Phase-transfer-catalysed synthesis of pyrroloindolines and pyridoindolines by a hydrogen-bond-assisted isocyanide cyclization cascade

Article abstract of DOI:10.1002/chem.201400192

A cascade reaction that generates pyrrolo- and pyridoindoline motifs from isocyanide precursors under phase-transfer conditions is described. This transformation proceeds at room temperature in the presence of a quaternary ammonium catalyst and base to generate functionalized products containing an all-carbon quaternary stereocentre. Quantum chemical calculations demonstrated that intramolecular general acid catalysis plays a key accelerating role through stabilization of developing charge in the transition state, and that the reaction is best described as a 5-endo dig cyclization, rather than an anionic 6π electrocyclization. Investigations employing chiral phase-transfer catalysts have given promising selectivities to date. Generating complexity: A cascade reaction that generates pyrrolo- and pyridoindoline motifs from isocyanide precursors under phase-transfer conditions is described. Quantum chemical calculations demonstrated that intramolecular general-acid catalysis plays a key accelerating role through stabilization of developing charge in the transition state, and that the reaction is best described as a 5-endo-dig cyclization, rather than an anionic 6π electrocyclization (see scheme).

Full text of DOI:10.1002/chem.201400192

DOI: 10.1002/chem.201400192
Communication
&
Cascade Reactions
Phase-Transfer-Catalysed Synthesis of Pyrroloindolines and
Pyridoindolines by a Hydrogen-Bond-Assisted Isocyanide
Cyclization Cascade
[a]
ˇ
Peter C. Knipe, Matija Gredicak, Artiom Cernijenko, Robert S. Paton,* and Martin D. Smith*
Abstract: A cascade reaction that generates pyrrolo- and
pyridoindoline motifs from isocyanide precursors under
phase-transfer conditions is described. This transformation
proceeds at room temperature in the presence of a quater-
nary ammonium catalyst and base to generate functional-
ized products containing an all-carbon quaternary stereo-
centre. Quantum chemical calculations demonstrated that
intramolecular general acid catalysis plays a key accelerat-
ing role through stabilization of developing charge in the
transition state, and that the reaction is best described as
a 5-endo dig cyclization, rather than an anionic 6p electro-
cyclization. Investigations employing chiral phase-transfer
catalysts have given promising selectivities to date.
Pyrrolo- and pyridoindoline motifs are core components of
a number of structurally complex natural product families pos-
sessing potent biological properties.[1,2] For example, (À)-phys-
ostigmine, one of the simplest naturally occurring pyrroloindo-
lines, is a clinically approved acetylcholinesterase inhibitor em-
ployed in the treatment of glaucoma, myasthenia gravis and
Alzheimer’s disease,[3] whereas (À)-communesin A exhibits
potent cytotoxicity towards P-388 murine lymphocytic leukae-
Figure 1. Representative pyrrolo- and pyridoindolines, common strategic dis-
mia cells (Figure 1).[4] The polypyrroloindoline family of alka-
loids, of which (À)-hodgkinsine B is an exemplar, have been
shown to possess antibacterial, antifungal, antiviral and analge-
sic properties (Figure 1).[5] Consequently, the synthesis of these
structural motifs and the natural products that contain them
has been the subject of much elegant and effective re-
search.[6–9] The majority of pyrroloindoline syntheses rely on
two strategic disconnections: electrophilic attack at C-3 of an
appropriately substituted tryptamine derivative, followed by in-
tramolecular trapping of the resulting iminium ion; and alkyla-
tion of oxindoles with subsequent manipulation.[7] Although
these methods are extremely robust, as was demonstrated by
their use in numerous total syntheses, there are some limita-
connections and strategy for isocyanide cyclization cascade.
tions to their scope. Both routes require electrophilic reagents
for the introduction of substitution at the indole C-3 position,
and employ substrates generally derived from tryptamine,
tryptophan or oxindole, leading to limited substitution pat-
terns in the pyrroloindolines obtained.
