Palladium-catalyzed multicomponent reaction (MCR) of propargylic carbonates with isocyanides

Article abstract of DOI:10.1021/acs.orglett.6b02999

A palladium-catalyzed multicomponent reaction (MCR) of propargylic carbonates with isocyanides is reported. Remarkably, the orderly insertion of isocyanides affords two types of valuable N-heterocyclic products (Z)-6-imino-4,6-dihydro-1H-furo[3,4-b]pyrrol-2-amines and (E)-5-iminopyrrolones in high yields. Systematic analysis of the reaction conditions indicates that the selectivity of these N-heterocyclic products can be controlled by ligands and temperature.

Full text of DOI:10.1021/acs.orglett.6b02999

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Multicomponent Reaction (MCR) of Propargylic
Carbonates with Isocyanides
Jianwen Peng,† Yang Gao,† Weigao Hu, Yinglan Gao, Miao Hu, Wanqing Wu,* Yanwei Ren,
and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed multicomponent reaction (MCR) of propargylic carbonates with isocyanides is reported.
Remarkably, the orderly insertion of isocyanides affords two types of valuable N-heterocyclic products (Z)-6-imino-4,6-dihydro-
1H-furo[3,4-b]pyrrol-2-amines and (E)-5-iminopyrrolones in high yields. Systematic analysis of the reaction conditions indicates
that the selectivity of these N-heterocyclic products can be controlled by ligands and temperature.
ulticomponent reactions (MCRs) have held a prom-
inent position in modern synthetic chemistry for the
Scheme 1. Palladium-Catalyzed MCRs of Isocyanides
M
facile construction of complex molecules from readily accessible
starting materials.1 Since the elegant pioneering work of
Passerini and Ugi with isocyanides as reaction components,
isocyanides have been strongly associated with the success of
MCRs.2 Recently, transition-metal-catalyzed MCRs involving
isocyanides have been widely explored.3 Particularly, due to the
high efficiency of palladium catalysis in C−N, C−O, and C−C
bond formation reactions,4 the palladium-catalyzed MCRs of
isocyanides have become an efficient strategy to synthesize
heterocyclic and carbocyclic compounds.5,6 However, the
reported methods mainly focused on a single insertion of
isocyanide via the aryl- or alkenyl-palladium intermediates
(Scheme 1, eq 1).7 To date, few successful examples of multiple
insertion of isocyanides have been disclosed. But the insertion
of isocyanides commonly occurred at one site which limited the
diversity of the products.8 On the other hand, the multi-
component reactions which allowed the tandem multiple
insertion of isocyanides in an orderly manner were considerably
rare.9
heterocycles, and carbocycles14 in high yields. Generally, an
allenylpalladium intermediate was involved via the oxidative
addition of palladium(0) catalysis to propargylic compounds. In
this context, we envisaged that the successive insertion of
isocyanides may be achieved through the same allenylpalladium
intermediate (Scheme 1, eq 2). First, isocyanide might go
through the 1,1-migratory insertion with the in situ formed
allenylpalladium intermediate I. Then another isocyanide could
react with the allenes moiety via nucleophilic addition.15 The
This might be attributed to the fact that isocyanides have
difficulty in exhibiting different reactivities under the same
reaction system, and the uncontrollable multiple insertion of
isocyanides is also a serious problem.10 Therefore, reaction with
intermediates bearing diverse potential reactive sites with
isocyanides may be an efficient strategy to achieve the orderly
insertion of isocyanides.
Recently, palladium-catalyzed transformations of propargylic
compounds have attracted much attention,11 providing various
valuable allenyl compounds,12 disubstituted allylic products,13
Received: October 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02999
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
newly formed intermediate A might become the active species
to construct valuable N-heterocyclic compounds. Herein, we
present our recent progress in palladium-catalyzed MCRs of
propargylic compounds with isocyanides to construct 6-imino-
4,6-dihydro-1H-furo[3,4-b]pyrrol-2-amines and 5-iminopyrro-
lones, which are useful skeletons in biochemistry.16
Table 2. Substrate Scope
Initially, propargylic carbonate (1a) and tert-butyl isocyanide
(2a) were chosen as model substrates in the presence of
Pd(PPh3)2Cl2 (5 mol %), PPh3 (10 mol %), and CsF (0.4
mmol) in DMSO (2 mL) at 80 °C (Table 1, entry 1).
a
Table 1. Optimization of Reaction Conditions
temp
yield of
yield of
b
b
entry
base
CsF
ligand
PPh3
solvent
(°C)
3a (%)
4a (%)
1
2
3
4
5
6
7
DMSO
CH3CN
DMF
80
50
31
CsF
CsF
CsF
K2CO3
Et3N
−
CsF
CsF
CsF
CsF
CsF
CsF
CsF
PPh3
80
42
26
PPh3
80
47
27
PPh3
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
80
35
22
PPh3
80
16
5
PPh3
80
20
9
PPh3
80
n.d.
85 (80)
10
n.d.
trace
68
c
8
PPh3
PPh3
rt
9
110
110
110
110
110
110
10
11
12
P(t-Bu)3
DPPE
DPPF
DPPF
DPPF
20
56
12
70
12
73
d
13
10
76
a
de
,
Reaction conditions A: 1 (0.20 mmol), 2 (0.70 mmol), Pd-
14
8
82 (75)
a
(PPh3)2Cl2(5 mol %), PPh3 (10 mol %), H2O (3.0 equiv), and CsF
Reaction conditions: 1a (0.20 mmol), 2a (0.70 mmol), Pd(PPh3)2Cl2
b
(2.0 equiv) in 2 mL of DMSO at room temperature for 8 h. Isolated
(5 mol %), ligand (10 mol %), base (2.0 equiv), and H2O (3.0 equiv)
in indicated solvent (2 mL) at 80 °C for 2 h. Determined by GC
analysis. Dodecane was used as an internal standard. Data in
parentheses were isolated yield. For 8 h. CsF (0.5 equiv), DPPF
c
d
b
yields. Hex-3-yne-2,5-diyl dimethyl dicarbonate as substrate. 2a (1.2
mmol).
c
d
e
(5 mol %). 2a (0.50 mmol) adding in three portions.
also be obtained albeit in moderate yield (52%). However, 3z
was not detected under the optimal reaction conditions. When
R3 was an alkyl group, the reaction proceeded smoothly to
afford the desired products 3y and 3aa in 50% and 68% yields,
respectively. We then evaluated the reactivity of various
isocyanides. Alkyl isocyanides such as 1,1,3,3-tetramethylbutyl-
isocyanide, adamantyl isocyanide, and cyclohexane isocyanide
were compatible in this reaction.
The selective formation of the 5-iminopyrrolone products
was also achieved under different reaction conditions. The
structure of 4a was also confirmed by X-ray crystallographic
analysis.18 Next, the substrate scope was examined (Table 3).
Various functional groups such as fluorine, chlorine, bromine,
iodine, trifluoromethyl, nitro, and acyl were tolerated. In
addition, terminal propargylic carbonate also transformed to
the desired product smoothly.
For the secondary and third propargylic carbonates, new
products 5a and 5b bearing an exocyclic double bond were
obtained in 80% and 85% yields, respectively (Scheme 2).
These results indicated that the multiple substituted alkenes
were more stable and higher energy was necessary to promote
the double bond isomerization.
Furthermore, this novel transformation and the following
hydrolysis reaction gave various maleimide products, which are
versatile building blocks and important synthons in organic
chemistry16b (Scheme 3).
Interestingly, two products, 3a and 4a, were isolated after 2 h.
Among various solvents tested, good conversions of the
reactants were detected, while the selectivity was still
unsatisfactory (entries 2−4). The yields of 3a and 4a were
decreased without a base or using another base instead of CsF
(entries 5−7). We were pleased to find that 3a could be
obtained as major product in 85% yield at room temperature
after prolonging the reaction time to 8 h, while the yield of 4a
dropped dramatically (entry 8). Further experiments indicated
that the selectivity of 4a could improve with an increasing in
temperature.17 Next, ligands were tested. DPPF was identified
as the best ligand in the formation of 4a (entries 9−12). Finally,
4a was isolated in 75% yield by reducing the amount of CsF to
0.5 equiv and adding the tert-butyl isocyanide (0.5 mmol) in
three portions at 110 °C for 2 h.
