Hydrogen Atom Transfer Induced Boron Retaining Coupling of Organoboronic Esters and Organolithium Reagents

Article abstract of DOI:10.1021/jacs.9b07960

α-Functionalization of alkyl boronic esters and homologation of aryl boronic esters by regioselective radical C(sp³)-H activation in boron-ate complexes is reported. Reaction of commercial or readily accessed aryl boronic acid pinacol esters with alkyl lithium reagents provides boron-ate complexes. Selective α-C-H abstraction by in situ generated trifluoromethyl radicals leads to radical anions that undergo electron transfer oxidation followed by 1,2-aryl/alkyl migration from boron to carbon to give the α-arylated/alkylated alkyl boronic esters. The valuable boronic ester functionality remains in the products and the cheap trifluoromethyl iodide acts as the oxidant in these C-C couplings. The 1,2-alkyl migration from boron to carbon is highly stereospecific allowing access to stereoisomerically pure boronic esters.

Full text of DOI:10.1021/jacs.9b07960

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Communication
Hydrogen Atom Transfer Induced Boron Retaining Coupling
of Organoboronic Esters and Organolithium Reagents
Dinghai Wang, Christian Mück-Lichtenfeld, and Armido Studer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07960 • Publication Date (Web): 27 Aug 2019
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Hydrogen Atom Transfer Induced Boron Retaining Coupling of
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Dinghai Wang, Christian Mück-Lichtenfeld, Armido Studer*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität, Corrensstraße 40, 48149 Münster, Germany
Supporting Information Placeholder
Scheme 1. Chemical modification of alkyl boronic esters at the
α-C-atom with organometallic compounds and homologation
of aryl boronic esters
ABSTRACT: -Functionalization of alkyl boronic esters and
homologation of aryl boronic esters by regioselective radical
C(sp3)H activation in boron-ate complexes is reported. Reaction
a) Matteson-type rearrangement
of commercial or readily accessed aryl boronic acid pinacol esters
OR'
OR'
OR'
R''
Lewis acid-induced
rearrangement
with alkyl lithium reagents provides boron ate complexes. Selective
-CH abstraction by in situ generated trifluoromethyl radicals
leads to radical anions that undergo electron transfer oxidation
followed by 1,2-aryl/alkyl migration from boron to carbon to give
the -arylated/alkylated alkyl boronic esters. The valuable boronic
ester functionality remains in the products and the cheap
trifluoromethyl iodide acts as the oxidant in these CC couplings.
The 1,2-alkyl migration from boron to carbon is highly
stereospecific allowing access to stereoisomerically pure boronic
esters.
R
B
R
B
R
B
+
R'' Metal
OR'
OR'
OR'
Matteson-type
reaction
R''
X
X
-halogenated alkyl
boronic ester
transition-metal-free
CC bond formation
(R'' = alkyl and aryl)
b) Nickel-catalyzed cross coupling of -haloalkyl boronic esters
OR'
OR'
OR'
B
R
B
cross coupling
Ni-catalyis
OR'
R
B
R
+
R'' Metal
OR'
OR'
Ni
R''
X
R''
-halogenated alkyl
boronic ester
transition-metal-catalysis
(R'' = alkyl)
Alkyl boronic esters are valuable reagents in synthesis. They are
readily accessed either from commercial sources or by using
established chemistry. Such boron compounds engage in various
coupling reactions.1 However, the valuable boron moiety is mostly
not retained in the product and chemical modification of alkyl
boronic esters keeping the boron entity is not well investigated. An
established and well investigated route for functionalization of
alkyl boronic esters uses pre-functionalized -halo derivatives as
substrates (Scheme 1a). In these Matteson-type rearrangements, the
boronic ester is first converted to its boron-ate complex upon
reaction with an alkyl or aryl-metal compound. The ate-complex is
then activated by a Lewis acid to induce a 1,2-alkyl/aryl migration
with concomitant substitution of the halide anion (X) to give an -
alkylated/arylated boronic ester.2 Alternatively, boron-ate
complexes bearing an -anionic leaving group can be generated by
-lithiation of alkyl carbamates and subsequent reaction with
boronic esters, as developed by Aggarwal for the preparation of
optically active alkyl boronic esters.3
c) H-transfer induced coupling of alkylboronic ester and organo metal reagents (this work)
OR'
OR'
radical-induced
rearrangement
OR'
R''
B
R
B
R
B
+
R
R'' Metal
OR'
OR'
OR'
H-atom abstraction
R''
H
non functionalized
alkyl boronic ester
transition-metal-free
CC bond formation
(R'' = alkyl and aryl)
d) Reaction design
OR'
OR'
OR'
OR'
R''
R''
R''
XY
X
R
B
R
B
R
B
X
+
R
B
OR'
OR'
OR'
- MY
OR'
H
R''
II
+
HX
I
III
(R'' = alkyl and aryl)
Challenges:
H
H
OR'
B
H
R'O
Aryl
XY
B
R''
OR'
R
OR'
R
H
H
direct oxidation of the boron-ate
complex by XY has to be
supressed
X
X
-Halo boronic esters have been used by Fu as substrates in Ni-
catalyzed cross couplings to provide -alkylated boronic esters
(Scheme 1b). These formal halide substitution reactions proceed
via dialkyl-Ni-complexes as intermediates.4 Both strategies
highlighted employ pre-functionalized alkyl boronic esters and
correspond to formal substitution reactions. Considering step
economy, the direct CH functionalization5 of alkyl boronic esters
would be even more attractive. Herein we disclose our results on
radical -CH functionalization of various alkyl boronic esters for
the preparation of -arylated and -alkylated boronic esters
(Scheme 1c).