As part of our on-going studies into the synthesis of substi-
tuted and polycyclic indolines,[10] isocyanides were identified as
a versatile functional group with the potential to act as a focal
point in the synthesis of pyrrolo- and pyridoindolines (Fig-
ure 1).ortho-Isocyanophenylacetonitriles have been demon-
strated to undergo enantioselective 5-endo-dig cyclization to
afford the corresponding indolenines under basic phase-trans-
fer-catalysed conditions,[11] and we envisaged extending this
methodology by introducing an intramolecular nucleophile to
trap the resulting indolenine,[12] leading to the formation of
pyrrolo- or pyridoindolines in a single operation. Nucleophilic
additions to isocyanide groups generally require activation
with a Brønsted or Lewis acid or an electrophile, and hence we
ˇ
[a] Dr. P. C. Knipe, Dr. M. Gredicak, A. Cernijenko, Dr. R. S. Paton,
Dr. M. D. Smith
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: robert.paton@chem.ox.ac.uk
martin.smith@chem.ox.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400192.
Chem. Eur. J. 2014, 20, 3005 – 3009
3005
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
reasoned that
a cyclization cascade could be mediated
Table 2. Substrate scope.
through an intramolecular hydrogen bond from a pendant
amide or carbamate.[13] Such a process would constitute a new
strategic approach to these privileged structural motifs, provid-
ing a new disconnection for total synthesis and the prepara-
tion of medicinally relevant structural analogues.
Isocyanide 1 (prepared in five steps from 2-nitrophenylace-
tonitrile)[14] was subjected to a variety of basic phase-transfer-
catalysed conditions to determine the viability of the reaction
(Table 1). Of the four quaternary ammonium salts investigated,
tetra-n-butylammonium chloride (TBAC) was the most effective
Table 1. Optimization of phase-transfer-catalysed synthesis of pyrroloin-
dolines.
Entry
Catalyst[a]
Base
t
Yield [%][b]
À
1
2
3
4
5
6
7
8
9
Bu4N+HSO4
50% KOH (aq.)
50% KOH (aq.)
50% KOH (aq.)
50% KOH (aq.)
KOH (s)
30 min
30 min
30 min
30 min
30 min
72 h
30 min
168 h
4 h
64
40
76
72
63
44
75
38
74
62
Me3(C16H33)N+BrÀ
Bu4N+ClÀ
Et4N+IÀ
Bu4N+ClÀ
Bu4N+ClÀ
K2CO3 (s)
Bu4N+ClÀ
50% NaOH (aq.)
50% KOH (aq.)
50% KOH (aq.)
50% KOH (aq.)
–
Bu4N+ClÀ (5 mol%)
Bu4N+ClÀ (2 mol%)
10
48 h
[a] Unless otherwise indicated, catalyst loading was 10 mol%. [b] Isolated
yield.
when 50% aqueous potassium hydroxide was employed
(Table 1, entry 3), giving the product in 76% yield after 30 min.
The use of other bases or of powdered solid potassium hy-
droxide led to diminished yields, and removal of the phase-
transfer-catalyst entirely slowed the reaction significantly, lead-
ing to low conversions, even after extended reaction times
(Table 1, entries 5–8). Lowering the catalyst loading also in-
creased reaction times and decreased yields (Table 1, entries 9–
10). Therefore, the optimized procedure employed 10 mol%
TBAC and 50% aqueous potassium hydroxide in toluene,
giving the desired pyrroloindoline 2 in 76% yield after 30 min
at room temperature.
