Diastereoselective synthesis of functionalised carbazoles via a sequential Diels-Alder/ene reaction strategy

Article abstract of DOI:10.1039/c5ra00499c

An operationally simple one-pot, three-component, diastereoselective synthesis of saturated carbazoles and related pyridazino[3,4-b]indoles, based on two sequential intermolecular pericyclic reactions, is described. The reaction sequence involves an intermolecular Diels-Alder (D-A) reaction of a 3-vinyl-1H-indole, containing an electron withdrawing N-protecting group, with a suitable dienophile. Due to the electron withdrawing nature of the N-protecting group the resultant D-A cycloadducts are sufficiently stabilised to allow for a subsequent in situ diastereospecific intermolecular ene reaction to take place with an added enophile, generating functionalised carbazoles with relative stereocontrol of up to four stereocentres.

Full text of DOI:10.1039/c5ra00499c

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Diastereoselective synthesis of functionalised
carbazoles via a sequential Diels–Alder/ene
reaction strategy†
Cite this: RSC Adv., 2015, 5, 16125
Joseph Cowell, Matokah Abualnaja, Stephanie Morton,‡ Ruth Linder,
Faye Buckingham, Paul G. Waddell, Michael R. Probert and Michael J. Hall
*
An operationally simple one-pot, three-component, diastereoselective synthesis of saturated carbazoles
and related pyridazino[3,4-b]indoles, based on two sequential intermolecular pericyclic reactions, is
described. The reaction sequence involves an intermolecular Diels–Alder (D–A) reaction of a 3-vinyl-1H-
indole, containing an electron withdrawing N-protecting group, with a suitable dienophile. Due to the
electron withdrawing nature of the N-protecting group the resultant D–A cycloadducts are sufficiently
stabilised to allow for a subsequent in situ diastereospecific intermolecular ene reaction to take place
with an added enophile, generating functionalised carbazoles with relative stereocontrol of up to four
stereocentres.
Received 9th January 2015
Accepted 19th January 2015
DOI: 10.1039/c5ra00499c
www.rsc.org/advances
unstable and are therefore typically oxidised or undergo an
in situ 1,3-H shi to rearomatise the indole. We postulated that
Introduction
if the intermediate D–A cycloadduct could instead be inter-
cepted via an alternative intermolecular reaction this would
provide a new multi-component route to functionalised carba-
zoles. Following on from our recent work on the D–A reactions
of vinyl-imidazoles,23,24 we decided to investigate if the D–A
cycloadducts of 3-vinyl-1H-indoles could be reacted in situ with
enophiles to give a new stereoselective three-component,
intermolecular D–A/intermolecular ene approach to the carba-
zole or pyridazino[3,4-b]indole scaffold (Fig. 1).25–29
Carbazole scaffolds are common in many bioactive compounds
(e.g. staurosporine)1,2 with the indolocarbazole scaffold in
particular being found in a number of molecules with potential
therapeutic application, several of which have entered clinical
trials for the treatment of cancer (midostaurin (PKC412), les-
taurtinib (CEP-701), CEP-751, CEP-1347, edotecarin and beca-
tecarin).3,4 Therefore there is
a growing interest in the
development of new synthetic routes to functionalised carbo-
zoles.5–9 Herein we describe our progress in the development of
a diastereoselective one-pot, three-component approach for the
synthesis of functionalised, partially saturated carbazoles and
pyridazino[3,4-b]indoles.
We decided to focus our investigation on the D–A reactions
of 3-vinyl-1H-indoles containing an electron withdrawing
Results and discussion
The vinyl-indole synthesis of carbazoles, originally developed by
Nolan, Pindur, Porter and others, involves the D–A cycloaddi-
tion of a 2- or 3-vinyl-1H-indole (typically either unprotected or
containing an electron donating N-protecting group) with a
dienophile.10–22 The resulting D–A cycloadducts are oen
School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
E-mail: michael.hall@newcastle.ac.uk
† Electronic supplementary information (ESI) available: 1H and 13C spectra for all
new compounds, crystal data and structure renement tables for compounds 2a,
2b, 2d, 3l, 3r, 3u and 3v. The crystallographic coordinates of 2a, 2b, 2d, 3l, 3r, 3u
and 3v have been deposited with the Cambridge Crystallographic Data Centre,
deposition nos. CCDC 952356, 1040305, 1040306, 952229, 1040307, 1040308
and 952357. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c5ra00499c
Fig. 1 Typical products of the D–A reaction between 3-vinyl-1H-
indoles and maleimides verses our proposed trapping of the D–A
cycloadduct via an intermolecular ene reaction.
‡ Authors contributed equally.
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DCM or iso-propanol. The addition of 20 mol% of 1,3-bis(3,5-
bis(triuoromethyl)phenyl)thiourea34 also showed no improve-
ment in the D–A reaction, whilst the addition of one equivalent
ꢁ
of TiCl4 at ꢀ78 C for 10 minutes resulted in an efficient D–A
reaction but was accompanied by the unwanted rear-
omatisation of the indole. Addition of one equivalent of AlCl3 or
Me2AlCl in DCM at r.t., followed by heating to reux gave low
yields of the desired product 2c along with recovered starting
material. Further optimisation resulted in a nal protocol
whereby 2 equivalents of Me2AlCl were added to a DCM solution
of 1b and the requisite 1H-pyrrole-2,5-dione at ꢀ78 ꢁC, followed
by warming to reux in DCM for 48 hours to give N-tosyl pro-
tected D–A cycloadducts 2(c–e) in good yields (Table 2). The
structures of 2(a), 2(b) and 2(d) were conrmed by single crystal
X-ray analysis and are consistent with an endo-selective D–A
reaction (see ESI†).
Scheme 1 Synthesis of N-tosyl-3-alkenyl-1H-indoles 1(a and b).
N-protecting group as we postulated that this would stabilise
the desired D–A cycloadducts sufficiently to allow either isola-
tion or further in situ chemistry.19,20 Despite the extensive body
of work that has been published on the vinyl-indole synthesis of
carbazoles,11–18 the incorporation of electron withdrawing N-
protecting groups has been less well studied with the
phenylsulfonyl group being the most common.25,30–33 We
therefore decide to focus our initial investigation on tosyl
protected systems and embarked on the synthesis of two N-
tosyl protected 3-alkenyl-indoles through reaction of 1H-
indole-3-carbaldehyde with tosyl chloride, followed by a Wittig
reaction with methylenetriphenyl-l5-phosphane or ethyl 4-(tri-
phenyl-l5-phosphanylidene)butanoate to give 1a and 1b
respectively (Scheme 1).
Next we examined the reactivity of N-tosyl protected endo-
cycloadducts 2(a–e) towards enophiles. Reaction of 2a with
nitrosobenzene proceeded well at r.t. in 18 hours to give the ene
adduct 3a in 68% isolated yield. We therefore reacted D–A
adducts 2(a–e) with nitrosobenzene and 1-methyl-2-
nitrosobenzene at r.t. in DCM, giving high yields of the corre-
sponding ene adducts 3(a, b and e–h). The ene reactions of
ꢁ
When we reacted 1-tosyl-3-vinyl-1H-indole 1a with 1-methyl-
1H-pyrrole-2,5-dione in DCM at reux for 48 hours, we were
pleased to isolate, in a 74% yield, the N-tosyl protected endo-
cycloadduct 2a, which showed little propensity towards spon-
taneous rearomatisation or oxidation. Whilst 4-phenyl-1,2,4-
2(a–c) also proceeded smoothly with PTAD at 0 C to give 3(c,
i
and j). The reaction of 2a with 2,3,4,5,6-penta-
uorobenzaldehyde under thermal conditions was unsuccess-
ful. However addition of one equivalent of Me2AlCl at ꢀ78 ꢁC to
a mixture of 2a and 2,3,4,5,6-pentauorobenzaldehyde resulted
in formation of the ene cycloadduct 3d as a 6 : 1 mixture of
diastereomers, epimeric at the exo-cyclic hydroxyl position35
(Table 3).
ꢁ
triazole-3,5-dione (PTAD) reacted rapidly with 1a at ꢀ78 C in
DCM to give the stable D–A cycloadduct 2b in 88% yield
(Table 1).
Attempts to react the more sterically demanding ethyl (Z)-5-
(1-tosyl-1H-indol-3-yl)pent-4-enoate 1b with 1H-pyrrole-2,5-
diones under thermal conditions proved unsuccessful with no
D–A reaction being observed aer prolonged heating in toluene,
Since both the D–A and ene reactions are performed in DCM
we then decided to examine the potential for reaction tele-
scoping by attempting a D–A/ene reaction sequence under
“domino” conditions.36 1-Tosyl-3-vinyl-1H-indole 1a, 1-methyl-
Table 1 D–A reactions of N-tosyl protected 1-tosyl-3-vinyl-1H-indole 1a
Starting material
Dienophile
Reaction Conditions
40 ꢁC, 48 h
R0
X
Yielda
76%
Product
1
1a
Me
CH
2ab
2
1a
ꢀ78 ꢁC, 3.5 h
Ph
N
88%
2bb
Isolated yields. b Structure conrmed by single crystal X-ray analysis.
a
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Table 2 D–A reactions of ethyl (Z)-5-(1-tosyl-1H-indol-3-yl)pent-4-enoate 1b
Starting material
Dienophile
Reaction conditions
R0
X
Yielda
Product
2c
1
2
1b
1b
2 eq. Me2AlCl, ꢀ78 ꢁC 30 min, then 40 ꢁC 48 h
2 eq. Me2AlCl, ꢀ78 ꢁC 30 min, then 40 ꢁC 48 h
Me
H
CH
CH
85%
64%
2db
3
1b
2 eq. Me2AlCl, ꢀ78 ꢁC 30 min, then 40 ꢁC 48 h
Ph
CH
71%
2e
a
Isolated yields. b Structure conrmed by single crystal X-ray analysis.
1H-pyrrole-2,5-dione and nitrosobenzene were stirred together deprotection of the products. Boc protection of 1H-indole-3-
for 5 days at r.t. in DCM, until 1a had been consumed by TLC. carbaldehyde proceeded in high yield (triethylamine, Boc
Examination of the crude reaction mixture showed the forma- anhydride, DCM, 18 h, r.t.), however attempts to synthesise tert-
tion of a number of by-products (including a rearomatised butyl 3-vinyl-1H-indole-1-carboxylate, by reaction of tert-butyl
isomer of D–A cycloadduct 2a) but the desired domino D–A/ene 3-formyl-1H-indole-1-carboxylate with methylenetriphenyl-l5-
product 3a could be isolated as a single diastereomer in a 40% phosphane, gave only a 13% yield of the desired product with
yield.
the major products arising from loss of the Boc group. We
To improve both the yield and reaction exibility whilst therefore focused our efforts on use of the DMAS (dimethyla-
maintaining operational simplicity we next examined a one-pot, minosulfonyl) and Cbz protecting groups, and synthesised N,N-
sequential addition approach. 1-Tosyl-3-vinyl-1H-indole 1a and dimethyl-3-vinyl-1H-indole-1-sulfonamide 1d (DMAS), benzyl-3-
5-methoxy-1-tosyl-3-vinyl-1H-indole 1c (synthesised as previ- vinyl-1H-indole-1-carboxylate 1e and benzyl-5-methoxy-3-vinyl-
ously via tosyl protection of 5-methoxy-1H-indole-3- 1H-indole-1-carboxylate 1f (Cbz) via appropriate protection of
carbaldehyde followed by a Wittig reaction with methylene- 1H-indole-3-carbaldehyde followed by reaction with methyl-
triphenyl-l5-phosphane) were reacted with 1-methyl-1H-pyrrole- enetriphenyl-l5-phosphane as previously.
2,5-dione or 1H-pyrrole-2,5-dione in reuxing DCM for 48 hours
N,N-Dimethyl-3-vinyl-1H-indole-1-sulfonamide 1d was reac-
to give the corresponding D–A cycloadducts. Nitrosobenzene, ted in DCM with 1H-pyrrole-2,5-dione, 1-methyl-1H-pyrrole-2,5-
1-methyl-2-nitrosobenzene, 2,3,4,5,6-pentauorobenzaldehyde dione, 1-phenyl-1H-pyrrole-2,5-dione and PTAD. Aer 48 hours
with one equivalent of Me2AlCl, or PTAD, were then added at 40 ꢁC for the maleimides, or 1 hour at ꢀ78 ꢁC for PTAD, the
directly to the reaction vessels containing the D–A cycloadducts D–A reactions were complete and in situ ene reactions with
and the ene reactions conducted were under the previously nitrosobenzene, 1-methyl-2-nitrosobenzene, 1,3-dibromo-2-
optimised conditions, depending on the enophile. This one-pot nitrosobenzene23 or 2,3,4,5,6-pentauorobenzaldehyde (cata-
three-component approach gave the corresponding D–A/ene lysed by one equivalent of Me2AlCl) were carried out to give
products 3(a–d and k–q) in excellent (70–89%) yields with no 69–77% isolated yields of the desired three-component D–A/ene
purication or work-up of the intermediate D–A cycloadducts products 3(t–x) (Table 4). Cbz protected 3-vinyl-1H-indoles
required (Table 4).
