An interrupted Ugi reaction enables the preparation of substituted indoxyls and aminoindoles

Article abstract of DOI:10.1016/j.tet.2008.08.055

In a variation of the classical Ugi reaction, an acid-promoted reaction between imines and isocyanides forms both 3-aminoindoles and substituted indoxyls. A recently reported triflyl phosphoramide is shown to be critical to obtain high yields under mild c

Full text of DOI:10.1016/j.tet.2008.08.055

Tetrahedron 65 (2009) 3096–3101
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An interrupted Ugi reaction enables the preparation of substituted
indoxyls and aminoindoles
*
John S. Schneekloth, Jr., Jimin Kim, Erik J. Sorensen
Department of Chemistry, Princeton University, Frick Chemical Laboratory, Princeton, NJ 08544, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2008
Received in revised form 19 August 2008
Accepted 20 August 2008
Available online 27 August 2008
In a variation of the classical Ugi reaction, an acid-promoted reaction between imines and isocyanides
forms both 3-aminoindoles and substituted indoxyls. A recently reported triflyl phosphoramide is shown
to be critical to obtain high yields under mild conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated with admiration to Professor
Justin Dubois, recipient of the Tetrahedron
Young Investigator Award
Keywords:
Multicomponent reactions
Synthetic methods
Isocyanides
Heterocycles
1. Introduction
halide to generate the putative nitrilium ion.8 A mild generation of
nitrilium ions is also at the heart of some powerful multicompo-
The nitrilium ion has been studied since the earliest days of
organic chemistry, although the preparation of a stable nitrilium
salt was not reported until 1955 by Klages and Meerwein.1 As
a result of this longstanding interest, a variety of powerful trans-
formations are based on nitrilium chemistry. These reactions
typically feature the attack of a heteroatom- or carbon-based nu-
cleophile at the electrophilic carbon of a nitrilium ion.2 They differ,
however, in the mechanisms by which the nitrilium ion is pro-
duced. In the Beckmann rearrangement, a nitrilium species is
generated by migration of a carbon–carbon bond (see Ref. 3). The
Houben–Hoesch cyclization4 (or Hoesch reaction5) utilizes
protonated or alkylated nitriles to generate aryl ketones, and is
a relative of the Friedel–Crafts reaction. The Ritter reaction relies on
the addition of water to a nitrilium ion generated by the reaction
between a nitrile and a carbocation as a general method for the
aminoacylation of carbocations.6 A closely related variant, the
Pinner reaction, involves the reaction between protonated nitriles
and alcohols to generate imidate esters.7 The Bischler–Napieralski
reaction is another common transformation that relies on de-
hydration of an amide or removal of the halide from an imidoyl
nent couplings in organic synthesis; mechanistically, the addition
of an isocyanide to an oxocarbenium or iminium ion to generate
a reactive nitrilium intermediate is a central step of the Passerini
and Ugi reactions, respectively.9 These multicomponent reactions
are of particular interest due to their wide functional group toler-
ance and ability to rapidly generate chemical diversity. In many
cases, multiple carbon–carbon bonds, carbon–heteroatom bonds,
and a stereogenic center are formed in a single operation. New
variations of these nitrilium-centered reactions are of interest to
the general field of chemical synthesis as they often prove useful for
the rapid construction of complex, biologically active molecules.
2. Results and discussion
In the course of planning a synthesis of a structurally complex
natural product, we were intrigued by the possibility that a nitri-
lium ion generated by the addition of an isocyanide to an iminium
ion might be intercepted by an electron-rich arene. Such a variation
on the classical Ugi reaction would result in the formation of an
additional carbon–carbon bond, and, in the case of an intra-
molecular reaction, a new heterocyclic ring. This interrupted Ugi
reaction would combine mechanistic elements of both the Ugi and
the Houben–Hoesch reactions. Prior studies on the Houben–
Hoesch reaction have established that the reaction between
* Corresponding author. Tel.: þ1 609 258 8135; fax: þ1 609 258 1980.
E-mail address: ejs@princeton.edu (E.J. Sorensen).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.055

J.S. Schneekloth et al. / Tetrahedron 65 (2009) 3096–3101
3097
Table 1
a protonated nitrile and an electron-rich arene can be quite effi-
cient. Livinghouse10 and Townsend11 have also established that
electron-rich arenes react with acylated isocyanides or alkylated
nitriles to form hydroquinoline derivatives and benzophenones,
respectively. Other related transformations have been reported as
well.5,12–14 While these reaction manifolds have proven useful,
a general strategy focused on generation of the reactive nitrilium
intermediate by addition of an isocyanide to an activated imine,
followed by intramolecular trapping with a pendant arene could
give direct access to different structural classes of useful hetero-
cyclic products.
Screen of acids for the interrupted Ugi reaction
H3CO
H3CO
Acid
1.5 eq. t-BuNC
HN
N
Ph
H3CO
N
0.05 M CH2Cl2
H3CO
Ph
1
Entry
Acid
Equiv
Yield (%)
1
2
3
4
5
6
7
8
9
None
HCl
Amberlyst-15
HBF4$OEt2
Tf2NH
TfOH
TfOH
2
N.A.
1.0
1.0
1.0
1.1
NR
50
NR
86
46
62
42
96
34
In practice, such a transformation might be accomplished by
replacing the carboxylic acid component of the Ugi reaction with
a Lewis acid or strong Brønsted acid and employing an aniline as
the amine component. In the absence of a nucleophilic counterion
1.1
0.3
1.1
0.1
in the reaction mixture, the
a-amino nitrilium ion would be free to
react selectively with the pendant nucleophilic
p
system. In the
Sc(OTf)3
case of aldimines, the resultant cyclized imines could tautomerize
to form 3-aminoindoles. The analogous ketimine-derived in-
termediates could lead to the production of indoxyls after hydro-
lysis of the initially formed bicyclic imine (Fig. 1). A previous report
has shown that it is feasible to generate 3-aminoindoles through
this type of cyclization. Two substrates were reported and the re-
action was shown to require several days with concentrated strong
acid and/or at high temperature (100 ꢀC): yields ranged from 27 to
68%.15 We felt that a milder procedure, which also extended the
reaction scope to indoxyls would be of general interest. Our first
attempt to study the reaction focused on the condensation of
benzaldehyde, 3,5-dimethoxyaniline, and tert-butyl isocyanide
(Table 1).