[a] Reactions were carried out on 0.1–0.2 mmol scale. [b] Isolated yields;
when applicable, these refer to the racemic reaction. [c] Asymmetric reac-
tion carried out on a 10 mg scale; yields were not determined. [d] Calcu-
lated from aniline precursor.[17]
With optimized reaction conditions in hand, we turned our
attention to investigate substrate scope and reaction limita-
tions (Table 2). The transformation maintained its effectiveness
upon changing the methyl carbamate group 2 to a benzamide
3 and was tolerant of both benzylic nitriles and esters (4 and
5). Introduction of different substituents on the aromatic ring
in the preparation of substrates 6–19 required slight changes
in the synthetic route.[14] Electron-withdrawing and -donating
substituents both in para- and meta- positions (with respect to
the aliphatic chain) had little or no influence on product yield
or reaction course. The pyrroloindoline synthesis was also suc-
cessful when ortho and meta-disubstituted isocyanides were
employed (17 and 18), and both benzyl carbamate and acet-
amide groups gave good reactivity (e.g., 19 and 16). Products
were generated exclusively as the cis-fused diastereoisomer, in
agreement with X-ray crystallographic analysis of 17 and con-
sistent with the much higher ring strain in the trans-isomer.[15]
In addition to the pyrroloindolines, pyridoindolines 20 and
21 were formed in high yields, demonstrating a tolerance of
both carbamate and amide substituents. Similar to the pyrro-
loindolines, X-ray crystallographic analysis (of 20) confirmed
that products were generated as a cis-fused diastereoisomer.[15]
Chem. Eur. J. 2014, 20, 3005 – 3009
www.chemeurj.org
3006
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Preliminary investigations into asymmetric phase-transfer catal-
ysis of this reaction have yielded promising enantiomeric ratios
of up to 76:24 (e.r.), in which cinchona-derived catalyst N-
(2,3,4-trifluorobenzyl)cinchoninium bromide was employed
(Table 2, compounds 2, 8, 15 and 21).[16]
the isocyanide, or in which the amide is rotated away and this
interaction is entirely absent: both possibilities were modelled,
locating a transition structure (TS) in each case (24 and 32, re-
spectively). Unequivocally, this NÀH···C interaction, with an HÀ
C separation of 2.21 ꢁ, was computed to provide stability in
the TS (by 6.5 kcalmolÀ1) leading to a kinetic acceleration of
ring closure. The origin of this kinetic effect is tied with prod-
uct stabilization by the Hammond postulate (Figure 3).
Based on the premise that the pendant amide or carbamate
proton is a key activating component of the reaction, we pro-
pose
a plausible mechanism for these transformations
(Figure 2). We reasoned that deprotonation at the benzylic po-
sition of 22 (necessarily acidified by the adjacent nitrile) would
lead to stabilized cyanocarbanion species 23, which could un-
Figure 3. Reaction free-energy profile for hydrogen-bonded and non-hydro-
gen-bonded cyclization manifolds. Energies (in italics) are quoted in kcal
molÀ1 (B2GP-PLYP/6-311+ +G(d,p)//CPCM-wB97XD/6-311+ +G(d,p) Grel at
298 K). Transition structures 24 and 33 are depicted.
The strength of the stabilizing NÀH···C hydrogen bond in 24
was determined to be 10.6 kcalmolÀ1,[22] a value comparable in
magnitude to NÀH···O hydrogen-bonding interactions found in
biological systems.[23] Therefore, the rapid carbocyclization ob-
served is a direct consequence of intramolecular hydrogen-
bonding catalysis; as a result, the reaction rate would be ex-
pected to increase in the presence of a kinetically more labile
proton donor. Indolenine carbanion 25 lies uphill (i.e., ender-
gonic) from 23 by 5.4 kcalmolÀ1, with subsequent exergonic ir-
reversible N to C proton transfer occurring readily via a TS (33)
only 4.8 kcalmolÀ1 above this intermediate to afford aza-anion
26. The relative ease computed for this second step corrobo-
rated the experimental observation of significant deuterium in-
Figure 2. a) Mechanistic proposal for synthesis of pyrrolo- and pyridoindo-
lines; b) experimental investigations into the role of the Brønsted acidic NÀH
†
proton. Values are an average over four runs.
