ZnMe2-Mediated, Direct Alkylation of Electron-Deficient N-Heteroarenes with 1,1-Diborylalkanes: Scope and Mechanism

Article abstract of DOI:10.1021/jacs.0c06827

The regioselective, direct alkylation of electron-deficient N-heteroarenes is, in principle, a powerful and efficient way of accessing alkylated N-heteroarenes that are important core structures of many biologically active compounds and pharmaceutical agents. Herein, we report a ZnMe2-promoted, direct C2- or C4-selective primary and secondary alkylation of pyridines and quinolines using 1,1-diborylalkanes as alkylation sources. While substituted pyridines and quinolines exclusively afford C2-alkylated products, simple pyridine delivers C4-alkylated pyridine with excellent regioselectivity. The reaction scope is remarkably broad, and a range of C2- or C4-alkylated electron-deficient N-heteroarenes are obtained in good yields. Experimental and computational mechanistic studies imply that ZnMe2 serves not only as an activator of 1,1-diborylalkanes to generate (α-borylalkyl)methylalkoxy zincate, which acts as a Lewis acid to bind to the nitrogen atom of the heterocycles and controls the regioselectivity, but also as an oxidant for rearomatizing the dihydro-N-heteroarene intermediates to release the product.

Full text of DOI:10.1021/jacs.0c06827

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Article
2
ZnMe-Mediated, Direct Alkylation of Electron Deficient N-
Heteroarenes with 1,1-Diborylalkanes: Scope and Mechanism
Woohyun Jo, Seung-yeol Baek, Chiwon Hwang, Joon Heo, Mu-Hyun Baik, and Seung Hwan Cho
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06827 • Publication Date (Web): 30 Jun 2020
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Journal of the American Chemical Society
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ZnMe2-Mediated, Direct Alkylation of Electron Deficient N-
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Woohyun Jo,†,‖ Seung-yeol Baek,‡,§,‖ Chiwon Hwang,† Joon Heo,‡,§ Mu-Hyun Baik,*,§,‡ and Seung
Hwan Cho*,†
†Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Rep. of Korea
‡Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Rep. of Korea
§Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, 34141, Rep. of Korea
Supporting Information Placeholder
ABSTRACT: The regioselective, direct alkylation of electron-deficient N-heteroarenes is, in principle, a powerful and efficient way
of accessing alkylated N-heteroarenes that are important core structures of many biologically active compounds and pharmaceutical
agents. Herein, we report a ZnMe2-promoted, direct C2- or C4-selective primary and secondary alkylation of pyridines and quinolines
using 1,1-diborylalkanes as alkylation sources. While substituted pyridines and quinolines exclusively afford C2-alkylated products,
simple pyridine delivers C4-alkylated pyridine with excellent regioselectivity. The reaction scope is remarkably broad, and a range
of C2- or C4-alkylated electron-deficient N-heteroarenes are obtained in good yields. Experimental and computational mechanistic
studies implicate that ZnMe2 serves not only as an activator of 1,1-diborylalkanes to generate (-borylalkyl)methylalkoxy zincate,
which acts as a Lewis acid to bind to the nitrogen atom of the heterocycles and controls the regioselectivity, but also as an oxidant
for rearomatizing the dihydro-N-heteroarene intermediates to release the product.
Introduction
Scheme 1. Alkylation of Electron Deficient N-Heteroarenes via
Nucleophilic Addition Strategy
Construction of carbon-carbon bonds is of central importance in
synthetic chemistry. In particular, efficient and selective methods
for the alkylation of simple electron-deficient N-heteroarenes, such
(a) Addition of organometallic reagents to electron deficient N-heteroarenes
as pyridines and quinolines, received much attention, in part
R3
N
R3
because of the ubiquity of alkylated pyridines and quinolines in
many natural products, pharmaceuticals, and agrochemicals.1
Although the direct alkylation of pyridines and quinolines are
possible using transition metal-catalyzed C–H activation
strategies,2 these methods often show limited scope, and installing
a methyl group proved particularly difficult. Recently, remarkable
success was achieved employing a Minisci-type C–H alkylation
reaction mediated by radicals, which enabled the rapid and direct
synthesis of methylated- or alkylated pyridines and quinolines.3,4
Fundamentally, a straightforward method for installing alkyls on
pyridines and quinolines may be to add carbon nucleophiles,
followed by the rearomatization of the N-heterocycle (Scheme 1a)
and previous implementations employed activated pyridines such
as N-oxidized, N-acylated, or N-alkylated heteroarenes.5,6 The
regioselective direct alkylation of simple pyridines and quinolines
remains underexplored, however. In 2013, Knochel and coworkers
R3 [M]
[M] = Li
[O]
R1
R1
R1
or
R1
or
R1
R3
N
R3
N
N
N
R2
MgX
R2
R2
ZnX
SiR3
(b) This work: Zinc-promoted deborylative alkylation of electron deficient N-heteroarenes
R2
R3
R1 R2
pinB Bpin
ZnMe2, LiOtBu
R1
R2
