Synthesis of substituted pyridines from cascade [1 + 5] cycloaddition of isonitriles to N-formylmethyl-substituted enamides, aerobic oxidative aromatization, and acyl transfer reaction

Article abstract of DOI:10.1021/ja401701x

A novel strategy for de novo synthesis of pyridines featuring an unprecedented α-addition of aldehyde and enamide to isonitrile as a key step is described. Under mild conditions, a cascade reaction involving Zn(OTf)₂-promoted [1 + 5] cycloaddition of isonitrile with N-formylmethyl-substituted enamide, facile aerobic oxidative aromatization and intermolecular acyl transfer from the pyridinium nitrogen to the 5-hydroxy oxygen, and finally acylation of the 4-amino group by an external acyl chloride efficiently afforded 2-substituted 4-acylamino-5-acyloxypyridines in good to excellent yields.

Full text of DOI:10.1021/ja401701x

Communication
pubs.acs.org/JACS
Synthesis of Substituted Pyridines from Cascade [1 + 5]
Cycloaddition of Isonitriles to N‑Formylmethyl-Substituted
Enamides, Aerobic Oxidative Aromatization, and Acyl Transfer
Reaction
Chuan-Hu Lei,† De-Xian Wang,† Liang Zhao,‡ Jieping Zhu,§ and Mei-Xiang Wang*,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Key Laboratory of Bioorganic Phosphorous and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084,
China
§Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fed
́ ́
erale de Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304, 1015
Lausanne, Switzerland
S
* Supporting Information
were pleased to discover that cascade reactions involving a [1 +
5] cycloaddition between isonitriles and N-formylmethyl-
substituted tertiary enamides followed by oxidative aromatiza-
tion and intermolecular acyl transfer indeed provide an efficient
approach to substituted pyridines (Scheme 1).
ABSTRACT: A novel strategy for de novo synthesis of
pyridines featuring an unprecedented α-addition of
aldehyde and enamide to isonitrile as a key step is
described. Under mild conditions, a cascade reaction
involving Zn(OTf)2-promoted [1 + 5] cycloaddition of
isonitrile with N-formylmethyl-substituted enamide, facile
aerobic oxidative aromatization and intermolecular acyl
transfer from the pyridinium nitrogen to the 5-hydroxy
oxygen, and finally acylation of the 4-amino group by an
external acyl chloride efficiently afforded 2-substituted 4-
acylamino-5-acyloxypyridines in good to excellent yields.
Scheme 1. De Novo Synthesis of Substituted Pyridines
ubstituted pyridines occur widely as natural products,
Spharmaceuticals, agrochemicals, and functional materials
and are also useful intermediates in organic synthesis.1,2 As a
consequence, a wealth of synthetic methods has been
developed.1−3 Among them, [5 + 1] cyclocondensation
reactions using ammonia as the nitrogen source,3 [3 + 3]
cyclocondensation reactions using enamines as three-atom
components,4 and metal-catalyzed or -mediated [4 + 2]5 and [2
+ 2 + 2]6 cycloaddition reactions and cycloisomerizations7 are
notable examples. However, efficient synthesis with high
chemo- and regioselectivity, which would enable access to
tailor-made functionalized pyridines, still remains challenging.8,9
We have recently demonstrated that tertiary enamides, which
