Creation of molecular complexities via a new Cu-catalyzed cascade reaction: A direct access to novel 2,2′-spirobiindole derivatives

Article abstract of DOI:10.1039/c4cc08911a

A Cu-mediated unprecedented cascade reaction in the presence of air afforded a conceptually new synthesis of 2,2′-spirobiindole derivatives. This reaction proceeds via the rearrangement of several bonds in a cyclopenta[b]indole framework including a facial selective intramolecular ring closure. The potential of this method is highlighted in the straightforward and single step synthesis of a paullone like compound. This journal is

Full text of DOI:10.1039/c4cc08911a

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Creation of molecular complexities via a new
Cu-catalyzed cascade reaction: a direct access
Cite this:DOI: 10.1039/c4cc08911a
to novel 2,20-spirobiindole derivatives†
Received 7th November 2014,
Accepted 20th November 2014
Bagineni Prasad, Raju Adepu, Atul Kumar Sharma and Manojit Pal*
DOI: 10.1039/c4cc08911a
www.rsc.org/chemcomm
A Cu-mediated unprecedented cascade reaction in the presence of accessibility, and consequently as a class they are rather uncom-
air afforded a conceptually new synthesis of 2,20-spirobiindole mon in the literature. In our efforts towards the identification of
derivatives. This reaction proceeds via the rearrangement of several novel molecules of potential biological significance, we have
bonds in a cyclopenta[b]indole framework including a facial selec- recently reported the synthesis of densely functionalized indoles
tive intramolecular ring closure. The potential of this method is via two unique single-step reactions (Scheme 1).4 In further con-
highlighted in the straightforward and single step synthesis of a tinuation of the research, we now wish to report a Cu-mediated
paullone like compound.
unprecedented cascade reaction leading to an array of
2,20-spirobi[indolin]-3-one based novel and complex derivatives.
Creation of new chemical space is one of the prime goals in both The degree of molecular complexity generated by this intra-
academic and industrial organizations as it helps in expanding molecular cascade reaction in a single-pot is not only remarkable
their IP (intellectual property) portfolio. The chemical trans- but also attractive from the viewpoint of IP generation (Scheme 2).
formations that aid this process are in high demand as these Thus, cyclopenta[b]indoles4b (1) on treatment with CuI in the
reactions generate novel molecules for IP creation and protec- presence of air afforded a range of spirobi[indolin]-3-one deriva-
tion. It is therefore desirable to continue to devote efforts to tives (2), the preliminary results of which are presented.
inventing new synthetic methodologies, which is considered to
be the most challenging task in organic synthesis.
We initiated our study by treating 1a with various catalysts,
bases, and solvents in the presence of air and the results are
Cascade reactions involving multiple bond forming events in a summarized in Table 1. Initially, the reaction was performed
single pot are known to play a central role in constructing using 1a, Cu(OAc)2 (1 equiv.) and Et3N in DMF at 120 1C under
heterocyclic and carbocyclic structures1 along with the introduc-
tion of the desired degree of complexity required by academic and
industrial R & D. Among various cascade reactions2 the catalytic
versions have emerged as the most active area of research
particularly in pursuance of concerns related to chemical hazards,
pollution and sustainability. Spiroindole derivatives have attracted
particular attention in medicinal/pharmaceutical chemistry
because of their numerous pharmacological properties. For
example, the spirooxiindole moiety has been found to be a core
structure in many synthetic pharmaceuticals3a,b and has become
Scheme 1 Our previous synthesis of densely functionalized indoles.4
an attractive template for the creation of new IP. Notably, despite
their potential usefulness, not much attention has been paid to
2,20-spirobi[indoline] derivatives,3c perhaps due to their non
Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli,
Hyderabad 500 046, India. E-mail: manojitpal@rediffmail.com;
Tel: +91 40 6657 1500
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectral data for all new compounds, copies of spectra and HPLC. CCDC
Scheme 2 Cu-mediated intramolecular cascade reaction of 1 leading to
novel 2,20-spirobi[indolin]-3-one derivatives (2).
993261. For ESI and crystallographic data in CIF or other format see DOI: 10.1039/
c4cc08911a
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Table 1 Optimization of reaction conditionsa
2a in 66% yield within 2 h (entry 12 in Table 1). Finally, the role
of the catalyst was also established by performing the reaction in
its absence, whereby no product was formed (entry 13 in
Table 1). Notably, the increase in the reaction time from 2 h to
8 h when performing the reaction in the absence of air under
nitrogen (entry 14, Table 1) indicated the key role of aerial
oxygen in the present reaction. Nevertheless, we preferred the
conditions of entry 12 over entry 8 (Table 1) due to the compar-
able reaction time and yield in addition to the involvement of an
inexpensive catalyst.