As has been observed in other studies of the Ugi reaction, we
found that an imine synthesis by precondensation of aniline and
carbonyl components markedly improved the chemical yield of 3-
aminoindole 1 and minimized the formation of undesired side
products. A variety of Brønsted and Lewis acids were screened
(Table 1). Moderate yields were observed with mineral acids such
as hydrochloric acid (entry 2), although no reaction was observed
with solid supported sulfonic acids such as Amberlyst-15 (entry 3).
Other acids such as p-toluenesulfonic acid, camphorsulfonic acid, or
carboxylic acids such as trifluoroacetic or pivalic acid all provided
only moderate yields of compound 1 (not shown). Some im-
provement was noted with stronger acids such as HBF4$OEt2 or
O
P
PhO
O O
S
H
2
PhO
N
CF3
triflic acid (entries 4 and 6–7). Although Lewis acids such as scan-
dium(III) triflate also catalyzed the reaction (entry 9), yields were
generally superior with Brønsted acids. The most notable increase
in yield was observed with the use of acid 2, a recently reported
triflyl phosphoramide.16 Acid 2 appears to provide a strong
Brønsted acid with a non-nucleophilic counterion, and is surpris-
ingly mild. Under optimized conditions, aminoindole 1 was pre-
pared in 2 h at rt in 96% yield.
We examined the substrate scope of the reaction by studying
a variety of arenes, aldehydes, and isocyanides (Table 2). In general,
aldimines were prepared by condensation in toluene in the pres-
ence of molecular sieves and used without purification. The re-
action was found to be tolerant of a number of substrates. Imines
derived from a variety of substituted benzaldehydes (Table 2, en-
tries 1–4) as well as ethyl glyoxalate (entries 9–17) performed well
in the reaction. Branched and linear aliphatic aldimines were also
shown to provide aminoindoles (entries 5 and 6). Substituted alkyl
and electron-rich aryl isocyanides such as p-methoxyphenyl
The Classical Ugi Reaction: a Four Component Coupling Reaction
R3
H
R
R
O
R3
O
C
NH2
O
Mumm
NH
R
N
N
O
R
R
O
R2
R3
O
R3
NH
Rearrangement O
N
O
H
N
R1
R1
+
R1
R2
C
R1
N
N
N
R2
R2
R2
R1
HO
EDG
The Interrupted Ugi Approach to Aminoindoles and Indoxyls
HN
R2
When
EDG
R1 = H
EDG
N
NHR3
NH2
+
EDG
EDG
Houben
-Hoesch
H
Aminoindoles
EDG
Ugi
acid
C
HN
R1
N
HN
R1
R2
R1
R2
O
R3
R2
N
N
R1
R2
C
R2
R3
Hydrolysis
N
R3
when R1≠H
HN
R1
O
R2
Indoxyls
Figure 1. Ugi-type reactions.

3098
J.S. Schneekloth et al. / Tetrahedron 65 (2009) 3096–3101
Table 2
the low nucleophilicity of this compound. Although several highly
Preparation of 3-aminoindoles
electron-rich anilines provided 3-aminoindoles in general with
good yield, the parent aniline (entry 9) was considerably less re-
active. However, this yield could be improved with prolonged re-
action time and a stronger acid.15,17
EDG
R'
1.1 eq. 2
HN
EDG
1.5 eq. R'-NC
R
N
R
0.05M CH2Cl2
2 h, rt
N
H
The interrupted Ugi reaction is also useful in the syntheses of
indoxyls (Table 3). The mild reaction conditions for these substrates
are particularly notable given the formation of a fully substituted
carbon and stand in contrast to the notoriously harsh conditions
often encountered in the Houben–Hoesch reaction. Ketimines were
generally found to require 24 h of reaction time at room tempera-
ture under reaction conditions otherwise identical to those of
aldimines. The electron-rich, sterically hindered imine in-
termediates initially proved resistant to acidic hydrolysis and
slowly decomposed under prolonged heating in 6 N HCl. After
some experimentation, it was found that the key hydrolysis step
could be accomplished smoothly by treatment of the imines with
10 equiv of K2CO3 in a warm THF/MeOH/H2O mixture.18 Several
substituted indoxyls were prepared in this manner (Table 3). Of
particular note is the highly hindered, camphor-derived substrate
(Table 3, entry 5). In this case, a product containing vicinal fully
Entry
1–4
Product
Yield (%)
1. Ar¼Ph, 96
2. Ar¼o-BrC6H4, 80
3. Ar¼p-ClC6H4, 86
4. Ar¼p-NO2C6H4, 81
H3CO
HN
Ar
N
H3CO
H
H3CO
HN
5
81
46
40
48
12
53
N
H
H3CO
H3CO
HN
6
Table 3
Preparation of indoxyls
N
H
CH3
H3CO
3
a) 2, 1.1 eq.
EDG
O
t-BuNC, 1.5 eq.
HN
EDG
24 h, rt
R
R'
7
N
Ph
b) K2CO3
THF/MeOH/H2O
55 °C, 4 h
N
N
H
H3CO
H
R
R'
H3CO
Entry
Substrate
H3CO
Product
Yield (%)
HN
8
H3CO
N
H
H3CO
O
1
92
H3CO
N
N
N
HN
H3CO
H
9a
CO2Et
N
H
O
H3CO
2a
56
58
HN
N
H
H3CO
O
O
10
11–12
13
CO2Et
N
H
H3CO
H3CO
O
H3CO
H3CO
3
N
HN
N
11. EDG¼OCH3, 30
12. EDG¼SCH3, 40
H
CO2Et
N
H
EDG
H3CO
H3CO
O
CH3
Ph
4
96
HN
H3CO
N
N
H
74
H3CO
CO2Et
H3C
Ph
N
H
CH3
H3C
CH3
H3C
14. R¼t-Bu, 72
HN
R
15. R¼p-OCH3C6H4, 25
16. R¼Cy, 62
H3CO
H3CO
H
14–17
CO2Et
N
17. R¼(S)-(CH3)CHC6H5, 68
5b
48
OCH3
H3C
N
H
N
H3C
N
OCH3
a
HBF4$OEt2 (1.1 equiv) was used in place of acid 2.
