Difunctionalization of C?C σ?Bonds Enabled by the Reaction of Bicyclo[1.1.0]butyl Boronate Complexes with Electrophiles: Reaction development, scope, and stereochemical origins

Article abstract of DOI:10.1021/jacs.0c07357

Difunctionalization reactions of C?C σ-bonds have the potential to streamline access to molecules that would otherwise be difficult to prepare. However, the development of such reactions is challenging because C?C σ-bonds are typically unreactive. Exploiting the high ring-strain energy of polycyclic carbocycles is a common strategy to weaken and facilitate the reaction of C?C σ-bonds, but there are limited examples of highly strained C?C σ-bonds being used in difunctionalization reactions. We demonstrate that highly strained bicyclo[1.1.0]butyl boronate complexes (strain energy ca. 65 kcal/mol), which were prepared by reacting boronic esters with bicyclo[1.1.0]butyl lithium, react with electrophiles to achieve the diastereoselective difunctionalization of the strained central C?C σbond of the bicyclo[1.1.0]butyl unit. The reaction shows broad substrate scope, with a range of different electrophiles and boronic esters being successfully employed to form a diverse set of 1,1,3-trisubstituted cyclobutanes (>50 examples) with high diastereoselectivity. The high diastereoselectivity observed has been rationalized based on a combination of experimental data and DFT calculations, which suggests that separate concerted and stepwise reaction mechanisms are operating, depending upon the migrating substituent and electrophile used.

Full text of DOI:10.1021/jacs.0c07357

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Article
Difunctionalization of C–C # Bonds Enabled by the Reaction
of Bicyclo[1.1.0]butyl Boronate Complexes with Electrophiles:
Reaction Development, Scope, and Stereochemical Origins
Steven Bennett, Alexander Fawcett, Elliott Denton, Tobias
Biberger, Valerio Fasano, Nils Winter, and Varinder K. Aggarwal
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07357 • Publication Date (Web): 04 Sep 2020
Downloaded from pubs.acs.org on September 4, 2020
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Difunctionalization of CC -Bonds Enabled by the Reaction of
Bicyclo[1.1.0]butyl Boronate Complexes with Electrophiles: Reaction
Development, Scope, and Stereochemical Origins
Steven H. Bennett,‡ Alexander Fawcett,‡ Elliott H. Denton, Tobias Biberger, Valerio Fasano,
Nils Winter, and Varinder K. Aggarwal*
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School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
ABSTRACT: Difunctionalization reactions of CC -bonds have the potential to streamline access to molecules that would
otherwise be difficult to prepare. However, the development of such reactions is challenging because CC -bonds are typically
unreactive. Exploiting the high ring-strain energy of polycyclic carbocycles is a common strategy to weaken and facilitate the reaction
of CC -bonds, but there are limited examples of highly strained CC -bonds being used in difunctionalization reactions. We
demonstrate that highly strained bicyclo[1.1.0]butyl boronate complexes (strain energy: ca. 65 kcal/mol), which were prepared by
reacting boronic esters with bicyclo[1.1.0]butyl lithium, react with electrophiles to achieve the diastereoselective difunctionalization
of the strained central CC -bond of the bicyclo[1.1.0]butyl unit. The reaction shows broad substrate scope, with a range of different
electrophiles and boronic esters being successfully employed to form a diverse set of 1,1,3-trisubstituted cyclobutanes (>50 examples)
with high diastereoselectivity. The high diastereoselectivity observed has been rationalized based on a combination of experimental
data and DFT calculations, which suggests that separate concerted and stepwise reaction mechanisms are operating depending upon
the migrating substituent and electrophile used.
bicyclo[1.1.0]butane bearing a bridgehead tert-butyl ester could
be cleaved by the homo-conjugate addition of an
Introduction
Methods for cleaving CC -bonds have recently risen to
prominence because they have the potential to streamline
chemical synthesis by enabling access to new chemical
transformations and molecules that would otherwise be difficult
to prepare.1 However, the development of such methods is
challenging because CC -bonds are typically strong, inert,
and geometrically inaccessible. Furthermore, overlap of the
high energy CC * orbital (which is usually not the LUMO of
the molecule) with the HOMO of the reagent/catalyst is difficult
to achieve. Thus, features that modulate the electronic structure
of CC -bonds are usually required to enable them to engage
in chemical reactions.
organocuprate. The enolate was
8
A Fox's difunctionalization of bicyclo[1.1.0]butyl esters:
O
O
Ar
O
R1-[Cu]
electrophile
OtBu
E
Ar
Ar
OtBu
OtBu
R1
R1
R1
[Cu]
E
B Reactions of alkenyl boronate complexes with electrophiles:

Bpin
R1
E
electrophile
-bond
Bpin
R1
E

C
C


difunctionalization
C Reactions of bicyclo[1.1.0]butyl boronate complexes with electrophiles (this work):
E

One method to activate CC -bonds is to use strain energy.
