Assembly of indenamine derivatives through in situ formed N-sulfonyliminium ion initiated cyclization

Article abstract of DOI:10.1039/c4cc00310a

An expedient route to structurally diverse indenamine derivatives through condensation of the readily accessible substituted cinnamylaldehydes and sulfonylamines under the catalysis of FeCl₃ has been developed, featuring high efficiency in the generation of two bonds and one ring in a single-step and water as the only by-product. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00310a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Assembly of indenamine derivatives through
in situ formed N-sulfonyliminium ion initiated
cyclization†
Cite this: Chem. Commun., 2014,
50, 4119
Received 14th January 2014,
Accepted 25th February 2014
Xiaohui Fan,*ab Hao Lv,a Yong-Hong Guan,a Hong-Bo Zhu,a Xiao-Meng Cuia and
Kun Guoa
DOI: 10.1039/c4cc00310a
www.rsc.org/chemcomm
An expedient route to structurally diverse indenamine derivatives Lewis acid catalyst because iron is an abundant, economical, and
through condensation of the readily accessible substituted cinnamyl- environmentally benign metal on earth and shows increasing and
aldehydes and sulfonylamines under the catalysis of FeCl3 has been promising catalytic abilities for the C–C and C–N bond formation.10
developed, featuring high efficiency in the generation of two bonds To our disappointment, the reaction failed to produce the designed
and one ring in a single-step and water as the only by-product.
cyclization product at room temperature as well as under reflux con-
ditions, whereas a small amount of intractable mixture was obtained
Iminium ions are reactive intermediates in organic chemistry that along with the recovery of unreacted aldehyde 1a. To implement our
play an important role in both laboratory and industry for the strategy, a number of other amines (e.g., aniline 2b, 4-nitroaniline 2c,
construction of carbon–carbon and carbon–heteroatom bonds, espe- piperidine 2d, and p-toluenesulfonamide 2e) were subsequently
cially for the synthesis of nitrogen-containing heterocycles.1 Repre- evaluated in this model reaction. Despite 2b–d being completely
sentative examples of these transformations are N-acyliminium ion immune to this transformation under various conditions, we were
cyclization and Pictet–Spengler reaction which have become power- pleased to find that our protocol was successfully performed upon
ful synthetic tools for the synthesis of many alkaloids.2,3 However, in using TsNH2 (2e) as the amine component and gave the desired
contrast to heterocycles, very few examples exist on the use of this cyclization product 3a in 89% isolated yield (Table 1, entry 1). These
strategy for the construction of all-carbon ring skeletons.4 Indenes results indicate that this cyclization reaction is facilitated with the
are important core structures present in many biologically active amines bearing a relatively strong electron-withdrawing group.
compounds,5 functional materials,6 and chemical catalysts,7 which Encouraged by the above results, a variety of solvents and Lewis
hold a special appeal to synthetic chemists and provide an ideal acids were then systematically investigated in the reaction of 1a with
target for developing and testing new synthetic strategies, particu- 2e (Table 1, entries 2–13). These examinations revealed that treating
larly those that are directed toward carbocyclic ring construction.8 1a (1.0 equiv.) with 1.2 equiv. of 2e in toluene at 40 1C for 4 h in the
We reasoned that this class of carbocycles might be accessed in one presence of 20 mol% FeCl3 gave the best result (98%, Table 1,
step by condensation of a cinnamaldehyde with an amine under the entry 2). Other Lewis acids such as FeCl3ꢀ6H2O, BF3ꢀOEt2, TiCl4, and
catalysis of Lewis acid through an in situ formed iminium ion CuI were found to be less effective or ineffective in promoting this
initiated intramolecular cyclization (Scheme 1). To our knowledge, transformation (Table 1, entries 10–13). Among the examined
this approach to indene frameworks has not been reported pre- Brønsted acids (e.g., TfOH, TsOH, and HCl), only triflic acid showed
viously. As one of our continuous interests in the synthesis of catalytic activity towards this reaction (Table 1, entries 14–16), and a
carbocyclic compounds,9 recently we launched a study to verify this moderate yield of 3a was obtained. Further investigation of this
hypothesis. The preliminary results are reported herein.