OCH3
OCH3
HBF4$OEt2 (1.1 equiv) was used in place of acid 2.
a
b
isocyanide were also successful (entry 14–17). An attempt to use
p-nitrophenyl isocyanide provided no product, presumably due to
Reaction time: 36 h, dr 5:1, relative stereochemistry assigned by NOE
correlation.

J.S. Schneekloth et al. / Tetrahedron 65 (2009) 3096–3101
3099
substituted carbons was easily formed, and the imine product was
isolated by column chromatography.
sulfate, and the dried solution was concentrated. Purification by
flash column chromatography (4:1 hexanes/ethyl acetate) afforded
102 mg of aminoindole (96%) as an amorphous yellow solid.
3. Conclusions
4.2.1. N-tert-Butyl-4,6-dimethoxy-2-phenyl-1H-indol-3-amine
(Table 2, entry 1)
In conclusion, we have developed
a mild transformation
combining mechanistic elements of the Ugi reaction and the
Houben–Hoesch cyclization. Two new carbon–carbon bonds and a
heterocyclic ring are formed in a single operation. The use of the
recently reported, strong Brønsted acid 2 proved critical to obtain
high yields under mild conditions. In many cases, the cyclization is
observed to occur at room temperature, often in as little as 2 h. The
acid-promoted reaction is straightforward to execute and useful in
the preparation of a wide variety of 3-aminoindoles as well as
several highly substituted indoxyls. It is anticipated that this re-
action will find broad use in the preparation of biologically active
molecules and natural products. A more complete study detailing
the scope of indoxyl formation, efforts to achieve stereoselective
reactions, and the application of the interrupted Ugi reaction in
natural product synthesis is currently underway in our laboratory.
TLC: Rf¼0.45 (20% EtOAc/hexanes); IR (film) 3349 (br), 2967,
2931, 2901, 2838,1624,1603,1514,1494,1465,1453,1431,1388,1360,
1350, 1295, 1265, 1219, 1201, 1150, 1130, 1072, 1043 cmꢂ1; 1H NMR
(500 MHz, CDCl3)
d
7.88 (d, J¼7.3 Hz, 2H), 7.68 (br s N–H, 1H), 7.37
(apt, J¼7.73 Hz, 2H), 7.21 (t, J¼7.3 Hz, 1H), 6.33 (s, 1H), 6.09 (s, 1H),
3.83 (s, 3H), 3.75 (s, 3H), 3.25–3.45 (br s N–H, 1H), 0.91 (s, 9H); 13C
NMR (125 MHz, CDCl3) d 157.4,154.9,135.8,134.4,128.3,127.1,126.9,
126.3, 121.2, 112.5, 91.4, 86.5, 55.8, 55.5, 54.8, 29.8; HRMS (ESI-TOF)
C20H24N2O2 calculated for [MþH]þ 325.1916, found 325.1913.
4.2.2. 2-(2-Bromophenyl)-N-(tert-butyl)-4,6-dimethoxy-1H-indol-
3-amine (Table 2, entry 2)
TLC: Rf¼0.80 (50% EtOAc/hexanes); IR (film) 3179, 2958, 2900,
2856, 1614, 1564, 1523, 1492, 1433, 1360, 1310, 1283, 1217, 1201,
1152, 1131, 1022 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.98 (br s N–H,
4. Experimental section
4.1. General
1H), 7.80 (dd, J¼1.7, 7.7 Hz, 1H), 7.62 (dd, J¼1.1, 8.0 Hz, 1H), 7.32 (dt,
J¼4.4, 12.0 Hz), 7.15 (dt, J¼1.8, 3.7 Hz, 1H), 6.42 (s, 1H), 6.17 (s, 1H),
3.91 (s, 3H), 3.83 (s, 3H), 3.55 (br s, N–H, 1H), 0.91 (s, 9H); 13C NMR
(125 MHz, CDCl3)
d 157.6, 155.0, 135.3, 135.0, 133.8, 133.1, 128.7,
All reactions were carried out under an atmosphere of Ar or N2
unless otherwise specified. Tetrahydrofuran (THF), toluene, and
methylene chloride (CH2Cl2) were dried by passing through acti-
vated alumina columns. Commercial reagents of high purity were
purchased and used without further purification, unless otherwise
noted. Reactions were monitored by thin-layer chromatography
127.3, 125.1, 122.7, 122.2, 110.9, 91.3, 86.4, 55.6, 55.5, 54.9, 29.6;
HRMS (ESI-TOF) C20H23BrN2O2 calculated for [MþH]þ 403.1021,
found 403.1005.
4.2.3. N-(tert-Butyl)-2-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-
3-amine (Table 2, entry 3)
(TLC) carried out on 0.25 mm Merck HPTLC silica gel plates (60 F254
)
TLC: Rf¼0.90 (50% EtOAc/hexanes); IR (film) 3349, 2968, 2840,
using UV light as a visualizing agent and aqueous ceric sulfate/
phosphomolybdic acid, ceric ammonium nitrate solution, ethanolic
p-anisaldehyde solution, or potassium permanganate and heat as
developing agents. E. Merck silica gel 60 (230–400 mesh) was used
for flash column chromatography. FTIR spectra were obtained on
a Perkin–Elmer Paragon 500 FT-IR. NMR spectra were obtained on
Bruker DRX-600, DRX-500, AMX-400, Varian Inova-500, and Inova-
400 instruments and calibrated to the residual solvent peak. The
multiplicities are abbreviated as follows: s¼singlet, d¼doublet,
t¼triplet, m¼multiplet, aps¼apparent singlet, apd¼apparent dou-
blet, apt¼apparent triplet, br s¼broad signal. Optical rotations were
recorded on a Perkin–Elmer model 241 polarimeter using a 1 mL,
1 dm cell. Mass spectra were obtained using an Agilent 6210 Time
of Flight-LC/MS.