dergo 5-endo-dig cyclization as a consequence of an intramo-
lecular hydrogen bond to the isocyanide, to give a transient
sp2 anion 25.[18] This anion could be quenched in an intramo-
lecular proton transfer, and the resulting aza-anion 26 could
attack the intermediate indolenine, generating the observed
pyrrolo- and pyridoindolines 27 after re-protonation. To investi-
gate the importance of the hydrogen-bond activation of the
isocyanide provided by the NÀH, we prepared isocyanide
N-methyl derivative 28 (which cannot function as a Brønsted
acid); after 24 h under the optimized cyclization conditions,
this substrate failed to generate the corresponding indolenine
29, with primarily starting material recovered.[19] Cyclization of
2H-labelled 30 under phase-transfer conditions led to 31, with
2
corporation at this position when an NÀ H-labelled substrate
was used. Closure of the second ring to form the cis-fused bi-
cycle 27 was computed to occur without an energetic barrier.
The key carbocyclization step may be classified as an anionic
5-endo-dig ring closure, but we were intrigued to establish
whether this reaction exhibits the characteristics of a pericyclic
(or pseudopericyclic) 6p electrocyclization.[24] The nuclear inde-
pendent chemical shift NICS(0) values were calculated at the
centre of the forming five-membered ring and of the fused ar-
omatic ring along the intrinsic reaction coordinate (IRC).[25]
Rather than using isotropic values, which are contaminated by
magnetic effects not related to aromaticity,[26] we focused on
the out-of-plane zz tensor component (Figure 4). For the cycli-
zation of isocyanide 22 the NICS(0)zz tensor of the forming
five-membered ring increases from À8.2 to 0.0 ppm along the
2
17% H incorporation observed (average of four experiments).
2
We attribute this to partial 2H/1H exchange (of the NÀ H)
under aqueous conditions, followed by cyclization by the
mechanism depicted.[20]
To probe the effect of the putative intramolecular hydrogen
bond on cyclization, the reaction free-energy profile of 22 was
studied. The carbocyclization step of 22 may occur through
a pathway, in which the amide NÀH proton is coordinated to
Chem. Eur. J. 2014, 20, 3005 – 3009
www.chemeurj.org
3007
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
gramme (FP7/2007-2013)/ERC grant agreement no. 259056. We
are grateful to the Croatian Science Foundation (to M.G., grant
no. 02.03./158), and to Dr. Barbara Odell and Dr. Russell Driver
for assistance with variable-temperature NMR spectroscopy
and X-ray crystallography analyses, respectively.
Keywords: density functional calculations · cascade reactions ·
heterocycles · hydrogen bonds · isocyanides · phase-transfer
catalysis
[1] For reviews of pyrroloindolines, see: a) M. Ishikura, K. Yamada, T. Abe,
Nat. Prod. Rep. 2010, 27, 1630; b) D. Crich, A. Banerjee, Acc. Chem. Res.
2007, 40, 151; c) A. Steven, L. E. Overman, Angew. Chem. 2007, 119,
5584; Angew. Chem. Int. Ed. 2007, 46, 5488; d) P. Ruiz-Sanchis, S. A.
Savina, F. Albericio, M. ꢂlvarez, Chem. Eur. J. 2011, 17, 1388; e) J. Kim, M.
Movassaghi, Chem. Soc. Rev. 2009, 38, 3035; f) D. Zhang, H. Song, Y. Qin,
Acc. Chem. Res. 2011, 44, 447.
[2] For reviews of pyridoindolines, see Ref. [1a] and: a) P. Siengalewicz, T.
Gaich, J. Mulzer, Angew. Chem. 2008, 120, 8290; Angew. Chem. Int. Ed.
2008, 47, 8170; b) Z. Zuo, D. Ma, Isr. J. Chem. 2011, 51, 434; c) J. D. Rain-
ier, V. R. Espejo, Isr. J. Chem. 2011, 51, 473; d) Z. Jin, Nat. Prod. Rep.