reaction under an argon atmosphere (Table 1, entries 17–18) reveals
Initial examination was carried out on the reaction of (E)-2-
methyl-3-phenylacrylaldehyde (1a, 1.0 equiv.) with benzamide
(2a, 1.2 equiv.) in toluene. FeCl3 (15 mol%) was selected as the
a School of Chemical and Biological Engineering, Lanzhou Jiaotong University,
Lanzhou, 730070, China. E-mail: fanxh@mail.lzjtu.cn
b Beijing National Laboratory for Molecular Science (BNLMS), Beijing, 100190,
China
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data. CCDC 965332 and 965333. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4cc00310a
Scheme 1 Design of the intramolecular cyclization reaction via an in situ
formed iminium ion.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 4119--4122 | 4119

View Article Online
Communication
ChemComm
Table 1 Optimization of the reaction conditionsa
Table 2 Reaction of 2e with various cinnamylaldehydesa
Entry Catalyst (mol%)
Solvent
T (1C)/t (h) Yieldb (%)
1
2
3
4
5
6
7
8
FeCl3 (15)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (15)
FeCl3ꢀ6H2O (20)
TiCl4 (20)
BF3ꢀOEt2 (20)
Cul (20)
Toluene
Toluene
Benzene 80/4
DCM 40/4
CH3NO2 100/4
THF
MeCN
40/4
40/4
89
98
78
85
64
0
30
Mess
0
79
56
82
0
71
Trace
0
60/12
80/12
80/4
60/12
40/4
40/4
40/4
40/12
40/12
40/12
40/12
80/8
DMF
EtOH
9
10
11
12
13
14
15
16
17c
18c
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
TfOH (20)
TsOH (20)
HCl (20)
FeCl3 (40)
FeCl3 (20) + H2O (5 mL) Toluene
96
95
40/4
a
Reaction conditions: 1a (0.2 mmol), 2e (0.24 mmol), solvent (3 mL).
Isolated yield. Under argon.
b
c
Scheme 2 Reaction of 1a with other sulfonylamines.
that the present reaction is catalyzed by Fe(III) species and a trace
amount of water can accelerate this reaction.11 Note that when (Z)-1a
was subjected to this reaction, an almost quantitative yield of 3a was
obtained after 2.5 h at 40 1C. This suggests that the substituted
cinnamaldehyde in Z configuration is more favorable for this
transformation.12
a
Reaction conditions: 1a–u (0.2 mmol), 2e (0.24 mmol), toluene (3 mL),
b
20 mol% FeCl3. Isolated yield.
Subsequently, several other sulfonylamines such as aldehyde has an a-substituent which is essential for this trans-
methane-sulfonamide (2f), benzenesulfonamide (2g), 4-chloro- formation. The only exception to this structural requirement is
benzenesulfonamide (2h), and 4-nitrobenzenesulfonamide (2i) 3,3-diphenylacrylaldehyde (1f), which can carry out this cyclization
were examined in this reaction (Scheme 2). Under the optimal without an additional a-substituent, presumably because of its
reaction conditions, 2f–h reacted smoothly with 1a to afford the special structure leading the carbonyl group and one of the phenyl
cyclization products 3af–ah in 91%, 82%, and 87% yields, rings in a cis fashion. Moreover, the electronic properties of
respectively. In contrast, 2i was found to be an unsuitable the phenyl ring also had an obvious impact on the outcome of
amine source for this transformation.13
the reaction. The presence of electron-withdrawing groups on the
With the optimized reaction conditions established, the scope phenyl ring would prevent the reaction (Table 2, 3r).15 With respect
of the reaction between various cinnamylaldehydes (E isomers) and to the aldehydes bearing an electron-donating group on the phenyl
p-toluenesulfonamide was investigated. As shown in Table 2, most ring, the results were more complicated. Despite the fact that either
of the a-substituted cinnamylaldehydes can smoothly react with alkyl or methoxy group substituted aldehydes, e.g., 1b and 1d,
TsNH2 with high efficiency to give the corresponding indenamine underwent this cyclization reaction smoothly, however, the alkyl
derivatives in good to excellent yields (Table 2, 3a–p). However, substituted substrate is more favorable for this transformation
cyclization failed to occur upon using simple (E)- or (Z)-cinnam- (Table 2, 3b–d). The reason for such differences in reactivity is
aldehyde as the substrates. Further employment of b-substituted unclear at this stage, the electronic properties and coordination
cinnamylaldehyde 1q as the substrate also failed to give the desired abilities of these substituents should be responsible for the observed
cyclization product 3q.14 These results reveal that the starting results. Upon subjecting (E)-2-methyl-3-m-tolylacryl-aldehyde (1m) to
4120 | Chem. Commun., 2014, 50, 4119--4122
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
this reaction, the sterically favorable product 3m together with its intermediate E or F is totally inhibited, which results in no cyclization
regioisomeric product 3n was obtained in 90% yield as an unsepa- product being obtained.
rated mixture. Furthermore, naphthyl substituted cinnamylalde-
In summary, a convenient and expeditious route to structurally
hydes 1o and 1p can also be applied to this reaction, providing a diverse indenamine derivatives via an in situ formed N-sulfonyl-
useful method for the construction of indene-containing polycarbo- iminum ion initiated cyclization protocol has been developed. This
cycles (Table 2, 3o–p). Interestingly, the crystal growth of 3o in the methodology features using economical and readily available sub-
mixing solution of ether and petroleum ether resulted in its C–C stituted cinnamylaldehydes and sulfonylamines as the starting
double bond regioisomeric single crystal 3o0 exclusively.16 The materials, and generation of water as the only by-product.
structures of compounds 3o0 and 3p were confirmed by X-ray It displays high efficiency in the construction of two bonds
crystallographic analysis.17 Notably, thiophene and furan cannot and one ring in a single-step. Efforts are currently underway in
be used as the heteroaromatic nucleophiles in this reaction, con- our laboratory to further refine this method in organic synthesis
tinued efforts geared towards conversion of 1s or 1t to its cyclization and will be reported in due course.
product resulted in an intractable mixture. In addition, cinnamic
We thank the Natural Science Foundation of China (21162013)
ketone such as (E)-3-methyl-4-phenylbut-3-en-2-one (1u) was also and Beijing National Laboratory for Molecular Sciences (BNLMS) for
found to be an unsuitable substrate for this reaction, which might financial support, and Prof. Zhi-Xiang Yu for helpful discussions.
be attributed to the difficulty in the formation of an iminium ion
intermediate from the ketone.
Notes and references
1 (a) J. Royer and M Bonin, Chem. Rev., 2004, 104, 2311; (b) S. F. Martin,
To gain some understanding of the mechanism, the imine
4a was tested in this reaction (Scheme 3).18 Under the catalysis
Acc. Chem. Res., 2002, 35, 895.
of FeCl3 or TfOH, 4a was smoothly transformed into the
cyclization product 3a in 96% and 97% yields, respectively. In
the absence of the catalyst, 4a could not be converted into 3a.
Therefore, we assumed that the iminium ion might be the
reactive intermediate in this reaction.
Based on the above results, a plausible mechanism for this
reaction is proposed in Scheme 4. The first step is the nucleophilic
addition of a sulfonylamine to the carbonyl group of the a-substituted
aldehyde with the aid of FeCl3 to give the intermediate A, which then
loses a FeꢁCl3(OH) group to afford the electrophilic iminium ion C.
The iminium ion C/E can undergo isomerization to F/G, followed by
an intramolecular Friedel–Crafts alkylation reaction would give rise to
the corresponding indenamine derivatives. In this ring closure reac-
tion, we speculate that the isomerizations of intermediate C to its less
stable resonance structure E and E to its sterically unfavorable
rotamer F are facilitated by the substrates bearing an a-substituent;
upon using aldehydes without an a-substituent, the formation of
2 (a) B. E. Maryanoff and H.-C Zhang, Chem. Rev., 2004, 104, 1431;
(b) E. D. Cox and J. M. Cook, Chem. Rev., 1995, 95, 1797; (c) T. A.
Blumenkopf and L. E. Overman, Chem. Rev., 1986, 86, 857.
3 For selected examples, see: (a) S. Gao, Y.-Q. Tu, X. Hu, S. Wang,
R. Hua, Y. Jiang, Y. Zhao, X. Fan and S. Zhang, Org. Lett., 2006,
8, 2373; (b) A. Padwa and M. D. Danca, Org. Lett., 2002, 4, 715;
(c) S. J. Danishefsky and J. S. Panek, J. Am. Chem. Soc., 1987, 109, 917;
(d) H. Abe, S. Aoyagi and C. Kibayashi, J. Am. Chem. Soc., 2005,
127, 1473; (e) S. M. Weinreb, Acc. Chem. Res., 2003, 36, 59.
4 (a) X. Yu and X. Lu, Adv. Synth. Catal., 2011, 353, 569; (b) P. Zhao,
F. Wang, K. Han and X. Li, Org. Lett., 2012, 14, 5506.
5 (a) X. Liao, L. M. Stanley and J. F. Hartwig, J. Am. Chem. Soc., 2011,
133, 2088; (b) H. Tye, S. G. Mueller, J. Prestle, S. Scheuerer,
M. Schindler, B. Nosse, N. Prevost, C. J. Brown, A. Heifetz and
C. Moeller, Bioorg. Med. Chem. Lett., 2011, 21, 34.
6 (a) X. Zhu, H. Tsuji, K. Nakabayashi, S.-I. Ohkoshi and E. Nakamura,
J. Am. Chem. Soc., 2011, 133, 16342; (b) J. Yang, M. V. Lakshmikantham
and M. P. Cava, J. Org. Chem., 2000, 65, 6739.
7 (a) B. Wang, Coord. Chem. Rev., 2006, 250, 242; (b) D. Zargarian,
¨
Coord. Chem. Rev., 2002, 233, 157; (c) H. G. Alt and A. Koppl, Chem.
Rev., 2000, 100, 1205.