differentiation of two alkyl groups
to induce alkyl migration
C(sp3)C(sp3) bond formation
regioselective CH activation
to induce aryl migration
C(sp2)C(sp3) bond formation
identification of an appropriate
radical chain carrier XY
e) Homologation of aryl boronic esters
OR'
OR'
B
radical-induced
homologation
OR'
R''
R
Aryl
R''
B
+
R''
B
Metal
OR'
OR'
OR'
H-atom abstraction
H
R
aryl boronic ester
transition-metal-free
C(sp2)C(sp3) bond formation
The suggested sequence commences with formation of a boron-
ate complex of type I by reacting an alkyl boronic ester with an aryl
or alkyl organometallic species (Scheme 1d).6,7,8,9,10 A reactive
radical X should then undergo regioselective H-abstraction at the
α-position to give the radical anion II. Such radical anions are
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known to be efficient single electron transfer (SET) reductants6d, 7a,
1
2
3
4
5
6
7
8
8f, 10 which deliver in the reaction with a terminal oxidant X-Y the
zwitter ion III along with the chain carrying radical X. III will
further react in a 1,2-alkyl/aryl migration to provide the targeted α-
functionalized boronic ester. However, there are several challenges
associated with that reaction design: a) the terminal oxidant X-Y
should be a mild SET-oxidant that does not directly react with the
starting boron-ate complex I (Ep/2 = 0.31 V vs SCE in CH3CN)11;
b) X-Y must be readily SET reduced by a radical anion II; c) radical
X derived from XY should be an efficient and selective H-
abstractor. In case of the aryl migration process leading to C(sp2)-
C(sp3) bond formation, regioselectivity of the H-abstraction step
must be controlled, since only -H-abstraction will lead to a
reducing radical anion. For the alkyl migration culminating in
C(sp3)-C(sp3) bond formation, along with the intra chain selectivity
control, the two alkyl substituents at the boron-ate complex have to
be differentiated by radical X.
Regarding the C(sp2)-C(sp3) bond formation, such a sequence
can also be achieved upon starting with an aryl boronic ester in
combination with an alkyl lithium species, since the same boron
ate-complex is generated as an intermediate (Scheme 1e). This
important fact allows the scientist to choose the starting
materials/reagents depending on their availability and costs. By
selecting aryl boronic esters as starting compounds, the sequence
corresponds to an unprecedented homologation12 using an alkyl
lithium reagent. Considering the prerequisites of our design, we
chose trifluoromethyl iodide as oxidant, since it is a weak oxidant
(Ep = -1.52 V vs SCE in DMF)13 that is SET reduced by various
radical anions. Moreover, the CF3-radical is reactive14 and should
allow for exothermic H atom abstractions from boron-ate
complexes.
Scheme 2. Substrate scope for C(sp2)-C(sp3) coupling a
Ir(ppy)3 (1 mol%)
CF3I (1.5 equiv)
O
Li
O
O
O
Et2O or THF
0 °C then rt
O
O
B
B
Li
+
Ar
B
Ar
1
R'
H
CH3CN/DMSO (10:1)
blue LED, 1 h
R
R'
R'
Ar
H
R
R
2
3
a) Alkyl-Aryl coupling
Bpin
9
Bpin
Bpin
Bpin
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
CF3
CF3
CF3
CF3
CF3
66% (8%)
55%b (11%)
F3C
63% (18%)
61%b (17%)
CF3
CF3
3c
3b
3d
3a
34% (39%)
67% (18%)
Bpin
Bpin
3f
52%, R = SiMe3
61%, R = t-Bu
33% (33%), R = Me
60%, R = H
Bpin
CF3
3g
3h
3i
Cl
F
Ph
3j
59%, R = Cl
3k
3l
3m
R
55% (24%), R = OTf
66%, R = OCF3
66%, R = CF3
CF3
29%c (35%)
Bpin
3n
3f 3m
57%
-
3e
Bpin CF3
Bpin
F
3o
48%, R = OMe
46%, R = F
53%, R = Cl
64%, R = CF3
R
3p
3q
3r
3s
59% (24%), R = OTf
54%d (12%)
50%b,d (8%)
Bpin
3t
38% (23%)
Bpin
3o 3s
-
3u
Bpin
Bpin
Cl
O
Cl
48%
51%b (16%)
O
We first studied radical-induced migration in boron-ate
complexes bearing an alkyl and an aryl substituent (Scheme 1e) and
commenced with aryl boronic esters 1 (arylBpin) in combination
with alkyl lithium reagents targeting the homologated boronic
esters 3. Reaction optimization was conducted with 3,5-
bistrifluoromethylphenylboronic acid pinacol ester and sec-butyl
lithium (Supporting Information). The boron-ate complex 2 was
generated by addition of sec-butyl lithium in diethylether at 0 °C.
The solvent was removed and crude 2 was redissolved in
acetonitrile. CF3I (1.5 equiv) was added as a solution in
dimethylsulfoxide. Different radical initiators were screened and
we found that the cascade works best with tris[2-phenylpyridinato-
C2,N]iridium(III) (Ir(ppy)3, 1mol%) as a smart15 photoinitiator.
Blue light irradiation for 1 hour at room temperature provided 3a
in 67% yield (Scheme 2a). As a side product, aryl boronic ester 1a
was identified (18%), likely resulting from competing 2-butyl
radical fragmentation of the SET-oxidized boron-ate complex 2a.
Initiation can also be achieved with Eosin Y, Rose Bengal and
Rhodamine B base or with Ru(bpy)3Cl2 (Supporting Information)
and for selected cases, we showed that initiation also works without
any photocatalyst by simple LED irradiation (365 nm). As expected
for a radical process, the cascade was fully inhibited in the presence
of TEMPO (2 equivalents). Reaction proceeds also well on
isopropyl boron-ate complexes (3b) but cyclic (3c,v-x), sterically
more demanding secondary-alkyl (3e) and linear alkyl systems (3d)
showed lower yields. Problems are direct SET-oxidation of the
boron-ate complex 2 leading to alkyl radical fragmentation to give
starting ester 1 that was identified as a side product (yields in
bracket). More challenging CH activation due to stronger and
sterically more shielded CH bonds also leads to a lowering of the
yield. Trifluoromethylation at sterically accessible aryl rings was
also observed (see SI for 3h, 3x) which suggested the generation of
a CF3 radical in the reaction.
40%c (16%)
46%b,c (10%)
3y
42%
c
3x
3w
43%
3v
b) Alkyl-Aryl coupling of natural product derived aryl components
Bpin
Bpin
Me
H
H
O
O
O
H
41%, from estrone
3aa
3z
61%, from -tocopherol
a Conducted at 0.2 mmol scale. Arylboronic ester identified as side
b
product (GC-yield in bracket). Conducted under 365 nm LED
irradiation without photocatalyst. c The boron ate complexes were
formed from the corresponding alkylboronic esters and aryl lithium
reagents. d Isolated as alcohol after H2O2/NaOH oxidative work-up.
Keeping sec-butyl lithium we showed that differently substituted
(ortho, meta and para) aryl boronic esters engage in the
homologation and the esters 3f-3u were isolated in 33-66% yields.
Various functionalities such as trimethylsilyl, chloro, fluoro,
trifluoromethylsulfonyl, trifluoromethyl, trifluoromethoxy and
acetal are tolerated. The method is also applicable to the
homologation of more complex natural product derived aryl
boronic esters, as documented by the synthesis of the estrone
derived 3y and the -tocopherol derivative 3z (Scheme 2b). The
tocopherol system bears three additional activated methine CH
bonds and a benzylic methylene moiety that all did not react,
showing that H-abstraction with the CF3-radical occurs with
excellent regioselectivity. Along these lines, the estrone derivative
carries a benzylic methine H-atom that is not interfering.
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non-strained and sterically least hindered iso-propyl group in most
1
2
3
4
5
6
7
8
cases gets selectively activated (6m,n,o). To our surprise, the
isopropyl substituent outcompeted an -methoxy-alkyl group and
an -ethylthiyl-alkyl group, although the methoxy and ethylthiyl
groups are known to stabilize C-radicals (6p, 72%; 6q, 63%).
