Toluene and its Derivatives as Atom-Efficient Benzylating Agents for Secondary Amines

Article abstract of DOI:10.1055/s-0037-1610342

Toluene as a replacement for common N -benzylating agents, such as benzyl bromide, can be an atom-efficient alternative reagent. Under nickel catalysis and mildly oxidative conditions, it is possible to activate toluene efficiently and use it directly for the benzylation of different 2-aminopyridines. The transformation is not restricted to simple toluene, but also substituted derivatives give the desired product in good yields. Effective cleavage of the pyridine moiety is presented.

Full text of DOI:10.1055/s-0037-1610342

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
de
D. Schönbauer et al.
Letter
Synlett
Toluene and its Derivatives as Atom-Efficient Benzylating Agents
for Secondary Amines
David Schönbauer
Florian Lukas
R1
10 mol% Ni(OTf)2
10 mol% PPh3
2.0 equiv NaHCO3
2.0 equiv C3F7I
H
R1
R2
R2
N
N
Michael Schnürch*
0
0
0
0-
0
0
0
3-2
9
4
6-9
2
9
4
+
N
N
H
140 °C, 24 h
Institute of Applied Synthetic Chemistry, TU Wien,
Getreidemarkt 9/163-OC, Vienna 1060, Austria
michael.schnuerch@tuwien.ac.at
R3
R3
20 examples, up to 80% yield
Received: 30.10.2018
Accepted after revision: 05.11.2018
Published online: 04.12.2018
ene towards an electrophilic species, which is difficult to
achieve. Within this contribution, we report an efficient
protocol to realize this goal taking advantage of radical
chemistry.
DOI: 10.1055/s-0037-1610342; Art ID: st-2018-b0629-l
Abstract Toluene as a replacement for common N-benzylating agents,
such as benzyl bromide, can be an atom-efficient alternative reagent.
Under nickel catalysis and mildly oxidative conditions, it is possible to
activate toluene efficiently and use it directly for the benzylation of dif-
ferent 2-aminopyridines. The transformation is not restricted to simple
toluene, but also substituted derivatives give the desired product in
good yields. Effective cleavage of the pyridine moiety is presented.
Upon our efforts to C-alkylate benzylic amines under
rhodium catalysis using toluene as solvent, it was found
that under certain conditions also a C-benzylated product
was formed, however, in low quantities (ca. 1%, see Scheme
1). By substituting toluene for d8-toluene, it could be quick-
ly proven that the newly introduced benzyl group originat-
ed indeed from the solvent. Since toluene activation for in-
troducing benzyl groups in a catalytic manner is extremely
rare in literature,10–23 we decided to investigate this trans-
formation further and started a screening campaign to im-
prove the yield in this transformation.
Interestingly, it was found that the yield of C-benzyla-
tion could not be improved to synthetically useful yields,
however, switching to copper or nickel catalysis, promising
yields of N-benzylated product 3 were observed and further
optimized (Table 1).
Since coupling between a C–H and an N–H should re-
quire an oxidant, our screening efforts focused on finding
the right combination of metal and oxidant. Metal salts in
combination with organic oxidants, often DTBP (di-t-butyl
peroxide) is a frequently applied combination for oxidative
coupling processes.24,25 In our case the combination of
Cu(OAc)2 and DTBP led to 23% yield of 3, a good starting
point for further optimization. Using only I2 as oxidant in
Key words C–H functionalization, benzylation, nickel catalysis, tolu-
ene activation, amines
Benzylation reactions of aromatic and aliphatic amines
are important transformations in synthetic chemistry since
the benzyl group is a frequently applied protecting group
for this functionality.1 Typically, N-benzylation is carried
out via the reaction with benzyl bromide2,3 or benzyl chlo-
ride,4 via reductive amination with benzaldehyde,5–7 or us-
ing benzylic alcohol in combination with a metal catalyst.8,9
All these transformations have in common the need for a
reactive functional group leading to the formation of an
acid equivalent (in case of a halide) or the requirement for a
subsequent transformation (e.g., reduction in case of reduc-
tive amination). In this regard it would be highly attractive
to use simple toluene as benzylating agent, since formally
only H2 would be produced as byproduct of such a transfor-
mation. However, this requires suitable activation of tolu-
H
N
5.0 mol% Ag2CO3
5.0 mol% [RhCl(cod)]2
3.5 equiv K2CO3
N
N
N
N
N
H
toluene
150 °C, 18 h
1
2 ~1%
3
Scheme 1 Finding of C-benzylated product
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
D. Schönbauer et al.
Letter
Synlett
Table 1 Reaction Optimizationa
the absence of metal delivered no desired product at all but
gave only iodination of the C5 position of pyridine in the
substrate. Inspired by a literature protocol for C(sp2)–H
benzylation with toluene,10 we applied a combination of 2-
iodohexafluoropropane as oxidant, Ni(OTf)2 as catalyst, and
Na2CO3 as base, which gave a significant improvement to
49% of product 3 (Table 1, entry 3), which could be im-
proved further to 66%, however, only at a long reaction time
of 66 h. Additional 1.5 equivalents oxidant increased the
yield to 72% (Table 1, entry 5). However, a base screening
identified sodium bicarbonate (Table 1, entry 8) as the most
efficient one, giving 65% yield but in only 24 h and with
only 2.0 equivalents oxidant. Other catalysts than Ni(OTf)2
gave inferior results (Table 1, entries 11–14) and control ex-
periments without metal catalyst gave significantly lower
yields of below 40% (Table 1, entries 15 and 16). Additional-
ly, triphenylphosphine is also necessary for efficient trans-
formation as its absence produced only 17% yield (see Sup-
porting Information).
Before carrying out a substrate scope evaluation, it was
of interest which structural motifs of the substrate are re-
quired for this transformation. First of all, the distance be-
tween the NH group and the phenyl ring was increased by
one CH2 group and the corresponding substrate N-
(phenethyl)-2-pyridine delivered 50% of the desired prod-
uct (5, Scheme 2). Next, simple N-ethylpyridine-2-amine
and N-allylpyridine-2-amine were tested as substrates to
see whether the presence of a phenyl ring is mandatory at
all. In both cases, essentially no product formation was ob-
served. Hence, a phenyl ring in proximity is necessary,
however, not directly as a benzyl group. Finally, simple N-
benzylaniline was tested but no product was observed, in-
dicating that the pyridine nitrogen might play an important
role in catalyst pre-coordination.
10 mol% catalyst
2.0 equiv base
2.0 oxidant
N
N
+
N
N
140 °C, 24 h
H
1
3
Entry Catalyst (10 mol%) Base (2.0 equiv) Oxidant (2.0 equiv) Yield (%)
1
Cu(OAc)2
–
DTBP
I2
23
0
2b
3
–
–
Ni(OTf)2, PPh3
Ni(OTf)2, PPh3
Ni(OTf)2, PPh3
Ni(OTf)2, PPh3
Ni(OTf)2, PPh3
Ni(OTf)2, PPh3
Ni(OTf)2, PPh3
Ni(OTf)2, PPh3
NiBr2, PPh3
Ni(dppp)2, PPh3
Pd(OAc)2, PPh3
FeCl2, PPh3
–
Na2CO3
Na2CO3
Na2CO3
K2CO3
C3F7I
C3F7I
C3F7I
C3F7I
C3F7I
C3F7I
C3F7I
C3F7I
C3F7Ie
C3F7Ie
C3F7I
C3F7I
C3F7I
C3F7I
49
66
72
43
30
65
35
23
28
30
50
25
10
40
4c
5d
6
7
Cs2CO3
NaHCO3
NaOAc
2-6-lutidine
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
K2CO3
8
9
10
11
12
13
14
15
16
–
a Reactions were run on a 0.22–0.27 mmol scale, 2 mL toluene was used,
reaction time 24 h, 140 °C, isolated yields.
b 100 °C, 40% iodinated substrate.
c 66 h reaction time.
d 3.5 equiv oxidant.
e 44 h reaction time.