1(e and f) also underwent D–A reactions with 1H-pyrrole-2,5-
We therefore continued with this approach, reacting 1a and dione, 1-methyl-1H-pyrrole-2,5-dione or PTAD followed by in
1c with PTAD as the dienophile followed by in situ addition of situ ene reactions with nitrosobenzene, 1-methyl-2-
enophiles (nitrosobenzene, 1-methyl-2-nitrosobenzene, or nitrosobenzene or PTAD to give 54–82% yields of 3(y–ll)
PTAD) again giving the D–A/ene products 3(e, f, r and s) cleanly (Table 4). The Cbz protected products 3(y–ll) were isolable by
and in good yields (Table 4).
silica gel chromatography but proved less stable than their
We then decided to examine the range of electron with- DMAS or Tos protected counterparts. NMR investigations of
drawing N-protecting groups tolerated in our one-pot D–A/ene these compounds showed evidence of decomposition in solu-
reaction sequence with a view towards exibility in the tion at r.t., however they could be stored as solids under an
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Table 3 Ene reactions of N-tosyl protected cycloadducts 2(a–e)
Starting material
R
R0
X
Enophile
Reaction conditions
r.t., 18 h
R00
Yielda
Product
1
2
2a
H
Me
CH
N(Ph)OH
68%
72%
3a
2a
2a
H
H
Me
Me
CH
CH
r.t., 18 h
N(o-Tol)OH
3b
3c
3
4
0
ꢁC, 2.5 h
73%
82%
1 eq. Me2AlCl, ꢀ78 ꢁC,
2a
H
Me
CH
CH(C6F5)OH
3db
15 min r.t., 18 h
5
6
7
8
2b
2b
2c
2e
H
Ph
Ph
Me
Ph
N
r.t., 18 h
r.t., 18 h
r.t., 24 h
r.t., 24 h
N(Ph)OH
74%
72%
59%
58%
3e
3f
H
N
N(o-Tol)OH
N(o-Tol)OH
N(o-Tol)OH
(CH2)2CO2Et
(CH2)2CO2Et
CH
CH
3g
3h
9
2c
(CH2)2CO2Et
(CH2)2CO2Et
Me
H
CH
CH
0
0
ꢁC, 6 h
ꢁC, 6 h
56%
56%
3i
3j
10
2d
a
Isolated yields. b Isolated as a 6 : 1 mixture of diastereomers.
ꢁ
atmosphere of nitrogen at ꢀ20 C for months at a time. Inter-
Finally we investigated the deprotection of our D–A/ene
estingly the ene reactions of 2,3,4,5,6-pentauorobenzaldehyde reaction products. Tosyl and DMAS protected compounds
with D–A cycloadducts 3(d, m, p and v) gave a mixture of diaste- 3(a–x) proved intransient to a range of basic (NaOH, KOH or
reomers at the exo-cyclic hydroxyl group, with ratios from 5 : 1 to KOEt in EtOH, MeOH or H2O with Bu4NBr) and reducing (Mg,
>25 : 1. The relative stereochemistry of 3v was conrmed through Mg/Hg or Na/Hg) deprotection conditions. We therefore
the solution of a single crystal X-ray structure (see ESI†) and is focused on the deprotection of Cbz protected compounds
consistent with an endo-selective ene reaction, providing some 3(y–ll). Initial attempts at Cbz removal with H2 and Pd/C proved
support for an ene mechanism in this reaction rather than a unsuccessful. Atmospheric pressure hydrogenation with
nucleophilic attack of the D–A cycloadducts to the carbonyl Adam's catalyst in either MeOH and EtOH resulted in the
carbon of the aldehyde in the manner of an vinylogous enamine.37 removal of the Cbz group from 3z, however unexpected
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Table 4 One-pot D–A/ene reactions of N-protected 3-vinyl-1H-indoles
Starting
Material
P
R%
R0
X
Enophile
R00
Reaction conditions
Product
Yielda
71%
1
2
1a
Tos
H
Me
CH
–N(Ph)OH
(i) 40 ꢁC, 48 h, (ii) r.t., 18 h
3a
3b
1a
1a
Tos
Tos
H
H
Me
Me
CH
CH
–N(o-Tol)OH
(i) 40 ꢁC, 48 h, (ii) r.t., 18 h
(i) 40 ꢁC, 48 h, (ii) 0 ꢁC, 4 h
71%
76%
3
4
3c
(i) 40 ꢁC, 48 h, (ii) Me2AlCl,
1a
Tos
H
Me
CH
–CH(C6F5)OH
3d
72%b
ꢀ78 ꢁC to r.t., 18 h
5
6
7
8
1a
1a
1a
1a
Tos
Tos
Tos
Tos
H
H
H
H
Ph
Ph
H
N
–N(Ph)OH
(i) ꢀ78 ꢁC, 4 h, (ii) r.t., 24 h
(i) ꢀ78 ꢁC, 4 h, (ii) r.t., 24 h
(i) 40 ꢁC, 48 h, (ii) r.t., 4 h
(i) 40 ꢁC, 48 h, (ii) r.t., 4 h
3e
3f
3k
3l
66%
66%
89%
82%c
N
–N(o-Tol)OH
–N(Ph)OH
CH
CH
H
–N(o-Tol)OH
(i) 40 ꢁC, 48 h, (ii) Me2AlCl,
0 ꢁC to r.t., 18 h
9
1a
Tos
H
H
CH
–CH(C6F5)OH
3m
71%d
10
11
1a
1c
Tos
Tos
H
H
H
CH
CH
(i) 40 ꢁC, 48 h, (ii) 0 ꢁC, 4 h
(i) 40 ꢁC, 48 h, (ii) r.t., 24 h
3n
3o
75%
76%
OMe
–N(o-Tol)OH
–CH(C6F5)OH
(i) 40 ꢁC, 48 h, (ii) Me2AlCl,
12
13
1c
1c
Tos
Tos
OMe
OMe
Me
H
CH
CH
3p
3q
70%e
72%
ꢀ78 ꢁC, 15 min then r.t., 18 h
(i) 40 ꢁC, 48 h, (ii) 0 ꢁC, 4 h
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Table 4 (Contd.)
Starting
Material
P
R%
R0
X
Enophile
R00
Reaction conditions
Product
Yielda
65%c
14
1a
Tos
H
Ph
N
(i) ꢀ78 ꢁC, 4 h, (ii) 0 ꢁC, 4 h
3r
(i) ꢀ78 ꢁC then r.t. 23 h,
15
16
1c
Tos
OMe
H
Ph
N
–N(o-Tol)OH
–N(o-Tol)OH
3s
3t
72%
74%
(ii) r.t., 23 h
1d
DMAS
Me
CH
(i) 40 ꢁC, 48 h, (ii) r.t., 3 h
(i) 40 ꢁC, 48 h, (ii) r.t., 18 h
–N(2,4-
(Br)2C6H4)-
OH
17
18
1d
1d
DMAS
DMAS
H
H
Ph
CH
CH
3u
3v
69%c
(i) 40 ꢁC, 48 h, (ii) Me2AlCl,
Me
–CH(C6F5)OH
77%c,f
ꢀ78 ꢁC, 1 h
19
20
21
22
1d
1d
1e
1e
DMAS
DMAS
Cbz
H
H
H
H
Ph
H
N
–N(o-Tol)OH
–N(o-Tol)OH
–N(Ph)OH
(i) ꢀ78 ꢁC, 1 h, (ii) r.t., 4 h
(i) 40 ꢁC, 48 h, (ii) r.t., 3 h
(i) 40 ꢁC, 24 h, (ii) r.t., 18 h
(i) 40 ꢁC, 24 h, (ii) r.t., 18 h
3w
3x
3y
3z
76%
77%
74%
78%
CH
CH
CH
Me
Me
Cbz
–N(o-Tol)OH
(i) 40 ꢁC, 24 h, (ii) 0 ꢁC,
1 h then r.t., 18 h
23
1e
Cbz
H
Me
CH
3aa
54%
24
25
1e
1e
Cbz
Cbz
H
H
H
H
CH
CH
–N(Ph)OH
(i) 40 ꢁC, 24 h, (ii) r.t., 18 h
(i) 40 ꢁC, 24 h, (ii) r.t., 4 h
3bb
3cc
70%
83%
–N(o-Tol)OH
26
1e
Cbz
H
H
CH
(i) 40 ꢁC, 24 h, (ii) 0 ꢁC, 1 h
3dd
58%
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Table 4 (Contd.)
Starting
Material
P
R%
R0
X
Enophile
R00
Reaction conditions
Product
Yielda
72%
27
28
29
30
31
32
33
1e
1e
1f
1f
1f
1f
1f
Cbz
H
Ph
N
–N(Ph)OH
(i) ꢀ78 ꢁC, 5 h, (ii) r.t., 3 h
3ee
3ff
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
H
Ph
Me
Me
H
N
–N(o-Tol)OH
–N(Ph)OH
(i) ꢀ78 ꢁC, 5 h, (ii) r.t., 18 h
(i) 40 ꢁC, 18 h, (ii) r.t., 1.5 h
(i) 40 ꢁC, 18 h, (ii) r.t., 3 h
(i) 40 ꢁC, 18 h, (ii) r.t., 2.5 h
(i) 40 ꢁC, 18 h, (ii) r.t., 3.5 h
(i) ꢀ78 ꢁC, 1.5 h, (ii) r.t., 20 h
68%
73%
74%
79%
76%
78%
OMe
OMe
OMe
OMe
OMe
CH
CH
CH
CH
N
3gg
3hh
3ii
–N(o-Tol)OH
–N(Ph)OH
H
–N(o-Tol)OH
–N(Ph)OH
3jj
Ph
3kk
34
1f
Cbz
OMe
Ph
N
–N(o-Tol)OH
(i) ꢀ78 ꢁC, 1.5 h, (ii) r.t., 24 h
3ll
82%
a
b
c
d
e
f
Isolated yields. 5 : 1 endo : exo. Structure conrmed by single crystal X-ray analysis. 25 : 1 endo : exo. 10 : 1 endo : exo. Only one
diastereomer observed.
nucleophilic substitutions of the hydroxy(aryl)amino group NMR could still be observed over time. The deprotection of
by MeOH or EtOH also occurred to give 4a and 4b respectively. indoles 3(y–ll) with H2 and Adam's catalyst in THF has allowed
This gave the rst indication that the removal of the elec- us to successfully demonstrate a one-pot, three-component
tronically stabilising N-protecting group perhaps unsurpris- approach to our target library of deprotected partially satu-
ingly lowers the activation energy barrier towards substitution rated carbazoles and pyridazino[3,4-b]indoles, which will be
chemistry at the indolylic position.38–40 Replacement of the the focus of future investigations (Table 5).
alcoholic solvent with THF resulted in a cleaner deprotection
of Cbz protected indoles 3(y–ll) to give 4(c–p) in 38–91% yields.
However the products 4(c–p) showed some evidence of
Conclusions
decomposition in CDCl3 aer a few hours at r.t., with the
In conclusion, we have developed
a practically simple
appearance of new peaks in the 1H NMR spectra. Therefore
NMR analysis of 4(c–p) was carried out in either d2-DCM or d6-
DMSO (depending on solubility) in which decomposition was
slowed, although the appearance of minor peaks in the 1H
three-component approach to Tos, DMAS and Cbz
protected partially saturated carbazoles and pyridazino[3,4-b]-
indoles, based on a one-pot D–A/ene reaction, including the
examination of
a
deprotection strategy of the Cbz
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Table 5 Deprotection of 3(y, z, bb and cc)
Starting material
R0
X
R00
R00
Solvent
Product
Yielda
1
2
3
4
3z
3z
3y
3z
Me
Me
Me
Me
CH
CH
CH
CH
–N(o-Tol)OH
–N(o-Tol)OH
–N(Ph)OH
H
H
H
H
MeOH
EtOH
THF
4a
4b
4c
4d
60%
24%
75%
87%
–N(o-Tol)OH
THF
5
3aa
Me
CH
H
THF
4e
91%
6
7
3bb
3cc
H
H
CH
CH
–N(Ph)OH
–N(o-Tol)OH
H
H
THF
THF
4f
4g
41%
70%
8
3dd
H
CH
H
THF
4h
64%
9
3ee
3ff
3gg
3hh
3ii
3jj
3kk
3ll
Ph
Ph
Me
Me
H
H
Ph
Ph
N
N
–N(Ph)OH
–N(o-Tol)OH
–N(Ph)OH
–N(o-Tol)OH
–N(Ph)OH
–N(o-Tol)OH
–N(Ph)OH
H
H
THF
THF
THF
THF
THF
THF
THF
THF
4i
4j
65%
44%
70%
70%
60%
85%
38%
61%
10
11
12
13
14
15
16
CH
CH
CH
CH
N
OMe
OMe
OMe
OMe
OMe
OMe
4k
4l
4m
4n
4o
4p
N
–N(o-Tol)OH
a
Isolated yields.
group. Current work is looking into controlling the reactivity ether 7 : 3, column diameter ¼ 4 cm, silica ¼ 20 cm) to give
and biological activity of the nal products as well as investi- 3-vinyl-1H-indole (0.636 g, 4.4 mmol, 95%) as a yellow powder.
gating enantioselective D–A/ene approaches for molecules of
this type.
Mp: 78.4–80.7 ꢁC; Rf: 0.76 (Pet(40/60)–EA, 1 : 1); 1H NMR
(300 MHz, CDCl3): dH 8.02 (1H, br s), 7.85–7.80 (1H, m),
7.32–7.28 (1H, m), 7.18 (1H, s), 7.18–7.09 (2H, m), 6.83 (1H, ddd,
J ¼ 17.7, 11.2, 0.5 Hz), 5.65 (1H, dd, J ¼ 17.7, 1.5 Hz), 5.11 (1H,
dd, J ¼ 11.2, 1.5 Hz); 13C NMR (101 MHz, CDCl3): d 136.8, 129.5,
125.7, 123.6, 122.6, 120.4, 120.2, 115.9, 111.4, 110.9; IR (neat):
nmax/cmꢀ1 3660, 2981.
