Synthesis of unique analogues of the ergoline skeleton using intramolecular [3+2] cycloaddition

Article abstract of DOI:10.1055/s-0033-1341053

A new methodology is described for the novel and rapid synthesis of unique analogues of the ergoline structure. After introduction of an allyl or alkynyl group in position C-4 on indole-3-carboxaldehyde, an intramolecular 1,3-dipolar cycloaddition using α-amino esters, directly provides novel ergoline-type compounds in good yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341053

1106▌
LETTER
lSetyternthesis of Unique Analogues of the Ergoline Skeleton Using Intramolecular
[3+2] Cycloaddition
Synthesis of Unique Analogues of the Ergoline Skeleton
Sébastien Picard, Frédéric Lecornué,* Georges Bashiardes*
Organic Synthesis Group, Institut de Chimie des Milieux et des Matériaux de Poitiers, UMR-CNRS 7285, TSA 51106, Université de Poitiers,
4 Rue Michel Brunet, Bât B28, 86073 Poitiers Cedex 9, France
Fax +33(5)49453501; E-mail: frederic.lecornue@univ-poitiers.fr; E-mail: gbashiardes@hotmail.com
Received: 08.01.2014; Accepted after revision: 02.03.2014
O
O
Abstract: A new methodology is described for the novel and rapid
synthesis of unique analogues of the ergoline structure. After intro-
duction of an allyl or alkynyl group in position C-4 on indole-3-car-
boxaldehyde, an intramolecular 1,3-dipolar cycloaddition using α-
amino esters, directly provides novel ergoline-type compounds in
good yields.
HO
Et2N
Me
Me
Me
N
N
N
D
H
H
H
C
A
B
Key words: intramolecular 1,3-dipolar cycloaddition, Stille reac-
tion, Sonogashira reaction, microwave, ergoline
N
N
N
H
H
H
ergoline (1)
lysergic acid (2)
LSD (3)
MeS
O
Me2N
Pr
N
The ergot alkaloids are derivatives containing the ergoline
ring system 1 (Figure 1). They display a large diversity of
pharmacological properties, that include central, peripher-
al, and neurohormonal activity due to binding to adrener-
gic, dopaminergic and serotonergic receptors.1 Lysergic
acid (2) has been a major synthetic target and so have been
the analogous derivatives LSD (3) or the anti-prolactin
drug cabergoline (4). Additionally, pergolide 5 is known
to act as a partial agonist at the dopamine receptor and has
been used for treating Parkinson’s disease.2 Several deriv-
atives in which the D ring is variably substituted are used
clinically as labor-inducing agents as well as anti-
migraine, analgesic, and anti-Parkinson’s therapeutics.3
Starting from indole-3-carboxaldehyde (6a) or 2-methyl-
indole-3-carboxaldehyde (6b), we report herein the diver-
gent synthesis of novel alkaloid-type derivatives 11 and
12, that are ergoline analogues, using an intramolecular
[3+2] cycloaddition as the key step to form the C and D
ring system (Scheme 1).
N
H
N
N
H
O
H
N
H
N
H
cabergoline (4)
pergolide (5)
Figure 1 Different ergolines and analogous structures
CO2R2
R2O2C
TMS
E
N
D
R3
D
N
R3
C
C
R1
R1
B
N
A
A
B
N
Boc
Boc
11
12
intramolecular
[3+2] cycloaddition
As outlined in Scheme 2, the synthesis of 7a,b was per-
formed in three steps from indole-3-carboxaldehydes
6a,b. Firstly, the Hollins procedure was found to be the
best technique to introduce iodine at C-4 of the indole
ring.4 Thus, the reaction of 6a or 6b and thallium(III) tri-
fluoroacetate in trifluoroacetic acid produced the thallium
intermediate in position C-4. This intermediate then react-
ed with potassium iodide to afford compounds 13a and
13b as the only regioisomers. Finally, N-Boc protection
afforded compounds 7a and 7b in 93% and 74% overall
yields, respectively.5
TMS
n
CHO
R1
CHO
R1
N
N
Boc
8 (n = 0)
or 9 (n = 1)
Boc
10
Stille
coupling
Sonogashira
coupling
I
CHO
R1
CHO
With these two iodo compounds in hand, we chose to first
introduce a vinyl or an allyl group at C-4 position by a
Stille6 reaction, using the procedure developed by the
R1
N
N
H
Boc
6
7
SYNLETT 2014, 25, 1106–1110
Advanced online publication: 27.03.2014
DOI: 10.1055/s-0033-1341053; Art ID: ST-2014-D0022-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic approach for the synthesis of analogues 11
and 12
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Synthesis of Unique Analogues of the Ergoline Skeleton
1107
I
ture of inseparable polar compounds was also observed.
