Catalytic Amide-Base System of TMAF and N(TMS)3 for Deprotonative Coupling of Benzylic C(sp3)-H Bonds with Carbonyls

Article abstract of DOI:10.1021/acs.orglett.9b00550

This paper describes that an amide-base generated in situ from tetramethylammonium fluoride (TMAF) and N(TMS)₃ catalyzes the deprotonative coupling of benzylic C(sp³)-H bonds with carbonyls to form stilbenes. A variety of methylheteroarenes (2-methylbenzothiophene, 2-methylbenzofuran, and 2-, 3-, or 4-methylpyridines) are used as nucleophiles. Application to enamine synthesis using DMF as an electrophile is also shown. The present system is effective for toluenes (4-phenyl-, 4-bromo-, 2-bromo-, and 4-chlorotoluenes) having low reactivity.

Full text of DOI:10.1021/acs.orglett.9b00550

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Amide−Base System of TMAF and N(TMS)3 for
Deprotonative Coupling of Benzylic C(sp3)−H Bonds with Carbonyls
Masanori Shigeno,* Kunihito Nakaji, Kanako Nozawa-Kumada, and Yoshinori Kondo*
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai, 980-8578,
Japan
S
* Supporting Information
ABSTRACT: This paper describes that an amide-base generated
in situ from tetramethylammonium fluoride (TMAF) and
N(TMS)3 catalyzes the deprotonative coupling of benzylic
C(sp3)−H bonds with carbonyls to form stilbenes. A variety of
methylheteroarenes (2-methylbenzothiophene, 2-methylbenzo-
furan, and 2-, 3-, or 4-methylpyridines) are used as nucleophiles.
Application to enamine synthesis using DMF as an electrophile is
also shown. The present system is effective for toluenes (4-
phenyl-, 4-bromo-, 2-bromo-, and 4-chlorotoluenes) having low reactivity.
rønsted base-induced deprotonative functionalization of
C−H bonds, which is one of the most fundamental and
B
important chemical transformations, is a powerful and
straightforward method in organic chemistry.1 In addition to
the well-studied deprotonative functionalizations of C(sp2)−H
bonds of arenes and heteroarenes, functionalizations of benzylic
C(sp3)−H bonds are of great importance because of their
potential application to the preparation of pharmaceuticals,
agrochemicals, and electronic materials containing arenes and
heteroarenes.1e−g,2 For the deprotonation of benzylic C(sp3)−
H bonds, stoichiometric amounts of strong bases based on
organometallic or dialkylamide reagents such as n-BuLi, n-BuLi/
t-BuOK, n-BuLi/t-BuOK/TMP-H (2,2,6,6-tetramethylpiperi-
dine), and LDA/t-BuOK, among others, are widely utilize-
d.1e−g,2,3 However, this approach has several drawbacks: (1)
requirement of air- and moisture-sensitive reagents; (2)
cryogenic conditions such as −78 °C to prevent warming of
the reaction mixture by exothermic deprotonation and to
minimize the occurrence of side reactions; (3) poor functional
group tolerance; and (4) laborious two-step protocol involving
deprotonation and subsequent coupling with an electrophile.
Accordingly, the development of an efficient and practical
system that facilitates the reaction of benzylic C(sp3)−H bonds
in various substrates is highly desirable.
Recently, KHMDS- or NaHMDS- (HMDS = hexamethyldi-
silazide),4 weaker bases than organometallic or dialkylamide
reagents, were found to catalyze or mediate the deprotonative
functionalizations of benzylic C(sp3)−H bonds with electro-
philes (Figure 1).5−7 The catalytic reactions were achieved by
the Kobayashi, Guan, and Schneider groups, which include the
coupling reactions of alkylazaarenes with α,β-unsaturated
amides,5a alkylazaarenes with styrenes,5b and allylbenzenes
with imines (Figure 1a).5d In these reactions, highly basic
intermediates such as amide enolates, benzyl anions, or N-alkyl-
N-methoxyphenylamide anions are generated, which likely
contribute to efficient deprotonation of the benzylic C(sp3)−
Figure 1. HMDS-amide-base-promoted deprotonative coupling
reactions of benzylic C(sp3)−H bonds.
H bonds in nucleophiles. This is referred to as a product base
system.6 An appropriate choice of electrophiles is critical for the
catalytic reaction, and aldehyde or ketone carbonyls that
generate less basic alkoxide intermediates are not employed.
