Silver-Catalyzed Cascade Reaction of N-Isocyaniminotriphenylphosphorane with Aldehydes: Synthesis of Unsymmetrical Azines

Article abstract of DOI:10.1002/ejoc.201901433

A direct synthesis of azines from the silver catalyzed domino interaction of N-isocyaniminotriphenylphosphorane and aldehydes is reported. The reaction proceeds through a tandem aza-Wittig, insertion, intramolecular cyclization and ring-opening processes.

Full text of DOI:10.1002/ejoc.201901433

A Journal of
Accepted Article
Title: Silver-catalyzed Cascade Reaction of N-
Isocyaniminotriphenylphosphorane with Aldehydes: Synthesis of
Unsymmetrical Azines
Authors: Yeming Wang, Yang Yu, Liping Zhao, and Yongquan Ning
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901433
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10.1002/ejoc.201901433
European Journal of Organic Chemistry
COMMUNICATION
Silver-catalyzed Cascade Reaction of
N-Isocyaniminotriphenylphosphorane with Aldehydes: Synthesis
of Unsymmetrical Azines
Yeming Wang,*[a] Yang Yu,[b] Liping Zhao,[a] Yongquan Ning*[b]
Abstract: A direct synthesis of azines from the silver catalyzed
domino interaction of N-isocyaniminotriphenylphosphorane and
aldehydes is reported. The reaction goes via tandem aza-Wittig,
insertion, intramolecular cyclization and ring-opening processes. The
use of DIPEA as a base and BF3·Et2O as additive significantly
enhance the yield of a range of unsymmetrical azines.
and our recent efforts on the silver-catalyzed isocyanides
reactions,[13] we herein reported
novel silver-catalyzed
cascade reaction of NIITP with aldehydes for constructing
unsymmetrical azines bearing CH=N-N=C(CN)-N=PPh3 skeletal
structure. It is the first time for NIITP to act as both
“phosphonium ylide” and “CN” sources.
a
Scheme 1. Reactions of NIITP.
Introduction
Over the past few decades, isocyanides have attracted more
attention in organic synthesis and represents one of the most
powerful amphiphilic species involved in various chemical
transformations.[1] This appealing property of isocyanides has
been quite effective in boosting research efforts on
multicomponent reactions. For instance, the success of the Ugi
reaction has particularly indicated the comprehensive utilization
for the synthesis of metal-isocyanides under both metal-
mediated and metal-catalyzed organic transformations.[2]
Isocyanides were also widely useful for insertion processes into
various metal-element bonds.[3] Functionalized isocyanides have
particularly received considerable attention for their ability to
form heterocycles.
The N-isocyaniminotriphenylphosphorane (NIITP), which
was reported by Fehlhammer and Weinberger in 1980, has been
extensively explored as the safe, easy-to-handle, and odorless
solid.[4] It can be used as a phosphonium ylide for converting the
carbon-oxygen double bond of a carbonyl compound into a
carbon-nitrogen double bond of an imine group,[5] and it can also
be served as a key intermediate in multicomponent reactions
(MCRs) (Scheme 1a) for the synthesis of various heterocycles
including 1,3,4-oxadiazoles,[6] 1,3,4-oxadiazepines,[7] furo[2,3-
c]pyrans,[8] pyrrolidine-2,5-diones,[9] and [1,2,4]triazolo[4,3-
c]quinazolines.[10] Besides the advances made so far, metals
have particularly not been introduced to the NIITP reactions.