2011, 28, 1143; e) U. Anthoni, C. Christophersen, P. H. Nielsen in Alka-
loids: Chemical & Biological Perspectives, Vol. 2 (Ed.: S. W. Pelletier), Per-
gamon, Oxford, 1999, pp. 163–236.
[3] a) B. G. Katzung, S. B. Masters A. J. Trevor, Basic and Clinical Pharmacolo-
gy, 11th ed., McGraw Hill, 2009; b) B. Witkop, Heterocycles 1998, 49, 9.
[4] A. Numata, C. Takahashi, Y. Ito, T. Takada, K. Kawai, Y. Usami, E. Matsu-
mura, M. Imachi, T. Ito, T. Hasegawa, Tetrahedron Lett. 1993, 34, 2355.
[5] a) A. Roth, B. Kuballa, P. Cabalion, R. Anton, Planta Med. 1985, 51, 289;
b) Y. Adjibadꢃ, H. Saad, B. Kuballa, J. P. Beck, T. Sꢃvenet, P. Cabalion, R.
Anton, J. Ethnopharmacol. 1990, 29, 127; c) H. E. A. Saad, S. H. El-Sharka-
wy, W. T. Shier, Planta Med. 1995, 61, 313; d) T. A. Amador, L. Verotta,
D. S. Nunes, E. Elisabetsky, Planta Med. 2000, 66, 770.
[6] For examples of total syntheses of pyrroloindolines, see: a) N. Boyer, M.
Movassaghi, Chem. Sci. 2012, 3, 1798; b) W. Zi, W. Xie, D. Ma, J. Am.
Chem. Soc. 2012, 134, 9126; c) H. Mitsunuma, M. Shibasaki, M. Kanai, S.
Matsunaga, Angew. Chem. 2012, 124, 5307; Angew. Chem. Int. Ed. 2012,
51, 5217; d) S. Y. Jabri, L. E. Overman, J. Am. Chem. Soc. 2013, 135, 4231.
[7] For exemplar recent methods of pyrroloindoline synthesis, see: electro-
philic attack at C3 of tryptamines: a) Z. Zhang, J. C. Antilla, Angew. Chem.
2012, 124, 11948; Angew. Chem. Int. Ed. 2012, 51, 11778; b) Y. Liu, H. Du,
Org. Lett. 2013, 15, 740; c) S. Zhu, D. W. C. MacMillan, J. Am. Chem. Soc.
2012, 134, 10815; d) T. Benkovics, I. A. Guzei, T. P. Yoon, Angew. Chem.
2010, 122, 9339; Angew. Chem. Int. Ed. 2010, 49, 9153; e) B. M. Trost, J.
Quancard, J. Am. Chem. Soc. 2006, 128, 6314; from oxindoles: f) R. He, C.
Ding, K. Maruoka, Angew. Chem. 2009, 121, 4629; Angew. Chem. Int. Ed.
2009, 48, 4559; g) T. Bui, S. Syed, C. F. Barbas III, J. Am. Chem. Soc. 2009,
131, 8758; h) C. Guo, J. Song, J.-Z. Huang, P.-H. Chen, S.-W. Luo, L.-Z.
Gong, Angew. Chem. 2012, 124, 1070; Angew. Chem. Int. Ed. 2012, 51,
1046; i) S. Ma, X. Han, S. Krishnan, S. C. Virgil, B. M. Stoltz, Angew. Chem.
2009, 121, 8181; Angew. Chem. Int. Ed. 2009, 48, 8037.
Figure 4. GIAO-B3LYP/6-311+ +G(d,p)//wB97XD/6-311+ +G(d,p) NICS(0)ZZ
values for the ring closure in TS 24 and a reference electrocyclization.
B3LYP/STO-3G HOMOs in each TS shown below.
IRC. In marked contrast, the same shielding tensor for the all-
carbon cyclization decreases from À12.2 to À20.4 ppm in the
TS, rising again to À15.0 ppm when the ring is formed. For ref-
erence, the NICS(0)zz value of benzene is À14.5 ppm at the
same level of theory. On this evidence, TS 24 does not display
the characteristic aromaticity of an electrocyclic ring closure.
