Alkaline-metal-catalyzed one-pot aminobenzylation of aldehydes with toluenes

Article abstract of DOI:10.1021/acs.orglett.9b02737

A novel and easily accessible MN(SiMe₃)₂ (M = Li or Na)/Cs₂CO₃ co-catalyzed benzylation of in situ generated N-(trimethylsilyl) aldimines with toluene derivatives has been successfully developed. The catalyst exhibits high chemoselectivity for deprotonation of toluenes at the benzylic position. The utility of this system is exemplified by the one-pot synthesis of a diverse array of bioactive 1,2-diarylethylamines with excellent efficiency and broad functional group tolerance.

Full text of DOI:10.1021/acs.orglett.9b02737

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Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Alkaline-Metal-Catalyzed One-Pot Aminobenzylation of Aldehydes
with Toluenes
Guoqing Liu,† Patrick J. Walsh,*,‡ and Jianyou Mao*,†
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center
for Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, P.R. China
‡Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: A novel and easily accessible MN(SiMe3)2 (M = Li or
Na)/Cs2CO3 co-catalyzed benzylation of in situ generated N-
(trimethylsilyl) aldimines with toluene derivatives has been successfully
developed. The catalyst exhibits high chemoselectivity for deprotonation
of toluenes at the benzylic position. The utility of this system is
exemplified by the one-pot synthesis of a diverse array of bioactive 1,2-
diarylethylamines with excellent efficiency and broad functional group
tolerance.
Scheme 1. Catalytic System for Toluene Deprotonation
atalytic benzylic C−H functionalization is an ideal
Cstrategy to exploit abundant chemical feedstocks such
as toluene derivatives and xylenes.1 To fully use these
inexpensive commodity chemicals, efficient and economical
approaches for chemoselective elaboration of benzylic C−Hs
over aromatic C−Hs is a high priority. Recent progress along
these lines has been impressive. These advances mainly fall
into three categories: (a) early examples relying on
stoichiometric and strong oxidants to produce benzylic
radicals;1a,2 (b) C−H insertions based on expensive transition
metal catalysts;3 and (c) contemporary transformations
involving precious Rh or Ir photoredox catalysts.4
Brønsted base mediated chemoselective deprotonative
functionalization of benzylic C−Hs is a useful strategy to
functionalize the more acidic benzylic position of toluene
derivatives over aromatic C−Hs. Classic systems include n-
BuLi,5 Schlosser’s superbase (n-BuLi/KOtBu),6 and many
others.6a,7 These base combinations have found applications in
pharmaceuticals and natural products synthesis, although they
can exhibit a high degree of substrate dependency. Until
recently, chemoselective benzylic deprotonation with sub-
stituted toluenes was often unachievable.8 This changed with
O’Shea and co-workers’ breakthrough development of
LiTMP/KOtBu, which takes advantage of an anion-migration
strategy.9 Using this tactic, a diverse array of toluene
derivatives could be deprotonated and functionalized with
excellent benzylic chemoselectivity.
Brønsted base-catalyzed benzylic functionalization of toluene
also holds promise but remains underdeveloped (Scheme 1).
Early efforts employed highly air-sensitive or pyrophoric
reagents. Pine and co-workers pioneered Na- or K-catalyzed
alkylation of alkylbenzenes with styrenes (Scheme 1a).10 The
high reactivity of these metals makes it difficult to control the
degree of functionalization, and in most cases, di- or
polyalkylated products were obtained. These metals require
great care for safe handling. Screttas and co-workers developed
three-component mixtures with n-BuLi/LiK-
(OCH2CH2NMe2)2/Mg(OCH2CH2OEt)2-catalyzed benzylic
dialkylations of toluene with ethylene via controlled sequential
addition of the starting materials (Scheme 1b).11 Emulating
O’Shea’s base, but employing catalytic LiTMP/KOtBu,
Received: August 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02737
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Kobayashi and co-workers realized the catalytic addition of
alkylarenes with imines and alkenes (Scheme 1c).12 This is an
excellent advance in the functionalization of toluene using
catalytic base; however, this method employs preformed
imines (four steps) to generate acceptable yields. More
recently, Kondo and co-workers advanced their in situ
generated onium amide bases13 and expanded applications in
deprotonation of substituted toluenes for the synthesis of
stilbenes (Scheme 1d).14 Takemoto, Matsuzaka, and their co-
workers reported ruthenium sulfonamide catalyzed deproto-
nation of toluene derivatives and condensation with aldehydes
to generate (E)-stilbenes (Scheme 1e).15 In addition to
deprotonative functionalization of benzylic C−Hs of toluenes,
slightly more acidic benzylic C−Hs (such as those of
heterocycles) have been used with catalytic base by
Kobayashi,16 Guan,17 Schneider18 and their co-workers.
We have been interested in benzylic functionalization of
toluenes using relatively weak bases, such as MN(SiMe3)2 (M
= Li, Na, and K).19 Our previous findings include that
cation−π interactions between the group(I) cation and toluene
can acidify the benzylic C−H bonds, facilitating the
deprotonation.19b Relying on this strategy, the weakly acidic
benzylic C−H bonds (pKa ≈ 43 of toluene in DMSO) could
be reversibly deprotonated with MN(SiMe3)2 (M = Li, Na,
and K; pKa ≈ 26 for HN(SiMe3)2 in THF) in the presence of
cesium salts.19a,c To prepare valuable bioactive motifs, the
corresponding benzyl anions were successfully trapped with in
situ generated imines and benzonitriles, generating a diverse
array of 1,2-diarylethylamines19c (Scheme 2a) and indoles19a
(Scheme 2b), respectively.
Based on our prior work,19c we started screening for catalytic
bases using benzaldehyde (1a, 0.1 mmol) and toluene (0.5
mL) as the model coupling partners. We employed 1.2 equiv of
base [LiN(SiMe3)2, NaN(SiMe3)2, and KN(SiMe3)2], 1 equiv
of which is needed for in situ formation of the aldimine,21
while the remaining 20 mol % promotes the catalytic
deprotonation and addition sequence (110 °C for 12 h,
Table 1, entries 1−3). Neither LiN(SiMe3)2 nor NaN(SiMe3)2
a
Table 1. Optimization of Reaction Conditions
b
entry
base
additives
base/additive
AY (%)
1
2
3
4
5
6
7
8
9
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
1.2:0
1.2:0
1.2:0
1.1:0.1
1.1:0.1
1.1:0.1
1.1:0.1
1.1:0.1
1.1:0.1
1.1:0.05
0
trace
35
80
80
78
34
0
CsBr
CsI
CsF
CF3CO2Cs
CsCl
CH3CO2Cs
Cs2CO3
0
93
10
a
b
Reactions conducted under argon on 0.1 mmol scale. Assay yields
1
determined by H NMR analysis of unpurified reaction mixtures by
integration against an internal standard (CH2Br2).
catalyzed the tandem reaction (entries 1 and 2). KN(SiMe3)2
mediated the amine transformation in 35% AY (entry 3, AY =
assay yield determined by 1H NMR integration of the
unpurified reaction mixture against an internal standard).
Based on our previous reports that NaN(SiMe3)2 (2 equiv)/
CsTFA (0.35 equiv) mediated the one-pot aminobenzyla-
tion,19c we examined the combinations of NaN(SiMe3)2 (1.1
equiv) with a variety of cesium salts under the conditions of
entry 3 (entries 4−10). Our previous use of stoichiometric
base (2 equiv) with 35 mol % of CsTFA (Scheme 2a)
exhibited only low catalytic activity with 1.1 equiv of base
(34% AY, entry 7). Fortunately, the combination of NaN-
(SiMe3)2 (1.1 equiv) with Cs2CO3 (5 mol %) generated the
desired product in 93% AY (entry 10). Other combinations
either gave low yields of the product (entries 4−7) or did not
mediate the reactions at all (entries 8 and 9).22 Ultimately, the
optimized conditions employed 1 equiv of benzaldehyde (1a),
1.1 equiv of NaN(SiMe3)2, 0.5 mL toluene, and 5 mol % of
Cs2CO3 at 110 °C for 12 h (entry 10).
With the optimized conditions in hand, we tested the scope
of aldehydes in this one-pot aminobenzylation reaction with
toluene (Scheme 3). In general, a diverse array of functional
groups and heterocyclic aldehydes were compatible under our
conditions. The parent benzaldehyde underwent this trans-
formation, generating the desired product 3aa in 90% isolated
yield. Benzaldehydes containing electron-donating substitu-
ents, such as 4-methoxy, 4-N,N-dimethylamino, and 4-t-Bu,
exhibited good performance, giving 3ba−3da in 65−81% yield.
Benzaldehydes bearing benzylic C−Hs (4-Me and 4-iPr) were
also tolerated, furnishing 3ea and 3fa in 66 and 79% yield,
respectively. This is surprising given the increased acidity of
the methyl group in 4-methyl benzaldehyde and the imine that
is formed from it, compared to the methyl group of toluene.
Scheme 2. MN(SiMe3)2-Mediated Benzylic C−H
Functionalizations
Herein, we advance a catalyst based on MN(SiMe3)2/
Cs2CO3 (M = Li or Na) that reversibly deprotonates the
benzylic C−Hs of toluene derivatives. Unlike our prior method
for the aminobenzylation of aldehydes, (Scheme 2a), which
used stoichiometric base and 35 mol % CsO2CCF3, this system
uses catalytic base (1 equiv base converts the benzaldehyde to
in situ generate N-(trimethylsilyl)imine, while the remaining
10 mol % of base catalyzes reversible deprotonation) and 5
mol % of Cs2CO3. The benzylic organometallic is trapped with
in situ formed N-(trimethylsilyl)imines, furnishing a diverse
array of 1,2-diarylethylamines in a synthetically efficient and
straightforward fashion. 1,2-Diarylethylamines are important
motifs that have found wide applications in drugs and natural
products.20
B
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Letter
a
corresponding products 3ab and 3ac in 85 and 77% yield,
respectively (Scheme 4). 2-Chloro- and 2-bromotoluenes
Scheme 3. Substrate Scope of Aldehydes
a
Scheme 4. Substrate Scope of Toluene Derivatives
a
b
Reactions conducted under argon on 0.2 mmol scale. 1.2 equiv of
c
LiN(SiMe3)2 and 0.1 equiv of Cs2CO3 were used. 1.2 equiv of
NaN(SiMe3)2 and 0.05 equiv of Cs2CO3 were used. 1.1 equiv of
NaN(SiMe3)2 and 0.1 equiv of Cs2CO3 were used. 1.1 equiv of
d
e
NaN(SiMe3)2 and 0.05 equiv of Cs2CO3 were used.
underwent the tandem reaction, generating the desired
products 3ad and 3ae in 79 and 60% yield. These products
are primed for further functionalization. Polymethyl-substi-
tuted toluenes, including xylenes and mesitylene, formed
aminobenzylation products 3af−3ai in 78−84% yield. 1-
Methylnaphthalene generated the expected amine product in
63% yield. Ethylbenzene underwent this transformation,
affording the desired product 3ak in 63% yield with 3:1
anti/syn selectivity. For reasons that are not clear, our catalyst
could not mediate the addition of 3-methoxy- or 4-
methoxytoluene to in situ generate N-(trimethylsilyl)imine
(see the Supporting Information for details).
a
b
Reactions conducted under argon on 0.2 mmol scale. 1.2 equiv of
c
NaN(SiMe3)2 and 5 mol % of Cs2CO3 were used. 1.2 equiv of
LiN(SiMe3)2 and 5 mol % of Cs2CO3 were used. 1.2 equiv of
LiN(SiMe3)2 and 10 mol % of Cs2CO3 were used.
d
Benzaldehydes possessing C−X bonds (X = F, I) at the para
position were potentially problematic due to benzyne
formation. Indeed, these substrates exhibited poor conversion
to the desired products under the standard conditions.
However, they gave good yields under slightly modified
conditions [LiN(SiMe3)2/Cs2CO3)], affording the correspond-
ing products 3ga and 3ha in 84 and 55% yield, respectively. 3-
Chloro benzaldehyde was a very good partner under the
standard conditions, affording 3ia in 80% yield. It is
noteworthy that these C−X bonds (X = F, Cl, and I) can be
easily elaborated through standard cross-coupling reactions.
Substrates bearing substituents at the ortho position, as
exemplified by 2-methylanisole, afforded 3ja in 79% yield. π-
Extended 1- and 2-naphthyl aldehydes exhibited excellent
reactivity, generating 3ka and 3la in 91 and 87% yield. We are
interested in fluoro-containing compounds because they are
prevalent in medicinal chemistry. We next tested the reactivity
of 4-(trifluoromethyl)- and 4-(trifluoromethoxy)-
benzaldehydes. When LiN(SiMe3)2/Cs2CO3 was used both
were compatible, giving the corresponding products 3ma and
3na in 87 and 62% yield, respectively. Additional functional
groups at the para position, such as 4-SMe, 4-Ph, and 4-OPh,
furnished the products 3oa−3qa in 75−81% yields. 1,2-
Heteroarylphenylethylamines could be prepared under our
conditions, as demonstrated by the generation of 3ra−3ua in
66−95% yield.
To demonstrate the scalability of this catalytic process, 5
mmol of 3-pyridinecarboxaldehyde (1t) was employed to react
with toluene (2a). Using the LiN(SiMe3)2/Cs2CO3 system,
73% yield of 3ta was obtained (Scheme 5).
Scheme 5. Scale-up of the Transformations
To gain insight into the mechanism, we next explored the
role of Cs2CO3 in this catalytic tandem transformation. As
illustrated in Table 1, neither LiN(SiMe3)2 nor NaN(SiMe3)2
could mediate this process alone. Therefore, we envisioned
that CsN(SiMe3)2, derived from metathesis between NaN-
(SiMe3)2 and Cs2CO3, was formed and played an important
role in the catalytic cycle. To explore this possibility,
independently prepared CsN(SiMe3)2 (0.1 equiv) was used
to catalyze the coupling of toluene to the preformed N-
(trimethylsilyl)imine (Scheme 6).21 A 94% assay yield of 3aa
was generated under the standard conditions. In comparison,
the mixed NaN(SiMe3)2 (10 mol %)/Cs2CO3 (5 mol %) and
NaN(SiMe3)2 (5 mol %)/CsN(SiMe3)2 (5 mol %) furnished
the product in 93 and 95% yield, respectively. As described in
our previous work, stoichiometric NaOTMS is formed.19c We
We next explored the reactivity of toluene derivatives using
the LiN(SiMe3)2/Cs2CO3 catalyst system in the amino-
benzylation of the parent benzaldehyde (1a). Toluenes
supporting electron-donating groups, such as 4-iPr (2b) and
2-OMe (2c), exhibited good performance, affording the
C
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addition of toluene to imines (see Supporting Information
for details). These data demonstrate that the CsN(SiMe3)2 (10
mol %) can catalyze this transformation. Furthermore, the
mixed system NaN(SiMe3)2 (5 mol %)/CsN(SiMe3)2 (5 mol
%) can also catalyze the reaction.
In conclusion, we have improved our recently developed
aminobenzylation of aldehydes by introducing a novel catalyst
[MN(SiMe3)2 (M = Li or Na)/Cs+] that can reversibly
deprotonate the weakly acidic benzylic C−H bonds of
toluenes. Using this system, a straightforward and practical
one-pot aminobenzylation of benzaldehydes with toluene
derivatives is disclosed, enabling the generation of a diverse
array of bioactive 1,2-diarylethylamines. Overall, this procedure
is much more synthetically efficient than addition of preformed
organometallics, like Grignard reagents, to preformed imines.23
Our catalytic deprotonation of toluenes complements classic
routes (Scheme 1) and stands out due to its simplicity.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02737.
Experimental procedures, characterization data, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pwalsh@sas.upenn.edu.
*E-mail: ias_jymao@njtech.edu.cn.
ORCID
(13) Inamoto, K.; Okawa, H.; Taneda, H.; Sato, M.; Hirono, Y.;
Yonemoto, M.; Kikkawa, S.; Kondo, Y. Chem. Commun. 2012, 48,
9771.
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Org. Lett. 2019, 21, 2588. (b) Shigeno, M.; Sasaki, K.; Nozawa-
Kumada, K.; Kondo, Y. Org. Lett. 2019, 21, 4515.
Patrick J. Walsh: 0000-0001-8392-4150
Jianyou Mao: 0000-0003-0581-3978
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We acknowledge the Nanjing Tech University (3980001601
and 39837112), National Natural Science Foundation of
China (21801128 to J.M.), and Natural Science Foundation of
Jiangsu Province, China (BK20170965 to J.M.), for financial
support. P.J.W. thanks the Petroleum Research Fund (59570-
ND1) and US National Science Foundation (CHE-1902509).
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