Recently, Bi’s group has reported the application of NIITP as a
“CN” source in the cyanation of alkynes (Scheme 1b)[11] and as
a “C=N-N” source in the [3+2] cycloaddition of alkynes for
synthesis of pyrazoles (Scheme 1c).[12] Inspired by these work
Results and Discussion
Our study began with NIITP 1 and 4-chloro-phenylaldehyde
2a as model substrates for the synthesis of asymmetrical azine
3a (Table 1). Extensively experiments involving various solvents,
bases and catalysts were conducted on these reagents for
optimization. Firstly, NIITP 1 and 4-chloro-phenylaldehyde 2a
was treated with DIPEA (0.5 equiv.) as base and stoichiometric
amount of Ag2CO3 at 100 °C in various solvents for 12 h. The
reaction proceeded smoothly in dioxane to afford azine 3a in 51%
yield (Table 1, entry 1), whereas other solvent systems including
DMF, DME, THF and toluene gave 3a as yields no more than 43%
(Table 1, entries 2-5). Attempts on extending the reaction to
other bases including Et3N, DABCO and K2CO3 (entries 6-8) did
not yield any better result. Interestingly, a decreased load of
catalyst Ag2CO3 (20 mol%) in dioxane resulted in a remarkable
increased yield of 3a (entry 9), which was attributed to the
possible decreased consumption of 1 to generate redundant
Ph3P=NNC-Ag. Further screening on a range of other silver
catalysts was also conducted in dioxane at 100 °C for 12 h
(entries 10-14). As shown in entry 10, AgOTf effectively
promoted the transformation and afforded the asymmetrical
azine 3a in 71% yield, while the yields were decreased
catalyzed by AgNO3, AgOAc, Ag2O and AgF (entries 11-14). It
was interesting to note that with the addition of BF3·Et2O to this
reaction, the yield rose up to 77% (entry 15).[14]
[a]
[b]
Dr. Yeming Wang; Dr. Liping Zhao
Institute of Chemical and Industrial Bioengineering
Jilin Engineering Normal University
Kaixuan Road, No.3050. Changchun, 130052, China.
E-mail: wangyeming2011@163.com
Yang Yu; Dr. Yongquan Ning
Department of Chemistry, Jilin Province Key Laboratory of Organic
Functional Molecular Design & Synthesis
Northeast Normal University
Renmin Street, No. 5268. Changchun, 130024, China.
E-mail:ningyq508@nenu.edu.cn
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10.1002/ejoc.201901433
European Journal of Organic Chemistry
COMMUNICATION
generate the ambiphilic N-isocyanoimine 4, which reacts with
Ag+ promoted by DIPEA and affords isocyanide-silver complex 5.
Then an insertion of NIITP 1 into C-Ag bond and subsequent
intramolecular cyclization lead to the formation of intermediate
diazetidine 7. Finally, azine product 3 would result by ring-
opening followed by the regeneration of the Ag+ and DIPEA.
Table 1. Optimization of the Reaction Conditions.[a,b]
Scheme 2. Exploration of the scope of aldehydes. [a,b]
Solvent
Base
[Ag]
Yield(%)[b]
Entry
1[c]
2[c]
3[c]
4[c]
5[c]
6[c]
7[c]
8[c]
9
10
11
12
13
14
15[d]
Dioxane
DMF
DME
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
DABCO
K2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOTf
AgNO3
AgOAc
Ag2O
AgF
Ag2CO3
51
trace
23
30
43
37
39
22
75
71
56
56
47
52
77
THF
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
[a] Reactions were performed with NIITP 1 (2.0 mmol, 4 equiv.), 4-chloro-
phenylaldehyde 2a (0.5 mmol), [Ag] (0.1 mmol, 20 mol%), base (0.25 mmol,
50 mol%) and solvent (4 mL) at 100 °C for 12 h. [b] Yields of the product was
determined by 1H-NMR analysis of crude reaction mixture. [c] [Ag] (0.5 mmol,
1.0 equiv.). [d] BF3·Et2O (0.15 mmol, 30 mol%) was added.
With the optimal reaction conditions in hand (Table 1, entry
15), scopes of aldehydes were explored. Thus NIITP 1 was
treated with various aldehydes 2 in the presence of 20 mol % of
Ag2CO3, 50 mol% of DIPEA and 30 mol% of BF3·Et2O.
Aldehydes bearing different electron-withdrawing and electron-
donating substituents reacted efficiently affording the desired
azines products 3 in moderate to high yields (Scheme 2). The
structure of product 3t was confirmed by X-ray single crystal
diffraction. Aromatic aldehydes bearing electron-donating groups
were particularly amenable to the optimal conditions and
furnished the desired azines in 75%-85% yields (3g-i). However,
with electron-withdrawing aromatic aldehydes and other ortho-
substituted analogues, the sigificant decreased yields were
observed (products 3b-e and 3m-n, respectively), demonstrating
that steric and electronic effect are crucial in this cascade
reaction. It is also noteworthy that 2-naphthaldehyde 2o and 2-
fluorenecarboxaldehyde 2p were responsive to this reaction,
and provided products 3o and 3p in 71% and 73% yield
respectively. We were also delighted to find that heteroaryl
aldehydes were tolerated and the corresponding azines
products obtained in moderate yields (products 3q-s). Related to
the above, aliphatic aldehydes were also investigated using the
optimal conditions. Gratifyingly, the aliphatic aldehydes afforded
the azine products in 31-65% (products 3t-v). All of these
heteroaryl- and alkyl-substituted azines in Scheme 2 are novel
compounds which could prove to be useful intermediates in
organic and medicinal chemistry research.
[a] Reactions were performed with NIITP 1 (2.0 mmol), aldehyde 2 (0.5 mmol),
Ag2CO3 (0.1 mmol, 20 mol%), DIPEA (0.25 mmol, 50 mol%) and BF3·Et2O
(0.15 mmol, 30 mol%) in dioxane (4 mL) at 100 oC for 12 h. [b] Isolated yields.
Scheme 3. Plausible mechanism.
Conclusions
In conclusion, we have developed a new, simple, and
efficient Ag-catalyzed cascade reaction NIITP with aldehydes to
construct unsymmetrical azines in moderate to high yields. In
this reaction, NIITP performed both roles as “phosphonium ylide”
and “CN” sources. Further research is still in progress.
On the basis of the experimental observations and literature
reports,[11,12]
a plausible mechanism for the Ag-catalyzed
cascade reaction of NIITP with aldehydes is proposed in
Scheme 3 below. With the aid of BF3·Et2O, intermolecular aza-
Wittig reaction of NIITP 1 with aldehyde 2 takes place to
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10.1002/ejoc.201901433
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[2]
[3]
V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin, V. Y. Kukushkin, Chem.
Rev. 2015, 115, 2698.
Experimental Section
a) S. Chakrabarty, S. Choudhary, A. Doshi, F.-Q. Liu, R. Mohan, M. P.
Ravindra, D. Shah, X. Yang, F. F. Fleming, Adv. Synth. Catal. 2014,
356, 2135; b) T. Vlaar, E. B. Ruijter, U. W. Maes, R. V. A. Orru, Angew.
Chem. Int. Ed. 2013, 52, 7084.
Typical synthetic procedure (with 3a as an example): To a dried
Schlenk flask N-Isocyanoiminotriphenylphosphorane 1 (604 mg, 2.0
mmol), 4-chlorobenzaldehyde 2a (70.3 mg, 0.5 mmol) and Ag2CO3 (27.5
mg, 0.10 mmol) were added under air atmosphere. After evacuated and
refilled with nitrogen 3 times, 1,4-dioxane (4 mL), DIPEA (41.3 L, 0.25
mmol) and BF3·Et2O (18.5 L, 0.15 mmol) was added in one portion to
the mixture by syringe. The mixture was stirred at 100 ºC for 12 h until
substrate 2a disappeared. After completion, the resulting mixture was
concentrated and extract with diethyl ether (3 x 15 mL), washed with
brine (3 x 40 mL). Then combined organic layer was dried over MgSO4
and concentrated. Finally, the crude product was further purified by flash
column chromatography and recrystallization with diethyl ether to gave
pure product 3a as a yellow solid in 77% yield.
[4]
[5]
B. Weinberger, W. P. Fehlhammer, Angew. Chem., Int. Ed. 1980, 19, 6.
a) E. Aller, P. Molina, Á. Lorenzo, Synlett. 2000, 2000, 526; b), M.
Rouhani; A. Ramazani, S. W. Joo, Ultrason. Sonochem. 2014, 21, 262.
For selected examples, see: a) A. Souldozi, A. Ramazani, Tetrahedron
Lett. 2007, 48, 1549; b) L. Cui, Q. Liu, J. Yu, C. Ni, H. Yu,Tetrahedron
Lett. 2011, 52, 5530; c) A. Ramazani, M. Khoobi, A. Torkaman, F. Z.
Nasrabadi, H. Forootanfar, M. Shakibaie, M. Jafari, A. Ameri, S. Emami,
M. A. Faramarzi, A. Foroumadi, A. Shafiee, Eur. J. Med. Chem. 2014,
78, 151; d) M. Adib, M. R. Kesheh, S. Ansari, H. R. Bijanzadeh, Synlett
2009, 2009, 1575; e) F. Brock meyer, D. Gerven, W. Saak, J. Martens,
Synthsis 2014, 46, 1603; f) A. Ramazani, A. Rezaei, Org. Lett. 2010, 12,
2852；g) M. Adib, E. Sheikhi, A. Kavoosi, H. R. Bijanzadeh, Synthesis
2010, 2010, 4082; h) F. Z. Nasrabadi, A. Ramazani, Y. Ahmadi, Mol.
Diversity 2011, 15, 791; i) J. R. Frost, C. C. G. Scully, A. K. Yudin, Nat.
Chem. 2016, 8, 1105.
[6]
Acknowledgments
This work was supported by Doctoral Research Initiation Fund
Project of Jilin Engineering Normal University (BSKJ201921,
BSKJ201823).
[7]
[8]
[9]
A. Souldozi, A. Ramazani, N. Bouslimanib, R. Welter, Tetrahedron Lett.
2007, 48, 2617.
M. Adib, S. Ansaria, L. Zhu, Rahimi-Nasrabadi, M. Helvetica Chimica
Acta. 2013, 96, 675.
a) M. Adib, S. Ansari, S. Fatemi, H. R. Bijanzadeh, L. Zhu, Tetrahedron
2010, 66, 2723; b) M. Adib, S. Ansari, H. R. Bijanzadeh, Synlett 2011,
2011, 619.
Keywords: N-Isocyaniminotriphenylphosphorane • aza-Witting
reaction • azines • Ag-catalysis • cascade reaction
[10] M. Adib, S. Ansari, S. Feizi, H. R. Bijanzadehb, Synlett 2010, 2010,
921.
[1]
For the selected reviews on isocyanides, see: a) A. Dömling, I. Ugi,
Angew. Chem. Int. Ed. 2000, 39, 3168; b) A. Dömling, Chem. Rev.
2006, 106, 17; c) L. El Kaim, L. Grimaud, Tetrahedron 2009, 65, 2153;
d) L. Banfi, R. Riva, A. Basso, Synlett 2010, 21, 23; e) A. V. Gulevich, A.
G. Zhdanko, R. V. A. Orru, V. G. Nenajdenko, Chem. Rev. 2010, 110,
5235; f) B. Zhang, A. Studer, Chem. Soc. Rev. 2015, 44, 3505; g) G.
Qiu, Q. Ding, J. Wu, Chem. Soc. Rev. 2013, 42, 5257; h) S. Lang,
Chem. Soc. Rev. 2013, 42, 4867.
[11] H. Wang, P. Mi, W. Zhao, R. Kumar, X. Bi, Org. Lett. 2017, 19, 5613.
[12] F. Yi, W. Zhao, Z. Wang, X. Bi, Org. Lett. 2019, 21, 3158. Similar work
was also reported by Lin’s Group: P. Mi, J. Lang, S. Lin, Chem.
Commun. 2019, 55, 7986.
[13] Y. Wang, R. K. Kumar, X. Bi, Tetrahedron Lett. 2016, 57, 5730.
[14] BF3·Et2O was necessary for this reaction, especially for the aldehydes
with electron-donating group.
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European Journal of Organic Chemistry
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This article is protected by copyright. All rights reserved.