HOTf-catalyzed sustainable one-pot synthesis of benzene and pyridine derivatives under solvent-free conditions

Article abstract of DOI:10.1039/c5gc02747k

Herein a versatile HOTf-catalyzed and solvent-free system for highly efficient one-pot synthesis of privileged benzene and pyridine derivatives has been developed using ketones and ketones with amines as simple substrates, respectively. The remarkable features of this "green" reaction include good to excellent yields, exclusive chemoselectivity and broad substrate/functional group tolerance.

Full text of DOI:10.1039/c5gc02747k

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Zhang, Q. Z.
Wang, K. Xu, Q. Y. Feng, W. Zhao, F. X. Xu, L. Y. Yan and W. yi, Green Chem., 2016, DOI:
10.1039/C5GC02747K.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Please do not adjust margins
Page 1 of 5
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02747K
Journal Name
COMMUNICATION
HOTf-Catalyzed Sustainable One-Pot Synthesis of Benzene and
Pyridine Derivatives under Solvent-free Conditions
Xu Zhang,a Zhiqiang Wang,a Kun Xu,a Yuquan Feng,a Wei Zhao,a Xuefeng Xu,a Yanlei
Yana and Wei Yib*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Moreover, the introduction of relatively expensive and toxic
transition-metals was also to some extent limited their application
potentials. Therefore, developing a more general, operationally
simple and versatile method for the synthesis of pyridine scaffold is
highly desirable.
On the other hand, it would be ideal and more straightforward to
adopt a “green chemistry” procedure such as metal-/solvent-free
reaction system with the simple and easily available starting
materials in view of economy and utility. However, to the best of our
knowledge, such sustainable and environmentally benign reaction
system for expeditious synthesis of pyridine derivatives is
underexplored and still remains a great challenge in modern organic
synthesis.
Herein a versatile HOTf-catalyzed and solvent-free system for
highly efficient one-pot synthesis of privileged benzene and
pyridine derivatives has been developed using ketones and
ketones with amines as simple substrates, respectively. The
remarkable features of this “green” reaction include good to
excellent yields, exclusive chemoselectivity and broad
substrate/functional group tolerance.
Since pyridine structures are widely found in numerous natural
products,1 electrochemicals,2 agrochemicals,3 pharmaceuticals,4 and
organic materials,5 the development of efficient methods for building
the pyridine motif has attracted considerable attention in organic
synthesis. As a result, a variety of versatile methodologies toward
their construction have been disclosed in the past decades.6,7 Among
them, the traditional thermal condensation of carbonyl compounds
represents a typical method for the synthesis of pyridines. However,
high temperature and harsh conditions are often involved in these
reactions.
To address the aforementioned drawbacks, one recent emerging
strategy to construct it via transition-metal-catalyzed cycloaddition
reaction.8-13 Indeed, such strategy could complement the traditional
methods in terms of activity, selectivity, reaction condition, substrate
scope and functional group tolerance. For example, Cheng,9
Ellman10 and Rovis11 groups independently revealed the Rh-
catalyzed C-H functionalization of α,β-unsaturated oximes/imines
with alkynes or alkenes, which gave convenient access to pyridine
products (eq 1). In 2013, Yoshikai group disclosed a beautiful
example for efficient synthesis of pyridines via Cu-catalyzed C-H
activation (eq 2).12 More recently, Wang and co-workers also
reported an efficient Ru-catalyzed dehydrative [4+2] cycloaddition
of enamides and alkynes, producing highly substituted pyridines (eq
3).13 However, these versatile reactions commonly required the
compulsive use of external oxidants and/or additives, which
produced stoichiometric amounts of related transition-metal wastes.
Previous report:
R3
R4
R2
R1
R4
R5
R1
N
R5
Cat. Rh
R2
R3
R
N
or
R3
(1)
or
R6
R2
R1
N
R6
R4
R3
R2
R1
R3
R4
R2
R1
Cat. Cu
Cat. Ru
(2)
(3)
NOAc
O
O
N
R1
R2
R5
R4
R1
R2
R4
N
R3
H
N
R3
R5
This work:
R2 NH2
R2
N
R1
Cat.
Cat.
