Organoborohydride-catalyzed Chichibabin-type C4-position alkylation of pyridines with alkenes assisted by organoboranes

Article abstract of DOI:10.1039/d0sc04808a

The first NaBEt3H-catalyzed intermolecular Chichibabin-type alkylation of pyridine and its derivatives with alkenes as the latent nucleophiles is presented with the assistance of BEt3, and a series of branched C4-alkylation pyridines, even highly congested all-carbon quaternary center-containing triarylmethanes can be obtained in a regiospecific manner. Therefore, the conventional reliance on high cost and low availability transition metal catalysts, prior formation of N-activated pyridines, organometallic reagents, and extra oxidation operation for the construction of a C-C bond at the C4-position of the pyridines in previous methods are not required. The corresponding mechanism and the key roles of the organoborane were elaborated by the combination of H/D scrambling experiments, 11B NMR studies, intermediate trapping experiments and computational studies. This straightforward and mechanistically distinct organocatalytic technology not only opens a new door for the classical but still far less well-developed Chichibabin-type reaction, but also sets up a new platform for the development of novel C-C bond-forming methods.

Full text of DOI:10.1039/d0sc04808a

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DOI: 10.1039/D0SC04808A
ARTICLE
Organoborohydride-Catalyzed Chichibabin-Type C4-Position
Alkylation of Pyridines with Alkenes Assisted by Organoborane
Ying Wang,a† Runhan Li,b† Wei Guan,b Yanfei Li,a Xiaohong Li,a Jianjun Yin,a Ge Zhang,a Qian Zhang,a
Received 00th January 20xx,
Accepted 00th January 20xx
Tao Xiong,a* and Qian Zhanga,c*
DOI: 10.1039/x0xx00000x
The first NaBEt3H-catalyzed intermolecular Chichibabin-type alkylation of pyridine and its derivatives with alkenes as the
latent nucleophiles is presented with the assistance of BEt3, and a series of branched C4-alkylation pyridines, even highly
congested all-carbon quaternary center-containing triarylmethanes can be obtainned in a regiospecific manner. Therefore,
the conventional reliance on high cost and low availability transition metal catalysts, prior formation of N-activated
pyridines, organometallic reagents, and extra oxidation operation for the construction of C–C bond at the C4-position of the
pyridines in previous methods are not required. The corresponding mechanism and the key roles of organoborane were
elaborated by the combination of H/D scrambling experiments, 11B NMR studies, intermediate trapping experiments and
computational studies. This straightforward and mechanistically distinct organocatalytic technology not only opens a new
door for the classical but still far less well-developed Chichibabin-type reaction, but also sets up a new platform for the
development of novel C–C bond-forming methods.
reductive coupling reaction of pyridines and pyridazines with
aryl alkenes through a successive dearomatization/reoxidation
process.9a In addition, Shi et. al. also reported an
Introduction
The development of direct C–C bond-forming reactions of
pyridine and its derivatives is of paramount importance,
because these motifs are among the most important
heterocyclic structural skeletons and exist diffusely in a large
number of natural products, agrochemicals, FDA approved
drugs and functional materials.1 Therefore, numerous of
methods,2 including traditional electrophilic aromatic
substitution (SEAr), nucleophilic aromatic substitution of
organometallic reagents (SNAr),3 metalation-trapping strategy
with the strong base,2a,d,f radical-based Minisci-type reactions,4
and transition-metal-catalyzed C–H bond activation
reactions,5,6 have been well established to predominantly
access to a wide range of C2- and C3-positions functionalized
pyridine-containing molecules. By comparison, the direct C–C
bond-forming at the C4-position of pyridines is far less
developed.
Until recently, several highly atom-economical and cost-
effective protocols, including the pioneering bimetallic Ni/Al
catalysis7 and subsequent mono-transition-metal catalysis (e.g.,
Co, Cr, and Y),8 enabled C4-position selective alkylation and
alkenylation of pyridines have been achieved in recent years
(Scheme 1 A). More recently, Buchwald and co-workers have
pioneeringly disclosed a Cu-catalyzed asymmetric C4-position
unprecedented Ni-catalyzed intramolecular asymmetric C–H
cyclization of pyridines with alkenes.10 In spite of these
significant advances, some limitations, such as no method
enabling to generate all-carbon quaternary centers so far,
relying on the non-environmentally benign and undesirable in
pharmaceutical industry transition metal catalysts and
frequently accompanying some undesired side reactions such
as β-hydride elimination, indicated that the development of
transition metal free C4-position C–C bond-forming reaction of
pyridines is in high demand.
The Chichibabin amination reaction,11a which undergoes a C2-
position addition of the amine anion to pyridine with the aid of
the coordination of pyridine to the sodium cation, followed by
an elimination of NaH to form 2-aminopyridine, provided a
straightforward and alternative strategy for the synthesis of
functionalized pyridines under transition metal free conditions.
Although this approach has been established more than one
hundred years, the analogous examples have rarely been
reported to date, and moreover, the strongly basic
organolithium reagents as nucleophiles are indispensable in
these conversions (Scheme 1 B).11b,c Further, the more
challenging direct construction of C–C bond at the C4-position
by this method is still unexplored to date. The major issues for
the sluggish progress in this field might ascribe to: 1) the
inherently low electrophilicity of pyridines; 2) the requirement
of strongly basic organometallics as nucleophiles that could
result in competitive deprotonation/metalation; 3) and the
reluctant elimination of hydride from the resulting σH adducts
a. Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis,
Department of Chemistry, Northeast Normal University, Changchun 130024,
China. E-mail: xiongt626@nenu.edu.cn; zhangq651@nenu.edu.cn.
b. Institute of Functional Material Chemistry, Department of Chemistry, Northeast
Normal University, Changchun 130024, China.
c. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
China.
to provide pyridine cores in these processes. Indeed, almost all
H
of these nucleophilic aromatic substitution of hydrogen (SN
)
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
A.
