Palladium-Catalyzed Synthesis of 1H-Indenes and Phthalimides via Isocyanide Insertion

Article abstract of DOI:10.1021/acs.orglett.7b02771

A new and versatile multicomponent domino strategy has been developed for the synthesis of a series of 1H-indene and phthalimide derivatives from simple and readily available starting materials. This process operating under mild conditions shows a broad substrate scope with moderate to excellent yields.

Full text of DOI:10.1021/acs.orglett.7b02771

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Palladium-Catalyzed Synthesis of 1H‑Indenes and Phthalimides via
Isocyanide Insertion
Xu Wang,† Wenfang Xiong,† Yubing Huang,† Jiayi Zhu,† Qiong Hu,† Wanqing Wu,*,†,‡
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, China
‡State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, China
S
* Supporting Information
ABSTRACT: A new and versatile multicomponent domino strategy has been developed for the synthesis of a series of 1H-
indene and phthalimide derivatives from simple and readily available starting materials. This process operating under mild
conditions shows a broad substrate scope with moderate to excellent yields.
Scheme 1. Palladium-Catalyzed MCRs of Isocyanides
ndenes are key structural units, widely found in
1
natural products,2 and functional
Ipharmaceutical drugs,
materials.3 They can also be used as valuable ligands in tailored
metallocene complexes for olefin polymerization.4 For these
reasons, many methods have been developed for the
construction of an indene skeleton.5−9 Among them, the
transition-metal-catalyzed [3 + 2] cyclization6 and cyclo-
addition reactions,7 Brønsted or Lewis acid catalyzed
Friedel−Crafts cyclization,8 and the ring expansion of
substituted cyclopropenes are notable examples.9 Despite
these advances, they often suffered from some limitations
(e.g., tedious synthetic sequences, special starting materials,
harsh conditions, and narrow functional group compatibility),
which greatly limited their applications. Moreover, chemo- and
regioselective synthesis of polysubstituted indene derivatives
still remains challenging.10 Therefore, the development of
simple and efficient methods to construct polysubstituted
indenes from readily available starting materials in one step is
highly desirable.
sp3 carbon atom as a nucleophilic partner to capture the active
palladium species has been less explored.15 Based on our
continuous interest in the development of isocyanides,16 we
report an efficient and convenient route for the synthesis of 1H-
indene and phthalimide derivatives via palladium-catalyzed
multicomponent reactions involving isocyanide insertion
(Scheme 1b).
Initially, 2-(2-bromophenyl)acetonitrile (1a), isonitrile (2a),
and aniline (3a) were treated in the presence of Pd(OAc)2 (10
mol %), PPh3 (10 mol %), and NEt3 (2 equiv) in DMSO at 100
°C for 12 h, and the desired 1H-indene product 4aaa was
observed in 77% yield (see entry 1 of Table S1 in the
Supporting Information (SI)). Notably, in the absence of
Isocyanides represent an important class of organic
molecules which have a broad range of applications in
biomedical chemistry and materials science owing to their
diverse variations.11 In the past decades, transition-metal-
catalyzed multicomponent reactions (MCRs) involving iso-
cyanides have attracted great attention as a powerful tool in
organic synthesis.12 Most of these strategies involved the
formation of aryl- or alkenyl-palladium species and sequential
coupling with different nucleophiles to afford various hetero-
cycle compounds (Scheme 1a).13,14 Although much progress
has been achieved in this area, the exploration of different
nucleophilic partners to trap the active Pd intermediates should
be very important. To the best of our knowledge, the use of an
Received: September 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Pd(OAc)2 or NEt3, no product 4aaa was detected (Table S1,
entries 2−4). Among various solvents tested, DMSO turned
out to be the most appropriate (Table S1, entries 5−8).
Moreover, replacement of Pd(OAc)2 with other palladium salts
resulted in lower yields (Table S1, entries 9−11). The effect of
base was also studied. When CH3CH2ONa was used as the
base, a 92% yield of 4aaa was obtained (Table S1, entries 12−
18). The investigations described above revealed that the
Pd(OAc)2/PPh3/CH3CH2ONa/DMSO system is the best
combination for promoting this multicomponent reaction
(Table S1, entry 18).
substituent at the meta-position also reacted smoothly and
afforded the target product 4aak in 84% yield. In addition,
some bulky amines, 3l, 3m, and 3n, were well tolerated in this
reaction system, giving the corresponding products 4aal, 4aam,
and 4aan in 80−92% yields, respectively. Gratifyingly, phenyl-
hydrazine 3o could also be successfully transformed to the 1H-
indene derivative 4aao in 64% yield. Next, we examined the
scope of 2-(2-bromophenyl)acetonitriles (1b−1g). It was
observed that 2-(2-bromophenyl)acetonitriles with an elec-
tron-withdrawing group, such as 5-CF3, 4-F, 4-Cl, and 6-Br, at
the aryl ring were well tolerated, affording the desired products
4baa−4eab in good yields (73−88%). The transformations of
2-(2-bromophenyl)acetonitriles bearing an electron-donating
group, such as 5-methoxy and 4,5-dimethoxy groups, also gave
the desired products 4faa and 4gab in 52% and 69% yields.