Experimental
3-Vinyl-1H-indole
In a Schlenk ask, methyltriphenylphosphonium iodide (2.14 g,
5.3 mmol) was dissolved in dry THF (13 mL). The solution was
cooled to ꢀ78 ꢁC and nbutyllithium (2.9 mL, 4.6 mmol) was
1a – 1-tosyl-3-vinyl-1H-indole
added over 10 minutes. The yellow solution was warmed to 0 ꢁC Into a Schlenk ask, was placed 1H-indole-3-carbaldehyde
and was le to stir for 1 hour before being cooled to ꢀ78 ꢁC. In a (5.0 g, 34.5 mmol) and DCM (100 mL). The resulting stirred
separate Schlenk ask, 1H-indole-3-carboxylate (0.67 g, solution was cooled to 0 ꢁC before triethylamine (12 mL,
4.6 mmol) was dissolved in THF (7 mL) and to the solution 86.2 mmol) was added dropwise via syringe. To the stirred
sodium bis(trimethylsilyl)amide (2.3 mL, 4.6 mmol) was added. solution, p-toluenesulfonyl chloride (7.23 g, 37.9 mmol) in DCM
This solution was transferred into the rst Schlenk ask and the was added dropwise over a period of 20 minutes. The solution
red solution was allowed to stir at room temperature for 1 hour. was stirred at 0 ꢁC for a further one hour before warming to
The reaction was poured into water (30 mL) and extracted with room temperature over 18 hours. The solution was washed into
ethyl acetate (2 ꢂ 20 mL). The combined organic layers were a separating funnel with DCM (20 mL) and washed with water
dried over MgSO4, ltered and the solvent removed under pres- (2 ꢂ 100 mL) and brine (100 mL). The organic extracts were
sure to leave the crude product as yellow oil. The product was dried over MgSO4, ltered and the solvent removed under
puried using column chromatography (petrol (40/60)–diethyl reduced pressure to give the crude product as a pale orange oil.
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The product was puried by recrystallisation from hot ethyl acetate 10 : 1) to give two fractions the rst containing ethyl (Z)-
acetate (150 mL) to give 1-tosyl-1H-indole-3-carbaldehyde 5-(1-tosyl-1H-indol-3-yl)pent-4-enoate (1.568 g, 3.94 mmol, 60%)
(8.38 g, 28 mmol, 82%) as orange crystals.
as a colourless oil, and a second fraction containing a 20 : 1
1
Mp: 145.3–148.8 ꢁC; Rf: 0.83 (Pet(40/60)–EA 1 : 4); H NMR mixture of (Z) and (E) ethyl-5-(1-tosyl-1H-indol-3-yl)pent-4-
(300 MHz, CDCl3): dH 10.11 (1H, s), 8.29–8.26 (1H, m), 8.19–8.16 enoate (0.294 g, 0.739 mmol, 11%) also as a colourless oil.
1
(1H, m), 8.16 (1H, s), 7.89–7.85 (1H, m), 7.78 (2H, d, J ¼ 8.4 Hz),
Rf: 0.70 (Pet(40/60)–EA 7 : 3); H NMR (400 MHz, CDCl3): dH
7.36–7.25 (2H, m), 7.22 (2H, d, J ¼ 8.4 Hz), 2.29 (3H, s); 13C NMR 7.97 (1H, d, J ¼ 7.9 Hz, 1H), 7.77 (2H, d, J ¼ 7.8 Hz), 7.57 (1H, s),
(101 MHz, CDCl3): d 185.3, 146.1, 136.2, 135.4, 134.1, 130.3, 7.49 (1H, d, J ¼ 7.9 Hz), 7.32 (1H, t, J ¼ 7.9 Hz), 7.25 (1H, t,
130.2, 127.2, 127.1, 126.2, 124.9, 122.5, 122.2, 113.1, 21.5; J ¼ 7.9 Hz), 7.20 (2H, d, J ¼ 7.8 Hz), 6.44 (1H, d, J ¼ 11.2 Hz),
IR (neat): nmax/cmꢀ1 3140, 1663; anal. calcd for C16H13NO3S: C, 5.78 (1H, dt, J ¼ 11.2, 7.5 Hz), 4.14 (2H, q, J ¼ 6.5 Hz), 2.67–2.62
64.20; H, 4.38; N, 4.68. Found: C, 63.97; H, 4.52; N, 4.72.
Schlenk ask was charged with
(2H, m), 2.48 (2H, t, J ¼ 6.9 Hz), 2.30 (3H, s), 1.24 (3H, t, J ¼ 6.5
A
methyl- Hz); 13C NMR (100 MHz, CDCl3): dC 172.8, 145.1, 135.1, 134.6,
triphenylphosphonium iodide (1.29 g, 3.2 mmol) dissolved in 132.1, 130.8, 129.9, 126.8, 124.9, 123.6, 123.4, 119.5, 118.96,
dry THF (25 mL) under a nitrogen atmosphere. The solution was 113.6, 60.5, 34.1, 25.2, 21.6, 14.3; IR (neat): nmax/cmꢀ1: 1727,
n
cooled to ꢀ78 C and butyllithium (1.81 mL, 2.97 mmol) was 1597. MS (pNSI): 415.2 (100%, [M + NH4]+), 398.1 (20%, [M +
ꢁ
added dropwise via syringe over 10 minutes. The solution was H]+), 420.1 (10%, [M + Na]+); HRMS (pNSI): calcd C22H24NO4S [M
warmed to 0 ꢁC and le to stir for 2 hours. In a separate Schlenk + H]+: 398.14120; observed: 398.14120.
ask, 1-tosylindoline-3-carbaldehyde (0.8 g, 2.7 mmol) was
dissolved in THF (5 mL). The indole solution was transferred via
cannula to the Schlenk ask containing the solution of meth-
1c – 5-methoxy-1-tosyl-3-vinyl-1H-indole
yltriphenylphosphonium iodide and the solution was stirred for To a stirred round bottomed ask was added 5-methoxy-1H-
18 hours. The reaction poured into water (50 mL) and extracted indole-3-carbaldehyde (0.70 g, 4.00 mmol) and DCM (20 mL)
with ether (3 ꢂ 40 mL). The organic layers were washed with and the solution was cooled to 0 ꢁC. To the stirred solution was
brine (20 mL), dried over MgSO4, ltered and the solvent was added triethylamine (1.40 mL, 10.0 mmol) and the resulting
ꢁ
removed under reduced pressure to leave the crude product as solution was stirred at 0 C for 1 hour. To the stirred solution
an orange oil. The crude product was puried by column was added p-toluenesulfonyl chloride (0.84 g, 4.40 mmol) in
chromatography (petrol (40/60)–ethyl acetate; 10 : 1, 2 cm DCM (10 mL) and the solution was stirred at room temperature
diameter column) to give 1-tosyl-3-vinyl-1H-indole (0.56 g, for 18 hours. The reaction was poured into water (50 mL) and
3.9 mmol, 70%) as a pale yellow powder.
extracted with DCM (3 ꢂ 20 mL). The combined organic extracts
Mp: 90.3–94.6 ꢁC; Rf: 0.86 (Pet(40/60)–EA, 1 : 1); 1H NMR were dried over MgSO4, ltered and the solvent was removed
(300 MHz, CDCl3): dH 7.93–7.90 (1H, m), 7.69 (2H, d, J ¼ 8.4 Hz), under reduced pressure to leave the crude product as a pale
7.70–7.65 (1H, m), 7.53 (1H, s), 7.29–7.19 (2H, m), 7.29–7.17 (2H, orange solid. The product was puried using column chroma-
m), 7.15 (2H, d, J ¼ 8.4 Hz), 6.70 (1H, app ddd, J ¼ 17.9, 11.3, tography (petrol (40/60)–ether–DCM 2 : 1 : 1, column diameter
0.7 Hz), 5.72 (dd, 1H, J ¼ 17.9, 1.2 Hz), 5.28 (1H, dd, J ¼ 11.3, 1.2 ¼ 2 cm, silica ¼ 15 cm) to give 5-methoxy-1-tosyl-1H-indole-3-
Hz), 2.26 (3H, s); 13C NMR (101 MHz, CDCl3): dC 145.1, 135.6, carbaldehyde (1.14 g, 3.48 mmol, 87%) as a pale brown powder.
135.2, 130.0, 129.1, 127.6, 126.9, 125.0, 124.2, 123.6, 121.0,
Mp: 126.1–128.4 ꢁC; Rf: 0.71 (Pet(40/60)–Et2O–DCM 2 : 1 : 1);
120.5, 115.4, 113.8, 21.7; IR (neat): nmax/cmꢀ1 3119, 3072; anal. 1H NMR (300 MHz, CDCl3): dH 10.07 (1H, s), 8.19 (1H, s),
calcd for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71. Found: C, 7.86–7.83 (1H, m), 7.84 (2H, d, J ¼ 8.5 Hz), 7.72 (1H, d, J ¼ 2.6
68.70; H, 5.21; N, 4.61.
Hz), 7.29 (2H, d, J ¼ 8.5 Hz), 7.02 (1H, dd, J ¼ 9.1, 2.6 Hz),
3.86 (3H, s), 2.38 (3H, s); 13C NMR (101 MHz, CDCl3): dC 185.6,
157.8, 146.2, 136.8, 134.4, 130.4, 129.8, 127.4, 127.2, 122.3,
116.2, 114.2, 104.1, 55.8, 21.8; IR (neat): nmax/cmꢀ1 3128, 2832,
1b – ethyl (Z)-5-(1-tosyl-1H-indol-3-yl)pent-4-enoate
In a Schlenk ask, (4-ethoxy-4-oxobutyl) triphenylphosphonium 1671; anal. calcd for C17H15NO4S: C, 61.99; H, 4.59; N, 4.25.
bromide (3.32 g, 7.26 mmol) was dissolved in dry THF (20 mL). Found: C, 61.77; H, 4.70; N, 4.29.
The solution was cooled to ꢀ78 ꢁC and sodium bis (trime-
In a Schlenk ask, methyltriphenylphosphonium iodide
thylsilyl) amide (1.00 M in THF, 8.58 mL, 8.58 mmol) was added (1.35 g, 3.34 mmol) was dissolved in dry THF (30 mL). The
n
dropwise over 10 min. The mixture was warmed to 0 ꢁC and le solution was cooled to ꢀ78 C and BuLi (1.2 mL, 3.03 mmol)
ꢁ
to stir. Aer
2
hours, 1-(toluene-4-sulfonyl)-1H-indol-3- was added over 5 minutes. The yellow solution was warmed to
ꢁ
carboxaldehyde (2.00 g, 6.60 mmol) was dissolved in dry THF 0 C ꢁand was allowed to stir for 1 hour before being cooled to
(10 mL) in a separate round bottomed ask, and transferred via ꢀ78 C. To the stirred solution, 5-methoxy-1-tosyl-1H-indole-3-
cannula into the reaction solution. The reaction mixture was carbaldehyde (1.00 g, 3.03 mmol) in DCM (10 mL) was added
stirred at room temperature and for 48 hours, quenched with and the solution was stirred at room temperature for 3 hours.
saturated NH4Cl(aq.) (30 mL), extracted with EtOAc (2 ꢂ 200 mL), The reaction was poured into water (40 mL) and extracted with
and the combined organic layers washed with brine, dried over ethyl acetate (3 ꢂ 20 mL). The combined organic layers were
MgSO4 and ltered. The solvent was removed under reduced dried over MgSO4, ltered and the solvent removed under
pressure to give a crude product as orange oil. The product was pressure to leave the crude product an orange oil. The product
puried by column chromatography (petrol (40/60)–ethyl was puried using column chromatography (petrol (40/60)–
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ethyl acetate 2 : 1, column diameter ¼ 2 cm, silica ¼ 16 cm) to dd, J ¼ 17.8, 11.2 Hz), 5.84 (1H, dd, J ¼ 17.8, 1.2 Hz), 5.38 (1H,
give 5-methoxy-1-tosyl-3-vinyl-1H-indole (0.79 g, 2.42 mmol, dd, J ¼ 11.3, 1.2 Hz), 2.86 (6H, s); 13C NMR (101 MHz, CDCl3): dC
80%) as a brown powder.
136.1, 128.2, 127.8, 125.2, 124.7, 123.1, 120.4, 118.8, 114.9,
1
Mp: 101.4–103.9 ꢁC; Rf: 0.66 (Pet(40/60)–EA 2 : 1); H NMR 114.0, 38.6; IR (neat): nmax/cmꢀ1 3123, 2945; anal. calcd for
(300 MHz, CDCl3): dH 7.87 (1H, d, J ¼ 9.0 Hz), 7.73 (2H, d, J ¼ 8.4
C
12H14N2O2S: C, 57.58; H, 5.64; N, 11.19. Found: C, 57.68; H,
Hz), 7.55 (1H, s), 7.19 (2H, d, J ¼ 8.3 Hz), 7.14 (1H, d, J ¼ 2.5 Hz), 5.75; N, 11.05.
6.93 (1H, dd, J ¼ 9.0, 2.5 Hz), 6.72 (1H, dd, J ¼ 17.9, 11.3 Hz),
5.73 (1H, dd, J ¼ 17.9, 1.1 Hz), 5.32 (1H, dd, J ¼ 11.3, 1.1 Hz),
3.82 (3H, s), 2.31 (3H, s); 13C NMR (101 MHz, CDCl3): dC 156.7,
1e – benzyl-3-vinyl-1H-indole-1-carboxylate
145.0, 135.1, 130.3, 130.1, 130.0, 127.6, 126.9, 124.9, 121.1, To a solution of 1H-indole-3-carbaldehyde (1.0 g, 6.9 mmol) in
115.2, 114.7, 113.7, 103.2, 55.8, 21.7; IR (neat): nmax/cmꢀ1 3128, DCM (20 mL) at 0 ꢁC was added triethylamine (1.8 mL,
2832, 1671; MS (pNSI): 328.1 (100%, (M + H)+), 350.1 (15%, (M + 17.3 mmol) dropwise. The solution was stirred at room
Na)+), 672.2 (2M + NH4)+; HRMS (pNSI): calcd for C18H18NO3S temperature for 1 hour before benzyl chloroformate (1.4 mL,
[M + H]+: 328.1002; observed: 328.1007.
8.3 mmol) was added. The solution was stirred for 18 hours aer
which it was poured into water and extracted with DCM (3 ꢂ 20
mL). The organic fractions were combined, dried with MgSO4,
ltered and the solvent was removed under reduced pressure to
1d – N,N-dimethyl-3-vinyl-1H-indole-1-sulfonamide
To a stirred round bottomed ask was added 1H-indole-3- give the crude product as an orange powder. The crude product
carbaldehyde (3.0 g, 20.7 mmol) and THF (70 mL) and the was puried by column chromatography (column diameter ¼
ꢁ
solution was cooled to 0 C. To the stirred solution was added 2.5 cm, eluent ¼ petrol (40/60)–ethyl acetate 2 : 1) to give benzyl-
sodium hydride (1.7 g, 41.4 mmol) in THF (30 mL) and the 3-formyl-1H-indole-1-carboxylate (1.74 g, 6.35 mmol, 92%) as a
ꢁ
resulting solution was stirred at 0 C for 1 hour. To the stirred pale orange powder.
solution was added dimethylsulfamoyl chloride (2.4 mL,
Mp: 91–92 ꢁC; Rf: 0.68 (Pet–EA, 2 : 1); 1H NMR (300 MHz,
20.7 mmol) and the solution was stirred at room temperature CDCl3): dH 10.06 (1H, s), 8.30–8.25 (1H, m), 8.23 (1H, s),
for 18 hours. The reaction was poured into water (100 mL) and 8.17 (1H, d, J ¼ 8.0 Hz), 7.50 (2H, app dd, J ¼ 7.7, 1.8 Hz),
extracted with DCM (3 ꢂ 60 mL). The combined organic extracts 7.42 (3H, app ddd, J ¼ 6.6, 5.1, 1.5 Hz), 7.38 (1H, app t, J ¼ 1.6
were dried over MgSO4, ltered and the solvent was removed Hz), 7.37–7.34 (1H, m), 5.49 (2H, s); 13C NMR (101 MHz, CDCl3):
under reduced pressure to leave the crude product as a pale red dC 185.8, 150.2, 136.1, 136.1, 134.3, 129.3, 129.0, 128.9, 126.5,
pink solid. The product was puried by recrystallization from 126.1, 125.0, 122.3, 122.3, 115.2, 69.9; IR (neat): nmax/cmꢀ1 3127,
ethyl acetate to give 3-formyl-N,N-dimethyl-1H-indole-1- 3008, 1733; MS (pNSI): 280.1 (100%, (M + H)+), 302.1 (96%, (M +
sulfonamide (97%, 5.07 g, 20.1 mmol) as a pink powder.
Na)+), 581.2 (25%, (2M + Na)+); HRMS (pNSI): calcd for
C
1
17H14NO3 [M + H]+: 280.0968; observed: 280.0970.
ꢁ
Mp: 149.0–150.9 C; Rf: 0.63 (Pet(40/60)–EA, 1 : 1); H NMR
(300 MHz, CDCl3): dH 10.08 (1H, s), 8.31 (1H, app dd, J ¼ 7.2, 1.4
To a stirred Schlenk ask, methylenetriphenylphosphorane
Hz), 8.09 (1H, s), 7.94–7.88 (1H, m), 7.40 (2H, app ddd, J ¼ 5.9, (2.38 g, 5.90 mmol) was dissolved in dry THF (30 mL). The
3.3, 1.6 Hz), 2.91 (6H, s); 13C NMR (101 MHz, CDCl3): dC 185.5, solution was cooled to ꢀ78 ꢁC and nBuLi (2.15 mL, 5.35 mmol)
137.3, 136.0, 126.1, 125.9, 124.9, 122.6, 120.8, 113.6, 38.6; IR was added over 10 minutes. The yellow solution was warmed to
(neat): nmax/cmꢀ1 3124, 2945, 1662; anal. calcd for C11H12N2O3S: 0 ꢁC and was le to stir for 1 hour before being cooled to ꢀ78
C, 52.37; H, 4.79; N, 11.10. Found: C, 52.23; H, 4.91; N, 10.92.
ꢁC. To the stirred solution, benzyl 3-formyl-1H-indole-1-
In a Schlenk ask, methyltriphenylphosphonium iodide carboxylate (1.50 g, 5.35 mmol) was added and the solution
(7.00 g, 17.4 mmol) was dissolved in dry THF (75 mL). The was stirred at room temperature for 3 hours. The reaction was
n
ꢁ
solution was cooled to ꢀ78 C and BuLi (6.4 mL, 15.9 mmol) poured into water (50 mL) and extracted with ethyl acetate
was added over 10 minutes. The yellow solution was warmed to (3 ꢂ 40 mL). The combined organic layers were dried with
0 ꢁC and was le to stir for 1 hour before being cooled to ꢀ78 ꢁC. MgSO4, ltered and the solvent removed under pressure to
To the stirred solution, 3-formyl-N,N-dimethyl-1H-indole-1- leave the crude product as yellow oil. The product was puried
sulfonamide (4.00 g, 15.9 mmol) was added and the solution using column chromatography (petrol (40/60)–ethyl acetate
was stirred at room temperature for 3 hours. The reaction was 2 : 1, column diameter ¼ 2 cm, silica ¼ 15 cm) to give benzyl-3-
poured into water (70 mL) and extracted with ethyl acetate vinyl-1H-indole-1-carboxylate (1.14 g, 4.07 mmol, 76%) as a
(3 ꢂ 50 mL). The combined organic layers were dried over yellow powder.
MgSO4, ltered and the solvent removed under pressure to leave
Mp: 43–45 ꢁC; Rf: 0.73 (Pet(40/60)–EA, 2 : 1); 1H NMR
the crude product as yellow oil. The product was puried using (300 MHz, CDCl3): dH 8.33 (1H, d, J ¼ 7.1 Hz), 7.91–7.86 (1H,
column chromatography (petrol (40/60)–diethyl ether 4 : 1, m), 7.74 (1H, s), 7.58–7.55 (2H, m), 7.52–7.44 (4H, m),
column diameter ¼ 3 cm, silica ¼ 14 cm) to give N,N-dimethyl-3- 7.43–7.36 (1H, m), 6.87 (1H, dd, J ¼ 17.8, 11.3 Hz), 5.96–5.87
vinyl-1H-indole-1-sulfonamide (3.11 g, 12.4 mmol, 78%) as a (1H, d, J ¼ 17.8 Hz), 5.51 (2H, s), 5.44 (1H, d, J ¼ 11.3 Hz); 13
C
pale orange powder.
NMR (101 MHz, CDCl3): dC 150.8, 135.1, 128.9, 128.9, 128.8,
Mp: 68.7–67.8 ꢁC; Rf: 0.63 (Pet(40/60)–EA 2 : 1); 1H NMR 128.6, 128.4, 128.0, 125.1, 123.6, 123.4, 120.2, 120.2, 115.5,
(300 MHz, CDCl3): dH 7.98 (1H, dd, J ¼ 8.0, 1.4 Hz), 7.85 (1H, dd, 115.0, 68.9; IR (neat): nmax/cmꢀ1 3153, 2962, 1729; MS
J ¼ 7.7, 1.5 Hz), 7.35 (2H, app ddd, J ¼ 7.0, 5.3, 1.6 Hz), 6.83 (1H, (pAPCI): 181.1 (50%), 260.1 (100%), 278.1 (25%, (M + H)+);
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HRMS (pAPCI): calcd for C18H16NO2 [M + H]+: 278.1176; 181.1 (32%), 260.1 (100%), 308.1 (28%, (M + H)+); HRMS
observed: 278.1173.
(pAPCI): calcd for C19H18NO3 [M + H]+: 308.1281; observed:
308.1277.
1f – benzyl-5-methoxy-3-vinyl-1H-indole-1-carboxylate
2a – (3aS*,10bS*)-2-methyl-10-tosyl-4,10,10a,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione
To a stirred Schlenk ask, methylenetriphenylphosphorane
(3.54 g, 8.70 mmol) was dissolved in dry THF (34 mL). The
solution was cooled to ꢀ78 ꢁC and nBuLi (3.1 mL, 7.87 mmol)
was added over 10 minutes. The yellow solution was warmed
Into a round bottomed ask, 1-tosyl-3-vinyl-1H-indole (2.0 g,
6.7 mmol) and DCM (10 mL) was added. To the stirred
solution, N-methylmalemide (0.75 g, 6.7 mmol) was added
and the solution was stirred at 40 ꢁC for 48 hours. The solvent
was removed under reduced pressure to leave the crude
product as orange oil. The product was puried by column
chromatography (petrol (40/60)–ethyl acetate, 4 : 1, column
diameter ¼ 4 cm, silica ¼ 15 cm) to give (3aS*,10bS*)-2-
methyl-10-tosyl-4,10,10a,10b-tetrahydropyrrolo[3,4-a]carba-
zole-1,3(2H,3aH)-dione (2.01 g, 5.0 mmol, 76%) as a white
powder.
ꢁ
to 0 C and was le to stir for 1 hour before being cooled to
ꢀ78 ꢁC. In a separate Schlenk ask, 5-methoxy-1H-indole-3-
carbaldehyde (1.38 g, 7.87 mmol) was dissolved in THF
(10 mL) and to the solution sodium bis(trimethylsilyl)amide
(7.87 mL, 7.87 mmol) was added. This solution was trans-
ferred into the rst Schlenk ask and the red solution was
allowed to stir at room temperature for 1 hour. The reaction
was poured into water (50 mL) and extracted with ethyl
acetate (2 ꢂ 30 mL). The combined organic layers were dried
with MgSO4, ltered and the solvent removed under pressure
to leave the crude product as yellow oil. The product was
puried using column chromatography (petrol (40/60)–
diethyl ether 2 : 1, column diameter ¼ 2.5 cm, silica ¼ 16 cm)
to give 5-methoxy-3-vinyl-1H-indole (1.38 g, 7.6 mmol, 97%)
as a yellow powder.
Mp: 204.2–208.0 ꢁC; Rf: 0.09 (Pet(40/60)–EA, 1 : 1); 1H NMR
(300 MHz, CDCl3): dH 7.72 (2H, d, J ¼ 8.0 Hz), 7.61 (1H, d,
J ¼ 8.5 Hz), 7.21–7.19 (2H, d, J ¼ 8.0), 7.21–7.16 (1H, m),
6.92 (1H, app t, J ¼ 7.5 Hz), 6.01–5.96 (1H, m), 4.47 (1H, dd,
J ¼ 7.0, 3.3 Hz), 3.99 (1H, app t, J ¼ 8.1 Hz), 3.12 (1H, app t,
J ¼ 8.1 Hz), 2.99–2.92 (1H, m), 2.76 (3H, s), 2.30 (3H, s), 2.11
(1H, ddd, J ¼ 18.0, 6.4, 2.4 Hz); 13C NMR (101 MHz, CDCl3): dC
178.9, 174.2, 144.7, 144.6, 137.4, 134.3, 130.4, 129.9, 127.5,
126.4, 123.9, 121.0, 115.4, 112.9, 61.6, 43.3, 37.2, 25.3, 25.1,
21.7; IR (neat): nmax/cmꢀ1 2981, 2889, 1694; MS (pNSI):
409.2 (61%, (M + H)+), 426.1 (100%, (M + (NH4))+), 834.3 (52%,
(2M + (NH4))+); HRMS (pNSI): calcd C22H21N2O4S [M + H]+:
409.1217; observed: 409.1218.
Mp: 190–193 ꢁC; Rf: 0.49 (Pet–Et2O, 2 : 1); 1H NMR
(300 MHz, CDCl3): dH 8.28 (1H, s), 7.66 (1H, d, J ¼ 2.4 Hz),
7.29 (1H, d, J ¼ 8.8 Hz), 7.24 (1H, d, J ¼ 2.7 Hz), 7.20–7.10 (2H,
m), 7.18 (1H, d, J ¼ 2.5 Hz), 7.15 (2H, dd, J ¼ 4.5, 2.1 Hz),
7.10 (1H, s), 5.95 (1H, dd, J ¼ 17.8, 1.5 Hz), 5.46 (1H, dd,
J ¼ 11.2, 1.5 Hz), 4.07 (3H, s); 13C NMR (101 MHz, CDCl3): dC
154.4, 132.5, 130.8, 126.4, 126.1, 114.2, 113.0, 112.0, 109.1,
102.0, 55.9; IR (neat): nmax/cmꢀ1 3410, 2925, 2836; MS (pNSI):
174.1 (100%, (M + H)+), 520.3 (100%, (3M + H)+); HRMS (pNSI):
calcd for C11H12NO [M + H]+: 174.0913; observed: 174.0912.
2b – 2-phenyl-11-tosyl-11,11a-dihydro-1H,5H-[1,2,4]triazolo
[10,20:1,2]pyridazino[3,4-b]indole-1,3(2H)-dione
To a stirred Schlenk ask, 5-methoxy-3-vinyl-1H-indole To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
(1.15 g, 6.61 mmol) was dissolved in THF (30 mL) and the indole (100 mg, 0.34 mmol) and DCM (7 mL) and the solution
solution was cooled to 0 ꢁC. To the stirred solution, sodium was cooled to ꢀ78 ꢁC. To the stirred solution was added
bis(trimethylsilyl)amide (7.27 mL, 7.27 mmol) was added and 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (60 mg, 0.34 mmol)
ꢁ
the solution was stirred for 30 minutes before benzyl chlor- and the resulting solution was stirred at ꢀ78 C for 3.5 hours
oformate (0.90 mL, 6.61 mmol) was added. The solution was before the solvent was removed under reduced pressure to leave
stirred for 30 minutes at room temperature before being added the crude product as a pale red solid. The product was puried
to water (50 mL) and extracted with ethyl acetate (3 ꢂ 30 mL). by column chromatography (petrol (40/60)–ether–DCM 2 : 1 : 1,
The combined organic washings were dried with MgSO4, column diameter ¼ 1 cm, silica ¼ 20 cm) to give 2-phenyl-11-
ltered and the solvent was removed under reduced pressure to tosyl-11,11a-dihydro-1H,5H-[1,2,4]triazolo[10,20:1,2]pyridazino-
give the crude product as an orange oil. The product was puri- [3,4-b]indole-1,3(2H)-dione (88%, 140 mg, 0.30 mmol) as a pale
ed using column chromatography (petrol (40/60)–ethyl acetate red powder.