1625, 1603, 1491, 1465, 1295, 1277, 1218, 1201, 1151, 1130 cmꢂ1 1H
;
NMR (500 MHz, CDCl3)
7.31 (d, J¼8.6 Hz, 2H), 6.39 (s, 1H), 6.16 (s, 1H), 3.89 (s, 3H), 3.82 (s,
3H), 0.98 (s, 9H); 13C NMR (125 MHz, CDCl3)
157.6, 154.9, 136.0,
d
7.85 (d, J¼8.6 Hz, 2H), 7.74 (br s N–H, 1H),
d
132.9, 131.6, 128.5, 128.0, 126.0, 121.7, 112.5, 91.6, 86.6, 55.9, 55.5,
54.8, 29.8; HRMS (ESI-TOF) C20H23ClN2O2 calculated for [MþH]þ
359.1526, found 359.1529.
4.2.4. N-(tert-Butyl)-4,6-dimethoxy-2-(4-nitrophenyl)-1H-indol-3-
amine (Table 2, entry 4)
TLC: Rf¼0.55 (50% EtOAc/hexanes); IR (film) 3401, 2966, 1625,
1589, 1509, 1332, 1292, 1271, 1219, 1201, 1151, 1130, 1108 cmꢂ1 1H
;
NMR (500 MHz, CDCl3)
2H), 7.83 (br s, N–H, 1H), 6.40 (s, 1H), 6.16 (s, 1H), 3.91 (s, 3H), 3.84
(s, 3H), 0.98 (s, 9H); 13C NMR (125 MHz, CDCl3)
158.7, 155.3, 145.0,
d
8.19 (d, J¼9.0 Hz, 2H), 8.13 (d, J¼9.0 Hz,
d
4.2. General procedure for the synthesis of 3-aminoindoles
(N-tert-butyl-4,6-dimethoxy-2-phenyl-1H-indol-3-amine,
Table 2, entry 1)
140.8, 137.1, 126.2, 125.5, 124.8, 123.9, 112.7, 92.1, 86.4, 56.6, 55.6,
54.7, 29.8; HRMS (ESI-TOF) C20H23N3O4 calculated for [MþH]þ
370.1766, found 370.1765.
Powdered 4 Å molecular sieves (300 mg) were added to a stirred
solution of 3,5-dimethoxyaniline (50 mg, 0.33 mmol, 1 equiv) and
4.2.5. N-tert-Butyl-2-cyclohexyl-4,6-dimethoxy-1H-indol-3-amine
(Table 2, entry 5)
benzaldehyde (35 mg, 0.33 mmol, 1 equiv) in toluene (300
m
L). The
TLC: Rf¼0.55 (50% EtOAc/hexanes); IR (film) 3350 (br), 2930,
resulting suspension was stirred at 23 ꢀC for 1 h, filtered through
Celite, and the filtrate was concentrated to afford the crude imine,
which was used without further purification. tert-Butylisocyanide
(41 mg, 0.49 mmol, 1.5 equiv) and 137 mg acid 2 (0.36 mmol,
1.1 equiv) in 3 mL dichloromethane (final concentration 0.05 M)
were added via syringe to a stirred solution of the crude imine in
dichloromethane (3.6 mL, final concentration 0.05 M) at 23 ꢀC. The
resulting orange solution was stirred for 2 h, and then partitioned
between saturated aqueous sodium bicarbonate solution (10 mL)
and dichloromethane. The organic layer was separated and the
aqueous layer was extracted with dichloromethane (2ꢁ10 mL). The
combined organic extracts were dried over anhydrous sodium
2852, 1627, 1595, 1519, 1456, 1299, 1199, 1153, 1095, 935 cmꢂ1 1H
;
NMR (500 MHz, CDCl3)
d 7.49 (br s, N–H, 1H), 6.37 (s, 1H), 6.14 (s,
1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.25 (br s, N–H, 1H), 2.97 (m, 1H),
1.73–1.94 (m, 5H), 1.47–1.33 (m, 4H), 1.26 (m, 1H), 1.15 (s, 9H); 13C
NMR (125 MHz, CDCl3)
d 156.5, 154.1, 134.9, 134.8, 117.1, 111.5, 91.0,
86.7, 55.6, 54.7, 54.0, 34.4, 33.8, 29.7, 26.7, 26.2; HRMS (ESI-TOF)
C20H30N2O2 calculated for [MþH]þ 331.2385, found 331.2384.
4.2.6. N-tert-Butyl-2-heptyl-4,6-dimethoxy-1H-indol-3-amine
(Table 2, entry 6)
TLC: Rf¼0.75 (50% EtOAc/hexanes); IR (film) 3204 (br), 2956,
2927, 2856, 1627, 1515, 1456, 1387, 1360, 1302, 1201, 1154, 1129,

3100
J.S. Schneekloth et al. / Tetrahedron 65 (2009) 3096–3101
1051 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.53 (br s, N–H, 1H), 6.36 (s,
119.2, 115.8, 108.5, 60.4, 54.4, 30.6, 16.1, 14.5; HRMS (ESI-TOF)
C
1H), 6.14 (s,1H), 3.87 (s, 3H), 3.80 (s, 3H), 2.71 (apt, J¼8.1 Hz, 2H),1.61
16H23N2O2S calculated for [MþH]þ 307.1480, found 307.1474.
(m, 2H),1.20–1.44 (m, 8H),1.13 (s, 9H), 0.88(t, J¼6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3)
d
156.4, 154.0, 135.0, 129.9, 118.4, 111.4, 90.9, 86.5,
4.2.13. Ethyl 1-(tert-butylamino)-3H-benzo[e]indole-2-carboxylate
(Table 2, entry 13)
55.6, 54.7, 54.0, 31.8, 29.7, 29.7, 29.5, 29.2, 26.0, 22.6,14.1; HRMS (ESI-
TOF) C21H34N2O2 calculated for [MþH]þ 347.2698, found 347.2696.
