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AgOTf-catalyzed dehydrative [3+2] annulation of

aziridines with 2-naphthols†
Cite this: Chem. Commun., 2017,
53, 8219
Trinadh Kaicharla,ab Anu Jacob,a Rajesh G. Gonnade c
and Akkattu T. Biju ‡*ab
Received 3rd May 2017,
Accepted 27th June 2017

DOI: 10.1039/c7cc03425c

rsc.li/chemcomm

The reaction of 2-naphthols with aziridines in the presence of AgOTf
resulting in a dehydrative, formal [3+2] annulation is reported. The
reaction allows the synthesis of functionalized benzoindolines, and
tolerates a broad range of functional groups. A preliminary study on
the mechanism of this reaction indicates an SN1-type ring-opening of
aziridines. This method is demonstrated for the one-pot synthesis
of benzoindoles.
Synthetic transformations employing readily available compounds
having a three-membered ring as a masked 1,3-dipolar equivalent
have emerged as one of the powerful synthetic strategies for
annulation reactions. Among the compounds having three-
membered rings, the utility of donor–acceptor cyclopropanes
has been widely demonstrated in Lewis acid-catalyzed [3+x]
annulation reactions (x = 2, 3, and 4) for the convenient access
to various carbocycles and heterocycles.1 Another class of
compounds having three-membered rings with a nitrogen atom
are aziridines, which are versatile building blocks (owing to
their high ring strain) for the synthesis of a variety of nitrogen-
containing bioactive molecules.2 Aziridines are valuable sub-
strates for transition-metal-catalyzed annulation reactions,3 and
an array of nucleophiles can open the aziridine ring to form
valuable products.4 A [3+2] cycloaddition reaction involving
aziridines is a straightforward method to access five-membered
nitrogen heterocycles. The cleavage of the carbon–carbon bond
of aziridines can generate azomethine ylides, which can undergo
a variety of cycloaddition reactions.5 Moreover, aziridines bearing an
electron-withdrawing N-substituent usually suffer carbon–nitrogen
bond rupture under mild Lewis acid conditions to generate
1,3-dipoles that undergo facile [3+2] cycloaddition with carbonyl
compounds,6 heterocumulenes7 and carbon–carbon multiple
bonds.8,9
In 2006, Joullié and co-workers demonstrated the Cu(I)-
catalyzed nucleophilic ring-opening of aziridines using phenols
leading to the formation of alkyl aryl ethers having an amine
moiety.10,11 Interestingly, the Lewis acid-catalyzed ring-opening
of aziridines using 2-naphthols as nucleophiles has received
only scant attention.12 We have recently reported the Lewis
acid-catalyzed selective reactions of 2-naphthols with donor–
acceptor cyclopropanes. Using Bi(OTf)3 as the Lewis acid, the
reaction afforded naphthalene-fused cyclopentanes in good yields
(Scheme 1, eqn (1)).13 Herein, we report the AgOTf-catalyzed reaction
of electron-deficient aziridines with 2-naphthols, which proceeds
in a dearomatization–rearomatization sequence of 2-naphthols.
The reaction afforded functionalized benzoindolines in moderate
to good yields (eqn (2)). Notably, benzoindolines are an important
class of heterocycles, and this skeleton is found in several natural
products and biologically active molecules.14
Inspired by our recent cyclopentannulation catalyzed by Lewis
acids,13 the present study was initiated by treating 2-naphthol 1a
with a donor acceptor aziridine (2-phenyl 3,3-dicarboethoxy

a
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL),
Dr Homi Bhabha Road, Pune-411008, India. E-mail: at.biju@ncl.res.in
b
Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India
c
Centre for Materials Characterization, CSIR-National Chemical Laboratory
(CSIR-NCL), Dr Homi Bhabha Road, Pune-411008, India
† Electronic supplementary information (ESI) available: Details on experimental
procedure, characterization data of all compounds, and single crystal X-ray data
of compound 3a. CCDC 1545103. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c7cc03425c
‡ Present address: Department of Organic Chemistry, Indian Institute of Science,
Bangalore-560012, India. E-mail: atbiju@orgchem.iisc.ernet.in; Fax: +91-80-23600529;
Tel: +91-80-22932646 Scheme 1 Lewis acid-catalyzed reaction of 2-naphthols with aziridines.