This verdict was further supported by inspection of the HOMO;
in compound 24, this orbital is formed from the delocalized ni-
trile a-anion attacking the in-plane CN p*, whereas in the refer-
ence electrocyclic TS the HOMO is delocalized over both rings.
Quantum chemical analysis has also ruled out the involvement
of “in-plane aromaticity”, as was described by Alabugin,[27] and
of a pseudopericyclic orbital interaction as defined by Lemal
and expounded by Birney and others.[28–30] Therefore, it is most
appropriate to describe the cyclization as an intramolecular hy-
drogen-bond-catalysed anionic 5-endo dig reaction.
A new cascade approach to the synthesis of pyrrolo- and
pyridoindolines has been developed, employing isocyanides as
a key focal point for the construction of the core bicyclic
framework under phase-transfer catalysis. Preliminary investi-
gations demonstrated that cinchona-derived ammonium salts
can direct the topicity of the reaction with promising levels of
enantioselectivity. Intramolecular hydrogen bonding was dem-
onstrated to have a profound stabilizing effect on the transi-
tion state of the cyclization, indicating that chiral hydrogen-
bond donors may serve as viable asymmetric catalysts for the
deployment of isocyanides in complexity-generating reactions.
We anticipate that the utility of isocyanides as a central com-
ponent in the construction of complex heterocycles under
both phase-transfer and hydrogen-bonding catalysis will be
further explored.
[8] For examples of recent total syntheses of pyridoindolines, see
Refs. [2a,c] and: a) Z. Zuo, D. Ma, Angew. Chem. 2011, 123, 12214;
Angew. Chem. Int. Ed. 2011, 50, 12008; b) T. Newhouse, C. A. Lewis, P. S.
Baran, J. Am. Chem. Soc. 2009, 131, 6360; c) M. Movassaghi, M. A.
Schmidt, Angew. Chem. 2007, 119, 3799; Angew. Chem. Int. Ed. 2007, 46,
3725.
[9] For exemplar recent methods for pyridoindoline synthesis, see Re-
fs. [7c,e,h] and: a) A. W. Schammel, G. Chiou, N. K. Garg, Org. Lett. 2012,
14, 4556; b) F. J. Robertson, B. D. Kenimer, J. Wu, Tetrahedron 2011, 67,
4327; c) J. Yang, H. Song, X. Xiao, J. Wang, Y. Qin, Org. Lett. 2006, 8,
2187.
[10] a) E. E. Maciver, S. Thompson, M. D. Smith, Angew. Chem. 2009, 121,
10164; Angew. Chem. Int. Ed. 2009, 48, 9979; b) E. E. Maciver, P. C. Knipe,
A. P. Cridland, A. L. Thompson, M. D. Smith, Chem. Sci. 2012, 3, 537.
[11] M. Li, P. A. Woods, M. D. Smith, Chem. Sci. 2013, 4, 2907.
[12] C. C. J. Loh, D. Enders, Angew. Chem. 2012, 124, 46; Angew. Chem. Int.
Ed. 2012, 51, 46.
Acknowledgements
The European Research Council has provided financial support
under the European Community’s Seventh Framework Pro-
Chem. Eur. J. 2014, 20, 3005 – 3009
www.chemeurj.org
3008
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[13] a) X. Li, S. J. Danishefsky, J. Am. Chem. Soc. 2008, 130, 5446; b) G. O.
Jones, X. Li, A. E. Hayden, K. N. Houk, S. J. Danishefsky, Org. Lett. 2008,
10, 4093; c) A. Dçmling, I. Ugi, Angew. Chem. 2000, 112, 3300; Angew.
Chem. Int. Ed. 2000, 39, 3168.
[14] See the Supporting Information for full experimental details.
