction of homoallylic amines bearing quaternary ste-
reogenic centers and the even more challenging contiguous
quaternary-quaternary centers. As before, less substituted
allylic borinic esters could also be employed and high
selectivity was again obtained when the secondary alkyl a-
substituent was employed (entries 5–7). In these cases control
experiments showed that the boronic esters were sufficiently
reactive to engage with imines, and interestingly the Z isom-
ers were favored whereas with borinic esters, E isomers were
formed with very high selectivity.
Figure 1. Generation of all possible four stereoisomers of a quaternary-
quaternary motif.
These reaction conditions were also effective for the
direct allylation of 3,4-dihydroisoquinoline as well as indole
(Scheme 2). Allylation of 3,4-dihydroisoquinoline with 1b
less than 30% conversion with aldimines[16] and less than 10%
conversion with ketimines after 2 days. However, using our
Lewis-base-activated conditions there was smooth formation
of the E-homoallylic amines exclusively, in good yield and
complete enantiospecificity (Table 2, entries 1–4). Particu-
larly noteworthy is reaction with the acetophenone-derived
Table 2: Allylation of N-TMS aldimine and ketimines.
Entry Boronic ester R4
Product
Yield[b,c]
81%
d.r.[d]
e.r.
Scheme 2. Allylation of 3,4-dihydroisoquinoline and indole.
1[a]
1
2
3
4
5
H
H
>99:1
98:2
afforded the resultant homoallylic amide in 81% yield and as
a single diastereoisomer. Reaction of 1b with indole was slow
presumably as the substrate had to first isomerize to the imine
tautomer.[17] Nevertheless, the substituted benzopyrrolidine 7
was formed in 74% yield as a single diastereoisomer. There
are few examples for the direct allylboration of dihydroiso-
quinolines[15h,n] and indoles,[15n,17] and this methodology allows
facile enantio- and diastereocontrolled access to functional-
ized amines which are useful precursors in the synthesis of
alkaloids.
The stereochemical assignment was established by X-ray
crystal structures of several compounds derived from the
ketone and imine allylation (see the Supporting Information
for details) and is in keeping with the model presented in
Scheme 1b. It should be noted that the alkoxide substituent
on boron is drawn in an axial position because a large
anomeric effect through boron is believed to be operative.[18]
To gain insight into the nature of the reactive intermedi-
ates, the course of the reaction was monitored by 11B NMR[9]
and in situ IR spectroscopy, using ReactIR (Scheme 3). Upon
addition of nBuLi to the boronic ester 1a (1320 cmꢀ1)[19] at
ꢀ788C, this signal disappeared instantaneously and was
replaced by a signal at 1380 cmꢀ1. This new signal is believed
to correspond to the boronate complex 8 and is consistent
with an upfield shift of the boron signal to d = 7 ppm.
Following addition of TFAA at ꢀ788C, the characteristic
anhydride signal at 1877 cmꢀ1 appeared instantly and
77%
48%
54%
>99:1
99:1
98:2
98:2
98:2
Me
Me
H
>99:1
91%
(72%)
73:27
(8:92)
98:2
(98:2)
76%
98:2
98:2
6
7
H
H
(87%) (13:87) (97:3)
80%
>99:1
97:3
(88%) (10:90) (98:2)
[a] 98:2 e.r. in each case. [b] Yield of isolated product. [c] Values in
brackets: direct reaction of boronic esters without additives (control
conditions). [d] Ratio 4/5: Determined by HPLC/SFC analysis of the
crude reaction mixture using a chiral stationary phase. TMS=trime-
thylsilyl.
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Scheme 3. Identification of reactive intermediates and reaction mon-
itoring using 11B NMR and in situ IR spectroscopy (see the Supporting
Information).
decreased in magnitude (to baseline) over a period of
30 minutes. At the same time a new signal at 1785 cmꢀ1
appeared and corresponded to the trifluoroacetate ester
bound to the pinacol in 9. 11B NMR spectroscopy was
indicative of the formation of a borinic ester signal at d =
51 ppm. A signal at 1725 cmꢀ1 stayed constant throughout the
course of the reaction and is attributed to the trifluoroacetate
anion. The course of the allylation could be monitored by the
immediate appearance of the ketone carbonyl at 1692 cmꢀ1
which gradually declined over a period of 2.5 hours at 08C.
This change was accompanied by an increase in the signal at
1320 cmꢀ1, corresponding to the formation of the boronic
ester 10. This showed that the reaction of the borinic ester
with acetophenone at 08C was complete after 2.5 hours.
These observations show that the reactions of borinic
esters with ketones are extremely facile and rapid, and are
complete in just a few hours at ambient temperature and
pressure. This contrasts with the very low reactivity of allylic
pinacol boronic esters, which have been shown to require high
pressure and extended reaction times in related reactions.[3]
In conclusion, we have employed traditionally unreactive
3,3-disubstituted allylic pinacol boronic esters in the allylation
of ketones, imines, and aromatic heterocycles. This has been
achieved by the in situ generation of reactive borinic esters,
which have the perfect balance between stability (no 1,3-
borotropic shift) and reactivity. Particularly noteworthy is the
ability to create adjacent quaternary-quaternary stereocen-
ters with essentially complete stereocontrol in the reactions
with ketones and ketimines. The methodology allows a sig-
nificant expansion in the scope of the ubiquitous allylboration
reaction.
Received: July 11, 2014
Published online: && &&, &&&&
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Keywords: allylic compounds · boron · diastereoselectivity ·
.
NMR spectroscopy · synthetic methods
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1985, 107, 7167.
[19] A notable IR absorption for boronic esters is a strong band at
1380 – 1310 cmꢀ1 corresponding to B-O stretch: “Structure,
Properties, and Preparation Of Boronic Acid Derivatives.
Overview of Their Reactions and Applications”: D. G. Hall,
Boronic Acids (Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2005,
chap. 1, pp. 1 – 99.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
J. L.-Y. Chen,
V. K. Aggarwal*
&&&& — &&&&
Highly Diastereoselective and
Enantiospecific Allylation of Ketones and
Imines Using Borinic Esters: Contiguous
Quaternary Stereogenic Centers
Goldilocks reactivity: 3,3-Disubstituted
allylic borinic esters possess the perfect
balance between reactivity and configu-
rational stability to react with both
access to adjacent quaternary stereocen-
ters with full stereocontrol. Synthesis of
all possible stereoisomers of a quater-
nary-quaternary motif is demonstrated.
TFAA=trifluoroacetic anhydride.
ketones and ketimines, allowing facile
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!