Lewis Acid-Catalyzed Selective Reductive Decarboxylative Pyridylation of N-Hydroxyphthalimide Esters: Synthesis of Congested Pyridine-Substituted Quaternary Carbons

Article abstract of DOI:10.1021/acscatal.9b03798

A practical and efficient Lewis acid-catalyzed radical-radical coupling reaction of N-hydroxyphthalimide esters and 4-cyanopyridines with inexpensive bis(pinacolato)diboron as reductant has been developed. With ZnCl₂ as the catalyst, a wide range of quaternary 4-substituted pyridines, including highly congested diarylmethyl and triarylmethyl substituents, could be selectively obtained in moderate to good yields with broad functional group tolerance. Combined theoretical calculations and experimental studies indicate that the Lewis acid could coordinate with the cyano group of the pyridine-boryl radical to lower the activation barrier of the C-C coupling pathway, leading to the formation of 4-substituted pyridines. Moreover, it could also facilitate the decyanation/aromatization of the radical-radical coupling intermediate.

Full text of DOI:10.1021/acscatal.9b03798

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Letter
Lewis Acid-Catalyzed Selective Reductive Decarboxylative
Pyridylation of N-Hydroxyphthalimide Esters: Synthesis
of Congested Pyridine-Substituted Quaternary Carbons
Liuzhou Gao, Guoqiang Wang, Jia Cao, Hui Chen, Yuming
Gu, Xueting Liu, Xu Cheng, Jing Ma, and Shuhua Li
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03798 • Publication Date (Web): 07 Oct 2019
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ACS Catalysis
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Lewis Acid-Catalyzed Selective Reductive Decarboxylative
Pyridylation of N-Hydroxyphthalimide Esters: Synthesis of
Congested Pyridine-Substituted Quaternary Carbons
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Liuzhou Gao,a,‡ Guoqiang Wang,a,‡ Jia Cao,a Hui Chen,a Yuming Gu,a Xueting Liu,a Xu Cheng,a,b
Jing Maa 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, School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210093, P. R. China
ABSTRACT: A practical and efficient Lewis acid-catalyzed radical-radical coupling reaction of N-hydroxyphthalimide
esters and 4-cyanopyridines with inexpensive bis(pinacolato)diboron as reductant has been developed. With ZnCl2 as the
catalyst, a wide range of quaternary 4-substituted pyridines, including highly congested diarylmethyl- and triarylmethyl-
substituents, could be selectively obtained in moderated to good yields with broad functional group tolerance. Combined
theoretical calculations and experimental studies indicate that the Lewis acid could coordinate with the cyano group of
pyridine-boryl radical to lower the activation barrier of the C-C coupling pathway, leading to the formation of 4-
substituted pyridines. Moreover, it could also facilitate the decyanation/aromatization of the radical-radical coupling
intermediate.
KEYWORDS: Lewis acid catalysis, radical-radical coupling, pyridines, quaternary carbons, late-stage.
a) Direct radical addition of pyridines (Minisci-type reaction)
Pyridines are essential structural units that exist in a
wide range of biologically active molecules,1 natural
[O], [Red] or
Photoredox catalysis
Alkyl-X
R
+
products2 and functional materials.3 Functionalization of
pyridines with conventional two-electron process,
including nucleophilic aromatic substitution (SNAr),4 and
transition-metal catalyzed C-H activation,5 has been
broadly investigated. However, sensitive organometallic
reagents6 or transition-metal catalysts7 are always
required in these processes. Moreover, the introduction of
congested tertiary substituents toward pyridines with
two-electron strategies is rather challenging.4a,8
R
Alkyl
N
X=COOH, I, SO2M,
B(OH)2, OH, H...