Under the optimal reaction conditions, we then examined
the scope of this reaction. As shown in Table 2, various
functional groups could be tolerated such as methyl, halogen,
ester, acyl, trifluoromethyl, and even nitrile groups. The
structure of 3d was further confirmed by X-ray crystallographic
analysis.18 The Z configuration of the imine structure was
resulted from the steric effect. Pleasingly, a heterocyclic
compound such as thiophene was tolerated with a 74% yield.
As for a substrate derived from a secondary alkynol, 3x could
B
DOI: 10.1021/acs.orglett.6b02999
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Organic Letters
Letter
a b
,
Table 3. Substrate Scope of 5-Iminopyrrolone
Scheme 5. A Tentative Mechanism
a
Reaction conditions B: all reactions were performed with 1 (0.20
mmol), 2 (0.50 mmol), Pd(PPh3)2Cl2 (5 mol %), DPPF (5 mol %),
H2O (3.0 equiv), and CsF (0.5 equiv) in 2 mL DMSO at 110 °C for 2
b
h; Isocyanide was added in three portions. Isolated yields.
Scheme 2. Scope of Secondary and Third Propargylic
Carbonates with Double Isocyanide Insertions
via the reductive elimination of V and subsequent aromatiza-
tion. Alternatively, in path b, H2O attacked at the C2 position
to produce the intermediate B which underwent reductive
elimination and isomerization to produce the 5-iminopyrro-
lones (4). This mechanism was consistent with the fact that
compounds 3 were the kinetically favored products, which were
obtained at room temperature. The steric effect favored the C4
attack when R1 = R2 = H. With the increase of steric hindrance
at the C4 position, the yields of products 3 dropped
dramatically (see Supporting Information for details). In
contrast, path b was the thermodynamically favored process
for the amide intermidate B, which was more stable than the
keteniminium intermediate III.
Scheme 3. Synthesis of maleimides
To gain some insights into the mechanism, 18O-isotope
labeling experiments were conducted. As depicted in Scheme 4,
In conclusion, an intriguing palladium-catalyzed multi-
component reaction (MCR) of propargylic carbonates with
isocyanides has been developed. Compared with the extensively
studied migratory insertion of isocyanides to aryl- or alkenyl-
palladium species, the in situ formed allenylpalladium species
bearing multiple reaction sites allowed the successive insertion
of multiple isocyanides in an orderly manner. A broad range of
(Z)-6-imino-4,6-dihydro-1H-furo[3,4-b]pyrrol-2-amines and
(E)-5-iminopyrrolones were synthesized efficiently. The
selectivity of the products can be controlled by the reaction
conditions. The detailed reaction mechanism and further
synthetic applications of this transformation are forthcoming.
Scheme 4. Mechanistic Studies
the 18O-containing products of 3a-18O and 4a-18O were
obtained in 73% and 61% yields, respectively. This result
indicated that the oxygen atoms of the products originated
from water. In addition, 3a and 4a cannot be transformed to
each other under the optimal reaction conditions, which
indicated two different pathways might be involved.
On the basis of the above-mentioned results, a tentative
mechanism for this palladium-catalyzed MCR is proposed
(Scheme 5).17 It was initiated by the oxidative addition of 1 to
the palladium(0) catalysis, delivering the allenylpalladium
species I5 which then transformed to the key intermediate A
via 1,1-migratiory insertion and the subsequent nucleophilic
attack of isocyanides.19 Next, H2O as a nucleophilic reagent
attacked the intermediate A (C2 or C4), determining the
selectivity in the formation of products 3 and 4. In path a, H2O
attacked at the C4 position to give the keteniminium
intermediate III17,20 which was then attacked by isocyanide
to form the intermediate IV. Finally, products 3 were obtained
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02999.
Typical experimental procedure and characterization for
all products (PDF)
Crystallographic data for 3d (CIF)
Crystallographic data for 4a (CIF)
C
DOI: 10.1021/acs.orglett.6b02999
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Organic Letters
Letter
Chichester, 2004; pp 543−564. (b) Marshall, J. A. Chem. Rev. 2000,
100, 3163. (c) Guo, L.; Duan, X.; Liang, Y. Acc. Chem. Res. 2011, 44,
111.
(12) For reviews, see: (a) Yu, S.; Ma, S. Chem. Commun. 2011, 47,
5384. For selected examples: (b) Mandai, T.; Ogawa, M.; Yamaoki,
H.; Nakata, T.; Murayama, H.; Kawada, M.; Tsuji, J. Tetrahedron Lett.
1991, 32, 3397. (c) Chen, Z.; Duan, X.; Wu, L.; Ali, S.; Ji, K.; Zhou, P.;
Liu, X.; Liang, Y. Chem. - Eur. J. 2011, 17, 6918.
(13) (a) Yoshida, M. Heterocycles 2013, 87, 1835. (b) Duan, X. H.;
Liu, X. Y.; Guo, L. N.; Liao, M. N.; Liu, W. M.; Liang, Y. M. J. Org.
Chem. 2005, 70, 6980. (c) Duan, X. H.; Guo, L. N.; Bi, H. P.; Liu, X.
Y.; Liang, Y. M. Org. Lett. 2006, 8, 5777.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cewuwq@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
ORCID
Huanfeng Jiang: 0000-0002-4355-0294
Author Contributions
†J.P. and Y.G. contributed equally.
Notes
(14) (a) Wang, F.; Tong, X.; Cheng, J.; Zhang, Z. Chem. - Eur. J.
2004, 10, 5338. (b) Bi, H. P.; Liu, X. Y.; Gou, F. R.; Guo, L. N.; Duan,
X. H.; Shu, X. Z.; Liang, Y. M. Angew. Chem., Int. Ed. 2007, 46, 7068.
(c) Lian, X.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 8255. (d) Ye, J.;
Ma, S. Angew. Chem., Int. Ed. 2013, 52, 10809.
(15) (a) Li, J.; Liu, Y.; Li, C.; Jia, X. Adv. Synth. Catal. 2011, 353, 913.
(b) Li, J.; Liu, Y.; Li, C.; Jia, X. Chem. - Eur. J. 2011, 17, 7409. (c) Jia,
S.; Su, S.; Li, C.; Jia, X.; Li, J. Org. Lett. 2014, 16, 5604.
(16) (a) Shishido, Y.; Ito, F.; Morita, H.; Ikunaka, M. Bioorg. Med.
Chem. Lett. 2007, 17, 6887. (b) Tekkam, S.; Alam, M. A.;
Jonnalagadda, S. C.; Mereddy, V. R. Chem. Commun. 2011, 47,
3219. (c) Kshirsagar, U. A.; Argade, N. P. Tetrahedron 2009, 65, 5244.
(d) Bessho, J.; Shimotsu, Y.; Mizumoto, S.; Mase, N.; Yoda, H.;
Takabe, K. Heterocycles 2004, 63, 1013.
(17) Early in 1993, Elsevier have tested the stoichiometric reaction of
(σ-allenyl) palladium(II) complexes with isocyanide. According to
their report, new vinylketenimine palladium complexes were obtained.
However, this intermediate is difficult to explain based on the present
experiment results. Wouters, J. M. A.; Klein, R. A.; Elsevier, C. J.
Organometallics 1993, 12, 3864.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Key Research and
Development Program of China (2016YFA0602900), the
National Natural Science Foundation of China (21490572,
2147205, and 21420102003), and Pearl River S&T Nova
Program of Guangzhou (201610010160) for financial support.
REFERENCES
■
(1) For reviews on multicomponent reactions (MCRs), see:
(a) Toure, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (b) Hudlicky,
T.; Reed, J. W. Chem. Soc. Rev. 2009, 38, 3117. (c) Domling, A.; Wang,
̈
W.; Wang, K. Chem. Rev. 2012, 112, 3083. (d) de Graaff, C.; Ruijter,
E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969.
(2) For reviews see: (a) Domling, A. Chem. Rev. 2006, 106, 17.
̈
(b) Lygin, A. V.; de Meijere, A. Angew. Chem., Int. Ed. 2010, 49, 9094.