Transtion-metal-catalyzed coupling of pyridines with alkenes and alkynes (ref.7-10)
Results and discussion
Optimization of reaction conditions
View Article Online
DOI: 10.1039/D0SC04808A
R'
D
N
R
D/H
H
H
H
R
R'
TM = Ni, Cu, Cr, Co,Y
TM
+
R
We initially selected styrene 1a and pyridine 2a as the pilot
substrates. After some trials, we delightedly found that the
reductive cross-coupling reaction in the presence of NaBEt3H as
hydride source with BEt3 as an additive indeed occurred, and
provided the C4-position selective branched product 3a in 90%
yield (Table 1, entry 1). Other hydride sources, such as KBEt3H,
LiBEt3H, LiBsBu3H, NaH and LiAlH4, were also effective “H-”
suppliers, providing 3a in the range of 34 to 90% yields (Table 1,
entries 2-6). Considering the reported significant effect of Lewis
acid in the reactivity profile and regioselectivity control of six-
membered heteroaromatic compounds,7,10,14 we subsequently
evaluated various Lewis acids. Experimental results showed
that B(n-Bu)3 exhibited comparable reactivity to BEt3, while
other Lewis acids including B(OiPr)3, Al(OiPr)3 and AlMe3 led to
the substantial decrease the yields (Table 1, entries 7-10).
Likewise, lowering the loading of either “H-” supplier or BEt3
also resulted in markedly decreased the yield (Table 1, entries
11-12). In addition, control experiments revealed that both
NaBEt3H and BEt3 were necessary for this transformation to
occur (Table 1, entries 13-14). Remarkably, combination of
catalytical amount of LiBsBu3H and BsBu3 instead of NaBEt3H
and BEt3 also showed excellent reactivity profile and the
branched coupling product 3a was afforded in excellent yield
(Table 1, entry 15). Unfortunately, we found that this reaction
condition
R
N
H
B.
Chichibabin-type C2-position C-C bond formation of pyridines (ref.11b,c)
D
D
N
D
H
H
H
R
H
Metal cation / Nu
Nu = RLi
R
R
R
N
Li
R
LiH
N
H
C.
State-of-the-art transtion-metal-free C4-position C-C bond formation of pyridines (ref.14)
D
D
Nu
H
1) Nucleophiles
(RM or Me3SiCmFn
H
H
H
H
R
)
BR3 (1.1 equiv)
R
+
R
+
N
H
N
2) PhI(O2CCF3)2
or chloranil
N
O
BR3
O
D. This work:
Catalytical Chichibabin-type C4-position alkylation of pyridines with alkenes
R2
Ar
R1
"H- + BR3"
R3
BR3
N
R2
R1
R2
N
R3
H
Ar
- "H- + BR3"
R1
R3
recyclable
Scheme 1 Direct C4-position C–C bond-forming of pyridines and Chichibabin-type
transformations
proceeded through departure of a proton via oxidative or
eliminative pathway rather than departure of a hydride anion
so far.12 To surmount these challenges, oxidative Chichibabin-
type two-step strategies (nucleophilic addition followed by
oxidative aromatization) for mainly access to C2-position
functionalized pyridine derivatives have been developed in
recent years.13 Recently, by introduction of the sterically bulky
Lewis acid to precisely control the regioselectivity, two
examples for direct C4-position C–C bond construction with
perfluoroalkylsilanes, Grignard, and organozinc reagents as
nucleophiles have also been successfully disclosed by Kanai, and
Knochel, respectively (Scheme 1 C).14 Despite these advances,
the presynthesis of activated pyridine salts, organometallics
and extra oxidation process are generally necessary.
Furthermore, the transition metal free catalytic version of
Chichibabin-type reaction has hitherto never been
demonstrated but is highly desirable, especially for directly
employing pyridines and readily available and bench-stable
alkenes as feedstocks.
Table 1 Optimization of reaction conditionsa
N
"H-" source (0.4 equiv)
additive (2.0 equiv)
+
THF, 100 oC,12 h
N
3a
1a
2a
entry
1
2
3
4
5
6
7
8
“H-” source
NaBEt3H
KBEt3H
LiBEt3H
LiBsBu3H
NaH
additive
BEt3
BEt3
BEt3
BEt3
Yield (%)b
90
79
80
64
90
34
89
20
15
35
73
15
0
BEt3
BEt3
LiAlH4
NaBEt3H
NaBEt3H
NaBEt3H
NaBEt3H
NaBEt3H
NaBEt3H
-
B(n-Bu)3
B(OiPr)3
Al(OiPr)3
AlMe3
BEt3
As
a
result of our continued interested in
hydrofunctionalization of alkenes and alkynes,15 herein, we
report an unprecedented NaBEt3H-catalyzed Chichibabin-type
C4-position alkylation of pyridines with alkenes as the latent
nucleophiles under the assistance of BEt3, wherein the
conventional transition metal catalyst,4-10 prior formation of N-
activated pyridines,2e,h,13,14 organometallic regents,2a-d,h,3,11a-d,14
and the extra oxidation operation9,14 were not required.
9
10
11c
12d
13
14
15e
BEt3
BEt3
NaBEt3H
LiBsBu3H
-
0
95
BsBu3
aReaction conditions: 1a (0.75 mmol, 1.5 equiv), 2a (0.5 mmol), NaBEt3H (0.2
mmol), BEt3 (1.0 mmol) in dry THF (1 mL) at 100 oC under N2 atmosphere. bYields
were determined by 1H NMR spectroscopy of the crude mixture, using CH2Br2 as
internal standard. c30 mol% NaBEt3H was used. d1.0 equiv BEt3 was used. e20 mol%
LiBsBu3H and 10 mol % BsBu3 were used.
Therefore, this method provides
a
convenient and
straightforward strategy to access an array of synthetic
important diarylmethanes and more challenging all-carbon
quaternary carbon center-containing triarylmethanes in a
perfect atom-economy manner (Scheme 1 D).
