Cascade double isocyanide insertion and C-N coupling of 2-iodo-2′-isocyano-1,1′-biphenyls

Article abstract of DOI:10.1039/c8ob00956b

A palladium-catalyzed double isocyanide insertion using 2-iodo-2′-isocyano-1,1′-biphenyls followed by copper-catalyzed intramolecular C-N coupling, delivering a unique heterocyclic structure containing both phenanthridine and carbazole scaffolds, has been developed. In this cascade process, four chemical bonds, including two C-C, one C-O, and one C-N bonds are formed consecutively without isolating an intermediate. The strategy of using a functionalized isocyanide in double insertion provides a quick approach for constructing heterocyclic systems with high bond-forming efficiency.

Full text of DOI:10.1039/c8ob00956b

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Cascade double isocyanide insertion and C-N coupling of
-iodo-2'-isocyano-1,1'-biphenyls
2
Received 00th January 20xx,
Accepted 00th January 20xx
Hongwei Sun, Shi Tang, Dengke Li, Yali Zhou, Jinbo Huang*, and Qiang Zhu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
8
A palladium-catalyzed double isocyanide insertion using 2-iodo- as intramolecular nucleophiles in isocyanide, such as amides,
9
10
2'-isocyano-1,1'-biphenyls
followed
by
copper-catalyzed aromatic C-H bonds, or alkenes to trap the imidoyl palladium(II)
intermediates, furnishing heterocycles including oxazoles,
phenanthridines, β-carbolines, and cyclic imines. In this
communication, a new type of functionalized isocyanide bearing an
intramolecular electrophile, 2-iodo-2'-isocyano-1,1'-biphenyls, was
investigated. Instead of the anticipated mono isocyanide insertion
product formation, double isocyanide insertion took place under
palladium catalysis. The cyclized intermediate could undergo
intramolecular C-N coupling in the presence of copper catalyst. A
unique heterocyclic structure containing both phenanthridine and
intramolecular C-N coupling, delivering a unique heterocyclic
structure containing both phenanthridine and carbazole
scaffolds, has been developed. In this cascade process, four
chemical bonds, including two C-C, one C-O, and one C-N bonds
are formed consecutively without isolating the intermediate. The
strategy of using functionalized isocyanide in double insertion
provides a quick approach to construct heterocyclic systems
with high bond-forming efficiency.
Isocyanide has a long history of being applied in Ugi, Passerini, and carbazole scaffolds was constructed in one pot with high bond-
related multicomponent reactions to generate molecular complexity forming efficiency (Scheme 1).
1
from simple chemical feedstock in one pot. In addition, the unique
carbene-like character of isocyanide enables it to act as radical
acceptor or participate in palladium-catalyzed imidoylation reaction
via isocyanide insertion, which has been studied extensively in
R1
Previous work:
N
Br
OEt
PdCl2
1
R2
R2
(
a) R NC
+
N
NaOEt
R1
2
recent years. However, the strong coordination ability of isocyanide
R1
R1
NH
N
with Pd(II) intermediates makes consecutive double or even multiple
insertion much easier than the analogous CO insertion. On the other
hand, selective double isocyanide insertion could be a synthetic
useful transformation in terms of high bond-forming efficiency.