5 : 1, column diameter ¼ 2.0 cm, silica ¼ 15 cm) to give benzyl-
Mp: 160.1–162.8 ꢁC; Rf: 0.14 (Pet(40/60)–Et2O–DCM
5-methoxy-3-vinyl-1H-indole-1-carboxylate (1.78 g, 4.7 mmol, 2 : 1 : 1); 1H NMR (300 MHz, CDCl3): dH 7.86 (2H, d, J ¼ 8.4 Hz),
71%) as a pale yellow oil.
7.63–7.55 (2H, m), 7.51–7.46 (2H, m), 7.46–7.42 (1H, m),
Rf: 0.82 (Pet(40/60)–EA, 5 : 1); 1H NMR (400 MHz), dH 8.09 7.42–7.39 (1H, m), 7.38–7.34 (2H, m), 7.26–7.22 (2H, m),
(1H, s), 7.66 (1H, s), 7.50 (2H, d, J ¼ 7.2 Hz), 7.45–4.37 (1H, 7.09 (1H, app td, J ¼ 7.5, 1.0 Hz), 6.26 (1H, td, J ¼ 2.6, 1.8 Hz),
m), 7.25 (1H, d, J ¼ 2.5 Hz), 6.96 (1H, dd, J ¼ 9.0, 2.2 Hz), 6.18 (1H, app dt, J ¼ 5.3, 2.7 Hz), 4.56–4.46 (1H, app td,
6.79 (1H, dd, J ¼ 17.8, 11.4 Hz), 5.80 (1H, d, J ¼ 17.8 Hz), 5.42 J ¼ 17.6, 2.8 Hz), 4.39 (1H, ddd, J ¼ 17.6, 5.2, 1.9 Hz), 2.37 (3H,
(2H, s), 5.34 (1H, d, J ¼ 11.4 Hz), 3.85 (3H, s); 13C NMR (101 s); 13C NMR (75 MHz, CDCl3): dC 152.7, 150.8, 144.7, 143.7,
MHz, CDCl3): dC 156.4, 135.2, 129.7, 128.9, 128.9, 128.7, 135.6, 134.8, 131.5, 130.4, 129.6, 128.9, 128.5, 128.1, 126.8,
128.6, 128.0, 124.1, 124.1, 120.0, 116.1, 114.8, 113.3, 103.3, 125.7, 125.2, 120.9, 117.4, 113.8, 74.8, 44.6, 21.4; IR (neat):
68.8, 55.8; IR (neat): nmax/cmꢀ1 2955, 2834, 1726; MS (pAPCI): nmax/cmꢀ1 3070, 2926, 1719; MS (pNSI): 473.1 (100%, (M + H)+),
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522.2 (30%); HRMS (pNSI): calcd for C25H21N4O4S [M + H]+: J ¼ 3.6, 7.1 Hz), 4.84 (1H, dd, J ¼ 3.6, 7.3 Hz), 4.18 (1H, t, J ¼ 7.3
473.1278; observed: 473.1277.
Hz), 4.12–4.05 (2H, m), 3.16–1.12 (1H, m), 3.10 (1H, t, J ¼ 7.3
Hz), 2.40 (2H, t, J ¼ 7.3 Hz), 2.35 (3H, s), 1.89–1.76 (2H, m),
1.20 (3H, t, J ¼ 7.5 Hz). 13C NMR (101 MHz, CDCl3): dC 178.3,
173.6, 172.7, 144.5, 144.1, 136.6, 133.8, 130.5, 129.8, 127.5,
126.6, 123.8, 120.0, 116.4, 115.5, 60.8, 59.6, 45.2, 44.0, 36.9, 33.0,
27.8, 21.5, 14.1; IR (neat): nmax/cmꢀ1: 3657, 2981, 1776, 1703; MS
(pNSI): 512.18 (100%, [M + NH4]+), 495.15 (55%, [M + H]+),
340.14 (31%, [M ꢀ Ts]); HRMS (pNSI): calcd C26H27N2O6S [M +
H]+: 495.1584; observed: 495.1585.
2c – ethyl-3-((3aS*,4R*,10bS*)-2-methyl-1,3-dioxo-10-tosyl-
1,2,3,3a,4,10,10a,10b-octahydropyrrolo[3,4-a]carbazol-4-yl)
propanoate
Dimethylaluminum chloride (1.0
M in hexane, 9.38 ml,
9.38 mmol) was added dropwise to a solution of N-methyl-
maleimide (0.521 g, 4.69 mmol) in dry DCM (15 mL) at ꢀ78 ꢁC.
The mixture le to stir for 30 min. A solution of ethyl-(Z)-5-(1-
tosyl-1H-indol-3-yl) pent-4-enoate (4.69 mmol, 1.863 g) in dry
DCM (15 mL) was added dropwise at ꢀ78 ꢁC. The reaction
mixture was then warmed to reux for 48 hours and quenched
with saturated NaHCO3(aq.) (20 mL) and extracted with DCM
2e – ethyl 3-((3aS*,4R*,10bS*)-1,3-dioxo-2-phenyl-10-tosyl-
1,2,3,3a,4,10,10a,10b-octahydropyrrolo[3,4-a]carbazol-4-yl)
propanoate
(2 ꢂ 100 mL). The combined organic layers were washed with Dimethyl aluminum chloride (1.0 M in THF, 2.39 mL, 2.39 mmol)
brine, dried over MgSO4 and ltered. The solvent was removed was added dropwise to a solution of N-phenylmaleimide (0.207 g,
under reduced pressure to give the crude yellow solid. The 1.19 mmol) in dry DCM (5 mL) at ꢀ78 ꢁC. The mixture le to stir
product was puried by column chromatography (petrol (40/60)– for 30 min. A solution of ethyl (Z)-5-(1-tosyl-1H-indol-3-yl) pent-4-
ethyl acetate 2 : 1) to yield ethyl 3-((3aS*,4R*,10bS*)-2-methyl- enoate (0.475 g, 1.19 mmol) in dry DCM (10 mL) was added. The
1,3-dioxo-10-tosyl-1,2,3,3a,4,10,10a,10b-octahydropyrrolo[3,4-a]-
carbazol-4-yl)propanoate in (2.038 g, 4.01 mmol, 85%) a bright saturated NaHCO3(aq.) (10 mL) and extracted with DCM (100 mL).
yellow solid. The organic layer was washed with brine, dried over MgSO4 and
reaction mixture was heated to reux for 48 h, quenched with
Mp: 187–188 ꢁC; Rf: 0.3 (Pet(40/60)–EA 2 : 1); 1H NMR ltered. The solvent was removed under reduced pressure to give
(400 MHz, CDCl3): dH 7.79 (2H, d, J ¼ 7.3 Hz), 7.62 (1H, d, the crude yellow solid product which was puried by column
J ¼ 7.0 Hz), 7.25–7.21 (4H, m), 6.95 (1H, t, J ¼ 7.0 Hz), 6.09 (1H, chromatography (petrol (40/60)–ethyl acetate 2 : 1) to yield ethyl
dd, J ¼ 3.7, 6.7 Hz), 4.85 (1H, dd, J ¼ 3.7, 6.9 Hz), 4.15 (1H, t, 3-((3aS*,4R*,10bS*)-1,3-dioxo-2-phenyl-10-tosyl-1,2,3,3a,4,10,10a,
J ¼ 6.9 Hz), 4.07 (2H, m), 3.15–3.12 (1H, m), 3.05–3.02 (1H, m), 10b-octahydropyrrolo[3,4-a]carbazol-4-yl)propanoate in (0.5095 g,
2.83 (3H, s), 2.43–2.36 (2H, m), 2.35 (3H, s), 1.91–1.75 (2H, m), 0.84 mmol, 71%) as a white solid.
1.19 (3H, t, J ¼ 7.3 Hz); 13C NMR (101 MHz, CDCl3): dC 178.6,
Mp: 201–203 ꢁC; Rf: 0.2 (Pet(40/60)–EA 2 : 1); 1H NMR
174.0, 172.79, 144.6, 144.0, 136.6, 134.0, 130.5, 130.0, 127.5, (400 MHz, CDCl3): dH 7.81 (2H, d, J ¼ 7.3 Hz), 7.60 (1H, d, J ¼ 7.3
126.6, 123.9, 121.0, 116.3, 115.4, 60.6, 59.9, 44.22, 42.98, 37.2, Hz), 7.34–7.21 (7H, m), 7.06 (2H, d, J ¼ 7.3 Hz), 6.97 (1H, t,
33.1, 28.3, 25.3, 21.70, 14.3; IR (neat): nmax/cmꢀ1: 1776, 1698; J ¼ 7.3 Hz), 6.20 (1H, dd, J ¼ 3.4, 7.1 Hz), 4.59 (1H, dd, J ¼ 3.4,
HRMS (pNSI): calcd
observed: 509.1731.
C
27H29N2O6S [M
+
H]+: 509.1741; 7.1 Hz), 4.18 (1H, t, J ¼ 7.3 Hz), 4.13–4.05 (2H, m), 3.26–3.20 (2H,
m), 2.45–2.40 (2H, m), 2.35 (3H, s), 1.89–1.85 (2H, m), 1.20 (3H,
t, J ¼ 6.9 Hz); 13C NMR (101 MHz, CDCl3): dC 177.5, 172.9, 172.7,
144.6, 144.3, 137.0, 134.1, 131.7, 130.7, 130.0, 129.0, 128.5,
2d – ethyl-3-((3aS*,4R*,10bS*)-1,3-dioxo-10-tosyl-
1,2,3,3a,4,10,10a,10b-octahydropyrrolo[3,4-a]carbazol-4-yl)
propanoate
127.6, 126.7, 126.3, 124.0, 120.9, 116.2, 115.5, 60.8, 60.0, 44.3,
43.1, 37.7, 33.2, 28.3, 21.6, 14.2; IR (neat): nmax/cmꢀ1: 1776,
1703; MS (pNSI): 588.21 (100%, [M + NH4]+), 1158.39 (33%, [2M
+ NH4]+); HRMS (pNSI): calcd C32H31N2O6S [M + H]+: 571.18;
observed: 571.1891.
Dimethyl aluminum chloride (1.0 M in hexane, 2.86 mL,
2.86 mmol) was added dropwise to a solution ꢁof N-maleimide
(0.14 g, 1.43 mmol) in dry DCM (5 mL) at ꢀ78 C. The mixture
le to stir for 30 min. A solution of ethyl-(Z)-5-(1-tosyl-1H-indol-
3-yl)-pent-4-enoate (0.57 g, 1.43 mmol) in dry DCM (10 mL) was
added. The reaction mixture was slowly heated to reux for 48 h,
quenched with saturated NaHCO3(aq.) (5 mL). The organic layer
3a – (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-2-methyl-10-
tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione
was extracted with DCM (1 ꢂ 100 mL), washed with brine, dried To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
over MgSO4 and ltered. The solvent was removed under indole (100 mg, 0.34 mmol), DCM (5 mL) and 1-methyl-1H-
reduced pressure to give the crude yellow solid product which pyrrole-2,5-dione (38 mg, 0.34 mmol). The resulting solution
was puried by column chromatography (petrol (40/60)–ethyl was heated at reux for 48 hours. The reaction was allowed to
acetate 2 : 1 gradient to 1 : 1 petrol–ethyl acetate) to yield ethyl 3- cool to room temperature, nitrosobenzene (40 mg, 0.34 mmol)
((3aS*,4R*,10bS*)-1,3-dioxo-10-tosyl-1,2,3,3a,4,10,10a,10b-octa-
hydropyrrolo[3,4-a]carbazol-4-yl)propanoate in (0.452 g, 0.91 18 hours. The solvent was removed under reduced pressure to
mmol, 64%) as a white solid. leave the crude product as a pale yellow solid which was puried
Mp: 218–220 ꢁC; Rf: 0.14 (Pet(40/60)–EA 1 : 1); 1H NMR by column chromatography (petrol (40/60)–ethyl acetate 4 : 1,
(400 MHz, CDCl3): dH 7.78 (2H, d, J ¼ 6.9 Hz), 7.64 (1H, d, J ¼ 6.8 column diameter cm, silica 16 cm) to give
Hz), 7.27–7.22 (4H, m), 6.98 (1H, t, J ¼ 7.8 Hz), 6.16 (1H, dd, (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-2-methyl-10-tosyl-
was added, and the solution was stirred at room temperature for
¼
1
¼
16136 | RSC Adv., 2015, 5, 16125–16152
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4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione pyrrole-2,5-dione (38 mg, 0.34 mmol) and the resulting solution
as a yellow powder (71%, 128 mg, 0.24 mmol). was heated at reux for 48 hours. The reaction was cooled to
1
Mp: 196.8–199.5 ꢁC; Rf: 0.64 (Pet(40/60)–EA, 1 : 1); H NMR 0 ꢁC before PTAD (60 mg, 0.34 mmol) was added. The reaction
(500 MHz, CD2Cl2): dH 7.94 (1H, d, J ¼ 8.4 Hz), 7.69 (2H, d, J ¼ 8.2 was stirred at 0 ꢁC for 4 hours. The solvent was removed under
Hz), 7.60 (1H, d, J ¼ 7.9 Hz), 7.32–7.25 (3H, m), 7.23 (2H, d, J ¼ 8.2 reduced pressure to leave the crude product as a pale red
Hz), 7.18–7.13 (3H, m), 7.02 (1H, t, J ¼ 7.3 Hz), 5.06 (1H, d, J ¼ 8.0 powder. The product was puried by column chromatography
Hz), 4.75 (1H, app. t, J ¼ 5.9 Hz), 4.72 (1H, s), 3.64 (1H, app q, J ¼ (petrol (40/60)–ethyl acetate 4 : 1, column diameter ¼ 1 cm,
7.2 Hz), 2.95 (3H, s), 2.43 (1H, app dt, J ¼ 13.6, 6.4 Hz), 2.35 (3H, silica ¼ 14 cm) to give (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-
s), 2.06 (1H, ddd, J ¼ 13.6, 7.2, 4.9); 13C NMR (101 MHz, CD2Cl2): 1,2,4-triazolidin-1-yl)-2-methyl-10-tosyl-4,5,10,10b-tetrahydro-
dC 178.1, 173.6, 150.7, 145.3, 137.5, 134.9, 131.4, 129.7, 128.9, pyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione (76%, 150 mg, 0.26
128.9, 126.8, 125.2, 124.2, 122.6, 121.7, 120.2, 117.2, 115.4, 58.0, mmol) as a white powder.
