Synthesis of Piperidinone and Azepanone Fused Indoles via a Wagner-Meerwein Type 1,2-Amide Migration of 2-Spiropseudoindoxyls

Article abstract of DOI:10.1055/s-0036-1588138

Spiropseudoindoxyls were synthesized by using a gold(III)-catalyzed intramolecular nitroalkyne redox-dipolar cycloaddition cascade. These compounds were then transformed into novel piperidinone and azepanone fused indoles via a straightforward hydrogenation. The reaction mechanism of this ring expansion is believed to proceed through a rare Wagner-Meerwein type 1,2-amide migration.

Full text of DOI:10.1055/s-0036-1588138

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
N. Marien et al.
Letter
Synlett
Synthesis of Piperidinone and Azepanone Fused Indoles via a
Wagner–Meerwein Type 1,2-Amide Migration of 2-Spiropseudo-
indoxyls
Niels Marien
Ting Luo
O
R2
O
N
Cl Au
Cl
O
Guido Verniest*
R2
H2O
O
N
1)
N
n = 1, 2
6 examples
up to 53% yield
(2 steps)
Research Group of Organic Chemistry, Department of
Chemistry and Department of Bio-engineering Sciences,
Faculty of Science and Bio-engineering Sciences, Vrije
Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels,
Belgium
n
n
R1
2) 5 atm H2, Pd/C
MeOH
rt, 16 h
N
R1
NO2
H
HO
guido.verniest@vub.ac.be
Received: 18.11.2016
Accepted after revision: 09.01.2017
Published online: 02.02.2017
DOI: 10.1055/s-0036-1588138; Art ID: st-2016-b0779-l
Abstract Spiropseudoindoxyls were synthesized by using a gold(III)-
catalyzed intramolecular nitroalkyne redox–dipolar cycloaddition cas-
cade. These compounds were then transformed into novel piperidinone
and azepanone fused indoles via a straightforward hydrogenation. The
reaction mechanism of this ring expansion is believed to proceed
through a rare Wagner–Meerwein type 1,2-amide migration.
Key words dihydro-γ-carbolinone, Wagner–Meerwein, indoles, 1,2-
acyl shift, spirocycles
Guido Verniest (born 1976) obtained his bio-engineering degree in
chemistry from Ghent University, Belgium in 2000 and started PhD
work on cyclobutanone and heterocyclic chemistry at the Department
of Organic Chemistry at Ghent University under the guidance of Norbert
De Kimpe. He obtained a PhD degree in 2004 and continued research in
organofluorine chemistry as a FWO Postdoctoral Fellow also at Ghent
University. In 2007, he undertook postdoctoral research in the laborato-
ry of Albert Padwa at Emory University, Atlanta, Georgia (USA) where
he worked on alkyne transformations towards heterocyclic compounds
using gold and platinum catalysis. In 2008, he returned to Belgium to
continue his work on organofluorine chemistry and, in 2010, he was
appointed as Lecturer at the Faculty of Science and Bio-Engineering
Sciences at the Vrije Universiteit Brussel (VUB) where he started his inde-
pendent career. His main research focus involves synthetic methodolo-
gy in heterocyclic organic chemistry, alkyne transformations and more
applied research towards the synthesis of novel sugar and peptide de-
rivatives.
Indoles are common motifs that are found in many nat-
ural products and biologically active molecules,1 and a large
variety of syntheses towards these structures are well doc-
umented. Strategies towards 2,3-disubstituted indoles in-
clude direct cyclizations to form the five-membered ring,
direct derivatizations of the indole core and rearrangement
reactions of indolone or indolenine derivatives.2 Regarding
the latter strategy, numerous examples have been de-
scribed that proceed through C-3 to C-2 migratory aryl or
alkyl 1,2-shifts. As an example, the Pictet–Spengler reaction
is believed to proceed via a spiroindolenine intermediate,
which subsequently rearranges through a 1,2-alkyl shift;3
such shifts are also known to proceed under gold catalysis.4
3,3-Disubstituted 3H-indolinium species are known to give
2,3-disubstituted indoles through the Ciamician–Plancher
rearrangement.5 When the C-2 of the indolinium salt bears
an alkyl substituent, this rearrangement is reversible and
proceeds through both C-2 to C-3 and C-3 to C-2 alkyl mi-
grations.6 Remarkably, such Wagner–Meerwein type migra-
tory 1,2-shifts from C-2 to C-3 to give 2,3-disubstituted in-
doles have barely been described. This rearrangement can
occur for example when 3-hydroxy-2,2-disubstituted indo-
lines are treated with acid to give the cationic C-3 interme-
diate. This reaction was reported in 1951 by Witkop and
Patrick7 and has only been described in a few examples
since then, including a recent approach towards polycyclic
indolines and indolenines starting from spiropseudoindox-
yls (2-spiroindol-3-ones).8
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
N. Marien et al.
Letter
Synlett
NHt-Bu
O
NHt-Bu
NHt-Bu
1 bar H2
O
O
O
N
O
O
O
O
1 bar H2
10% Pd/C
10% Pd/C
N
N
MeOH
2h
OH
N
O
N
N
MeOH
16 h
H
H
65% conversion
OH
1a
2a
3a
overlap on TLC/HPLC
Scheme 1 Serendipitous over-reduction of 1a towards fused indole 3a
O
In a previous study by our group regarding the synthesis
of 2-spiropseudoindoxyls, the selective N–O cleavage of 1a
towards 2a was investigated.9 For most examples, the reac-
tion reached completion in two hours and afforded near-
quantitative yields. However, in one case (Scheme 1), the
‘closed’ 1a and ‘open’ pseudoindoxyl 2a gave completely
overlapping signals on both TLC and HPLC, suggesting at
first sight that no conversion took place. After a prolonged
reaction time (ca. 16 h), a significant conversion was ob-
served towards dihydro-γ-carbolinone 3a rather than the
envisioned spiropseudoindoxyl 2a. Compounds containing
this dihydro-γ-carbolinone core are known to display inter-
esting bioactivities (e.g., Alosteron, a 5-HT3 serotonin re-
ceptor antagonist).10 Although this transformation was an
unexpected discovery, the conditions that were used ap-
peared to be too mild to obtain full conversion. A further
optimization towards the synthesis of 3 was therefore nec-
essary.
COOH
Ugi reaction
R2
5 mol% 7
toluene, rt
N
R1
R1
n
or T3P, DIPEA,
2° amine,
CH2Cl2, Δ,16 h
NO2
NO2
5a–g (69–99%)
4
O
N
O
O
O
R2
O
R2
N
N
n
N
R1
R1
Cl Au
Cl
O
N
O
rt, 2–8 h
O
7
1a–g
6
1d n = 1, R1 = 4-OMe,
R2 = CH2C(O)NHt-Bu (93%)
1e n = 2, R1 = H,
R2 = CH2C(O)NHt-Bu (99%)
1f n = 2, R1 = H,
R2 = Bn (80%)
1g n = 2, R1 = 5-Cl,
R2 = Bn (79%)
1a n = 1, R1 = H,
R2 = CH2C(O)NHt-Bu (84%)
1b n = 1, R1 = 4-Me,
R2 = CH2C(O)NHt-Bu (92%)
1c n = 1, R1 = 4-F,
R2 = CH2C(O)NHt-Bu (93%)
The starting materials 1 for this optimization study and
for the subsequent exploration of the scope of the reaction
were synthesized from carboxylic acids 4 in a simple two-
step approach (Scheme 2). Both the Ugi reaction and amide
bond formation through activation of 4 with T3P (n-propa-
nephosphonic acid anhydride) gave amides 5 in good
yields. Treatment of 5 with catalytic amounts of gold cata-
lyst 711 at room temperature resulted in cycloisomerization
towards isatogen 6, followed by spontaneous [3+2]-cy-
cloaddition to afford pseudoindoxyls 1 in excellent yields.9
Given our group’s ongoing interest in azepinone con-
taining polyheterocycles,12 substrate 1e was chosen as a
model substrate for the screening of hydrogenation condi-
tions, expecting that the ring expansion of a six-membered
to a seven-membered ring would be more difficult than
conversion of 1a into 3a. The original 1 bar hydrogenation
was chosen as a benchmark and resulted in ca. 45% conver-
sion of 2e after 16 hours at room temperature (Table 1).
However, conversion stagnated afterwards, and even pro-
longed reaction times (up to 7 days) did not drive the reac-
tion further towards completion. This difficulty in hydroge-
nation probably arises from the steric hindrance caused by
the adjacent spirocyclic lactam. A simple increase in hydro-
gen pressure was attempted while keeping solvent and cat-
Scheme 2 Synthesis of spiropseudoindoxyls 1 from carboxylic acids 4
alyst the same. This already led to a significant increase in
conversion, while also giving rise to the formation of side
product 8 through partial hydrogenation of the benzene
ring of intermediate 2e.13
Either increasing or lowering the reaction temperature
(entries 3 and 4) was largely inefficient because this result-
ed in either a loss of hydrogenation chemoselectivity or
conversion, respectively. A solvent switch to ethanol also
had a detrimental effect on the formation of 3e. Other hy-
drogenation catalysts were also screened (entries 6 and 7)
but in these cases no indole formation was observed. How-
ever, the use of PtO2 as a catalyst facilitated a clean conver-
sion of 1e into 8, providing a facile entry to these fused
spiropyrrolinones 8. Finally, generation of a catalytic
amount of HCl in situ through hydrogenation of chloroben-
zene was evaluated (entry 8)14 but this also did not lead to
an increased formation of indoles 3e. After this limited opti-
mization study, it was decided to use the conditions de-
scribed in entry 2 (Table 1) to evaluate the scope of the re-
action.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
N. Marien et al.
Letter
Synlett
Table 1 Evaluation of Reaction Conditions for the Synthesis of 3e from 1e
NHt-Bu
O
O
O
N
NHt-Bu
NHt-Bu
N
H
O
O
O
O
O
H2
O
H2
OH
catalyst
catalyst
8
N
N
solvent
solvent
NHt-Bu
N
O
N
H
O
O
OH
2e
N
1e
N
OH
H
3e
Entry
Conditions
Ratio 2e/3e/8a
1
2
3
4
5
6
7
8
1 bar H2, 10 mol% Pd/C, MeOH, r.t.
5 bar H2, 10 mol% Pd/C, MeOH, r.t.
5 bar H2, 10 mol% Pd/C, MeOH, 10 °C
5 bar H2, 10 mol% Pd/C, MeOH, 70 °C
5 bar H2, 10 mol% Pd/C, EtOH, r.t.
5 bar H2, 10 mol% Pt/C, MeOH, r.t.
5 bar H2, 10 mol%PtO2, MeOH, r.t.
56:41:3
23:59:18
60:16:24
complex mixture
16:7:77
93:0:7
36:0:64
5 bar H2, 10 mol% Pd/C, MeOH, r.t., 10 mol% PhCl
44:28:28
a Ratios based on HPLC analysis; reactions were performed on 50 mg scale (0.025 mM); full conversion of 1e into 2e, 8 and/or 3e was observed in all cases
(HPLC).
While conversion of 1e into 3e was deemed acceptable,
isolation of 3 from the reaction mixture proved to be chal-
lenging. Indoles 3 displayed very poor solubility in most or-
ganic solvents, except for dimethyl sulfoxide (DMSO) and
warm AcOH. Considering the need to remove the heteroge-
neous Pd/C catalyst either by filtration or centrifugation,
this lack of solubility was unfortunate. A minor washing
step with DMSO after filtration was therefore introduced
during workup to circumvent this issue as much as possi-
ble. After evaporation of the methanol, the crude reaction
mixture in DMSO was purified further by direct reverse-
phase (C18) flash chromatography.
To evaluate the scope of this reaction, a number of
spiropseudoindoxyls 1 were subjected to the optimized re-
action conditions (Scheme 3). In the case of five-membered
rings 1a–d, no side product 8 formation was observed and
conversions were in general quite clean. Both electron-do-
nating and electron-withdrawing groups were tolerated
and the desired dihydro-γ-carbolinones 3a–d could be iso-
lated. For six-membered rings 1e–f, we expected yields to
be lower due to byproduct 8 formation and therefore a
more difficult chromatographic purification. This was
largely consistent with experimental observations, as indo-
loazepinones 3e–f were isolated in relatively low yields.
When a chlorine atom was used as a substituent in 1g, hy-
drogenative dechlorination and indole formation occurred
equally fast, resulting in the formation of 3f rather than 3g.
R2
O
N
O
O
R2
5 bar H2
10% Pd/C
R1
N
n
R1
N
H
N
O
MeOH
25°C, 16 h
n
HO
1
3
3a n = 1, R1 = H,
R2 = CH2C(O)NHt-Bu (55%)
3b n = 1, R1 = 4-Me,
R2 = CH2C(O)NHt-Bu (51%)
3c n = 1, R1 = 4-F,
R2 = CH2C(O)NHt-Bu (57%)
3d n = 1, R1 = 4-OMe,
R2 = CH2C(O)NHt-Bu (35%)
3e n = 2, R1 = H,
R2 = CH2C(O)NHt-Bu (31%)
3f n = 2, R1 = H,
R2 = Bn (17%)
3g n = 2, R1 = 5-Cl,
R2 = Bn (0%)
Scheme 3 Scope evaluation using the optimized conditions
Concerning the reaction mechanism, it is noteworthy
that only migration of the amide carbonyl was observed
(Scheme 4, path A), because alkyl groups are also known to
migrate after acid treatment of 3-hydroxy-2,2-dialkylindo-
lines.15 The 1,2-shift of an amide functionality in indolines
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
N. Marien et al.
Letter
Synlett
of type 2 (spirocyclic or not) has not been described previ-
ously. It has been shown that in azapinacol-type migra-
tions, substituents that stabilize a cationic center have larg-
er migratory aptitude because of the proposed 3-center-2-
electron transition state (cf. 11).16 Next to these electronic
properties of the migrating groups, the stability of the cat-
ionic intermediate also needs to be taken into account. In
our case, the migrating carbonyl group can stabilize the
generated positive charge at C through delocalization from
the amide N-atom (cf. 12). In addition, this migration leads
to a stabilized intermediate 13, whereas in the case of an al-
kyl migration the generated positive charge is destabilized
by the electron-withdrawing amide carbonyl group (cf. 14).
This result is consistent with the migration of ester groups
over alkyl groups in related Wagner–Meerwein type rear-
rangements.15–17 We were able to identify only one paper in
which a 1,2-acyl shift was observed in substituted 3-hy-
droxyindolines;8f in that case, the reduction of duocarmycin
induced the C-2 to C-3 migration of an ester carbonyl group.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588138.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References and Notes
(1) (a) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.;
Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620.
(b) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489.
(2) (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(b) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195.
(c) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29.
(3) (a) Trzupek, J. D.; Li, C.; Chan, C.; Crowley, B. M.; Heimann, A. C.;
Danishefsky, S. J. Pure Appl. Chem. 2010, 82, 173. (b) Zheng, C.;
Wu, Q.-F.; You, S.-L. J. Org. Chem. 2013, 78, 4357.
(4) (a) Hashmi, A. S. K.; Yang, W.; Rominger, F. Chem. Eur. J. 2012,
18, 6576. (b) Hashmi, A. S. K.; Yang, W.; Rominger, F. Adv. Synth.
Catal. 2012, 354, 1273. (c) Hashmi, A. S. K.; Yang, W.; Rominger,
F. Angew. Chem. Int. Ed. 2011, 50, 5762.
(5) (a) Ciamician, G.; Plancher, G. Ber. Dtsch. Chem. Ges. 1896, 29,
2475. (b) Hallett, D. J.; Gerhard, U.; Goodacre, S. C.; Hitzel, L.;
Sparey, T. J.; Thomas, S.; Rowley, M.; Ball, R. G. J. Org. Chem.
2000, 65, 4984. (c) Loh, C. C. J.; Raabe, G.; Enders, D. Chem. Eur. J.
2012, 18, 13250.
O
O
O
O
O
OH
H2
H2
NR
NR
OH
NR
OH
Pd/C
Pd/C
N
O
N
H
N
H
(6) Plancher, G. Atti Accad. Naz. Lincei, Cl. Sci. Fis., Mat. Nat., Rend.
1900, 9, 115.
1
2
9
(7) Witkop, B.; Patrick, J. B. J. Am. Chem. Soc. 1951, 73, 1558.
(8) (a) Li, G.; Xie, X.; Zu, L. Angew. Chem. Int. Ed. 2016, 55, 10483.
Other papers describing this rearrangement: (b) Berti, C.; Greci,
L.; Poloni, M. J. Chem. Soc., Perkin Trans. 1 1981, 6, 1610.
(c) Stoermer, D.; Heathcock, C. H. J. Org. Chem. 1993, 58, 564.
(d) Finch, N.; Gemenden, C. W.; Hsu, I. H.-C.; Kerr, A.; Sim, G. A.;
Taylor, W. I. J. Am. Chem. Soc. 1965, 87, 2229. (e) Wenkert, E.;
Shi, Y.-J. Synth. Commun. 1989, 19, 1071. (f) Asai, T.; Tsukada, K.;
Ise, S.; Shirata, N.; Hashimoto, M.; Fujii, I.; Gomi, K.;
Nakagawara, K.; Kodama, E. N.; Oshima, Y. Nat. Chem. 2015, 7,
737. (g) Nagamura, S.; Kanda, Y.; Asai, A.; Kobayashi, E.; Gomi,
K.; Saito, H. Chem. Pharm. Bull. 1996, 44, 933. (h) Dhara, K.;
Mandal, T.; Das, J.; Dash, J. Angew. Chem. Int. Ed. 2015, 54,
15831. (i) Guller, R.; Borschberg, H.-J. Tetrahedron: Asymmetry
1992, 3, 1197. (j) Huang, J.-R.; Qin, L.; Zhu, Y.-Q.; Song, Q.; Dong,
L. Chem. Commun. 2015, 51, 2844.
O
O
R
O
NR
C
NR
OH
N
path A
N
H
N
H
N
H
OH
11
OH
10
12
O
OH
R
N
O
NR
path B
N
H
NR
N
OH
H
N
H
O
10'
O
H
14
13
stabilized
carbenium ion
less stabilized
carbenium ion
(9) (a) Marien, N.; Brigou, B.; Pinter, B.; De Proft, F.; Verniest, G. Org.
Scheme 4 Mechanistic proposal
Lett. 2015, 17, 270. (b) For
a similar approach towards
spiropseudoindoxyls, see: Kumar, C. V. S.; Ramana, C. V. Org.
Lett. 2014, 16, 4766. (c) For pioneering work in gold-catalyzed
o-nitro alkynyl transformations, see: Asao, N.; Sato, K.;
Yamamoto, Y. Tetrahedron Lett. 2003, 44, 5675.
In conclusion, we synthesized piperidinone and azepa-
none fused indoles through a Wagner–Meerwein type 1,2-
amide migration of 2-spiroindolinones. The proposed am-
ide migration is unprecedented in indolines and offers a
simple procedure that facilitates access to these interesting
polyheterocycles.18–21
(10) Camilleri, M.; Northcutt, A. R.; Kong, S.; Dukes, G. E.; McSorley,
D.; Mangel, A. W. Lancet 2000, 355, 1035.
(11) Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejovic, E.
Angew. Chem. Int. Ed. 2004, 43, 6545.
(12) (a) Schurgers, B.; Van Lommen, G.; Verniest, G. Eur. J. Org. Chem.
2015, 3572. (b) Jida, M.; Van der Poorten, O.; Guillemyn, K.;
Urbanczyk-Lipkowska, Z.; Tourwé, D.; Ballet, S. Org. Lett. 2015,
17, 4482.
Acknowledgment
(13) Pfeiffer, G.; Bauer, H. Liebigs Ann. Chem. 1980, 564.
(14) Rahaim, R. J. Jr.; Maleczka, R. E. Jr. Org. Lett. 2011, 13, 584.
(15) Kagan, J.; Agdeppa, D. A. Jr.; Mayers, D. A.; Singh, S. P.; Walters,
M. J.; Wintermute, R. D. J. Org. Chem. 1976, 41, 2355.
The authors acknowledge the Vrije Universiteit Brussel (starting grant
for G.V. and AAP-PhD Fellowship for N.M.) and the Research Fund-
Flanders (FWO-KN249) for financial support.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
N. Marien et al.
Letter
Synlett
(16) (a) Berner, D.; Dahn, H.; Vogel, P. Helv. Chim. Acta 1980, 63,
2538. (b) Berner, D.; Cox, P. D.; Dahn, H. J. Am. Chem. Soc. 1982,
104, 2631.
dichloro(2-pyridinecarboxylato)gold (11.4 mg, 0.029 mmol) in
one portion. The resulting mixture was stirred at room tem-
perature for 4 h. Subsequently, the reaction was concentrated in
vacuo, followed by the addition of ethyl acetate (6 mL, 0.1 M rel-
ative to 1a). This resulted in the formation of a gray precipitate,
which was separated by decantation. The decanted organic
phase was filtered through a silica plug, washed with additional
EtOAc and concentrated in vacuo. Both the precipitate and the
solid obtained from the EtOAc fraction were deemed pure based
on HPLC and NMR analysis and combined to afford the desired
spiropseudoindoxyl 1a (84%, 0.17 g, 0.5 mmol) as a gray solid.
Mp 206–207 °C (decomp.). IR (neat): 3332, 2970, 2933, 1682
(17) Kong, C.; Driver, T. G. Org. Lett. 2015, 17, 802.
(18) Synthesis of carboxylic acids 4; Typical procedure for 4a. A
flame-dried, three-necked, flat-bottom flask was charged with
DMSO (35 mL). CO2 was dried by sublimating dry ice and
bubbled through two wash bottles containing concentrated sul-
furic acid, similar to Vogel’s procedure. The dried CO2 was
bubbled through the DMSO solution for 5 min before adding the
reagents. Caesium fluoride (3.12 g, 20.5 mmol) was dissolved in
the stirring mixture and 1-(2-nitrophenyl)-2-trimethylsily-
lacetylene (3.00 g, 13.7 mmol) was added subsequently by
using a syringe. After reaction for 2 h at room temperature, the
mixture was acidified with 2 M aq HCl and extracted with ethyl
acetate (5 × 75 mL). The combined organic phases were concen-
trated to a total volume of ca. 150 mL, washed with brine
(5 × 150 mL), dried over magnesium sulfate, filtered and con-
centrated in vacuo to afford the desired carboxylic acid 4a (90%,
2.36 g, 12.3 mmol) as a pale-pink solid. 1H NMR (250 MHz,
DMSO-d6): δ = 14.22 (br s, 1 H), 8.23 (dd, J = 7.5, 1.5 Hz), 7.75–
7.95 (m, 3 H). 13C NMR (63 MHz, DMSO-d6): δ = 153.9, 149.5,
135.5, 134.1, 131.8, 125.2, 124.8, 87.3, 79.1.
(br), 1606, 909, 727 cm–1 1H NMR (500 MHz, CDCl3): δ = 7.71
.
(m, 2 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.33 (t, J = 7.5 Hz; 1 H), 5.94
(br s, 1 H), 4.03–3.86 (m, 4 H), 3.83 (dd, J = 9.5, 5.2 Hz, 1 H), 3.50
(dd, J = 10.0, 4.9 Hz), 3.41 (m, 1 H), 1.38 (s, 9 H). 13C NMR (125
MHz, CDCl3): δ = 195.1, 168.6, 166.2, 162.9, 137.8, 126.9, 126.1,
124.3, 119.0, 83.0, 73.3, 51.9, 51.2, 48.7, 44.6, 28.9. HRMS: m/z
[M + H]+ calcd: 344.1605; found: 344.1606.
(21) Hydrogenation towards indoles 3; Typical procedure for 3a.
A Teflon insert for a Parr hydrogenation vessel was flushed with
argon and charged with spiropseudoindoxyl 1a (240 mg, 0.70
mmol). After dissolving this solid in methanol (10 mL; ca. 0.05
M), the resulting solution was flushed again with argon. Palla-
dium on carbon (74 mg, 10wt%, 0.07 mmol.) was added in one
portion, followed by rinsing of the insert walls with methanol if
necessary. The reaction mixture was then subjected to 5 bar of
hydrogen in a Parr series 4793 high-pressure vessel and stirred
for 16 h at room temperature. Subsequently, the reaction
mixture was transferred to a vial of appropriate size and centri-
fuged to afford a semiclear solution, which was filtered through
a plug of Celite. The precipitated solid was washed with MeOH
(2 × 5 mL) and DMSO (1 mL) in MeOH (5 mL) and the centrifu-
gation/filtration steps were repeated. The resulting solution
was concentrated in vacuo until only the DMSO (ca. 1 mL)
remained. This crude mixture was purified by reverse-phase
column chromatography with liquid loading and using Milli-Q
water+0.1% TFA / acetonitrile+0.1% TFA as eluents (see the Sup-
porting Information for gradient details). Acetonitrile and tri-
fluoroacetic acid were evaporated and the remaining water was
removed by freeze-drying to afford the desired fused indole 3a
(55%, 126 mg, 0.38 mmol) as a white solid. Mp 241–242 °C. IR
(19) Synthesis of amides 5; Typical procedure for 5a. A round-
bottom flask was charged with carboxylic acid 4a (250 mg, 1.3
mmol) dissolved in methanol (0.1 M). Subsequently, formalde-
hyde (37% in water; 97 μL, 1.3 mmol) and allylamine (98 μL, 1.3
mmol) were added and the resulting mixture was stirred for 15
min at room temperature. tert-Butyl isocyanide (148 μL, 1.3
mmol) was added and the reaction was heated to 50 °C and
stirred overnight. Upon completion, the reaction mixture was
concentrated in vacuo, dissolved in EtOAc (25 mL), and washed
with aqueous saturated NaHCO3 (25 mL), 1 M aq HCl (25 mL)
and brine (25 mL). The organic phase was dried over magne-
sium sulfate, filtered, and concentrated in vacuo. The resulting
crude mixture was purified by silica gel column chromatogra-
phy (EtOAc/hexanes, 50%) to afford the desired amide 5a (75%,
0.34 g, 0.98 mmol) as a red oil. Rf 0.27 (EtOAc/hexanes, 50%). IR
(neat): 3325, 3088, 3064, 2974, 2224, 1684, 1648, 1567,
1341 cm–1 1H NMR (250 MHz, CDCl3): δ = 8.08 (m, 1 H), 7.73
.
(m, 1 H), 7.60 (m, 2 H), 6.09 and 5.84* (br s, 1 H), 5.88–5.63 (m,
1 H), 5.20 (m, 2 H), 4.36 and 4.11* (d, J = 6.0 Hz, 2 H), 4.17 and
3.90* (s, 2 H), 1.27 and 1.25* (s, 9 H). 13C NMR (63 MHz, CDCl3):
δ = 167.0 and 168.8*, 154.7 and 154.3*, 149.4, 136.3 and 136.1*,
133.7 and 133.6*, 132.0 and 131.6, 131.0, 125.2, 119.1, 115.9,
87.5 and 87.2*, 85.3 and 84.5*, 52.9 and 51.63*, 51.8 and 51.56*,
49.7 and 48.6*, 28.7. HRMS: m/z [M + H]+ calcd: 344.1605;
found: 344.1612. * Double signals due to rotamers across the C–
N bond of the amide as well as the carbamate.
(neat): δ = 1660, 1623, 1489, 1454, 1218, 1177, 785, 741 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 11.60 (br s, 1 H), 7.91 (d,
J = 7.5 Hz, 1 H), 7.53 (br s, 1 H), 7.41 (d, J = 7.5 Hz, 1 H), 7.11 (m,
2 H), 5.00 (br s, 1 H), 4.08 (d, J = 15.4 Hz, 1 H), 3.94 (d,
J = 15.4 Hz, 1 H), 3.77 (m, 2 H), 3.66 (dd, J = 9.2, 8.5 Hz, 1 H),
3.57 (dd, J = 12.2, 6.4 Hz, 1 H), 3.24 (qt, J = 5.7 Hz, 1 H), 1.28 (s,
9 H). 13C NMR (125 MHz, DMSO-d6): δ = 168.4, 164.1, 144.6,
136.2, 125.2, 121.6, 120.6, 119.6, 111.7, 105.2, 61.6, 50.2, 49.8,
48.8, 36.3, 28.6. HRMS: m/z [M + H]+ calcd: 330.1812; found:
330.1810.
(20) Gold-catalyzed cycloisomerization towards spiropseudoin-
doxyls 1; Typical procedure for 1a. A round-bottom flask was
charged with amide 5a (200 mg, 0.58 mmol) and dissolved in
toluene (6 mL; 0.1 M relative to 1a). To this solution was added
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E