N
N
N
N
N
H
H
H
N
N
H
6
8
10
4
N
N
N
N
N
N
N
5
50%
7
3%
9
11
Scheme 2 Structural motif evaluation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
D. Schönbauer et al.
Letter
Synlett
With the established reaction conditions,26 different 2-
aminopyridines were subjected to the protocol giving satis-
factory yields of 50–80% (Scheme 3) in the majority of the
examples. In previous work of our group on this type of
substrate we saw a significant influence of the residues in
3-position of the pyridine ring (R1) on the outcome of the
reaction, which can be summarized as ‘the larger the bet-
ter’.27 The substrate unsubstituted in position 3 did not lead
to significant product formation in this report dedicated to
arylation reactions, and the 3-phenyl-substituted product
performed best. In case of N-benzylation the situation is
different. The unsubstituted substrate 12 works as well as
the 3-methylated one 3 but the more sterically demanding
phenyl group (13) in position 3 of pyridine led to a decrease
in yield. The attachment of a chloro group led also to a low
yield (14), showing the additional electronic influence of
the substituent in 3-position.
a methoxy group is used (18). On the contrary, electron-
withdrawing CF3 in para position increases the yield to 80%
of the desired product (19).
Using toluene as benzylating agent has surely its bene-
fits, however, it is of limited applicability. Hence, we were
interested whether also substituted toluene derivatives
could be applied as benzylating agents. In a first attempt
xylenes and mesitylene were the obvious choice for initial
experiments. As seen in Scheme 4, the results in this proto-
col are significantly better as compared to the benzylation
with toluene, delivering the same compounds in 20–30%
higher yields (compare compounds 15, 16, and 17). Notably,
when 4-methylanisol was used, 78% of the expected prod-
uct were isolated, which is a substantial improvement to
the previously reported 34% (18). When 4-fluorotoluene
was used as solvent in the transformation, only 41% of the
desired product (21a) were formed. This unexpected out-
come was accompanied by isolation of 38% of a bisfluoro-
benzylated (21b) side product. This side-product formation
clearly requires cleavage of the initially present benzyl
group. It can be hypothesized that the first benzylation oc-
curs as expected delivering the desired product 21a, which
subsequently undergoes cleavage of the unsubstituted ben-
zyl group leaving space for another benzylation with the
more abundant 4-fluorotoluene and thus forming side
product 21b. That electron-poor toluene derivatives are
clearly the best benzylating agents in this transformation
might explain why such a byproduct is only formed in this
example in considerable amounts. In several other exam-
ples, minor amounts (<3%) of bisbenzylated products were
observed in GC/MS but could never be isolated.
10 mol% Ni(OTf)2
10 mol% PPh3
2.0 equiv NaHCO3
2.0 equiv C3F7I
R1
R1
N
R2
R2
+
N
N
H
N
140 °C, 24 h
N
N
N
N
N
N
R2
3
65%
12 68%
R2 = H 24% 13a
Me 12% 13b
When we tested 4-chlorotoluene and 4-bromotoluene,
small, not-isolable amounts of bishalobenzylated products
(Cl or Br derivatives of 21b) were detected again. Interest-
ingly, as additional byproduct the debenzylated compounds
22a and 23a (Scheme 4) were formed in 13% yield each. Un-
fortunately, the more pronounced byproduct profile led to
considerably lower yields of the desired products 22 and 23
(Scheme 4). Methyl-4-methylbenzoate was also tested as
reaction partner but gave only low conversion and led to an
inseparable mixture of product and substrate. Using p-tolu-
idine as benzyl source showed no conversion at all.
Cl
N
N
N
N
N
N
R2
2 = H 31%a 14a
Me 20%a 14b
54%
16
R
15 51%
N
N
N
N
N
N
OMe
CF3
Finally, we used also ethyl benzene as solvent. As seen
in Scheme 4, 11% of the branched product 24 were isolated.
Although the reaction was not complete after the usual re-
action time and 58% of starting material were recovered, it
shows that more demanding substrates can undergo the
transformation. Its slower reaction rate is probably caused
by the steric demand of the ethyl benzene.
Regarding the mechanism of the transformation, a radi-
cal pathway is likely as addition of TEMPO inhibits product
formation completely. This is in alignment to literature,
where mechanistic calculations28 and other reports10,29–31
suggest the formation of an isoheptafluoropropyl radical in
17 53%
18 34%
19 80%
Scheme 3 Substrate scope with toluene as benzylating agent. Reactions
were run on a 0.4–0.5 mmol scale, 2 mL toluene was used, reaction
time 24 h, 140°C, isolated yields. a Yield is determined by 1H NMR spec-
troscopy, since separation of substrate and product was not possible.