2 | J. Name., 2012, 00, 1-3
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ARTICLE
exhibited narrow substrate scope. It is worth noting that all the could otherwise be difficult to access.19 After briefly screening
View Article Online
DOI: 10.1039/D0SC04808A
reactions occurred at the 4-position of pyridine and 2-position the reaction conditions, to our delight, the alkylation reaction
alkylated pyridine was not observed.
Substrate scope
of 1,1-dibenzylethene with pyridine could proceed with
relatively lower loading of organoborohydride and milder
conditions (30 mol% NaBEt3H, 70 oC). The corresponding
coupling product 4a was afforded in 93% yield in a regiospecific
manner. Additionally, this reaction could be also performed at
room temperature, despite in relatively low yield and
requirement of prolonged reaction time (80% yield, 48 h). As
illustrated in Scheme 2B, various diversely functionalized 1,1-
diarylethylenes, including these aryl groups having alkyl,
methoxyl, methylthio, siloxy, silyl, alkenyl, phenyl, boronate,
fluoro-, chloro-, naphthyl- and heteroaryl, were found to be
valid substrates to furnish the corresponding products 4b-4o in
moderate to excellent yields. In addition, some representative
examples using NaH as the hydride supplier were also carried
out and corresponding expected products were indeed
obtained with similar reactivities compared with that of
NaBEt3H, as demonstrated by 3a-3d, 4a-4c. Additionally, to
demonstrate the practicality of this approach, we carried out
gram-scale synthesis of products 3a and 4a under the optimal
reaction conditions (See supporting information for details).
There were negligible changes in the chemical yields (88%, 79%
yields for 3a and 4a, respectively), suggesting that large-scale
chemical production might be possible.
With these optimized reaction conditions in hand, we then
examined the substrate scope of this NaBEt3H-catalyzed
Chichibabin-type alkylation of pyridines. As illustrated in
Scheme 2A, an array of styrenes bearing a variety of functional
groups, including -alkyl, -aryl, -OCH3, -OSiR3, -SCH3, -F, -Cl, -Br, -
OCF3, and -CF3, could be effectively cross-coupled with pyridine
and delivered corresponding products 3a-3v in generally good
to excellent yields with exclusive regioselectivities. The styrenes
1l and 1m containing silyl ether functional group and a relatively
strong acidic benzylic C–H bond, were well- tolerated under this
reaction conditions, providing corresponding products 3l and
3m in good yields. The accommodation of silyl ether and aryl
halides provided more opportunities for further elaborations. In
addition, lower reactivities of electron-donating functional
group, such as para-OMe and -Me substituted styrenes than
styrenes bearing electron-withdrawing functional groups (e. g.
-F, -Cl, -Br, and -OCF3,) was also observed, as demonstrated by
3f, 3i versus 3p-3t, 3v. Heteroaromatic substituted alkene, a
common scaffold in bioactivate relevant targets, was also
coupled with pyridine efficiently, furnishing expected product
3w in 75% yield. 1,4-Divinylbenzene and (-)-menthol-derived
styrene could also be converted into corresponding mono-
Mechanistic investigation
pyridation product 3x and 3y in moderate yields. The more To gain preliminary insight into the mechanism, a series of
steric hindrance α-methyl styrene, which can't be used as the control experiments were performed. As illustrated in Scheme
intermolecular coupling partner under the metal catalysis 3, a series of isotope labeling experiments were carried out
conditions,7-10 to our delight, was found to be suitable substrate firstly. The use of 2a-d5 (> 99% D) instead of 2a reacting with
to afford a quaternary carbon center-containing product 3z. In styrene under standard reaction conditions, 0.66
D
addition to terminal alkenes, aryl substituted internal alkenes incorporation at the β-position methyl of the product 5 was
were also compatible and the respective products 3aa and 3ab observed, which means the C4-pisition D atom of the pyridine
were obtained in good yields. Subsequently, a further study was indeed participated in the catalytic cycle (eq. 1). In addition,
initiated to explore the substrate scope regarding the pyridines. when commercially available LiAlD4 was used as hydride
Various alkyl-, aryl substituted pyridine derivatives could also be supplier instead of NaBEt3H, the coupling product 6 with 0.48 D
effectively alkylated with styrene, giving desired products 3ac- at the β-position was obtained and this result suggests the
3ah in the range of 50%-89% yields. Thienyl, methoxyl and addition of deuterium anion to alkene occurred (eq. 2).
synthetically versatile -B(pin) (pin = pinacolate) substituted Simultaneously, 0.36 D at the ortho-position of pyridine core in
pyridines, as well as fused pyridine derivatives found also valid
6 was observed. To explain this phenomenon, control
substrates for this transformation, delivering the corresponding experiment with 4-phenylpyridine as substrate in the presence
products 3ai-3am. For ortho-substituted pyridines, we noticed of LiAlD4 was performed, and 0.32 D incorporation at the ortho-
that these reactions became sluggish and required increased position of 4-phenylpyridine was also observed (See supporting
reaction temperature, which might be attributed to the steric information for details), indicating that a hydrogen/deuterium
hindrance.