are known to be stable and chemically inert because of the
electron-withdrawing acyl group, are unique nucleophiles.10−14
In the presence of a Lewis or Brønsted acid, “stable” tertiary
enamides can undergo intramolecular nucleophilic addition to a
range of electrophiles, including epoxides,10 aldehydes,11
imines,12 and activated ketones,13 yielding diverse heterocyclic
compounds with excellent selectivity. As a continuation of this
research program, we designed an unprecedented [1 + 5]
strategy for the construction of a six-membered nitrogen
heterocyclic framework. The key step involves an α-addition of
a tertiary enamide and an aldehyde to an isocyanide carbon,15
which was envisioned to act as a one-carbon component. We
We initiated our study by examining the reaction between N-
formylmethyl-substituted tertiary enamide 1a and 4-methox-
yphenyl isonitrile (2a) (Table 1). In acetonitrile at ambient
temperature, Lewis acids such as FeCl3, Co(OAc)2, NiCl2,
CuBr2, Cu(OAc)2, [Cu(CH3CN)4]PF6, and InCl3 catalyzed
either no reaction or the oligomerization of isonitrile (Table 1,
entries 1−9). While virtually no reaction took place when 20
mol % Sc(OTf)3, Sm(OTf)3, or SnCl2 was used (entries 10−
12), a stoichiometric amount of SnCl2 was found to be effective
in promoting the reaction of 1a with 2a (entry 13). Zn(OTf)2
was also able to drive the reaction to completion, albeit with a
Received: February 16, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
a
a
Table 1. Lewis Acid-Effected Reactions of 1a with 2a
Table 2. Zn(OTf)2-Mediated Reaction of 1a with 2a
b
b
entry
Lewis acid (mol %)
time
product (% yield )
entry Zn(OTf)2 (mol %)
solvent
temp
rt
time
yield (%)
c
1
2
FeCl3 (20)
7 days
15 min
1 day
1 day
3 days
1 day
2 days
2 days
2 days
6 days
3 days
9 days
2.5 h
−
1
2
100
100
100
100
100
100
50
CH3CN
CH2Cl2
THF
10 h
91
d
FeCl3 (100)
oligomers
rt
3 h
75
d
3
FeCl3·6H2O (100)
Co(OAc)2 (20)
NiCl2 (20)
oligomers
3
rt
3 days
4 days
7 h
19
c
4
−
4
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
rt
23
c
5
−
5
40 °C
reflux
rt
89
d
6
CuBr2 (20)
oligomers
6
1.5 h
2 days
2 days
2 days
6 h
61
d
7
Cu(OAc)2 (20)
[Cu(CH3CN)4]PF6 (20)
InCl3 (20)
oligomers
7
86
c
8
−
8
20
rt
trace
trace
77
c
9
−
9
10
reflux
rt
c
10
11
12
13
14
Sc(OTf)3 (20)
Sm(OTf)3 (20)
SnCl2 (20)
4a (trace)
10
100
4a (trace)
a
The 1a/2a ratio was 1:1.2, and the concentration of 1a in acetonitrile
was 20 mM. Isolated yields. The concentration of 1a was 100 mM.
b
c
4a (trace)
SnCl2 (100)
4a (45) + 5a (19)
4a (45) + 5a (16)
4a (59) + 5a (17)
4a (63) + 5a (18)
a
Zn(OTf)2 (100)
SnCl2 (100)
1 day
2.5 h
Table 3. Synthesis of Substituted Pyridines 5
e
15
e
16
Zn(OTf)2 (100)
1 day
a
The 1a/2a ratio was 1:1.2, and the concentration of 1a in acetonitrile
b
c
d
was 20 mM. Isolated yields. No reaction. Oligomers of isonitrile of
2a. 4Å MS was added.
e
b
entry
1
R
time (h)
5
yield (%)
longer reaction time (entry 14). The addition of 4 Å molecular
sieves (4Å MS) was beneficial to the reaction, leading to the
formation of 5-benzoyloxy-4-(4-methoxyphenyl)amino-2-phe-
nylpyridine (4a) and 4-[N-benzoyl-N-(4-methoxyphenyl)-
amino]-5-benzoyloxy-2-phenylpyridine (5a) in yields of 63
and 18%, respectively, after workup (entry 16).
1
2
1a
1b
1c
1d
1e
1f
Ph
10
7
5a
5b
5c
5d
5e
5f
91
85
75
90
82
91
87
64
82
84
77
4-FC6H4
3
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
4-NO2C6H4
4-PhC6H4
4-MeC6H4
4-MeOC6H4
8
4
7
5
7
6
8
While other reactions such as direct intramolecular attack by
the enamide at the tethered aldehyde, leading to dihydropyr-
role,13 and the Passerini reaction16 could have taken place,
insertion of isonitrile 2a into enamide 1a prevailed over these
competitive pathways under the above-described conditions. In
addition, the formation of pyridines 4a and 5a implied that
oxidative aromatization and benzoyl transfer occurred. On the
basis of this mechansitic hypothesis and also to facilitate
isolation of the product, we slightly modified the workup
procedure to include leaving the crude organic extracts exposed
to air at room temperature overnight followed by addition of an
excess amount of benzoyl chloride (3a). To our delight, the
reaction produced 5a exclusively in 91% yield (Table 2, entry
1). Solvent screening indicated that dichloromethane, tetrahy-
drofuran (THF), and toluene were less effective reaction media,
leading to decreased yields and long reaction times (entries 2−
4). Although heating accelerated the reaction, the yield
deteriorated (entries 5 and 6). Performing the reaction in the
presence of 0.5 equiv of Zn(OTf)2 still produced 5a in a good
yield (entry 7). However, further reducing the Zn(OTf)2
loading lowered the reaction efficiency significantly (entries 8
and 9). Increasing the concentration from 20 to 100 mM led to
faster conversion of reactants at the expense of a reduced yield
of 5a, as the Passerini reaction involving water to give the
corresponding α-hydroxyacetamide16 became competitive
(entry 10 vs entry 1).
7
1g
1h
1i
10
16
8
5g
5h
5i
8
9
10
11
1j
5
5j
1k
5
5k
a
The 1a/2a ratio was 1:1.2, and the concentration of 1 in acetonitrile
was 20 mM. Isolated yields.
b
enamides acted as excellent substrates to react with isonitrile
2a, producing corresponding products 5a−k in good to
excellent yields. However, the reaction rate was influenced by
the nature of the substituent on the enamide benzene ring. For
example, halogen- (1b−g) and phenyl-substituted (1i)
enamides completed the reaction with 2a within 10 h (entries
1−7 and 9), while 4-nitrophenyl-substituted reactant 1h took a
longer reaction time (16 h) to form 5h in 64% yield (entry 8).
The presence of an electron-donating group on the phenyl
moiety significantly accelerated the rate of reaction, as the
reactions of 1j and 1k with 2a reached completion in 5 h,
forming 5j and 5k in good yields (entries 9−11). Since the
nucleophilic addition of isonitrile 2a to the aldehyde of 1 to
afford a nitrilium intermediate was the common initiating step
for all of the enamides, we assumed that the overall reaction
rate was mainly determined by the reactivity of the tertiary
enamide moiety. Tertiary enamides containing an electron-
richer aromatic substituent clearly showed higher enaminic
reactivity.
Under the optimized conditions, the reaction scope was
investigated (Table 3). All of the tested aryl-substituted tertiary
B
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Journal of the American Chemical Society
Communication
In addition to aryl-substituted enamides 1a−k, enamides
bearing an alkenyl or alkyl substitutent participated in the
reaction equally well. Under identical conditions, 2-cyclo-
hexenyl- and 2-cyclohexyl-substituted pyridine derivative 5l and
5m were synthesized in yields of 60 and 70%, respectively
(Chart 1).
is transferred chemoselectively to the 5-hydroxy oxygen atom
while the externally added acyl chloride 3 acylates only the 4-
amino group. No scrambling products were observed. Notice-
ably, the reaction of acetyl-substituted enamide 1o with 2a and
3a furnished the desired product 5u in only 30% yield along
with the α-hydroxyacetamide byproduct derived from the
Passerini reaction (21%).16 This indicates the lower nucleo-
philic reactivity of acetyl-substituted enamide 1o compared
with aroyl-substituted enamides 1a and 1n, allowing the
addition of a water molecule to the nitrilium intermediate. It
is important to point out that in contrast to their secondary
enamide analogues, which are aza−ene components in
nucleophilic reactions,17 the nucleophilicity of tertiary enamides
1 is correlated with the electron density of the enaminic carbon,
which is mainly dictated by delocalization of nitrogen lone-pair
electrons into carbon−carbon double bond. In comparison with
acetyl-substituted enamide 1o, the higher nucleophilicity of
aroyl-substituted enamides is most likely due to the cross-
conjugation effect between the aryl and carbonyl moieties,
which concomitantly alleviates the delocalization of the
nitrogen lone-pair electrons into the carbonyl group. The
cross-conjugation effect has been substantiated by the
observation of a lower energy barrier for CC=O−N bond
rotation in benzamide relative to acetamide.18
To shed light on the mechanistic pathway for the N-to-O
acyl transfer process, a crossover experiment was conducted.
Treatment of equimolar amounts of enamides 1f and 1n with
isonitrile 2a followed by auto-oxidation and reaction with
benzoyl chloride 3a under our standard conditions led to the
formation of a mixture of four pyridine products. As evidenced
by HPLC-MS analysis, they are two pairs of constitutional
isomers, with one isomer containing an O-benzoyl substituent
and the other an O-4-methylbenzoyl substituent. These results
indicate that the acyl group is transferred in an intermolecular
fashion. This point was further validated by adding external 3-
hydroxypyridine into the reaction mixture, which led to the
observation of 3-benzoyloxypyridine (see the SI).
On the basis of the aforementioned experimental results, the
plausible reaction mechanism shown in Scheme 1 is proposed.
Zn(OTf)2-promoted nucleophilic addition of isonitrile 2 to the
aldehyde of enamide 1 affords nitrilium intermediate A, which
is trapped by the enamide to provide N-acyliminium ion B.
Tautomerization then gives a mixture of heterocyclic
intermediates C and D. Oxidative aromatization of D proceeds
under aerobic conditions to afford N-acylpyridinium ion E,
which is an excellent acylating agent by analogy to the N-acyl-4-
dimethylaminopyridine adduct. Intermolecular transfer of the
N-acyl group to the 5-hydroxy group yields trisubstituted
pyridine 4. Acylation of the 4-amino group by external acyl
chloride 3 then furnishes the final product 5. While trapping of
reactive nitrilium intermediates by heteroatom nucleophiles is
well-known,15 carbon nucleophiles have been rarely used for
this purpose.19 To the best of our knowledge, the work
reported here represents the first example wherein enamides
serve as nucleophiles to intercept nitrilium intermediates.
In summary, we have established an unprecedented method
for the construction of pyridine rings through a cascade
reaction of tertiary enamides with isonitriles. The sequence
leading to the pyridine comprises an initial [1 + 5]
cycloaddition of an isonitrile with an N-formylmethyl-
substituted enamide, a facile aerobic oxidative aromatization,
intermolecular acyl transfer from the pyridinium nitrogen to the
oxygen of the 5-hydroxy group, and finally acylation of the 4-
Chart 1. Synthesized Pyridine Derivatives 5l−r
The reaction was readily expanded to other isonitriles,
including aliphatic ones. The reaction of phenyl isonitrile (2b)
with 1a, for instance, furnished product 5n in 77% yield. 4-
Bromophenyl isonitrile (2c), a less nucleophilic isonitrile,
underwent a similar reaction to afford product 5o, albeit with a
decreased reaction velocity and a diminished yield. When
aliphatic isonitriles were employed under identical conditions,
unexpected and markedly varied results were obtained. For
example, benzyl isonitrile (2d) needed 48 h to complete its
reaction with enamide 1a to afford 5p in 70% yield. The
reactions of n-butyl isonitrile (2e) and cyclohexyl isonitrile (2f)
were extremely slow, affording products 5q and 5r in yields of
36 and 15% after 4 and 5 days, respectively (Chart 1). As
revealed by 1H NMR spectroscopy [see the Supporting
Information (SI)], the strikingly abnormal reactivity of 2e
and 2f was due to their strong association with zinc ion. To
circumvent this problem, excess amounts of these aliphatic
isonitriles were used. In the presence of 4 equiv of 2e or 2f, the
reaction proceeded much more efficiently to give an improved
yield of 60% for 5q or 41% for 5r, respectively, after an identical
consecutive reaction sequence (Chart 1).
To understand the effect of the N-acyl group on the
reactivity of the enamide and the regioselectivity of the acyl
transfer process, three-component reactions were conducted
using different enamides and acyl chlorides. The tandem
reaction between 1a and 2a followed by oxidative aromatization
and subsequent acylation with acetyl chloride (3b) yielded
product 5s in 66% yield (Scheme 2). A similar reaction of 4-
methylbenzoylated enamide 1n with 2a and 3a produced 5t in
85% yield. It is noteworthy that the N-acyl group of enamide 1
Scheme 2. Sequential Three-Component Reactions
C
dx.doi.org/10.1021/ja401701x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(11) Tong, S.; Wang, D.-X.; Zhang, L.; Zhu, J.; Wang, M.-X. Angew.
Chem., Int. Ed. 2012, 51, 4417.
(12) Tong, S.; Xu, Y.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X.
amino group by an external acylating agent. The high reaction
efficiency and wide reaction scope make this method a fast and
straightforward route to diversely substituted pyridines that are
analogues of acetylcholinesterase (AChE) inhibitors.20 The
finding that the enamide is an effective C-nucleophilic partner
in the α-addition of the isonitrile should open new avenues for
further exploration of the synthetic potential of isonitriles.
Tetrahedron 2012, 68, 6492.
(13) Yang, L.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Am. Chem.
Soc. 2009, 131, 10390. (b) Yang, L.; Lei, C.-H.; Wang, D.-X.; Huang,
Z.-T.; Wang, M.-X. Org. Lett. 2010, 12, 3918.
(14) For reviews of enamides, see: (a) Carbery, D. R. Org. Biomol.
Chem. 2008, 6, 3455. (b) Gopalaiah, K.; Kagan, H. B. Chem. Rev. 2011,
111, 4599.
ASSOCIATED CONTENT
* Supporting Information
■
(15) (a) Domling, A. Chem. Rev. 2006, 106, 17. (b) El Kaim, L.;
̈
S
Grimaud, L. Tetrahedron 2009, 65, 2153.
Procedures, characterization and spectroscopic data, X-ray
structures (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Banfi, L.; Riva, R. Org. React. 2005, 65, 1.
(17) (a) Maji, B.; Lakhdar, S.; Mayr, H. Chem.Eur. J. 2012, 18,
5732 and references therein. (b) Matsubara, R.; Kobayashi, S. Acc.
Chem. Res. 2008, 41, 292.
AUTHOR INFORMATION
Corresponding Author
wangmx@mail.tsinghua.edu.cn
■
(18) (a) Oki, M. Applications of Dynamic NMR Spectrocopy to Organic
̅
Chemistry; VCH: Weinheim, Germany, 1985; pp 43−46. (b) Rogers,
M. T.; Woodbrey, J. C. J. Phys. Chem. 1962, 66, 540.
(19) (a) Deyrup, J. A.; Vestling, M. M.; Hagan, W. V.; Yun, H. Y.
Tetrahedron 1969, 25, 1467. (b) Schneekloth, J. S.; Kim, J.; Sorensen,
E. J. Tetrahedron 2009, 65, 3096.
Notes
The authors declare no competing financial interest.
(20) Shutske, G. M.; Kapples, K. J.; Tomer, J. D.; Hrib, N. J.; Jurcak,
J. J. EP 0477903A2, 1991.
ACKNOWLEDGMENTS
We acknowledge the National Natural Science Foundation of
China and Tsinghua University for financial support.
■
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