TLC: Rf¼0.30 (25% EtOAc/hexanes); IR (film) 3310, 2969, 1668,
1430,1263,1130 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
9.27 (d, J¼8.3 Hz,
4.2.7. N-tert-Butyl-6-methoxy-2-phenyl-1H-indol-3-amine (Table
2, entry 7)
1H), 9.05(br s,1H), 7.85 (d, J¼8.0 Hz,1H), 7.66(d, J¼8.9 Hz,1H), 7.56 (t,
J¼7.6 Hz, 1H), 7.43 (t, J¼7.5 Hz, 1H), 7.40 (d, J¼8.9 Hz, 1H), 4.46 (q,
J¼7.1 Hz,2H), 4.17(brs,1H),1.45(t, J¼7.1 Hz, 3H),1.26(s, 9H);13CNMR
TLC: Rf¼0.48 (20% EtOAc/hexanes); IR (film) 3349, 2968, 1622,
1166 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
7.81 (dd, J¼8.3, 1.1 Hz,
(125 MHz, CDCl3) d 162.4, 133.9, 132.7, 129.8, 129.5, 128.3, 127.7, 125.5,
3H), 7.50 (d, J¼8.6 Hz, 1H), 7.43 (t, J¼7.8 Hz, 2H), 7.29 (t, J¼7.5 Hz,
1H), 6.83 (d, J¼2.2 Hz, 1H), 6.80 (dd, J¼8.7, 2.2 Hz, 1H), 3.87 (s,
3H), 2.84 (br s, 1H), 1.05 (s, 9H); 13C NMR (125 MHz, CDCl3)
125.0, 123.7, 119.4, 118.8, 112.9, 60.4, 56.8, 29.6, 14.5; HRMS (ESI-TOF)
C19H23N2O2 calculated for [MþH]þ 311.1759, found 311.1758.
d
156.5, 135.3, 133.9, 130.2, 128.6, 127.2, 126.9, 123.0, 120.2, 109.4,
4.2.14. Ethyl 3-(tert-butylamino)-5,6-dimethoxy-1H-indole-2-
carboxylate (Table 2, entry 14)
94.2, 55.7, 55.1, 30.4; HRMS (ESI-TOF) C19H23N2O calculated for
[MþH]þ 295.1810, found 295.1811.
TLC: Rf¼0.15 (25% EtOAc/hexanes); IR (film) 3348, 2971, 1684,
1540, 1256, 1173, 1094 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 8.59 (br s,
4.2.8. N-tert-Butyl-4,6-dimethoxy-2-(naphthalen-2-yl)-1H-indol-
3-amine (Table 2, entry 8)
1H), 7.16 (s, 1H), 6.67 (s, 1H), 4.70 (br s, 1H), 4.36 (q, J¼7.1 Hz, 2H),
3.87 (s, 3H), 3.83 (s, 3H), 1.37 (t, J¼7.1 Hz, 3H), 1.28 (s, 9H); 13C NMR
TLC: Rf¼0.90 (50% EtOAc/hexanes); IR (film) 3351 (br), 2958,
(125 MHz, CDCl3) d 162.4, 150.2, 144.8, 133.5, 131.2, 117.1, 116.1,
2904, 2387,1734,1601,1507,1453,1427,1387,1293,1266,1219,1199,
102.9, 93.3, 60.3, 56.0, 55.8, 54.8, 30.5, 14.5; HRMS (ESI-TOF)
1146,1126,1032 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
8.34 (d, J¼8.5 Hz,
C17H25N2O4 calculated for [MþH]þ 321.1814, found 321.1821.
1H), 8.09 (s,1H), 7.88 (br s, N–H,1H), 7.78–7.85 (m, 3H), 7.40–7.48 (m,
2H), 6.44 (s,1H), 6.18 (s,1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.53 (br s, N–H,
4.2.15. Ethyl 5,6-dimethoxy-3-(4-methoxyphenylamino)-1H-
indole-2-carboxylate (Table 2, entry 15)
1H), 1.00 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 157.6, 155.0, 136.2,
133.6,132.3,127.7,127.6,127.6,127.0,126.3,126.0,125.4,123.7,122.0,
112.7, 91.5, 86.6, 55.9, 55.6, 54.8, 29.9; HRMS (ESI-TOF) C24H26N2O2
calculated for [MþH]þ 375.2067, found 375.2062.
TLC: Rf¼0.23 (33% EtOAc/hexanes); IR (film); 3351, 2934, 1670,
1510, 1245, 1174, 1093 cmꢂ1 1H NMR (500 MHz, C6D6)
; d 7.76 (br s,
1H), 7.57 (br s, 1H), 7.01 (d, J¼8.8 Hz, 2H), 6.84 (s, 1H), 6.70 (d,
J¼8.8 Hz, 2H), 6.09 (s,1H), 4.17 (q, J¼7.1 Hz, 2H), 3.44 (s, 3H), 3.29 (s,
3H), 3.26 (s, 3H), 1.05 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
4.2.9. Ethyl 3-(tert-butylamino)-1H-indole-2-carboxylate (Table 2,
entry 9)
d
162.4, 155.0, 150.6, 144.0, 136.5, 131.7, 121.4, 114.1, 112.1, 110.5,
TLC: Rf¼0.30 (25% EtOAc/hexanes); IR (film) 3154, 2976, 1689,
102.9, 93.6, 60.1, 56.0, 55.9, 55.6, 14.6; HRMS (ESI-TOF) C20H23N2O5
1544, 1252, 1098 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
8.34 (br s, 1H),
calculated for [MþH]þ 371.1606, found 371.1594.