With the optimized conditions in hand, we further investigated
the substrate scope of this new cascade reaction. Thus, a variety of
cyclopenta[b]indoles4b (1) were employed in this Cu-mediated
reaction (Table 2). The presence of halogens (F, Cl, Br, entries 3,
4, 6–13, 15 and 16, Table 2), electron donating groups (e.g. Me and
OMe, entries 5, 10 and 1–17, Table 2) and an electron withdrawing
group (NO2, entry 17, Table 2) on the indole ring of 1 was tolerated.
The reaction proceeded well in all these cases affording the desired
product in good to acceptable yields. In general, better yields of 2
were observed when an electron donating group was present. We
also examined the effect of the nature of the sulfonamide moiety
present in 1. Accordingly, cyclopentaindole 1 containing alkyl
(entries 1 and 6, Table 2), aryl (entry 7, Table 2) and heteroaryl
(entries 2–5 and 8–17, Table 2) sulfonamide groups was employed
and the reaction proceeded as usual to afford the corresponding
Entry Catalyst
Solvent/base
Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
1 eq. Cu(OAc)2
DMF–Et3N
DMF–Et3N
DMF–Cs2CO3
DMF–Cs2CO3
DMF–Cs2CO3
DMF
3
3
2
2
3
3
6
25
30
56
60
10c
60
58
70
65
56
50
66
0
1 eq. Cu(OTf)2
1 eq. Cu(OAc)2
1 eq. Cu(OTf)2
1 eq. Cu(OTf)2
1 eq. Cu(OTf)2
20 mol% Cu(OTf)2
20 mol% Cu(OTf)2
DMF
DMF–H2O (7 : 3) 1.5
9
10 mol% Cu(OAc)2ꢀH2O DMF–H2O (7 : 3) 1.5
10
11
12
13
14
5 mol% CuI
5 mol% CuI
10 mol% CuI
No catalyst
DMF–H2O (7 : 3)
DMF–H2O (1 : 1)
DMF–H2O (7 : 3)
DMF–Cs2CO3
4
4
2
6
8
10 mol% CuI
DMF–H2O (7 : 3)
60d
a
All the reactions were performed using 1a (0.1 mmol) and a catalyst in
the presence/absence of a base (1 equiv.) in a solvent (2 mL) at 120 1C
b
c
under air. Isolated yield. 1 equiv. of benzoquinone was added.
d
Reaction was performed under nitrogen.
air and the product 2a was obtained in a 25% yield after 3 h products. We then examined the reaction of compounds 1r–t
(entry 1 in Table 1). Though unexpected, we were delighted to individually with different substitution patterns (Scheme 3).5
observe the formation and isolation of 2a that was character- While 1r and 1s afforded 2r and 2s, respectively, in acceptable
ized as a novel spirobi[indolin]-3-one derivative. Its 3D archi- yield, 1t afforded 2t in low yield.
tecture attracted our attention and prompted us to explore this
new reaction further. The use of a different catalyst Cu(OTf)2
(entry 2 in Table 1) and base Cs2CO3 (entry 3 in Table 1)
afforded 2a in 30% and 56% yields, respectively. The combi-
nation of Cu(OTf)2/Cs2CO3 afforded 2a in 60% yield (entry 4 in
Table 1) whereas the product formation was almost suppressed
in the presence of benzoquinone (entry 5 in Table 1). An
unidentified polar material was obtained as a side product in
this case. Until this, we were not aware of the role of the base in
the present cascade reaction. However, we observed that the
reaction proceeded well in the absence of base when performed
in the presence of Cu(OTf)2 (entry 6 in Table 1). Next, to avoid
the use of a stoichiometric amount of catalyst we wanted to
make this method a truly catalytic one. Accordingly, the reac-
tion was performed using 20 mol% of Cu(OTf)2. To our satis-
faction, the reaction proceeded well to afford the expected
product in a 58% yield (entry 7 in Table 1) though the reaction
time was a bit longer at 6 h. We then examined the use of
aqueous DMF in place of DMF alone. To our surprise the
reaction was completed within 1.5 h affording a better yield
of 2a (entry 8 in Table 1). Indeed, the use of a lower quantity of
Cu(OAc)2ꢀH2O also provided a similar outcome (entry 9, Table 1).