O
HOTf ( 5 mol %)
HOTf ( 5 mol %)
(4)
a.School of Chemistry and Pharmacony Engineering, Nanyang Normal University,
Nanyang 473061, P. R. China
R1
Solvent-free
under air
Solvent-free
R1
under air
R1
R1
R1
b.VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key
Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, Shanghai 201203, P. R. China
In accordance with the above information and inspired by recent
c. Email: yiwei.simm@simm.ac.cn.
advances,8-13 we here describe a new, mild and efficient one-pot
construction of pyridine derivatives with broad substrate/functional
group tolerance via HOTf-catalyzed chemoselective condensation
reaction of simple ketones and amines. Besides, the developed
Fax: +86-21-20231000-1715; Tel: +86-21-20231000-1715
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 5
COMMUNICATION
Journal Name
tolerated. Tolerance to the fluoro (3c, 3e, 3r and 3t) and chloro (3m)
catalytic system have also been applied successfully in benzene
synthesis, in which ketones were used as the sole substrate (eq 4).
Notably, the two reactions proceeded smoothly in air under metal-
/solvent-free conditions and obviated the need of additional ligands,
oxidants or additives to induce the catalytic turnover, thus rendering
this “greener” methodology as a highly versatile and eco-friendly
alternative to the existing methods for building privileged benzene
and pyridine units.
View Article Online
functional groups was especially noteworthy since they were very
DOI: 10.1039/C5GC02747K
useful precursors for further synthetic transformations. Interestingly,
the heteroaromatic amines and ketones also served as suitable
substrates as exemplified by the synthesis of 3f and 3k-l,
respectively. Notably, alkyl amine substrates could be
accommodated in the catalytic system, giving their corresponding
products in good yields (84% for 3g, 87% for 3h, 90% for 3i and 88%
for 3j). Gratifyingly, the HOTf-catalyzed cyclization reaction also
tolerated the polyaromatic acetonaphthone substrates, producing the
interesting 3n-o in decent isolated yields. It should be emphasized
that, the electronic property of the substituent on the benzene ring in
the substrates had an obvious influence on the reaction outcome, and
in the present study, the substrates bearing electron-donating group
gave relatively higher yields than those bearing the electron-
withdrawing group [e.g. 3b (-CH3, 92%) vs 3c (-F, 78%) and 3p (-
CH3, 91%) vs 3m (-Cl, 81%)].
Table 1. Optimization studiesa
Ph
Cat. HOTf ( 5 mol %)
O
1
Ph
NH2
Solvent, T, 12 h
Under air
Ph
N
3a
Ph
Ph
2
Scheme 1. Scope of substrates a
Entry
Catalyst
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
-------
HOTf
HOTf
Solvent
DMF
T (oC)
120
120
120
100
80
Yieldb(%)
31
1
2
R2
DMSO
Toluene
Toluene
Toluene
CH3CN
CCl4
24
Cat. HOTf ( 5 mol %)
O
R2
NH2
3
80
120 oC, 12 h
R1
R1
N
3
R1
Solvent-free and Under air
4
64
1
2
5
43
R
N
R
6
80
NR
NR
56
S
7
80
8
Dioxane
Toluene
Toluene
----------
80
9
10 c
120
120
120
NR
NR
87
Ph
N
Ph
Ph
N
Ph
Ph
N
Ph
Ph
Ph
3g: 84%
3d: R = CH3, 91%
3e: R = F, 72%
3f: 89%
3a: R = H, 87%
3b: R = CH3, 92%
3c: R = F, 78%
11
4
4
4
aReaction conditions: acetophenone 1 (1.0 mmol), benzylamine 2 (0.75 mmol),
HOTf (0.025 mmol, 5 mol%), solvent (0 or 1 mL), 12 h, under air. bisolated yields.
cRunning the reaction under nitrogen atmosphere.
N
N
Ph
N
Ph
3j: 88%
3i: 90%
3h: 87%
At the outset of this study, we chose HOTf as the catalyst and
employed readily available acetophenone 1a and benzylamine 2a as
the model substrates. To our delight, the desired 2,4,6-
triphenylpyridine 3a was obtained in 31% isolated yield under the
initial conditions (table 1, entry 1). A preliminary survey of solvents
showed that toluene was the optimal solvent (entries 1-8). An
attempt to lower the reaction temperature cut down the yield sharply
(entries 3-5). Next, a control experiment revealed that HOTf was
indispensable in this reaction (entry 9). Further experiment
demonstrated that the oxygen in air played a vital role in determining
the reaction process (entry 10). Since solvent-free chemistry has
recently attracted much attention due to their economic viability and
environmental benignness, we finally were interested in determining
the catalytic activity of catalyst HOTf under solvent-free conditions.
Very gratifyingly, the reaction of substrates 1a and 2a in the absence
of solvent under otherwise identical conditions gave the anticipated
product 3a with an improved yield of 87% (entry 11).
N
O
N
N
O
S
S
Cl
Cl
3m: 81%
3l: 84%
3k: 77%
R
R
R
N
N
N
3s: R = CH3, 89%
3t: R = F, 85%
3p: R = H, 91%
3q: R = CH3, 95%
3r: R = F, 87%
3n: R = CH3, 82%
3o: R = F, 78%
a
Reaction conditions: ketone 1 (1.0 mmol), amine 2 (0.75 mmol), HOTf (0.025
mmol, 5 mol%), at 120 oC under air for 12 h. Isolated yields.
With this “green” catalytic system in hand, we sought to explore
the scope of substrates and generality of this reaction, the results of
which are summarized in Scheme 1. To our delight, we found that
the established catalytic system proved to be broadly applicable, thus
delivering the corresponding products 3a-3t in good to excellent
yields with exclusive chemoselectivity. Both substitutions at the
para- (for amine substrates: 3a-b, 3n-o and 3p-r; for ketone
substrates: 3i, 3m and 3p-r), and meta- (for amine substrates: 3d-e
and 3s-t; for ketone substrates: 3j and 3s-t) position were all well-
Considering the remarkably broad substrate scope displayed by the
HOTf catalysis, we performed a series of experiments to explore the
reaction mechanism. As shown in Scheme 2, we first were interested
to probe the role of amine substrate in the catalytic cycle since the
results from Scheme 1 revealed that the C-N bond breaking of
amines was occurred in the reaction. To our surprise, trisubstituted
benzene scaffold was smoothly obtained with 82% yield, when only
substrate 1a was submitted to the above catalytic system (Scheme
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
Green Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
2a). Similarly, other ketones reacted smoothly giving the HOTf, followed by oxidation under air to providVeiewthAerticdleeOsnirliende
corresponding cyclotrimerization products 4b-d in good yields. The product 3a. However, more detailed studiDesOI:a1r0e.1s0t3il9l/Cr5eGquCi0r2e7d47tKo
results suggested that the enol form generated by epimerization of unambiguously confirm the proposed mechanism.
protonated ketone might be a key intermediate in the catalytic
cycle.14 Moreover, it also opened up a new and attractive way for Scheme 3. Proposed mechanism
O
efficient synthesis of benzene motif.
Cat. [HOTf]
under air
1a
Aldol reaction
Ph
NH2
2a
Ph CHO
Ph
Ph
Scheme 2. Mechanistic studies
intermediate 7a
intermediate 5a
H2O
NH4OTf
R
a)
R OH
OH
Cyclo-
Cat. HOTf ( 5 mol %)
O
1
trimerization
NH3OTf
OH
O
via
NH4OTf
R
120 oC, 12 h
Solvent-free and Under air
Isomerization
HO
R
R
R
R
R
OH
enol form
Ph
Ph
enol form
Ph
4
intermediate 8a
1a
H2O
Ph
Ph
Cond-
ensation
Cyclization
Oxidation
3a
7a + 8a
Ph
N
Ph
Cat. [HOTf] + H2O
Ph
N
Ph
intermediate 9a
4b: 89%
4a: 82%
4c: 93%
4d: 87%
b)
CHO
Cat. HOTf ( 5 mol %)
120 oC, 12 h
Conclusions
NH2
NH4OTf
2a
O
5a: 94% yield
Solvent-free and Under air
In summary, we have developed a new, mild and effective HOTf-
catalyzed and solvent-free system for one-pot synthesis of privileged
benzene and pyridine scaffolds with exclusive chemoselectivity and
broad substrate/functional group tolerance, in which ketones and
ketones with amines were respectively employed as simple and
easily available substrates. Through the mechanistic studies, several
key intermediates have been speculated or identified and a possible
reaction mechanism has also been proposed. Based on the above
knowledge, further studies on the scope, mechanism and application
of this catalytic reaction are currently underway in our laboratories.
c)
R2
N
Cat. HOTf ( 10 mol %)
toluene, 120 oC, 12 h
R2 CHO
NH4OAc
R1
R1
R1
3 or 6
R
R
N
R
R
F
F
F
F
N
N
N
F
F
6a: R = CH3, 80%
6b: R = F, 69%
6c: R = CH3, 76%
6d: R = F, 62%
3b: R = CH3, 84%
3c: R = F, 73%
6e: R = CH3, 64%
6f: R = F, 53%
Acknowledgment
Ph
d)
O
substrate 1a and ammonium acetate
3a: 89% yield
Ph
The authors thank the National Natural Science Foundation of China
(21502100, 21302105, 21443007 and 81502909), the Shanghai
Municipal Natural Science Foundation (15ZR1447800) and
Research fund for the key scientific research program
of Henan Educational Committee (15A150021).
Standard conditions
7a
Ph
N
Subsequently, additional experiments were conducted to define
the other possible intermediates. As shown in Scheme 2b, treatment
of amine 2a with catalyst HOTf in the absence of ketone substrate
under the standard conditions gave the product benzaldehyde 5a in
excellent yield. Further reaction of aldehyde and ketone in the
presence of ammonium acetate gave the desired pyridine products
3b-c and 6a-f in decent yields (Scheme 2c). Taken together, these
results revealed that the produced aldehyde should be another key
intermediate of the reaction. Considering the easily formation of
chalcone in the presence of benzaldehyde and acetophenone via the
well-known aldol reaction, we finally speculated that chalcone
species might also be a key intermediate for the versatile reaction.
Thus, chalcone 7a was prepared and designated as a substrate to
provide further insight into the catalytic cycle (Scheme 2d). As
expected, the reaction of 7a and 1a in the presence of ammonium
acetate under otherwise identical conditions occurred successfully to
give the desired product 3a in 89% isolated yield, which confirmed
our speculation.
On the basis of our experimental results and literature precedents,
a plausible reaction mechanism is proposed in Scheme 3. First, the
reaction of amine 2a with the catalyst HOTf provides the aldehyde
5a and amine salt as the main products. Then, two reactions were
occurred simultaneously: the one is the reaction of intermediate 5a
with 1a via a standard aldol reaction to produce the chalcone 7a, and
the other is the reaction of amine salt with the enol from of 1a to
afford the imine 8a. Finally, the produced 7a and 8a undergoes a
typical condensation and subsequently cyclization to yield the
dihydropyridine 9a along with the regeneration of the active catalyst
Notes and references
1
(a) J. P. Michael, Nat. Prod. Rep., 2005, 22, 627; (b) M.
Abass, Heterocycles 2005, 65, 901; (c) V. C. Gibson, C.
Redshaw and G. A. Solan, Chem. Rev., 2007, 107, 1745.
(a) B. Pepin-Donat, A. de Geyer and A. Vialla, Polymer,
1998, 39, 6673; (b) M. J. Plater, M. Mckay and T. Jackdon, J.
Chem. Soc., Perkin Trans.1, 2000, 2695; (c) J. Pang, E. J.-P.
Marcotte, C. Seward, R. S. Brown and S. N. Wang, Angew.
Chem., Int. Ed., 2001, 40, 4042; (d) Y. Shirota, J. Mater.
Chem., 2005, 15, 75; (e) F. Ono, Y. Ishikura, Y. Tada, M.
Endo and T. Sato, Synlett., 2008, 15, 2365.
2
3
4
(a) S. Kang, B. Song, J. Wu, M. He, D. Hu, L. Jin, S. Zeng,
W. Xue and S. Yang, Eur. J. Med. Chem., 2013, 67, 14.
(a) S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011,
54, 3451; (b) TP. Whitehead, C. Havel, C. Metayer, N. L.
Benowitz and P. Jacob, Chem. Res. Toxicol., 2015, 28, 1007;
(c) P. L. Lanza, M. F. Pack, Z. Li, S. A. Krajewski and M. A.
Blank, Aliment Pharmacol. Ther., 2000, 14, 1663; (d) D. F.
Fisher and R. Sarpong, J. Am. Chem. Soc., 2010, 132, 5926;
(e) C.-X. Yuan, C.-T. Chang, A. Axelrod and D. Siegel, J.
Am. Chem. Soc., 2010, 132, 5924.
5
(a) X.-C. Hang, T. Fleetham, E. Turner, J. Brooks and J. Li,
Angew. Chem., Int. Ed., 2013, 52, 6753; (b) G. Cheng, Y.
Weng, X. Yang and X. Cui, Org. Lett., 2015, 17, 3790.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 5
COMMUNICATION
6 For selected reviews of pyridine synthesis, see (a) J. A. Varela
Journal Name
View Article Online
and C. Saa, Chem. Rev., 2003, 103, 3787; (b) G. Zeni and R. C.
Larock, Chem. Rev., 2006, 106, 4644; (c) B. Heller, (d) M.
Hapke, Chem. Soc. Rev., 2007, 36, 1085; (e) M. Schlosser and
F. Mongin, Chem. Soc. Rev., 2007, 36, 1161; (f) B.
Groenendaal, E. Ruijter and R. V. A. Orru, Chem.
DOI: 10.1039/C5GC02747K
Commun., 2008, 5474; (g) Y. Nakao, Synthesis, 2011, 2011
,
3209; (h) J. A. Bull, J. J. Mousseau, G. Pelletier and A. B.
Charette, Chem. Rev., 2012, 112, 2642.
7
For representative achievements on pyridine synthesis, see: (a)
M. Yoshida, T. Mizuguchi and K. Namba, Angew. Chem., Int.
Ed., 2014, 53, 14550; (b) D. G. Stark, L. C. Morrill, P.-P. Yeh,
A. M. Z. Slawin, T. T. J. C. ÓRiordan and A. D. Smith,
Angew. Chem., Int. Ed., 2013, 52, 11642; (c) Z. Shi and T.-P.
Loh, Angew. Chem., Int. Ed., 2013, 52, 8584; (d) Y. Jiang,
C.-M. Park and T.-P. Loh, Org. Lett., 2014, 16, 3432; (e) C.-
H. Lei, D.-X. Wang, L. Zhao, J. Zhu and M.-X. Wang, J. Am.
Chem. Soc., 2013, 135, 4708; (f) P. Huang, R. Zhang, Y.
Liang and D. Dong, Org. Lett., 2012, 14, 5196; (g) C. Allais,
F. Lieby-Muller, T. Constantieux and J. Rodriguez, Adv.
Synth. Catal., 2012, 354, 2537; (h) K. Kral and M. Hapke,
Angew. Chem., Int. Ed., 2011, 50, 2434; (i) T. J. Donohoe, J.
A. Basutto, J. F. Bower and A. Rathi, Org. Lett., 2011, 13
,
1036; (j) T. Sakai and R. L. Danheiser, J. Am. Chem. Soc.,
2010, 132, 13203; (k) F. Sha and X. Huang, Angew. Chem.,
Int. Ed., 2009, 48, 3458.
For selected examples, see: (a) S. Pankajakshan, Y.-H. Xu, J.
K. Cheng, M. T. Low and T.-P. Loh, Angew. Chem., Int. Ed.,
2012, 51, 5701; (b) Y.-H. Xu, Y. K. Chok and T.-P. Loh,
8
Chem. Sci., 2011, 2, 1822; (c) H. Zhou, W.-J. Chung, Y.-H.
Xu and T.-P. Loh, Chem. Commun., 2009, 3472; (d) H. Zhou,
Y.-H. Xu, W.-J. Chung and T.-P. Loh, Angew. Chem., Int.
Ed., 2009, 48, 5355; (e) K.-D. Hesp, R.-G. Bergman and J.-A.
Ellman, J. Am. Chem. Soc., 2011, 133, 11430; (f) Y. Liu, D.
Li and C.-M. Park, Angew. Chem., Int. Ed., 2011, 50, 7333;
(g) H. Huang, X. Ji, W. Wu, L. Huang and H. Jiang, J. Org.
Chem., 2013, 78, 3774; (h) T. Yamakawa and N. Yoshikai,
Org. Lett., 2013, 15, 196; (i) I. V. Rassokhina, V. Z. Shirinian,
I. V. Zavarzin, V. Gevorgyan and Y. A. Volkova, J. Org.
Chem., 2015, 80, 11212.
9
(a) C.-Z. Luo, J. Jayakumar, P. Gandeepan, Y.-C. Wu and C.-
H. Cheng, Org. Lett., 2015, 17, 924; (b) K. Parthasarathy, M.
Jeganmohan and C.-H. Cheng, Org. Lett., 2008, 10, 325; (c)
C.-H. Cheng and K. Parthasarathy, Synthesis, 2009, 1400; (d)
K. Parthasarathy and C.-H. Cheng, J. Org. Chem., 2009, 74
,
9359.
10 (a) D. A. Colby, R. G. Bergman and J. A. Ellman, J. Am.
Chem. Soc., 2008, 130, 3645; (b) S. Duttwyler, C. Lu, A. L.
Rheingold, R. G. Bergman and J. A. Ellman, J. Am. Chem.
Soc., 2012, 134, 4064; (c) R. M. Martin, R. G. Bergman and J.
A. Ellman, J. Org. Chem., 2012, 77, 2501.
11 (a) T. K. Hyster and T. Rovis, Chem. Commun., 2011, 47
,
11846; (b) J. M. Neely and T. Rovis, J. Am. Chem. Soc., 2013,
135, 66; (c) J. M. Neely and T. Rovis, J. Am. Chem. Soc.,
2014, 136, 2735.
12 Y. Wei and N. Yoshikai, J. Am. Chem. Soc., 2013, 135, 3756.
13 J. Wu, W. Xu, Z-X. Yu and J. Wang, J. Am. Chem. Soc.,
2015, 137, 9489.
14 Y. Zhao, J. Li, C. Li, K. Yin, D. Ye and X. Jia, Green Chem.,
2010, 12, 1370.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02747K
Graphical Abstract