For example, the central CC bond in [1.1.1]propellane is
highly strained (98 kcal/mol of strain energy),2 which enables it
to react with many radicals and nucleophiles.3 In several cases,
these reactions provide rare examples of the difunctionalization
of a CC single bond, wherein the CC bond is cleaved and
replaced by a new substituent ( H) on each carbon atom.4
Bicyclo[1.1.0]butanes5 are another class of highly strained
carbocycles (63.9 (experimental)/66.3 (calculated)2 kcal/mol of
strain energy) which have been used in CC bond activation
reactions;6 however, in contrast to [1.1.1]propellane, there are
limited examples of bicyclo[1.1.0]butanes being used in CC
bond difunctionalization reactions.7 In a notable report, Fox
E

electrophile
Li
Bpin
R1
Bpin
R1
Bpin
R1
CC -bond
difunctionalization
1
Figure 1. (A) Fox’s homo-conjugate addition of organocuprates
followed by electrophilic trapping for the difunctionalization of
bicyclo[1.1.0]butyl esters.8 (B) The reaction of alkenyl boronate
complexes with electrophiles. (C) Proposed reaction of
bicyclo[1.1.0]butyl boronate complexes with electrophiles.
then trapped by an electrophile, resulting in the formal
difunctionalization of the central CC -bond of the
bicyclo[1.1.0]butane (Figure 1A).8 Whilst this chemistry
demonstrated a groundbreaking use of bicyclo[1.1.0]butanes,
showed that the central strained -bond of
a
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the cyclobutane products were often obtained with modest
cyclohexylpinacol boronic ester (Figure 2B). However, analysis
diastereoselectivity. Considering these limited precedents, we
were interested in developing alternative methods to achieve the
difunctionalization of CC -bonds by exploiting highly
strained intermediates.
of the reaction mixture with 11B NMR spectroscopy revealed
that only 75% of the cyclohexylpinacol boronic ester had been
converted to the corresponding bicyclo[1.1.0]butyl boronate
complex 3. The subsequent reaction between 3 and a model
electrophile, benzaldehyde,22 proceeded smoothly within 1 h at
78 °C to give borylcyclobutane 4 in 45% yield with >95:5 d.r.
Alkenyl boronate complexes react with electrophiles,9 as well
as electrophilic radicals10 and palladium/nickel complexes
(Figure 1B).11 The electrophile (E+) reacts at the -carbon of the
O
A
alkene group and induces
a concomitant 1,2-metalate
9
c
S
Br
a, b
Li
Br
rearrangement, where the carbon substituent, R1, migrates to the
-carbon of the alkene group. This results in the formal
carbofunctionalization of the CC -bond. Relief of ring strain
in small heterocycles, including epoxides,12 aziridines,13
azetidinium ions,14 and 1-azabicyclo[1.1.0]butanes,15 has also
been used to trigger 1,2-metalate rearrangements. In a merger
of these two concepts, we questioned whether a boronate
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Cl
d
5
, 56% (6.4 g)
2
e
Br
O
O
B
N
Br
O
N
OH
Br
Ph
Bpin
Bpin
Cy
f
g
Bpin
Cy
complex
bearing
the
highly
strained
carbocycle
bicyclo[1.1.0]butane (1) would provide sufficient strain energy
to facilitate reaction with an electrophile to trigger 1,2-metalate
rearrangement with concomitant cleavage of its strained central
bond (Figure 1C). By analogy to the alkenyl boronate
complexes, the migrating group, R1, would migrate to the
-carbon with simultaneous cleavage of the central CC
-bond of the bicyclo[1.1.0]butyl unit and formation of a CE
bond at the -carbon. This step would represent a formal
carbofunctionalization of a CC -bond, albeit a highly strained
one, wherein the carbon-based migrating group and the
electrophile are added across the central bond of the
bicyclo[1.1.0]butyl unit.
3
6
, without MeOH:
59%, 98:2 d.r.
4
2
, from : 45%
2
5
75% from
5
from : 75%
quant. from
with MeOH: 83%,
gram-scale: 78% (1.4 g)
all >95:5 d.r.
>99:1 d.r.
5
(both from
)
Br
C
Bpin
Bpin
H
g
MeO
(95:5 e.r.)
MeO
7
, 68%, >95:5 d.r.
95:5 e.r. (100% e.s.)
Figure 2. (A) Preparation of bicyclo[1.1.0]butyl lithium from
dibromocyclopropane 2 and sulfoxide 5. (B) The reaction of
bicyclo[1.1.0]butyl lithium with cyclohexylpinacol boronic ester to
form bicyclo[1.1.0]butyl boronate complex 3, and the subsequent
The products of this reaction would be 1,1,3-trisubstituted
cyclobutanes bearing two easily varied substituents
(electrophile and migrating group) as well as a boronic ester,
which itself can be readily converted into a range of functional
groups.16 Current methods to prepare 1,1,3-trisubstitued
reaction of
3 with benzaldehyde and DBDMH to give
borylcyclobutane products 4 and 6. (C) Enantiospecific reaction of
cyclobutanes
are
limited,17
especially
with
high
a
bicyclo[1.1.0]butyl boronate complex with DBDMH.
diastereoselectivity, so this method could provide a unique
entry point to this particular class of substituted cyclobutanes.
Furthermore, cyclobutanes are of increasing value in medicinal
chemistry because they can function as rigid, C(sp3)-rich
bioisosteres of phenyl rings18 to help chemists ‘escape
flatland’,19 so this method could find application in the modular
preparation of diverse cyclobutane-containing building blocks
for use in medicinal chemistry discovery programs.