These observations clearly indicate that the reaction is not
moisture sensitive. To make the process more economic without
significantly affecting the product yield, we examined the use of
a cheaper catalyst, i.e. CuI in aqueous DMF (entries 10–12,
Table 1). We found that 10 mol% CuI in 7 : 3 DMF : H2O afforded
Table
2
Synthesis of 2,20-spirobi[indolin]-3-one derivatives (2) from
cyclopentaindoles (1)a
Time Yieldb
Entry Compound (1) R1, R2, R3 Product (2) R1, R2, R3 (h)
(%)
1
2
3
4
5
6
7
8
H, Me, H 1a
H, Me, H 2a
2
66
66
72
59
63
54
65
64
60
66
52
62
64
61
63
57
42
H, 2-Thienyl, H 1b
H, 2-Thienyl, Cl 1c
H, 2-Thienyl, Br 1d
H, 2-Thienyl, Me 1e
F, Me, H 1f
F, C6H4Me-p, H 1g
F, 2-Thienyl, H 1h
F, 2-Thienyl, Br 1i
F, 2-Thienyl, OMe 1j
Cl, 2-Thienyl, Cl 1k
Cl, 2-Thienyl, OMe 1l
Br, 2-Thienyl, OMe 1m
Me, 2-Thienyl, H 1n
Me, 2-Thienyl, Cl 1o
Me, 2-Thienyl, Br 1p
Me, 2-Thienyl, NO2 1q
H, 2-Thienyl, H 2b
H, 2-Thienyl, Cl 2c
H, 2-Thienyl, Br 2d
H, 2-Thienyl, Me 2e
F, Me, H 2f
F, C6H4Me-p, H 2g
F, 2-Thienyl, H 2h
F, 2-Thienyl, Br 2i
F, 2-Thienyl, OMe 2j
Cl, 2-Thienyl, Cl 2k
Cl, 2-Thienyl, OMe 2l 1.5
Br, 2-Thienyl, OMe 2m 1.5
Me, 2-Thienyl, H 2n
Me, 2-Thienyl, Cl 2o
Me, 2-Thienyl, Br 2p
Me, 2-Thienyl, NO2 2q
1.5
1.5
2
2
1.5
2
1.5
2
1.5
2
9
10
11
12
13
14
15
16
17
2
1.5
2
4
a
All the reactions were performed using 1 (0.1 mmol), 10 mol% of CuI
in DMF : H2O (7 : 3) (1.5 mL) at 120 1C for 1.5–4 h in the presence of air.
b
Isolated yield.
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Scheme 3 Cu-mediated intramolecular cascade reaction of 1r–t.
Fig. 2 ORTEP representation of 2j. Thermal ellipsoids are drawn at 50%
probability level.
All the synthesized compounds were well characterized by
spectral (NMR, IR and MS) data. For example, the IR (1718 cmꢁ1
)
and 13C NMR [dC 197.2 (Cf)] spectra of 2b indicated the presence
of a –CQO group. Its 1H NMR signals in the aliphatic region at
1
d 3.90 (d, 1Ha), 3.55 (dd, 1Hb1), 2.88 (td, 1Hb), 2.08–2.00 (m, 1Hc )
and 1.93 (dd, 1Hc) clearly identified the respective protons
whereas the 13C NMR signals at dc 50.2 (Cc), 49.7 (Ca), 32.6 (Cb)
and 95.9 (Cg) identified three aliphatic and one sp3 quaternary
carbon, respectively. The 1H–1H COSY spectra of 2b indicated
that (i) Ha coupled with Hb and Hb1, (ii) Hb coupled with Hb1, Hc,
1
1
1
Hc and Ha, (iii) Hb coupled with Hb, Hc, Hc and Ha, (iv) Hc
coupled with Hb1, Hb and Hc1, and (v) Hc1 coupled with Hb1, Hb
and Hc. The H–13C HMQC spectra revealed that (i) Ca coupled
1
with Ha, (ii) Cb coupled with Hb and Hb1 and (iii) Cc coupled with
1
Hc and Hc . The DEPT spectrum of 2b showed the presence of 7
quaternary, 2 CH2 and 12 CH carbons. Moreover, the proposed
arrangement was confirmed by HMBC correlations (Fig. 1).
Finally, the molecular structure of a representative compound
2j was confirmed unambiguously by single crystal X-ray diffrac-
tion study (Fig. 2).6
Scheme 4 The proposed reaction mechanism.
A proposed reaction mechanism involving the reaction of 1
with aerial oxygen in the presence of CuI in the first step
leading to the intermediate E-1 is shown in Scheme 4.7 An
intramolecular ring closure aided by HI involving the –CQN–
moiety and the proximate amidic nitrogen of E-1 affords E-2.
The subsequent ring opening of the fused cyclopentane ring of
E-2 followed by the cleavage of the peroxide bond furnishes the
spiro intermediate E-3. This step is facilitated by the participa-
tion of the fused indoline moiety of E-2, which after being a
charged species in E-3 undergoes subsequent aromatization to
give E-4. The regeneration of CuI8a from E-4 completes the
catalytic cycle and affords E-5. A further intramolecular ring
closure8b,c of E-5 aided by HI furnished the desired product 2.8d
This ring closure and thereby the product yield can be influ-
enced by the nature of R3 i.e. electron donating or withdrawing
group (see Table 2). A similar pathway can be presented with
Cu(II)X2 (X = OAc, OTf etc.) catalysts by replacing the –OCu
moiety with –OCuX. It is evident that the presence of a base
added externally is not necessary in this pathway. However, the
catalyst is required to facilitate the initial step and thereby the
entire process. It appears that benzoquinone can perhaps
compete with oxygen in the first step affording an adduct
similar to E-1 thereby decreasing the yield of the desired
product (entry 5, Table 1). While the precise reason for the
faster reaction observed in aqueous DMF in comparison to
DMF alone (entry 7 vs. 8 and 12, Table 1) was not clearly
understood, the ability to absorb and retain a higher volume
of oxygen by aqueous DMF was perhaps enhanced to a great
extent due to the presence of water. However, the presence of a
larger volume of water did not improve the reaction time or
yield (entry 10 vs. 11, Table 1) due to the lesser solubility of 1 in
1 : 1 aqueous DMF.
Because each cyclopentaindole (1, Table 2) is a B1 : 1
mixture of enantiomers (confirmed by chiral HPLC of 1c), it
Fig. 1 Compound 2b and its HMBC correlations.
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Weinheim, Germany, 2006; (b) T. J. J. Muller, Metal Catalyzed
Cascade Reactions, Springer, New York, 2006. For an in depth
account, see: (c) L. Q. Lu, J. R. Chen and W. J. Xiao, Acc. Chem.
Res., 2012, 45, 1278.
2 (a) For a recent book, see: P.-F. Xu and W. Wang, Catalytic
Cascade Reactions, John Wiley & Sons, Inc., Hoboken, New Jersey,
2014; (b) R. A. Bunce, Tetrahedron, 1995, 48, 13103; (c) L. F.
Tietze and U. Belifuss, Angew. Chem., Int. Ed., 1993, 32, 131;
(d) M. Ihara and K. Fukumoto, Angew. Chem., Int. Ed., 1993,
32, 1010; (e) C. P. Jasperse, D. P. Curran and T. L. Fevig, Chem.
Rev., 1991, 91, 1237.
´
3 (a) B. Tan, G. Hernandez-Torres and C. F. Barbas, III, J. Am. Chem.
Soc., 2011, 133, 12354; (b) A. Bazgir, Z. Noroozi Tisseh and P. Mirzaei,
Tetrahedron Lett., 2008, 49, 5165; (c) for a recent synthesis of similar
class of compounds, see: W. Ding, Q.-Q. Zhou, J. Xuan, T.-R. Li, L.-Q.
Lu and W.-J. Xiao, Tetrahedron Lett., 2014, 55, 4648.
Scheme 5 One-step synthesis of paullone like compound 3.
4 (a) B. Prasad, B. Y. Sreenivas, D. Rambabu, G. R. Krishna, C. M. Reddy,
K. L. Kumar and M. Pal, Chem. Commun., 2013, 49, 3970; (b) B. Prasad,
B. Y. Sreenivas, G. R. Krishna, R. Kapavarapu and M. Pal, Chem. Commun.,
2013, 49, 6716.
5 We thank reviewers for suggesting these experiments.
6 Crystal data of 2j: molecular formula = C22H17FN2O4S2, formula
weight = 456.50, crystal system = monoclinic, space group = P2(1)/c,
a = 9.0012 (2) Å, b = 11.6897 (3) Å, c = 19.0204 (5) Å, V = 1999.06 (9) Å3,
T = 296 K, Z = 4, Dx = 1.517 Mg mꢁ3, m(Mo-Ka) = 0.31 mmꢁ1, 14591
reflections measured, 3409 independent reflections, 2957 observed
reflections [I 4 2.0s(I)], Rint = 0.027, Goodness of fit = 1.05. CCDC
993261.
7 For the generation of a E-1 type intermediate from the fused indole
derivatives, see: (a) R. W. Clawson Jr., R. E. Deavers III, N. G.
Akhmedov and B. C. G. Soderberg, Tetrahedron, 2006, 62, 10829;
(b) the possibility of a Wagner-Meerwein type rearrangement of E-1
leading to the corresponding spiro derivative (cf. B. Witkop and
B. Patrick, J. Am. Chem. Soc., 1951, 73, 2188) was unlikely as that
would generate an unfavourable and strained 4-membered ring.
8 (a) For similar reactions of Cu(I)alkoxides with alkyliodides, see:
G. M. Whitesides, J. S. Sadowski and J. Lilburn, J. Am. Chem. Soc.,
1974, 96, 2829; (b) for a similar type of intramolecular cyclization
under Rh-catalyzed dehydrogenative conditions, see: P. Patel,
B. N. Reddy and C. V. Ramana, Tetrahedron, 2014, 70, 510; (c) to
understand and visualize physically the three-dimensional position
of atoms in E-5 during its intramolecular ring closure a ball-and-
stick model was used. The model clearly shows (see ESI† for images)
that the orientation of ethanol side chain of E-5 is flexible and can
bring the –CH2OH group in a close proximity to the –NH– moiety
thereby facilitating the ring closure; (d) though our attempt to
isolate any of these intermediates in pure form was not successful,
however, systematic MS analysis of reaction sample after 1, 2 and
3 h indicated the presence of unprotonated E-5. For example, the
peak at 441 (in addition to 423 of product 2s) in the MS spectra of
the reaction sample of 1s after 1 h accounted for M + 1 signal of the
corresponding E-5 which was decreased as the reaction progressed
further.
afforded 2 also as a 1 : 1 mixture of enantiomers9 (not 2 pairs,
confirmed by chiral HPLC of 2c); the present reaction appears
to be a facial selective one, i.e. separate re and si face attack
occurred during the intramolecular ring closure of the indivi-
dual enantiomers of E-1 (Scheme 4).
To demonstrate the potential of this method, compound 2a was
converted to 3 possessing a paullone10 like structural framework in
a single step (Scheme 5). Thus, 2a when treated with methanolic
KOH participated in a sequential demesylation followed by ring
opening and subsequent aromatization to afford 3. The presence of
two NH groups and a –CH2CH2– moiety in 3 was confirmed by the
appearance of two D2O exchangeable signals at d 9.42 (bs, 1H) and
3.85 (bs, 1H) along with two triplets at d 3.36 (t, J = 6.0 Hz, 2H) and
2.86 (t, J = 6.0 Hz, 2H) in the 1H NMR spectra. Moreover, the 13
C
NMR including DEPT experiments showed the presence of 7
quaternary carbons along with 8 CH and 2 aliphatic CH2 groups
that confirmed the structure of 3.
In conclusion, we have described a Cu-mediated unprece-
dented cascade reaction of cyclopenta[b]indoles in the presence
of air to furnish an array of 2,20-spirobi[indolin]-3-one based novel
and complex molecules useful for academic and industrial R & D.
This operationally simple, straightforward and inexpensive yet
innovative method involves the rearrangement of several bonds
including a facial selective intramolecular ring closure in which
Cu plays a key role. One-step and direct synthesis of a paullone
like compound highlighted the potential of this method. The
present research results could be a new and useful addition to
indole chemistry as well as cascade reactions.
9 HPLC of the crude product indicated the presence of a single
diasteromer along with some minor impurities. For example,
HPLC of crude 2a showed a major peak at 14 min [460%;
diluent, MeCN : H2O (80 : 20)] with no other significant peak within
ꢂ2 min.
BP and RA thank CSIR, New Delhi, India for research fellow-
ships. Authors thank the management of DRILS for support.
10 Paullones belong to a family of benzazepinones and are known to
possess promising antitumoral along with cyclin-dependent kinases
(CDKs) inhibitory properties, see: C. Schultz, A. Link, M. Leost,
D. W. Zaharevitz, R. Gussio, E. A. Sausville, L. Meijer and C. Kunick,
J. Med. Chem., 1999, 42, 2909.
Notes and references
1 For excellent books, see: (a) L. F. Tietze, G. Brasche and
K. M. Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH,
Chem. Commun.
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