Organocatalytic reductive coupling of aldehydes with 1,1-diarylethylenes using an: In situ generated pyridine-boryl radical

Article abstract of DOI:10.1039/c7sc05225a

A pyridine-boryl radical promoted reductive coupling reaction of aldehydes with 1,1-diarylethylenes has been established via a combination of computational and experimental studies. Density functional theory calculations and control experiments suggest that the ketyl radical from the addition of the pyridine-boryl radical to aldehydes is the key intermediate for this C-C bond formation reaction. This metal-free reductive coupling reaction features a broad substrate scope and good functional compatibility.

Full text of DOI:10.1039/c7sc05225a

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Organocatalytic Reductive Coupling of Aldehydes with 1,1-
Diarylethylenes Using the in situ Generated Pyridine-Boryl Radical
Jia Cao+ac, Guoqiang Wang+a, Liuzhou Gaoa, Xu Chengb, and Shuhua Li*a
Received 00th January 20xx,
Accepted 00th January 20xx
A pyridine-boryl radical promoted reductive coupling reaction of aldehydes with 1,1-diarylethylenes has
been established via a combination of computational and experimental studies. Density functional theory
calculations and control experiments suggest that the ketyl radical from the addition of the pyridine-boryl
radical to aldehyde is the key intermediate for this C-C bond formation reaction. This metal-free reductive
coupling reaction features a broad substrate scope and good functional compatibility.
DOI: 10.1039/x0xx00000x
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radical can act as a persistent radical13 for the synthesis of
organoboronate derivatives.14 Because the precursors
(pyridines and B2pin2) of these pyridine-boryl radicals are
inexpensive and stable,15 the development of new chemical
transformations with these pyridine-boryl radicals is attractive.
In this work, we further explored pyridine-boryl radical
chemistry in the organocatalytic reductive coupling of
aldehydes with 1,1-diarylalkenes (Scheme 1, bottom), which,
to the best of our knowledge, has not been reported
previously.
Introduction
Carbon-carbon bond formation is the most important
transformation in organic synthesis.1 The catalytic reductive
coupling of olefins with carbonyl compounds is one of the
most economical C-C bond constructing method, due to the
abundant source of olefins and carbonyl compounds.2
Traditionally, transition metal catalysts have played privileged
roles in these transformations, including the metal-catalyzed
C=O reductive coupling (Scheme 1, top),3-5 and redox-triggered
C=O coupling via H2 transfer (Scheme 1, middle).4 However,
sensitive organometallic reagents or transition-metal catalysts
are usually required in these reactions. In contrast,
organocatalytic reductive coupling of olefins with carbonyl
derivatives for C-C bond formation in the presence of sensitive
functional groups or congested structural environments is still
rare.5d
Boron containing radicals are important reactive
intermediates in organic synthesis.6-13 In this context, our
group recently revealed that the pyridine-ligated boryl radical
(Py-Bpin∙) could be readily generated from (pinacolato)diboron
(B2pin2) through a cooperative catalysis involving two 4-
cyanopyridine molecules.11 This kind of the pyridine-boryl
radical was used for the catalytic reduction of azo-
compounds,11 or as a carbon-centered radical for the synthesis
of 4-substituted pyridines.12 Moreover, the pyridine-boryl
Scheme 1. Reductive coupling of carbonyl compounds with olefins.
Results and discussion
a.
Key Laboratory of Mesoscopic Chemistry of Ministry of Education, Institute of
It will be shown that the reductive coupling of aldehydes and
olefins can be promoted by the in situ generated pyridine-
boryl radical, following the proposed pathway as shown in
Scheme 2. The proposed catalytic cycle consists of the
following four steps: (1) activation of the B−B bond of B2pin2
by pyridines to form a pyridine-boryl radical (Int1); (2) the
addition of the pyridine-boryl radical to aldehyde 1a to
generate a new ketyl radical (Int3), and the pyrdine catalyst is
Theoretical and Computational Chemistry, School of Chemistry and Chemical
Engineering, Nanjing University, Nanjing, 210093 (P. R. China), E-mail:
shuhua@nju.edu.cn
b.