Abbreviated reaction conditions: a 2 (1.2 equiv), MeLi (1.2 equiv),
Et2O, 78 to 50 °C, 1.5 h. b tBuLi (1.2 equiv), 78 °C, 20 min. c i)
MgBr2
(2.4 equiv),
78 °C,
2 h.
ii) methyl
4-
t
methylbenzenesulfinate (1.0 equiv). d 5 (1.3 equiv), BuLi (1.3 or
2.6 equiv), 78 °C, 2-methyltetrahydrofuran. e 78 °C, 5 min, then
r.t., 15 min. benzaldehyde (1.3 equiv), 78 °C, 1 h. g DBDMH
f
(1.2 equiv), 78 °C, 1 min.
To increase the yield of the reaction we needed to increase the
conversion of the boronic ester to the boronate complex. We
In this article, we present our success in realizing this concept,
providing full details of the design and development of
bicyclo[1.1.0]butyl boronate complexes and the exploration of
their reactivity with a broad array of electrophiles, resulting in
the diastereoselective difunctionalization of the central CC
-bond of the bicyclo[1.1.0]butyl unit.20 Using a combination
of experimental results and DFT calculations, the origins of
stereocontrol in these reactions has been rationalized.
therefore sought to synthesize and isolate
a
latent
bicyclo[1.1.0]butyl nucleophile from which we could generate
bicyclo[1.1.0]butyl lithium cleanly and quantitatively.
Bicyclo[1.1.0]butyl sulfoxide 5 was prepared on multi-gram
scale in 56% yield by the treatment of bicyclo[1.1.0]butyl
lithium with magnesium bromide23 followed by methyl
4-methylbenzene sulfinate. This sulfoxide was found to be a
crystalline compound which was stable at ambient temperature
under N2. Its structure was confirmed by single crystal X-ray
crystallography. Treatment of sulfoxide 5 at 78 °C with tert-
butyl lithium in the presence of cyclohexylpinacol boronic ester
quantitatively formed the corresponding boronate complex 3 as
determined by 11B NMR spectroscopy. Subsequent treatment of
3 with benzaldehyde gave borylcyclobutane 4 in 75% yield with
>95:5 d.r. This reaction was found to be scalable: when using
Results and Discussion
Formation and Initial Reactions of Bicyclo[1.1.0]butyl
Boronate Complexes
To prepare bicyclo[1.1.0]butyl boronate complexes, we
required access to bicyclo[1.1.0]butyl lithium,21 a reactive
intermediate that had previously been prepared from
dibromocyclopropane 2 (Figure 2A). Employing this method,
bicyclo[1.1.0]butyl lithium was generated and treated with
1.0
g (4.76 mmol) of cyclohexylpinacol boronic ester,
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borylcyclobutane 4 was obtained in 78% yield (1.38 g,
products. Although the origin for the increase in yield and
2
3
4
5
6
7
8
9
3.71 mmol) with >95:5 d.r. Finally, to get an appreciation of the
reactivity of boronate complex 3, its reaction with
benzaldehyde was followed by ReactIR at 78 ˚C (see
Supporting Information). This revealed that the reaction was
completed within just 5 min, showing the extraordinarily high
reactivity of these strained boronate complexes24 and gave us
confidence that they would react with a range of other
electrophiles.
selectivity is unclear, it is possible that hydrogen bonding
between methanol and the Lewis basic oxygen atoms of the
pinacol unit stabilizes the intermediate boronate complex 3,
tempering its reactivity, thereby resulting in increased
selectivity. This strategy of adding a hydrogen bond donor to
the reaction mixture before addition of the electrophile was
found to be a general strategy for improving both the yield and
diastereoselectivity
of
reactions
between
certain
bicyclo[1.1.0]butyl boronate complexes and electrophiles. We
also found that, in some instances, addition of a hydrogen
bonding donor also led to considerably cleaner reactions (vide
infra). Finally, we treated the bicyclo[1.1.0]butyl boronate
complex derived from an enantioenriched secondary boronic
ester (95:5 e.r.) with DBDMH in the presence of methanol and
it gave the corresponding bromocyclobutane 7 in 68% yield,
>95:5 d.r. and 95:5 e.r., which demonstrated that the 1,2-
migration step of this reaction proceeds with complete
enantiospecificity (e.s.) (Figure 2C).
We next investigated the reaction of bicyclo[1.1.0]butyl
boronate complex 3 with electrophilic brominating reagents
(Figure 2B), but the results were initially disappointing. The
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reaction of
3
with 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH) yielded 59% of 6 with 98:2 d.r. alongside significant
quantities of unidentified side-products. In related chemistry,
where alkenyl boronate complexes were reacted with a range of
electrophiles, it was discovered that diastereoselectivity could
be increased by the addition of hydrogen bond donors such as
methanol or trifluoroethanol.25 Thus, we added a small amount
of methanol (10% by volume) after boronate complex
formation, before addition of DBDMH, which led to a
significant increase in yield and selectivity to give 6 in 83%
yield and >99:1 d.r. and without any contaminating side-
Reaction of Bicyclo[1.1.0]butyl Boronate Complexes
with Electrophiles: Electrophile and Boronic Ester Scope
The scope of the electrophile was investigated using the
E
electrophile
(1.2 or 1.3 equiv)
Electrophile
Product
Electrophile
Cl
Product
Bpin
Cy
Bpin
Cy
78 C, 1 h
to r.t., 1 h
O
O
Cl
Ph
4, 6, 8 28

14
, 83%
>95:5 d.r.