However, for the 5-membered ring analogue, H-abstraction by the
CF3-radical occurred preferably next to the N-atom (6r, 76%, rr =
4:1; 6s, 58%, rr = 32:1). For the sterically hindered primary
alkylboronic ester 4v, H-abstraction selectivity at the isopropyl
group was exclusive (6v, rr > 99:1). These results indicate, that
along with CH bond strength, conformational effects and steric
shielding play an important role. -Functionalization also works
with tert-alkyl groups as migrating substituents (6t,u).
Scheme 3. Substrate scope for C(sp3)-C(sp3) coupling a
Li
O
O
H
Ir(ppy)3 (1 mol%)
CF3I (1.5 equiv)
O
O
H
R'''
O
O
O
R''
O
R
B
H
B
Li
R'''
B
B
H
CH3CN/DMSO (10:1)
blue LED, 1 h
Et2O or THF
0 °C then rt
R'
R'''
R''
R'
R'
R'
R''
R
R
R
R'''
R''
4
5
6
a) Alkyl-Alkyl coupling
Bpin
9
Bpin
Bpin
Bpin
Bpin
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
Studies were continued by investigating stereospecific reactions
(Scheme 3b). With readily accessed17 enantioenriched tertiary alkyl
boronic esters, isopropyl insertion was achieved in good yields and
excellent stereospecificity (es = 97%) under retention of absolute
configuration (6w). tert-Butyloxycarbonyl (Boc)-protected
piperidine was stereoselectively -borylated using established
methodology.18 The corresponding isopropyl lithium derived ate-
complex reacts with the CF3-radical with high chemoselectivity (rr
= 10:1) at the isopropyl group. Subsequent stereospecific migration
affords 6x in excellent stereoselectivity (44%, es > 99%).
Enantiopure boronic esters can also be prepared from chiral alkenes
via diastereoselective hydroboration or borylation of a chiral alkyl
halide. Boron-ate complex formation with isopropyl lithium
followed by radical-mediated -CH-activation leads to the
homologation products conserving the initial stereochemistry, as
documented for natural product derived terpenes and steroids (48-
70%, 6y-6ab). For 6y-6ab, regioselectivity was complete.
6a
49%
6b
72% (13%)
6d
6e
70% (20%)
6c
29%
56% (31%), dr = 1:1
44%b, (36%)
77%b (15%)
35%b (16%)
65%b (19%)
55%b (34%), dr = 1:1
Bpin
Bpin
Bpin
Bpin
Bpin
6h
6j
6g
66%, rr = 9:1
6i 74%, rr = 12:1
62%, rr = 2.2:1
49%, rr = 1.3:1
6f
38% (35%)
Bpin
65%b, rr = 7:1
BPin
Bpin
Bpin
BPin
6n
6o
6l
6m
70%, rr = 31:1
64%b, rr = 31:1
56%, rr = 25:1
48%, rr = 13:1
65%, rr = 29:1
6k
53%, rr = 11:1
49%b, rr = 10:1
53%b, rr = 24:1
Boc
N
Boc
Bpin
Bpin
BPin
N
Bpin
Bpin
SEt
OMe
6t
50%
Ph
6p
6q 63%
6r
6s 58%, rr = 32:1
Bpin
72%
76%, rr = 4:1
To better understand the regioselectivities for the -CH
abstraction, DFT calculations were conducted for two
representative compounds. Energies were obtained with the
PWPB95-D3 double hybrid functional19, and take solvent effects
implicitly into account with the CPCM model20 (Figure 1). The
thermodynamic driving force of H-abstraction from the benzylic
position of ethyl benzene is larger by 5.9 kcal/mol than for the
boron-ate complex. However, the free energy barrier of H-transfer
from the anionic complex is lower by 4 kcal/mol (13.2 kcal/mol)
which corresponds to a selectivity of around 103:1 over ethyl
benzene. Due to the electrophilicity of the CF3-radical, polar effects
operate. This confirms the both extremely facile and regioselective
reaction of the CF3-radical next to the B-atom. We have already
shown7a that electron transfer from the radical anion II (see Scheme
1d) to CF3I is highly exothermic. In the complex, the σ*-orbital of
CF3I overlaps with the SOMO of the radical anion II and hence a
nearly barrier less SET is expected generating the zwitter ion III
which rearranges without barrier to the product IV.7a
Bpin
BPin
Me
O
H
n-Bu
6u
32%
from gemfibrozil
6v
50%, rr > 99:1
6w 30%, 97% ee
es = 97%
from dehydroabietic acid
b) Stereospecific coupling
H
H
Bpin
H
Bpin
Bpin Boc
H
H
H
N
R
H
H
H
BPin
6aa
6ab
, R = OMe, 69%, dr > 99:1
, R = Cl, 48%, dr > 99:1
from cholesterol
6y
6z
49%, dr > 99:1
from menthol
6x
70%, dr = 93:7
s.m. dr = 92:8
from pinene
44%
rr = 10:1, 73% ee
es > 99%
a
Conducted at 0.2 mmol scale. Alkylboronic ester identified as a
side product (GC-yield in bracket). b Conducted under 365 nm LED
irradiation without photocatalyst.
