Direct access to isoindolines through tandem Rh(III)-catalyzed alkenylation and cyclization of N-benzyltriflamides

Article abstract of DOI:10.1039/c3cc49486a

The rhodium-catalyzed oxidative alkenylation of N-benzyltriflamides with olefins followed by an intramolecular cyclization via C-H bond activation is described. This method results in the direct and efficient synthesis of highly substituted isoindoline fr

Full text of DOI:10.1039/c3cc49486a

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Direct access to isoindolines through tandem
Rh(III)-catalyzed alkenylation and cyclization
of N-benzyltriflamides†
Cite this: Chem. Commun., 2014,
50, 2350
Received 14th December 2013,
Accepted 6th January 2014
Neeraj Kumar Mishra, Jihye Park, Satyasheel Sharma, Sangil Han, Mirim Kim,
Youngmi Shin, Jinbong Jang, Jong Hwan Kwak, Young Hoon Jung and In Su Kim*
DOI: 10.1039/c3cc49486a
www.rsc.org/chemcomm
The rhodium-catalyzed oxidative alkenylation of N-benzyltriflamides
with olefins followed by an intramolecular cyclization via C–H bond
activation is described. This method results in the direct and efficient
synthesis of highly substituted isoindoline frameworks.
The isoindoline heterocycles have demonstrated potential in organic
and medicinal chemistry as they exhibit diverse biological activities
and interesting chemical properties. For example, the isoindoline
motif is present in molecules that act as selective PPARd agonists,
molecular chaperone Hsp90 inhibitors, endothelin-A receptor antago-
nists, and dipeptidyl peptidase inhibitors.1 Moreover, isoindoline
Scheme 1 Catalytic oxidative olefination and cyclization protocols.
derivatives are very crucial constituents in the field of materials oxidative olefination and aza-Michael reaction of secondary benz-
science as attractive candidates for organic light-emitting devices.2 amides with a,b-unsaturated alkenes (Scheme 1).10 In addition, a
Therefore, the development of novel and highly efficient strategies for great deal of effort has been devoted to the selective olefination of
the formation of these heterocyclic architectures is an area of great arenes with various directing groups such as pyridinyl,11 hydroxyl,12
interest in organic synthesis. Transition-metal-catalyzed C–H bond esters,13 anilides,14 carbamates,15 and ketones/amides.16 A triflamide
activation has emerged as an atom economical process to produce moiety as a directing group was first introduced by Yu for the
structurally diverse organic molecules due to the minimization of palladium-catalyzed C–H bond functionalization, and can be trans-
stoichiometric metallic waste. Thus, the cross-coupling reactions via formed to a range of synthetically useful functional groups.17 Our
C–H bond activation can lead to an improved overall efficiency of the continued efforts in rhodium- or palladium-catalyzed C–H bond
desired transformation.3 Since the pioneering efforts of Fujiwara and activation and oxidative acylation reactions18 prompted us to explore
Moritani,4 remarkable progress has been made in the oxidative the coupling reaction of N-benzyltriflamides with olefins.
olefination of arenes using alkenes in palladium catalysis to directly
In our initial study, N-(2-methoxybenzyl)triflamide (1a) and
functionalize arene C–H bonds.5 In contrast to the vast majority of n-butyl acrylate (2a) were chosen as model substrates for optimizing
reports on the palladium-catalyzed olefinations, the oxidative C–H the reaction conditions (see ESI† for the optimization table). After
olefinations using rhodium catalysts, which often allow lower catalytic extensive screening of amine protection groups such as Ac, Bz, Piv,
loadings, higher selectivities, and a broad substrate scope, have been Ts, COCF3 and SO2CF3 (Tf), benzylamine 1a with a triflamide
much less explored.6 For instance, Matsumoto and Yoshida described directing group was found to couple with 150 mol% of acrylate 2a
an oxidative coupling reaction between benzenes and ethylene using in the presence of 10 mol% of Pd(OAc)2 and 200 mol% of Cu(OAc)2
cyclometalated Rh(III) catalysts to afford styrenes.7 Notably, Satoh and in DCE solvent at 110 1C for 24 h to give the alkenylation compound
Miura8 and Ackermann,9 respectively, reported Rh(III)- and Ru(II)- 3aa in 27% yield. After screening of solvents in the presence of
catalyzed oxidative coupling and intramolecular cyclization between palladium catalysts, DMF was found to be the most effective solvent
benzoic acids and acrylates. Li disclosed Rh(III)-catalyzed tandem in this coupling reaction to give 3a in 17% yield. To our delight, the
combination of [RhCp*Cl2]2 and Cu(OAc)2ÁH2O in DMF promoted
the coupling of 1a and 2a to provide our desired product 3a in 62%
yield. After further optimization, we found that the AcOH additive
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
E-mail: insukim@skku.edu; Fax: +82 31 292 8800; Tel: +82 31 290 7788
facilitated high levels of catalytic activity. Thus the best results were
obtained by the use of 2.5 mol% of [RhCp*Cl2]2 and 200 mol% of
† Electronic supplementary information (ESI) available: Experimental details and
spectroscopic data for all compounds. See DOI: 10.1039/c3cc49486a
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Table 1 Scope of N-benzyltriflamidesa
Table 2 Scope of olefinsa
a
Reaction conditions: 1a (0.3 mmol), 2b–2j (0.45 mmol), [RhCp*Cl2]2
(2.5 mol%), Cu(OAc)2ÁH2O (200 mol%), DMF–AcOH (3 : 1, 1 mL), 110 1C
b
for 24 h in sealed tubes. Yield isolated by column chromatography.
c
d
2g and 2h (0.6 mmol). MeCN was used as a solvent.
substrates for this transformation, affording the corresponding
products 4b–4h. Interestingly, a,b-unsaturated ketones 2i and 2j
gave a separable mixture of isoindolines (4% for 2i and 16% for 2j)
and the alkylated compounds (20% for 2i and 55% for 2j) under
DMF–AcOH conditions (see ESI† for details).19 After further opti-
a
Reaction conditions: 1a–1p (0.3 mmol), 2a (0.45 mmol), [RhCp*Cl2]2 mization, we found that MeCN solvent provided our desired
(2.5 mol%), Cu(OAc)2ÁH2O (200 mol%), DMF–AcOH (3 : 1, 1 mL), 110 1C
products 4i and 4j as the major compounds in satisfactory yields.
b
for 24 h in sealed tubes. Yield isolated by column chromatography.
c
d
Further reductive cleavage of the triflate group of 3a using LiAlH4
was performed to give the corresponding free (NH)-isoindoline in
72% yield (see ESI† for details).
2a (0.6 mmol), 40 h. 2a (1.2 mmol), 40 h.
Cu(OAc)2ÁH2O in DMF–AcOH (3 : 1) solvents under otherwise identical
Encouraged by these results, we further examined the inter-
conditions, affording the desired isoindoline 3a in high yield (91%). molecular and intramolecular competition experiments between
With the optimized reaction conditions in hand, the scope our triflamide group and carboxylic acid group reported by Satoh
and limitation of N-benzyltriflamides were examined (Table 1). The and Miura,8 as shown in Scheme 2.
coupling of ortho-substituted N-benzyltriflamides 1b–1e and n-butyl
First, an intermolecular competition experiment between
acrylate (2a) was found to be favored in the olefination and sub- N-(2-methoxybenzyl)triflamide (1a) and 2-methoxybenzoic acid (5a)
sequent cyclization reaction to afford our desired products 3b–3e in was conducted under the standard reaction conditions. Exposure of
high yields. This reaction was also compatible with meta-substituted 1 equiv. of n-butyl acrylate (2a) to equimolar quantities of 1a and 5a
N-benzyltriflamides 1f–1h in the presence of 200 mol% of 2a for provided a separable mixture of isoindoline 3a (28%) and phthalide
40 h furnishing the corresponding products 3f–3h in good yields. 5b (42%), respectively. The intramolecular competition experiment
Particularly noteworthy were the regioselectivity found at the more of 6a with both triflamide and carboxylic acid groups under other-
sterically accessible position and the tolerance of the reaction condi- wise identical conditions afforded a mixture of 6b (18%) and 6c
tions to the chloro moiety, which provides a versatile synthetic handle (41%). Based on these results, it is indicated that the carboxylic acid
for further functionalization of the products. Subsequently, we tried to moiety might be more rapidly involved in C–H bond activation and
perform the coupling reaction between symmetrical N-benzyl- the intramolecular cyclization process.
triflamide 1i and acrylate 2a under the optimal reaction conditions,
To gain a mechanistic insight into these reactions, the following
but we obtained a mixture of isoindolines derived from mono- and experiments were conducted (Scheme 3). A hydrogen–deuterium
bis-olefination. Thus, compounds 1i–1m were treated with 4 equiv. exchange experiment using AcOD showed that the cleavage of the
of 2a for 40 h under otherwise identical conditions to afford the
4-alkenylated isoindolines 3i–3m in good to high yields. In addition,
a-substituted N-benzyltriflamides 1n and 1o displayed a relatively
decreased reactivity under the present reaction conditions. In contrast,
the reaction of 1p with 2a provided the alkenylated compound 3p and
no further aza-Michael reaction took place.10
To further explore the substrate scope and limitations, a range
of olefins 2b–2j was screened to couple with 1a under optimal
reaction conditions, as shown in Table 2. To our pleasure, olefins
Scheme 2 Competition experiments.
2b–2h with electron-withdrawing groups proved to be good
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T. Ikler, P. Savage, S. S. Shetty, D. DelGrande and A. Y. Jeng, Bioorg.
Med. Chem. Lett., 2001, 11, 1737; (c) S. V. Goethem, P. V. der Veken,
V. Dubois, A. Soroka, A.-M. Lambeir, X. Chen, A. Haemers,
S. Scharpe, I. D. Meester and K. Augustyns, Bioorg. Med. Chem. Lett.,
2008, 18, 4159.
2 (a) Y. Ding and A. S. Hay, J. Polym. Sci., Part A: Polym. Chem., 1999,
37, 3293; (b) B.-X. Mi, P.-F. Wang, M.-W. Liu, H.-L. Kwong,
N.-B. Wong, C.-S. Lee and S.-T. Lee, Chem. Mater., 2003, 15, 3148.
3 For selected reviews on C–H bond activation, see: (a) L. Ackermann,
Chem. Rev., 2011, 111, 1315; (b) S. H. Cho, J. Y. Kim, J. Kwak and
S. Chang, Chem. Soc. Rev., 2011, 40, 5068; (c) J. Wencel-Delord,
¨
T. Droge, F. Kiu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740;
Scheme 3 Mechanistic studies.
(d) O. Baudoin, Chem. Soc. Rev., 2011, 40, 4902; (e) L. McMurray,
F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885;
( f ) J. L. Bras and J. Muzart, Chem. Rev., 2011, 111, 1170.
4 I. Moritani and Y. Fujiwara, Tetrahedron Lett., 1967, 8, 1119.
5 For selected examples of Pd-catalyzed C–H olefination of arenes
with alkenes, see: (a) S. H. Cho, S. J. Hwang and S. Chang, J. Am.
Chem. Soc., 2008, 130, 9254; (b) C. E. Houlden, C. D. Bailey,
´
J. G. Ford, M. R. Gagne, G. C. Lloyd-Jones and K. I. Booker-
Milburn, J. Am. Chem. Soc., 2008, 130, 10066; (c) D.-H. Wang,
K. M. Engle, B.-F. Shi and J.-Q. Yu, Science, 2010, 327, 315;
(d) B. F. Shi, Y.-H. Zhang, J. K. Lam, D.-H. Wang and J.-Q. Yu,
J. Am. Chem. Soc., 2010, 132, 460; (e) K. M. Engle, D.-H. Wang and
J.-Q. Yu, Angew. Chem., Int. Ed., 2010, 49, 6169; ( f ) T. Nishikata and
B. H. Lipshutz, Org. Lett., 2010, 12, 1972; (g) C. Zhu and J. R. Falck,
Org. Lett., 2011, 13, 1214.
6 For selected reviews on Rh-catalyzed C–H olefination of arenes with
alkenes, see: (a) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem.
Rev., 2010, 110, 624; (b) G. Song, F. Wang and X. Li, Chem. Soc. Rev.,
2012, 41, 3651.
Scheme 4 Proposed reaction mechanism.
7 T. Matsumoto, R. A. Periana, D. J. Taube and H. Yoshida, J. Catal.,
2002, 206, 272.
8 (a) K. Ueura, T. Satoh and M. Miura, Org. Lett., 2007, 9, 1407;
(b) S. Mochida, K. Hirano, T. Satoh and M. Miura, J. Org. Chem.,
2009, 74, 6295.
9 L. Ackermann and J. Pospech, Org. Lett., 2011, 13, 4153.
10 F. Wang, G. Song and X. Li, Org. Lett., 2010, 12, 5430.
11 N. Umeda, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2009,
74, 7094.
12 F. Wang, G. Song, Z. Du and X. Li, J. Org. Chem., 2011, 76, 2926.
13 (a) S. H. Park, J. Y. Kim and S. Chang, Org. Lett., 2011, 13, 2372;
(b) T. Besset, N. Kuhl, F. W. Patureau and F. Glorius, Chem.–Eur. J.,
2011, 17, 7167.
14 (a) F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 2010, 132, 9982;
(b) M. Kim, J. Park, S. Sharma, S. Han, S. H. Han, J. H. Kwak,
Y. H. Jung and I. S. Kim, Org. Biomol. Chem., 2013, 11, 7427.
15 (a) T.-J. Gong, B. Xiao, Z.-J. Liu, J. Wan, J. Xu, D.-F. Luo, Y. Fu and
L. Liu, Org. Lett., 2011, 13, 3235; (b) C. Feng and T.-P. Loh, Chem.
Commun., 2011, 47, 10458.
16 (a) F. W. Patureau, T. Besset and F. Glorius, Angew. Chem., Int. Ed.,
2011, 50, 1064; (b) B. Li, J. Ma, W. Xie, H. Song, S. Xu and B. Wang,
Chem.–Eur. J., 2013, 19, 11863.
17 (a) J.-J. Li, T.-S. Mei and J.-Q. Yu, Angew. Chem., Int. Ed., 2008, 47, 6452;
(b) X. Wang, T.-S. Mei and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 7520;
(c) S. Sharma, J. Park, E. Park, A. Kim, M. Kim, J. H. Kwak, Y. H. Jung
and I. S. Kim, Adv. Synth. Catal., 2013, 355, 332; (d) J. Park, A. Kim,
S. Sharma, M. Kim, E. Park, Y. Jeon, Y. Lee, J. H. Kwak, Y. H. Jung and
I. S. Kim, Org. Biomol. Chem., 2013, 11, 2766.
18 (a) S. Sharma, E. Park, J. Park and I. S. Kim, Org. Lett., 2012, 14, 906;
(b) M. Kim, J. Park, S. Sharma, A. Kim, E. Park, J. H. Kwak, Y. H. Jung
and I. S. Kim, Chem. Commun., 2013, 49, 925; (c) J. Park, M. Kim,
S. Sharma, E. Park, A. Kim, S. H. Lee, J. H. Kwak, Y. H. Jung and
I. S. Kim, Chem. Commun., 2013, 49, 1654.
ortho-C–H bond was a reversible metalation–proto(deutero)demeta-
lation process. To further probe the role of a rhodium catalyst,
copper salt and AcOH, several experiments were performed. A trace
amount of 3a was obtained without using copper acetate or AcOH
(condition A), while 71% and 95% yields of 3a were isolated in the
absence of a Rh catalyst (conditions B and C), which indicated that
Cu(OAc)2ÁH2O or AcOH is crucial to facilitate intramolecular
cyclization.
On the basis of collective data, a plausible reaction mechanism
is proposed as illustrated in Scheme 4. First, the coordination of
triflamide 1a to a Rh(III) catalyst facilitates the formation of a
rhodacycle I, which can undergo migratory insertion of olefin 2a
to generate intermediate II. Subsequently, the b-H elimination of
II followed by reductive elimination affords compound 3aa and a
Rh(I) species, which is then reoxidized by Cu(II) to regenerate
Rh(III). The formed olefin 3aa presumably reacts with Cu(II) or
AcOH to undergo the aza-Michael addition5g,10,17a,20 followed by
subsequent enolate protonation to give isoindoline 3a.
In conclusion, we developed a facile and efficient strategy for
the construction of isoindolines via rhodium(III)-catalyzed oxi-
dative ortho-alkenylation of N-benzyltriflamides with olefins
followed by intramolecular cyclization.
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Tech-
nology (No. 2013R1A2A2A01005249).
19 Rh(III)-catalyzed oxidative alkylation of arenes with enones or allylic
alcohols, see: (a) T. Hayashi, M. Takahashi, Y. Takaya and
M. Ogasawara, J. Am. Chem. Soc., 2002, 124, 5052; (b) Z.-M. Sun
and P. Zhao, Angew. Chem., Int. Ed., 2009, 48, 6726; (c) L. Huang,
Q. Wang, J. Qi, X. Wu, K. Huang and H. Jiang, Chem. Sci., 2013,
4, 2665.
Notes and references
1 (a) C. A. Luckhurst, L. A. Stein, M. Furber, N. Webb, M. J. Ratcliffe, 20 For tandem C(sp3)–H olefination and aza-Michael addition, see:
G. Allenby, S. Botterell, W. Tomlinson, B. Martin and A. Walding,
Bioorg. Med. Chem. Lett., 2011, 21, 492; (b) P. J. Kukkola, N. A. Bilci,
M. Wasa, K. M. Engle and J.-Q. Yu, J. Am. Chem. Soc., 2010,
132, 3680.
2352 | Chem. Commun., 2014, 50, 2350--2352
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