7.84 (d, J¼8.3 Hz, 1H), 7.30 (m, 2H), 7.08 (ddd, J¼8.1, 4.9, 3.0 Hz, 1H),
4.42 (q, J¼7.1 Hz, 2H), 1.44 (t, J¼7.1 Hz, 3H), 1.35 (s, 9H); 13C NMR
4.2.16. Ethyl 3-(cyclohexylamino)-5,6-dimethoxy-1H-indole-2-
carboxylate (Table 2, entry 16)
(125 MHz, CDCl3)
d 162.7, 135.9, 134.0, 125.9, 123.2, 119.4, 116.5,
111.8, 60.4, 54.5, 30.7, 29.8, 14.6; HRMS (ESI-TOF) C15H21N2O2 cal-
TLC: Rf¼0.12 (25% EtOAc/hexanes); IR (film); 3356, 2931, 1665,
culated for [MþH]þ 261.1603, found 261.1598.
1489, 1256, 1172, 1096 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.74 (br s,
1H), 7.10 (s, 1H), 6.68 (s, 1H), 4.35 (q, J¼7.1 Hz, 2H), 3.91 (s, 6H), 3.70
(br s, 1H), 2.09 (d, J¼11.4 Hz, 2H), 1.79 (d, J¼13.0 Hz, 2H), 1.63 (d,
J¼13.2 Hz, 1H), 1.39 (t, J¼7.1 Hz, 3H), 1.31 (m, 5H); 13C NMR
4.2.10. Ethyl 7-(tert-butylamino)-5H-[1,3]dioxolo[4,5-f]indole-6-
carboxylate (Table 2, entry 10)
TLC: Rf¼0.30 (25% EtOAc/hexanes); IR (film) 3328, 2975,1682,1465,
(125 MHz, CDCl3) d 162.6, 150.8, 144.2, 132.5, 111.7, 103.0, 93.8, 59.6,
1251, 1038 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
8.22 (br s, 1H), 7.15 (s,
56.4, 55.9, 54.0, 34.3, 25.8, 24.8, 14.8; HRMS (ESI-TOF) C19H27N2O4
1H), 6.70 (s,1H), 5.96 (s, 2H), 4.67 (br s,1H), 4.38 (q, J¼7.1 Hz, 2H), 1.41 (t,
calculated for [MþH]þ 347.1970, found 347.1968.
J¼7.1 Hz, 3H), 1.29 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 162.3, 148.2,
143.2, 132.0, 118.6, 116.5, 101.0, 100.4, 91.5, 60.2, 54.7, 30.6, 14.6; HRMS
4.2.17. (S)-Ethyl 5,6-dimethoxy-3-(1-phenylethylamino)-1H-
indole-2-carboxylate (Table 2, entry 17)
(ESI-TOF) C16H21N2O4 calculatedfor [MþH]þ 305.1501, found305.1499.
TLC: Rf¼0.30 (33% EtOAc/hexanes); IR (film) 3357, 2977, 1663,
4.2.11. Ethyl 3-(tert-butylamino)-6-methoxy-1H-indole-2-
carboxylate (Table 2, entry 11)
1490, 1336, 1257, 1174 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 7.69 (br s,
1H), 7.45 (d, J¼8.2 Hz, 2H), 7.31 (t, J¼7.7 Hz, 2H), 7.21 (t, J¼7.4 Hz,
1H), 6.80 (s, 1H), 6.59 (s, 1H), 5.01 (q, J¼6.5 Hz, 1H), 4.39 (q,
J¼7.1 Hz, 2H), 3.85 (s, 3H), 3.63 (s, 3H), 1.63 (d, J¼6.8 Hz, 3H), 1.41 (t,
TLC: Rf¼0.25 (20% EtOAc/hexanes); IR (film) 3336, 2972, 1684,
1628, 1254, 1095 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d 8.20 (br s, 1H),
7.70 (d, J¼9.0 Hz, 1H), 6.73 (dd, J¼9.0, 2.1 Hz, 1H), 6.69 (d, J¼2.1 Hz,
J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 162.5, 150.5, 146.2,
143.8, 132.3, 128.6, 126.8, 125.6, 103.1, 93.4, 59.6, 56.1, 55.7, 55.5,
1H), 5.02 (br s,1H), 4.39 (q, J¼7.1 Hz, 2H), 3.84 (s, 3H),1.42 (t, J¼7.1 Hz,
3H),1.34(s, 9H);13CNMR(125 MHz,CDCl3)
d
162.6, 159.2, 137.2, 124.2,
25.8, 14.7; [
a]
158 (c 1.0, CHCl3); HRMS (ESI-TOF) C21H25N2O4
D
20
118.1, 114.9, 110.7, 93.3, 60.1, 55.4, 54.3, 30.7, 29.8, 14.6; HRMS (ESI-
calculated for [MþH]þ 369.1814, found 321.1815.
TOF) C16H23N2O3 calculated for [MþH]þ 291.1708, found 291.1704.
4.3. General procedure for the synthesis of indoxyls (40,60-
dimethoxyspiro[cyclohexane-1,20-indolin]-30-one, Table 3,
entry 1)
4.2.12. Ethyl 3-(tert-butylamino)-6-(methylthio)-1H-indole-2-
carboxylate (Table 2, entry 12)
TLC: Rf¼0.42 (25% EtOAc/hexanes); IR (film); 3337, 2974, 1673,
1560, 1230, 675 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
8.16 (br s, 1H),
tert-Butylisocyanide (52 mg, 0.62 mmol,1.5 equiv) and a solution
of 175 mg acid 2 (0.46 mmol, 1.1 equiv) in 3.3 mL dichloromethane
were added via syringe to a solution of imine (100 mg, 0.41 mmol,
1.0 equiv) in dichloromethane (5 mL). The resulting solution was
7.73 (d, J¼8.6 Hz, 1H), 7.14 (s, 1H), 7.00 (d, J¼8.7 Hz, 1H), 4.96 (br s,
1H), 4.40 (q, J¼7.1 Hz, 2H), 2.54 (s, 3H), 1.43 (t, J¼7.1 Hz, 3H), 1.34 (s,
9H); 13C NMR (125 MHz, CDCl3)
d 162.6, 136.5, 136.4, 123.4, 121.7,

J.S. Schneekloth et al. / Tetrahedron 65 (2009) 3096–3101
3101
stirred at 23 ꢀC for 24 h and then was concentrated at reduced
1155, 1110, 1062, 1052, 1003, 952 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
pressure to afford an oily residue. Potassium carbonate (565 mg,
4.1 mmol, 10 equiv) was added to a stirred solution of the residue in
tetrahydrofuran/water/methanol (1:1:1, 8 mL). A reflux condenser
was attached to the flask, and the reaction mixture was heated to
55 ꢀC for 4 h. The reaction mixture was cooled to 23 ꢀC and the
volatile solvents were evaporated under reduced pressure. The
resulting aqueous solution was extracted with dichloromethane
(3ꢁ10 mL). The combined organic extracts were dried over
anhydrous sodium sulfate, and the dried solution was concentrated.
Purification by flash column chromatography (3:2 hexanes/ethyl
acetate) afforded 112 mg (92%) of indoxyl as a white, crystalline
solid. Note: 1.1 equiv of HBF4$OEt2can be used in place of acid 2 for
the preparation of indoxyls with little loss in yield. Additionally,
hydrolysis conditions may decompose 2 and result in contaminating
amounts of phenol if longer hydrolysis time is necessary. In this case,
HBF4$OEt2 is used in place of 2.
d
5.84 (d, J¼2.1 Hz, 1H), 5.75 (d, J¼2.1 Hz, 1H), 4.44 (br s, N–H, 1H),
3.77 (s, 3H), 3.76 (s, 3H), 2.22 (d, J¼13.0 Hz, 1H), 1.91–1.99 (m, 2H),
1.69 (t, J¼4.5 Hz, 1H), 1.44–1.55 (m, 2H), 1.35 (s, 9H), 1.11 (m, 1H),
1.06 (s, 3H), 0.84 (s, 3H), 0.57 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
164.4, 159.6, 158.5, 155.6, 105.0, 88.9, 87.4, 80.4, 55.6, 55.3, 54.0,
53.2, 51.7, 45.4, 42.5, 30.2, 29.4, 25.8, 20.9, 20.5, 11.2; HRMS (ESI-
TOF) C23H34N2O2 calculated for [MþH]þ 371.2693, found
371.2688.
Acknowledgements
This work was supported by the National Institute of General
Medical Sciences (GM074763), Merck Research Laboratories,
Boehringer Ingelheim, a Johnson & Johnson Focused Giving Award,
and Princeton University. J.S.S. thanks the NIH for a postdoctoral
fellowship (F32GM078910).
4.3.1. 40,60-Dimethoxyspiro[cyclohexane-1,20-indolin]-3’-one (Table
3, entry 1)
References and notes
TLC: Rf¼0.45 (50% EtOAc/hexanes); IR (film) 3321 (br), 3007,
1. (a) Klages, F.; Grill, W. Liebigs Ann. Chem. 1955, 594, 21–32; (b) Meerwein, H.
Angew. Chem. 1955, 67, 374–380; (c) Meerwein, H.; Laasch, P.; Mersch, R.; Spille,
J. Chem. Ber. 1956, 89, 209–224.
2. For discussions of nitrilium salt chemistry, see: (a) Zil’berman, E. N. Russ. Chem.
Rev. 1960, 29, 331–344; (b) Kanemasa, S. Sci. Synth. 2004, 19, 53–63.
3. (a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988–993; (b) Donaruma, L. G.;
Heldt, W. Z. Org. React. 1960, 11, 1–156; (c) Tatsumi, T. In Beckmann Re-
arrangement; Sheldon, R. A., Bekkum, H., Eds.; Wiley: New York, NY, 2001;
pp 185–204.
2933, 2850,1659,1615,1586,1513,1454,1377,1330,1245,1217,1157,
1099 cmꢂ1
;
1H NMR (500 MHz, CDCl3)
d
5.89 (s, 1H), 5.78 (s, 1H),
5.09 (br s, N–H, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 1.68–1.90 (m, 5H),
1.32–1.46 (m, 5H); 13C NMR (125 MHz, CDCl3)
199.8, 169.1, 162.7,
d
160.1, 103.8, 90.0, 87.2, 67.5, 55.7, 55.6, 33.0, 24.7, 22.7; HRMS (ESI-
TOF) C15H19NO3 calculated for [MþH]þ 262.1433, found 262.1435.
4. (a) Hoesch, K. Ber. 1915, 48, 1122–1133; (b) Houben, J. Ber. 1926, 59B, 2878–
2891; (c) Ruske, W. Houben–Hoesch and Related Syntheses. In Friedel–Crafts
and Related Reactions; Olah, G. A., Ed.; Interscience: New York, NY, 1964; Vol. 3,
pp 383–497.
5. For an example of a ‘‘Hoesch Reaction’’ relevant to this work, see: Davey, A. E.;
Schaeffer, M. J.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 1992, 2657–2666.
6. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045–4048; (b) Ritter, J. J.;
Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048–4050; (c) For a review, see: Bishop, R.
Ritter-type Reactions. In Comprehensive Organic Synthesis Trost, B.M., Flemming
I. eds.; Vol. 6, 261–300; (d) For examples of Ritter-like reactions between ni-
triles and halonium ion intermediates, see: Hassner, A.; Levy, L. A.; Gault, R.
Tetrahedron Lett. 1966, 27, 3119–3123.
4.3.2. 60-Methoxyspiro[cyclohexane-1,20-indolin]-30-one
(Table 3, entry 2)
Note: tetrafluoroboric acid diethyl etherate (1.1 equiv) was used.