exchange could be proceeded directly between pyridines and
The success with sterically hindered α-methyl styrene as LiAlD4. Moreover, we also conducted the reaction under
substrate encourages us to examine whether 1,1-diaryl alkenes optimal conditions with both LiAlD4 as hydride source and 2a-d5
could be used as the valid coupling components to synthesize as substrates, the corresponding deuterated product
7
structurally more intriguing all-carbon quaternary carbon containing 1.0 D in the methyl group was observed, which
center-containing triarylmethanes. These compounds are well- clearly reveals again that the newly introduced D atom in
known substructures in photochromic agents,16 leuco dye methyl group of the product entirely comes from the hydride
precursors,17 materials and medicinal chemistry,18 whereas that
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
N
N
N
N
N
N
N
N
A
View Article Online
DOI: 10.1039/D0SC04808A
H3C
Me
Me
Me
Me
Me
Me
Me
Me
tBu
4-CF3C6H4
H3CS
Me
H3C
C6H5
3c,
c
c
[d]
c
3g,
97%
3h,
c
94%
3a,
3d,
90%, (90%)
77%, (85%)
3f,
44%
3b,
3e,
87%,
55%, (40%)
96%, (91%)
N
N
N
N
N
N
N
N
H3CO
TBSO
H3CO
Me
Me
Me
MeO
Me
Me
Me
Me
Me
OCH3
H3CO
OCH3
92%
F
e
3l,
N
85%
3j,
N
3m, 60%
96%
3i,
3k,
72%
20%
3p,
89%
3o,
3n,
76%
N
N
N
N
N
N
F
Cl
Br
F3C
Me
Me
Me
Me
Me
Me
Me
Et
Me
S
F
F3CO
e
3r,
3t,
3u,
3w, 75%
3x,
57%
94%
3s,
84%
42%
84%
3q,
3v, 80%
86%
N
N
Me
N
N
N
N
Me
N
N
Me
Me
iPr
Et
Me
Me
O
Me
Me
Me
OMe
Me
Me
3aa,
3ae, 66%f
f
3af,
89%
3ad,
91%
3y,
72%
54%
3ac,
3z,
75%
50%
3ab,
78%
N
N
N
N
N
N
C6H5
N
C6H5
OCH3
BPin
S
Me
Me
Me
Me
Me
Me
Me
f
f
3am,
f
70%
3aj,
67%
3al,
56%
3ai,
60%
3ah,
75%
3ag,
70%
3ak,
50%
N
N
N
N
N
B
OTBS
OCH3
Me
Me
Me
4e
Me
Me
OCH3
c
Me
Me
c
c
, 90%
4a
4b,
75%, (92%)
, 93%, (90%)
4c
, 90%, (64%)
4d
, 97%
N
N
N
N
N
Bpin
O
O
O
Me
Me
Me
Me
4j
Me
4h
SiMePh2
SCH3
, 47%
4i
, 63%
4f
, 89%
4g
, 44%
, 71%
N
N
N
N
N
Cl
OCH3
F
Me
Me
Me
4m
Me
Me
S
Ph
4o
, 78%
4n
, 84%
4l, 45%g
, 90%
4k
, 91%
Scheme 2 Substrate scope of alkenes and pyridines.a,b aReaction conditions for A: styrenes (0.75 mmol, 1.5 equiv), pyridines (0.5 mmol), NaBEt3H (0.2 mmol), BEt3 (1.0
mmol) in dry THF (1.0 mL) at 100 oC for 12 hours under N2 atmosphere; yield was determined by 1H NMR spectroscopy of the crude mixture, using CH2Br2 as internal
standard. bReaction conditions for B: 1,1-diaryl alkenes (0.75 mmol, 1.5 equiv), pyridine (0.5 mmol), NaBEt3H (0.15 mmol), BEt3 (1.0 mmol) in dry THF (1.0 mL) at 70 o
C
for 12 hours under N2 atmosphere; isolated yields. cUsing NaH instead of NaBEt3H. d24% Alkene was recovered. e57% Alkene was recovered. fThese reactions were carried
out at 140 oC. g50% Alkene was recovered.
supplier and the para-position H atom of pyridine (eq. 3). BEt3-activated pyridine could readily generate and might be
Collectively, these isotopic labeling experimental results involved in this reaction. Moreover, the peak of BEt3 was
indicate the C4-pisition D atom of the pyridine departed as completely disappeared that suggests their strong interaction,
hydride anion and could then participate in the catalytic cycle. which might provide the potential clue of using stoichiometric
Moreover, several 11B NMR experiments were also conducted BEt3 in this Chichibabin-type alkylation reaction. Pleasing, either
to elucidate the possible intermediates in this transformation. the mixture of NaBEt3H and 4-fluorostyrene (1 : 1) or the
As shown in Figure 1A, two peaks were observed from the reaction of pyridine with 4-fluorostyrene under the standard
commercially available NaBEt3H solution (1.0 M in THF) and conditions, the same new signal was formed at -15.0 ppm, and
confirmed as BEt3 (δ = 86.5 ppm) and tetraorganoborate anion was confirmed as tetradentate benzylorganoborate anion
[BEt3H]- (δ = -16.8 ppm), respectively. This experiment indicates species,21 which means the tetradentate benzylorganoborate
that a dissociation equilibrium existed in the NaBEt3H solution. anion intermediate is likely involved in this catalytic reaction.
In addition, the 1 : 1 ratio of pyridine and BEt3 in THF showed a Besides, other signals, including tetradentate [BEt3H]- and the
new peak at 2.8 ppm, assigned as their complex,20 which means
4 | J. Name., 2012, 00, 1-3
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D
D
N
D
D
intermediate of the coupling between 1,1-dibenzVyileewtAhreticnleeOanlninde
pyridine, but the signal of the anDaOloIg: 1o0u.1s039t/eDt0raSCd0e4n8t0a8tAe
benzylorganoborate anion species was not detected by 11B
NMR experiment. Instead, a deep red color was formed
immediately when 1.1 equiv. NaBEt3H was added to the
solution of 1,1-dibenzylethene, which suggested 1-sodium-1,1-
diphenylethane was likely generated rather than its
corresponding organoborate.22 This probable intermediate was
further supported by trapping experiment with MeOH,
providing 1,1-diphenylethane 9 in 95% yield (Figure. 1B,
bottom).
NaBEt3H (50 mol%)
BEt3 (2 equiv)
THF, 100 oC, 12 h
D
D
D
D
( 1 )
D
D
+
0.66
D
N
H
H
1a
2a-
d5
5
36 % D
N
LiAlD4 (50 mol%)
BEt3 (2 equiv)
THF, 100 oC, 12 h
( 2 )
+
D
0.48 D
N
2
H
6
H
1a
D
N
D
D
LiAlD4 (50 mol%)
BEt3 (2 equiv)
THF, 100 oC, 12 h
D
D
D
D
( 3 )
D
D
D
+
1.0 D
N
H
H
7
To further shed light on the details of this transformation, we
conducted density functional theory (DFT) calculations. The
calculated free energy profile showed that the lone pair of N
atom in pyridine interacts with the empty orbital of B atom of
BEt3 to produce a relatively stable complex Sub2 with Gibbs free
energy change (ΔG°) of 4.1 kcal/mol (Figure 2A). Thus, the
Sub2 directly participates in the reaction. As shown in Figure 2B
(yellow line), NaBEt3H is initially combined with styrene through
the electrostatic interaction to form intermediate 1’ (5.1
kcal/mol exergonic), followed by an insertion of hydride ion into
C–C double bond process assisted by BEt3 to generate
intermediate 2’ and release the BEt3 (5.3 kcal/mol, via TS-1).
Then, 2’ could isomerize to a more stable intermediate 3’ (4.3
kcal/mol exergonic). The following nucleophilic addition of 3’ to
Sub2 occurs via TS2 to afford intermediate 4’ (20.0 kcal/mol).
By contrast, the nucleophilic addition to C2-position of Sub2 is
less favorable with a higher energy barrier of 22.3 kcal/mol
(Figure S18). Finally, as Lewis acid the BEt3 is again involved in
the hydride ion transfer to provide the target product 5’ (via TS-
3) and simultaneously regenerate the NaBEt3H. The hydride ion
transfer is the rate-determining step of the whole reaction,
which requires a moderate Gibbs activation energy (ΔG°⧧) value
of 25.0 kcal/mol relative to 3’. The present calculations are
consistent with the experimental results. This reaction can be
achieved at a temperature of 373 K. Moreover, we also
investigated the hydride ion insertion process without the extra
BEt3 (Figure 2B, black line). Obviously, these results clearly show
that the participation of the BEt3 dramatically accelerates the
insertion process and following reaction steps. Actually, the one
of key roles of BEt3 is generation of the stable intermediates 3’
and 4′, which are more stable than corresponding intermediates
7′ and 8′ and then lead to significantly stabilize the potential
energy surface and lower the energy barrier of the rate-
determining step. In addition, we have also presented the
molecular orbital distributions and energy levels of 3′, 4′, 7′ and
8′ in Figures 2b, respectively. The BEt3 coordination stabilizes
the HOMO levels of 3′ and 4′, respectively, leading the increases
in their HOMO-LUMO energy gaps, which makes the
intermediate 3′ and 4′ more stable (Figure S17). On the other
hand, the experimental phenomenon with 1,1-diaryl alkenes as
the alkylating reagents suggested that the tetradentate
benzylorganoborate anion species might be not involved in this
transformation (Figure 1B, bottom). This observation is further
2a-
1a
d5
Scheme 3 H/D Scrambling experiments.
complex of BEt3 with pyridine were also observed in the last 11
B
NMR experiment. In addition, the peaks at 55 and 53.5 in these
11B NMR spectra were likely to be Et2BOR analogues,21a which
indicates the decomposition of BEt3 might occur. To further
confirm the intermediate of this transformation, we proposed
that the tetraorganoborate anion intermediate might be
trapped by an oxidation step to form corresponding alcohol
(Figure 1B, top). Indeed, the reaction of 4-phenylstyrene with a
o
stoichiometric quantity of LiBEt3H in THF at 70 C, followed by
the treatment with an equimolar amount of methanesulfonic
acid and oxidation with NaOH/H2O2, 56% 1-phenylethanol 8
was isolated. This experimental result also provided positive
evidence that the tetradentate benzylorganoborate anion
species is generated in this NaBEt3H-catalyzed Chichibabin-type
alkylation reaction. Moreover, we also investigated the possible
a
BEt3
NaBEt3
H
-
[BEt3H]
BEt3
Et3
B N
BEt
1.0 equiv
3 + 1.0 equiv pyridine
-
BEt3
NaBEt
H
4-fluorostyrene
1.0 equiv
+ 1.0 equiv
3
F
0.5 equiv NaBEt3
H
pyridine
4-fluorostyrene
1.0 equiv
+ 1.0 equiv
Et3
B N
2.0 equiv BEt3
4-FC6H4
Et2BOR
b
BEt3
Me
BEt2
Na
CH3SO3
OH
Me
Ph
H
NaOH/H2O2
Me
THF, 70 o
C
+
Ph
Ph
Ph
NaBEt3
H
8
, 56 %
(1.1 equiv)
Me
Na
NaBEt3H (1.2 equiv)
THF, 70 oC, 12 h
CH3OH
Me
9
, 95 %
Figure 1. Intermediate investigation experiments
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J. Name., 2013, 00, 1-3 | 5
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ARTICLE
Journal Name
H
H
N
View Article Online
DOI: 10.1039/D0SC04808A
Sub1a =
A
B
BEt3
G = 4.1 kcal/mol
+
N
H
N
BEt3
Sub2 =
Et3B
TS1
HOMO
TS5
H
TS6
TS4
BEt3
Na
Na
Na
Na
BEt3
H
17.3
TS6
H
N
BEt3
N
H
BEt3
7'
BEt3
Na
3.84 eV
BEt3
H
15.6
TS2
N
BEt3
13.1
H
BEt3
TS4
TS3
11.7
8'
H
Na
BEt3
H
TS5
7'
Sub2
Na
29.2
NaBEt3H
3'
H
H
NaBEt3H
+
BEt3
5.77 eV
BEt3
8.1
TS2
BEt3
Na
6'
N
Na
BEt3
20.7
0.0
NaHBEt3
BEt3
2.6
0.2
7'
3.8
8'
TS1
TS3
6'
BEt3
3.4
25.0
Na
N
Sub1a
BEt3
BEt3
BEt3
Sub2
8'
5.3
5.1
1'
4.33 eV
20.0
7.6
2'
H
BEt3
BEt3
10.3
BEt3
11.9
4'
Na
Na
H
BEt3
11.5
5'
3'
H
Na
Na
H
2'
1'
BEt3
4'
N
BEt3
4.82 eV
3'
N
H
BEt3
BEt3
5'
4'
Substrate
Addition
H- Transfer
H- Insertion
C
D
Na
BEt3
H
BEt3
H
Na
BEt3
Na
H
H
N
H
BEt3
12.5
TS9
N
12.5
TS7
Et3B
BEt3
6.3
TS8
BEt3
BEt3
Sub2
1.7
10
+
20.7
NaHBEt3
0.0
NaHBEt3
20.7
Sub1b
3.4
11

H
8.2
Na
BEt3
N
9

Et3B
Na
BEt3
BEt3
Na
H
BEt3
11.6
Na
12

H
BEt3
N
H
H
Substrate
Addition
H- Insertion
H- Transfer
Figure 2. Calculated energy profiles of NaBEt3H-catalyzed alkylation reaction of pyridine with alkene. A, Calculated energy profile of pyridine with BEt3. B, DFT-computed
reaction pathway for NaBEt3H -catalysed alkylation of styrene with pyridine. C, The relative Gibbs energies and structures of different CB interactions between styrene
and 1,1-diphenylethene. D, DFT-computed reaction pathway for NaBEt3H -catalysed alkylation of diphenylethene with pyridine
supported by DFT calculations. The formation of CB bond kcal/mol relative to 9’, lower than that of styrene (25 kcal/mol).
during this process is energetically disfavored (Figure 2C, This is also consistent with the experimental results.
bottom, 10’→10”, 3.0 kcal/mol endergonic). Whereas the CB
On the basis of above experimental observations and
bond could significantly stabilize similar intermediate 6’ in the computational studies, a plausible mechanism of this NaBEt3H-
alkylation of pyridine with styrene (Figure 2C, top, 6’ →3’, 15.3 catalyzed Chichibabin-type alkylation reaction is depicted in
kcal/mol exergonic). Moreover, the Gibbs energy profiles of the Scheme 4. An addition of the hydride catalyst to alkene could
alkylation between 1,1-diphenylethene and pyridine was also occur firstly in the presence of organoborane, furnishing
provided (Figure 2D), and calculated result showed that the “organoborate” intermediate I,22 which has been recognized as
Gibbs activation energy of the rate-determining step is 20.7 a class of particularly versatile synthetic intermediate in organic
6 | J. Name., 2012, 00, 1-3
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Journal Name
synthesis.23 Intermediate
ARTICLE
I
could then undergo an
Conflicts of interest
View Article Online
DOI: 10.1039/D0SC04808A
intermolecular regioselective addition to organoborane-
activated heteroarenes II leading to σH-adduct intermediate III
and IV. Finally, an elimination of hydride anion, a Chichibabin-
type-like process,11 could occur with the assistance of
organoborane to furnish the expected alkylation product
simultaneously regenerate the hydride catalyst to participate
the next catalytic cycle. For the mechanism of alkylation of
pyridine with 1,1-diaryl alkenes, according to the experimental
phenomenon and computational studies, free 1,1-diphenyl
stabilized carbon anion intermediate rather than its
tetradentate benzylorganoborate species might react directly
with intermediate II to provide the product 4 and regenerate
the hydride catalyst. The relatively high loading of NaBEt3H and
BEt3 under the present catalytic conditions might be ascribed to
the ineluctable trace amount of water in the reaction, the
strong interaction of BEt3 with pyridine cores and the
There are no conflicts to declare.
Acknowledgements
We acknowledge the NSFC (21672033, 21801039 ， and
21831002), Jilin Educational Committee (JJKH20190269KJ), the
Fundamental Research Funds for the Central Universities, and
Ten Thousand Talents Program for generous financial support.
Notes and references
1
(a) J. W. Daly, H. M. Garraffo and T. F. Spande, in Alkaloids:
Chemical and Biological Perspectives, Vol. 13, (Ed.: W. W.
Pelletier), Elsevier: New York, 1999; 92-104; (b) E. Vitaku, D.
T. Smith and J. T. Njardarson, J. Med. Chem. 2014, 57, 10257-
10274; (c) Y. G. Skrypink and T. F. Doroshenko, Mater. Sci.
1996, 32, 537-544; (d) N. Leclerc, S. Sanaur, L. Galmiche, F.
Mathevet, A.-J. Attias, J. -L. Fave, J. Roussel, P. Hapiot, N.
Lemaître and B. Geffroy, Chem. Mater. 2005, 17, 502-513.
For leading reviews, see: (a) V. Snieckus, Chem. Rev. 1990, 90,
879–933; (b) P. Gros and Y. Fort, Eur. J. Org. Chem. 2002,
3375–3383; (c) M. Schlosser and F. Mongin, Chem. Soc. Rev.
2007, 36, 1161–1172; (d) P. C. Gros and Y. Fort, Eur. J. Org.
Chem. 2009, 4199–4209; (e) M. Ahamed and M. H. Todd, Eur.
J. Org. Chem. 2010, 5935–5942; (f) Y. Nakao, Synthesis 2011,
3209–3219; (g) C.-X. Zhuo, W. Zhang and S.-L. You, Angew.
Chem. Int. Ed. 2012, 51, 12662–12686; (h) J. A. Bull, J. J.
Mousseau, G. Pelletier and A. B. Charette, Chem. Rev. 2012,
112, 2642–2713; (i) Q. Ding, X. Zhou and R. Fan, Org. Biomol.
Chem. 2014, 12, 4807–4815; (j) K. Murakami, S. Yamada, T.
Kaneda and K. Itami, Chem. Rev. 2017, 117, 9302–9332.