Institute of Chemistry and Biomedical Sciences, Jiangsu Key Laboratory of
Advanced Organic Material, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing, 210093 (P. R. China)
School of Chemistry and Chemical Engineering, Yan’an University, Yan’an 716000
(P. R. China)
+ These authors contributed equally to this work.
ectronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
c.
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regenerated; (3) the addition of the new ketyl radical to 1,1- with a CF3 group at the C3 position has a slightly higher
diphenylethylene to yield a diaryl-stabilized radical species activation barrier than that with the same group at the C4
(Int4); and (4) the hydrogen abstraction of Int4 from an position (D>E). These results indicate that the activation
appropriate H-source to yield the final reductive coupling barrier of pyridines correlates closely with the resonance
product. In addition, one molecule of Int4 may also abstract a effect and the inductive effect of the substituents. According
hydrogen atom from another molecule of Int4 to give the to the calculated activation barriers, five pyridines (A, B, C, D, E)
reductive coupling product and another disproportionation with barriers of no more than 28.5 kcal/mol are possible
product. To make this catalytic cycle happen, it is necessary to candidates for cleaving the B-B bond of B2pin2.
inhibit the possible radical-radical C-C coupling reaction
between the pyridine-boryl radical and the ketyl radical, as
Table 1. Optimization of the reaction conditions.[a]
observed between
α,β-unsaturated ketones and 4-
cyanopyridine in the presence of B2pin2.12 Thus, other
pyridines with different substituents may be better catalysts
than 4-cyanopyridine for the proposed reaction. With a
pyridine-boryl radical bearing
a suitable substituent, its
reactivity might be tuned so that the newly generated ketyl
radical could react with 1,1-diphenylethylene to yield a diaryl-
stabilized radical species, which then undergoes a hydrogen
atom abstraction from an appropriate hydrogen source to
produce the reductive coupling product.
Pyridines with different R
substituents
Entry
Hydrogen source
ratio [3a/3a′][b]
1
2
3
4
5
6
7
TMe-1,4-CHD
TMe-1,4-CHD
TMe-1,4-CHD
TMe-1,4-CHD
TMe-1,4-CHD
Et3SiH
4-CN (A)
28%: 0%
78%: 6% (70%)[c]
16%: 2%
4-(4-cyanophenyl) (B)
4-Ph (C)
4-CF3 (D)
21%: 1%
3-CF3 (E)
0%
4-(4-cyanophenyl) (B)
4-(4-cyanophenyl) (B)
62%:16%
52%:16%
--
[a] Reaction conditions: isobutyraldehyde (0.2 mmol), B2(pin)2 (0.2 mmol), catalyst
(0.04 mmol), 1,1-diphenylethylene (0.4 mmol), H-donor (0.2 mmol), 24 hours, 120 °C,
MTBE (1 mL). [b] Yields were determined by 1H-NMR analysis of the crude mixture
using CH2Br2 as the internal standard. [c] isolated yield of 3a. TMe-1,4-CHD=1,3,5-
trimethyl-1,4-cyclohexadiene.
In order to determine a suitable combination of a pyridine
catalyst and
a hydrogen source, we conducted an initial
investigation on the reaction between isobutyraldehyde 1a and 1,1-
diphenylethylene 2 (see Table S1 to S3 for details). As shown in
Table 1, heating a mixture of isobutyraldehyde 1a (1.0 equiv.), 1,1-
diphenylethylene (2.0 equiv.), B2pin2 (1.0 equiv.) in the presence of
1,3,5-trimethyl-1,4-cyclohexadiene (a hydrogen source, 1.0 equiv.)