TLC: Rf¼0.40 (50% EtOAc/hexanes); IR (film) 3342 (br), 2932, 2856,
1665, 1614, 1496, 1456, 1357, 1311, 1268, 1245, 1215, 1159, 1099,
1042, 973 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.52 (d, J¼8.6 Hz, 1H),
6.39 (dd, J¼8.6, 2.1 Hz, 1H), 6.28 (d, J¼2.1 Hz, 1H), 5.07 (br s, N–H,
1H), 3.83 (s, 3H), 1.86 (m, 2H), 1.74 (m, 3H), 1.35–1.48 (m, 5H); 13C
NMR (125 MHz, CDCl3) d 202.4, 167.5, 162.0, 126.4, 113.9, 108.6, 94.7,
7. (a) Pinner, A.; Klein, F. Ber. 1877, 10, 1889–1897; (b) Pinner, A.; Klein, F. Ber. 1878,
11, 1475–1487; For reviews, see: (c) Zil’berman, E. N. Russ. Chem. Rev. 1962, 31,
615–633; (d) The Chemistry of Amidines and Imidates; Patai, S., Rappaport, Z.,
Eds.; Wiley: New York, NY, 1991; Vol. 2.
8. (a) Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903–1908; (b) For a review, see:
Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74–150.
9. For comprehensive reviews on the Ugi and Passerini reactions, see: (a) Dom-
ling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (b) Domling, A. Chem.
Rev. 2006, 106, 17–89.
10. Livinghouse, T. Tetrahedron 1999, 55, 9947–9978 and references therein.
11. (a) Casillas, L. K.; Townsend, C. A. J. Org. Chem. 1999, 64, 4050–4059; (b) Udwary,
D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124, 5294–5303.
12. For other related examples of intramolecular nitrilium trapping with arenes,
see: (a) Lack, O.; Weber, L. Chimia 1996, 50, 445–447; (b) Winkler, J. D.; As-
selin, S. M. Org. Lett. 2006, 8, 3975–3977; (c) Kobayashi, K.; Takanohashi, A.;
Hashimoto, K.; Morikawa, O.; Konishi, H. Tetrahedron 2006, 62, 10379–10382;
With heteroatom nucleophiles: (d) Groebke, K.; Weber, L.; Mehlin, G. Synlett
1998, 661–663; (e) Blackburn, C. Tetrahedron Lett. 1998, 39, 5469–5472; (f)
Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998,
67.5, 55.5, 32.9, 24.8, 22.7; HRMS (ESI-TOF) C14H17NO2 calculated
for [MþH]þ 232.1332, found 232.1330.
4.3.3. 50,60-Dimethoxyspiro[cyclopentane-1,20-indolin]-30-one
(Table 3, entry 3)
TLC: Rf¼0.30 (50% EtOAc/hexanes); IR (film) 3312 (br), 2958, 2907,
1655,1624,1585,1498, 1463,1441, 1380,1316,1229,1209,1145, 1099,
1029, 1002 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.03 (s,1H), 6.33 (s,1H),
4.57 (brs, N–H,1H), 3.91 (s, 3H), 3.84(s, 3H), 2.07 (m, 2H),1.96(m, 2H),
1.82 (m, 2H), 1.68 (m, 2H); 13C NMR (125 MHz, CDCl3)
203.0, 158.1,
d
157.4, 144.2, 112.4, 104.2, 94.7, 75.3, 56.2, 56.2, 38.1, 25.5; HRMS (ESI-
TOF) C14H17NO3 calculated for [MþH]þ 248.1281, found 248.1276.
4.3.4. 4,6-Dimethoxy-2-methyl-2-phenylindolin-3-one
(Table 3, entry 4)
´
39, 3635–3638; (g) Bienyame, H.; Bouzid, K. Angew. Chem., Int. Ed. 2005, 44,
TLC: Rf¼0.35 (50% EtOAc/hexanes); IR (film) 3307 (br), 2970,
6521–6525.
13. Harcourt, D. N.; Hussain, F.; Taylor, N. J. Chem. Soc., Perkin Trans. 1 1986, 1329–
1338 and references therein.
14. For a related transformation see the Povarov reaction, see: (a) Povarov, L. S.
Russ. Chem. Rev. 1967, 36, 656–670; (b) Jorgensen, K. A. Angew. Chem. 2000, 112,
3702–3733; Angew. Chem., Int. Ed. 2000, 39, 3558–3588; (c) Kobayashi, S.;
2932, 2847, 1673, 1616, 1588, 1514, 1462, 1376, 1328, 1206, 1157,
1118 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
7.48 (d, J¼7.20 Hz, 2H), 7.30
(t, J¼7.5 Hz, 2H), 7.22 (t, J¼7.3 Hz, 1H), 5.96 (s, 1H), 5.81 (s, 1H), 5.06
(br s, N–H, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 1.72 (s, 3H); 13C NMR
´
Akiyama, R.; Kitagawa, H. J. Comb. Chem. 2001, 3, 196–204; (d) Carranco, I.; Dıaz,
J. L.; Jime´nez, O.; Vendrell, M.; Albericio, F.; Royo, M.; Lavilla, R. J. Comb. Chem.
2005, 7, 33–41 and references therein.
(125 MHz, CDCl3)
d 197.3, 169.5, 163.0, 160.5, 140.7, 128.5, 127.4,
125.5, 102.3, 90.3, 87.0, 69.0, 55.7, 55.7, 24.5; HRMS (ESI-TOF)
C17H17NO3 calculated for [MþH]þ 284.1280, found 284.1281.
15. Deyrup, J. A.; Vestling, M. M.; Hagan, W. V.; Yun, H. Y. Tetrahedron 1969, 25,
1467–1478.
16. Rueping, M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed.
2008, 47, 593–596.
17. There is some evidence to suggest that less electron rich arenes function
by attack on a dicationic intermediate. For a discussion of dications in the
Houben–Hoesch reaction, see: Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K.
J. Am. Chem. Soc. 1995, 117, 3037–3043.
4.3.5. (ꢃ)-(E)-N-((1S,2R,4R)-40,60-Dimethoxy-1,7,7-trimethyl-
spiro[bicyclo[2.2.1]heptane-2,20-indoline]-30-ylidene)-2-
methylpropan-2-amine (Table 3, entry 5)
TLC: Rf¼0.35 (50% EtOAc/hexanes); IR (film) 3431 (br), 2954,
2868, 1646, 1608, 1503, 1467, 1453, 1384, 1356, 1314, 1221, 1204,
18. Modification of a procedure from reference 11a.