The positioning of the residue seems to be of negligible
influence as all methylated substrates (15, 16, and 17) give
essentially the same yields of 51–54%. The decrease in the
yield of about 15% compared to our model substrate 3 could
be explained by the difference in electronics. All electron-
donating substituents on the phenyl ring of the substrate
lead to a decrease in yield. This effect is most pronounced if
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
D. Schönbauer et al.
Letter
Synlett
10 mol% Ni(OTf)2
10 mol% PPh3
2.0 equiv NaHCO3
2.0 equiv C3F7I
N
+
N
N
H
N
140 °C, 24 h
R
1
R
N
N
N
N
N
N
15 82%
16 71%
17 77%
N
N
N
N
N
N
R2
MeO
F
2 = H 41% 21a
= F 38%a 21b
20 77%
R
18 78 %
Scheme 5 Comparison with benzyl bromide. Reactions were run at
140 °C.
N
N
N
N
N
N
1) 2.0 equiv MeOTf
DCM, 0–4 °C overnight
2) 2 N NaOH, MeOH,
50 °C, 6 h
Cl
Br
N
N
H
N
22 18%
23 31%
24 11%
3
25 97%
Scheme 6 Removal of the pyridine group
N
N
N
N
H
H
Cl
Br
Toluene and its derivatives were efficiently activated us-
ing heptafluoro-2-iodopropane as mild oxidant and nickel
as catalyst. Several 2-aminopyridines were benzylated in
usually good yields, giving an orthogonal approach to ter-
tiary amines. Additionally, an efficient cleavage of the pyri-
dine group makes secondary benzylated amines accessible.
22a 13%
23a 13%
Scheme 4 Substrate scope with toluene derivatives as benzylating
agents. Reactions were run on a 0.40–0.50 mmol scale, 2 mL solvent
was used, reaction time 24 h, 140 °C, isolated yields. a Compound 21b
was isolated as side product.
related transformations. However, significant more experi-
mental evidence is required to propose a mechanism able
to explain all our experimental findings.
Supporting Information
Supporting information for this article is available online at
A comparison with benzyl bromide as alkylating agent
shows that the transformation is faster and higher yielding
(see Scheme 5). The reaction was run under the same con-
ditions (140 °C, toluene, and NaHCO3). As these conditions
are usually not used for standard alkylation reactions, we
also probed the substrate with acetonitrile using NaH or K2CO3
as base with NaI as catalyst. In none of the mentioned ex-
periments it was possible to achieve more than 50% yield.
The removal of the pyridine via alkylation with methyl-
triflate and consecutive basic hydrolysis proceeded
smoothly with 97% yield, giving an alternative approach for
the synthesis of benzylated amines (Scheme 6).32
https://doi.org/10.1055/s-0037-1610342.
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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D. Schönbauer et al.
Letter
Synlett
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PPh3 (0.1 equiv), and Ni(OTf)2 (0.1 equiv), and transferred into
an argon-filled glove box. Then solvent (2 mL, ca. 35 equiv) and
2-iodoperfluoropropane (2.0 equiv) were added in this order to
avoid evaporation of the later and the vessel was sealed. The vial
was placed in a heater previously set to 140 °C and magnetically
stirred at 750 rpm for 23 h. The reaction mixture was filtered
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N,N-Dibenzyl-3-methyl-2-pyridinamine (3)
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N-Benzyl-3-methyl-2-pyridinamine (1, 53.4 mg, 269.3 μmol)
was used as starting material with toluene as solvent and
treated according to the general procedure for N-benzylation.
After workup 110 mg crude material were purified by column
chromatography. After purification the desired product 3 (50.1
mg, 173.2 μmol, 65%) was obtained as yellow oil. Rf = 0.40
(LP/EtOAc, 10:1) GC/MS: STD 10 min; r.t, 7.82 min; 288.2 (M,
0.5), 197.1 (100), 91.0 (50), 79.0 (26), 65.0 (50). 1H NMR (400
MHz, CDCl3): δ = 8.13 (ddd, J = 4.88, 1.96, 0.71 Hz, 1 H), 7.40
(ddd, J = 7.35, 1.87, 0.89 Hz, 1 H), 7.26 (m, 10 H), 7.20 (m, 2 H),
6.82 (dd, J = 7.34, 4.81 Hz, 1 H), 4.32 (s, 4 H), 2.38 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 161.5, 145.4, 139.6, 139.1, 128.4,
128.3, 126.9, 125.8, 118.2, 54.6, 18.9 ppm. HRMS for C20H20N2:
m/z [M + H]+ calcd: 289.1705; found: 289.1626.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E