N
via radcial addition to pyridines
b) Radical ipso-substitution of 4-cyanopyridine via photoredox catalysis
CN
Alkyl
Photocatalyst
Alkyl-X
+
visible light or UV light
N
X=COOH, OH,
C or H
N
via radical-radcial coupling
c) This work: decarboxylative pyridylation of NHPI esters via LA catalysis
R1 R2
CN
O
R3
ZnCl2
With the prosperity of radical chemistry, we could
construct complex molecules via radical-mediated
processes.9,10 For example, the classical Minisci-type
reactions11 with different kinds of radical precursors,
including alkyl carboxylic acid,12 boronates,13 alkyl
halides,14 sulfinates,15 sulfonyl halides,16 alcohols,17
olefins,18 and alkanes,19 have been extensively developed
for the C-H functionalization of electron-deficient
heteroarenes. This strategy proceeds through the direct
addition of carbon radical to heteroaromtic bases, which
always involves competitive low-energy pathways, and
therefore the regioselectivity of this type reaction is
difficult to control.20 Although Baran21 and co-workers
have performed systematic investigations on the
regiochemistry of Minisci reactions and provided some
practical guidelines to this issue, the tunability of
R1
R2
+
ONPhth
B2(pin)2
R3
N
N
via radical cross-coupling
.
easy preparation
LA NC
N
-CN-Bpin
fragmentation reaction
R1
R2
B(pin)
R3
.
.
.
wide substrated scope
quaternary carbon center readily scalable
Scheme 1. Radical-mediated strategies for the
functionalization of pyridines.
regioselectivity of pyridine is difficult. In addition to
Minisci reactions, radical based ipso-substitution of
pyridine nitriles is another approach for the synthesis of
substituted pyridines. Recently, MacMillan,22 Opatz’s23
and Inoue24 groups have independently reported the
pyridylation of alkyl carboxylic acid, alcohol oxalate salts,
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C-C or sp3 C-H bond (Scheme 1b) with pyridine nitriles
may proceed through three different pathways (Cγ-C, Cα-
1
2
3
4
5
6
7
8
under the irradiation of visible light or UV-light. These
methods always involve the radical-radical coupling
between the pyridine nitrile radical anions with another
in situ generated carbon radical, leading to ipso-
substituted pyridine products. However, transition-metal
photocatalysts or the nearly stoichiometric amount of
organic photocatalysts and UV-light irradiation are
required in those transformations. In this regard, the
development of practical and efficient strategies that
enables to generate substituted pyridines under mild
condition would be of great synthetic value. We herein
C, and B-C pathways), due to three different resonance
structures of Int1. With 2-phenyl-propan radical and 4-
cyanopyridine-boryl radical as the model reactants, the
activation barriers of these three pathways calculated
with M06-2X at the 6-31G** level are 7.6, 10.3 and 15.0
kcal/mol, respectively (see Fig. S2 in SI for details).
Although the B-C coupling pathway might be excluded,
we still need to tune the reaction condition to suppress
the competitive Cα-C pathway, which is a major challenge
to achieve the desired reaction. In addition, the possible
H-atom abstraction reaction or self-reaction of the
decarboxylative carbon radicals should also be suppressed
by tuning the reaction condition.
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report
a
ZnCl2-catalyzed reductive decarboxylative
pyridylation of N-hydroxyphthalimide (NHPI) esters via
the radical-radical coupling of the neutral 4-
cyanopyridine-boryl radical25 with the decarboxylative
carbon radical, which is mechanistically different from
Minisci-type reactions or photoredox catalyzed ipso-
substitution strategy. Moreover, the protocol reported
here could avoid the regioselectivity issue in Minisci
reactions, and a series of quaternary carbons containing
pyridine-4-yl moiety could be obtained in good efficiency.
Using 4-cyanopyridine and NHPI ester 1aa as model
substrates in the decarboxylative pyridylation reaction in
the presence of B2pin2, we observed the formation of Cγ-C
coupling product 3aa in 48% yield at 80 oC, with 10% yield
of byproduct 3aa’ (Figure 1, entry 3, see Table S1 and Fig.
S15 in SI for details). After extensive examination of
different reaction parameters, the optimal reaction
conditions were achieved with 10 mol% of ZnCl2 as the
catalyst. The desired coupling product 3aa could be
obtained in 76% yield (74% isolated yield) with excellent
regioselectivity (Cγ/Cα>20:1). Other Lewis acids28 (such as
B(C6F5)3, AlMe2Cl, MgCl2, AlCl3, FeCl3, Zn(OAc)2) could
also facilitate the Cγ-C coupling pathway, providing the
target 3aa in 51% to 72% yields, while the use of BF3.Et2O
as the catalyst led to a decreased yield (30%).
Reaction Design
a.
CN
CN
B2(pin)2
R1
N
N
R2
R3
(pin)B
radical-radical coupling
Int1
O
N
R3
R1
R2
Int1
ONPhth
desired product
R1 R2
Int2
fragmentation
R3
1
CN
Me
Me
O
(1) B2pin2, ZnCl2 (10 mol%)
MTBE, 80 oC, 24h
Me
Ph
Me
Ph
b.
CN
Me
Me
CN
CN
CN
CN
C
ONPhth
+
+
N
HN
3aa'
(2) Na2CO3 aq, Air
Ph
N
N
N
N
N
(pin)B
(pin)B
(pin)B
(pin)B
C
3aa
2
1aa
Int1
yield (%)b
ratio (3aa:3aa')c
Resonance structures of Int1
entry
deviation from standard condition
1
2
3
4
5
none
76%
N.R.
>20:1
N.R.
R2
R1 R3
R3
R2
CN
CN
R1
no B2pin2
no ZnCl2
N
N
48%
4.8:1
CN
(pin)B
(pin)B
Int2
N
BF3.Et2O, B(C6F5)3, AlMe2Cl instead of ZnCl2
30%-58%
56%-72%
5.8:1-13:1
8:1-19:1
radical-radical
coupling
(pin)B
R1 R3
R2
R1 R3
R2
MgCl2, AlCl3, FeCl3, Zn(OAc)2 instead of ZnCl2
CC pathway
BC pathway
CC pathway
Figure 1. Optimization of the decarboxylative pyridylation
G = 7.6 kcal/mol
G = -21.3 kcal/mol
G = 15.0 kcal/mol
G = -12.3 kcal/mol
G = 10.3 kcal/mol
G = -22.2 kcal/mol
a
of NHPI 1aa. Reaction conditions: 1aa (0.2 mmol), 2 (0.3
mmol), B2(pin)2 (0.24 mmol), ZnCl2 (10 mol%) in MTBE
(1.0 mL), under Ar. aNMR yield, using benzyl ether as
Scheme 2. Reaction design of the decarboxylative
pyridylation of NHPI ester.
c
internal standard. Ratio was determined by the GC-MS
analysis.
Recently, our group25c and Fu group26 independently
described that the persistent pyridine-boryl radical27
generated from the B2pin2 and pyridines induce the
reductive fragmentation of redox-active esters (RAEs) to
form carbon radicals, which could be further trapped by
1,1-disubtituted alkenes or the boryl radical to generate
the C-C or C-B products. This strategy intrigued our
interest in construction of the synthetically valuable 4-
subtituted pyridines via the ipso-substitution of 4-
cyanopyridines with RAEs as the radical precursors,
which are easily available from the abundant carboxylic
acids, as shown in Scheme 2a. One can see from Scheme
2b that the radical-radical coupling reaction between the
pyridine-boryl radical (Int1) and carbon radical (Int2)
After identifying the optimal conditions, we next
explored the scope and generality of this decarboxylative
pyridylation protocol. As shown in Table 1, a broad range
of N-hydroxyphthalimide derivatives of tertiary carboxylic
acids could be served as radical precursors to react with 4-
cyanopyridine-boryl radical to afford the corresponding
4-substituted pyridines with a quaternary carbon in good
to high yields. This protocol exhibits wide functional
group tolerances, and we obtained the desired products in
good to excellent yields, including products containing
halogens (F (3qd), Cl (3ab, 3qc), Br (3c)), esters (3f),
alkene (3g), alkyne (3h, 3i), ether (3j), Boc carbamate
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Table 1. Substrate scope of the NHPI ester and pyridine.a
1
2
3
4
R''
R*
CN
R''
R'
R
(1) B2(pin)2, Additives
R'
R
R*
MTBE, 70-80 o
C
ONPhth
+
N
(2) Na2CO3 aq, Air
O
N
2
3
1
5
6
7
8
A. Tertiary alkyl radical
Me Me
1
Me Me
3aa
3ab
3ac
3ad
, R = H, 74%,
Me Me
Me Me
1
, R = 4-Cl, 84%,
1
N
R1
, R = 4-Ph, 75%,
N
N
N
1
Br
Me
(pin)B
TMS
, R = 4-OMe, 63%.
3b
3c
3d
, 78%
, 73%
, 80%
Me
MeS
9
O
10
11
12
13
14
15
16
17
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22
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45
46
O
Me
Me
O
Me
Me
Me
Me
N
N
N
N
N
N
3e
3f
, 54%
, 82%
3g
3h
3i
3j
, 88%
, 85%
, 63%
, 65%
I
OCF3
Boc
N
CF3
Me Me
O
Me
Me
Me
Me
Me
S
N
N
N
N
N
N
N
b
3k
3l
, 70%
, 72%
3m
3n
3o
, 92%
, 90%
, 71%
3p
, 75%
O
Cl
N
N
N
N
N
N
F
Cl
b
3qa
3qb
3qc
3qd
3qe
3qf
, 52%
, 58%
,
87%
, 90%
, 89%
, 65%
B. Di- and triarylmethyl radical
Me
MeO
MeO CF3
H
Me
Ph
N
N
N
N
N
c
3uc
3v
3r
3s
, 55%
, 40%
, 77%
R3
, 75%
Me
3ub
, 92%
3ua
, 80%(14% )
C. Primary and secondary alkyl radical
Me
Me
2
R2
3xa
3xb
3xc
3xd
, R =Me, 47%,
2
, R =Et, 50%,
N
N
2
, R =i-Pr, 54%,
N
3
d
d
N
2
3ta
N
,R =Me, 35%
3tc
, 34%
, R =cyclopentyl, 49%.
3
d
3wa
3wb
, 48%
, 43%
3tb
,R =Et, 38%
D. Pyridines
Me Me
4
3za
3zb
3zc
3zd
3ze
, R =F, 62%,
R4
Me Me
X
Me Me
Me Me
N
4
, R =Cl, 51%,
CN
4
, R =Br, 33%,
N
N
4
N
N
, R =CN, 57%.
4
, R =Me, 42%.
3y
3zf/3zg
3zh
3zi
, n.d.
, 32%
, X=F/Cl, n.d.
, n.d.
aReaction conditions: NHPI ester 1 (0.2 mmol), B2(pin)2 (1.2 equiv.), 4-cyanopyridine (1.5 equiv.), ZnCl2 (10
mol%), MTBE (1.0 mL), 80 C, 24 hours. 70 C. Without ZnCl2. With 2.0 equiv. 4-cyanopyridine. (n.d.=not
detected).
a
0
b
0
c
d
(3k), heterocycles (azetidine (3k), furan (3l), thiophene
afford the congested quaternary carbon pyridines in 52-
92% yields (3e-3s). Moreover, RAEs derived from α-
quaternary aliphatic acids could also smoothly transform
into the corresponding pyridylation products 3ta-3tc in
acceptable yields (34%-38%). Tri- or tetraarylmethane
derivatives are important building blocks with wide
applications in molecular devices,30 organic frameworks,31
and pharmaceutical chemistry.32 But they have not been
widely investigated due to the difficulty of synthesis.33
With our method, NHPI ester of 2,2-diphenylacetic acid
1ua-1uc and 2,2,2-triphenylacetic acid 1v could be
employed as the radical precursor, leading to 3ua-3v in
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(3p), tetrahydropyrane (3qf)). More importantly,
functional groups, such as aryl boronic ester, aryl iodide,
alkyne silane were also well tolerated with this protocol,
and desired product 3d, 3i, 3n was obtained in good
yields. Compounds 3r and 3s with α-methoxyl α-
trifluoromethyl subsitutents were also generated in 77%
and 75% yields, respectively. In addition to the broad
functional group compatibility, another feature of our
protocol is in the construction of sterically congested
structures, which are difficult in the classical Minisci-type
reactions.8,17d,29 For example, the transformation could
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40-92% yield. Our method is not limited to tertiary pyridylation products derived from ibuprofen, naproxen,
1
2
3
4
5
6
7
8
carboxylic acids. The secondary carboxylic acid NHPIs are
also good alkyl radical precursors, affording the
corresponding pyridine derivatives (3ua, 3wa-3xd) in
moderate to good yields (43%-80%). However, the
primary carboxylic acid NHPI 1y (derived from 3-
phenylpropanoic acid) gave a yield of only 32% (3y) due
to several competing pathways.34 Thus, this protocol is
less effective for primary carboxylic acids. Next, we also
probed the scope of the pyridines in the reaction. Under
similar condition, 4-cyano-substituted pyridines with
halides (F, Cl, Br), cyano or methyl substituents at the C3-
position of pyridine ring were well tolerated and the
corresponding pyridylation products 3za-3ze were
obtained in 33-62% yields. However, 2-position
substituted pyridines, including 2-fluoro-4-cyanopyridine,
2-chloro-4-cyanopyridine, 2,4-dicyanopyridine and 2-
cyanopyridine were not tolerated in this reaction (3zf-
3zh), presumably due to the fact that these pyridines are
not able to activate the B-B bond of B2(pin)2 to generate
the corresponding pyridine-boryl radical for initiating the
radical-radical coupling reaction.
carprofen, pranoprofen, flurbiprofen could be obtained in
good to high yields (4a-4h, 41-92%). Finally, this ZnCl2
catalyzed Cγ selective decarboxylative pyridylation
process was amenable to gram-scale synthesis. As shown
in Scheme 3b, in the presence of 2.5 mol% ZnCl2 catalyst
loading, gram quantities of pyridine-4-yl substituted
quaternary alkanes 3aa could be prepared with the NHPI
esters 1aa in 77% yield. For the 2,2-diphenylacetic acid
NHPI ester 1ua, in the absence of ZnCl2, only 14% yield of
the pyridylation product was obtained. With 20 mol%
ZnCl2 as the catalyst, the yield of the desired product 3ua
could significantly increase to 75%.
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Mechanistic investigations. To gain more mechanistic
insight into this reaction, the control experiments and
density functional theory (DFT) calculations were
conducted. First, the involvement of a free carbon radical
intermediate (obtained from the decarboxylation of NHPI
esters) could be confirmed by the isolation of ring-
opening product 6a in 42% yield under standard
conditions, using substrate 5a as the radical clock
(Scheme 4a).
a.
a.
Me
Me Me
Me Me
O
Ph
Cl
standard condition
Ph
O-NPhth
5a
N
N
N
N
MeO
N
H
6a 42%
,
fragmentation
NC
4a
4b
4c
, 45%
, 76%
, 70%
from Ibuprofen
from Naproxen
from (±)Carprofen
N
B(pin)
ring-opening
Me Me
Me
Me
Ph
Ph
radical-radical coupling
/aromatization
Me
N
N
b.
N
O
F
N
CN
N
without ZnCl2
Me Me
Ph
O
4d
4e
4f
, 41%
, 86%
, 67%
F
B2pin2 (1.2 equiv)
Me
Me
Eq. 1
B(pin)
from (±)Pranoprofen
from (±)Flurbiprofen
ONPhth
ONPhth
+
+
NC
N
THF-d8, 60 o , 24 h
C
Ph
Me
Me
Me
N
tBu
Me
1aa
Int3
m/z [M+H]+
found. 351.2237
Si
O
11B NMR
found. 23.82
=
O
with 10mol% ZnCl2
CN
N
N
Me Me
Ph
Me
Me
B2pin2 (1.2 equiv)
4g
4h
, 92%
, 90%
Eq. 2
THF-d8, 60 o , 24 h
Ph
1aa
C
N
b.
3aa
CN
N
Me Me
(1) ZnCl2 (2.5 mol%), B2(pin)2
MTBE, 80 oC, 36h
Me Me
Scheme 4. a. Radical clock experiment performed under
standard condition. b. NMR and HRMS analysis on the
crude reaction mixtures.
ONPhth
+
O
(2) Na2CO3 aq, Air
N
1aa
2
3aa
, 77%
12 mmol
8 mmol
Then, DFT calculations with M06-2X functional35 were
conducted to probe the role of ZnCl2 in this reductive
coupling reaction of RAE and 4-cyanoppyridine. Our
calculations suggest that the introduction of ZnCl2 do not
have significant effect on the reaction between pyridine-
boryl radical Int1 and NHPI ester 1aa, the corresponding
barrier of the key transition state (cleavage of N-O bond)
is slightly lowered from 23.7 kcal/mol to 22.1 kcal/mol (see
Fig. S1 and S3, SI). Therefore, the coupling between
radicals Int1 and Int2 with ZnCl2 was investigated to
elucidate the impact of ZnCl2 on this reaction (Figure 2a).
The computed free energy profile and the key transition
states of this reaction are listed in Figure 2b and 2c. First,
ZnCl2 and 4-cyanopyridine-boryl radical could form a
stable Lewis adduct (Int1-ZnCl2), in which the nitrogen
CN
N
(1) ZnCl2, B2(pin)2
MTBE, 80 oC, 36h
(2) Na2CO3 aq, Air
ONPhth
+
O
N

1ua
6 mmol
2
3ua
3ua
3ua
without ZnCl2
with ZnCl2 (10 mol%)
with ZnCl2 (20 mol%)
, 14%
, 51%
, 75%
9 mmol
Scheme 3. Synthetic potentials. a. Late-stage 4-
pyridiylation of drug molecules. b. Gram-scale
experiments. (0.2mmol scale).
To demonstrate the synthetic potentials of this
transformation in medicinal chemistry, a series of NHPI
esters derived from commercially available anti-
inflammatory drugs (Scheme 3a) were synthesized and
subjected to standard conditions. Decarboxylative
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(a)
(b)
CN
N
CN
Me
Me
1
2
3
4
Ph
ZnCl2
Me
Me
N
(pin)B
CN
+
radical-radical
coupling
Ph
N
Me
Ph
Me
(pin)B
B(pin)
Int1
Int3
Int2
Int3'
5
6
7
8
9
G
(kcal/mol)
Me
Me
Ph
Me
Ph
CN
ZnCl2
Me
Ph
Me
N
Me
CN
N
(pin)B
CN
ZnCl2
(pin)B
ZnCl2
N
N
(pin)B
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Me
Ph
Me
CN ZnCl2
(pin)B
TSI-II
TSIII-IV
TSII-III
TSI-V
TSI-V
-0.7
TSI-II
-5.4
C-C
C-C
0.0
Int1+ZnCl2
TSII-III
-9.1
11.0
6.3
-11.7
I
Me
Ph
Me
Int1
A
)
-ZnCl2
+
(
N
18.1
(pin)B
Me
TSIII-IV
-27.8
Me
Ph
Me
ZnCl2
CN
-27.2
II
Ph
IV
Me
Int2
-30.3
V
-30.3
III
2.5
N
3aa
(-36.4)
Me
Ph
Me
Me
Int1
Me
Ph
ZnCl2
CN
Me
CN
Ph
Me
-42.3
IV
ZnCl2
N
Int1-ZnCl2
+
(pin)B-CN
N
N
ZnCl2
CN
(pin)B
(pin)B
(pin)B
V
III
II
C-C/C-C coupling pathway
(c)
2.50
2.76
2.13
2.48
1.51
2.05
2.05
TSI-II
TSI-V
TSIII-IV
TSII-III
Figure 2. (a) Model reaction used in the computational study of the Mechanism. (b) Potential energy surfaces of the
ZnCl2 catalyzed selectivity radical-radical coupling reaction of Int1 and Int2 (All energies are with respect to the separate
reactant and ZnCl2). (c) Optimized structures of transition states.
atom of cyano is coordinated to the Zn(II) center (ΔG = -
11.7 kcal/mol). Then, the radical-radical coupling reaction
between radicals Int2 and Int1-ZnCl2 at the Cγ position or
Cα position generates 1,4-dihydropyridine intermediate II
(via TSI-II), and 1,2-dihydropyridine intermediate V (via
TSI-V). The Cγ-C pathway is the kinetically more favorable
pathway, which requires a much lower barrier than the
Cα-C coupling pathway (6.3 v.s. 11.0 kcal/mol). The free
energy barrier of the Cγ-C coupling pathway is somewhat
lowered in the presence of ZnCl2 (reduced from 7.6
kcal/mol to 6.3 kcal/mol). For TSI-II and TSI-V, the
enlarged energy barrier difference (ΔΔG≠= -4.7 kcal/mol)
between these two competing pathways could account for
the experimental observed improvement in product-
selectivity with ZnCl2 as the catalyst (3aa/3aa’, from 4.8:1
to >20:1). Additionally, ZnCl2 could also facilitate the
decyanation/aromatization of the 1,4-dihydropyridine
intermediate Int3. Dissociation of cyanide from II with
the assistance of ZnCl2 (TSII-III) followed by migration of
The activation barrier of these two transition states are
18.1 and 2.5 kcal/mol, respectively. For the dissociation of
cyanide from intermediate II, our post-Hartree-Fock
calculations with the cluster-in-molecule local correlation
method36 (see supporting information for details) also
lead to a barrier of 22.0 kcal/mol, being slightly higher
than the M06-2X result (TSII-III, 18.1 kcal/mol). Without
ZnCl2, the dissociation of cyanide requires a free energy
barrier of 35.7 kcal/mol, which is difficult to occur at the
present condition (see Fig. S5 in SI for details).
Furthermore, NMR experiments were performed to verify
the calculated mechanism for this ZnCl2-catalyzed
reductive coupling reaction. The reaction of 1aa, 4-
cyanopyridine and B2pin2 was analyzed by 1H NMR
spectroscopy in the presence or absence of ZnCl2 (Scheme
4b, see Fig. S11-12 in SI). Without ZnCl2 (Eq. 1), a set of
signals observed at δH = 6.35 and 4.45 ppm could be
assigned to a 1,4-dihydropyridine intermediate Int3. The
1
calculated H NMR chemical shift (δH = 6.91 and 4.78
the cyanide from ZnCl2-CN to the Bpin center (TSIII-IV
gives the desired decarboxylative/pyridylation product.
)
ppm) of Int3 by the Gauge-independent atomic orbital
(GIAO) method at B97-2/pcSseg-2 level37 is consistent
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with experimental values described above. Additionally, provide new inspiration of the utility of Lewis acid in
1
2
3
4
5
6
7
8
the structure of Int3 was further confirmed by HRMS and
radical chemistry.
11B NMR experiments (see Fig. S13 and S14 in SI for
ASSOCIATED CONTENT
details).
Therefore,
the
involvement
of
1,4-
dihydropyridine (via Cγ-C coupling pathway) could be
confirmed by our experimental studies. Under a similar
condition, when a catalytic amount of ZnCl2 was added
(Eq. 2), the signals that correspond to 1,4-dihydropyridine
intermediate disappeared and the aromatized product
3aa was observed (Scheme 4b, see Fig. S13). This result
indicates that the use of ZnCl2 is crucial to prompt the
rearomatization of 1,4-dihydropyridine intermediate,
which is consistent with our DFT calculations. In addition,
a trace amount of 4-cyanopyridine-boryl radical dimer of
Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org. Free energy profiles. Optimization
geometries.
Experiment
procedure,
compound
characterization, and spectra.
9
AUTHOR INFORMATION
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60
Corresponding Author
*shuhua@nju.edu.cn.
1
Int1 was also detected by the H NMR and confirmed by
Author Contributions
‡L.Z.G. and G.Q.W. contributed equally to this work.
1
our calculated H NMR chemical shift (see Fig. S11 and
S12). Taking these experimental and computational
Funding Sources
results into consideration,
a
ZnCl2 catalyzed
This work was supported by the National Natural Science
Foundation of China (21833002 and 21673110), and the
program B for Outstanding PhD candidate of Nanjing
decarboxylative coupling pathway is proposed in Scheme
5. First, the pyridine-boryl radical Int1 mediated
fragmentation of NHPI ester 1 leads to the generation of
carbon radical Int2 as evidenced by radical-clock
experiment. Then, the radical-radical coupling of Int1-
ZnCl2 complex and Int2 at the γ-position of the pyridine-
University
(201901B021).
Notes
The authors declare no competing financial interests.
boryl
radical
generates
the
1,4-dihydropyridine
ACKNOWLEDGMENT
intermediate. Subsequent elimination of the cyano-Bpin
with the assistance of ZnCl2 forms the desired 4-
substituted pyridines and regenerates the ZnCl2 catalyst.
Along the reaction pathway, ZnCl2 works as a bifunctional
catalyst. It not only facilitates the Cγ-C coupling pathway,
but also contributes to the lowering of the activation
barrier of the rearomatization of 1,4-dihydropyridine
intermediate.
All calculations in this work were performed on the IBM
Blade cluster system in the High Performance Computing
Center of Nanjing University. We also thank Dr. Zhigang Ni
(Nanjing University) for his help in doing post-Hartree-Fock
calculations for the rate-determining step.
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R1 R2
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N
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wide substrated scope
quaternary carbon center readily scalable
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