O
X
N
22
, 66%
3
O
>95:5 d.r.c
Bpin
Cy
Bpin
Cy
N
Cl
Electrophile
O
Product
X = Br or I
OH
O
I
I
O
15
, 55%
>95:5 d.r.
[X-ray]
Ph
HO
N
4
, 75% (78%,
1.4 g), >95:5 d.r.
23
, 75%
CO2
O
Bpin
Cy
>95:5 d.r.c
N
I
Bpin
Cy
Bpin
Cy
OH
OH
H
O
Ph
O
O
8
16
, 79%
>95:5 d.r.
, 76%
MeOH
24
, 81%
>95:5 d.r.
Bpin
Cy
Bpin
Cy
Bpin
Cy
NHR
OH
9
, R = SO2Ph
70%, 93:7 d.r.a
D
NR
Ph
17
25
, 64%
, 70%
D2O
>95:5 d.r.
>95:5 d.r.
10
, R = POPh2
38%, >95:5 d.r.a
Bpin
Cy
Bpin
Cy
Bpin
Cy
O
OH
O
Ph
11
90:10 d.r.
[X-ray]
, 68%
O
Ph
18
>95:5 d.r.
26
, 73%
, 66%
Cl
81:19 d.r.a
BF4
Ph
Bpin
Cy
Bpin
Cy
Bpin
Cy
O
OH
19
Ar = 4-OMe-Ph, , 64%
20
4-CF3-Ph, , 70%
H Cl
N
Cl3C
O
O
O
O
Ar
12
27
, 54%
73:27 d.r.
, 63%
I
N
>95:5 d.r.b
21
3-pyridyl, , 55%
Cl3C
O
Cl
Ar
Bpin
Cy
Bpin
Cy
Bpin
Cy
all >95:5 d.r.
O
Br
Br
NC
O
O
S
6
, 83%
O
N
MeO
13
, 39%
>95:5 d.r.
28
, 60%
>95:5 d.r.c
Ts
CN
O
Bpin
Cy
Bpin
Cy
85:15 d.r.b
N
MeO
CN
Bpin
Cy
[X-ray]
Br
Figure 3. Electrophile scope of the reaction of bicyclo[1.1.0]butyl boronate complex 3 with electrophiles. All reactions were conducted
using 0.24 mmol of 3 formed as described in Figure 2 via sulfoxide 5. All yields refer to isolated yield of pure material. All d.r.s were
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measured using 1H NMR spectroscopy before purification. aTFE added before addition of the electrophile. b tBuOH added before addition of
the electrophile. cMethanol added before addition of the electrophile.
3
4
5
6
7
8
9
bicyclo[1.1.0]butyl boronate complex of cyclohexylpinacol
boronic ester (3) as the model intermediate (Figure 3). Firstly,
in addition to benzaldehyde (4), the reaction proceeded well
using a range of carbonyl-containing functional groups and
imines, including, acetophenone (8),26 N-benzylidenebenezene-
sulfonamide (9),27 N-benzylidene-diphenylphosphinic amide
(10), benzoyl chloride (11), Troc-Cl (12), methyl cyanoformate
(Mander’s reagent) (13) and -iodo/bromo acetophenone. The
last of which underwent chemoselective 1,2-addition of 3 to the
ketone followed by a 3-exo-tet cyclization to deliver the
corresponding epoxide 14. Carbon dioxide could also be used
as an electrophile, reacting with boronate complex 3 to give
carboxylic acid 15 in good yield and d.r. A range of different
aldehydes could also be used, including primary and tertiary
alkyl (16 and 17, respectively), ,-unsaturated (which
exclusively gave the 1,2-addition product 18), and
(hetero)aromatic aldehydes (1921). In all cases, excellent
yields and diastereomeric ratios were achieved. Next, much like
with DBDMH, the use of 1,3-dichloro-5,5-dimethylhydantoin
(DCDMH) and 1,3-diiodo-5,5-dimethylhydantoin (DIDMH)
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14
15
16
17
18
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22
23
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both
delivered
the
corresponding
halogenated
borylcyclobutanes 22 and 23, respectively, in excellent yields
and with >95:5 d.r. The boronate complex 3 could also be
protonated using methanol, to give the unfunctionalized
borylcyclobutane 24 in excellent yield, and deuterated using
deuterium oxide to give the deuterated
tBuLi
A
Conditions A
Conditions B
Li
OH
TFE, 78 C, 5 min, then
O
S
(1.3 equiv)
Ph
Bpin
R1
benzaldehyde (1.3 equiv)
benzaldehyde
(1.3 equiv)
+
Bpin
R1
or
Bpin
R1
MeTHF, 78 C, 5 min
then r.t., 15 min
then 78 C, 15 min
78 C, 1 h
78 C, 1 h
then r.t., 1 h
then r.t., 1 h
4
29 60

,
5
(1.30 equiv)
OH
Secondary boronic esters:
OH
Tertiary boronic esters:
B
OH
Ph
OH
Ph
OH
Ph
OH
Ph
OH
Ph
Ph
Bpin
Ph
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
R
Ph
Ph
C5H11
t
40
, R = Bu
60%, >95:5 d.r.A
41
N
43
, 68%
Boc
30
, 72%
42
44
, 57%
, 74%
>95:5 d.r.
100% d.s.A
>95:5 d.r.A
>95:5 d.r.A
, R = Ad,
75%, >95:5 d.r.A
4
29
, 75% (78%, 1.4 g)
>95:5 d.r.A
, 69%
>95:5 d.r.A
>95:5 d.r.A
Natural product and drug derivatives:
51
>95:5B
, 52%
OH
OH
OH
*
Ph
OH
46
, 67%, >95:5 d.r.,
100% d.s.B
OH
Ph
H
Ph
Ph
OH
Ph
Ph
(from lithocholic acid)
(from cholesterol)
Bpin
H
Bpin
Bpin
H
Bpin
Bpin
Bpin
H
O
OTBS
TBSO
H
H
O
45
F
, 56%
>95:5 d.r.A
(from gemfibrozil)
F
H
H
5
31
33
, 68%
, 74%
>95:5 d.r.A
32
, 66%
>95:5 d.r.A
1:1.35 d.r.*
100% d.s.A
[X-ray]
Primary boronic esters:
OH
OH
Ph
OH
OH
OH
Ph
OH
Ph
Ph
Ph
OH
Ph
Ph
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Ph
50
Ph
49
Bpin
47
, without TFE: 51%
79:21 d.r.A
with TFE: 68%
>95:5 d.r.B
48
, 47%
, 53%
, 47%
80:20 d.r.B
>95:5 d.r.B
>95:5 d.r.B
34
35
93:7 d.r.A
36
, 70%
>95:5 d.r.A
, 60%
, 60%
>95:5 d.r.B
Aryl/Vinyl boronic esters:
OH
OH
R
OH
Ph
OH
OH
OH
Ph
Ph
B
OH
Ph
52
Ph
, R = H, 57%
Ph
B
Bpin
Bpin
53
Ph
, R = 4-CF3, 29%
Bpin
Bpin
OTBS
Bpin
54, R = 4-Cl, 51%B
Bpin
B
Bpin
55
, R = 2-OMe, 5-Me, 33%
Ph
N
5
B
56
, R = 3-F, 4-OMe, 48%
all >95:5 d.r.
BocN
C
R
58
59
, R = H, 30%
37
, 67%
>95:5 d.r.B
[X-ray]
60
, 15%
38
39
, 68%
>95:5 d.r.A
, 40%
>95:5 d.r.A
C
57
, R = F, 41%
, 51%
>95:5 d.r.B
>95:5 d.r.B
both 95:5 d.r.
Figure 4. (A) General reaction conditions for the (B) boronic ester scope of the reaction of bicyclo[1.1.0]butyl boronate complexes with
benzaldehyde. All reactions were conducted using 0.24 mmol of the boronic ester unless otherwise specified. AConditions A were used.
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BConditions B were used. CProducts isolated as the corresponding alcohols following oxidation of the boronic ester with a mixture of NaOH
and H2O2. All yields refer to isolated yield of pure material. All d.r.s were measured using 1H NMR spectroscopy before purification. d.s. =
diastereospecificity.28
4
5
6
7
8
9
borylcyclobutane 25 in good yield and as a single diastereomer.
Finally, highly reactive electrophiles such as tropylium
tetrafluoroborate (26), Eschenmoser’s salt (27), and tosyl
cyanide (28) were also successful electrophiles but gave lower
diastereoselectivity with or without addition of a hydrogen bond
donor.
hexylpinacol boronic ester and benzaldehyde as the electrophile
(see Supporting Information for further details). These modified
conditions were applied to a number of other primary
substrates, including methyl (48), benzyl (49), and phenethyl
(50) boronic esters, delivering the borylcyclobutane products
with mostly >95:5 d.r. and in modest to good yields. A
derivative of lithocholic acid29 was also successful, giving
borylcyclobutane 51 in 52% yield and >95:5 d.r.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
It is noteworthy that many of the electrophiles that have reacted
successfully here, such as methanol, carbon dioxide and alkyl
aldehydes, have never previously been reacted with boronate
complexes of any type, highlighting the unique reactivity of
bicyclo[1.1.0]butyl boronate complexes.
These modified conditions turned out to be beneficial for aryl
boronic esters too, which otherwise returned borylcyclobutane
products contaminated with minor side products. Using these
conditions, a number of aryl boronic esters featuring a range of
substitution patterns and functional groups were employed,
giving the borylcyclobutane products (5257) with high purity.
Whilst the d.r.s were consistently high, only moderate yields
were obtained due to the instability of the products to flash
column chromatography. Medicinally relevant pyridines were
also successfully employed but the borylcyclobutane products
58 and 59 proved unstable on silica, readily undergoing
protodeboronation. As such, in situ oxidation was performed
and the corresponding alcohols were isolated in moderate yield
with 95:5 d.r. Finally, vinylpinacol boronic ester was also used,
delivering allylic boronic ester 60 in 15% yield with >95:5 d.r.