We postulate that the vinyl group is either at a great dis-
tance or in an unfavorable orientation such that it cannot
react with the generated azomethine ylide to achieve cy-
cloaddition.
CHO
R1
N
H
CHO
R1
1. Tl(OCOCF3)3
F3CCO2H, r.t., overnight
2. KI, H2O, r.t., 4 h
N
H
6a R1 = H
6b R1 = Me
13a,b
I
TMS
CHO
Boc2O, DMAP
THF, r.t., 2 h
R1
I
CHO
CHO
TMS
(1.2 equiv)
H
N
Boc
7a R1 = H, 93%
7b R1 = Me, 74%
(3 steps)
PdCl2(Ph3P)2 (0.05 equiv)
CuI (0.1 equiv), THF
0 °C to r.t., 2 h, 96%
N
N
Boc
Boc
7a
10
Scheme 2 Iodination and N-Boc protection of 6a and 6b
Scheme 4 Sonogashira reaction with compound 7
group of Buchwald and co-workers (Scheme 3).7 Com-
pound 7a and tributylvinylstannane, in the presence of
catalytic amount of Pd(Ph3P)4, afforded the vinyl precur-
sor 8 in excellent 94% yield. Similarly, the allyl group was
introduced by Pd-catalyzed reaction of allyltributylstan-
nane with 7a or 7b to afford 9a or 9b in 87% and 80%
yield, respectively.8 These compounds were readily iso-
lated after purification by eluting through a short column
of silica gel and the resulting white solids were washed
with pentane to remove any traces of tin residues.
O
O
H
H
CO2Me
14c
N
Ph
N
Me
OMe
OEt
N
H
14a
14b
Figure 2 α-Amino esters used in cycloadditions with 8, 9 and 10
R2O2C
R3
amino ester
14a–c
(2 equiv)
X
N
CHO
toluene
(Δ) reflux or MW
N
I
CHO
Boc
N
CHO
n-Bu3Sn
Boc
15a–c
8
(1.1 equiv)
N
Pd(Ph3P)4 (0.05 equiv)
THF, reflux, overnight
94%
N
Scheme 5 [3+2] Cycloaddition between 8 and 14
Boc
Boc
7a
8
However the study was pursued using the allyl derivatives
9a and 9b for the 1,3-dipolar cycloaddition (Scheme 6) in
the presence of α-amino esters 14a–c (Figure 2). In this
case, condensation led directly to the expected novel alka-
loids 11. The cycloaddition reactions were achieved suc-
cessfully by condensation of 9a or 9b and 14a–c in
toluene under conventional thermal conditions or under
microwave irradiation. Tetracyclic and pentacyclic com-
pounds 11a–e were isolated as a mixture of two diastereo-
mers except for 11b (Figure 3) in good to excellent yields
under both sets of conditions (Table 1).12
I
CHO
R1
CHO
R1
n-Bu3Sn
(1.1 equiv)
Pd(Ph3P)4 (0.05 equiv)
THF, reflux, overnight
N
N
Boc
Boc
9a R1 = H, 87%
9b R1 = Me, 80%
7a,b
Scheme 3 Stille reaction with compounds 7a,b
In parallel, a Sonogashira reaction was employed on com-
pound 7a to synthesize the alkyne precursor 10 (Scheme
4).9 Inspired by the procedure of Johnson and co-work-
ers,10 a mixture of compound 7a and trimethylsilylacety-
lene in the presence of a catalytic amount of Pd(II)/CuI
afforded compound 10 in 96% yield.11
R2O2C
N
amino ester
14a–c
(2 equiv)
CHO
R1
R3
R1
Having obtained these precursors, we proceeded to study
the 1,3-dipolar cycloaddition between α-amino esters
14a–c (Figure 2) and vinyl derivative 8 (Scheme 5). Con-
trary to our expectations, in all experiments the formation
of desired compounds 15a–c was not observed. The start-
ing material was recovered in up to 60% yield and a mix-
toluene
(Δ) reflux or MW
N
N
Boc
11a–e
Boc
9a R1 = H
9b R1 = Me
Scheme 6 [3+2] Cycloaddition between 9a,b and 14
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1106–1110

1108
S. Picard et al.
LETTER
served that the starting material 10 was completely con-
sumed contrary to the observations with 8. This suggests
that the alkyne function is indeed relatively accessible to
react with the azomethine ylide.
CO2Me
CO2Et
N
MeO2C
N
N
Me
CO2R2
N
N
N
TMS
Boc
Boc
Boc
11c
dr = 60:40
TMS
NR1
11b
11a
dr = 70:30
CHO
CO2Me
amino ester
14a–b (2 equiv), S8
MeO2C
N
Me
N
toluene, (Δ) reflux
N
N
Boc
24 h
Boc
10
16
N
N
CO2Me
Me
CO2Et
N
Boc
11d
dr = 95:5
Boc
11e
dr = 80:20
TMS
TMS
N
Ph
Figure 3 Compounds 11a–e obtained by [3+2] cycloaddition
Table 1 Comparative Yield of Cycloaddition Reactions
N
N
Boc
16a, 38%
Boc
Product R1
Thermala Microwaveb
16b, 87%
Entry Reagents
Yield
(%)
Time
(min)
Yield
(%)
Scheme 7 [3+2] Cycloaddition between 10 and 14
In conclusion, aldehydes 8–10 have been prepared from
the indole-3-carboxaldehydes 6a,b. Intramolecular [3+2]-
cycloadditions with α-amino ester derivatives were
achieved efficiently under both thermal or microwave
conditions. Thus, we have developed a convenient meth-
odology to access novel alkaloid-type analogues of the er-
goline structure, in good to excellent overall yield.
1
2
3
4
5
9a + 14a
9a + 14b
9a + 14c
9b + 14a
9b + 14c
11a
11b
11c
11d
11e
H
95
75
97
84
90
15
45
10
20
15
99
90
98
97
95
H
H
Me
Me
a All reactions were carried out at reflux in toluene for 24 h.
b All reactions were carried out at 110 °C under 100 W irradiation.
Acknowledgment
Financial support from CNRS and the University of Poitiers is gra-
tefully acknowledged. S.P. thanks the Ministère de l’Enseignement
Supérieur et de la Recherche for a doctoral grant. Practical assi-
stance from S. Jebert is also acknowledged.
Under conventional thermal conditions, the reaction was
complete after several hours at reflux. Under microwave
irradiation, the reaction was performed using a minimal
amount of toluene.12 Microwave irradiation reduced the
time of the reaction and significantly increased the yield,
especially for entries 2 and 4 (Table 1). Moreover, an add-
ed advantage of using microwave irradiation conditions
resided in the observation that the crude reaction mixture
was practically devoid of side products, allowing a very
simple purification by filtration through a short column of
silica gel without prior workup.
References and Notes
(1) (a) Ninomiya, I.; Kigushi, T. In The Alkaloids: Chemistry
and Pharmacology; Vol. 38; Brossi, A., Ed.; Academic
Press: San Diego, 1990, 1. (b) Stadler, P. A.; Floss, H. G. In
Natural Products and Drugs Development; Krogsgaard-
Larsen, P.; Christensen, S. B.; Kofod, H., Eds.; Munksgaard:
Copenhagen, 1984, 467.
(2) Lieberman, A. N.; Leibowitz, M.; Neophytides, A.;
Kupersmith, M.; Mehl, S.; Kleinberg, D.; Serby, M.;
Goldstein, M. Lancet 1979, 314, 1129.
(3) Somei, M.; Yokoyama, Y.; Murakami, Y. In The Alkaloids;
Vol. 54; Academic Press: San Diego, 2000, 191.
(4) Hollins, R. A.; Colnago, L. A.; Salim, V. M.; Seidl, M. C.
J. Heterocycl. Chem. 1979, 16, 993.
(5) General Procedure for the Synthesis of 7a,b: Under a
nitrogen atmosphere, a solution of indole-3-carboxaldehyde
(6a) or 2-methylindole-3-carboxaldehyde (6b; 1 mmol) and
thallium trifluoroacetate (1.2 mmol) in trifluoroacetic acid (2
mL/mmol) was stirred overnight at r.t. and the solvent was
then removed under reduced pressure. The residue was
dissolved in H2O (4 mL/mmol) and then KI (4 mmol) was
added. The reaction mixture was stirred for 4 h at r.t.,
The study was pursued further using the alkyne precursor
with the hypothesis that the dipole generated should be in
the same plane as the azomethine ylide. Indeed, when the
aldehyde 10 was condensed with α-amino ester 14a or
14b, pyrroles 16a and 16b were isolated in 38% and 87%
yields, respectively (Scheme 7).13 These reactions were
performed in toluene, under conventional thermal condi-
tions, in the presence of sulfur, following a procedure
known in our laboratory to afford directly the expected
pyrrole compound in one pot.14 In the case of 16a, the re-
action also produced a mixture of inseparable polar com-
pounds, similar to the condensation of 8 and 14, probably
due to a secondary polymerization reaction. We also ob-
Synlett 2014, 25, 1106–1110
© Georg Thieme Verlag Stuttgart · New York

LETTER
quenched with aq sat. Na2S2O3 and then extracted several
Synthesis of Unique Analogues of the Ergoline Skeleton
1109
1741, 1686, 1640, 1255, 1149, 1010, 918 cm–1. HMRS (EI):
m/z calcd for C17H19NO3Na: 308.12626; found: 308.12584.
1-(tert-Butoxycarbonyl)-4-allyl-2-methylindole-3-
carboxaldehyde (9b): 80% yield; white powder; mp 168
°C. 1H NMR (300 MHz, CDCl3): δ = 1.71 (s, 9 H), 2.94 (s, 3
H), 3.86 (d, J = 5.4 Hz, 2 H), 4.87 (dd, J = 17.2, 1.7 Hz, 1 H),
5.07 (dd, J = 10.2, 1.7 Hz, 1 H), 6.06 (ddt, J = 17.2, 10.2, 5.4
Hz, 1 H), 7.14 (d, J = 7.9 Hz, 1 H), 7.27 (t, J = 7.9 Hz, 1 H),
8.01 (d, J = 7.9 Hz, 1 H), 10.42 (s, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 15.3, 28.6, 40.0, 86.1, 113.7, 116.6, 119.5,
125.0, 125.8, 126.5, 132.4, 136.6, 137.3, 147.3, 150.1,
188.6. IR: 3075, 3011, 1751, 1665, 1272, 1142, 1004, 927
cm–1. MS (EI): m/z (%) = 300.0 (70) [MH]+, 251.7 (61),
200.4 (56), 176.6 (31), 143.3 (47), 122.8 (100).
times with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was
dissolved in anhyd THF (10 mL/mmol), and then DMAP
(1.5 mmol) was added, followed by the addition of Boc2O (2
mmol). The reaction mixture was stirred for 2 h at r.t.,
quenched with an aq sat. NH4Cl solution, and then extracted
with Et2O several times. The combined organic layers were
washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The crude residue was
purified by chromatography on silica, eluting with pentane–
EtOAc (95:5), to give 7a,b.
1-(tert-Butoxycarbonyl)-4-iodoindole-3-carboxaldehyde
(7a): 93% yield; white powder; mp 108 °C. 1H NMR (300
MHz, CDCl3): δ = 1.67 (s, 9 H), 7.08 (t, J = 8.0 Hz, 1 H),
7.82 (d, J = 8.0 Hz, 1 H), 8.32 (d, J = 8.0 Hz, 1 H), 8.38 (s,
1 H), 11.22 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 28.0,
83.1, 86.0, 115.4, 120.7, 126.2, 130.2, 132.3, 135.6, 136.9,
148.0, 185.8. IR: 3155, 3055, 1752, 1670, 1253, 1149 cm–1.
MS (EI): m/z (%) = 372.1 (47) [MH]+, 338.7 (61), 272.4
(100), 214.4 (48).
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) For a review on Sonogashira reaction,
see: Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
(10) Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582.
(11) 1-(tert-Butoxycarbonyl)-4[(trimethylsilyl)ethynyl]-
indole-3-carboxaldehyde (10): Under a nitrogen
atmosphere, a solution of 1-(tert-butoxycarbonyl)-4-
iodoindole-3-carboxaldehyde (7a; 1 mmol),
1-(tert-Butoxycarbonyl)-4-iodo-2-methylindole-3-
carboxadehyde (7b): yield: 74%; white powder; mp 109
°C. 1H NMR (300 MHz, CDCl3): δ = 1.67 (s, 9 H), 2.91 (s, 3
H), 6.97 (t, J = 8.1 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 8.14
(d, J = 8.1 Hz, 1 H), 11.22 (s, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 15.2, 28.1, 81.8, 86.2, 115.0, 117.5, 125.3,
129.8, 135.8, 136.3, 146.1, 149.1, 187.7. IR: 3136, 3054,
1751, 1665, 1254, 1139 cm–1. HMRS (EI): m/z calcd for
C15H16INO3Na: 408.00727; found: 408.00846.
dichlorobis(triphenylphosphine)palladium (0.05 mmol),
copper(I) iodide (0.1 mmol) and trimethylsilylacetylene (1.2
mmol) in anhyd THF (10 mL/mmol) was stirred for 10 min
at 0 °C and then Et3N (3 mmol) was added dropwise. The
reaction mixture was stirred for 2 h at r.t., quenched with an
aq sat. NH4Cl solution and then extracted with Et2O. The
organic layer was dried over MgSO4, filtered and
concentrated under reduced pressure. The crude mixture was
purified by chromatography on silica, eluting with pentane–
Et2O (90:10), to give 10 in 96% yield as a white powder; mp
136 °C. 1H NMR (300 MHz, CDCl3): δ = 0.30 (s, 9 H), 1.68
(s, 9 H), 7.32 (t, J = 8.0 Hz, 1 H), 7.50 (dd, J = 8.0, 1.0 Hz,
1 H), 8.26 (dd, J = 8.0, 1.0 Hz, 1 H), 8.36 (s, 1 H), 10.99 (s,
1 H). 13C NMR (75 MHz, CDCl3): δ = –0.3, 28.0, 85.8, 99.4,
104.3, 114.6, 116.3, 121.4, 124.9, 127.7, 129.3, 130.8,
136.0, 148.6, 187.6. IR: 2151, 1749, 1676, 1252, 1149, 859
cm–1. HMRS (EI): m/z calcd for C19H23NO3NaSi:
(6) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100,
3636. (b) For a review of the Stille reaction, see: Heravi, M.
M.; Hashemi, E.; Azimian, F. Tetrahedron 2014, 70, 7.
(7) Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem.
1994, 59, 7164.
(8) General Procedure for the Synthesis of 8 and 9: Under a
nitrogen atmosphere, a solution of 7 (1 mmol),
tetrakis(triphenylphosphine)palladium (0.05 mmol) and
allyltributylstannane or tributylvinylstannane (1.1 mmol) in
anhyd THF (10 mL/mmol) was heated overnight at reflux.
The reaction mixture was quenched with brine and then
extracted several times with Et2O. The combined organic
layers were dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by
chromatography on silica, eluting with pentane–EtOAc
(90:10).
1-(tert-Butoxycarbonyl)-4-vinylindole-3-carboxaldehyde
(8): 94% yield; white powder; mp 90 °C. 1H NMR (300
MHz, CDCl3): δ = 1.70 (s, 9 H), 5.42 (d, J = 10.9 Hz, 1 H),
5.75 (d, J = 17.3 Hz, 1 H), 7.37 (t, J = 7.9 Hz, 1 H), 7.54 (d,
J = 7.9 Hz, 1 H), 7.94 (dd, J = 17.3, 10.9 Hz, 1 H), 8.14 (d,
J = 7.9 Hz, 1 H), 8.27 (s, 1 H), 10.05 (s, 1 H). 13C NMR (75
MHz, CDCl3): δ = 28.0, 85.7, 114.4, 115.6, 121.4, 123.0,
123.9, 125.9, 133.0, 136.7, 137.0, 138.6, 148.4, 184.9. IR:
3127, 3092, 1753, 1686, 1255, 1152, 996, 908 cm–1. HMRS
(EI): m/z calcd for C16H17NO3Na: 294.11061; found:
294.11092.
1-(tert-Butoxycarbonyl)-4-allylindole-3-carboxaldehyde
(9a): 87% yield; white powder; mp 91 °C. 1H NMR (300
MHz, CDCl3): δ = 1.70 (s, 9 H), 4.01 (d, J = 6.0 Hz, 2 H),
4.91 (dd, J = 17.1, 1.7 Hz, 1 H), 5.04 (dd, J = 10.2, 1.7 Hz,
1 H), 6.06 (ddt, J = 17.1, 10.2, 6.0 Hz, 1 H), 7.19 (d, J = 8.0
Hz, 1 H), 7.36 (t, J = 8.0 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H),
8.30 (s, 1 H), 10.08 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ
= 28.1, 39.4, 85.6, 113.4, 115.6, 122.8, 125.1, 125.8, 126.0,
134.3, 137.0, 137.3, 137.5, 148.6, 185.4. IR: 3115, 3075,
364.13499; found: 364.13352.
(12) General Procedure for the Synthesis of 11:
Thermal Conditions: A solution of 8 or 9 (1 mmol) and α-
amino ester 14 (2 mmol) in toluene (10 mL) was stirred and
heated at reflux for 24 h. After evaporation of the solvent
under reduced pressure, the crude product was purified by
short column chromatography on silica.
Microwave Conditions: In a pyrex tube (2 × 15 mm), 8 or
9 (1 mmol) and α-amino ester 14 (2 mmol) in toluene (0.5
mL) were submitted to microwave irradiation (CEM
Discoverer apparatus; 100 W, 110 °C) for 5 min. After
cooling, the crude product was purified by short column
chromatography on silica gel.
1-(tert-Butoxycarbonyl)-8-methyl-9-methyl-6,6a,7,8,9a-
pentahydro-9-azaindeno[4,5,6-cd]indole-2,8-
dicarboxylate (11a): 95% yield (Δ) and 99% yield (MW);
yellow oil as a mixture of two diastereomers which were
separated by column chromatography. Major diastereomer:
yellow oil. 1H NMR (300 MHz, CDCl3): δ = 1.68 (s, 9 H),
1.87–2.02 (m, 1 H), 2.13–2.25 (m, 1 H), 2.63 (s, 3 H), 2.81–
2.91 (m, 2 H), 3.07 (dd, J = 18.2, 7.4 Hz, 1 H), 3.53 (dd, J =
9.8, 4.9 Hz, 1 H), 3.74 (s, 3 H), 4.35 (d, J = 4.3 Hz, 1 H), 6.98
(d, J = 8.0 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.53 (s, 1 H),
7.76 (d, J = 8.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ =
28.2, 30.2, 34.2, 36.2, 38.0, 51.6, 58.9, 63.7, 83.6, 112.6,
115.1, 120.4, 121.7, 125.1, 128.7, 129.4, 133.0, 150.2,
174.8. IR: 3019, 2980, 2951, 1735, 1718, 1439, 1370, 1301,
1281, 1256, 1216, 1149, 1120, 755, 667 cm–1. HMRS (EI):
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1106–1110

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S. Picard et al.
LETTER
407.19663. Minor diastereoisomer: viscous oil. 1H NMR
m/z calcd for C21H26N2O4Na: 393.17903; found: 393.17895.
Minor diastereomer: yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 1.66 (s, 9 H), 1.85–1.96 (m, 1 H), 2.17–2.32 (m,
1 H), 2.43–2.55 (m, 1 H), 2.73 (s, 3 H), 2.87 (dd, J = 15.7,
12.0 Hz, 1 H), 3.13 (dd, J = 15.7, 3.9 Hz, 1 H), 3.76 (s, 3 H),
3.99 (dd, J = 8.7, 2.0 Hz, 1 H), 4.02 (dd, J = 8.4, 6.5 Hz, 1
H), 7.00 (d, J = 8.0 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.45
(s, 1 H), 7.76 (d, J = 8.0 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 28.2, 32.5, 33.6, 37.3, 43.7, 51.7, 64.0, 65.7,
83.4, 112.9, 117.3, 119.4, 120.5, 125.2, 130.2, 132.0, 133.6,
150.2, 174.6. IR: 3016, 2980, 1740, 1702, 1458, 1440, 1370,
1240, 1216, 1153, 755, 666 cm–1. HMRS (EI): m/z calcd for
C21H26N2O4Na: 393.17903; found: 393.17801.
(300 MHz, CDCl3): δ = 1.66–1.80 (m, 10 H), 2.30–2.56 (m,
5 H), 2.67–2.80 (m, 4 H), 3.22 (dd, J = 15.6, 3.9 Hz, 1 H),
3.69 (dd, J = 8.8, 6.3 Hz, 1 H), 3.76 (s, 3 H), 3.95 (d, J = 10.8
Hz, 1 H), 6.97 (d, J = 8.0 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H),
7.78 (d, J = 8.0 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ =
16.1, 28.4, 32.0, 33.0, 39.3, 39.6, 52.1, 64.7, 68.5, 83.4,
113.4, 115.4, 120.4, 124.0, 129.2, 130.5, 130.6, 135.0,
151.0, 175.1. IR: 2980, 2929, 1734, 1446, 1370, 1327, 1214,
1146, 1098, 755, 668 cm–1. HMRS (EI): m/z calcd for
C22H28N2O4Na: 407.19468; found: 407.19622.
2-(tert-Butoxycarbonyl)-7a-methyl-1-methyl-
6a,9,10,11a-tetrahydro-6H-indolo[4,3-f,g]pyrrolo-[1,2-
a]indole-2,7a-dicarboxylate 11e: 90% yield (Δ) and 95%
yield (MW); viscous oil, mixture of two inseparable
diastereoisomers (ratio 80:20). 1H NMR (300 MHz, CDCl3):
δ = 1.50–3.20 (m, 46 H), 3.78 (s, 6 H), 4.00 (dd, J = 11.5, 2.0
Hz, 1 H), 4.47 (d, J = 5.2 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 2 H),
7.17 (t, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.0 Hz, 2 H). 13C NMR
(75 MHz, CDCl3): δ = 14.7, 14.9, 25.8, 26.4, 28.2, 28.3,
31.4, 32.5, 37.8, 38.5, 40.1, 41.1, 42.8, 43.1, 50.5, 52.2, 52.4,
57.5, 64.5, 71.9, 83.6, 84.7, 113.3, 113.4, 114.0, 120.1,
120.4, 123.7, 123.9, 124.9, 126.6, 128.6, 130.5, 133.8,
134.0, 134.5, 136.8, 150.0, 174.0. IR: 3020, 2980, 1729,
1442, 1385, 1374, 1296, 1281, 1213, 1151, 1132, 755, 670
cm–1. HMRS (EI): m/z calcd for C24H30N2O4Na: 433.21033;
found: 433.21232.
1-(tert-Butoxycarbonyl)-8-ethyl-9-benzyl-6,6a,7,8,9a-
pentahydro-9-azaindeno[4,5,6-cd]indole-2,8-
dicarboxylate (11b): 75% yield (Δ) and 90% yield (MW);
viscous yellow oil as a single diastereomer. 1H NMR (300
MHz, CDCl3): δ = 1.18 (t, J = 7.1 Hz, 3 H), 1.68 (s, 9 H),
1.95–2.08 (m, 1 H), 2.10–2.20 (m, 1 H), 2.71–2.84 (m, 1 H),
2.90–3.00 (m, 2 H), 3.62 (dd, J = 9.3, 5.1 Hz, 1 H), 3.96 (d,
J = 13.6 Hz, 1 H), 4.05 (q, J = 7.1 Hz, 2 H), 4.19 (d, J = 13.6
Hz, 1 H), 4.48 (d, J = 4.7 Hz, 1 H), 7.00 (d, J = 7.2 Hz, 1 H),
7.15–7.30 (m, 6 H), 7.53 (s, 1 H), 7.77 (d, J = 7.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 14.2, 28.3, 30.6, 34.5, 38.2,
52.3, 57.0, 60.3, 60.8, 83.6, 112.6, 116.1, 120.2, 122.3,
125.7, 126.9, 128.2, 128.5, 130.1, 133.1, 133.2, 139.3,
150.1, 174.8. IR: 3020, 2980, 1725, 1440, 1394, 1371, 1346,
1215, 1152, 1130, 756, 669 cm–1. HMRS (EI): m/z calcd for
C28H32N2O4Na: 483.22598; found: 483.22678.
(13) General Procedure for the Synthesis of 16: A solution of
10 (1 mmol), α-amino ester 14 (2 mmol) and sulfur (approx.
100 mg) in toluene (10 mL) was stirred and heated at reflux
for 24 h. After evaporation of the solvent under reduced
pressure, the crude product was purified by short column
chromatography on silica gel.
2-(tert-Butoxycarbonyl)-7a-methyl-6a,9,10,11a-
tetrahydro-6H-indolo[4,3-fg]pyrrolo-[1,2-a]indole-2,7a-
dicarboxylate (11c): 97% yield (Δ) and 98% (MW); viscous
oil, mixture of two inseparable diastereomers (ratio 60:40).
1H NMR (300 MHz, CDCl3): δ = 1.50–3.40 (m, 40 H), 3.78
(s, 6 H), 4.08 (d, J = 10.0 Hz, 1 H), 4.59 (d, J = 4.9 Hz, 1 H),
7.01 (d, J = 7.8 Hz, 2 H), 7.24 (t, J = 7.8 Hz, 2 H) 7.49 (s, 1
H), 7.69 (s, 1 H), 7.75–7.90 (m, 2 H). 13C NMR (75 MHz,
CDCl3): δ = 25.9, 26.7, 28.2, 31.5, 31.6, 37.6, 38.5, 39.7,
41.1, 42.1, 42.2, 51.2, 51.6, 52.5, 52.6, 57.3, 64.5, 76.1, 83.4,
83.6, 112.8, 113.0, 115.4, 117.7, 118.5, 120.3, 120.5, 122.6,
125.0, 125.2, 129.2, 129.9, 130.3, 131.6, 150.0, 177.1,
177.6. IR: 3020, 2980, 2952, 1727, 1439, 1386, 1371, 1297,
1281, 1215, 1152, 1132, 756, 669 cm–1. HMRS (EI): m/z
calcd for C23H28N2O4Na: 419.19468; found: 419.19534.
1-(tert-Butoxycarbonyl)-8-methyl-1,9-methyl-
2-tert-Butyl-7-methyl-6-(trimethylsilyl)-8-
methylpentaleno[1,2,3-cd]indole-2,7-dicarboxylate
(16a): 38% yield; white powder; mp 116 °C. 1H NMR (300
MHz, CDCl3): δ = 0.34 (s, 9 H), 1.64 (s, 9 H), 3.90 (s, 3 H),
4.03 (s, 3 H), 7.14 (s, 1 H), 7.21 (dd, J = 8.2, 7.7 Hz, 1 H),
7.32 (dd, J = 7.7, 1.0 Hz, 1 H), 7.98 (dd, J = 8.2, 1.0 Hz, 1
H). 13C NMR (75 MHz, CDCl3): δ = 0.3, 28.2, 38.2, 51.4,
86.1, 97.8, 104.0, 107.9, 114.8, 116.0, 125.7, 134.6, 143.1,
116.4, 117.4, 124.7, 126.3, 150.4, 162.2. IR: 1721, 1710,
1364, 1314, 1250, 1158, 1101, 842 cm–1. MS (EI): m/z (%)
= 425.0 (18) [MH]+, 370 (24), 369.0 (100), 337 (55), 325
(19), 143.1 (27) 122 (65).
6,6a,7,8,9a-pentahydro-9-azaindeno[4,5,6-cd]indole-2,8-
dicarboxylate (11d): 84% yield (Δ) and 97% yield (MW);
viscous oil as a mixture of two diastereomers which were
separated by column chromatography. Major diastereomer:
viscous oil. 1H NMR (300 MHz, CDCl3): δ = 1.68 (s, 9 H),
2.07–2.16 (m, 1 H), 2.30–2.49 (m, 5 H), 2.62 (s, 3 H), 2.83
(d, J = 8.2 Hz, 2 H), 3.76 (s, 3 H), 4.03 (dd, J = 8.5, 5.6 Hz,
1 H), 4.21 (d, J = 4.1 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H), 7.14
(t, J = 8.0 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H). 13C NMR (75
MHz, CDCl3): δ = 14.6, 28.3, 31.9, 34.5, 34.8, 38.4, 51.3,
57.1, 63.2, 83.4, 113.1, 114.4, 119.9, 123.9, 127.4, 129.6,
134.1, 134.5, 151.1, 175.1. IR: 3021, 2980, 2950, 1728,
1454, 1370, 1328, 1215, 1145, 1102, 756, 668 cm–1. HMRS
(EI): m/z calcd for C22H28N2O4Na: 407.19468; found:
2-tert-Butyl-7-ethyl-6-(trimethylsilyl)-8-
benzylpentaleno[1,2,3-cd]indole-2,7-dicarboxylate(16b):
87% yield; white powder; mp 129 °C. 1H NMR (300 MHz,
CDCl3): δ = 0.26 (s, 9 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.64 (s,
9 H), 4.27 (q, J = 7.1 Hz, 2 H), 5.56 (s, 2 H), 7.15–7.35 (m,
8 H), 7.98 (d, J = 8.2 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
δ = 0.1, 14.3, 28.2, 53.5, 60.4, 83.4, 97.8, 103.8, 107.9,
114.7, 116.2, 125.6, 133.7, 142.9, 115.9, 124.6, 126.1,
127.3, 127.7, 128.7, 116.4, 137.7, 150.1, 161.8. IR: 2973,
2143, 1731, 1715, 1434, 1394, 1366, 1336, 1315, 1265,
1156, 1102, 842 cm–1. HMRS (EI): m/z calcd for
C30H34N2O4NaSi: 537.21856; found: 537.21889.
(14) Bashiardes, G.; Safir, I.; Mohamed, A. S.; Barbot, F.;
Laduranty, J. Org. Lett. 2003, 5, 4915.
Synlett 2014, 25, 1106–1110
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