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Table 1 Optimization of reaction conditionsa

Entry Lewis acid (x mol %) Solvent Temp (1C) Yield of 3ab (%)
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1 Bi(OTf)3 (20) DCE 80 62

2 Bi(OTf)3 + KPF6 DCE 80 66
3 Cu(OTf)2 (20) DCE 80 67
4 Sc(OTf)3 (20) DCM 80 o5
5 Yb(OTf)3 (20) DCE 80 o5
6 Fe(OTf)3 (20) DCE 80 27
7 AgSbF6 (20) DCE 80 31
8 BF3OEt2 (20) DCE 80 24
9 TfOH (20) DCE 80 44
10 AgOTf (20) DCE 80 72
11 AgOTf (20) DCE 60 64
12 AgOTf (20) DCE 100 74
13 AgOTf (10) THF 70 o5
14 AgOTf (10) DME 80 o5
15 AgOTf (20) DCM 45 58
16 AgOTf (10) Toluene 80 62
17 AgOTf (10) DCE 80 78 (74)
a
All reactions were carried out in 0.25 mmol of 1a and 0.3 mmol of 2a
in 1.0 mL solvent unless otherwise specified. b The yields were deter-
mined by 1H NMR analysis of crude products using CH2Br2 as the Scheme 2 Substrate scope of the dehydrative annulation reaction: varia-
internal standard, yield of isolated product in 0.5 mmol scale is given tion of aziridines: general conditions: 1a (0.5 mmol), 2 (0.60 mmol), AgOTf
parentheses. (10 mol%), DCE (2.0 mL), at 80 1C and 12 h. Yields of isolated products
are given. a Structure confirmed by X-ray analysis. b Reaction was run on
0.25 mmol scale.
N-tosyl aziridine) under Lewis acidic conditions. Disappointingly,
the reactions did not afford the expected benzoindoline product.
Then the aziridine component was changed to 2-phenyl N-tosyl crystal X-ray analysis.17 Moreover, aziridines having substituents on
aziridine 2a. Gratifyingly, the treatment of 1a with 2a in the presence the 3-position and 2-position of the ring as well as the disubstituted
of Bi(OTf)3 in dichloroethane (DCE) afforded the expected benzo- 2-aryl aziridines underwent smoothly the dehydrative annulation
indoline 3a in 62% yield (Table 1, entry 1). Notably, the O-alkylation with 1a, affording the desired products in good yields (3h–3m). It is
of 2-naphthol was not observed under these conditions. The reac- noteworthy that the reaction performed using 2-vinyl aziridine
tions performed using a combination of Bi(OTf)3, KPF6 and Cu(OTf)2 resulted in the formation of the desired product 3n in 42% yield.
furnished slightly better results (entries 2 and 3). The reaction In addition, commonly used electronically different sulfonyl
performed using other commonly used Lewis acids resulted in groups can be used for the N-substitution on aziridine, and the
reduced yields of 3a (entries 4–8). Interestingly, the reaction carried corresponding products were formed in moderate to good yields
out using TfOH resulted in the formation of 3a in 44% yield (3o–3q).18 Interestingly, a disubstituted aziridine derived from
(entry 9).15 The use of AgOTf improved the yield of 3a to 72% indene afforded the pentacyclic compound 3r in 32% yield.
(entry 10), and hence further optimization reactions were performed Furthermore, the reaction of 2-naphthol with 2-methyl-3-phenyl-
using AgOTf. The suitable reaction temperature was found to be 1-tosylaziridine under the present reaction conditions furnished
80 1C as the reaction performed at 60 1C resulted in a low yield of 3a the mixture of diastereomers 3s and 3s 0 in B1 : 1 ratio.19
and the reaction carried out at 100 1C furnished almost the same Next, the generality of the present methodology was examined
results (entries 11 and 12). The variation of solvents indicated that by using a variety of substituted 2-naphthol derivatives (Scheme 3).
DCE is the best solvent for this transformation (entries 13–16). Substituents such as OMe and Br at the 7-position of 2-naphthol
Finally, reducing the loading of AgOTf resulted in improved did not affect the outcome of the reaction affording the desired
reactivity furnishing 3a in 74% isolated yield (entry 17).16 products 3t and 3u in 52% and 70% yields, respectively. In
With the reaction conditions for the [3+2] dehydrative addition, several substituents at the 6-position of 2-naphthol
annulation of aziridines with 2-naphthols in hand, we then were also tolerated well, and in all cases, the functionalized
examined the substrate scope of this annulation. First, the effect benzoindoline was formed in good yields (3v–3y). Moreover,
of variation on aziridines was tested (Scheme 2). The parent aryl and alkyl substitutions at the 4-position of 2-naphthol were
2-phenyl aziridine worked well and a series of aziridines having also tolerated well thus expanding the scope of this annulation
substituents such as Me, t-Bu, Br, Cl, F, and Ph at the 4-position of reaction (3z–3aa).
the 2-aryl ring are well tolerated, and in all cases, the function- To get insight into the mechanism of this dehydrative
alized benzoindoline was formed in good yields (3a–3g). In the annulation, we have performed a mechanistic experiment.
case of compound 3a, the structure was confirmed by single When the reaction of 1a was carried out using enantiomerically