(c) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G.
́
Chem. Rev. 2010, 110, 5235. For a selected example: (d) Szymanski,
W.; Velema, W. A.; Feringa, B. L. Angew. Chem., Int. Ed. 2014, 53,
8682.
(3) For reviews, see: (a) Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev.
2013, 42, 5257. (b) Sharma, U. K.; Sharma, N.; Vachhani, D. D.; Van
der Eycken, E. V. Chem. Soc. Rev. 2015, 44, 1836. (c) Boyarskiy, V. P.;
Bokach, N. A.; Luzyanin, K. V.; Kukushkin, V. Y. Chem. Rev. 2015,
115, 2698.
(18) CCDC 1457794 (3d) and CCDC 1457793 (4a) contain the
supplementary crystallographic data. These data can also be obtained
free of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
(19) Nucleophilic and then 1,1-migratory insertion of isocyanides
may also potentially form the intermediate A.
(4) (a) Negishi, E.-i., Ed. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley Interscience: New York, 2002. (b) Beccalli, E.
M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007,
107, 5318. (c) Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736.
(5) For reviews, see: (a) Vlaar, T.; Ruijter, E.; Maes, B. U. W.; Orru,
R. V. A. Angew. Chem., Int. Ed. 2013, 52, 7084. (b) Lang, S. Chem. Soc.
Rev. 2013, 42, 4867.
(20) Ariyaratne, J. K. P.; Green, M. L. M. J. Chem. Soc. 1963, 2976.
(6) (a) Jiang, H.; Liu, B.; Li, Y.; Wang, A.; Huang, H. Org. Lett. 2011,
13, 1028. (b) Li, Y.; Zhao, J.; Chen, H.; Liu, B.; Jiang, H. Chem.
Commun. 2012, 48, 3545. (c) Liu, B.; Yin, M.; Gao, H.; Wu, W.; Jiang,
H. J. Org. Chem. 2013, 78, 3009. (d) Liu, B.; Gao, H.; Yu, Y.; Wu, W.;
Jiang, H. J. Org. Chem. 2013, 78, 10319.
(7) (a) Vlaar, T.; Ruijter, E.; Znabet, A.; Janssen, E.; de Kanter, F. J.
J.; Maes, B. U. W.; Orru, R. V. A. Org. Lett. 2011, 13, 6496. (b) Liu, B.;
Li, Y.; Yin, M.; Wu, W.; Jiang, H. Chem. Commun. 2012, 48, 11446.
(c) Vidyacharan, S.; Murugan, A.; Sharada, D. S. J. Org. Chem. 2016,
81, 2837.
(8) (a) Pan, Y. Y.; Wu, Y. N.; Chen, Z. Z.; Hao, W. J.; Li, G. G.; Tu,
S. J.; Jiang, B. J. Org. Chem. 2015, 80, 5764. (b) Kobiki, Y.; Kawaguchi,
S.; Ogawa, A. Org. Lett. 2015, 17, 3490. (c) Tian, Y.; Tian, L.; He, X.;
Li, C.; Jia, X.; Li, J. Org. Lett. 2015, 17, 4874.
(9) Odabachian, Y.; Tong, S.; Wang, Q.; Wang, M. X.; Zhu, J. Angew.
Chem., Int. Ed. 2013, 52, 10878.
(10) (a) Takei, F.; Yanai, K.; Onitsuka, K.; Takahashi, S. Chem. - Eur.
J. 2000, 6, 983. (b) Wu, Z. Q.; Ono, R. J.; Chen, Z.; Bielawski, C. W. J.
Am. Chem. Soc. 2010, 132, 14000. (c) Xue, Y.; Zhu, Y.; Gao, L.; He, X.;
Liu, N.; Zhang, W.; Yin, J.; Ding, Y.; Zhou, H.; Wu, Z. J. Am. Chem.
Soc. 2014, 136, 4706.
(11) For reviews on palladium-catalyzed reactions of propargylic
carbonates, see: (a) Tsuji, J.Palladium Reagents and Catalysts; Wiley:
D
DOI: 10.1021/acs.orglett.6b02999
Org. Lett. XXXX, XXX, XXX−XXX