8 For selected recent examples of indene synthesis, see: (a) X.-Y. Shi
and C.-J. Li, Org. Lett., 2013, 15, 1476; (b) K. B. S. Magar and Y. R. Lee,
Org. Lett., 2013, 15, 4288; (c) D. H. Dethe and G. Murhade, Org. Lett.,
2013, 15, 429; (d) J. Zhao and D. A. Clark, Org. Lett., 2012, 14, 1668;
(e) B. Meng and S. Ma, Org. Lett., 2012, 14, 2674; ( f ) X.-C. Wang,
M.-J. Zhong and Y.-M. Liang, Org. Biomol. Chem., 2012, 10, 3636;
(g) C.-R. Liu, T.-T. Wang, Q.-B. Qia and S.-K. Tian, Chem. Commun.,
2012, 48, 10913; (h) D. Eom, S. Park, Y. Park, T. Ryu and P. H. Lee,
Org. Lett., 2012, 14, 5392; (i) L. Ye, Y. Wang, D. H. Aue and L. Zhang,
J. Am. Chem. Soc., 2012, 134, 31; ( j) A. S. K. Hashmi, I. Braun,
Scheme 3 Control experiments.
¨
¨
P. Nosel, J. Schadlich, M. Wieteck, M. Rudolph and F. Rominger,
Angew. Chem., Int. Ed., 2012, 51, 4456; (k) X. Jia, D. A. Petrone and
M. Lautens, Angew. Chem., Int. Ed., 2012, 51, 9870; (l) L. Liu, Y. Fan,
Q. He, Y. Zhang, D. Zhang-Negrerie, J. Huang, Y. Du and K. Zhao,
J. Org. Chem., 2012, 77, 3997; (m) D. L. Usanov and H. Yamamoto,
Org. Lett., 2012, 14, 414; (n) K. V. Sajna and K. C. Kumara Swamy,
J. Org. Chem., 2012, 77, 5345; (o) Y. Liu, J. Zhu, J. Qian and Z. Xu,
J. Org. Chem., 2012, 77, 5411.
9 (a) X. Fan, M.-X. Tang, L.-G. Zhuo, Y.-Q. Tu and Z.-X. Yu, Tetrahedron
Lett., 2009, 50, 155; (b) X. Fan, L.-G. Zhuo, Y.-Q. Tu and Z.-X. Yu,
Tetrahedron, 2009, 65, 4709.
10 For reviews and select examples, see: (a) C. Bolm, J. Legros, J. L. Paih
and L. Zani, Chem. Rev., 2004, 104, 6217; (b) C.-L. Sun, B.-J. Li and
Z.-J. Shi, Chem. Rev., 2011, 111, 1293; (c) H. Li, W. Li, W. Liu, Z. He
and Z. Li, Angew. Chem., Int. Ed., 2011, 50, 2975; (d) X. Fan, L.-A. Fu,
N. Li, H. Lv, X.-M. Cui and Y. Qi, Org. Biomol. Chem., 2013, 11, 2147;
(e) S.-Y. Zhang, Y.-Q. Tu, C.-A. Fan, F.-M. Zhang and L. Shi, Angew.
Chem., Int. Ed., 2009, 48, 8761.
Scheme 4 Plausible mechanism.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 4119--4122 | 4121

View Article Online
Communication
ChemComm
11 Under the argon atmosphere and optimized reaction conditions, only 15 (E)-2-methyl-3-(4-nitrophenyl)acrylaldehyde also failed to give the
57% yield of 3a was obtained after 12 h along with the unreacted 1a. cyclization product.
12 Isomerization of the C–C double bond in iminium ion to its 16 In order to remove the N-tosyl group, several typical conditions were
Z configuration is essential for this transformation. Therefore, the
reaction is facilitated with the cinnamylaldehydes in Z configuration.
13 Besides 2i, CF3CONH2 and CF3SO2NH2 were also found to be
unsuitable amine sources for this reaction, which might be attri-
buted to their lower nucleophilicity that would inhibit the formation
of iminium ions. The sulfonamide 2h can take place this reaction
tested to 3a (see ESI†). However, these conditions result in the
isolation of its C–C double bond regioisomer exclusively. These
results suggest that the C–C double bond in resulting indenamine
products might be liable to rearrangement to the more substituted
double bond. In the case of 3o, the rearrangement may be promoted
by itself.
probably because the chlorine atom is a relatively weak electron- 17 CCDC 965332 (3o0) and 965333 (3p), see the (ESI†) for details.
withdrawing group as compared to the nitryl group.
14 1q was partly converted into the corresponding sulfonylimine
(62% yield).
18 The sulfonylimine derived from cinnamaldehyde was also tested to
this reaction, it failed to give the cyclization product under various
conditions.
4122 | Chem. Commun., 2014, 50, 4119--4122
This journal is ©The Royal Society of Chemistry 2014