(a) J. L. Jeffrey and R. Sarpong, Org. Lett. 2012, 14, 5400-5403;
b) F.-F. Zhuo, W.-W. Xie, Y.-X. Yang, L. Zhang, P. Wang, R. Yuan
and C.-S. Da, J. Org. Chem. 2013, 78, 3243-3249.
For recent reviews on Minisci reaction, see: (a) M. A. J.
Duncton, MedChemComm. 2011, 2, 1135-1161; (b) R. S. J.
Proctor and R. J. Phipps, Angew. Chem. Int. Ed. 2019, 58,
13666–13699; For Selected Examples, See: (c) F. Minisci, R.
Bernardi, F. Bertini, R. Galli and M. Perchinummo,
Tetrahedron. 1971, 27, 3575–3579; (d) Y. Fujiwara, V.
Domingo, I. B. Seiple, R. Gianatassio, M. D. Bel and P. S. Baran,
J. Am. Chem. Soc. 2011, 133, 3292–3295; (e) G. A. Molander,
V. Colombel and V. A. Braz, Org. Lett. 2011, 13, 1852–1855; (f)
D. A. Nagib and D. W. C. MacMillan, Nature 2011, 480, 224–
228; (g) Y. Fujiwara, J. A. Dixon, F. O. Hara, E. D. Funder, D. D.
Dixon, R. A. Rodriguez, R. D. Baxter, B. Herle, N. Sach, M. R.
Collins, Y. Ishihara and P. S. Baran, Nature 2012, 492, 95–99;
(h) A. P. Antonchick and L. Burgmann, Angew. Chem., Int. Ed.
2013, 52, 3267–3271; (i) R. A. Garza-Sanchez, A. Tlahuext-Aca,
G. Tavakoli and F. Glorious, ACS Cat. 2017, 7, 4057–4061；(j)
W. -M. Cheng, R. Shang and Y. Fu, ACS Cat. 2017, 7, 907–911；
(k) R. S. J. Proctor, H. J. Davis and R. J. Phipps, Science 2018,
360, 419–422.
decomposition of BEt3.
Na+ + [BEt3H]-
N
"NaH" + BR3
2
R'
H
BR3
N
+
R
N
NaH
Na
Na
H
R'
R3B
H
R'
BR3
BR3
Na
H
H
H
R'
III
IV
I
H
BR3
H
N
BR3
N
3
4
II
BR3
Scheme 4 Plausible mechanism.
Conclusions
In summary, we have developed the first NaBEt3H-catalyzed
Chichibabin-type alkylation of pyridines with alkenes in the
presence of BEt3 in a perfect atom-economical and regiospecific
fashion. This method allows for facile access an array of
branched C4-alkylation pyridines, without the requirement of
conventional transition metal catalyst, prior formation of N-
activated pyridines, organometallic reagents, and oxidation
process. Moreover, the highly congested all-carbon quaternary
center-containing triarylmethanes could also be efficiently
synthesized. The corresponding mechanism and the key roles of
organoborane were also elaborated by the combination of H/D
scrambling experiments, 11B NMR studies, intermediate
trapping experiments and computational studies. This novel
and mechanically complementary methodology could not only
open a new door for the classical but still infantile Chichibabin-
type reaction, but also set up a new platform for the
development of novel C–C bond-forming methods. Explorations
of the potential of this organoborohydride catalysis for C–C
bond formations is currently underway in our lab.
5
Selected literatures of C2-selectivity, see: (a) R. F. Jordan and
D. F. Taylor, J. Am. Chem. Soc. 1989, 111, 778–779; (b) S.
Rodewald and R. F. Jordan, J. Am. Chem. Soc. 1994, 116, 4491–
4492; (c) M. Murakami and S. Hori, J. Am. Chem. Soc. 2003,
125, 4720–4721; (d) J. C. Lewis, R. G. Bergman and J. A. Ellman,
J. Am. Chem. Soc. 2007, 129, 5332–5333; (e) Y. Nakao, K. S.
Kanyiva and T. Hiyama, J. Am. Chem. Soc. 2008, 130, 2448–
2449; (f) A. M. Berman, J. C. Lewis, R. G. Bergman and J. A.
Ellman, J. Am. Chem. Soc., 2008, 130, 14926–14927; (g) B.-T.
Guan and Z. Hou, J. Am. Chem. Soc. 2011, 133, 18086–18089;
(h) H. Kaneko, H. Nagae, H. Tsurugi and K. Mashima, J. Am.
This journal is © The Royal Society of Chemistry 20xx
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Page 8 of 9
ARTICLE
Journal Name
Chem. Soc. 2011, 133, 19626–19629; (i) B. Liu, Y. Huang, J. Lan, 20 A. V. Fedorov, A. A. Ermoshkin, A. Mejiritski and VDie.wCA.rNticelecOkenlrinse,
F. Song and J. You, Chem. Sci. 2013, 4, 2163–2167; (j) D. G. Macromolecules. 2007, 40, 3554-3560D. OI: 10.1039/D0SC04808A
Johnson, J. M. Lynam, N. S. Mistry, J. M. Slattery, R. J. Thatcher 21 (a) R. B. Bedford, N. J. Gower, M. F. Haddow, J. N. Harvey, J.
and A. C. Whitwood, J. Am. Chem. Soc. 2013, 135, 2222–2234;
(k) G. Song, W. N. O. Wylie and Z. Hou, J. Am. Chem. Soc. 2014,
136, 12209–12212; (l) H. Nagae, H. Tsurugi and K. Mashima, J.
Nunn, R. A. Okopie and R. F. Sankey, Angew. Chem. Int. Ed.
2012, 51, 5435-5438; (b) M. Wang, X. Pu, Y. Zhao, P. Wang, Z.
Li, C. Zhu and Z. Shi, J. Am. Chem. Soc. 2018, 140, 9061–9065.
Am. Chem. Soc. 2015, 137, 640–643; (m) A. Kundu, M. Inoue, 22 H. C. Brown and S. -C. Kim, J. Org. Chem. 1984, 49, 1064–1071.
H. Nagae, H. Tsurugi and K. Mashima, J. Am. Chem. Soc. 2018, 23 C. G.Watson, P. J. Unsworth, D. Leonori, & V. K. Aggarwal,
140, 7332–7342.
Lithium-Boron Chemistry: A Synergistic Strategy in Modern
Synthesis. In Lithium Compounds in Organic Synthesis. Luisi, R.;
Capriati, V., eds.; Wiley, 2014, 397-422.
6
7
8
9
Selected literatures of C3-selectivity, see: (a) M. Ye, G.-L. Gao
and J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 6964–6967; (b) M.
Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A. Morris
and J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 19090–19093; (c) P.
Guo, J. M. Joo, S. Rakshit and D. Sames, J. Am. Chem. Soc. 2011,
133, 16338–116341.
(a) C. -C. Tsai, W. -C. Shih, C. -H. Fang, C. -Y. Li, T. -G. Ong and
A. G. P. Yap, J. Am. Chem. Soc. 2010, 132, 11887–11889; (b) Y.
Nakao, Y. Yamada, N. Kashihara and T. Hiyama, J. Am. Chem.
Soc. 2010, 132, 13666–13668; (c) W. -C. Lee, C. -H. Chen, C. –
Y . Liu, M. -S. Yu, Y. -H. Lin and T. G. Ong, Chem. Commun. 2015,
51, 17104–17107.
(a) T. Andou, Y. Saga, H. Komai, S. Matsunaga and M. Kanai,
Angew. Chem. Int. Ed. 2013, 52, 3213–3216 ； (b) Y. Li, G.
Deng and X. Zeng, Organometallics. 2016, 35, 747–750;
Transition-metal-mediated Alkylation with Additional Hydride
Source, see: (c) T. Mizumori, T. Hata and H. Urabe, Chem. Eur.
J. 2015, 21, 422–426.
(a) M. W. Gribble, Jr, S. Guo and Buchwald, S. L. J. Am. Chem.
Soc. 2018, 140, 5057-5060; (b) M. W. Gribble, Jr, R. Y. Liu and
S. L. Buchwald, J. Am. Chem. Soc. 2020, 142, 11252–11269.
10 W.-B. Zhang, X.-T. Yang, J. -B. Ma, Z.-M. Su and S.-L. Shi, J. Am.
Chem. Soc. 2019, 141, 5628–5634.
11 (a) A. E. Chichibabin and O. A. Zeide, J. Russ. Phys. Chem. Soc,
1914, 46, 1216; (b) J. C. W. Evans and C. F. H. Allen, Org. Synth.
1938, 18, 70; (c) J. L. Jeffrey and R. Sarpong, Org. Lett. 2012,
14, 5400–5403; Transition-metal-catalysed Chichibabin-type
C2-position functionalization, see: (d) M. Tobisu, I. Hyodo and
N. Chatani, J. Am. Chem. Soc. 2009, 131, 12070, and also see
ref. 8a. Related fluorination reaction, see: (e) P. S. Fier and J.
F. Hartwig, Science 2013, 342, 956–960.
12 (a) M. Mąkosza and K. Wojciechowski, Chem. Rev. 2004, 104,
2631-2666; (b) M. Mąkosza, Chem. Soc. Rev. 2010, 39, 2855–
2868; (c) O. N. Chupakhin and V. N. Charushin, Tetrahedron
Lett. 2016, 57, 2665–2672.
13 For reviews, see: (a) D. M.Stout and A. I. Meyers, Chem. Rev.
1982, 82, 223-243; (b) R. Lavilla, J. Chem. Soc., Perkin Trans. 1
2002, 1141-1156; (c) H. Andersson,; R. Olsson and F. Almqvist,
Org. Biomol. Chem. 2011, 9, 337-346; (d) J. A. Bull, J. J.
Mousseau, G. Pelletier and A. B. Charette, Chem. Rev. 2012,
112, 2642.
14 (a) Q. Chen, X. M. du Jourdin and P. Knochel, J. Am. Chem. Soc.
2013, 135, 4958–4961; (b) M. Nagase, Y. Kuninobu and M.
Kanai, J. Am. Chem. Soc. 2016, 138, 6103–6106.
15 (a) G. Xu, H. Zhao, B. Fu, A. Cang, G. Zhang, Q. Zhang, T. Xiong
and Q. Zhang, Angew. Chem. Int. Ed. 2017, 56, 13130–13134;
(b) G. Xu, B. Fu, H. Zhao, Y. Li, G. Zhang, Y. Wang, T. Xiong and
Q. Zhang, Chem. Sci. 2019, 10, 1802–1806; (c) B. Fu, X. Yuan,
Y. Li, Y. Wang, Q. Zhang, T. Xiong and Q. Zhang, Org. Lett. 2019,
21,3576−3580. (d) G. Zhang, Y. Liang, T. Qin, T. Xiong, S. Liu,
W. Guan and Q. Zhang, CCS Chemistry 2020, doi:
10.31635/ccschem.020.202000434.
16 D. F. Duxbury, Chem. Rev. 1993, 93, 381−433.
17 P. Ryss and H. Zollinger, Fundamentals of the chemistry and
application of dyes; Wiley VCH, 1972.
18 M. S. Shchepinov and V. A. Korshun, Chem. Soc. Rev. 2003, 32,
170−180.
19 M. Nambo and C. M. Crudden, ACS Catal. 2015, 5, 4734–4742.
8 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0SC04808A
Cat.
"H- + BR3"
R2
R1
Ar
R3
R2
R1
BR3
N
R2
N
R3
H
Ar
- "H- + BR3"
R1
R3
recyclable
no N-activated pyridines


hydride catalysis
perfect atom economy


 no transition metal catalyst
all-carbon quaternary center
no organometallic regents