However, only a few examples of such reaction mode have been
reported by concise selection of nucleophiles and other reaction
X
Pd(OAc)2
Cs2CO3
R2
R2
1
(
b)
R NC
+
+
N
NH2
R1
N
OAc
N
N
Pd(PPh3)4
DBU
1
3
(c) R NC
NH
R1
conditions. In 2004, Whitby discovered that double isocyanide
insertion proceeded selectively from aryl bromides and simple
isocyanide like tert-butylisocyanide and cyclohexylisocyanide in the
presence of strong nucleophilic alkoxide to give acyclic α-
This work:
4
iminoimidates (a, Scheme 1). Later on, Tu and Jiang used 2-
N
N
NC
[
Pd]
CuI
C-N coupling
O
iodoanilines containing an intramolecular nucleophile as substrates
to provide cyclic 3-iminoindol-2-amines through palladium-
5
catalyzed double imidoylation (b, Scheme 1). Recently, Wang
O
R
R
R
I
double insertion
NH
R
R
I
N
developed a novel synthesis of 2H-pyrroles from acetyloximes by
[
Pd], Nu
observed
incorporating two isocyano groups between oxime nitrogen and the
6
nucleophilic α carbon followed by tautomerization (c, Scheme 1). In
N
all of these cases, isocyanide only serves as a C1 synthon. To take
full advantage of structural diversity of isocyanide, the so-called
functionalized isocyanide strategy has been applied in palladium-
catalyzed imidoylation to construct various N-containing
anticipated
but not found
R
Nu
Scheme 1. Palladium-catalyzed double isocyanide insertion
7
heterocycles. In this context, we utilized different functional groups
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Initially, our efforts were focused on the reaction of 2-iodo-2'-
isocyano-1,1'-biphenyl 1a under palladium catalysis (Scheme 2). We
anticipated that 2a’ could be achieved from intramolecular
isocyanide insertion followed by quenching the imidoyl palladium(II)
1
2
3
4
5
6
7
8
9
1
Pd(OAc)
2
(10)
(10)
(10)
(10)
CuI (20)
67
48
56
65
59
65
80
70
72
c
Pd(OAc)
2
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (15)
CuI (10)
CuI (20)
CuI (20)
CuI (15)
Pd(acac)
2
2
Pd(TFA)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
(5)
(2)
2
2
(10)
(10)
(10)
Pd(OAc)
2
d
Pd(OAc)
2
d
e
0
Pd(OAc)
2
(2)
(2)
90
84
d
11
Pd(OAc)
2
a
Standard reaction conditions: an aqueous solution of K CO (0.12
2
3
mmol) in water (0.15 mL) was added to a mixture of 1a (0.1 mmol),
Pd(OAc) (x mol%), CuI (y mol%) in DMSO (1.5 mL) via syringe
2
o
bump within 15 min and stirred for another 30 min, 23 C, in Ar.
b
Scheme 2. Stepwise double isocyanide insertion and C-N coupling
1
Yields were determined by H NMR using CH Br as an internal
2
2
c
standard. PPh
d
(0.01 mmol) was added. CuI was added to the
3
intermediate with water as a nucleophile. Instead, only compound 2a,
mixture 30 min later after completion of the reaction of 1a with
e
Pd(OAc) , and the reaction was stirred for an additional 30 min.
2
generated from double isocyanide insertion, was isolated in 65%
2 3
yield in the presence aqueous solution of K CO (1.2 equiv) as a
Isolated yield.
base. Considering the presence of aryl iodide in phenanthridinyl
amide 2a, an additional scaffold of carbazole could be formed
through intramolecular Ullmann reaction. Indeed, when CuI was
added to a solution of 2a in DMSO, a unique heterocyclic structure
With the optimal reaction conditions in hand, we investigated the
scope of this reaction by using various substituted 2-iodo-2'-
1
isocyano-1,1'-biphenyls (Table 2). Firstly, the scope of R group on
3
a containing both phenanthridine and carbazole scaffolds was
formed in high yield.
Since both reactions were taking place in DMSO using K
the A ring was studied. Generally, substrates with electron-donating
groups at either the C-4 or C-5 position were reactive and provided
the desired products (3b, 3c, 3f, 3g) in moderate to excellent yields
2
3
CO as
a base, a one-pot protocol without isolation of intermediate 2a was
(
76-95%). Besides, fluoro- and chloro-substituted 2-iodo-2'-
isocyano-1,1'-biphenyl afforded the corresponding product 3d and
e in good yield (92%, 68%). However, the cascade reaction of
steric demanding ortho-methyl substituted 1i did not give the desired
i, and only a mixture of unidentified products was produced. And
then investigated, and the results were summarized in Table 1. To
simplify the procedure, substrate 1a and both catalysts (Pd(OAc)
10 mol%), CuI (20 mol%) were premixed in DMSO (1.5 mL). An
aqueous solution of K CO was added to the mixture via a syringe
2
3
(
2
3
3
bump during a period of 15 minutes. The desired product 3a was
traces of compound 3h were observed when using trifluoromethyl-
substituted 2-iodo-2'-isocyano-1,1'-biphenyl as substrates.
obtained in 67% NMR yield after stirring for another 30 minutes
(
entry 1, Table 1). The structure of 3a was unambiguously confirmed
1
1
Next, we examined the effect of the substitution pattern on the B
ring of the substrates. Methyl-substituted substrates at either C-5′ or
C-4′ position afforded the corresponding products 3l and 3o in
excellent yield. Moreover, substrates with a methyl substitute in the
more sterically encumbered C-6′ position or C-3′ position delivered
the corresponding products 3j and 3r in yields of 71% and 88%,
respectively. Notably, 6′-Methoxy or 4′-methoxy-substituted
substrates also gave the corresponding products 3k and 3p in good to
excellent yields (71% and 98%). Substrates containing a fluoro or a
phenyl group could also be converted into the desired products 3m
and 3n in good yields. Furthermore, disubstituted substrates at both
ring A and ring B were well tolerated, affording 3s (83%) and 3t
by x-ray diffraction analysis. The presence of PPh
not helpful for the formation of 3a (48%, entry 2). Variation of
palladium salts from Pd(OAc) to Pd(TFA) and Pd(acac) could not
improve the yield of 3a (entries 3-4). Notably, the loading of catalyst
Pd(OAc) or CuI have some impact on the yield of 3a. When CuI
3
as a ligand was
2
2
2
2
was added 30 minutes later after 1a was all consumed, 3a was
formed in 72% yield (entry 9). Following the stepwise procedure, the
reduced catalyst loading of Pd(OAc)2 (2 mol %) was beneficial,
delivering 3a in 90% isolated yield (entry 10). However, the yield of
3
a dropped to 84% when the loading of CuI was reduced to 15
mol% (entry 11).
a
Table 1 Optimization of the reaction conditions
(
92%) smoothly. However, cyano-substituted 2-iodo-2'-isocyano-
,1'-biphenyl only afforded trace amount of the corresponding
1
product 3g. It was notable that the reaction time for the first step
varied from 0.5 to 4 h as determined by TLC analysis.
a
Table 2 Substrate scope
b
Entry
[Pd] (mol%)
[Cu] (mol%)
Yield (%)
2
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1
3
R2
generated in situ delivers aryl palladium intermediate A. The
following coordination and migratory insertion of the intramolecular
isocyanide moiety affords the key imidoyl palladium(II) species B.
Instead of being trapped by a nucleophile, intermediate B undergoes
1
.Pd(OAc)2 (2 mol%)
K2CO3 (1.2 equiv)
DMSO/H2O = 10/1
23 °C, Ar, 0.5 - 4 h
5
R1
4
6
NC
1
N
N
R
A
R2
2
'
1
'
3
1
3'
2
I
2
a second isocyanide insertion intermolecularly with another
B
R
O
6
'
4'
2. CuI (20 mol%), 0.5 h
molecule of substrate 1a to give intermediate C. Base assisted ligand
exchanged with hydroxide (OH) and subsequent reductive
elimination delivers intermediates D with the regeneration of active
5
'
1
3
R1
1
4
Pd(0). Then, the intermediate D tautomerizes to amide 2a which
can be isolated as a stable product. Finally, a typical intramolecular
R
15
Ullmann reaction of in the presence of CuI gives 3a.
N
N
N
N
R
O
O
N
O
N
R
3
a, 90%
R
3
3
3
f, R = Me, 94%
g, R = OMe, 95%
h, R = CF3, trace
3
3
3
3
b, R = Me, 95%
c, R = i-Pr 76%
d, R = F 92%
e, R = Cl 68%
R
R
N
N
N
N
R
O
N
O
O
N
R
Scheme 4 Proposed mechanism
In summary, we have developed an unprecedented cascade
palladium-catalyzed double isocyanide insertion/copper-catalyzed
Ullmann C‒N formation to construct a unique heterocyclic structure
containing both phenanthridine and carbazole scaffolds from
substituted 2-iodo-2'-isocyano-1,1'-biphenyls as a unique class of
functionalized isocyanide. The process creates four chemical bonds,
including two C-C, one C-O and one C-O bonds without isolating
the intermediate. The target products can be hydrolysed to useful
carbazole and phenanthridine derivatives under mild conditions. The
current transformation provides the first example of using
functionalized isocyanide in double insertion to construct
heterocyclic systems with high bond-forming efficiency.
3
i, 0%
3j, R = Me 71%
3l, R = Me 98%
3m, R = F 70%
3
k, R = OMe 71%
3
n, R = Ph 91%
R1
R2
O
F
R1
NR2
N
N
N
O
N
O
N
O
O
o, R1 = Me, R2 = H, 90%
p, R1 = OMe, R2 = H, 98%
q, R1 = CN, R2 = H, trace
r, R1 = H, R2 = Me, 88%
3
3
3
3
F
3
s, 83%
3t,
92%
Acknowledgement
a
Reaction conditions: an aqueous solution of K
2 3
CO (0.12 mmol) in
We are grateful to the National Natural Science Foundation of China
water (0.15 mL) was added to a mixture of 1 (0.1 mmol), Pd(OAc)
2
(
2 mol%), in DMSO (1.5 mL) via syringe bump within 15 min, 0.5 - of State Key Laboratory of Respiratory Disease, China (SKLRD-
NNSFC) (21672215, 21472190 and 21532009) and the Foundation
(
o
4
h, 23 C, in Ar. Then, CuI (20 mol%) was added to the mixture, 30 QN-201708) for financial support.
o
min, 23 C, in Ar.
Notes and references
Hydrolysis of 3a gave carbazole 4 and phenanthridine derived
carboxylic acid 5 in excellent yields by treating 3a with 10.0 equiv
State Key Laboratory of Respiratory Disease, Guangzhou
Institutes of Biomedicine and Health, Chinese Academy of
Sciences, Guangzhou 510530, P. R. China.
12
of t-BuOK in t-BuOH and H O (Scheme 3).
2
University of Chinese Academy of Sciences, Beijing 100049, P.
R. China.
*
*
E-mail: huang_jinbo@gibh.ac.cn
E-mail: zhu_qiang@gibh.ac.cn.
1
(a) I. Ugi, Isonitrile Chemistry, Academic Press: New York, 1971.
(b) A. Dömling, I. Ugi, Angew. Chem., Int. Ed. 2000, 39, 3168. (c)
Scheme 3 Hydrolysis of 3a
A plausible mechanism was proposed in Scheme 4 for this
cascade reaction. Initially, oxidative addition of aryl iodide on Pd(0)
A. Ricci, Amino Group Chemistry: From Synthesis to the Life
Sciences, Wiley-VCH: Weinheim, 2008. (d) A. V. Lygin, A. de
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Meijere, Angew. Chem., Int. Ed. 2010, 49, 9094. (e) S. Sadjadi, M. 14 H. Jiang, B. Liu, Y. Li, A. Wang, H. Huang, Org Lett. 2011, 13,
M. Heravi, Tetrahedron 2011, 67, 2707. (f) V. G. Nenajdenko, 1028.
Isocyanide Chemistry, Wiley-VCH: 15 For selected reviews, see: (a) G. Evano, N. Blanchard, M. Toumi,
Weinheim, Germany, 2012. (g) S. Rostamnia, RSC Adv. 2015, 5,
Chem. Rev. 2008, 108, 3054. (b) F. Monnier, M. Taillefer, Angew.
Chem., Int. Ed. 2009, 48, 6954. (c) C. Sambiagio, S. P. Marsden,
A. J. Blacker, P. C. McGowan, Chem. Soc. Rev. 2014, 43, 3525.
(d) X. Ribas, I. Güell. Pure Appl. Chem. 2014, 86, 345.
9
2
7044. (h) A. Kruithof, E. Ruijter, R. V. A. Orru, Chem. Asian J.
015, 10, 508. (i)T. Kaur, P. Wadhwa, S. Bagchi, A. Sharma,
Chem. Commun. 2016, 52, 6958. (j) A. Varadi, T. C. Palmer, R.
N. Dardashti, S. Majumdar. Molecules 2016, 21, 19. (k) J. Lei, J.
Huang, Q. Zhu, Org. Biomol. Chem. 2016, 14, 2953. (l) S.
Sadjadi, M. M. Heravi, N. Nazari, RSC Adv. 2016, 6, 53203. (m)
T. Kaur, P. Wadhwa, S. Bagchi, A. Sharma, Chem. Commun.
2
016, 52, 6958.
2
(a) V. G. Nenajdenko, R. Ramón, N. Kielland, R. Lavilla,
Isocyanide Chemistry: Applications in Synthesis and Material
Science, Wiley-VCH Verlag GmbH & Co. KGaA, 2012. (b) T.
Vlaar, E. Ruijter, B. U. W. Maes, R. V. A. Orru, Angew. Chem.,
Int. Ed. 2013, 52, 7084. (c) G. Qiu, Q. Ding, J. Wu, Chem. Soc.
Rev. 2013, 42, 5257. (d) S. Lang, Chem. Soc. Rev. 2013, 42, 4867.
(
d) V. P. Boyarskiy, N. A. Bokach, K. V. Luzyanin, V. Y.
Kukushkin, Chem. Rev. 2015, 115, 2698. (e) B. Song, B. Xu,
Chem. Soc. Rev. 2017, 46, 1103.
3
(a) M. Murakami, H. Masuda, T. Kawano, H. Nakamura, Y. Ito, J.
Org. Chem. 1991, 56, 1. (b) S. Kazuyoshi, T. Tomoaaki, K.
Kimiko, Y. Yasuhiro, Chem. Lett. 1991, 20, 921. (c) G. Bez, C.-G.
Zhao, Org. Lett. 2003, 5, 4994. (d) R. J. Whitby, C. G. Saluste, M.
Furber, Org. Biomol. Chem. 2004, 2, 1974. (d) C. Masdeu, E.
Gomez, N. A. O. Williams, R. Lavilla, Angew. Chem., Int. Ed.
2
007, 46, 3043. (e) A. L. Johnson, A. M. Willcocks, P. R.
Raithby, M. R. Warren, A. J. Kingsley, R. Odedra, Dalton Trans.
009, 922. (f) Y. He, Y.-C. Wang, K. Hu, X.-L. Xu, H.-S. Wang,
2
Y.-M. Pan, J. Org. Chem. 2016, 81, 11813. (g) Z.-B. Chen, Y.
Zhang, Q. Yuan, F.-L. Zhang, Y.-M. Zhu, J.-K. Shen, J. Org.
Chem. 2016, 81, 1610. (h) Y. Tian, L. Tian, C. Li, X. Jia, J. Li,
Org. Lett. 2016, 18, 840. (i) S. B. Nallapati, B. Prasad, B. Y.
Sreenivas, R. Sunke, Y. Poornachandra, C.G. Kumar, B. Sridhar,
S. Shivashankar, K. Mukkanti, M. Pal, Adv. Synth. Catal. 2016,
3
58, 3387. (j) X. Wang, W. Xiong, Y. Huang, J. Zhu, Q. Hu, W.
Wu, H. Jiang, Org. Lett. 2017, 19, 5818.
4
5
6
7
R. J. Whitby, C. G. Saluste, M. Furber, Org. Biomol. Chem.
2
Y.-Y. Pan, Y.-N. Wu, Z.-Z. Chen, W.-J. Hao, G. Li, S.-J. Tu, B.
Jiang, J. Org. Chem. 2015, 80, 5764.
G. C. Senadi, T.-Y. Lu, G. K. Dhandabani, J.-J. Wang, Org. Lett.
004, 2, 1974.
2
017, 19, 1172.
(a) W. D. Jones, W. P. Kosar, J. Am. Chem. Soc. 1986, 108,
640. (b) U. Belluco, R. A. Michelin, M. Mozzon, R. Bertani,
G. Facchin, L. Zanotto, L. Pandolfo, J. Organomet. Chem. 1998,
57, 37. (c) D. P. Curran, W. Du, Org. Lett. 2002, 4, 3215. (d) T.
5
5
Nanjo, C. Tsukano, Y. Takemoto, Org. Lett. 2012, 14, 4270.
(a) J. Wang, S. Luo, J. Huang, T. Mao, Q. Zhu, Chem. Eur. J.
8
9
2014, 20, 11220. (b) J. Wang, S. Luo, J. Li, Q. Zhu, Org. Chem.
Front. 2014, 1, 1285.
(a) J. Li, Y. He, S. Luo, J. Lei, J. Wang, Z. Xie, Q. Zhu, J. Org.
Chem. 2015, 80, 2223. (b) J. Wang, D.-W. Gao, J. Huang, S.
Tang, Z. Xiong, H. Hu, S.-L. You, Q. Zhu, ACS Catal. 2017, 7,
3
832. (c) Z. Xiong, J. Wang, Y. Wang, S. Luo, Q. Zhu, Org.
Chem. Front. 2017, 4, 1768. (d) S. Tang, J. Wang, Z. Xiong, Z.
Xie, D. Li, J. Huang, Q. Zhu, Org. Lett. 2017, 19, 5577.
0 J. Wang, S. Tang, Q. Zhu, Org. Lett. 2016, 18, 3074.
1 Crystallographic data for compound 3a (CCDC 1582339) has
been provided as a CIF file in the ESI.
1
1
12 (a) T. Itahara, Bull. Chem. Soc. Jpn. 1981, 54, 305. (b) P. G.
Gassman, P. K. G. Hodgson, R. J. Balchunis, J. Am. Chem. Soc.
1
976, 98, 1275.
1
3 (a) Y.-J. Liu, H. Xu, W.-J. Kong, M. Shang, H.-X. Dai, J.-Q. Yu,
Nature 2014, 515, 389; (b) Y. Ito, M. Suginome, T. Matsuura, M.
Murakami, J. Am. Chem. Soc. 1991, 113, 8899.
4
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