and 4-cyanopyridine A (0.2 equiv.) in tert-butyl methyl ether
(MTBE) at 120 °C, the desired reductive coupling product 3a was
observed in 28% yield (entry 1), together with a small amount of
pyrdine-aldehyde adducts (12% yield, see supporting information
for details). When 4-(4-pyridinyl)benzonitrile B was used as the
catalyst (entry 2), the NMR yield of 3a improved to 78%, and the
yield of a byproduct 3a’ from the disproportionation of the diaryl
radical intermediate (Int4) was 6%. However, when other pyridines
(for example C, D, or E, entry 3-5) were adopted, the yield of 3a
decreased significantly. If Et3SiH was chosen as the hydrogen source,
the yield of 3a is somewhat lower than that with 1,3,5-trimethyl-
1,4-cyclohexadiene as a hydrogen source (entry 6). In the absence
Scheme 2. Proposed mechanism for the reductive coupling of isobutyraldehyde and
1,1-diphenylethylene.
To find out suitable pyridines which can react with B2pin2
to form the corresponding pyridine-boryl radical under mild
conditions, we first performed density functional theory (DFT)
calculations with the M06-2X[16] functional to screen a series of
pyridines. A careful analysis of stationary points revealed that
the formation of the pyridine-boryl radical proceed through a
[3,3]-sigmatropic rearrangement/homolytic C-C bond cleavage
[17]
pathway
rather than via the direct homolytic cleavage of
[11,18]
the B-B bond
(see Figures S1 and S2 in supporting
information for details). As shown in Figures S1-S12, the [3,3]-
sigmatropic rearrangement is the rate-determining step for
the formation of the corresponding pyridine-boryl radical. The
activation barrier of this step with different pyridines is highly
dependent on the substituent in the pyridine ring. Pyridines
with an electron-withdrawing group at the C4 position, such as
CN (A), 4-cyano phenyl (B), Ph (C), CF3 (D), have lower barriers
than the unsubstituted pyridine, and pyridines with an
electron-donating group (CH3, CH3O, N(CH3)2). The pyridine
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of a hydrogen source (entry 7), the ratio of 3a/3a’ was 52%: 16%,
suggesting that the addition of a hydrogen source is important for
improving the yield of 3a (see Table S2).
With the optimum conditions (Table 1, entry 2), we
explored the generality of this transformation with a series of
alkyl and aryl aldehydes. As shown in Table 2, the reductive
coupling reactions of several fully aliphatic aldehydes
Table 2. Substrate scope for the reductive coupling of aldehydes or ketones
with 1,1-diphenylethylene.[a]
proceeded with good efficiency (1a-1d). It was noteworthy
that aldehydes with C=C double bonds (1e), methylthio (1f), or
furyl (1h) functionalities on the alkyl chain were tolerated,
giving the reductive coupling products in moderate to good
yields. The
α-branched aldehyde (1i-1r), in particular,
pivaldehyde (1q) and 1-adamantylcarboxaldehyde (1r), also
reacted well to afford the desired products in good yields. It
should be mentioned that the substrates with congested
structure environment show less reactivity in transtion-metal
catalyzed reductive coupling of olefins and aldehydes, possibly
because the coordination between metal centre and the
corresponding substrates is difficult to occur.4c However, our
method is also suitable for the bukyl aldehydes (1q and 1r).
Beside alkyl aldehydes, aryl aldehydes
(1s, 1t) bearing
electron-donating groups (CH3, CH3O) could also serve as the
coupling partners, furnishing corresponding products in
moderate yields. In addition to aldehydes, alkyl ketones (1u
-
1w) also reacted smoothly to provide the desired alcohols in
27-42% yield.
Diarylalkanes are an important pharmacophore in drugs.19
It would be attractive to apply this metal-free method in the
late stage functionalization of medicinally related molecules.
As shown in Table 2C, an abietic acid derivative (1x) and
gemfibrozil derivative
(1y) reacted smoothly with 1,1-
diphenylethylene to form 3x and 3y in acceptable yields,
respectively.
Next, the scope of 1,1-diarylalkenes (
(Table 3 ). Both the symmetric (4a ) and unsymmetric (4e
1,1-diarylalkenes were converted into the corresponding
products in moderate to good yields with modest
4) was examined
a
-d
-o)
5
diastereoselectivities. The reaction tolerated substrates
bearing various functional groups on the benzene ring, such as
halogen functionalities (4c
CH3S (4i), CO2Me (4j), tBu (4k). More importantly, 1,1-
diarylalkenes containing heterocyclic structures (4m ), such
, 4d), CF3 (4e), CN (4f, 4g), MeO (4h),
-o
as benzofuran (4o) and thioxanthene (4p), also reacted
smoothly to give the expected products in reasonable yields.
Additionally, we also tested the reactivity of other alkenes with
pivaldehyde 1q (Table 3
other alkenes, including ethyl 2-phenylacrylate (4q), styrenes
4r 4s) or aliphatic olefin (4t), generally gave little or no
b). However, our results show that
(
,
desired product. The reason why 1,1-diarylalkenes are suitable
coupling partners of ketyl radicals may be due to (1) the radical
stabilization effect of two aryl groups, and (2) the less
nucleophilicity of present boron-ketyl radicals (compared with
typical ketyl radicals).5b Thus, this protocol provides a metal-
free reductive coupling method of 1,1-diarylalkenes with
aldehydes (via the radical addition mechanism), which
traditionally requires transition metal catalysts, or
organometallic reagents.12-16
[a] Reaction conditions: aldehyde (0.2 mmol), B2(pin)2 (0.2 mmol), 4-(4-
pyridinyl)benzonitrile (0.04 mmol), 1,1-diphenylethylene (0.4 mmol), 1,3,5-
trimethyl-1,4-cyclohexadiene (0.2 mmol), MTBE (1.0 mL), 24 h, 120 °C. Isolated
yield. The diastereoselectivities (d. r.) was determined by 1H NMR analysis of the
crude mixture. Boc=tert-butoxycarbonyl.
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transition state structures are displayed in Figure 1 (the
optimized structures of all minimum species are shown in
Figure S12). First, the coordination of the oxygen atom of
isobutyraldehyde to the boron atom of the pyridine-boryl
Table 3. Substrate scope for the reductive coupling of pivaldehyde with 1,1-
diarylethylenes.[a]
radical Int1 generates a boron-containing intermediate (Int2
)
via TS1, with a barrier of 13.3 kcal/mol. Then, the breaking of
the B-N bond in Int2 yields a ketyl radical (Int3) and
regenerates the 4-(4-pyridinyl)benzonitrile catalyst. This
process is exothermic by 4.5 kcal/mol, with a barrier of 3.2
kcal/mol (relative to Int2), suggesting that the formation of the
ketyl radical (Int3) from Int2 is possible. Next, the addition of
Int3 to the β-position of 1,1-diphenylethylene to form a diaryl-
stabilized radical (Int4) via TS3 is exothermic by 15.6 kcal/mol,
with a barrier of 15.5 kcal/mol (with respect to the radical
Int3). Finally, the final product is obtained with a hydrogen
atom abstraction from 1,3,5-trimethyl-1,4-cyclohexadiene via
TS4 with a barrier of 26.3 kcal/mol (relative to the radical Int4)
The whole reductive coupling reaction is exergonic by 11.7
kcal/mol (with respect to the reactants 1a and Int1). These
results suggest that the studied reaction is thermodynamically
and kinetically feasible under the experimental conditions. In
addition, our calculations suggest that the direct single
electron transfer (SET) process between pyridine-boryl radical
and isobutyraldehyde is highly endergonic (see details in
Figure S13 and Figure S14). Thus, the SET mechanism for the
present reaction can be excluded.
(a)
1,1ꢀdiarylethylenes
tBu
tBu
OH
OH
5b, R = CH3, 64%
5c, R = F, 41%
5d, R = Cl, 61%
R
R
5a: 70%
tBu
tBu
.
tBu
OH
OH
OH
CN
CF3
5l: 76%
d.r. = 1:1.1b
5e: 72%
5f
: 46%
d.r. = 1:1.5
d.r. = 1:1.0
tBu
tBu
OH
5g, R = CN, 48%, d.r. = 1:1.1
5h, R = OMe, 52%, d.r. = 1:1.0
5i, R = SMe, 58%, d.r. = 1:1.2
5j, R = CO2Me, 40%, d.r. = 1:1.1
5k, R = tBu, 40%, d.r. = 1:0.8
OH
O
O
R
5m: 68%
d.r. = 1:1.2
tBu
tBu
tBu
OH
OH
OH
O
O
O
S
5n: 68%
5o:34%
5p: 25%
d.r. = 1:1.1
d.r. = 1:1.2
(b) other alkenes
Me
5
Ph
CO2Et
4q: n.d.
4r: n.d.
4s
: n.d.
4t: n.d.
[a] Reaction conditions: pivaldehyde (0.2 mmol), B2(pin)2 (0.2 mmol), 4-(4-
pyridinyl)benzonitrile (0.04 mmol), 1,1-diarylethylene (0.4 mmol), 1,3,5-trimethyl-1,4-
cyclohexadiene (0.2 mmol), MTBE (1.0 mL), 24 h, 120 °C. Isolated yield. The
diastereoselectivities (d. r.) were determined by 1H NMR analysis of the crude mixture.
[b] The diastereoselectivities (d. r.) was determined by GC-MS analysis of the crude
mixture. tBu = tert-butyl.
To understand the mechanism of the reductive coupling of
1,1-diarylalkenes with aldehydes, we have performed DFT
calculations with the M06-2X functional to explore the free
Figure 1.Computed Gibbs free energy profile of the reductive coupling reaction
energy profile of the proposed mechanism for the reaction between isobutyraldehyde (1a) and 1,1-diphenylethylene (2) promoted by 4-(4-
pyridinyl)benzonitrile-boryl radical (Int1). The optimized structures of transition states
between isobutyraldehyde (1a) and 1,1-diphenylethylene (2) in
in the reaction path are also displayed. Interatomic distances are in Å.
the presence of Int1 as an reactive intermediate. Our
theoretical studies have shown that the generation of Int1
from B2pin2 and 4-(4-pyridinyl)benzonitrile is exergonic by 13.4
kcal/mol (see Figure S4). The calculated free energy profile and
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(1)
HRMS to detect the formation of the proposed O-boron
intermediate (Int6, Figure S17). The 11B NMR of the crude reaction
mixture displays resonances at ∼21 ppm, which is consistent with
the signal of a boron atom bound to three oxygen atoms.21 In
addition, our HRMS analysis (with 4-vinylpyridine as the substrate)
also indicates the formation of the O-boron intermediate (Int7), as
shown in Figure S18. Moreover, we have performed a radical-clock
study using cyclopropanecarboxaldehyde as the substrate. The
experimental results indicate that some ketyl radicals first convert
into the corresponding carbon radicals (via a ring-opening process)
and then add to the alkene to form the ring-opening product
(Scheme 3d). The experiments described above provide a strong
evidence on the involvement of a radical addition step betw0een
the ketyl radical and 1,1-diarylethylene in this reaction.
(a)
(2)
400
entry sample (in MTBE)
EPR
200
0
4ꢀ(4ꢀpyridinyl)
benzonitrile
(1)
active
+
-200
B2(pin)2
-400
4ꢀ(4ꢀpyridinyl)
(2)
inactive
benzonitrile
3480
3500 3510
Magnetic filed / G
3490
(b)
O
OH
OH
Ph
SH
(1) Standard conditions
(2) 2M Na2CO3, air
Ph
+
+
1g
(c)
3g, n. d
44%
N
(1) B2(pin)2, MTBE
20 mol% 4ꢀ(4ꢀpyridinyl)
benzonitrile, 120 °C, 24 h
O
m/z [M+H]+: Conclusions
OH
+
+
calc.
N
In summary, we have established the organocatalytic reductive
(2) 2M Na2CO3, air
299.2118
found.
N
1q
coupling of aldehydes with 1,1-diarylalkenes via a combination of
computational and experimental studies. This study showed that 4-
(4-pyridinyl)benzonitrile is a suitable catalyst for cleaving the B−B
bond of B2pin2, and the ketyl radical from the addition of the in situ
generated pyridine-boryl radical to aldehyde is a key intermediate
for the C-C bond formation. The reaction is practical, and applicable
to a broad range of aldehydes and 1,1-diarylalkenes with good
functional group tolerance. DFT calculations and control
experiments were conducted to verify the proposed mechanism.
This pyridine-boryl radical promoted radical addition mechanism
represents a metal-free reductive coupling reaction of aldehydes
with 1,1-diarylalkenes. Further studies will be directed toward the
development of new transformations involving the readily formed
pyridine-boryl radicals with the aid of combined theoretical and
experimental studies.
6
299.2118
hydrogen source
N
B(pin)
B(pin)
O
(pin)B
O
N
O
N
ketyl radical
Int4-like
N
(d)
Ph
O
(1) Standard conditions
(2) 2M Na2CO3, air
O
+
+
Ph
Ph
Ph
20%
7,
Scheme 3. Controlled experiments.
In addition to DFT calculations described above, we also
conducted several experiments to verify the proposed pathway.
First, EPR signal was observed for the reaction of 4-(4-
pyridinyl)benzonitrile and B2(pin)2, which supports the formation of
the proposed pyridine-boryl radical, as shown in Scheme 3a. Second,
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grants No. 21333004 and No.
21361140376, No. 21572099) and China Postdoctoral Science
Foundation (Grant No. 2017M620198). All calculations in this
work have been done on the IBM Blade cluster system in the
High Performance Computing Center of Nanjing University.
the involvement of the ketyl radical was confirmed by
a
competition experiment (Scheme 3b). It has been reported that
thiols are quick hydrogen atom donors that can interfere the radical
reaction.20 When the hydrogen source 1,3,5-trimethyl-1,4-
cyclohexadiene was replaced by 3-methylbenzenethiol, the ketyl
radical quickly abstracted
a
hydrogen atom from 3-
methylbenzenethiol to yield the reductive product, 3-phenyl-1-
propanol, so that its addition to 1,1-diphenylethylene (to form the
reductive coupling product) was inhibited (see page S20). This result
clearly indicated the involvement of the ketyl radical. Third, the
generation of the radical species Int4 (or its analogues) via the
addition of the ketyl radical to the β-position of arylethene was
confirmed by an intermolecular trapping experiment (Scheme 3c).
When 2-vinylpyridine and trimethylacetaldehyde was subjected to
the standard reaction condition, the species 6 could be detected by
HRMS analysis for the crude reaction mixture (see page S21). This
result suggests that in this reaction, the radical species Int4-like was
further trapped by another 2-vinylpyridine molecule. However, in
the presence of 2-vinylpyridine as a substrate, the yield of 6 is quite
low and its isolation from the reaction mixture was not successful.
Besides, we further conducted analysis of 11B NMR spectrum and
Conflicts of interest
There are no conflicts to declare.
Notes and references
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K. D. Nguyen, B. Y. park, T. Luong, H. Sato, V. J. Garza and M. J. Krische. Science,
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Marshall and N. D. Adamas, J. Org. Chem. 1999, 64, 5201. (d) J. A. Marshall
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6 | J. Name., 2012, 00, 1-3
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Chemical Science
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DOI: 10.1039/C7SC05225A
Journal Name
COMMUNICATION
Graphical abstracts
Organocatalytic Reductive Coupling of Aldehydes with 1,1-Diarylethylenes Using the in situ Generated
Pyridine-Boryl Radical
Jia Cao,+ Guoqiang Wang,+ Liuzhou Gao, Xu Cheng, and Shuhua Li*
A pyridine-boryl radical promoted reductive coupling reaction of aldehydes with 1,1-diarylethylenes has been established.
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