We further addressed the regioselectivity of the H-abstraction for
the cyclopentyl isopropyl complex 5j and the cyclohexyl isopropyl
homologue 5m where a surprising reversal of the regioselectivity
was experimentally observed. In agreement with the experiment,
calculations revealed the H-abstraction in 5m at the isopropyl
group to be favored by 3 kcal/mol. For the ate complex 5j, where
the experiment showed a slight preference for H-abstraction at the
cyclopentyl group, calculations revealed similar activation barriers
for the two competing processes with a barrier leading to the
preferred product which is 0.3 kcal/mol lower (see SI). Of note,
intermolecular H-transfer reactions to C-radicals are rarely used in
organic chemistry, since such HAT-processes are generally too
slow. Due to its high reactivity as H-abstracting species, the CF3-
radical is unique in that sense.21
We next investigated the more challenging -CH alkylation of
alkyl boronic esters 4 (Scheme 3) first focusing on symmetrical
dialkyl boron ate complexes 5, where the two alkyl substituents do
not need to be differentiated. Pleasingly, -butylation of butyl
boronic ester with butyl lithium worked and 6a was isolated in 49%
yield. Moderate to good yields were noted for cyclic and non-cyclic
-branched alkyl boronic esters (6b-6f, 35-77% yield). For
unsymmetrical dialkyl boron-ate complexes 5, in selected cases,
excellent site selectivity was achieved. For the cyclopentyl-butyl
ate-complex, H-abstraction occurred with a 9:1 selectivity at the
cyclopentyl moiety (66%, 6h). The selectivity is understood
considering that the secondary-alkyl CH bond is weaker than the
methylene CH bond, as also observed for 6i (74%, rr = 12:1).
Cyclopropane has stronger CH bonds than other alkanes.16 This
reactivity trend is well reflected by the regioselectivities obtained,
where the three-membered ring does preferably act as the migrating
moiety (6k,l). Considering secondary-alkyl CH activation, the
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Figure 1. DFT studies. Transition states, activation barriers and
free energies of hydrogen atom transfer of phenyl isopropyl boron-
ate complex (left) and ethyl benzene (right) with the CF3-radical.
Finally, we studied the initiation step of the cascade and found
the trifluoromethyl iodide to be efficiently reduced by the
photoexcited Ir-complex, as analyzed by Stern-Volmer quenching
(Supporting Information). As an alternative initiation step, the
boron ate complex can be oxidized by the photoexcited Ir-complex,
albeit less efficiently. The quantum yield of the process22 was
determined to be 8.8, showing that the Ir-complex mainly acts to
initiate the radical chain (see Scheme 1d) and is best described as a
smart initiator.15 This is in line with the observation that various
organic and inorganic redox systems initiate the chain with similar
efficiency and that initiation also proceeds in the absence of any
photocatalyst. For reactions run without any smart redox initiator,
initiation likely proceeds by direct reduction of the CF3I/DMSO
complex with the boron-ate complex upon irradiation.
We are confident that the herein introduced radical CC
couplings will significantly enlarge the portfolio of boron
chemistry. The starting materials are easily accessed and special
equipment is not required to run these valuable sequences.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: xxx.
Experimental details and characterization data (PDF)
NMR spectrum of new compounds (PDF)
DFT calculations (PDF)
AUTHOR INFORMATION
Corresponding Author
studer@uni-muenster.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the Alexander von Humboldt foundation
(postdoctoral fellowship to D.W.) and the European Research
Council ERC (advanced grant agreement No. 692640) for
supporting this work.
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Am. Chem. Soc. 2017, 139, 6038-6041; (b) Panda, S.; Ready, J. M., Tandem
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OR'
B
OR'
B
R'' Metal
R
R
H-atom abstraction
radical-induced
rearrangement
OR'
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Boron retaining
TM free C-C coupling
Regioselective
Stereospecific
Broad substrate scope
OR'
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non functionalized
alkyl boronic ester
R
B
OR'
via
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TOC-grafic
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