[15] CCDC-946432 (17) and CCDC-946433 (20) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg,
S. Dapprich, A. D. Daniels, ꢄ. Farkas, J. B. Foresman, J. V. Ortiz, J. Cio-
slowski, D. J. Fox, Gaussian, Inc., Wallingford CT, 2009. For a full descrip-
tion of computational methods see the Supporting Information.
[22] Obtained by second-order perturbation theory of the basis set of natu-
ral bonding orbitals (NBOs): E. D. Klendening, A. E. Reed, J. E. Carpenter,
F. Weinhold, NBO Version 6.0.
[16] S. Shirakawa, K. Maruoka, Angew. Chem. 2013, 125, 4408; Angew. Chem.
Int. Ed. 2013, 52, 4312.
[17] Due to instability, the corresponding isocyanides were used in cycliza-
tion reactions without prior isolation. Consequently, yields for 10 and
17 are quoted from their respective amines.
[23] R. S. Paton, J. M. Goodman, J. Chem. Inf. Model. 2009, 49, 944.
[24] R. B. Woodward, R. Hoffmann, J. Am. Chem. Soc. 1965, 87, 395.
[25] a) M. Bꢅhl, C. V. Wullen, Chem. Phys. Lett. 1995, 247, 63; b) P. v. R. Schley-
er, C. Maerker, A. Dransfeld, H. Jiao, N. J. R. v. E. Hommes, J. Am. Chem.
Soc. 1996, 118, 6317.
[18] Related mechanisms have been proposed in the synthesis of indoles
and pyrroloindoles: a) Y. Ito, K. Kobayashi, T. Saegusa, J. Org. Chem.
1978, 43, 1011; b) E. T. Pelkey, L. Chang, G. W. Gribble, Chem. Commun.
1996, 1909.
[19] Starting material (28, 49%) was recovered and a product of isocyanide
hydrolysis and oxidation was isolated (17%); see the Supporting Infor-
mation.
[20] The value is an average over four experiments and is too high to be
due to statistical incorporation of 2H by intermolecular protonation
from 2HÀOH generated in situ. For full details, refer to the Supporting
Information.
[21] Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Men-
nucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro,
M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Ko-
bayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyen-
gar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B.
[26] a) C. Corminboeuf, T. Heine, G. Seifert, P. v. R. Schleyer, J. Weber, Phys.
Chem. Chem. Phys. 2004, 6, 273; b) H. Fallah-Bagher-Shaidaei, C. S. Wan-
nere, C. Corminboeuf, R. Puchta, P. v. R. Schleyer, Org. Lett. 2006, 8, 863.
[27] K. Gilmore, M. Manoharan, J. I.-C. Wu, P. v. R. Schleyer, I. V. Alabugin, J.
Am. Chem. Soc. 2012, 134, 10584.
[28] a) S. Ham, D. M. Birney, Tetrahedron Lett. 1994, 35, 8113; b) D. M. Birney,
P. E. Wagenseller, J. Am. Chem. Soc. 1994, 116, 6262; c) D. M. Birney, J.
Org. Chem. 1994, 59, 2557; d) P. E. Wagenseller, D. M. Birney, D. Roy, J.
Org. Chem. 1995, 60, 2853.
[29] a) M. T. Nguyen, T. K. Ha, R. A. More, O’Ferrall, J. Org. Chem. 1990, 55,
3251; b) A. D. Allen, M. A. McAllister, T. T. Tidwell, Tetrahedron Lett. 1993,
34, 1095; c) M. W. Wong, C. Wentrup, J. Org. Chem. 1994, 59, 5279;
d) R. S. Paton, S. E. Steinhardt, C. D. Vanderwal, K. N. Houk, J. Am. Chem.
Soc. 2011, 133, 3895.
[30] J. A. Ross, R. P. Seiders, D. M. Lemal, J. Am. Chem. Soc. 1976, 98, 4325.
Received: January 17, 2014
Published online on February 12, 2014
Chem. Eur. J. 2014, 20, 3005 – 3009
www.chemeurj.org
3009
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim