Metal-Free Synthesis of C-4 Substituted Pyridine Derivatives Using Pyridine-boryl Radicals via a Radical Addition/Coupling Mechanism: A Combined Computational and Experimental Study

Article abstract of DOI:10.1021/jacs.7b00823

Density functional theory investigations revealed that the pyridine-boryl radical generated in situ using 4-cyanopyridine and bis(pinacolato)diboron could be used as a bifunctional “reagent”, which serves as not only a pyridine precursor but also a boryl radical. With the unique reactivity of such radicals, 4-substituted pyridine derivatives could be synthesized using α,β-unsaturated ketones and 4-cyanopyridine via a novel radical addition/C-C coupling mechanism. Several controlled experiments were conducted to provide supportive evidence for the proposed mechanism. In addition to enones, the scope could be extended to a wide range of boryl radical acceptors, including various aldehydes and ketones, aryl imines and alkynones. Lastly, this transformation was applied in the late-stage modification of a complicated pharmaceutical molecule.

Full text of DOI:10.1021/jacs.7b00823

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Article
Metal-Free Synthesis of C-4 Substituted Pyridine Derivatives
Using Pyridine-boryl Radicals via a Radical Addition/Coupling
Mechanism: A Combined Computational and Experimental Study
Guoqiang Wang, Jia Cao, Liuzhou Gao, Wenxin Chen, Wenhao Huang, Xu Cheng, and Shuhua Li
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Feb 2017
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Metal-Free Synthesis of C-4 Substituted Pyridine Derivatives Using
Pyridine-boryl Radicals via a Radical Addition/Coupling Mechanism:
A Combined Computational and Experimental Study
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Guoqiang Wang,a Jia Cao,a,c Liuzhou Gao,a Wenxin Chen,b Wenhao Huang,b Xu Cheng,b,d,* and
Shuhua Lia,*
aKey Laboratory of Mesoscopic Chemistry of Ministry of Education, Institute of Theoretical and Computational
Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China
bInstitute of Chemistry and Biomedical Sciences, Jiangsu Key Laboratory of Advanced Organic Material, School of
Chemistry and Chemical Engineering, Nanjing University 210023, P. R. China
cCollege of Chemistry and Chemical engineering, Yan’an University, Yan’an 716000, P. R. China
dState Key Laboratory of Elemento-organic Chemistry, Nankai University, P. R. China
Supporting Information Placeholder
ABSTRACT: Density functional theory investigations revealed that the pyridine-boryl radical generated in situ using 4-
cyanopyridine and bis(pinacolato)diboron could be used as a bifunctional “reagent”, which serves as not only a pyridine precur-
sor but also a boryl radical. With the unique reactivity of such radicals, 4-substituted pyridine derivatives could be synthesized
using α, β-unsaturated ketones and 4-cyanopyridine via a novel radical addition/C-C coupling mechanism. Several controlled
experiments were conducted to provide supportive evidence for the proposed mechanism. In addition to enones, the scope
could be extended to a wide range of boryl radical acceptors, including various aldehydes and ketones, aryl imines and alkynones.
Lastly, this transformation was applied in the late-stage modification of a complicated pharmaceutical molecule.
1.
INTRODUCTION
mainly localized on C4 rather than on B (Figure 1, right).7, 8
Thus, the radical 1 may act as a carbon radical in some reac-
tions. The in situ generated pyridine-boryl radical (1) from 4-
cyanopyridine and B2(pin)2 may provide opportunities for the
development of other new reactions, in particular reactions
that lead to the synthesis of pyridine derivatives via the car-
bon-carbon radical coupling reactions.
Organoboron reagents are commonly described as reactive
radical precursors in many organic reactions.1 For example,
organoboranes are usually used as radical initiators or for
generating carbon radicals.2, 3 Lewis-borane complexes, espe-
cially N-heterocyclic carbene boranes4 can be readily used in
radical reductive reactions4a,b and as co-initiators4e in photo-
polymerizations. In these systems, the radical reactions al-
ways occur via an innate chain mechanism.
From a synthetic view, the synthesis of diverse functional-
ized pyridine derivatives is of particular interest, given that
the pyridine core is an important class of structural unit
found in pharmaceutical compounds9 and functional materi-
als.10 Transition metal catalysts have played privileged roles
in the synthesis of pyridine derivatives, including the direct
C-H bond activation, radical reactions, and cross-coupling
reactions.11-13 On the other hand, the use of organometallic
reagents such as organolithium and Grignard reagents, pro-
vides a transition-metal-free strategy for synthesis of 2- or 4-
substituted pyridines.14-16 In these systems, preactivated pyri-
dines or stoichiometric amounts of Lewis acids are usually
required.16 Given the considerable importance of pyridine
derivatives, it is highly desirable to develop other effective
strategies for the synthesis of pyridine derivatives.
Figure 1. The dual characteristics of pyridine-boryl radical
(1). Left: B radical reactivity; Right: calculated spin density
distribution of 1 (at the UM06-2X/6-31G(d,p) level).
Recently, we reported that the B-B bond of
bis(pinacolato)diboron (B2(pin)2) could be homolytically
cleaved to generate a pyridine-boryl radical (1) through a
cooperative catalysis involving two 4-cyanopyridine mole-
cules.5 The radical 1 could react as a base-stabilized boryl
radical in the catalytic reduction of azo-benzene compounds
(Figure 1, left).5, 6 Furthermore, our theoretical calculations
(see Figure S1 for details) suggest that the spin density in 1 is
Thus, we speculate that the pyridine-boryl radical (1) could
be used as a precursor to synthesize the 4-substituted pyri-
dines via a persistent radical cross-coupling mechanism.17, 18
α, β-unsaturated ketones (enones) are selected as functional-
ization reagents due to their high boryl radical stabilization
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energies. The proposed mechanism is shown in Scheme 1.
details). First, the coordination of 2-cyclohexenone to the
1
2
3
4
5
6
7
8
First, the homolytical cleavage of the B-B bond of B2(pin)2 by
4-cyanopyridine generates boryl radical 1;5 then the boryl
radical addition from 1 to enone 2b generates a new radical
intermediate (Int2); and then the radical cross-coupling re-
action of 1 and Int2 generates a dearomitized pyridine in-
termediate (Int3). Subsequently, the hydrolysis and aromati-
zation of Int3 lead to 4-substituted pyridine (3b). In this
process, the radical 1 generated in situ could be considered as
a bifunctional “reagent”, which not only serves as a pyridine
precursor but also acts as a boryl radical. Herein, we report a
combined computational and experimental study to show
that the above proposed strategy provides a metal-free ap-
proach for synthesis of 4-substituted pyridine derivatives. In
addition to α, β-unsaturated ketones, a broad range of some
other commercially available compounds, for example, alde-
hydes, ketones, alkyne ketones and aryl imines can be used
as functionalization reagents.
boron atom of the pyridine-boryl radical 1 generates a tetra-
coordinated boryl intermediate (Int1) via TS1, with a barrier
of 10.6 kcal/mol. Then, the dissociation of 4-cyanopyridine
from Int1 yields an enone-boryl radical (Int2). Due to the
formation of a strong B-O bond and the resonance stabiliza-
tion effect, this radical intermediate is only 1.8 kcal/mol in
free energy above the separated 1 and 2-cyclohexenone, and
the corresponding barrier is 8.4 kcal/mol. These results sug-
gest that the formation of a new radical (Int2) with enone
(2b) via the boryl radical addition is possible, and Int2 may
be consider as a transient radical for subsequent cross cou-
pling reactions. Then, the C-C coupling reaction between
radical 1 and Int2 at β-carbon atom of Int2 generates a 1,4-
addition intermediate (Int3) via TS3 (Figure 2, blue line),
with a barrier of 11.5 kcal/mol, and the whole process is exo-
thermic by 20.5 kcal/mol (with respect to the radical 1 and
reactant 2b). In addition to the 1, 4-addition pathway, the
radical coupling reaction between 1 and Int2 can also gener-
ate a 1,2-addition intermediate (Int4) via TS4, with a lower
barrier of 10.5 kcal/mol (Figure 2, red line). However, the
generation of Int4 is only exothermic by 18.6 kcal/mol (with
respect to the radical 1 and reactant 2b). A possible equilibri-
um between 1,4-addition and 1, 2-addition pathway is sug-
gested in Scheme 3. The dissociation barrier for the carbon-
carbon bond of Int4 is 29.1 kcal/mol, suggesting a reversible
dynamic process for the 1,2-addition pathway. Thus, we
speculate that the 1,4-addition pathway would be a thermo-
dynamically favorable pathway, and the 1,4-addition product
3b might be the major product.
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Scheme 1. Speculated mechanism for the synthesis of
4-substituted pyridine using the pyridine-boryl radi-
cal (1) via radical addition/coupling pathway.
2.
RESULTS AND DISCUSSIONS
2.1 Computational investigations
Initially, we performed unrestricted density functional
theory (DFT) calculations with the M06-2X funtional19 to
investigate the thermodynamic change for the homo-
coupling of radical 1 (see Supporting information for compu-
tational details). As displayed in Scheme 2, the formation of
the dimeric species 0f 1, IntC4-C4, via C4-C4 bond formation is
exothermic by 2.9 kcal/mol with a barrier of 10.9 kcal/mol,
suggesting the dimerization reaction of radical 1 is reversible
(See Figure S2 in supporting information for other possible
dimerization pathways). The existence of the dimeric species
1
of 1 was further verified by H NMR and HRMS studies (See
Figure S8 in Supporting information). Thus, the radical 1
might be considered as a persistent radical for subsequent
cross-coupling reactions.
Scheme 2. Calculated free energy change (
ΔG) for
the dimerization reaction of pyridine-boryl radical 1.
Figure 2. Computed Gibbs free energy (in kcal/mol) profile
for the reaction between the radical 1 and 2-cyclohexenone
(2b) in benzene. The blue line denotes the 1,4-addition
pathway and the red line corresponds to the 1,2-addition
pathway. Distances are in Å.
For the model reaction between the radical 1 and 2-
cyclohexenone (2b), we have computationally investigated
the energetics of the proposed mechanism. The free energy
profile is shown in Figure 2 (see supporting information for
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Scheme 3.
Journal of the American Chemical Society
With cyclopent-2-en-1-one (2a) and cyclohept-2-en-1-one
A
possible equilibrium between 1,4-
1
2
3
4
(2c) as the substrates (Table 2), 1,4-addition also occurred
more favorably than 1,2-addition at 70°C, as observed for 2b.
These results suggest that 1,4-addition is thermodynamically
favorable, which is consistent with our DFT calculations.
addition and 1,2-addition pathway (Energy is in
kcal/mol).
5
6
7
Table 2. Temperature effect on the product distribu-
tion.a
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Yield (ratio, 3:4)
Yield (ratio, 3:4)
Substrates
(T= 70 °C)
(T= r.t.)
2.2 Experimental studies
43% (1.8:1)b, e
50% (1:1)c, e
In order to validate the predicted reactivity of the pyri-
dine-boryl radical (1) and its reaction with enones, we con-
ducted initial reactions using 2-cyclohexenone (2b) as the
substrate (Table 1). Preliminary attempts generated the pyri-
dine addition product in 59% yield and with a mixture of
regioisomers (3b/ 4b = 42%:17%， entry 1). After further op-
timization of the reaction conditions, methyl tert-butyl ether
(MTBE) was found to be a suitable solvent for this reaction,
the reaction yield and regioselectivity increased to 81% and
62:19, respectively, at 70 °C in the presence of 1.5 equivalent
4-cyanopyridine (entry 10). One can see from Table 1 that the
reaction temperature is important for improving the regiose-
lectivity (entries 8-10). At room temperature and 40°C, 3b
and 4b were formed with lower 1,4-addition/1,2-addition
selectivity.
62% (>20:1)d
59% (4:1)c
aReaction conditions: enones (0.2 mmol), 4-cyanopyridine
(0.3 mmol), B2(pin)2 (0.24 mmol), MTBE (1.0 mL), isolated
yield refer to the combined yield of all isomers, the ratio
1
was determined by H NMR analysis of the crude mixture.
c
bThe reaction time was 24h. The reaction time were 48h.
e
dThe reaction time was 36h. The ratio was determined by
GC-MS analysis of the crude mixture due to the peak over-
lap in the 1H NMR spectrum.
With the optimized condition in hand (Table 1, entry 10),
we explored the radical addition/coupling reaction with vari-
ous combinations of enones and pyridines (Table 3). At first,
cyclic enones with different patterns of substitution were
evaluated. It was found that even with β-methyl group the
1,4-addition products were generated with moderate selectiv-
ity in the case of 3e-3f. Dimethyl substituted cyclohexeone 2g
reversed the selectivity and the 1,2-addition product 4g be-
came the major product. 2h with α-phenyl group gave the 1,
4-addition 3h in trans configuration only. The reaction of
acetylcyclohexene-2 (2i) and 4-cyanopyridine produced a
mixture of 3i and 4i in a 1.8:1 ratio. The more bulky substrate
3j offered only the 1,4-addition product 3j in 62% yield with
trans configuration as predominant species. When β-ionone
2k was adopted, the corresponding 1, 2-addition product 3k
could be prepared in 59% yield. Subsequently, a variety of
acyclic enones were subjected to this transformation. Enone
2l gave the 1,4-addition product 3l with a ratio of 3.6:1 to its
1,2-addition product 4l. By introducing a phenyl group into
the enone molecule, complete regioselectivity of 1,4-addition
could be achieved and 3m-3o could be furnished in moderate
to acceptable yield. In turn, several dimethyl acyclic enones
were screened with standard condition. The 1,4-addition
could offer the pyridine substituted with quaternary carbon
center as the major product for 3q and 3r and the only prod-
uct for 3s-3u.
Table 1. Optimization of the reaction conditions.a
Ratio (3b/4b)b
Entry
t (h)
T (°C)
Solvent
1
2
16
16
16
16
16
16
16
24
48
40
40
40
40
40
40
40
40
r.t.
EA
42%:17%
19%:7%
CH2Cl2
CH3CN
THF
3
28%:8%
42%:11%
38%:19%
40%:18%
43%:17%
61%:23%
55%:20%
4
5
Toluene
Pentane
MTBE
MTBE
MTBE
6
7
8c
9c
62%:19%
(70%, 3.7:1)d
10c
24
70
MTBE
aReaction conditions: 2-cyclohexenone (0.2 mmol), 4-
cyanopyridine (0.2 mmol), B2(pin)2 (0.24 mmol), solvent
(1.0 mL). bYields and the ratio of 3b to 4b were deter-
To obtain more functionalized pyridine derivatives, we
surveyed the reactions of 2-cyclohepten-1-one with other 4-
cyanopyridine derivatives, as shown in Table 3. 4-
cyanopyridines bearing substituents at C-3 position, such as
F, Cl, and methyl, provided 1,4-addition products 3v, 3w and
3x in 60%, 63% and
1
mined by H NMR analysis of the crude reaction mixture
with CH3NO2 as an internal standard. c0.3 mmol 4-
cyanopyridine was used. d Isolated yield.
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Table 3. Substrate scope.a
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4
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aReaction conditions: enones (0.2 mmol), 4-cyanopyridine (0.3mmol), B2(pin)2 (0.24 mmol), MTBE (1.0 mL), 24h, 70 °C, isolat-
ed yields refer to the combined yield of all isomers, the major isomer is depicted, the ratio was determined by 1H NMR analy-
sis of the crude mixture. bReacted at room temperature, for 48h. cFor 36 h. dReacted at 40 °C, for 36h.
51% isolated yield, respectively. Highly sensitive thioether
and bromo moieties which usually lead to side reactions un-
der transition-metal catalysis were tolerated well in the pre-
sent boryl radical system. Corresponding 1, 4-addition prod-
ucts 3y and 3z were obtained in moderate yields. However,
with the 4-cyanopyridines bearing a substituent at C-2 posi-
tion (for example, 2-fluorine-4-cyanopyridine), desired prod-
uct was not detected.20
We further demonstrated the synthetic application of this
protocol in the synthesis or modification of medicinally re-
lated molecules (Scheme 4). When enone 2A was subjected
to our reaction conditions in the presence of 4-cyanopyridine
(1.5 equiv) and B2(pin)2 (1.2 equiv), the aromatase inhibitor
3A9 could be obtained in 40% yield. Hydrocortisone acetate
2B, a pharmaceutical reagent featuring an ester, two unpro-
tected alcohols and an alkyl ketone, can be facilely converted
1
aDetermined by H NMR analysis of the isolated mixture of
into the tertiary alcohol adduct 3B in moderate yield (44%, d.
r.= 2.6:1) with these sensitive groups remaining intact. Alt-
hough the relative configuration of the major isomer could
not be assigned, our protocol exhibits good functional group
tolerance indeed.
diastereomers.
2.3 Mechanistic investigations
In addition to the investigations of the temperature effect
on the regioselectivity, further experimental studies were
conducted to verify the proposed reaction pathway. Firstly,
Scheme 4. Applications to medicinally relevant sub-
strates.
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HRMS was performed to detect the possible intermediate. As
involvement of radical intermediate in the proposed path-
1
2
3
4
shown in Scheme 5a, an aromatized boron-enolate interme-
diate (Int3’) could be detected by crude HRMS analysis of the
reaction mixture of 2c and 4-cyanopyridine. However, the
direct detection of the Int3-like species was not successful,
possibly due to its rapid aromatization.
ways.
2.4 Expanding the substrate scope
Scheme 6. The extended scope of the radical addi-
tion/coupling mechanism.
5
6
Scheme 5. Controlled experiments.
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Secondly, the generation of the boron-enolate species was
confirmed by intramolecular trapping reaction (Scheme 5b).
When the 3, 4-dicyanopyridine was subjected to the standard
conditions, compound 5 with fused ring scaffold was isolat-
ed, indicating that an intramolecular trapping of the boron-
enolate via a nucleophilic addition reaction occurred. The
conformation of fused ring 5 can be determined by DFT cal-
culations (See Scheme S4 in supporting information for de-
tails).
In order to test the protocol’s diversity, we explored
whether other commercially available carbonyl derivatives
could be used as coupling partners for the synthesis of 4-
substituted pyridines. Further experiments indicated that
aryl aldehydes, aryl ketone, arylimines, 4-(trimethylsilyl)-3-
butyn-2-one, as well as aliphatic aldehyde or ketone were
suitable substrates for the synthesis of 4-substituted pyri-
dines via our proposed strategy (Scheme 6). As shown in
Scheme 6a, under slightly modified reaction conditions (see
Table S1 in supporting information for details), benzalde-
hydes with either electron-donating or electron-withdrawing
group (9b-d) underwent the reaction to give 10b-d in mod-
erate to good yields. Halides, such as F, Cl, and Br were well
tolerated (10b, 10c and 10h) with this radical protocol. The
position of substituents on the phenyl ring showed weak
Thirdly, the involvement of radical intermediate was
probed with the rigid cycloprop[a]inden-6(1H)-one 6 as radi-
cal clock. In the presence of 3-chloro-4-cycano pyridine and
B2(pin)2 at 70 oC, the product 7 was generated from the open-
ing of fused cyclopropyl group (another 1, 2-addition product
8 was obtained, Scheme 5c). This result also indicates the
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influence on the reactivity (9e-g). Acetophenone (9i) afford-
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boryl radical reactivity of the pyridine-boryl radical for the construc-
tion of C-B bond appeared: Zhang, L.; Jiao, L. J. Am. Chem. Soc. 2017,
139, 607-610.
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and is reported for some other N-heterocycles ligated boryl radicals,
see: Tehfe, M. A.; Schweizer, S.; Chany, A. C.; Ysacco, C.; Clément, J.
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3. CONCLUSIONS
In summary, a metal-free approach to the synthesis of C-4
substituted pyridine derivatives was predicted computation-
ally and verified experimentally. Theoretical calculations
revealed that the in situ generated pyridine-boryl radical
using 4-cyanopyridine and B2(pin)2 exhibits a carbon-radical
characteristic, and this boryl radical can be used as a bifunc-
tional “reagent”, which acts as not only a pyridine precursor
but also a boryl radical. The combined computational and
experimental study showed that the 4-substituted pyridine
derivatives could be synthesized using α, β-unsaturated ke-
tones via the proposed radical addition/coupling mechanism
with 4-cyanopyridine and B2(pin)2 as starting material. Sever-
al controlled experiments were conducted to probe the
mechanistic details. Then, the reaction was further expanded
to a wide range of boryl radical acceptors, including various
aldehydes and ketones, aryl imines and alkynone. Applica-
tion of this transformation in the modification of a compli-
cated pharmaceutical molecule was described. The reactions
occur under mild conditions without the use of any transi-
tion-metal catalysts or organometallic reagents. Efforts to
apply this in situ generated new boryl radical to other reac-
tions with the help of combined theoretical and experimental
studies are underway in our laboratory.
ASSOCIATED CONTENT
Supporting Information
Computational investigations, experiment procedure, com-
pound characterization, spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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*shuhua@nju.edu.cn
*chengxu@nju.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (Grants No. 21333004, No. 21361140376,
No. 21572099 and No. 21332005). This work was partially
sponsored by Qing Lan Project. All calculations in this work
have been done on the IBM Blade cluster system in the High
Performance Computing Center of Nanjing University. We
dedicate this work to professor Qi-Lin Zhou on the occasion
of his 60th birthday.
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(20) For the reactions of 2c with 2-substituted-4-cyanopyridines,
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S3 in supporting information for details.
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