R1
+
or
N
N
R3
N
R2
Bpin
R3
N
ZnMe2
likely via:
H
R1
LiOtBu
Li
R1
R2 Me
H
R2
R3
Bpin
R1
N
Me Bpin
or
N
Me Zn
OtBu
Zn OtBu
pinB
Me Zn
OtBu
(-borylalkyl)methylalkoxy zincate
described
a BF3·OEt2-promoted, C4-selective alkylation of
Despite these advances, the reactions required an extra step for the
rearomatization of 1,2-dihydro-N-heteroarene intermediates,
generated by nucleophilic attack of organometallic reagents on N-
heteroarenes. In this context, Sarpong et al. described the oxidant-
free, direct C2-alkylation of pyridyl alcohol using alkyl lithiums as
nucleophiles; but, the reaction showed a limited scope of
pyridines.9
Recently, we disclosed a base-promoted, C2-selective primary
and secondary alkylation of pyridine- and quinoline-N-oxides
employing 1,1-diborylalkanes as alkylation reagents.10 This
pyridines and quinolines using Grignard or organozinc species as
alkylating reagents.7 Kanai and Kuninobu reported a C4-selective
perfluoroalkylation of pyridines and quinolines with
perfluoroalkyltrimethylsilane using a sterically bulky borane such
as B(C6F4-4-CF3)3 as an activator.8a
A
C2-selective
trifluoromethylation of quinolines with trifluoromethyl
trimethylsilane in the presence of trifluoroacetic acid, KHF2, and
1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone was also
reported.8b
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Table 1. Evaluation of Reaction Conditions for the Methylation of 1a with 2aa b
1
2
3
4
5
6
7
8
Me
Me
N
additive
base
+
pinB
Bpin
solvent
120 oC, 3 h
N
Me
1a
2a
3a
entry
1
additive (equiv)
BF3·Et2O (1.0)
B(C6F5)3 (1.0)
ZnMe2 (1.0)
ZnMe2 (0.5)
ZnMe2 (1.0)
ZnMe2 (1.0)
ZnEt2 (1.0)
ZnPh2 (1.0)
Zn(OtBu)2 (1.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
ZnMe2 (2.0)
-
base (equiv)
yield of 3a (%)b
solvent
temp (°C)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
NaOtBu (2.0)
KOtBu (2.0)
LiOMe (2.0)
NaOMe (2.0)
KOMe (2.0)
LiOtBu (1.0)
LiOtBu (0.5)
LiOtBu (2.0)
LiOtBu (2.0)
LiOtBu (2.0)
-
toluene
toluene
toluene
toluene
THF
<1
<1
48
23
37
38
40
42
<1
78 (78)c
24
8
2
9
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
5
6
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
5
61
<1
70
62
66
48
<1
<1
120
120
ZnMe2 (2.0)
aConditions: 1a (0.10 mmol), 2a (2.0 equiv), additive (0.50-2.0 equiv), base (0.50-2.0 equiv) and solvent (1.0 mL) at 120 °C for 3 h. b1H-
NMR yield was determined using 1,1,2,2-tetrachloroethane as an internal standard. cIsolated yields are given in parentheses.
process was thought to proceed by the nucleophilic attack of in situ
generated -borylcarbanion to pyridine-, quinoline-N-oxides, and
to be an activator in the Ni-catalyzed C-H alkenylation and
arylation of pyridine derivatives,11 we surveyed the effect of
dialkylzinc as an additive. Adding 1.0 equivalent of ZnMe2 under
the reaction conditions, the desired C2-methylated product (3a)
was formed in 48% yield (entry 3), suggesting that the combination
of 2a, LiOtBu, and ZnMe2 facilitates the methylation of 1a.
Reducing the quantity of ZnMe2 to 0.5 equivalent decreased the
yield of 3a (entry 4). Other ethereal solvents such as THF and 1,4-
dioxane also lowered the yield (entries 5 and 6). Alternative zinc
reagents such as ZnEt2 or ZnPh2 proved inferior to ZnMe2 (entries
7 and 8), and Zn(OtBu)2 did not promote the methylation (entry 9).
The highest yield of 3a was obtained when 2.0 equivalents of
ZnMe2 was added (entry 10). Subsequent screening of bases
revealed that LiOtBu was most effective for the methylation of 1a
(entries 10-15). Interestingly, the product 3a was obtained even 1.0
and 0.5 equivalents of LiOtBu (entries 16 and 17). Further
lowering of the reaction temperature decreased the reaction
efficiency (entries 18 and 19). Control experiments showed that
both ZnMe2 and LiOtBu were crucial for the reaction (entries 20
and 21). Of note, the reaction of quinoline (1b) with deuterated
diborylmethane (2a-d2) led to the deuterium containing C2-
methylated product 3b-d3, indicating that the methylation source
was solely derived from 2a, not from ZnMe2 (vide infra).
subsequent
deborylative
aromatization,
thus
affording
deoxygenated C2-alkylated pyridines and quinolines. Although
these reactions provide an attractive route to C2-alkylated electron-
deficient N-heteroarenes, the need to prepare and isolate N-oxides
made them less attractive. We envisioned that an appropriate Lewis
acid additive might enhance the electrophilicity of the electron-
deficient N-heteroarenes enough to offer a solution. Herein, we
report a successful ZnMe2-promoted, substrate-dependent direct
C2- or C4-selective alkylation of pyridines and quinolines using
1,1-diborylalkanes as bench-top stable alkyl nucleophiles (Scheme
1b). The reaction affords a wide range of primary and secondary
alkylated pyridines and quinolines with excellent regioselectivity.
Although substituted pyridines and quinolines exclusively
provided C2-alkylated products, simple pyridine gave C4-alkylated
pyridine with high regioselectivity. The mechanism of this useful
reaction was investigated in detail by combining experimental and
computational methods.
Results and Discussion
Reaction Development. First, we sought to identify a suitable
Lewis acid for the reaction of lepidine (1a) with diborylmethane
(2a) in the presence of the base LiOtBu. When 1a and 2a were
subjected to a stoichiometric amount of a boron Lewis acid such as
BF3·Et2O or B(C6F5)3 in toluene at 120 °C (Table 1, entries 1 and
2),7,8 no desired product 3a was obtained, presumably owing to the
formation of a boron-alkoxide adduct. Since dialkylzinc is known
Scope for the C2-Selective Alkylation of Substituted
Pyridines and Quinolines. With the optimized reaction conditions
in hand, the scope of electron-deficient N-heteroarene substrates
was explored (Table 2a). Simple quinoline and quinolines bearing
electron-donating substituents at the C4-, C6-, C7-, and C3-position
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Table 2. Scope for the C2-Selective Alkylation of Substituted Pyridines and Quinolinesa
1
2
3
4
ZnMe2 (2.0-3.0 equiv)
R2 R3
R1
LiOtBu (2.0-3.0 equiv)
R1
+
R3
toluene, 120 oC, 3 h
pinB
Bpin
N
N
R2
5
(a) scope of N-heteroarene
6
7
8
9
Me
Ph
Me
Me
R
N
N
Me
Me
N
Me
N
Me
N
Me
N
Me
3a
3b
3c
3d
3g
, 70%
3h
, 80%
, 78%
, 64%
, 73%
, R = Ph, 78%
, R = OMe, 73%
, R = Me, 78%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3e
3f
Ph
O
O
Ph
Me
X
Ph
N
N
N
N
Me
N
Me
N
Me
N
Me
N
Me
c,d
b
b
3o
, 58%
3i
3j
3k
, 65%
3l
, 67%
3m
, 78%
3n
, 58%
, X = Br, 45%
, X = Cl, 50%
MeO
TMSO
Ph
N
Me
Me
N
Me
N
MeO
N
Me
N
Me
N
N
Me
N
Me
Me
b,c,d
c,d
c,d
b
b
b,c
3p
3q
3r
3s
, 47%
3t
, 30%
3u
, 66%
, 64%
, 45%
, 45%
(b) scope of 1,1-diborylalkane
R
O
Me
N
Ph
O
N
Me
N
N
Me
Me
N
b
b
c
4a
, R = Me, 88%
4b
4c
, 75%
4d
, 73%
4e
, 57%
4f
, 72%
, R = H, 64%
Ph
OH
Ph
Me
Ph
Me
O
O
N
N
Me
Me
Ph
N
Ph
Me
N
N
b,c
b
b,d
d
c
4g
, 61%
4h
4i
4j
, 73%
4k
, 73%
, 40%
, 68%
Ph
N
MeO
MeO
Me
Me
Me
Me
Me
Me
N
Me
N
N
N
Me
Me
Me
Me
Me
b
c
c
b
b,c,d
4l
, 64%
4m
4n
, 71%
4o
, 60%
4p
, 52%
, 61%
Me
Ph
H
H
O
OTBS
OTBS
Me
F
H
H
H
H
O
O
N
N
N
H
O
F
H
Me
H
Me
O
H
N
Me
Me
Me
Me
Me
Me
O
H
b,c,e
b,c,d,e
b,c,e
b,c,e
4q
4r
4s
4t
, 77%
, 78%
, 58%
, 62%
Me
Me
Me
Me
O
O
TMSO
standard
conditions
TMSO
O
H
N
N
O
O
MeO
+
MeO
Bpin
O
H
O
O
O
pinB
O
N
O
Me
Me
N
O
b,c,e
Me
4u
, 32%
Me
aConditions: 1 (0.20 mmol), 2 (2.0 equiv), LiOtBu (2.0 equiv), ZnMe2 (2.0 equiv) and toluene (2.0 mL) at 120 C for 3 h. 3.0 Equiv of
LiOtBu and ZnMe2 were used. The reaction was performed for 12 h. THF was used as a solvent instead of toluene. The reaction was
o
b
c
d
e
performed on 0.10 mmol scale.
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gave the methylated products 3b-3h in good yields. 6-Chloro- and
Scheme 2. Probe for a Radical Mechanism
1
2
3
4
5
6
7
8
6-bromoquinoline were successfully reacted with 2a, leaving the
chloro and bromo groups intact (3i and 3j) for further elaboration.
The reaction conditions were compatible with quinolines
containing morpholinyl (3k and 3l), alkenyl (3m), and alkynyl (3n)
moieties, although 3k and 3l required 3.0 equivalents of ZnMe2 and
LiOtBu for satisfactory yields. The reaction conditions could also
be applied to directly methylate 4-phenylpyridine derivatives and
the corresponding mono-methylated products 3o – 3q were
obtained with excellent selectivity in the THF after a prolonged
reaction time (12 h). The reaction of 3-phenylpyridine with 2a
solely afforded 2-methyl-5-phenylpyridine (3r). When 2,2'-
bipyridine derivative such as 6-(sec-butyl)-2,2'-bipyridine was
employed as a substrate, the product 3s was formed in synthetically
acceptable yields. Isoquinoline was amenable for the coupling
partner to yield 3t in the presence of an excess amount of LiOtBu
and ZnMe2, albeit with a low yield. The reaction of O-TMS-
protected-quinine furnished 3u in moderate yield in the presence of
3.0 equivalents of LiOtBu and ZnMe2 after 12 h.
Next, we turned our attention to investigate the scope of the 1,1-
diborylalkane reactant (Table 2b). The reactions of quinoline with
1,1-diborylalkanes containing a simple alkyl chain (4a – 4c), an
alkene (4d), a masked aldehyde (4e), and aryl (4f and 4g) groups
led to the primary alkylated products in moderate to good yields.
Quinoline bearing tertiary alcohol group smoothly proceeded the
alkylation, affording 4h in moderate yield. 4-Phenylpyridine also
underwent the mono-alkylation reaction, affording 4i and 4j in
good yield. We were pleased to observe that the C2-selective
secondary alkylation of quinoline and pyridine derivatives could be
achieved by employing internal 1,1-diborylalkanes as nucleophiles.
Reactions of quinolines (4k – 4o) or 4-phenylpyridine (4p) with
various internal 1,1-diborylalkanes displayed good efficiencies
under the standard reaction conditions. Notably, the zinc-mediated
alkylation could be accomplished using 1,1-diborylalkanes derived
from biologically active compounds.12 The reactions of quinoline
or 4-phenylpyridine with 1,1-diborylalkanes prepared from
lithocholic acid (4q and 4r) and diacetone-D-glucose (4s) delivered
the corresponding alkylated products in moderate to good yields.
1,1-Diborylalkane containing fluorinated liquid crystal material
also readily reacted with quinoline, giving the corresponding
product 4t in good yield. Finally, to test this novel method in the
context of a more complex synthesis, we carried out the C2-
(a) Radical inhibition experiment in the presence of 9,10-dihydroanthracene (DHA)
DHA (5.0 equiv)
ZnMe2 (2.0 equiv)
Me
N
Me
LiOtBu (2.0 equiv)
+
pinB
Bpin
toluene
120 oC, 3 h
N
Me
1a
2a
3a
, 72%
9
(b) Radical clock experiment
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
Me
ZnMe2 (3.0 equiv)
O
3v
, 15%
LiOtBu (3.0 equiv)
+
pinB
Bpin
+
toluene
120 oC, 3 h
N
O
2a
1v
N
R
5
R = Bpin, , <1%
6
R = H, , <1%
retardation in the reaction rate. Furthermore, when the quinoline
substrate bearing a pendent alkene moiety at C3 position was
subjected with 2a under the reaction conditions, the C2-methylated
product 3v was exclusively obtained in a low yield; No other
cyclized products 5 and 6 were detected. These experiments rule
out a mechanism involving a radical intermediate.
A nucleophilic aromatic substitution mechanism can reasonably
be considered, but previous studies indicated that LiOtBu alone
was incapable of generating nucleophilic species from 1,1-
diborylalkanes.10,14 Thus, the combination of ZnMe2 and LiOtBu
appears important for generating an active nucleophile under the
reaction conditions. When 1,1-diborylethane 2b was treated with
benzophenone (7) in the presence of ZnMe2 and LiOtBu in toluene
at 50 °C (Scheme 3), the corresponding -hydroxyboronate ester 8
was obtained in 82% yield. No reaction took place when ZnMe2 or
LiOtBu was solely employed under the reaction conditions,
confirming that both ZnMe2 and LiOtBu must be present.
Scheme 3. Capturing Potential Nucleophile by the Reaction of
2b with Benzophenone
alkylation employing
a complex N-heteroarene and 1,1-
O
diborylalkane bearing biologically relevant molecule. When O-
TMS-protected-quinine and 1,1-diborylalkane derived from
diacetone-D-glucose were allowed to react under the reaction
conditions, the corresponding product 4u was obtained, albeit in
low yield. While several elegant strategies for the late-stage
alkylation of electron-deficient N-heteroarenes have been
developed,3 most approaches have primarily focused on
introducing simple alkyl groups to complex electron-deficient N-
heteroarenes. Therefore, we anticipate that the developed protocol
would offer a powerful platform for the synthesis of highly
complex C2-alkylated N-heteroarenes.
Ph
Ph
7
8
yield (%) of
Bpin
Me
additive
Bpin
Me
additive
Ph
Ph
ZnMe2, LiOtBu
ZnMe2
82%
<1%
<1%
toluene, 50 o
C
pinB
OH
LiOtBu
2b
8
Subsequently, we monitored the reaction of 2a, ZnMe2, and
LiOtBu in toluene-d8 at 50 °C by 1H NMR spectroscopy (Figure 1)
and observed that 2a was consumed over time, while new 1H NMR
signals were observed at 1.04 and 0.30 ppm corresponding to
MeBpin. Importantly, the intensity of the 1H NMR signal at –0.68
ppm for ZnMe2 was decreased, and new signals at 1.34 and –0.20
ppm appeared, which we assigned to be the MeZn(OtBu)
species.15,16
The mechanism for the generation of the reactive nucleophile
shown in Scheme 4 incorporates all observations discussed so far,
and Figure 2 shows the DFT-calculated Gibbs free energy profile
for the reaction of quinoline (1b) and diborylmethane (2a, R2 = R3
= H) as model substrates.17 The reaction initiates with a methyl
transfer from ZnMe2 to 2a assisted by LiOtBu via the intermediate
914 to yield the methyl-boronate complex 1018 and the MeZn(OtBu)
species. The activated intermediate 10 can easily liberate MeBpin
Mechanistic Studies for the C2-Selective Alkylation of
Substituted Pyridines and Quinolines. To gain insight into the
mechanism of the C2-selective alkylation of substituted pyridines
and quinolines, we performed a series of experiments combined
with density functional theory (DFT) calculations. Since it is well-
established that ZnMe2 can initiate radical reactions,13 we
examined whether our reaction involves a radical pathway. Radical
inhibition experiments were carried out by adding a radical
scavenger, 9,10-dihydroanthracene (DHA), to the reaction. The
reaction of 1a and 2a with an excess amount of DHA (5.0 equiv)
under the optimized reaction conditions furnished the desired C2-
methylated product 3a in 72% yield, and there was no significant
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Scheme 4. First Part of Proposed Mechanism for the
Generation of Potential Nucleophiles
1
2
ZnMe2
+
LiOtBu
3
4
5
6
7
8
2Li
pinB
Bpin
tBu
Li
Me
Zn
Me
Me
Me
2a
O
pinB
Bpin
Me
Zn
O
tBu
MeZn(OtBu)
10
9
9
10
11
12
13
14
15
16
17
18
19
MeBpin
Li
Li
MeZn(OtBu)
pinB
ZnMe
H2C Bpin
H2C Bpin
OtBu
11
12
binding to a nearby MeZn(OtBu) species to give a stable zincate
intermediate 12 at –12.9 kcal/mol.20 By engaging a quinoline
substrate 1b, the zincate intermediate 12 can form the energetically
slightly higher 13 at –10.9 kcal/mol.
For the reaction to proceed, the borylmethyl functionality must
be released from the resting state 13 and nucleophilically attack the
N-heteroarene. Our calculations indicate that the Zn–C bond can be
cleaved via 13-TS to afford the transient intermediate 14 at 11.4
kcal/mol, where the borylmethyl anion moved away from the
zincate and is electrostatically stabilized by the lithium cation. This
step highlights the role of the zincate as a nucleophile carrier that
captures the nucleophilic anionic borylmethyl group and delivers it
to the electrophilic reaction partner.
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Monitoring the reaction of 2a, ZnMe2, and LiOtBu in
toluene-d8 at 50 °C by 1H NMR spectroscopy.
traversing the transition state 10-TS, which is 23.1 kcal/mol higher
in energy than the resting state complex 2a'. Binding one
equivalent of LiOtBu to zinc is important for this C–B cleavage
step, as the barrier becomes much too high at 34.8 kcal/mol without
it.19 This finding is in good agreement with the experimental
observation that the reaction does not proceed without the LiOtBu
additive. The immediate product of the C–B bond cleavage is the
transient anionic borylmethyl intermediate 11 that is stabilized by
Several control experiments were carried out to challenge these
insights from the calculations, as summarized in Table 3. First,
quinoline (1b) and boron-ate species 10, generated in situ from 2a
Gsol
kcal/mol
Bpin
Li
O
O
pinB
Me
Li
B
pinB
Me
Li
B
Li
H2C
10-TS
(19.60)
OtBu
O
O
OtBu
Zn Me
N
Zn Me
tBuO Zn Me
tBuO Zn Me
N
14C4-TS
(18.83)
Bpin
2a'-TS
(13.80)
14C4-TS
5.06
13-TS
(13.03)
14C2-TS
(13.77)
Bpin
H2C
Li
OtBu
Zn Me
14
N
11
11.44
9.21
14C2-TS
Bpin
H2C
Li
pinB
Bpin
Li
Me
OtBu
pinB
Li
tBuO
Bpin
OtBu
Zn Me
10
ZnMe
N
Zn Me
0.05
N
2a
-boryl
carbanion
0.00
pinB
2a'
-3.52
15C2
-9.32
O
Li
Li
pinB
Li
B
O
pinB
Me
B
15C4
O
pinB
Zn OtBu
13
OtBu
O
Me
-12.66
-10.89
Li
12
N
Zn Me
tBuO Zn Me
Me Bpin
tBuO Zn Me
-12.91
Me
Bpin
zincate
Diborylalkane Activation
Zincate Generation
Alkylation
Figure 2. Free energy profile for the C2-selective alkylation of quinoline (1b) with diborylmethane (2a).
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Table 3. Product Distributions for the Methylation of Quinoline
Figure 3 illustrates the DFT-optimized structures of the two
1
2
3
4
5
6
7
8
with Boron-ate Complex 10a
transition states, 14C2-TS and 14C4-TS, which show that the local
geometry of how the zincate MeZn(OtBu) interacts with the
quinoline is significantly different. In the energetically more
favorable 14C2-TS, the MeZn(OtBu) fragment is coordinated to the
nitrogen atom in a more symmetric fashion where both Lewis
acidic Zn and Li sites can interact with the Lewis basic nitrogen of
the quinoline in a nearly square-planar geometry. The N–Li and C–
C2 distances are 2.43 and 2.44 Å, respectively, whereas the C–Li
distance is found to be 2.25 Å. For the zincate species to deliver the
borylmethyl anion to the C4 position, a significant structural
distortion is required where the N–Li distance increases to 3.12 Å,
which indicates that there is little to no interaction between these
Lewis acid/base pairs. Similarly, the C–C4 distance is also much
longer at 2.55 Å, giving rise to the much higher energy of this
alternative transition state. Thus, the regioselectivity is a direct
consequence of the nitrogen heteroatom acting as a Lewis basic
directing group by offering an anchor point for the zincate species,
which functions as a delivery vehicle of the borylmethyl anion.
With these detailed computational results in hand, deuterium
labeling experiments were carried out to identify the proton source
during the protodeboronation, as summarized in Scheme 5. We
initially performed the background experiment by using 1b and 2a
as substrates in toluene-d8 under the reaction conditions to establish
that no deuterium was incorporated into product 3b, eliminating the
MeLi
pinB
Bpin
toluene
-78 o
2a
C
Li
pinB
Bpin
Me
Me
N
Me
N
10
with or w/o ZnR2
+
+
N
Me
toluene
120 oC, 3 h
N
Me
9
1b
3b
16
17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H-NMR yield (%)b
entry
ZnR2
base
3b
16
<1
<1
<1
4
17
1
2
3
4
5
MeZn(OtBu)
LiOtBu
48
42
40
6
<1
<1
<1
10
7
MeZn(OtBu)
-
ZnMe2
LiOtBu
LiOtBu
-
-
-
8
9
aConditions: 1b (0.20 mmol), 10 (0.40 mmol), ZnR2 (0.40 mmol, if
necessary), LiOtBu (0.40 mmol, if necessary) and toluene (2.0 mL)
at 120 °C for 3 h. b1H-NMR yield was given using 1,1,2,2-
tetrachloroethane as an internal standard.
Scheme 5. Deuterium-Labeling Experiments for the
Methylation of Quinolines
and MeLi in toluene at –78 °C, were treated with 2.0 equivalents of
MeZn(OtBu), prepared by the reaction of tBuOH and ZnMe2,16 in
toluene at 120 °C. Interestingly, the C2-methylated product 3b was
produced in the presence (Table 3, entry 1) or the absence of
LiOtBu (entry 2) while the reaction in the absence of the Zn(II)
additive afforded mixtures of C2-methylated (3b), C4-methylated
(16), and C2/C4-dimethylated (17) products in very low yields
(entries 4 and 5). These results provide two important clues: (i) The
reactive intermediate 10 is likely to be the nucleophilic species, as
suggested by the DFT-calculations, and (ii) the zinc additive, such
as MeZn(OtBu) and ZnMe2, plays a key role in controlling the
regioselectivity.
(a)
0% D
ZnMe2/LiOtBu
+
pinB
Bpin
H/D
toluene-d8, 120 o
C
N
H
N
2a
2a
3b
-d
1b
(b)
(c)
52% D
H/D
ZnMe2/LiOtBu
+
pinB
Bpin
toluene, 120 o
C
N
D
N
3b
-d
1b
-d (98% D)
45% D
In good agreement with the experimental observations, our
calculations show that the C2-alkylation is kinetically much
preferred over the C4-alkylation, as illustrated in red in Figure 2.
The borylmethyl anion attacks the C2-carbon via 14C2-TS located
D
D
ZnMe2/LiOtBu
toluene, 120 o
H/D
D
+
N
pinB
Bpin
C
N
H
D
1b
2a-
d2
3b
-d3
at 13.8 kcal/mol to form the dearomatized intermediate 15C2
.
(>99% D)
Alternatively, attack at the C4-carbon can be furnished via
transition state 14C4-TS, which is found to be 5.1 kcal/mol higher
in energy. We considered alternative pathways such as the binding
of ZnMe2 to the quinoline instead of MeZn(OtBu) and found them
to be higher in energy, but the preference of the C2-alkylation was
maintained even in those scenarios, confirming that the C2-
preference is intrinsic for the quinoline substrate.19 To better
understand this regioselectivity, the optimized structures of the
transition states were examined closely.
64% D
(d)
D
D
ZnMe2/LiOtBu
toluene, 120 o
H/D
D
+
N
pinB
Bpin
C
N
D
D
3b
-d3
1b
1b
-d (98% D)
2a-
d2
(>99% D)
35% D
(e)
H/D
N
D
N
3b
3e
-d
-d (98% D)
ZnMe2/LiOtBu
+
18% D
H/D
pinB
Bpin
toluene, 120 o
C
MeO
(f)
MeO
2a
14C2-TS
14C4-TS
N
H
N
-d
1e
2.339
0% D
2.249
D
D
ZnMe2/LiOtBu
H/D
H
2.548
+
N
toluene, 120 o
C
pinB
Bpin
N
CH3
H
3b
2a-
d2
3b
2.433
2.439
(>99% D)
3.116
Figure 3. DFT-optimized geometries of the 14C2-TS and the 14C4
TS.
-
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Scheme 6. Deuterium-Labeling Experiments for the Secondary
Scheme 7. Additive Effects for the Aromatization of 1,2-
1
Alkylation of Quinolines
Dihydroquinoline Intermediate
2
3
4
5
6
7
(a)
(a)
81% D
1H NMR yield (%)
3a
Me
Me
additive
of
ZnMe2/LiOtBu
additive
Me Me
+
H/D
Me
LiOtBu
<1%
<1%
80%
toluene, 120 o
C
toluene
120 oC, 3 h
N
N
D
pinB
Bpin
N
H
Me
MeZn(OtBu)
ZnMe2
N
Me
Me
1b
2h
4k
-d
-d (98% D)
18
3a
50% D
(b)
8
9
(b)
pinB
Bpin
40% D
H/D
H/D
Me
2a
N
D
D
N
ZnPh2/LiOtBu
toluene, 120 o
via
+
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1b
4k
-d
-d (98% D)
ZnMe2/LiOtBu
Me Me
pinB Bpin
N
N
D
C
+
42% D
toluene, 120 o
C
1b
-d (98% D)
MeO
3b
-d
MeO
detected by
2H-NMR
2h
H/D
Me
Me
N
H
N
N
D
Me
Zn Ph
1e
4l
-d
19
(1b) and diborylmethane (2a) as model substrates. As described
above in Figure 2, the zincate coordinated dearomatized
intermediate 15C2 may be generated by the nucleophilic attack of
the zincate 12 to 1b. Because the developed transformation
proceeds even in the presence of a substoichiometric amount of
LiOtBu (Table 1, entry 17), we assume that the alkoxide can be
released from 15C2 to give intermediate 20. The released alkoxide
is expected to generate intermediate 9 by combining with ZnMe2.21
From intermediate 20, two plausible pathways for the
aromatization can be imagined. One pathway (path a) involves
intermolecular deprotonation of the C2-H in 20 by LiOtBu upon
liberation of Zn(0)22 and a formally anionic methyl group, which
could be captured by 2a to give the methyl-boron-ate complex 10,
and the benzylic boronate ester 21. Indeed, we found that the
reaction of 1b with 2a under the standard reaction conditions in the
presence of 1.0 equiv of deuterated tert-butanol afforded the
deuterated product 3b-d with 56% deuterium incorporation
(Scheme 8b). This result supports our proposed pathway that tert-
butanol works as the proton source during the protodeboronation.
Alternatively, the methyl group of Zn could deprotonate the C2-H
of 20, thus leading to 21 upon releasing Zn(0) and methane. Then,
the protodeboronation of 21 would generate the C2 methylated
quinoline 3b by the action of 9 or LiOtBu as activators of Bpin and
tert-butanol or -C-H of 2a as proton sources.
solvent as a proton source (Scheme 5a). The reaction of C2-
deuterated quinoline (1b-d) with 2a in toluene resulted in the
formation of the deuterated product 3b-d with 52% deuterium
incorporation at the benzylic position (Scheme 5b). Treatment of
1b and deuterated diborylmethane (2a-d2) under the reaction
conditions delivered the corresponding product 3b-d3, which
contained an excess quantity of deuterium at benzylic position
(Scheme 5c). Furthermore, the reaction of 1b-d and 2a-d2 led to the
product 3b-d3 with 64% deuterium incorporation, clearly
suggesting that both C2-H of 1b and α-C-H of 2a may serve as the
source of hydrogen during the protodeboronation step. Crossover
experiment of deuterated quinoline (1b-d) and 6-methoxyquinoline
(1e) with 2a resulted in H/D scrambling in both products 3b-d and
3e-d, indicating that the protodeboronation occurred
intermolecularly rather than in an intramolecular manner (Scheme
5e). When 2-methylquinoline (3b) and 2a-d2 were subjected to the
standard conditions, no H/D exchange was observed, suggesting
that the protonation did not take place after the formation of the
product, but occurred during the reaction progress (Scheme 5f).
This protodeboronation pathway is particularly interesting because
it proceeds in a distinctly different pathway than the deborylative
alkylation of electron-deficient N-heterocyclic N-oxides with 1,1-
diborylalkanes.10
Since internal 1,1-diborylalkanes did not contain -C–H bonds,
deuterium-labeling experiments were further surveyed for the
secondary alkylation of N-heteroarene (Scheme 6). The reaction of
1b-d with propane-2,2-diboronate ester 2h afforded 4k-d with 81%
deuterium incorporation. Cross-over experiments showed a similar
trend with the methylation reaction, and H/D scrambling was
observed in both products 4k-d and 4l-d. These results clearly
indicate that C2–H of N-heteroarene solely acted as the proton
source for the protodeboronation when internal 1,1-diborylalkanes
were employed as nucleophiles.
To understand which source is responsible for the aromatization
of the dearomatized quinoline intermediate, we performed
experiments by reacting an independently prepared 2,4-dimethyl-
1,2-dihydroquinoline 18 with different additives, as summarized in
Scheme 7a. Whereas LiOtBu and MeZn(OtBu) had a negligible
effect, ZnMe2 in degassed toluene converted 18 to 3a in 80 % yield.
In addition, treatment of C2-deuterated quinoline with 2a in the
presence of ZnPh2 and LiOtBu generated deuterobenzene, which
was confirmed by 2H NMR spectroscopy (Scheme 7b). These
results indicate that ZnMe2 can act as an oxidant for the
aromatization of 18, which has some precedence in a similar zinc-
mediated aromatization of 1,2-dihydroquinoline in the context of
Ni-catalyzed arylation of quinoline via zinc amide species like
19.11b,d
Scheme 8. Second Part of Proposed Mechanism for the
Protodeboronation and Aromatization
(a)
Li
ZnMe2
Bpin
Bpin
N
H
N
H
Zn Me
tBuO Zn Me
9
15C2
20
path a
path b
LiOtBu
2a
Bpin
Bpin
Bpin
N
H
N
H
N
Zn Me
Zn(0), 10
tBuOH
Zn(0)
CH4
Zn Me
20a
21
20b
9 or LiOtBu
proton source
tBuOH
or -C-H of 2a
(X = Me or OtBu)
X
Bpin
H
N
3b
(b)
tBuOD
56% D
H/D
(1.0 equiv)
ZnMe2/LiOtBu
Based on these experimental results, we propose the final portion
of the proposed reaction mechanism (Scheme 8a) using quinoline
+
pinB
Bpin
N
toluene, 120 o
C
N
1b
2a
3b-d
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Bpin
Table 4. Scope for the C4-Selective Alkylation of Pyridinea
Bpin
C
H
Li
H
Li
C
1
R2
R3
Ph
Ph
ZnMe2 (2.0 equiv)
OtBu
OtBu
2
3
4
R2 R3
pinB Bpin
LiOtBu (2.0 equiv)
N
N
Zn Me
+
Zn Me
G(sol)
(kcal/mol)
THF
120 oC, 3 h
N
22QC4-TS
22C2-TS
N
5
6
7
8
1x
2
23
5.27
Ph
Me
Me
Me
1.94
9
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22QC2-TS
22C4-TS
b
23a
, 50%
(C4:C2 = 10:1)
23b
, 46%
23c
, 45%
(C4:C2 = 6.3:1)
(C4:C2 = 9.1:1)
Bpin
Bpin
C
H
H
Li
Li
C
Me
Me
Me
Me
Ph
Ph
OtBu
OtBu
Me
N
N
Me
H
Zn Me
Zn Me
H
H
G(sol) = G(gas) + G(solv)
N
N
TBSO
b,c
b
C2 C4
(kcal/mol)
23d
, 60%
23e
, 56%
(C4:C2 = 13:1)
(C4:C2 = 10:1)
-0.71
-0.12
2.06
1.94
-4.15
-5.60
0.33
E(SCF)
G(gas)
aConditions: 1x (0.20 mmol), 2 (2.0 equiv), LiOtBu (2.0 equiv),
ZnMe2 (2.0 equiv) and THF (2.0 mL) at 120 C for 3 h. The
reaction was performed for 12 h. c3.0 Equiv of LiOtBu and ZnMe2
were used.
o
b
G(solv)
G(sol)
-5.27
Figure 4. Comparison of free energies between the quinoline (1b)
and pyridine (1x) at the regioselctive alkylation step with 3-
phenylpropyl-1,1-diborylalkane (2f).
1x with 1,1-diborylalkanes afforded the primary alkylated products
(23b and 23c) with good-to-excellent C4-selectivity, while 23b
required a prolonged reaction time (12 h) for giving satisfactory
yields. C4-selective secondary alkylation could also be achieved,
thereby providing 23d in the presence of 3.0 equivalents of ZnMe2
and LiOtBu after 12 h. Complex 1,1-diborylalkane derived from
lithocholic acid also led to 23e with high C4-selectivity.
Investigation for the C4-Alkylation of Pyridine. To examine
whether the developed alkylation process could also be applied for
the regioselective alkylation of pyridine, we conducted DFT
calculations using the pyridine 1x and 3-phenylpropyl-1,1-
diborylalkane 2f as model substrates (Figure 4). The reaction
energy profile for the pyridine substrate shows a reasonable energy
barrier indicating that the developed alkylation process should
apply to the simple pyridine substrate.23 However, the
regioselectivity calculation in the alkylation step shows
unexpectedly that the Gibbs free energy of the C2-alkylation
process (22C2-TS) is ~1.9 kcal/mol higher in energy than the C4-
alkylation process (22C4-TS), which implies that the C4-alkylation
is feasible when pyridine is employed as a substrate. This inverted
regioselectivity in the pyridine system is further studied with the
detailed analysis of energy components in both substrates. As
shown in Figure 4, the regioselectivity in the quinoline system is
mainly determined by the difference of the electronic energy
(E(SCF)). The solvation energy (G(solv)) for the two regioisomers
displays a difference of only 0.3 kcal/mol in the transition state.
Interestingly, the energy components are notably different in the
pyridine system. Unlike the quinoline substrate, where the LUMO
is localized in the extended π-conjugated system having the pz-
orbital population of 0.06 and 0.18 in the C2- and C4-center,
respectively, the pyridine substrate has a more electrophilic C4-
center in which the LUMO is highly delocalized with the pz-orbital
population of 0.35. The favorable interaction at the C4-center in the
pyridine substrate with the carbanion nucleophile stabilizes the
transition state and leads to the decreased energy gap of G(gas)
from 5.6 kcal/mol to 0.1 kcal/mol. Furthermore, the contracted ring
size affects the polarizability of the transition state complex. This
feature is reflected in the difference of G(solv) energies that
contribute to the regioselectivity.
Computational Details
All calculations were carried out using density functional theory
(DFT)24 implemented in Jaguar 9.1 suite of program.25 Geometry
optimizations were carries out with the M0626 functional and the
6-31G** basis set.27 For the Zn center, the Los Alamos LACVP28
basis set was applied, which includes effective core potentials. With
the optimized geometries, single point energies were re-evaluated
using triple-ζ quality of basis set, cc-pVTZ(-f),29 where Li, B and
Zn atoms were computed with LACV3P basis. Frequency
calculations were performed at the same level as the geometry
optimizations, and zero-point energies and entropy correction terms
were derived. Solvation correction energies were evaluated from
the self-consistent reaction field (SCRF) approximations,30 which
is the solution for the linearized Poisson-Boltzmann equations with
a proper dielectric constant (ε =2.379 for toluene solvent in the
quinoline system and ε =7.6 for THF solvent in the pyridine system).
Several transition states were found by using the quadratic
synchronous transit search method (QST).31 Final solution phase
Gibbs free energies were computed as follows:
G(Sol) = G(gas) + G(solv)
G(gas) = H(gas) - TS(gas)
(eq 1)
(eq 2)
(eq 3)
(eq 4)
H(Gas) = E(SCF) + ZPE
ΔG(Sol) = ΣG(Sol) for products - ΣG(Sol) for reactants
G(Sol) is the solvation corrected Gibbs free energy; G(gas) is the
gas phase free energy; H(gas) is the enthalpy in the gas phase; T is
the temperature (120 oC, 393.15 K); S(gas) is the entropy in the gas
phase; E(SCF) is the electronic energy converged from the self-
consistent field method; ZPE is the vibrational zero-point energy;
and S for the vibrational entropy correction. Note that here entropy
refers specifically to the vibrational/rotational/translational entropy
With this somewhat surprising computational result in mind, we
carried out the reaction for the primary and secondary alkylation of
pyridine (Table 4). Choosing 1x and 2f as model substrates, we
found that C4-alkylated product 23a was obtained in the presence
of 2.0 equivalents of ZnMe2 and LiOtBu in THF at 120 oC with high
regioselectivity.19 Under these reaction conditions, the reactions of
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Methylation Reactions. Angew. Chem., Int. Ed. 2013, 52, 12256-12267. (h)
of the solute(s). The solvent entropies are implicitly included in the
Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural
Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles
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1
2
3
continuum model.
Conclusion
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Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C−H Bond
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2642-2713.
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9
In summary, we developed a ZnMe2-mediated, direct C2- or C4-
alkylation of electron-deficient N-heteroarenes using 1,1-
diborylalkanes as alkylating agents. The reaction scope is broad,
and various electron-deficient N-heteroarene and 1,1-diborylalkane
substrates can be employed, thus affording a range of C2- or C4-
alkylated electron-deficient N-heteroarenes in good yields.
Furthermore, 1,1-diborylalkanes bearing pharmaceutically relevant
compounds can be applied to the C2- or C4-alkylation of electron-
deficient N-heteroarenes, even including complex quinoline, thus
highlighting the utility of this new protocol. Mechanistic studies
revealed three roles for zinc additive in this reaction; (i) generation
of -borylcarbanion from 1,1-diborylalkanes with the combination
of LiOtBu, (ii) activation of electron-deficient N-heteroarenes to
increase the electrophilicity of the C2- or C4-position, and (iii)
oxidation of dihydro-N-heteroarene intermediates. In addition, we
observed that -C-H of 1,1-diborylalkane and/or C-H of dihydro-
N-heteroarene could serve as proton sources for the
protodeboronation of the remaining Bpin unit.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data. Cartesian coordinates
of DFT-optimized structures, benchmark calculations, and
computational details. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*mbaik2805@kaist.ac.kr
*seunghwan@postech.ac.kr
Author Contributions
‖
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Science, ICT & Future Planning (NRF-
2019R1AC2004925). M.-H. B. acknowledges support from the
Institute for Basic Science (IBS-R10-A1) in Korea.
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R2
R3
R1 R2
pinB Bpin
ZnMe2, LiOtBu
R1
1
2
R2
R1
+
or
N
N
R3
N
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R2
R3
ZnMe2
likely via:
H
Bpin
R1
LiOtBu
Li
R1
R2 Me
H
R2
R3
Bpin
R1
N
Me Bpin
or
N
Me Zn
OtBu
Zn OtBu
N
pinB
Me Zn
OtBu
(-borylalkyl)methylalkoxy zincate
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment