Concise Total Syntheses of Paullone and Kenpaullone via Cyanide-Catalyzed Intramolecular Imino-Stetter Reaction

Article abstract of DOI:10.1055/s-0036-1588749

Highly concise total syntheses of paullone and kenpaullone were developed. Cyanide-catalyzed intramolecular imino-Stetter reaction of aldimines derived from methyl 2-aminocinnamate derivatives and 2-nitrobenzaldehyde provided 2-(2′-nitrophenyl)indole-3-acetic acid derivatives. Subsequent reduction of the nitro group with zinc under acidic conditions to an amino group followed by spontaneous lactam formation allowed for the total syntheses of paullone and kenpaullone to be completed in two steps starting from commercially available materials. The direct use of a nitro group as the precursor of an amino group present in the phenyl ring at the 2-position in the indole ring significantly streamlined the total syntheses of these target molecules..

Full text of DOI:10.1055/s-0036-1588749

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
A
special topic
S. E. Lee et al.
Special Topic
Synthesis
Concise Total Syntheses of Paullone and Kenpaullone via Cyanide-
Catalyzed Intramolecular Imino-Stetter Reaction
OHC
O
CO2Me
O
Sang Eun Lee
R
R
R
CN– (cat.)
Seong Jong Lee
Cheol-Hong Cheon*
OMe
OMe
O2N
imino-Stetter
reaction
N
N
NH2
H
O2N
R = H or Br
O2N
Department of Chemistry, Korea University,
145 Anam-ro, Seongbuk-gu, Seoul 02841,
Republic of Korea
commercially available
not isolated
reduction of
NO2 to NH2
cheon@korea.ac.kr
O
CO2Me
spontaneous
lactam
NH
R
R
formation
N
N
H
H
H2N
Paullone (R = H)
Kenpaullone (R=Br) 72%
50%
not isolated
two separation steps
Received: 01.02.2017
O
Accepted after revision: 22.02.2017
Published online: 14.03.2017
DOI: 10.1055/s-0036-1588749; Art ID: ss-2017-c0063-st
Paullone (1a)
R = H
NH
C
R
9
Kenpaullone (1b)
Alsterpaullone (1c)
R = Br
R = NO2
B
A
D
N
Abstract Highly concise total syntheses of paullone and kenpaullone
were developed. Cyanide-catalyzed intramolecular imino-Stetter reac-
tion of aldimines derived from methyl 2-aminocinnamate derivatives
and 2-nitrobenzaldehyde provided 2-(2′-nitrophenyl)indole-3-acetic
acid derivatives. Subsequent reduction of the nitro group with zinc un-
der acidic conditions to an amino group followed by spontaneous lact-
am formation allowed for the total syntheses of paullone and ken-
paullone to be completed in two steps starting from commercially
available materials. The direct use of a nitro group as the precursor of
an amino group present in the phenyl ring at the 2-position in the in-
dole ring significantly streamlined the total syntheses of these target
molecules.
H
Figure 1 Structures of paullone and its derivatives
Considering their interesting biological activities and
structural features, several distinct approaches have been
developed for the syntheses of paullone and its deriva-
tives.2–7 The first strategy involves the formation of a B-ring
from phenylhydrazine 2 with the seven-membered cyclic
ketone 3 via Fischer indolization (Scheme 1 a).2 Using this
strategy, Kunick et al. reported several examples for the to-
tal synthesis of paullone and its derivatives. The second
strategy involves the formation of a seven-membered C-
ring by several disconnections (Scheme 1 b).3–5 One ap-
proach in this strategy was the amide formation between
indole-3-acetic acid 4 and 2-halogenated aniline deriva-
tives 5, followed by intramolecular Heck coupling at the C-2
position of the indole moiety of the resulting indole-3-acet-
amide derivatives 6.3 Alternatively, paullone and its deriva-
tives were prepared from 2-functionalized indole-3-acetic
acid derivatives 7 and N-protected 2-halogenated aniline
derivatives P-5 by arylation at the C-2 position in the indole
ring followed by C-ring formation through amide formation
of the resulting 2-arylindole-3-acetic acid derivatives 8.4
For example, Baudoin et al. constructed 2-functionalized
indole-3-acetic acid derivatives 7 by palladium-catalyzed
borylation at the 2-position of the indole ring. Subsequent
Suzuki coupling reaction of the resulting 2-indoleboronic
acid 7 with N-protected 2-haloaniline derivatives P-5,
deprotection of the amino group, and intramolecular amide
formation completed the total synthesis of paullone.
Key words paullone, kenpaullone, total synthesis, cyanide-catalyzed
imino-Stetter reaction, umpolung of aldimines
Because paullone (1a) and its derivatives 1b,c (Figure 1)
exhibit interesting biological activities such as the potent
inhibition of cyclin-dependent kinase (CDK) and glycogen
synthase kinase 3 (GSK 3), it is important to develop effi-
cient synthetic routes for paullone and its derivatives.1 The
biological activities of paullone and its derivatives show a
strong dependence on the substitution pattern in the in-
dole moiety, particularly an electron-withdrawing substit-
uent at the C-9 position of the indole ring; therefore, signif-
icant efforts have been made to develop a more facile meth-
od for preparing paullone derivatives.2–7
In addition to their biological activities, paullone and its
derivatives have unique structural features; they contain a
tetra-fused heterocyclic structure bearing a seven-mem-
bered biaryl lactam ring (C-ring) between the indole and
aryl moieties.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
S. E. Lee et al.
Special Topic
Synthesis
a) Previous work - five-membered B ring formation
O
O
NH2
NH
NH
NH
NH
NH
+
R
R
R
Fischer Indolization
B
O
R
N
H
2
3
1
b) Previous work - seven-membered C ring formation
Amide formation followed by intramolecular Heck coupling
H2N
O
O
HO2C
NH
X
R
R
C
5 (X = Br, I)
X
intramolecular
Heck coupling
amide
formation
N
N
N
H
H
H
4
6
1
C-2 arylation followed by lactam formation
H
N
P
O
O
R'O2C
OR'
X
R
R
P-5 (X = Br, I)
C
deprotection;
Y
lactam
formation
arylation at
C-2 position
N
N
H
N
H
H
HN
Y = B(OR)2
P
7
8
1
c) Previous work - B and C ring formation
H
N
from isonitrile
P
R'O2C
O
X
R
P-5 (X = Br, I)
R
HSnBu3/AIBN
OR'
Y
B
O
or
N
B2(pin)2, Cu(I) (cat.)
NC
H
OR'
9
7
R
Y = B(pin), SnBu3
deprotection;
via α-aminonitriles
P
B
O
HN
N
O
lactam
formation
H
HN
R
O
OR'
P
CN
8
R
O
OR'
t-BuONa
N
11
H
NH
NH2
HCN
HN
R
C
10
12
P
B
O
N
H
d) This work
O
1
O
O
OR'
R
O2N
R
R
OR'
CN– (cat.)
OR'
reduction;
13
B
imino-Stetter
reaction
spontaneous
cyclization
N
N
NH2
H
O2N
O2N
not isolated
10
14
I
Scheme 1 Previous synthetic routes for the total synthesis of paullone and its derivatives
The third strategy involves the formation of a B-ring
followed by the formation of a seven-membered C-ring
(Scheme 1 c).6,7 The research groups of Beneteau and
Chatani adopted this strategy and successfully completed
the total synthesis of paullone.6 In their approaches, the
boron species at the 2-position of the indole ring. Subse-
quent arylation of indole 7 with N-protected 2-haloaniline
derivatives P-5 generated a 2-(N-protected 2′-aminophe-
nyl)indole-3-acetic acid derivative 8, which was further
converted to paullone via deprotection followed by lactam
formation. In 2008, Opatz et al. developed a new synthetic
route to access paullone using this bond disconnection.7
Treatment of the Strecker product 12, obtained from 2-ami-
nocinnamic acid derivatives 10 and N-protected 2-amino-
radical cyclization of cinnamic acid derivatives 9 bearing an
6a,8
isonitrile group at the ortho-position with HSnBu3
or
copper-catalyzed borylative cyclization of isonitrile 96b pro-
vided indole-3-acetic acid derivatives 7 bearing either tin or
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
S. E. Lee et al.
Special Topic
Synthesis
benzaldehyde 11, with a stoichiometric amount of a strong
base provided similar indole-3-acetic acid derivatives 8.
Subsequent deprotection of the amino group and intramo-
lecular amide formation provided the paullone product.
Despite these successful results in the previous total
syntheses of paullone and its derivatives, most of the previ-
ous syntheses required relatively lengthy synthetic se-
quences with respect to the size and complexity of these
target molecules. This is probably because most of the pre-
vious approaches directly utilized ortho-functionalized ani-
line derivatives, either 5 or 11, as the precursor of the ami-
no group present in the seven-membered C-ring, requiring
lengthy synthetic sequences in not only the preparation of
parent 2-functionalized anilines9 but also the protec-
tion/deprotection of the amino group in the required ani-
line derivatives. Thus, it is highly desired to develop a more
efficient synthetic route for paullone and its derivatives uti-
lizing readily available starting materials for the prepara-
tion of a sufficient amount of the sample for further biolog-
ical evaluation.
Herein, we report highly concise total syntheses of
paullone (1a) and kenpaullone (1b) from commercially
available 2-aminocinnamic acid derivatives 10 and 2-nitro-
benzaldehyde (13). Cyanide-catalyzed imino-Stetter reac-
tion of the aldimines I derived from 2-aminocinnamic acid
derivatives 10 and 2-nitrobenzaldehyde (13) provided 2-
(2′-nitrophenyl)indole-3-acetic acid derivatives 14. Subse-
quent reduction of the nitro group in the phenyl group at
the 2-position to an amino group under acidic conditions
provided 2-(2-aminophenyl)indole-3-acetates, which un-
derwent spontaneous lactam formation under the same
conditions to afford paullone and kenpaullone in only two
separation steps from commercially available starting ma-
terials (Scheme 1 d).
(a) Retrosynthetic analysis of paullone and its derivatives
O
O
O
NH
R
R
OR'
H
+
NH2
10
O2N
13
N
H
1
reduction;
lactamization
aldimine
formation
O
O
OR'
R
CN– (cat.)
OR'
R
N
imino-Stetter
reaction
N
H
O2N
O2N
I
14
5-exo-trig
cyclization
CN–
O
O
R
R
proton transfer
OR'
CN
OR'
CN
H
N
N
H
O2N
O2N
II
III
(b) Working hypothesis of imino-Stetter reaction
Scheme 2 (a) Retrosynthetic analysis for the synthesis of paullone and
its derivatives, and (b) working hypothesis of imino-Stetter reaction
Very recently, our group developed a new method to ac-
cess 2-substituted indole-3-acetic acid derivatives from al-
dimines obtained from 2-aminocinnamic acid derivatives
and aromatic/α,β-unsaturated aldehydes via cyanide-cata-
lyzed imino-Stetter reaction.10,11 Based on this protocol, we
hypothesized that the key intermediates 14 in our approach
for the total synthesis of paullone and its derivatives could
be prepared using a similar protocol from aldimines I de-
rived from 2-aminocinnamic acid derivatives 10 and 2-ni-
trobenzaldehyde (13) in the presence of cyanide. The cya-
nide adducts II of aldimines I could undergo proton transfer
from the α-carbon atom to the nitrogen atom, generating
umpolung III of aldimines. Imino-Stetter reaction of the re-
sulting carbanionic intermediates III would afford indole-3-
acetic acid derivatives 14 bearing an o-nitrophenyl group at
the C-2 position (Scheme 2 b).
Although most of the previous approaches utilized N-
protected 2-functionalized aniline derivatives, either 5 or
11,3–7 we envisioned that if a nitro group were used as the
precursor of the amino group present in the phenyl moiety
at the 2-position in the indole ring, the synthetic sequence
for paullone and its derivatives would be significantly
streamlined because 1) 2-nitrobenzaldehyde (13) is com-
mercially available and 2) the direct use of a nitro group as
the precursor of the amino group would eliminate the pro-
tection/deprotection of the amino group.
Based on this idea, the retrosynthetic analysis of
paullone and its derivatives is described in Scheme 2.
Paullone and its derivatives could be prepared from 2-(2′-
nitrophenyl)indole-3-acetates 14 through the reduction of
the nitro group to an amino group, followed by lactam for-
mation. Indole-3-acetic acid derivatives 14 could be pre-
pared from aldimines I derived from 2-aminocinnamates
10 and 2-nitrobenzaldehyde (13), which would be the key
for the success in our approach.
With this idea in mind, we first started the total synthe-
sis of paullone (1a) by optimizing the imino-Stetter reac-
tion of aldimine Ia derived from methyl 2-aminocinnamate
(10a) and 2-nitrobenzaldehyde (13) (Table 1). When aldi-
mine Ia was subjected to the reaction conditions10 previ-
ously used for imino-Stetter reaction with a catalytic
amount of cyanide, rather disappointingly, the desired in-
dole product 14 was obtained in a very low yield only, and a
considerable amount of aldimine Ia remained unreacted
(Table 1, entry 1). To increase the yield of indole product 14,
the same transformation was performed with 30 mol% of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
S. E. Lee et al.
Special Topic
Synthesis
cyanide. Although the yield of 14 increased, rather unex-
pectedly, a few by-products, iminonitrile A and dihydro-
quinoline B, were obtained in low yields (entry 2).
O
O
OMe
OMe
NaCN
H
H
CN
N
N
Table 1 Optimization of Imino-Stetter Reaction of Ia
O2N
Ia
O2N
II
O
proton
transfer
hydride
transfer
OMe
O
k1
k2
OMe
NaCN (x mol%)
N
O
O
H
4 Å MS, DMF
temp (°C), 6 h
N
O2N
14
OMe
CN
OMe
CN
O2N
H
O
O
+
N
Ia
N
H
(1.0 mmol)
OMe
OMe
CN
O2N
III
A
O2N
+
N
N
+ Ia
imino-Stetter
Reaction
O2N
O2N
O
A
H
O
B
OMe
OMe
Entry
NaCN (x mol%)
Temp (°C)
Yield (%) of 14 (ratio A/B)a,b
N
1
10
30
60
60
60
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
trace (N.D.)
12 (10:9)
32 (29:26)
53 (26:16)
51 (21:13)
N.D.
N
H
O2N
O2N
B
14
2
3
100
100
50
Scheme 3 A rationale for the formation of indole 14 and by-products
A and B from cyanide adduct II
4
5
transfer, that is, k1 > k2, this reaction was carried out with a
stoichiometric amount of cyanide expecting that the rate of
hydride transfer (k2) will decrease by decreasing the con-
centration of hydride acceptor, namely free aldimine Ia,
leading to the improvement of the yield of the desired in-
dole product 14. When the reaction was performed with a
stoichiometric amount of cyanide, to our delight, the yield
of the desired indole product 14 increased to 32%, even
though we could not prevent the formation of by-products
(Table 1, entry 3). When the reaction was performed at
room temperature, the yield of indole product 14 was fur-
ther improved to 52% (entry 4). Furthermore, the amount of
cyanide was reduced to 50 mol% without any loss of its effi-
ciency (entry 5). However, when the reaction was per-
formed with less than 50 mol% of cyanide, the yield of the
desired product 14 decreased, and a large amount of aldi-
mine Ia remained unreacted in the reaction mixture (en-
tries 6 and 7). In addition, the reaction could be performed
using a one-pot protocol starting from methyl 2-aminocin-
namate (10) and 2-nitrobenzaldehyde (13) without the iso-
lation of aldimine intermediate Ia, and the desired product
14 was obtained in a similar yield (entry 8). Furthermore,
the same transformation could be carried out in a 10 mmol
scale without any loss of its efficiency (entry 9).
6
20
7
10
N.D.
8c
9d
50
50 (N.D.)
52 (N.D.)
50
a The values in parentheses indicate the yields of by-products A and B.
b N.D.: Not determined.
c Reaction was performed using 10 and 13 without the isolation of aldimine
Ia.
d Reaction conducted in 10 mmol scale.
With these results in hand, we sought to rationalize the
formation of indole 14 along with other by-products
(Scheme 3). Cyanide adduct II, generated by the addition of
cyanide to aldimine Ia, could undergo two possible reaction
pathways.12 As expected, cyanide adduct II underwent pro-
ton transfer from the α-carbon atom to the nitrogen atom
providing carbanionic intermediate III. Subsequent intra-
molecular imino-Stetter reaction to the adjacent α,β-unsat-
urated ester moiety furnished the expected indole product
14. On the other hand, the hydride transfer in cyanide ad-
duct II could provide iminonitrile A.13 The resulting hydride
undergoes Michael addition to the α,β-unsaturated ester
moiety in aldimine Ia, and subsequent addition of the re-
sulting enolate to aldimine moiety leads to dihydroquino-
line B.
With this indole compound 14 in hand, the total syn-
thesis of paullone (1a) was completed (Scheme 4). Reduc-
tion of the nitro group with zinc metal in acetic acid to an
amino group provided the corresponding amino compound
15.14 This spontaneously underwent lactam formation un-
der the same conditions affording paullone (1a) in quanti-
These results strongly indicate that the cyanide adduct
II had the two pathways (proton transfer and hydride trans-
fer),12 and the two pathways probably compete with each
other. To increase the rate of proton transfer over hydride
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

E
S. E. Lee et al.
Special Topic
Synthesis
tative yield (Scheme 4). Overall, we completed the total
synthesis of paullone (1a) in 52% overall yield in two steps
starting from commercially available materials.
cyanide-catalyzed imino-Stetter,15 we were able to com-
plete the total synthesis of kenpaullone (1b) in only two
steps from commercially available starting materials.
In conclusion, we have developed highly concise total
syntheses of paullone (1a) and kenpaullone (1b) starting
from commercially available materials. Cyanide-catalyzed
imino-Stetter reactions of aldimines derived from 2-amino-
cinnamate derivatives and 2-nitrobenzaldehyde provided
the corresponding indole-3-acetic acid derivatives 14 and
16 bearing a 2′-nitrophenyl moiety at the 2-position of the
indole ring. Subsequent reduction of the nitro group to an
amino group with zinc under acidic conditions and sponta-
neous lactam formation of the resulting amino group al-
lowed us to complete the total syntheses of paullone and
kenpaullone. The direct use of a nitro group as the precur-
sor of the amino group in the lactam ring present in
paullone and kenpaullone significantly streamlined the to-
tal syntheses of paullone and kenpaullone leading to the
completion of these target molecules in only two steps
starting from commercially available materials. Further ap-
plication of imino-Stetter reaction to the total synthesis of
other indole alkaloids and the elucidation of role of bro-
mine substituent on imino-Stetter reaction are currently
underway.
O
O
NH
OMe
Zn, AcOH
MeOH, 60 °C
N
N
H
H
quantitative
O2N
14
paullone (1a)
O
OMe
lactam
formation
reduction
N
H
H2N
15
not isolated
Scheme 4 End game in the total synthesis of paullone (1a)
With this successful result in hand, we further attempt-
ed to extend this strategy to the total synthesis of ken-
paullone (1b) (Scheme 5). In this case, methyl 2-amino-5-
bromocinnamate (10-Br) was used instead of methyl 2-
aminocinnamate (10). When aldimine Ib, in situ derived
from methyl 2-amino-5-bromocinnamate (10-Br) and 2-ni-
trobenzaldehyde (13), was subjected to the optimized con-
ditions for the synthesis of paullone, rather surprisingly, the
desired indole product 16 was obtained in 74% yield with-
out any formation of by-products such as the correspond-
ing iminonitrile and dihydroquinoline. Furthermore, the
amount of cyanide could be decreased to 10 mol% without
any loss of the efficiency in this transformation. Subsequent
treatment of indole 16 with zinc in acidic conditions pro-
vided the desired kenpaullone (1b) in quantitative yield via
the reduction of the nitro group to an amino group fol-
lowed by spontaneous lactam formation. Although at this
moment, we do not clearly understand the role of the bro-
mine substituent at the 5-position in aldimines during the
All the reactions were carried out in oven-dried glassware under an
argon atmosphere, unless otherwise noted. Except as otherwise indi-
cated, all the reactions were magnetically stirred and monitored by
analytical TLC using pre-coated silica gel glass plates (0.25 mm) with
F254 indicator. Visualization was accomplished by UV light (254 nm).
Flash column chromatography was performed using silica gel 60
(230–400 mesh). Yields refer to chromatographically and spectro-
scopically pure compounds, unless otherwise noted. Methyl 2-amino-
cinnamate (10) and its 5-bromo analogue 10-Br were purchased from
Aldrich. Other commercial grade reagents and solvents were used
without further purification. 1H NMR and 13C NMR spectra were re-
corded using 500 and 125 MHz spectrometers, respectively. TMS (δ =
0.0) and a residual NMR solvent, either CDCl3 (δH: 7.26, δC: 77.16) or
DMSO (δH: 2.50, δC: 39.52), were used as internal standards for 1H
NMR and 13C NMR spectra, respectively. The 1H NMR spectra are re-
ported as follows: δ (position of proton, multiplicity, coupling con-
stant J, and number of protons). Standard abbreviations for indicating
multiplicities are used. High-resolution mass spectra (HRMS) were
recorded on quadrupole time-of-flight mass spectrometer (QTOF-MS)
using electrospray ionization (ESI).
O
O
O
H
Br
OMe
13
Br
OMe
O2N
N
Dean–Stark distillation
toluene, 120 °C
NH2
10-Br
O2N
Ib
Synthesis of Paullone (1a)
not isolated
O
O
Methyl 2-[2-(2-Nitrophenyl)-1H-indol-3-yl]acetate (14)
OMe
NH
A solution of methyl 2-aminocinnamate (10; 1.8 g, 10 mmol) and 2-
nitrobenzaldehyde (13; 1.5 g, 10 mmol) in toluene (100 mL) was
stirred at 120 °C for overnight using a Dean–Stark apparatus, and the
reaction was monitored by 1H NMR analysis. After completion of the
aldimine formation, the reaction mixture was concentrated under re-
duced pressure. Then, the crude mixture was dissolved in DMF (50
mL), and NaCN (0.24 g, 5 mmol) and 4Å MS (1.5 g) were added to the
reaction mixture. The mixture was stirred at r.t. and the reaction
NaCN
(10 mol%)
Br
Br
Zn, AcOH
4 Å MS, DMF, rt
MeOH, 60 °C
N
N
H
H
O2N
72%
quantitative
kenpaullone (1b)
16
with 100 mol% NaCN 74%
Scheme 5 Total synthesis of kenpaullone (1b)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
S. E. Lee et al.
Special Topic
Synthesis
progress was monitored by TLC. After complete consumption of aldi-
mine Ia, the mixture was filtered to remove 4Å MS and the filtrate
was concentrated under reduced pressure. Chromatography (EtOAc/
hexane, 1:5 v/v, 1:3 v/v, and then 1:2 v/v) furnished 14 as a yellow
liquid in 52% (1.6 g, 5.2 mmol mg) yield along with other by-products
A and B (Table 1).
1H NMR (CDCl3, 500 MHz): δ = 8.29 (br, 1 H), 7.99 (d, J = 8.1 Hz, 1 H),
7.69 (m, 2 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.6 (m, 1 H), 7.36 (d, J = 8.1 Hz, 1
H), 7.25 (m, 1 H), 7.18 (m, 1 H), 3.63 (s, 5 H).
13C NMR (CDCl3, 125 MHz): δ = 172.2, 149.9, 136.1, 133.8, 132.8,
130.9, 129.9, 127.9, 126.7, 124.6, 123.3, 120.4, 119.4, 111.3, 108.4,
52.2, 30.8.
HRMS (ESI): m/z [M + Na]+ calcd for C17H14N2O4Na: 333.0846; found:
333.0846.
Synthesis of Kenpaullone (1b)
Methyl 2-[5-Bromo-2-(2-nitrophenyl)-1H-indol-3-yl]acetate (16)
Same protocol for the synthesis of 14 was followed, except 10-Br was
used instead of 10. Compound 16 was obtained as a yellow solid in
72% yield (0.56 g, 1.4 mmol); mp 151–152 °C.
1H NMR (CDCl3, 500 MHz): δ = 8.30 (br, 1 H), 8.02 (d, J = 8.1 Hz, 1 H),
7.77 (s, 1 H), 7.70 (m, 2 H), 7.63 (m, 1 H), 7.33 (dd, J = 8.6, 1.6 Hz, 1 H),
7.24 (d, J = 8.5 Hz, 1 H), 3.65 (s, 3 H), 3.57 (s, 2 H).
13C NMR (CDCl3, 125 MHz): δ = 171.8, 149.8, 134.7, 133.8, 133.0,
132.2, 130.2, 129.6, 126.2, 126.2, 124.7, 122.1, 113.7, 112.8, 108.0,
52.3, 30.6.
HRMS (ESI): m/z [M + Na]+ calcd for C17H13BrN2O4Na: 410.9951;
found: 410.9952.
Compound A
Kenpaullone [9-Bromo-7.12-dihydroindolo[3,2-d][1]benzazepin-
6(5H)-one, 1b]
1H NMR (CDCl3, 500 MHz): δ = 8.18 (dd, J = 8.2, 1.3 Hz, 1 H), 7.89 (m, 3
H), 7.80 (m, 1 H), 7.73 (d, J = 7.2 Hz, 1 H), 7.53 (m, 1 H), 7.41 (m, 1 H),
7.28 (m, 1 H), 6.46 (d, J = 16 Hz, 1 H), 3.81 (s, 3 H).
13C NMR (CDCl3, 125 MHz): δ = 167.2, 147.9, 147.2, 139.9, 138.3,
134.3, 132.7, 131.4, 131.3, 129.9, 128.7, 127.9, 127.6, 125.4, 120.2,
119.1, 110.5, 52.0.
Same protocol for the synthesis of paullone (1a) was followed, except
16 was used instead of 14. Kenpaullone (1b) was obtained as a pale
yellow solid in quantitative yield (0.46 g, 1.4 mmol); mp >250 °C.
Spectroscopic data were in good agreement with those reported in
the literature.3d
HRMS (ESI): m/z [M + Na]+ calcd for C18H13N3O4Na: 358.0798; found:
358.0799.
1H NMR (DMSO-d6, 500 MHz): δ = 11.83 (br, 1 H), 10.16 (s, 1 H), 7.92
(d, J = 1.7 Hz, 1 H), 7.74 (d, J = 6.7 Hz, 1 H), 7.39 (m, 2 H), 7.27 (m, 3 H),
3.53 (s, 2 H).
13C NMR (DMSO-d6, 125 MHz): δ = 171.6, 136.1, 135.7, 134.1, 128.5,
128.4, 127.1, 124.6, 123.8, 122.4, 122.4, 120.5, 113.5, 111.8, 107.2,
31.4.
HRMS (ESI): m/z [M + Na]+ calcd for C16H11BrN2ONa: 348.9947; found:
348.9949.
Compound B
1H NMR (CDCl3, 500 MHz): δ = 7.90 (m, 2 H), 7.56 (ddd, J = 8.3, 7.1, 1.2
Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.32 (m, 1 H), 7.25 (m, 1 H), 7.18 (dtd,
J = 8.6, 7.7, 0.8, 2 H), 5.7 (t, J = 6.3 Hz, 1 H), 3.77 (s, 3 H), 3.12 (dd, J =
16.3, 6.1 Hz, 1 H), 2.89 (dd, J = 16.5, 6.4 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): δ = 170.8, 160.1, 146.8, 135.1, 133.0,
132.9, 129.8, 125.3, 123.6, 122.0, 120.4, 113.2, 110.9, 59.8, 52.5, 40.8.
HRMS (ESI): m/z [M + Na]+ calcd for C17H14N2O3Na: 317.0897; found:
317.0905.
Acknowledgment
This work was supported by the National Research Foundation of
Korea (NRF) grants funded by the Korean Government (NRF-
20100020209 and NRF-2015R1D1A1A01057200). C.-H.C. is also
thankful for financial support from an NRF grant funded by the Kore-
an Government (NRF-2014-011165, Center for New Directions in Or-
ganic Synthesis).
Paullone [7,12-Dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 1a]
To a solution of 14 (0.31 g, 1 mmol) in MeOH (10 mL) were added Zn
(0.32 g, 5 mmol) and AcOH (0.57 mL, 10 mmol) and the reaction mix-
ture was stirred at 60 °C overnight. After complete consumption of 14,
the mixture was cooled to r.t. Then, the mixture was filtered to re-
move the remaining Zn and the filtrate was concentrated in vacuo.
The mixture was partitioned between aq NH4Cl and EtOAc. The or-
ganic layer was dried (MgSO4) and concentrated in vacuo. The crude
mixture was further purified by fresh column chromatography on sil-
ica to furnish paullone (1a) as a pale yellow solid in quantitative yield
(0.24 g, 0.99 mmol); mp >250 °C. Spectroscopic data were in good
agreement with those reported in the literature.2–7
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588749.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References
1H NMR (DMSO-d6, 500 MHz): δ = 11.60 (br, 1 H), 10.11 (s, 1 H), 7.75
(dd, J = 7.7, 1.6 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 1 H), 7.44 (d, J = 8.1 Hz, 1 H)
7.37 (d, J = 6.9 Hz, 1 H), 7.27 (m, 2 H), 7.18 (m, 1 H), 7.08 (m, 1 H), 3.50
(s, 2 H).
(1) (a) Zaharevitz, D. W.; Gussio, R.; Leost, M.; Senderowicz, A. M.;
Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E. A. Cancer Res.
1999, 59, 2566. (b) Leost, M.; Schultz, C.; Link, A.; Wu, Y.-Z.;
Biernat, J.; Mandelkow, E.-V.; Bibb, J. A.; Snyder, G. L.;
Greengard, P.; Zaharevitz, D. W.; Gussio, R.; Senderowicz, A. M.;
Suasville, E. A.; Kunick, C.; Meijer, L. Eur. J. Biochem. 2000, 267,
5983. (c) Pies, T.; Schaper, K.-J.; Leost, M.; Zaharevitz, D. W.;
Gussio, R.; Meijer, L.; Kunick, C. Arch. Pharm. (Weinheim) 2004,
337, 486. (d) Tolle, N.; Kunick, C. Curr. Top. Med. Chem. 2011, 11,
1320.
13C NMR (DMSO-d6, 125 MHz): δ = 171.6, 137.4, 135.4, 132.5, 128.0,
126.9, 126.6, 123.7, 122.9, 122.3, 122.1, 119.1, 118.0, 111.5, 107.6,
31.6.
HRMS (ESI): m/z [M + Na]+ calcd for C16H12N2ONa: 271.0842; found:
271.0843.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
S. E. Lee et al.
Special Topic
Synthesis
(2) (a) Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.; Gussio, R.;
Sausville, E. A.; Meijer, L.; Kunick, C. J. Med. Chem. 1999, 42,
2909. (b) Kunick, C.; Schultz, C.; Lemcke, T.; Zaharevitz, D. W.;
Gussio, R.; Jalluri, R. K.; Sausville, E. A.; Leost, M.; Meijer, L.
Bioorg. Med. Chem. Lett. 2000, 10, 567. (c) Wieking, K.;
Knockaert, M.; Leost, M.; Zaharevitz, D. W.; Meijer, L.; Kunick, C.
Arch. Pharm. (Weinheim) 2002, 335, 311. (d) Kunick, C.;
Lauenroth, K.; Leost, M.; Meijer, L.; Lemcke, T. Bioorg. Med.
Chem. Lett. 2004, 14, 413. (e) Stukenbrock, H.; Mussmann, R.;
Geese, M.; Ferandin, Y.; Lozach, O.; Lemcke, T.; Kegel, S.;
Lomow, A.; Burk, U.; Dohrmann, C.; Meijer, L.; Austen, M.;
Kunick, C. J. Med. Chem. 2008, 51, 2196.
(3) (a) Joucla, L.; Putey, A.; Joseph, B. Tetrahedron Lett. 2005, 46,
8177. (b) Avila-Zarraga, J. G.; Lujan-Montelongo, A.;
Covarrubias-Zuniga, A.; Romero-Ortega, M. Tetrahedron Lett.
2006, 47, 7987. (c) Joucla, L.; Popowyca, F.; Lozach, O.; Meijer,
L.; Joseph, B. Helv. Chim. Acta 2007, 90, 753. (d) For another
approach through this disconnection via photocyclization of
indole-3-acetamide derivatives, see: Li, Z.; Lu, N.; Wang, L.;
Zhang, W. Eur. J. Org. Chem. 2012, 1019.
(9) N-Protected 2-aminobenzaldehyde 11 was generally prepared
from o-nitrobenzaldehyde in 4 steps. For recent examples, see:
(a) Storz, M. P.; Maurer, C. K.; Zimmer, C.; Wagner, N.; Brengel,
C.; de Jong, J. C.; Lucas, S.; Musken, M.; Haussler, S.; Steinbach,
A.; Hartmann, R. W. J. Am. Chem. Soc. 2012, 134, 16143.
(b) Raven, W.; Selig, P. Org. Lett. 2014, 16, 5192.
(10) (a) Lee, S. J.; Seo, H.-A.; Cheon, C.-H. Adv. Synth. Catal. 2016, 358,
1566. (b) Seo, H.-A.; Cheon, C.-H. J. Org. Chem. 2016, 81, 7917.
(11) For the application of this approach toward skeleton-divergent
total syntheses of rutaecarpine and luotonin A, see: Kwon, S. H.;
Seo, H.-A.; Cheon, C.-H. Org. Lett. 2016, 18, 5280.
(12) For similar competing pathways from cyanide adducts II of ald-
imines, see: Seo, H.-A.; Cho, Y.-H.; Lee, Y.-S.; Cheon, C.-H. J. Org.
Chem. 2015, 80, 11993.
(13) For previous examples of the formation of iminonitriles from
the cyanide adducts II of aldimines without any additives, see:
Jursic, B. S.; Douelle, F.; Bowdy, K.; Stevens, E. D. Tetrahedron
Lett. 2002, 43, 5361.
(14) For previous examples of the reduction of nitro group with zinc
metal, see: (a) Ferenc, D.; Opatz, T. Org. Lett. 2006, 8, 4473.
(b) Kratz, F.; Warnecke, A. J. Org. Chem. 2008, 73, 1546.
(c) Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori, M.;
Kawasaki, T. Org Lett. 2009, 11, 197. (d) Cid, M. B.; Duce, S.;
Morales, S.; Rodrigo, E.; Ruano, J. L. G. Org. Lett. 2010, 12, 3586.
(e) Xu, Z.; Hu, W.; Liu, Q.; Zhang, L.; Jia, Y. J. Org. Chem. 2010, 75,
7626.
(15) For previous examples of the difference in reactivity depending
on Br substituents, see: (a) Cho, C.-G.; Kim, Y.-W.; Lim, Y.-K.;
Park, J.-S.; Lee, H.; Koo, S. J. Org. Chem. 2002, 67, 290. (b) Gao, L.;
Hwang, G.-S.; Ryu, D. H. J. Am. Chem. Soc. 2011, 133, 20708.
(c) Shim, S. Y.; Kim, J. Y.; Nam, M.; Hwang, G.-S.; Ryu, D. H. Org
Lett. 2016, 18, 160.
(4) Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem.
2002, 67, 1199.
(5) Although it was not shown in Scheme 1, another strategy via
the seven-membered C-ring formation through free radical
cyclization of N-[2-(1H-indol-2-yl)phenyl]-N-benzyl-2-iodoac-
etamides has been reported, see: Bremner, J. B.; Sengpracha, W.
Tetrahedron 2005, 61, 5489.
(6) (a) Henry, N.; Blu, J.; Beneteau, V.; Merour, J.-Y. Synthesis 2006,
3895. (b) Tobisu, M.; Fujihara, H.; Koh, K.; Chatani, N. J. Org.
Chem. 2010, 75, 4841.
(7) Ferenc, D.; Opatz, T. Synthesis 2008, 3941.
(8) For the original study on the indolization from isonitrile 9, see:
Peng, G.; Chen, X.; Fukuyama, T. J. Am. Chem. Soc. 1994, 116,
3127.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G