Received: February 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00550
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In addition, poorly reactive toluene derivatives are unsuitable for
use as nucleophiles in such cases.8 The Walsh group reported
that the coupling reactions of the toluenes with aryl aldehydes,
which proceed via the aldimine formation from the aldehyde, are
mediated by a stoichiometric amount of NaHMDS with a
catalytic amount of Cs(O2CCF3) (Figure 1b).7,9 However, a
large excess amount of toluenes (more than 30 equiv) was
required for the reaction.
N(TMS)3 (2 equiv), and 2a (2 equiv) provided 3aa in 88%
isolated yield.22−24
The optimized conditions were applied to the reaction of
methylheteroarenes 4a−e (Figure 2). 2-Methylbenzothiophene
Our group has contributed to the development of
deprotonative carbon−carbon bond formation by using an
amide base generated in situ from a catalytic amount of fluoride
or alkoxide salt and a stoichiometric amount of aminosilane.10
The system was applied to the transformations of C(sp2)−H
bonds of heteroarenes such as benzothiophene, benzothiazole,
benzofuran, and indole derivatives with carbonyls, as well as
those of C(sp3)−H bonds at the α-position of carbonyl
compounds such as N,N-diethylacetamide and t-butyl acetate.
As related studies, the transformations of acidic C(sp3)−H
bonds in trifluoromethane and difluoromethyl phenyl sulfone
were also shown by the amide base;11 however, the system has
essentially not been applied to the transformations of the
benzylic C(sp3)−H bonds. In this paper, we describe in situ
generated amide base catalyzed coupling reactions of benzylic
C(sp3)−H bonds with carbonyls to form stilbenes via
deprotonative coupling and dehydration (Figure 1c).12−14 In
addition to various methylheteroarenes, poorly reactive toluene
derivatives (4-phenyl-, 4-bromo-, 2-bromo-, and 4-chloroto-
luenes) could be employed in this reaction.15 The obtained
stilbene is the core structural motif of functional and biologically
active materials.16 The present reaction is an alternative to the
conventional Wittig or Heck olefination.17−19 Enamine syn-
thesis using DMF as an electrophile is also shown.
Initially, 4-cyanotoluene 1a, which has a reactive benzylic
proton (pKa = 31, DMSO),20 was examined in the coupling
reaction with diphenyl benzophenone 2a (Table 1). A variety of
a
Table 1. Optimization of the reaction of 1a and 2a
Figure 2. Reactions of methylheteroarenes and carbonyls. (a)
Reactions were conducted on a 0.2 mmol scale. (b) Isolated yields.
(c) TMAF (30 mol %) and N(TMS)3 (3 equiv) were used. (d)
Reaction was conducted at 80 °C. (e) DMI was used as a solvent. (f)
Reaction was conducted at 40 °C.
b
entry
fluoride or alkoxide source
yield (%)
4a reacted with 2a to afford stilbene 5aa in 98% yield. Tricyclic
ketones such as xanthone 2b, thioxanthone 2c, and dibenzosu-
berenone 2d gave the corresponding stilbenes 5ab, 5ac, and 5ad
in 87%, 90%, and 63% yields, respectively. Then the reactions of
alkyl aryl ketones 2e and 2f were investigated. Sterically
hindered pivalophenone 2e underwent the coupling reaction
to furnish 5ae in 90% yield. Isobutyrophenone 2f, bearing a
C(sp3)−H bond at the α-position of carbonyl, was also coupled
with 4a to form a Z/E mixture of 5af-1 in 32% yield (Z/E =
90:10) along with the formation of 5af-2 in 23% yield.25,26 The
reactions of 2-methylbenzofuran 4b with 2a, 4,4′-dimethox-
ybenzophenone 2g, 4,4′-difluorobenzophenone 2h, and 4,4′-
dichlorobenzophenone 2i gave the corresponding coupling
products 5ba, 5bg, 5bh, and 5bi in 97%, 87%, 77%, and 85%
yields, respectively. Use of pivalaldehyde 2j and 4-
(dimethylamino)benzaldehyde 2k as electrophiles furnished
5bj and 5bk in 87% and 63% yields, respectively. Next,
methylpyridines 4c−e were employed in the reaction. 4- and 2-
methylpyridines 4c and 4d, with pKa values of 32.2 and 3421
(THF) corresponding to the benzylic positions, respectively,
1
2
3
4
5
6
7
8
NaOEt
NaO-t-Bu
KOEt
KO-t-Bu
CsF
73
67
76
76
75
89
TMAF
TMAF
cd
,
quant (88)
77
e
TBAT
a
b
Reactions were conducted on a 0.2 mmol scale. Yields were
determined by H NMR analysis. TMAF (20 mol %), N(TMS)3 (2
equiv), and 2a (2 equiv) were used. Yield in parentheses denotes
isolated yield. Tetrabutylammonium difluorotriphenylsilicate.
c
1
d
e
fluoride or alkoxide salts were screened in the presence of
N(TMS)3.21 The reactions using alkoxide salts of NaOEt, NaO-
t-Bu, KOEt, and KO-t-Bu afforded stilbene 3aa in 67−76%
NMR yields. Then the use of fluoride salts in the reaction was
examined. In the presence of tetramethylammonium fluoride
(TMAF), the reaction proceeded most efficiently to form 3aa in
89% NMR yield. Increased amounts of TMAF (20 mol %),
B
DOI: 10.1021/acs.orglett.9b00550
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
provided coupling products 5ca and 5da in 91% and 78% yields.
Note that 3-methylpyridine 4e having a larger pKa of 37.721
(THF) also coupled with 2a to give 5ea in 76% yield.
The scale-up of the current reaction was performed (Scheme
S3). The reaction of 4a (5.0 mmol) with 2b afforded 1.34 g of
5ab (4.11 mmol) in 82% yield.
3bd in 90% and 80% yields, respectively. Then the reaction of 4-
bromotoluene 1c was examined. In the reaction using n-BuLi/t-
BuOK/TMP-H, debromination occurs as a side reaction.28 To
our delight, with our system, wherein CsF was used as a fluoride
salt, the bromine moiety was tolerated to furnish the
corresponding product 3ca in 72% yield (Table S1).29,30 The
reactions of 1c with 2b and 2c also proceeded to form the
corresponding stilbenes 3cb and 3cc in 88% and 80% yields,
respectively.31,32 Uses of 2-bromotoluene 1d and 4-chloroto-
luene 1e in the reactions with 2b resulted in the formations of
3db and 3eb in 70% and 62% yields, respectively. In this system,
toluene was also employed in the reactions with 2a and 2b;
however, no desired products were obtained (results not
shown).
This type of transformation can be employed for the synthesis
of enamines using DMF as an electrophile (Figure 3).
Reactions with stoichiometric amounts of NaHMDS and
KHMDS were carried out for comparison with the catalytic
system of the amide base generated in situ.33 The use of 3 equiv
of NaHMDS or KHMDS in the reactions of 1b and 1c afforded
much lower yields of the coupling products than those observed
with our catalytic system (Figure 4; Scheme 1), which revealed
Figure 3. Enamine synthesis with DMF or N-methylformanilide as an
electrophile. (a) Reactions were conducted on a 0.2 mmol scale. (b)
Isolated yields. (c) TMAF (20 mol %) and N(TMS)3 (2.0 equiv) were
used. (d) TMAF (30 mol %) was used. N-Methylformanilide 7 (2.0
equiv) was used as an electrophile. DMI (1.0 mL) was used as a solvent.
Scheme 1. Reactions of 1b and 1c with Carbonyls in the
a,b
Presence of KHMDS or NaHMDS
Methylheteroarenes 4a, 4b, and 4c were employed to furnish
the desired enamines in 95%, 96%, and 66% yields, respectively.
N-Methylformanilide 7 was also used as an electrophile, which
resulted in the formation of 8a in 38% yield.
We next examined whether toluene derivatives having a high
pKa are suitable substrates for our protocol (Figure 4).15 4-
Phenyltoluene 1b, which has a pKa value of 38.5727 (THF)
corresponding to the benzylic position, reacted with 2b in the
presence of TMAF (30 mol %) and N(TMS)3 (3 equiv) to
provide 3bb in 80% yield after treatment with HCl. Coupling
reactions of 1b with 2c and 2d also took place to form 3bc and
a
b
Reactions were conducted on a 0.2 mmol scale. Yields were
1
determined by H NMR analysis.
the merit of the present protocol. It should also be noted that the
amide base generated in situ from KOEt/N(TMS)3 gave the
products (11, 12, and 3ca) in a higher yield than did the same
cation of KHMDS (Table S1; Scheme 1 (2)). Such a trend was
also observed in the reactions using NaOEt/N(TMS)3 and
NaHMDS (Table S1; Scheme 1 (2)). From these results, the key
features of the current system can be established: that is, the
ammonium or alkali metal cation can control the reactivity of the
amide base, and the strong O−Si bond formation is a driving
force for the reaction.
The mechanism of the transformation is depicted in Figure 5.
Amide base A generated in situ from TMAF and N(TMS)3
triggers the deprotonation of the benzylic C(sp3)−H bond of
1.11a The resulting benzylic anion B adds to 2 to give alkoxide C.
Figure 4. Reactions of poorly reactive toluenes with carbonyls. (a)
Reactions were conducted on a 0.2 mmol scale. (b) Isolated yields. (c)
DMPU was used as a solvent. (d) CsF (30 mol %), N(TMS)3 (3.0
equiv), and 2a (3.0 equiv) were used. (e) DMF was used as a solvent.
(f) Reaction was conducted at 80 °C.
C
DOI: 10.1021/acs.orglett.9b00550
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ORCID
Masanori Shigeno: 0000-0002-9640-8283
Kanako Nozawa-Kumada: 0000-0001-8054-5323
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
No. 16H00997 in Precisely Designed Catalysts with Custom-
ized Scaffolding (Y.K.), JSPS KAKENHI Grant No. 17K15419
(M.S.), Grand for Basic Science Research Projects from The
Sumitomo Foundation (M.S.), Yamaguchi Educational and
Scholarship Foundation (M.S.), and also the Platform Project
for Supporting Drug Discovery and Life Science Research
funded by Japan Agency for Medical Research and Development
(AMED) (M.S., K.N.K., and Y.K.).
REFERENCES
■
Figure 5. Proposed mechanism of the in situ generated amide base
promoted deprotonative coupling to form stilbenes.
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stilbenes. The system was applicable to the transformation of
various methylheteroarenes as well as poorly reactive toluenes.
The present catalytic system was more effective than conven-
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poorly reactive C−H bonds.
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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.orglett.9b00550.
Experimental details of synthetic procedures, reactions of
cyanotoluenes and electrophiles (Scheme S1), stilbene
formation using wet DMF as a solvent (Scheme S2),
scale-up of the reaction of 4a with 2b (Scheme S3),
optimization of the reaction of 1c and 2a (Table S1),
spectra data for obtained products, and 1H and 13C NMR
spectra (PDF)
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Soc. 2000, 122, 2391. t-BuOK/LiTMP: (d) Yamashita, Y.; Suzuki, H.;
Sato, I.; Hirata, T.; Kobayashi, S. Angew. Chem., Int. Ed. 2018, 57, 6896.
KCH2SiMe3/N,N,N′,N″,N′′-pentamethyldiethylenetriamine: (e) Sato,
I.; Yamashita, Y.; Kobayashi, S. Synthesis 2019, 51, 240. Also see the
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amount of KHMDS/Zn(HMDS)2 induced the deprotonations of
benzylic C(sp3)−H bonds of toluene, m-xylene, and mesitylene under
heating conditions. See: Clegg, W.; Forbes, G. C.; Kennedy, A. R.;
Mulvey, R. E.; Liddle, S. T. Chem. Commun. 2003, 406.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mshigeno@m.tohoku.ac.jp.
*E-mail: ykondo@m.tohoku.ac.jp.
D
DOI: 10.1021/acs.orglett.9b00550
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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́
(c) Bleger, D.; Kreher, D.; Mathevet, F.; Attias, A.-J.; Schull, G.; Huard,
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(20) Bordwell, F. G.; Algrim, D.; Vanier, N. R. J. Org. Chem. 1977, 42,
1817.
(21) The pKa value of HN(TMS)2, a conjugate acid of the amide base
employed in this study, is 25.8 (THF). Fraser, R. R.; Mansour, T. S.;
Savard, S. J. Org. Chem. 1985, 50, 3232. pKa values of methylpyridines
4c−e are also noted in this literature.
(22) The reactions performed in the absence of TMAF (20 mol %) or
N(TMS)3 (2 equiv) exhibited no product formation, highlighting the
necessity of both TMAF and N(TMS)3.
(23) Compound 1a also affords the stilbenes in the reaction with 4-
(dimethylamino)benzaldehyde and benzaldehyde in 87% and 70%
yields, respectively. The former product was obtained as an E/Z
isomeric mixture (E/Z = 93:7). 2-Cyanotoluene also coupled with 2a to
yield the product in 89% yield (Scheme S1).
(24) In the present study, anhydrous DMF was used as a solvent.
However, it was confirmed that, even using wet DMF, the reactions of
1a and 4a with 2a proceeded to give the corresponding products in high
yields of 87% and 94% yields, respectively (Scheme S2).
(25) 2-Ethylbenzothiophene was employed in the reaction with 2a,
however, which resulted in no desired product formation (results not
shown).
(26) Use of dicyclohexyl ketone in the reaction with 4a did not
provide the coupling product (results not shown).
(27) Bors, D. A.; Kaufman, M. J.; Streitwieser, A., Jr. J. Am. Chem. Soc.
1985, 107, 6975.
(28) Das, M.; O’Shea, D. F. Tetrahedron 2013, 69, 6448.
(29) In the reaction of 1c and 2a, CsF was found to be effective
compared with TMAF or alkoxide salts (Table S1).
(30) Walsh and co-workers also recently demonstrated that the
reactions of 2-bromotoluene 1d (large excess) and aldimines proceed
with the tolerance of the bromine moiety by using a stoichiometric
amount of NaHMDS and a catalytic amount of Cs(O2CCF3). See ref
7a.
(31) When CsF (30 mol %) was used instead of TMAF, 3cb and 3cc
were formed in NMR yields of 69% and 75%, respectively.
(32) The reactions of 1c with 2f and 2j were conducted but did not
form the coupling products (results not shown).
(33) For recent examples of deprotonative functionalizations using a
stoichiometric amount of NaHMDS or KHMDS, see: (a) Wang, D.-Y.;
Yang, Z.-K.; Wang, C.; Zhang, A.; Uchiyama, M. Angew. Chem., Int. Ed.
2018, 57, 3641. (b) Ogawa, N.; Yamaoka, Y.; Takikawa, H.; Tsubaki,
K.; Takasu, K. J. Org. Chem. 2018, 83, 7994. (c) Costil, R.; Dale, H. J. A.;
Fey, N.; Whitcombe, G.; Matlock, J. V.; Clayden, J. Angew. Chem., Int.
Ed. 2017, 56, 12533. (d) Diaz Ropero, B. P. F.; Elsegood, M. R. J.;
Fairley, G.; Pritchard, G. J.; Weaver, G. W. Eur. J. Org. Chem. 2016,
2016, 5238. (e) Bhanuchandra, M.; Yorimitsu, H.; Osuka, A. Org. Lett.
2016, 18, 384.
(13) Chiba and co-workers demonstrated that a stoichiometric
amount of NaH−LiI composite proceeded the directed metalation at
the benzylic position and the intramolecular addition to the amide
carbonyls. (a) Huang, Y.; Chan, G. H.; Chiba, S. Angew. Chem., Int. Ed.
2017, 56, 6544. A similar type of reaction proceeds by using LDA.
(b) MacNeil, S. L.; Gray, M.; Gusev, D. G.; Briggs, L. E.; Snieckus, V. J.
Org. Chem. 2008, 73, 9710.
(14) A stoichiometric amount of alkali metal fluoride (CsF or KF)−
Al2O3 composites or alkoxide bases promote deprotonative coupling
reactions of relatively reactive benzylic C(sp3)−H bonds of toluenes
having an electron-withdrawing group, electron-deficient methyl
azaarenes, or cyclic diarylmethanes (fluorene, xanthene, and
̈
thioxanthene) with aldehydes. (a) Hellwinkel, D.; Goke, K.; Karle, R.
Synthesis 1994, 1994, 973. (b) Rangnekar, D. W.; Lokhande, S. B.
Indian J. Chem. 1986, 25, 485. (c) Takahashi, K.; Okamoto, T.; Yamada,
K.; Iida, H. Synthesis 1977, 1977, 58. (d) Kaiser, E. M.; Hartzell, S. L. J.
Org. Chem. 1977, 42, 2951. (e) Luo, F.-T.; Chen, C.-H. Heterocycles
2001, 55, 1663.
(15) n-BuLi was previously used for the deprotonative coupling
reactions of poorly reactive toluenes with diarylketones. (a) Suzuki, T.;
Sakano, Y.; Iwai, T.; Iwashita, S.; Miura, Y.; Katoono, R.; Kawai, H.;
E
DOI: 10.1021/acs.orglett.9b00550
Org. Lett. XXXX, XXX, XXX−XXX