Moreover, the sterically hindered 1,1,3,3-tetramethylbutyl
isocyanide (2b) and adamantyl isocyanide (2c) were
compatible with the reaction conditions, leading to the
formation of 4aba and 4aca in 57% and 61% yields,
respectively. Unfortunately, the transformations of other
isocyanides substituted with an aryl group or a primary or
secondary alkyl group failed to afford the corresponding
products 4ada−4afa under the optimized conditions. When
using methyl 2-(2-bromophenyl)acetate instead of 2-(2-bromo-
phenyl)acetonitrile 1a, the desired product 9 was afforded in
poor yield. The ester group presumably is not conducive to the
formation of intermediate B (see Scheme 6).
With the optimal reaction conditions in hand, a variety of
substituted 2-(2-bromophenyl)acetonitriles, isocyanides, and
anilines were examined (Scheme 2). To our delight, various
Scheme 2. Synthesis of 1H-Indenes Form 2-(2-
Bromophenyl)acetonitriles, Isonitriles, and Amines
a
Subsequently, we explored the scope of the palladium-
catalyzed isocyanide insertion reaction using 2-bromobenzo-
nitriles and anilines as starting materials. Pleasingly, the desired
product phthalimide17 6aaa was obtained in 21% yield with the
combination of Pd(OAc)2 (10 mol %), PPh3 (20 mol %), and
NEt3 (2 equiv) in 1,4-dioxane at 80 °C for 12 h (see entry 1 of
Table S2 in the SI). The reaction did not work if either
Pd(OAc)2 or the NEt3 was absent (Table S2, entries 2−4). The
screening of different solvents led to the discovery that toluene
was the most effective, forming the product 6aaa in 52% yield
(Table S2, entries 5−8). Some bases, such as t-BuOK, K2CO3,
CH3ONa, Cs2CO3, and CsF, were also tested, but the reaction
did not work well under these conditions (Table S2, entries 9−
13). With other palladium salts a relatively lower yield of 6aaa
was observed (Table S2, entries 14−17). An obvious
improvement in the yield could be obtained as the temperature
was increased to 100 °C (Table S2, entries 18−19).
Fortunately, a series of phthalimides could be synthesized
through this protocol. As shown in Scheme 3, anilines bearing
electron-donating (e.g., 4-OMe, 4-Me, 3-Me, 2-Me, 3,5-
dimethyl, 3,4-dimethyl) and electron-withdrawing (e.g., 4-F,
4-Cl, 4-Br) groups on the phenyl rings were converted to the
corresponding products 6aab−6aar in moderate to good yields
(62−79%). It was found that the sterically hindered anilines
were well tolerated regardless of the position of their
substituents (e.g., 4-Me, 3-Me, 2-Me, 3,5-dimethyl, 3,4-
dimethyl), providing the desired products 6aac−6aar in 70−
75% yields. Naphthalen-1-amine (3l) was also transformed to
the expected product 6aal in 70% yield. Delightfully, the
benzylamine substrates 3s and 3t could be converted to the
target phthalimides (6aas−6aat) in moderate yields as well.
Furthermore, different substituents on 2-bromobenzonitriles,
such as 5-OMe, 4-Me, 4-F, 4-Cl, and 5-CF3, were fully
tolerated, and the conversion delivered the desired products
6baa−6faa in 42−57% yields.
a
All reactions were carried out under the following conditions: 1 (0.1
mmol), 2 (0.2 mmol), 3 (0.2 mmol), Pd(OAc)2 (10 mol %), PPh3 (10
mol %), CH3CH2ONa (2.0 equiv), DMSO (0.5 mL) at 100 °C for 12
h. Isolated yield is given. ND = not detected.
anilines bearing an electron-donating or -withdrawing group at
the benzene ring participated well in the reaction. Anilines 3b−
3g possessing an electron-rich group at the para-position, such
as −OMe, −Me, −iPr, −NH2, −OH, −OPh, transferred to the
desired products 4aab−4aag in 82−89% yields. The reactions
of anilines having an electron-deficient group at the para-
position, including −F, −Cl, and −Br groups, furnished the
corresponding products 4aah−4aaj in 74−81% yields. The
crystallization of compound 4aac from anhydrous ethanol gave
single crystals suitable for X-ray analysis. Aniline 3k with a
B
DOI: 10.1021/acs.orglett.7b02771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Phthalimides Form 2-
Bromobenzonitriles, tert-Butylisonitrile, and Amines
Scheme 5. Control Experiments
a
a
All reactions were carried out under the following conditions: 5 (0.12
mmol), 2a (0.15 mmol), 3 (0.1 mmol), Pd(OAc)2 (10 mol %), NEt3
(2.0 equiv), toluene (1 mL) at 100 °C for 12 h, followed by the
addition of HCl (4 M, 0.5 mL) for 1 h. Isolated yield is given.
However, when 7aa was treated with 2 equiv of H2O under the
optimal conditions, compound 8 could not be detected
(Scheme 5c), indicating that the reaction should not undergo
a hydrolysis process. Moreover, the 15N-labeling experiment
was also utilized to achieve more insight into this reaction
process (Scheme 5d), which indicated that the nitrogen atom
of imine in 4aaa was derived from aniline 3a. In addition, tert-
butyl amine (m/z = 74.0964) could be detected in the reaction
mixture by ESI-MS (Scheme 5e), suggesting that 4aaa was
formed through an amine exchange reaction between 3a and
7aa. Without 3a, 5a and 2a were treated under the standard
conditions (Scheme 5f), N-(tert-Butyl)-2-cyanobenzamide 12
([M + Na]+ = 225.1001) was detected in HRMS spectra,
suggesting that the intermediate II was formed13d (see Scheme
6).
The reaction could be easily scaled up to 2 mmol under the
standard conditions and delivered the desired product 4aaj in
62% yield (Scheme 4a). The synthetic potential of these 1H-
Scheme 4. Scale-up Synthesis and Further Modification of
a
4aaj
On the basis of the above results and previous reports, we
proposed a plausible reaction mechanism for this trans-
formation detailed in Scheme 6. In path I, oxidative addition
of 1a to the L2Pd(0) catalyst facilitates the formation of aryl
palladium species A, which would undergo cyclopalladation
with concomitant C−H bond cleavage to give a four-membered
Scheme 6. Possible Reaction Mechanism
a
For details of the reaction conditions, see the SI.
indene was demonstrated by further modification of 4aaj.
Hydrolysis of 4aaj provided the 2-(tert-butylamino)-1-oxo-1H-
indene-3-carbonitrile 8 in 94% yield (Scheme 4b). Arylation of
4aaj afforded product 10 in 77% yield (Scheme 4c). The
reduction reaction also proceeded smoothly to give product 11
in 91% yield under mild conditions (Scheme 4d).
A series of control experiments were then carried out to gain
more insight into the reaction mechanism (Scheme 5). Initially,
the reaction of 2-(2-bromophenyl)acetonitrile (1a) with tert-
butylisonitrile (2a) was performed under the optimal
conditions, and 7aa was formed in 98% yield (Scheme 5a).
When 7aa was treated with aniline 3a, the target product (E)-2-
(tert-butylamino)-1-(phenylimino)-1H-indene-3-carbonitrile
(4aaa) was obtained in 93% yield (Scheme 5b), which
suggested that 7aa might be an intermediate in this reaction.
C
DOI: 10.1021/acs.orglett.7b02771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) (a) Hu, P.; Lee, S.; Herng, T. S.; Aratani, N.; Gonca
̧
lves, T. P.;
palladium-cyclic species B. Next, the double insertion of
isocyanide 2a into the Pd−C bond would produce the
intermediate C, and reductive elimination of C generates the
intermediate D. Isomerization of intermediate D forms
compound 7aa. Finally, the desired product 4aaa is obtained
via an amine exchange reaction between aniline 3a and 7aa. In
path II, the first step is the formation of palladium species I
through the oxidative addition of 5a with L2Pd(0), followed by
the insertion of 2a to give intermediate II, which would react
with 3a to yield the intermediate III. Immediately, reductive
elimination of III provides intermediate IV and L2Pd(0). Then,
the nucleophilic addition of amidine to the nitrile forms
intermediate V ([M + H]+ = 278.1654). Finally, the hydrolysis
of V under acidic conditions releases the final product 6aaa.
In conclusion, we have successfully established a flexible and
efficient strategy for the construction of 1H-indene and
phthalimide derivatives involving palladium-catalyzed migratory
insertion of isocyanides with easily available starting materials.
The reaction proceeds with mild conditions and facile
operation and displays wide functional group compatibility.
Given these advantages, the present method may be highly
useful in synthetic chemistry.
Qi, Q.; Shi, X.; Yamada, H.; Huang, K.-W.; Ding, J.; Kim, D.; Wu, J. J.
Am. Chem. Soc. 2016, 138, 1065−1077. (b) Zhu, X.; Tsuji, H.;
Nakabayashi, K.; Ohkoshi, S.-I.; Nakamura, E. J. Am. Chem. Soc. 2011,
133, 16342−16345.
(4) (a) Ren, S.; Igarashi, E.; Nakajima, K.; Kanno, K. I.; Takahashi, T.
J. Am. Chem. Soc. 2009, 131, 7492−7493. (b) Alt, H. G.; Koppl, A.
Chem. Rev. 2000, 100, 1205−1221.
̈
(5) (a) Chan, C. K.; Hsueh, N. C.; Tsai, Y. L.; Chang, M. Y. J. Org.
Chem. 2017, 82, 7077−7084. (b) Das, B. G.; Chirila, A.; Tromp, M.;
Reek, J. N.; Bruin, B. D. J. Am. Chem. Soc. 2016, 138, 8968−8975.
(6) (a) Park, E. J.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130,
17268−17269. (b) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J.
Am. Chem. Soc. 2011, 133, 2154−2156. (c) Muralirajan, K.;
Parthasarathy, K.; Cheng, C. H. Angew. Chem., Int. Ed. 2011, 50,
4169−4172. (d) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J.
Am. Chem. Soc. 2006, 128, 202−209.
(7) Egi, M.; Shimizu, K.; Kamiya, M.; Ota, Y.; Akai, S. Chem.
Commun. 2015, 51, 380−383.
(8) (a) Manojveer, S.; Balamurugan, R. Org. Lett. 2015, 17, 3600−
3603. (b) Muthusamy, S.; Sivaguru, M. Org. Lett. 2014, 16, 4248−
4251.
(9) (a) Hu, B.; Xing, S.; Wang, Z. Org. Lett. 2008, 10, 5481−5484.
(b) Zhu, Z.-B.; Shi, M. Chem. - Eur. J. 2008, 14, 10219−10222.
(10) (a) Jana, A.; Misztal, K.; Zak, A.; Grela, K. J. Org. Chem. 2017,
82, 4226−4234. (b) Eom, D.; Park, S.; Park, Y.; Ryu, T.; Lee, P. H.
Org. Lett. 2012, 14, 5392−5395.
(11) (a) Song, B.; Xu, B. Chem. Soc. Rev. 2017, 46, 1103−1123.
(b) Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.; Novellino,
E.; Tron, G. C.; Zhu, J. Chem. Soc. Rev. 2017, 46, 1295−1357.
(c) Hojoh, K.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2017, 139,
2184−2187. (d) Tong, S.; Zhao, S.; He, Q.; Wang, Q.; Wang, M.-X.;
Zhu, J. Angew. Chem., Int. Ed. 2017, 129, 1−6. (e) Kim, J.; Hong, S. H.
Chem. Sci. 2017, 8, 2401−2406. (f) Zhang, X.; Wang, X.; Gao, Y.; Xu,
X. Chem. Commun. 2017, 53, 2427−2430. (g) Wu, X.; Geng, X.; Zhao,
P.; Zhang, J.; Wu, Y.-D.; Wu, A.-X. Chem. Commun. 2017, 53, 3438−
3441.
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.7b02771.
Experimental procedures, condition screening table,
characterization data, and copies of NMR spectra for
all products (PDF)
Crystallographic data for 4aac (CIF)
(12) (a) Sharma, U. K.; Sharma, N.; Vachhani, D. D.; Vander Eycken,
E. V. Chem. Soc. Rev. 2015, 44, 1836−1860. (b) Boyarskiy, V. P.;
Bokach, N. A.; Luzyanin, K. V.; Kukushkin, V. Y. Chem. Rev. 2015,
115, 2698−2779. (c) Xu, P.; Wang, F.; Wei, T.-Q.; Yin, L.; Wang, S.-
Y.; Ji, S.-J. Org. Lett. 2017, 19, 4484−4487. (d) Chen, Z.-B.; Zhang, Y.;
Yuan, Q.; Zhang, F.-L.; Zhu, Y.-M.; Shen, J.-K. J. Org. Chem. 2016, 81,
1610−1616. (e) He, Y.; Wang, Y.-C.; Hu, K.; Xu, X.-L.; Wang, H.-S.;
Pan, Y.-M. J. Org. Chem. 2016, 81, 11813−11818. (f) Ahmadi, F.;
Bazgir, A. RSC Adv. 2016, 6, 61955−61958.
(13) (a) Saluste, C. G.; Whitby, R. J.; Furber, M. Angew. Chem., Int.
Ed. 2000, 39, 4156−4158. (b) Zhu, F.; Li, Y.; Wang, Z.; Orru, R. V.;
Maes, B. U.; Wu, X.-F. Chem. - Eur. J. 2016, 22, 7743−7746.
(c) Saluste, C. G.; Whitby, R. J.; Furber, M. Tetrahedron Lett. 2001, 42,
6191. (d) Jiang, H.; Liu, B.; Li, Y.; Wang, A.; Huang, H. Org. Lett.
2011, 13, 1028−1031.
(14) (a) Qiu, G.; Wang, Q.; Zhu, J. Org. Lett. 2017, 19, 270−273.
(b) Gao, Q.; Zhou, P.; Liu, F.; Hao, W.-J.; Yao, C.; Jiang, B.; Tu, S.-J.
Chem. Commun. 2015, 51, 9519−9522. (c) Tian, Y.; Tian, L.; Li, C.;
Jia, X.; Li, J. Org. Lett. 2016, 18, 840−843. (d) Senadi, G. C.; Lu, T.-Y.;
Dhandabani, G. K.; Wang, J.-J. Org. Lett. 2017, 19, 1172−1175.
(15) (a) Qiu, G.; Ding, Q.; Wu, J. Chem. Soc. Rev. 2013, 42, 5257−
5269. (b) Pan, Y.-Y.; Wu, Y.-N.; Chen, Z.-Z.; Hao, W.-J.; Li, G.; Tu, S.-
J.; Jiang, B. J. Org. Chem. 2015, 80, 5764−5770.
(16) (a) Hu, W.; Li, J.; Xu, Y.; Li, J.; Wu, W.; Liu, H.; Jiang, H. Org.
Lett. 2017, 19, 678−681. (b) Peng, J.; Gao, Y.; Hu, W.; Gao, Y.; Hu,
M.; Wu, W.; Ren, Y.; Jiang, H. Org. Lett. 2016, 18, 5924−5927.
(17) (a) Wu, X.-F.; Oschatz, S.; Sharif, M.; Flader, A.; Krey, L.;
Beller, M.; Langer, P. Adv. Synth. Catal. 2013, 355, 3581−3585.
(b) Chen, J.; Natte, K.; Spannenberg, A.; Neumann, H.; Beller, M.;
Wu, X.-F. Org. Biomol. Chem. 2014, 12, 5578−5581. (c) Chen, J.;
Natte, K.; Wu, X.-F. Tetrahedron Lett. 2015, 56, 342−345.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: cewuwq@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
ORCID
Huanfeng Jiang: 0000-0002-4355-0294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Program on Key Research
Project (2016YFA0602900), the National Natural Science
Foundation of China (21490572 and 21420102003), and Pearl
River S&T Nova Program of Guangzhou (201610010160) for
financial support.
REFERENCES
■
(1) (a) Clegg, N. J.; Paruthiyil, S.; Leitman, D. C.; Scanlan, T. S. J.
Med. Chem. 2005, 48, 5989−6003. (b) Alcalde, E.; Mesquida, N.;
Lop
́
ez-Per
́
ez, S.; Frigola, J.; Merce,
́
R. J. Med. Chem. 2009, 52, 675−
687.
(2) (a) Deng, J.; Zhou, S.; Zhang, W.; Li, J.; Li, R.; Li, A. J. Am. Chem.
Soc. 2014, 136, 8185−8188. (b) Yamada, K.; Lear, M. J.; Yamaguchi,
T.; Yamashita, S.; Gridnev, I. D.; Hayashi, Y.; Hirama, M. Angew.
Chem. 2014, 126, 14122−14126. (c) Lane, A. L.; Nam, S. J.; Fukuda,
T.; Yamanaka, K.; Kauffman, C. A.; Jensen, P. R.; Fenical, W.; Moore,
B. S. J. Am. Chem. Soc. 2013, 135, 4171−4174.
D
DOI: 10.1021/acs.orglett.7b02771
Org. Lett. XXXX, XXX, XXX−XXX