The scope of the boronic ester was next explored, using
benzaldehyde as a model electrophile (Figure 4). As with the
formation of bicyclo[1.1.0]butyl boronate complex 3 (Figure 2),
each boronic ester tested was mixed with sulfoxide 5 at 78 °C
and then treated with tert-butyl lithium to form the
corresponding
bicyclo[1.1.0]butyl
boronate
complex
intermediate. These boronate complexes were treated with
benzaldehyde without any additional additives (conditions A),
or with TFE followed by benzaldehyde (conditions B) if
conditions
A
resulted in modest yield and/or
diastereoselectivity, or an unclean reaction profile (Figure 4A).
A range of secondary boronic esters was first investigated and
the scope was found to be very broad (Figure 4B). With respect
to cyclic substrates, use of indanyl (29), 4-N-Boc-piperidinyl
(30), 4-tetrahydropyranyl (31), 1,1-difluoro-4-cyclohexyl (32),
Rationale for the Stereochemical Outcome and Reaction
Mechanism
The relative stereochemistry of borylcyclobutane products 6,
11, 15, 31, and an oxidized derivative of 37 were confirmed by
X-ray crystallography. In all cases, regardless of the boronic
ester or electrophile used, a cis relationship between the
migrating
a
derivative of pinene (33), cyclopropyl (34),
tetramethylcyclopropyl (35) and cyclododecyl (36) boronic
esters all delivered the corresponding functionalized
borylcyclobutane products in good to excellent yields and very
high diastereoselectivity. Acyclic boronic esters worked
equally well, with 1,1-phenylpropyl (37), isopropyl (38), and an
-alkoxy (39) boronic ester giving the corresponding products
in good yields and very high diastereoselectivity. Tertiary
boronic esters could also be employed, with tert-butyl (40),
adamantyl (41), 1,1-phenylcyclopropyl (42), substituted
cyclobutane (43)20a and bicyclo[2.2.2]octane (44) all giving the
functionalized borylcyclobutane products in excellent yield and
selectivity. Compound 43 was formed with complete
diastereospecificity. A small number of natural product and
drug-derived boronic esters were also successfully reacted,
including those derived from gemfibrozil (45) and cholesterol
(46), the latter being formed with complete enantio- and
diastereospecificity. In both cases, the cyclobutane products
were obtained with excellent diastereoselectivity.
A
E
electrophile, E+
O
Bpin
O
R1
61
B
E+
R1
concerted
(exo)
1
major cis
diastereomer
B
R1
G
(kcal/mol)
O
O
O
O
B
B
R1
R1
G

1
A
B
Me
iPr 0.6
1.3
E+
(exo)
E+
(exo)
HOMO A
HOMO B
(R1 = Me)
(R1 = Me)
R1
O
O
concerted
61
trans
diastereomer
61
cis
O
B
B
E
E+
O
The reaction of boronate complexes derived from primary
boronic esters were more challenging as they initially reacted
with benzaldehyde to give the corresponding borylcyclobutane
with low d.r. For example, when the boronate complex derived
from n-hexylpinacol boronic ester was allowed to react with
benzaldehyde, borylcyclobutane 47 was formed with 79:21 d.r.
In order to address this issue, we explored the use of additives,
particularly hydrogen bonding donors/acceptors, because these
had previously been successful in improving the d.r. with
several electrophiles (vide supra). From a range of additives, we
discovered that by adding 2,2,2-trifluoroethanol (TFE) (10% by
volume) after formation of the boronate complex, the
diastereoselectivity was increased to >95:5 d.r. when using n-
R1
diastereomer
62
C
Br
Br
Br
Br
O
Bpin
Cy
Bpin
Cy
Bpin
Cy
THF
O
3
Br
Br
Br
Br
O
O
Bpin
Bpin
Cy
63
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Figure 5. (A) Concerted reaction pathway leading to the major cis
combination of these two reaction pathways results in low
diastereomer of 61. (B) Calculated conformations and HOMO
energies of bicyclo[1.1.0]butyl boronate complexes and how these
factors influence the stereocontrol in reactions with electrophiles.
(C) Proposed mechanism for the formation of side-product 63 by
the reaction of 3 with DBDMH and THF.
diastereoselectivity. Supporting evidence for this stepwise
pathway comes from the observation of a THF-incorporation
product 63 when bicyclo[1.1.0]boronate complex 3 was
allowed to react with DBDMH in THF (Figure 5C). We propose
that a carbocation intermediate, formed after reaction of 3 with
DBDMH, is trapped by THF to give an adduct which is
subsequently ring-opened by an adventitious bromide anion to
give the side-product 63. This observation suggests that
group and the electrophile was observed.
Our model for the origin of stereocontrol is shown in Figure 5.
For bicyclo[1.1.0]butyl boronate complex 1, the migrating
group, R1, and the central CC -bond have to align anti-
periplanar for 1,2-migration to occur. This orientation provides
orbital overlap between the HOMO BR1) and the LUMO
*(CC) of the bicyclo[1.1.0]butyl unit.3032 In this
conformation, the reaction of the electrophile with 1 occurs on
the exo face of the -carbon. The HOMO CC) of the
bicyclo[1.1.0]butyl unit, which has significant electron density
protruding from the exo face, can interact with an
electrophile32,33 to induce 1,2-migration of R1 to the -carbon,
cleavage of the central CC bond of the bicyclo[1.1.0]butyl
unit, and formation of the CE bond at the -carbon. This
concerted process leads to the borylcyclobutane product 61 with
a cis relationship between R1 and E, as is observed in the
products obtained from this reaction (Figure 5A). To test this
mechanistic proposal and understand why lower
diastereoselectivity was observed for some boronic esters and
electrophiles, we conducted DFT calculations to probe the
9
carbocationic intermediate 62 is
a plausible reaction
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
intermediate with this R1/electrophile combination. By contrast,
when larger R1 substituents were used, such as isopropyl which
gave 38 with >95:5 d.r., the more populated conformer B is also
the more reactive conformer, resulting in the concerted pathway
dominating to give cis-61 with high diastereoselectivity. When
more reactive electrophiles are used, such as tropylium
tetrafluoroborate which resulted in 26 with 81:19 d.r., both
conformers A and B can react rapidly with the electrophile via
stepwise and concerted pathways, respectively, resulting in
lower diastereoselectivity which reflects the relative
populations of conformers A and B. Less reactive electrophiles,
such as palladium(II)-aryl complexes which give high
diastereoselectivity with all R1 groups,20a always react through
the concerted pathway via the more reactive conformer B,
leading to high diastereoselectivity for all sizes of R1 groups.
It is also possible to rationalize the formation of the minor trans
product by either the syn-periplanar 1,2-migration of the R1
group upon the reaction of the electrophile at the exo face of the
-carbon of the bicyclo[1.1.0]butyl unit, or by the approach and
reaction of the electrophile from the endo face of the -carbon
with anti-periplanar 1,2-migration of the R1 group. However,
we consider both of these alternatives to be less plausible than
the proposed stepwise pathway because the former does not
have the required alignment of molecular orbitals for 1,2-
migration and our calculations show that such a conformation
of 1 is an energetic maxima (see Supporting Information), and
the latter does not have sufficient interaction between the
HOMO of the bicyclo[1.1.0]butane and the electrophile for
efficient reaction.3033
conformational
preferences
and
reactivity
of
bicyclo[1.1.0]butyl boronate complexes bearing different R1
substituents (Figure 5B). Using Gaussian with the M06-2X
functional and 6-311G(d,p) as the basis set, it was found that 1
bearing a small methyl R1 substituent strongly favors a
conformation with an approximate 60° dihedral angle between
the BR and the central CC bond of the bicyclo[1.1.0]butyl
unit (conformer A), and with the larger pinacol group
occupying open space. The other conformer (conformer B) has
R1 aligned anti-periplanar to the central CC -bond of the
bicyclo[1.1.0]butyl unit, which is the orientation required for
the concerted reaction pathway. Based on the relative energy
difference, at the reaction temperature of 78 °C, a 59:1 ratio of
conformers A:B was calculated. By contrast, a larger isopropyl
R1 substituent on 1 showed a 1:2.4 ratio of conformers in favor
of conformer B; the larger R1 substituent now preferentially
occupies open space. These calculations also showed that
conformer B has a higher energy HOMO than conformer A (1.3
and 2.0 kcal/mol higher for methyl and isopropyl, respectively),
making conformer B more reactive than conformer A for both
R1 substituents.
Derivation of the Borylcyclobutane Products
Molecules featuring boronic esters are highly versatile synthetic
building blocks because they can be converted into a broad
OR
OR
boronic ester
Ph
Ph
transformation
Bpin
Cy
FG
Cy
a R = H
4
, R = H
b
R = CH3
64
, R = CH3
Based on these computational results, we can now rationalize
the diastereoselectivity experimentally observed. To account
for the lower diastereoselectivity observed experimentally
when smaller migrating R1 substituents or more reactive
electrophiles were used, we propose that a stepwise reaction
pathway that proceeds via an intermediate carbocation is also
operative. When small R1 substituents were used, such as
methyl which gave 48 with an 80:20 d.r., a concerted reaction
pathway via the more reactive, but sparsely populated,
conformer B dominates to give cis-61 (Figure 5A). Reaction via
the more highly populated but less reactive conformer A at the
exo face of the -carbon leads to the carbocationic intermediate
62 which undergoes 1,2-migration of R1 giving trans-61. The
>98:2 d.r., 100% d.s.
OH
OR
OR
OMe
Ph
Ph
Ph
Ph
OH
Cy
NHBoc
Cy
BF3K
Cy
Cy
b
b
c
66a
66b
67a
, 82%
, 52%
a
d
65
68
, 95%
, 90%
c
67b
, 79%
, 82%
OR
OR
OH
Ph
Ph
O
F
Ph
Ph
Bpin
Cy
N
Cy
Ph
Cy
72
71
, 87%
, 49%
e
f
69a
69b
70a
70b
, 74%
, 46%
>95:5 d.r.h
>95:5 d.r.g
e
f
, 77%
, 78%
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Figure 6. Derivation of the borylcyclobutane products.
Abbreviated reaction conditions: aH2O2/NaOH; bH2NOMe, KOtBu,
unique cyclobutanes are now readily accessible. For this reason,
2
and because cyclobutanes are of increasing value in medicinal
chemistry, we believe that this method will find application in
the preparation of cyclobutane-containing building blocks for
use in medicinal chemistry discovery programs.
c
d
e
3
4
5
6
then Boc2O; vinyl lithium, then I2, then NaOMe; KHF2; ArLi,
then NBS; ArLi, then 2,2,2-trichloroethyl chloroformate, then
H2O2/NaOH; Et3SiH, TFA; TBAF. All yields refer to isolated
yield of pure material.
f
g
h
ASSOCIATED CONTENT
Supporting Information.
7
8
9
range of other valuable functional groups.16 Because the
products feature a unique 1,1,3-trisubstituted borylcyclobutane
emblem, we wanted to demonstrate that they too can be
functionalized using these methods (Figure 6). Using 4, or its
O-methyl protected analog 64, the tertiary boronic ester was
transformed into the corresponding alcohol 65, amine 66,34
alkene 67,35 and the trifluoroborate salt 68.36 Furthermore, the
boronic ester was arylated to give both the furan 6937 and
pyridine 7048 using transition metal-free cross-coupling
chemistry. In all cases, good to excellent yields of the
functionalized products were obtained with complete
diastereospecificity (d.s.).28 The alcohol functional group of 4
could also be removed using a mixture of trifluoroacetic acid
and triethylsilane, to give alkane 71 in 49% yield. Since
cyclobutanes can be bioisosteres of aromatic rings, this
arylcyclobutylmethane structure could potentially be
considered a bioisostere of the highly pharmaceutically
prevalent diarylmethane moiety. Finally, the treatment of
boronic ester 52 with TBAF effected protodeboronation39 to
give 72 in 87% yield.
Detailed experimental procedures, and characterization
data for all compounds (PDF).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Crystallographic information for compound 5 (cif)
Crystallographic information for compound 6 (cif)
Crystallographic information for compound 11 (cif)
Crystallographic information for compound 25 (cif)
Crystallographic information for compound 31 (cif)
Crystallographic information for compound 37-[O] (cif)
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*v.aggarwal@bristol.ac.uk
ORCID
Steven H. Bennett: 0000-0001-8076-485X
Alexander Fawcett: 0000-0003-1880-3269
Elliott H. Denton: 0000-0003-0816-3851
Tobias Biberger: 0000-0003-1473-3101
Valerio Fasano: 0000-0003-1819-4483
Varinder K. Aggarwal: 0000-0003-0344-6430
Summary and Conclusions
In summary, we have described the development of
bicyclo[1.1.0]butyl boronate complexes and explored how they
react with a range of electrophiles. It was found that
bicyclo[1.1.0]butyl boronate complexes can be quantitatively
formed in situ by reaction of pinacol boronic esters with
bicyclo[1.1.0]butyl lithium. These complexes were
demonstrated to react with over twenty different electrophiles
to give the corresponding functionalized borylcyclobutanes in
good to excellent yield and with high diastereoselectivity. The
boronic ester scope was also shown to be broad, encompassing
a range of primary, secondary, tertiary, vinyl, aryl and
heteroaryl boronic esters, including a number derived from
natural products and drug molecules. The retention of the
boronic ester functional group in the cyclobutane products
significantly increases their value because the boronic ester can
be transformed into many other functional groups.
Author Contributions
‡These authors contributed equally; listed alphabetically.
Funding Sources
This work was supported by the EPSRC (EP/I038071/1) and
H2020 ERC (670668). T.B. thanks the Bayer Science and
Education Foundation for awarding an Otto–Bayer Fellowship,
V.F. thanks the University of Bristol for awarding the EPSRC
Doctoral Prize Fellowship (EP/R513179/1), and N.W. thanks the
Alexander von Humboldt Stiftung for awarding the Feodor Lynen-
Forschungsstipendium.
This process proceeds through a unique CC -bond
carbofunctionalization mechanism, where a migrating carbon-
based boronic ester substituent and an electrophile are added
across a CC -bond. The high diastereoselectivity observed
has been rationalized by separate concerted and stepwise
reaction mechanisms operating, depending upon the migrating
substituent and electrophile used. Larger migrating substituents
and less reactive electrophiles react via a concerted mechanism
to give the cis product with high diastereoselectivity, whereas
smaller migrating substituents and more reactive electrophiles
react via both concerted and stepwise pathways which leads to
lower diastereoselectivity.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors thank Drs E. L. Myers (NUI Galway), A. Noble and
M. Silvi for helpful discussions, Dr. H. A. Sparkes for X-ray
analysis, and Dr. Julien Lefranc (Bayer AG, Berlin) for organizing
DSC studies conducted on sulfoxide 5.
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Bond Activations via Oxidative Addition to Transition
Metals, Chem. Rev. 2015, 115, 94109464. (c)
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diastereomerically-enriched 1,1,3-trisubstituted cyclobutane
products with three synthetic branchpoints, the boronic ester
substituent, the electrophile, and the boronic ester itself. When
only considering the building blocks used in this report, >5000
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H
H
Bpin
electrophile
Bpin
Li
Bpin
Li
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boronic ester
transformation
H
 modular construction
 1, 2 and 3 boronic esters
 diastereoselective and enantiospecific
 >20 different electrophiles
 >60 unique cyclobutane products
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