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Scheme 3 Variation of the 2-naphthol moiety: general conditions: 1
(0.5 mmol), 2a (0.6 mmol), AgOTf (10 mol%), DCE (2.0 mL), at 80 1C and
12 h. Yields of isolated products are given.
pure 2-phenyl N-tosyl aziridine (R)-2a under the optimized
conditions, the reaction afforded the benzoindoline 3a in 72%
yield and 53 : 47 er. The complete erosion of ee sheds light on the
SN1 pathway in the present case, and the reaction likely proceeds
via a stable benzylic carbocation intermediate (Scheme 4).
Scheme 4 Reaction using chiral aziridine.
A proposed mechanism of this transformation is shown in
Scheme 5. It is reasonable to assume that the Lewis acid
(AgOTf) coordination to the N-tosyl aziridine (via the Ag coor-
dination to the tosyl oxygen) results in the carbon–nitrogen
bond scission leading to the generation of the 1,3-zwitterionic
intermediate A.6c,20 The generation of the benzylic carbocation
intermediate A was evident from the reaction carried out using
(R)-2a under the present reaction conditions.21 The nucleophi-
lic addition of 2a at the a-position to A results in the formation
of ketone intermediate B, where Ag is coordinated to both the
carbonyl and nitrogen. Intramolecular cyclization generates the
intermediate C, which upon elimination of a molecule of H2O
results in the formation of benzoindoline 3a.
The synthetic potential of the AgOTf-catalyzed dehydrative
[3+2] annulation of aziridines with 2-naphthols has been demon-
strated in a one-pot synthesis of benzoindole derivatives. Thus,
the treatment of 1a with 2a under the optimized reaction condi-
tions followed by the addition of DDQ resulted in the formation of
the benzoindole 4a in 71% yield (Scheme 6, eqn (3)). Moreover,
the cleavage of the N–Ts bond in 3a has been accomplished using
sodium in naphthalene, and the unprotected benzoindoline 5a
was isolated in 72% yield (eqn (4)).
In conclusion, we have developed the AgOTf-catalyzed dehydra-
tive annulation of electron-deficient aziridines and 2-naphthols
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Scheme 5 Tentative mechanism of the reaction.
Scheme 6 Synthetic transformations.
leading to the synthesis of biologically important benzoindoline
derivatives in moderate to good yields. The reaction proceeds via
an SN1-type ring-opening of aziridines to generate the 1,3-dipolar
intermediate, which undergoes [3+2] annulation with naphthols
to afford the desired product. Further studies on the detailed
mechanism of this methodology and related transformations of
2-naphthols are in progress in our laboratory.
This study was supported by Science and Engineering
Research Board (SERB-DST), Government of India (Grant No.
SR/S1/OC/12/2012). T. K. thanks CSIR for the SPM fellowship.
We thank Dr P. R. Rajamohanan for the excellent NMR support
and Dr B. Santhakumari for the HRMS data.
Notes and references
1 For reviews on D–A cyclopropanes, see: (a) R. Talukdar, A. Saha and
M. K. Ghorai, Isr. J. Chem., 2016, 56, 445; (b) H. K. Grover,
M. R. Emmett and M. A. Kerr, Org. Biomol. Chem., 2015, 13, 655;
(c) F. De Nanteuil, F. De Simone, R. Frei, F. Benfatti, E. Serrano and
J. Waser, Chem. Commun., 2014, 50, 10912; (d) M. A. Cavitt, L. H. Phun
and S. France, Chem. Soc. Rev., 2014, 43, 804; (e) T. F. Schneider,
J. Kaschel and D. B. Werz, Angew. Chem., Int. Ed., 2014, 53, 5504;
( f ) C. A. Carson and M. A. Kerr, Chem. Soc. Rev., 2009, 38, 3051;
(g) F. De Simone and J. Waser, Synthesis, 2009, 3353; (h) H.-U. Reissig
and R. Zimmer, Chem. Rev., 2003, 103, 1151.
2 For reviews on aziridines, see: (a) H. Ohno, Chem. Rev., 2014,
114, 7784; (b) D. J. Mack and J. T. Njardarson, ACS Catal., 2013,
3, 272; (c) A. L. Cardoso and T. M. V. D. Pinho e Melo, Eur. J. Org.
Chem., 2012, 6479; (d) S. Stanković, M. D’hooghe, S. Catak, H. Eum,
M. Waroquier, V. V. Speybroeck, N. De Kimpe and H.-J. Ha, Chem.
Soc. Rev., 2012, 41, 643; (e) P. Dauban and G. Malik, Angew. Chem.,
Int. Ed., 2009, 48, 9026; ( f ) A. K. Yudin, Aziridines and epoxides in
organic synthesis, Wiley-VHC Verlag Gmbh & Co., KGaA, Weinheim,
Germany, 2006.
Chem. Commun., 2017, 53, 8219--8222 | 8221

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3 For a review, see: (a) C.-Y. Huang and A. G. Doyle, Chem. Rev., 2014,
114, 8153; For selected recent reports, see: (b) Y. Takeda, A. Kuroda,
W. M. C. Sameera, K. Morokuma and S. Minakata, Chem. Sci., 2016,
7, 6141; (c) Y. Takeda, Y. Ikeda, A. Kuroda, S. Tanaka and S. Minakata,
J. Am. Chem. Soc., 2014, 136, 8544.
4 For reviews, see: (a) P. Lu, Tetrahedron, 2010, 66, 2549; (b) X. E. Hu,
Tetrahedron, 2004, 60, 2701.
5 For reviews, see: (a) T. Hashimoto and K. Maruoka, Chem. Rev.,
2015, 115, 5366; (b) G. Pandey, P. Banerjee and S. R. Gadre, Chem.
Published on 27 June 2017. Downloaded by Indian Institute of Technology Kanpur on 4/1/2024 2:05:18 PM.
Rev., 2006, 106, 4484; (c) I. Coldham and R. Hufton, Chem. Rev.,
2005, 105, 2765; (d) C. Najera and J. M. Sansano, Curr. Org. Chem.,
2003, 7, 1105.
6 For selected reports, see: (a) R. Maeda, R. Ishibashi, R. Kamaishi,
K. Hirotaki, H. Furuno and T. Hanamoto, Org. Lett., 2011, 13, 6240;
(b) B. Kang, W. A. Miller, S. Goyal and S. T. Nguyen, Chem. Commun.,
2009, 3928; (c) S. Gandhi, A. Bisai, B. A. B. Prasad and V. K. Singh, J. Org.
Chem., 2007, 72, 2133; (d) M. K. Ghorai and K. Ghosh, Tetrahedron Lett.,
2007, 48, 3191; (e) V. K. Yadav and V. Sriramurthy, J. Am. Chem. Soc.,
2005, 127, 16366.
7 For selected reports, see: (a) A. Bhattacharyya, C. V. Kavitha and
M. K. Ghorai, J. Org. Chem., 2016, 81, 6433; (b) L. Gao, K. Fu and
G. Zheng, RSC Adv., 2016, 6, 47192; (c) R. A. Craig II, N. R. O’Connor,
A. F. G. Goldberg and B. M. Stoltz, Chem. – Eur. J., 2014, 20, 4806;
(d) M. Sengoden and T. Punniyamurthy, Angew. Chem., Int. Ed.,
2013, 52, 572; (e) T. Munegumi, I. Azumaya, T. Kato, H. Masu and
S. Saito, Org. Lett., 2006, 8, 379; ( f ) B. M. Trost and D. R. Fandrick,
J. Am. Chem. Soc., 2003, 125, 11836; ( g) C. D. Butler, A. G. Inman and
H. Alper, J. Org. Chem., 2000, 65, 5887.
8 For selected reports, see: (a) M.-B. Zhou, R.-J. Song and J.-H. Li, Angew.
Chem., Int. Ed., 2014, 53, 4196; (b) P. A. Wender and D. Strand, J. Am.
Chem. Soc., 2009, 131, 7528; (c) J. Fan, L. Gao and Z. Wang, Chem.
Commun., 2009, 5021; (d) J. S. Yadav, B. V. S. Reddy, S. K. Pandey,
P. Srihari and I. Prathap, Tetrahedron Lett., 2001, 42, 9089.
9 For selected reports on the interception of aziridines with the indole
C2–C3 double bond, see: (a) A. Mal, M. Sayyad, I. A. Wani and
M. K. Ghorai, J. Org. Chem., 2017, 82, 4; (b) Z. Chai, Y. M. Zhu,
P. J. Yang, S. Wang, S. Wang, Z. Liu and G. Yang, J. Am. Chem. Soc.,
2015, 137, 10088; (c) Y. Huang, C. Zheng, L. Pan, Q. Jin and G. Zhao,
J. Org. Chem., 2015, 80, 10710; (d) L. Wang, D. Yang, F. Han, D. Li,
8222 | Chem. Commun., 2017, 53, 8219--8222
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D. Zhao and R. Wang, Org. Lett., 2015, 17, 176; (e) M. Nakagawa and
M. Kawahara, Org. Lett., 2000, 2, 953.
10 P. Li, E. M. Forbeck, C. D. Evans and M. M. Joullié, Org. Lett., 2006,
7, 5105.
11 For a related ring-opening of aziridines, see: M. Bera, S. Pratihar and
R. Roy, J. Org. Chem., 2011, 76, 1475.
12 D. Yang, L. Wang, F. Han, D. Li, D. Zhao and R. Wang, Angew.
Chem., Int. Ed., 2015, 54, 2185.
13 T. Kaicharla, T. Roy, M. Thangaraj, R. G. Gonnade and A. T. Biju,
Angew. Chem., Int. Ed., 2016, 55, 10061.
14 (a) K. M. Cook, S. T. Hilton, J. Mecinovic, W. B. Motherwell,
W. D. Figg and C. J. Schofield, J. Biol. Chem., 2009, 284, 26831;
(b) Y. Matsumoto, R. Tsuzuki, A. Matsuhisa, T. Yoden, Y. Yamagiwa,
I. Yanagisawa, T. Shibanuma and H. Nohira, Bioorg. Med. Chem.,
2000, 8, 393.
15 TfOH is known to catalyze several organic transformations originally
catalyzed by metal triflates. For selected reports, see: (a) G. Lemière,
B. Cacciuttolo, E. Belhassen and E. Duñach, Org. Lett., 2012, 14, 2750;
(b) D. C. Rosenfeld, S. Shekhar, A. Takemiya, M. Utsunomiya and
J. F. Hartwig, Org. Lett., 2006, 8, 4179.
16 For details, see the ESI†.
17 Crystallographic data for 3a have been deposited with the Cam-
bridge Crystallographic Data Centre as deposition number CCDC
1545103.
18 It may be noted that the reactions performed using N-Boc, N-alkyl,
or N-aryl aziridines did not afford the benzoindolines under the
present reaction conditions.
19 The present dehydrative [3+2] annulation is limited to aziridines
only, and the performed reaction using styrene oxide or 2-phenyl-1-
tosyl azetidine did not afford the desired product under the opti-
mized conditions.
20 It may be noted that intermediate A resembles the azomethine ylide,
and for related reports, see: (a) B. Alcaide, P. Almendros, J. M. Alonso
and M. F. Aly, J. Org. Chem., 2001, 66, 1351; (b) H. A. Dondas, R. Grigg,
W. S. MacLachlan, D. T. MacPherson, J. Markandu, V. Sridharan and
S. Suganthan, Tetrahedron Lett., 2000, 41, 967; (c) R. Grigg, M. Thornton-
Pett, J. Xu and L.-H. Xu, Tetrahedron, 1999, 55, 13841.
21 For details of closely related aziridine ring-opening in an SN1 pathway,
see ref. 6c.
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