1
40.5, 39.5, 25.0, 23.3, 21.4; IR (neat): nmax/cmꢀ1 3661, 2990, 2886,
Mp: 183.4–187.7 ꢁC; Rf: 0.05 (Pet(40/60)–EA 1 : 1); H NMR
1690; MS (pNSI): 407.1 (66%, (M ꢀ (C6H5NOH))+), 516.2 (49%, (M (400 MHz, CDCl3): dH 7.84 (2H, d, J ¼ 8.4 Hz), 7.67 (1H, d, J ¼ 8.2
+ H)+), 533.2 (100%, (M + NH4)+), 1031.3 (57%, (2M + H)+), 1053.3 Hz), 7.52 (1H, d, J ¼ 7.6 Hz), 7.46–7.31 (5H, m), 7.29–7.19 (2H,
(13%, (2M + Na)+); HRMS (pNSI): calcd for C28H26N3O5S [M + H]+: m), 7.17 (2H, d, J ¼ 8.3 Hz), 5.55 (1H, app t, J ¼ 4.7 Hz), 5.08 (1H,
516.1588; observed: 516.1584.
d, J ¼ 7.7 Hz), 3.66 (1H, ddd, J ¼ 10.5, 7.7, 5.8 Hz), 2.96 (3H, s),
Note: 1H NMR run at 35 ꢁC, broad signals observed at room 2.49 (1H, app dt, J ¼ 14.8, 5.3 Hz), 2.28 (3H, s), 2.14 (1H, ddd,
temperature.
J ¼ 14.8, 10.5, 5.5 Hz); 13C NMR (101 MHz, CDCl3): dC 177.4,
173.4, 153.6, 152.8, 145.5, 137.0, 135.3, 132.3, 130.8, 130.0,
129.3, 128.5, 127.5, 126.9, 125.7, 125.6, 124.3, 119.4, 115.4,
114.9, 47.8, 40.3, 39.0, 28.4, 25.4, 21.7; IR (neat): nmax/cmꢀ1
3665, 2984, 2884, 1699; MS (pNSI): 601.2 (100%, (M + NH4)+),
1184.3 (13%, (2M + NH4)+); HRMS (pNSI): calcd for C30H29N6O6S
[M + NH4]+: 601.1864; observed: 601.1861.
3b – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-2-methyl-10-
tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione
To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
indole (100 mg, 0.34 mmol), DCM (5 mL) and 1-methyl-1H-
pyrrole-2,5-dione (38 mg, 0.34 mmol). The resulting solution
was heated at reux for 48 hours. The reaction was allowed to
cool to room temperature, 1-methyl-2-nitrosobenzene (42 mg,
0.17 mmol) was added and the solution was stirred at room
temperature for 18 hours. The solvent was removed under
reduced pressure to leave the crude product as a pale yellow
solid. The product was puried by column chromatography
(petrol (40/60)–ethyl acetate 4 : 1, column diameter ¼ 1 cm,
silica ¼ 14 cm) to give (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)
amino)-2-methyl-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]-
carbazole-1,3(2H,3aH)-dione (71%, 128 mg, 0.24 mmol) as a
yellow powder.
3d – (3aS*,5S*,10bS*)-5-((S*)-hydroxy(peruorophenyl)
methyl)-2-methyl-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]
carbazole-1,3(2H,3aH)-dione
To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
indole (100 mg, 0.34 mmol) DCM (5 mL) and 1-methyl-1H-
pyrrole-2,5-dione (38 mg, 0.34 mmol) and the resulting solution
was heated at reux for 48 hours. The reaction was cooled to
ꢀ78 ꢁC and 2,3,4,5,6-pentauorobenzaldehyde (0.04 mL,
0.34 mmol) was added followed by DMAC (1 M in hexane, 0.34
mL, 0.34 mmol). The reaction was stirred at ꢀ78 ꢁC for
15 minutes before being allowed to warm to room temperature.
The reaction was stirred at room temperature for 18 hours. The
reaction was poured into saturated sodium bicarbonate solu-
tion (10 mL) and extracted with DCM (2 ꢂ 10 mL). The
combined organic layers were dried with MgSO4, ltered and
the solvent was removed under reduced pressure to give the
crude product as a pale brown solid. The product was puried
by column chromatography (petrol (40/60)–ethyl acetate 3 : 1,
column diameter ¼ 2 cm, silica ¼ 15 cm) to give a separable 5 : 1
mixture of (3aS*,5S*,10bS*)-5-((S*)-hydroxy(peruorophenyl)
methyl)-2-methyl-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]-
carbazole-1,3(2H,3aH)-dione and (3aS*,5S*,10bS*)-5-((R*)-
hydroxy(peruorophenyl)methyl)-2-methyl-10-tosyl-4,5,10,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione (72%, 149
mg, 0.25 mmol).
Mp: 193.0–196.7 ꢁC; Rf: 0.59 (Pet(40/60)–EA 1 : 1); 1H NMR
(400 MHz, CD2Cl2): dH 7.89 (1H, d, J ¼ 8.3 Hz), 7.65 (2H, d, J ¼ 8.4
Hz), 7.40 (1H, d, J ¼ 7.9 Hz), 7.28 (1H, d, J ¼ 7.7 Hz), 7.21–7.18
(3H, m), 7.13–6.99 (4H, m), 5.04 (1H, d, J ¼ 8.1 Hz), 4.87 (1H, s),
4.27 (1H, app t, J ¼ 5.4 Hz), 3.73 (1H, app td, J ¼ 8.0, 6.1 Hz), 2.91
(3H, s), 2.58 (1H, app dt, J ¼ 12.9, 6.2 Hz), 2.32 (3H, s), 2.25 (3H,
s), 1.95 (1H, ddd, J ¼ 12.9, 7.8, 4.5 Hz); 13C NMR (101 MHz,
CD2Cl2): dC 178.2, 173.6, 149.3, 145.3, 137.3, 134.9, 131.6, 130.9,
129.7, 129.7, 129.2, 126.8, 126.2, 125.0, 124.9, 124.1, 121.4, 120.5,
115.3, 57.3, 40.6, 39.4, 25.0, 24.6, 21.4, 18.3; IR (neat): nmax/cmꢀ1
3662, 2990, 2886, 1701; MS (pNSI): 407.1 (98%, (M ꢀ ((o-CH3) ꢀ
C6H4NOH))+), 530.2 (52%, (M + H)+), 547.2 (65%, (M + NH4)+),
1059.3 (100%, (2M + H)+); HRMS (pNSI): calcd for C29H28N3O5S
[M + H]+: 530.1744; observed: 530.1743.
Major diastereomer: Mp: 120.4–121.7 ꢁC; Rf: 0.24 (Pet(40/60)–
EA 3 : 1); 1H NMR (300 MHz, CDCl3): dH d 7.85 (3H, app d, J ¼ 8.4
Hz), 7.31–7.22 (4H, m), 7.22–7.14 (1H, m), 5.13 (1H, d, J ¼ 8.1 Hz),
4.99 (1H, d, J ¼ 7.5 Hz), 3.71–3.52 (2H, m), 3.01 (3H, s), 2.38 (3H,
3c – (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-
1-yl)-2-methyl-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]
carbazole-1,3(2H,3aH)-dione
To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H- s), 2.20–2.10 (1H, m), 1.67 (1H, app td, J ¼ 13.8, 5.3 Hz); 13C NMR
indole (100 mg, 0.34 mmol), DCM (5 mL) and 1-methyl-1H- (101 MHz, CDCl3): dC 177.7, 173.3, 145.3, 137.4, 135.4, 129.8,
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129.7, 129.6, 127.2, 125.3, 123.9, 120.1, 119.9, 115.2, 70.2, 41.5, (5H, m), 7.43–7.40 (1H, m), 7.47 (2H, app t, J ¼ 7.7 Hz), 7.40–7.37
39.1, 36.9, 28.7, 25.2, 21.7; IR (neat): nmax/cmꢀ1 3371, 2981, 2889, (1H, m), 7.18 (2H, app t, J ¼ 7.8 Hz), 7.11 (2H, d, J ¼ 8.2 Hz), 6.97
1690; MS (pNSI): 605.1 (40%, (M + H)+), 622.1 (88%, (M + NH4)+), (2H, app q, J ¼ 7.2 Hz), 6.85 (1H, d, J ¼ 7.5 Hz), 6.50 (1H, d, J ¼
627.1 (100%, (M + Na)+), 643.1 (17%), 709.1 (15%); HRMS (pNSI): 7.8 Hz), 5.93 (1H, s), 5.24 (1H, d, J ¼ 13.5 Hz), 4.44 (1H, s), 3.11
calcd for C29H21F5N2NaO5S [M + Na]+: 627.0984; observed: (1H, d, J ¼ 13.5 Hz), 2.29 (3H, s), 1.91 (3H, s); 13C NMR (101
627.0968. Note: 13C NMR missing peaks due to C–F coupling.
MHz, CDCl3): dC 153.3, 150.3, 148.7, 145.4, 135.1, 133.7, 132.0,
131.7, 131.3, 130.6, 129.6, 129.3, 128.7, 127.9, 127.2, 127.0,
126.8, 125.9, 124.9, 124.8, 122.6, 118.0, 116.8, 107.0, 59.1, 44.5,
21.7, 17.8; IR (neat): nmax/cmꢀ1 3068, 2981, 1713; MS (pAPCI):
138.1 (100%), 157.0 (82%), 262.1 (55%), 279.1 (76%),
317.1 (50%), 391.3 (37%), 471.1 (21%), 594.2 (10%, (M + H)+);
HRMS (pAPCI): calcd for C32H28N5O5S [M + H]+: 594.1806;
observed: 594.1801.
3e – 6-(hydroxy(phenyl)amino)-2-phenyl-11-tosyl-5,6-dihydro-
[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-1,3(2H,11H)-
dione
To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
indole (100 mg, 0.34 mmol) and DCM (5 mL) and the solution
was cooled to ꢀ78 ꢁC. To this solution PTAD (70 mg, 0.34 mmol)
was added and the reaction was stirred at ꢀ78 ꢁC for 3.5 hours.
The reaction was warmed to room temperature, nitrosobenzene
(44 mg, 0.34 mmol) was added and the reaction was stirred for
18 hours. The solvent was removed under reduced pressure to
3g – ethyl 3-((3aS*,4S*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-2-
methyl-1,3-dioxo-10-tosyl-1,2,3,3a,4,5,10,10b-
octahydropyrrolo[3,4-a]carbazol-4-yl)propanoate
leave the crude product as a pale yellow oil. The product was A solution of 2-nitrosotoluene (0.035 g, 0.29 mmol) and ethyl
puried by column chromatography (column diameter ¼ 1 cm, 3-((3aS*,4R*,10bS*)-2-methyl-1,3-dioxo-10-tosyl-1,2,3,3a,4,10,10a,
silica ¼ 16 cm, eluent ¼ petrol (40/60)–ether–DCM 2 : 1 : 1) to 10b-octahydropyrrolo[3,4-a]carbazol-4-yl)propanoate (0.150 g,
give 6-(hydroxy(phenyl)amino)-2-phenyl-11-tosyl-5,6-dihydro- 0.29 mmol) in dry DCM (10 mL) was stirred at room tempera-
[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-1,3(2H,11H)- ture for 24 hours. The solvent was removed under reduced
dione (72%, 54 mg, 0.09 mmol) as a white powder.
pressure to give the crude green solid product which was puri-
Mp: 176.1–180.0 ꢁC; Rf: 0.48 (Pet(40/60)–Et2O 2 : 1); 1H NMR ed by column chromatography (petrol (40/60)–ethyl acetate
(400 MHz, CDCl3): dH 8.03 (1H, d, J ¼ 8.3 Hz), 7.62 (2H, d, J ¼ 8.1 2 : 1) to give ethyl 3-((3aS*,4S*,5S*,10bS*)-5-(hydroxy(o-tolyl)
Hz), 7.56 (2H, d, J ¼ 7.6 Hz), 7.46 (2H, app t, J ¼ 7.7 Hz), amino)-2-methyl-1,3-dioxo-10-tosyl-1,2,3,3a,4,5,10,10b-octahy-
7.42–7.36 (1H, m), 7.23–7.07 (7H, m), 7.05–6.99 (2H, m), dropyrrolo[3,4-a]carbazol-4-yl)propanoate (0.109 g, 0.17 mmol,
6.59 (1H, d, J ¼ 7.4 Hz), 5.81 (1H, br s), 5.18 (1H, d, J ¼ 13.5 Hz), 59%) as a bright yellow solid.
4.59 (1H, s), 3.23 (1H, d, J ¼ 13.5 Hz), 2.30 (3H, s); 13C NMR
Mp: 190–192 ꢁC; Rf: 0.26 (Pet(40/60)–EA 2 : 1); 1H NMR
(101 MHz, DMSO-d6): dC 152.7, 152.2, 150.5, 146.0, 134.9, 132.9, (400 MHz, CDCl3): dH 7.95 (1H, d, J ¼ 7.2 Hz), 7.61 (2H, d, J ¼ 7.2
132.5, 131.8, 130.4, 129.8, 129.3, 129.2, 128.5, 127.3, 127.3, Hz), 7.18 (2H, d, J ¼ 7.2 Hz), 7.10 (1H, d, J ¼ 7.2 Hz), 7.05 (1H, t, J
125.5, 125.4, 122.5, 119.8, 117.6, 116.6, 108.6, 55.9, 44.6, 21.6; IR ¼ 7.2 Hz), 6.81 (1H, t, J ¼ 7.2 Hz), 6.65 (1H, t, J ¼ 7.5 Hz), 6.19
(neat): nmax/cmꢀ1 2981, 2884, 1714; MS (pAPCI): 138.1 (100%), (1H, t, J ¼ 7.5 Hz), 5.88 (1H, d, J ¼ 7.2 Hz), 5.46 (1H, d, J ¼ 7.2
157.0 (95%), 213.1 (50%), 248.1 (86%), 279.1 (62%), 317.1 (33%), Hz), 4.99 (1H, br s), 4.95 (1H, d, J ¼ 7.2 Hz), 4.30 (1H, d, J ¼ 4.6
333.1 (29%), 471.1 (31%), 564.2 (11%), 580.2 (10%, (M + H)+); Hz), 4.11 (2H, q, J ¼ 7.0 Hz), 3.80–3.75 (1H, m), 3.01 (3H, s),
HRMS (pAPCI): calcd for C31H26N5O5S [M + H]+: 580.1649; 2.70–2.54 (4H, m), 2.41 (3H, s), 2.33 (3H, s), 1.92–1.85 (1H, m),
observed: 580.1640.
1.24 (3H, t, J ¼ 7.0 Hz). 13C NMR (101 MHz, CDCl3): dC 178.2,
173.3, 149.9, 144.6, 139.9, 137.1, 134.1, 131.9, 130.6, 130.3,
129.4, 128.7, 127.0, 125.7, 124.8, 124.4, 123.6, 122.1, 118.9,
118.0, 115.7, 60.6, 57.8, 45.1, 42.4, 40.0, 32.5, 25.2, 23.3, 21.6,
18.5, 14.3; IR (neat): nmax/cmꢀ1: 3655, 2980, 1702; MS (pNSI):
507.15 (100%, [M ꢀ (Tol-N-OH)]), 652.20 (55%, [M + Na]+);
HRMS (pNSI): calcd C34H35N3O7S [M + Na]+: 652.2088; observed:
652.2082.
3f – 6-(hydroxy(o-tolyl)amino)-2-phenyl-11-tosyl-5,6-dihydro-
[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-1,3(2H,11H)-
dione
To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
indole (100 mg, 0.34 mmol) and DCM (5 mL) and the solution
cooled to ꢀ78 ꢁC. To this solution PTAD (70 mg, 0.34 mmol) was
added and the reaction was stirred at ꢀ78 ꢁC for 3.5 hours. The
reaction was warmed to room temperature and 1-methyl-2-
nitrosobenzene (42 mg, 0.34 mmol) was added and the reac-
tion was stirred for 18 hours. The solvent was removed under
3h – ethyl 3-((3aS*,4S*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-
1,3-dioxo-2-phenyl-10-tosyl-1,2,3,3a,4,5,10,10b-
octahydropyrrolo[3,4-a]carbazol-4-yl)propanoate
reduced pressure to leave the crude product as a pale yellow oil. A solution of 2-nitrosotoluene (0.016 g, 0.13 mmol) and ethyl
The product was puried by column chromatography (column 3-((3aS*,4R*,10bS*)-1,3-dioxo-2-phenyl-10-tosyl-1,2,3,3a,4,10,
diameter ¼ 1 cm, silica ¼ 14 cm, eluent ¼ petrol (40/60)–ether– 10a,10b-octahydropyrrolo[3,4-a]carbazol-4-yl)propanoate (0.08 g,
DCM 2 : 1 : 1) to give 6-(hydroxy(o-tolyl)amino)-2-phenyl-11- 0.13 mmol) in dry DCM (10 mL) was stirred at room temperature
tosyl-5,6-dihydro-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole- for 24 hours. The solvent was removed under reduced pressure
1,3(2H,11H)-dione as a white powder (78%, 60 mg, 0.10 mmol). to give the crude yellow product which was puried by column
Mp: 149.7–153.1 ꢁC; Rf: 0.32 (Pet(40/60)–Et2O–DCM 2 : 1 : 1); chromatography (petrol (40/60)–ethyl acetate 2 : 1) to give ethyl
1H NMR (300 MHz, CDCl3): dH 7.99 (1H, d, J ¼ 8.3 Hz), 7.61–7.58 3-((3aS*,4S*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-1,3-dioxo-2-
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phenyl-10-tosyl-1,2,3,3a,4,5,10,10b-octahydropyrrolo[3,4-a]-
propanoate (0.105 g, 0.21 mmol) in dry DCM (10 mL) was stirred
carbazol-4-yl)propanoate in (0.415 g, 0.059 mmol, 58%) as a at 0 ꢁC for 6 h. The solvent was removed to give the crude white
bright yellow solid.
solid product which was puried by trituration from DCM to
1
ꢁ
Mp: 182–184 C; Rf: 0.34 (Pet(40/60)–EA 2 : 1); H NMR (400 yield ethyl 3-((3aS*,4S*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-
MHz, CDCl3): dH 7.94 (1H, d, J ¼ 6.7 Hz), 7.64 (2H, d, J ¼ 6.7 Hz), triazolidin-1-yl)-1,3-dioxo-10-tosyl-1,2,3,3a,4,5,10,10b-octahy-
7.45–7.37 (5H, m), 7.20–7.00 (4H, m), 6.84 (1H, t, J ¼ 6.9 Hz), dropyrrolo[3,4-a]carbazol-4-yl)propanoate in (57%, 0.08 g, 0.119
6.66 (1H, t, J ¼ 6.9 Hz), 6.24 (1H, t, J ¼ 6.2 Hz), 5.95 (1H, d, J ¼ mmol) as a white solid.
6.9 Hz), 5.66 (1H, d, J ¼ 6.4 Hz), 5.20 (1H, d, J ¼ 7.4 Hz), 4.99
Mp: 269–271 ꢁC; 1H NMR (300 MHz, d6-DMSO): dH 11.44 (1H,
(1H, br s), 4.39 (1H, d, J ¼ 4.0 Hz), 4.08 (2H, q, J ¼ 7.2 Hz), 4.03– br s), 10.68 (1H, br s), 7.87–7.76 (3H, m), 7.51–7.39 (4H, m), 7.29–
3.98 (1H, m), 2.72–2.61 (4H, m), 2.42 (3H, s), 2.33 (3H, s), 2.14– 7.25 (6H, m), 5.69 (1H, d, J ¼ 6.1 Hz), 5.28 (1H, d, J ¼ 6.8 Hz), 4.05
2.08 (1H, m). 1.20 (3H, t, J ¼ 7.2 Hz); 13C NMR (101 MHz, CDCl3): (2H, q, J ¼ 6.8 Hz), 3.45 (1H, dd, J ¼ 6.8, 11.3 Hz), 3.58–3.52 (1H,
dC 177.0, 173.3, 172.2, 150.1, 144.6, 137.1, 134.2, 131.0, 131.8, m), 2.67–2.65 (1H, m), 2.25 (3H, s), 2.49–2.44 (2H, m), 1.80–1.70
130.5, 130.3, 129.4, 129.0, 128.6, 128.5, 127.0, 126.5, 125.8, (1H, m), 1.18 (3H, t, J ¼ 6.8 Hz); 13C NMR (101 MHz, d6-DMSO):
124.8, 124.5123.5, 122.2, 119.1, 118.1, 115.6, 60.0, 57.7, 45.3, 178.6, 175.0, 172.99, 154.4, 153.1, 145.5, 136.6, 134.9, 133.1, 131.7,
42.6, 40.0, 32.4, 23.1, 21.6, 18.5, 14.5; IR (neat): nmax/cmꢀ1: 3858, 130.4, 129.4, 128.6, 127.6, 127.1, 126.3, 125.6, 124.5, 119.3, 115.9,
3826, 1709, 1595; MS (pNSI): 569.17 (100%, [M ꢀ N(OH)(o-Tol)]), 114.9, 60.3, 45.2, 43.0, 38.0, 30.7, 23.6, 21.4, 14.5; IR (neat): nmax
/
692.24 (30%, [M + H]+); HRMS (pNSI): calcd C39H36N3O7S [M ꢀ cmꢀ1: 3659, 1775, 1692; MS (pNSI): 687.22 (100%, [M + NH4]+),
H]+: 690.2268; observed: 690.2266.
1356.41 (27%, [2M + NH4]+), 692.17 (12%, [M + Na]+); HRMS
(pNSI): calcd C34H35N6O8S [M + H]+: 687.2232; observed: 687.2229.
3i – ethyl 3-((3aS*,4S*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-
triazolidin-1-yl)-2-methyl-1,3-dioxo-10-tosyl-
1,2,3,3a,4,5,10,10b-octahydropyrrolo[3,4-a]carbazol-4-yl)
propanoate
3k – (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-10-tosyl-
4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-
dione
A solution of 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (0.052 g, To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
0.29 mmol) and ethyl 3-((3aS*,4R*,10bS*)-2-methyl-1,3-dioxo- indole (100 mg, 0.34 mmol), DCM (5 mL) and 1H-pyrrole-2,5-
10-tosyl-1,2,3,3a,4,10,10a,10b-octahydropyrrolo[3,4-a]carbazol- dione (33 mg, 0.34 mmol) and the resulting solution was
4-yl)propanoate (0.150 g, 0.29 mmol) in dry DCM (10 mL) was heated at reux for 48 hours. The reaction was cooled to room
stirred at 0 ꢁC for 6 hours. The solvent was removed under temperature and nitrosobenzene (36 mg, 0.34 mmol) was
reduced pressure to give the crude product which was puried added. The reaction was stirred at room temperature for 4 hours
by column chromatography (petrol (40/60)–ethyl acetate 1 : 1) to before the solvent was removed under reduced pressure to leave
give ethyl 3-((3aS*,4S*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4- the crude product as a white solid. The product was puried by
triazolidin-1-yl)-2-methyl-1,3-dioxo-10-tosyl-1,2,3,3a,4,5,10,10b- trituration from DCM to give (3aS*,5S*,10bS*)-5-(hydroxy-
octahydropyrrolo[3,4-a]carbazol-4-yl)propanoate
in
(56%, (phenyl)amino)-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]-
carbazole-1,3(2H,3aH)-dione (89%, 151 mg, 0.30 mmol) as a
0.110 g, 0.161 mmol) as a white solid.
Mp: 264–265 ꢁC; Rf: 0.30 (Pet(40/60)–EA 1 : 1); 1H NMR white powder.
1
(400 MHz, CDCl3): dH 8.86 (1H, br s), 7.78 (2H, d, J ¼ 7.0 Hz),
Mp: 203.7–206.9 ꢁC; Rf: 0.15 (Pet(40/60)–EA 2 : 1); H NMR
7.71 (1H, d, J ¼ 7.9 Hz), 7.47 (1H, d, J ¼ 7.9 Hz), 7.44–7.40 (1H, (300 MHz, DMSO-d6): dH 11.26 (1H, s), 8.45 (1H, s), 7.88 (1H, d,
m), 7.36–7.30 (3H, m), 7.23–7.17 (2H, m), 7.02 (2H, d, J ¼ 7.0 J ¼ 8.3 Hz). 7.76 (2H, d, J ¼ 8.2 Hz), 7.42 (1H, d, J ¼ 7.8 Hz), 7.33
Hz), 5.66 (1H, d, J ¼ 6.2 Hz), 5.04 (1H, d, J ¼ 6.5 Hz), 4.08 (2H, (2H, d, J ¼ 8.2 Hz), 7.29–7.04 (5H, m), 6.89 (1H, t, J ¼ 7.2 Hz),
q, J ¼ 6.2 Hz), 3.44 (1H, dd, J ¼ 6.5, 11.9 Hz), 3.02 (3H, s), 5.17 (1H, d, J ¼ 7.8 Hz), 4.88 (1H, app t, J ¼ 4.4 Hz), 3.65 (1H, app
2.68–2.51 (3H, m), 2.15 (3H, s), 2.14–2.09 (1H, m), 1.90–1.82 td, J ¼ 8.8, 5.9 Hz), 2.32 (3H, s), 2.36–2.27 (1H, m), 1.81 (1H, ddd,
(1H, m), 1.20 (3H, t, J ¼ 6.2 Hz); 13C NMR (101 MHz, CDCl3): J ¼ 14.0, 9.4, 5.0 Hz); 13C NMR (101 MHz, DMSO-d6): dC 179.4,
dC 176.6, 173.4, 173.2, 153.6, 152.6, 145.2, 136.8, 135.5, 132.1, 174.7, 152.0, 144.7, 136.4, 135.0, 131.5, 129.8, 128.9, 128.4,
130.7, 129.7, 129.3, 128.6, 127.2, 126.8, 125.6, 124.2, 119.0, 126.6, 124.4, 123.4, 121.2, 120.7, 120.6, 117.0, 114.4, 56.8, 41.5,
114.8, 114.4, 60.8, 44.3, 42.0, 39.3, 30.9, 25.4, 23.0, 21.5, 14.2; 40.6, 25.2, 20.9; IR (neat): nmax/cmꢀ1 3452, 2981, 1715; MS
IR (neat): nmax/cmꢀ1: 3659, 1775, 1691; MS (pNSI): 701.23 (pNSI): 393.1, (100%, (M ꢀ (C6H5NOH)+)), 502.1 (14%, (M + H)+),
(100%, [M + NH4]+), 1384.44 (17%, [2M + NH4]+); HRMS 519.2 (96%, (M + NH4)+), 524.1 (17%, (M + Na)+), 1003.3 (40%,
(pNSI): calcd C35H34N5O8S [M + H]+: 684.2123; observed: (2M + H)+), 1025.3 (15%, (2M + Na)+); HRMS (pNSI): calcd for
684.2115.
C
27H24N3O5S [M + H]+: 502.1431; observed: 502.1428.
3j – ethyl 3-((3aS*,4S*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-
triazolidin-1-yl)-1,3-dioxo-10-tosyl-1,2,3,3a,4,5,10,10b-
octahydropyrrolo[3,4-a]carbazol-4-yl)propanoate
3l – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-10-tosyl-
4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-
dione
A solution of 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (0.037 g, To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
0.21 mmol) and ethyl 3-((3aS*,4R*,10bS*)-1,3-dioxo-10-tosyl- indole (100 mg, 0.34 mmol), DCM (5 mL) and 1H-pyrrole-2,5-
1,2,3,3a,4,10,10a,10b-octahydropyrrolo[3,4-a]carbazol-4-yl)- dione (33 mg, 0.34 mmol) was added and the resulting
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solution was heated at reux for 48 hours. The reaction was (pAPCI): 157.0 (79%), 221.1 (61%), 393.1 (15%, (M
ꢀ
cooled to room temperature and 1-methyl-2-nitrosobenzene (41 (C6F5COH)+)), 443.1 (51%), 573.1 (8%, (M ꢀ H2O)+), 591.1
mg, 0.34 mmol) was added. The reaction was stirred at room (100%, (M + H)+); HRMS (pAPCI): calcd for C28H20F5N2O5S [M +
temperature for 4 hours before the solvent was removed under H]+: 591.1008; observed: 591.1001. Note: 13C NMR missing peaks
reduced pressure to leave the crude product as a pale yellow due to C–F coupling.
solid. The product was puried by column chromatography
(petrol (40/60)–ether–DCM 2 : 1 : 1, column diameter ¼ 2 cm,
3n – (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-
silica ¼ 14 cm) to give (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)
1-yl)-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
amino)-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione (82%, 143 mg, 0.28 mmol) as a yellow
powder.
1,3(2H,3aH)-dione
To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
indole (100 mg, 0.34 mmol), DCM (5 mL) and 1H-pyrrole-2,5-
dione (33 mg, 0.34 mmol). The resulting solution was heated
at reux for 48 hours. The reaction was cooled to 0 ꢁC and PTAD
was added. The solution was stirred at 0 ꢁC for 4 hours and the
solvent was removed under reduced pressure to give the crude
product as pale red. The product was puried by column chro-
matography (diameter ¼ 1.5 cm, silica ¼ 17 cm, eluent ¼ petrol
(40/60)–EA 1 : 1) to give (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-
1,2,4-triazolidin-1-yl)-10-tosyl-4,5,10,10b-tetrahydropyrrolo-
[3,4-a]carbazole-1,3(2H,3aH)-dione (23%, 0.044 g, 0.08 mmol) as
an off white solid.
1
Mp: 171.1–174.0 ꢁC; Rf: 0.13 (Pet(40/60)–EA 2 : 1); H NMR
(400 MHz, CDCl3): d 7.90 (1H, d, J ¼ 8.4 Hz), 7.73 (2H, d, J ¼ 8.2
Hz), 7.77 (1H, s), 7.35 (2H, dd, J ¼ 15.7, 7.9 Hz), 7.20 (3H, app d, J
¼ 8.2 Hz), 7.09 (2H, d, J ¼ 7.5 Hz), 7.07–7.00 (2H, m), 5.17 (1H, d,
J ¼ 8.1 Hz), 4.75 (1H, s), 4.39 (1H, app t, J ¼ 5.1 Hz), 3.80 (1H,
app q, J ¼ 8.3, 5.7 Hz), 2.64 (1H, app dt, J ¼ 13.1, 5.5 Hz), 2.34
(3H, s), 2.26 (3H, s), 1.96 (1H, ddd, J ¼ 15.9, 7.9, 3.7 Hz); 13C
NMR (75 MHz, CDCl3): dC 178.3, 173.4, 149.3, 144.7, 137.4,
135.8, 131.3, 130.9, 129.8, 129.6, 129.5, 129.0, 127.0, 126.3,
125.1, 124.7, 123.7, 121.5, 120.1, 115.3, 57.3, 42.0, 40.8, 26.0,
21.4, 18.3; IR (neat): nmax/cmꢀ1 3294, 2981, 1713; MS (pAPCI):
293.1 (16%), 332.1 (13%), 342.1 (16%), 393.1 (100%, (M ꢀ (o-Tol)
N(OH))+), 489.1 (54%, (M ꢀ H2O)+), 516.2 (26%, (M + H)+);
HRMS (pAPCI): calcd for C28H26N3O5S [M + H]+: 516.1588;
observed: 516.1576.
Mp: 206.4–209.7 ꢁC; Rf: 0.10 (Pet(40/60)–EA 2 : 1); 1H NMR
(400 MHz, DMSO-d6): dC 11.37 (1H, s), 10.77 (1H, s), 7.82 (2H, d, J
¼ 8.3 Hz), 7.72 (1H, d, J ¼ 7.9 Hz), 7.48–7.43 (2H, m), 7.42–7.35
(4H, m), 7.28 (2H, d, J ¼ 8.5 Hz), 7.25–7.18 (2H, m), 5.46 (1H, app
t, J ¼ 4.9 Hz), 5.19 (1H, d, J ¼ 7.7 Hz), 3.77–3.65 (1H, m), 2.41 (1H,
app dt, J ¼ 9.8, 5.1 Hz), 2.26 (3H, s), 2.24–2.16 (1H, m); 13C NMR
(101 MHz, CDCl3): dH 178.8, 173.6, 153.6, 152.4, 145.4, 136.9,
135.3, 132.2, 130.9, 129.9, 129.2, 128.4, 127.5, 126.9, 125.7, 125.6,
124.2, 119.3, 115.1, 114.8, 47.3, 41.5, 40.2, 28.8, 21.7; IR (neat):
nmax/cmꢀ1 3194, 2981, 2980, 1699; MS (pNSI): 587.2 (100% (M +
NH4)+), 592.1 (30% (M + Na)+); HRMS (pNSI): calcd for
C29H27N6O6S [M + NH4]+: 587.1707; observed: 587.1706.
3m – (3aS*,5S*,10bS*)-5-((S*)-hydroxy(peruorophenyl)
methyl)-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione
To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
indole (100 mg, 0.34 mmol), DCM (5 mL) and 1H-pyrrole-2,5-
dione (33 mg, 0.34 mmol). The resulting solution was heated
at reux for 48 hours. The reaction was cooled to 0 ꢁC and
pentauorobenzaldehyde (67 mg, 0.34 mmol) and DMAC (1 M
in hexane, 0.34 mL, 0.34 mmol) were added. The solution was
stirred at 0 ꢁC for 1 hour and then warmed to room temperature
3o – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-7-methoxy-
10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione
for 18 hours. The reaction was poured into sodium bicarbonate To a stirred round bottomed ask was added 6-methoxy-1-tosyl-
(15 mL) and extracted with DCM. The combined organic layers 3-vinyl-1H-indole (111 mg, 0.34 mmol), DCM (5 mL) and 1H-
were dried with MgSO4, ltered and the solvent was removed pyrrole-2,5-dione (33 mg, 0.34 mmol). The resulting solution
under reduced pressure to give the crude product as an off white was heated at reux for 48 hours. The reaction was cooled to
solid. The product was puried by column chromatography room temperature and 1-methyl-2-nitrosobenzene (41 mg,
(diameter ¼ 1.5 cm, silica ¼ 15 cm, eluent ¼ petrol (40/60)–EA 0.34 mmol) was added. The reaction was stirred at room
2 : 1) to give (3aS*,5S*,10bS*)-5-((S*)-hydroxy(peruorophenyl) temperature for 24 hours before the solvent was removed under
methyl)-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole- reduced pressure to leave the crude product as a pale yellow
1,3(2H,3aH)-dione (71%, 0.1427 g, 0.24 mmol) as an off white solid. The product was puried by column chromatography
solid.
(petrol (40/60)–ethyl acetate 2 : 1) to give (3aS*,5S*,10bS*)-5-
1
Mp: 181.3–185.1 ꢁC; Rf: 0.22 (Pet(40/60)–EA 2 : 1); H NMR (hydroxy(o-tolyl)amino)-7-methoxy-10-tosyl-4,5,10,10b-tetrahydro
(400 MHz, CDCl3): dH 8.03 (1H, br s), 7.81 (3H, app d, J ¼ 7.9 Hz), pyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione (76%, 141 mg, 0.26
7.28 (1H, d, J ¼ 8.0 Hz), 7.25–7.22 (3H, m), 7.16 (1H, app t, J ¼ mmol) as a light brown solid.
7.6 Hz), 5.08 (1H, d, J ¼ 8.3 Hz), 5.05 (1H, d, J ¼ 7.4 Hz), 3.61–
Mp: 185 ꢁC decomposed; Rf: 0.26 (Pet(40/60)–EA 4 : 3); 1H
3.66 (1H, m), 3.49–3.57 (1H, m), 2.34 (3H, s), 2.09 (1H, dd, J ¼ NMR (400 MHz, DMSO-d6): dH 11.19 (1H, s), 8.34 (1H, s), 7.69
14.0, 4.5 Hz), 1.74 (1H, app td, J ¼ 13.9, 5.3 Hz); 13C NMR (101 (1H, d, J ¼ 9.1 Hz), 7.61 (2H, d, J ¼ 8.2 Hz), 7.27 (2H, d, J ¼ 8.2
MHz, CDCl3): dC 177.4, 173.0, 145.3, 137.4, 135.5, 129.8, 129.7, Hz), 7.08–6.97 (2H, m), 6.95–6.85 (2H, m), 6.72 (1H, dd, J ¼ 9.1,
129.1, 127.1, 125.5, 123.9, 120.2, 120.0, 115.3, 70.2, 42.5, 40.3, 2.4 Hz), 6.40 (1H, s), 5.07 (1H, d, J ¼ 7.9 Hz), 4.20 (1H, app t, J ¼
36.8, 28.5, 21.7; IR (neat): nmax/cmꢀ1 3240, 2981, 1717; MS 4.4 Hz), 3.76 (1H, app q, J ¼ 8.4 Hz), 3.47 (3H, s), 2.53–2.47 (1H,
16140 | RSC Adv., 2015, 5, 16125–16152
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m), 2.28 (s, 3H), 2.08 (s, 3H), 1.75 (1H, ddd, J ¼ 13.6, 9.8, 4.4 Hz); diameter ¼ 2 cm, silica ¼ 16 cm, eluent ¼ petrol (40/60)–EA
13C NMR (101 MHz, DMSO-d6): dC 180.5, 175.4, 156.3, 151.7, 1 : 1) to give (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-tri-
145.3, 134.7, 133.1, 131.1, 131.0, 130.8, 130.3, 129.7, 127.1, azolidin-1-yl)-7-methoxy-10-tosyl-4,5,10,10b-tetrahydropyrrolo-
126.4, 124.6, 122.1, 121.2, 115.9, 113.8, 103.3, 57.1, 55.3, 42.2, [3,4-a]carbazole-1,3(2H,3aH)-dione (75%, 0.152 mg, 0.25 mmol)
26.9, 21.5, 21.3, 18.5; IR (neat): n(max)/cmꢀ1 3388, 3071, 2552, as a pale yellow powder.
1
1727; MS (pNSI): 355.1 (50%), 371.1 (100%), 423.1 (57%), 445.1
Mp: 189.9–193.3 ꢁC; Rf: 0.07 (Pet(40/60)–EA 1 : 1); H NMR
(30%), 546.2 (5%, (M + H)+), 568.2 (16%, (M + Na)+), 584.1 (21%); (400 MHz, CDCl3): dH 9.31 (1H, br), 7.67 (2H, d, J ¼ 7.5 Hz), 7.55
HRMS (pNSI): calcd for C29H28N3O6S1 [M + H]+: 546.1693; (1H, d, J ¼ 8.8 Hz), 7.38–7.23 (5H, m), 7.00 (2H, d, J ¼ 7.8 Hz),
observed: 546.1690.
6.90 (1H, s), 6.80 (1H, d, J ¼ 8.9 Hz), 5.53 (1H, br s), 5.18 (1H, d, J
¼ 6.7 Hz), 3.74–3.69 (1H, m), 3.64 (3H, s), 2.48–2.55 (1H, m),
2.17 (3H, s), 2.12–2.02 (2H, m); 13C NMR (101 MHz, CDCl3): dC
179.0, 173.9, 156.9, 153.7, 152.7, 145.2, 135.1, 132.7, 131.5,
131.0, 129.8, 129.2, 128.4, 128.0, 127.2, 125.6, 115.9, 115.5,
3p – (3aS*,5S*,10bS*)-5-((S*)-hydroxy(peruorophenyl)
methyl)-7-methoxy-2-methyl-10-tosyl-4,5,10,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione
114.3, 101.9, 55.7, 47.6, 41.6, 40.1, 28.8, 21.6; IR (neat): nmax
/
To a stirred round bottomed ask was added 5-methoxy-1-tosyl-
3-vinyl-1H-indole (112 mg, 0.34 mmol), DCM (5 mL) and 1-
methyl-1H-pyrrole-2,5-dione (38 mg, 0.34 mmol). The reaction
was heated at reux for 48 hours. The reaction was cooled to
ꢀ78 ꢁC and pentauorobenzaldehyde (0.04 mL, 0.34 mmol) and
DMAC (1 M in hexane, 0.34 mL, 0.34 mmol) were added. The
solution was stirred at ꢀ78 ꢁC for 15 minutes and then at room
temperature for 18 hours. The solvent was removed under
reduced pressure to give the crude product as an off white solid.
cmꢀ1 2972, 2885, 1781, 1709; MS (pNSI): 617.2 (69%, (M +
NH4)+), 622.1 (100%, (M + Na)+), 644.1 (48%); HRMS (pNSI):
calcd for C30H29N6O7S [M
617.1817.
+
NH4]+: 617.1813; observed:
3r – 6-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-2-phenyl-11-
tosyl-5,6-dihydro-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]
indole-1,3(2H,11H)-dione
The product was puried by column chromatography (column To a stirred round bottomed ask was added 1-tosyl-3-vinyl-1H-
diameter ¼ 2 cm, silica ¼ 15 cm, eluent ¼ petrol (40/60)–EA indole (100 mg, 0.34 mmol) and DCM (5 mL). The resulting
3 : 1) to give a 8 : 1 mixture of (3aS*,5S*,10bS*)-5-((S*)-hydroxy- solution was cooled to ꢀ78 ꢁC and then PTAD (70 mg, 0.34 mmol)
(peruorophenyl)methyl)-7-methoxy-2-methyl-10-tosyl-4,5,10, was added. The reaction was stirred at ꢀ78 ꢁC for 3.5 hours. The
10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione and reaction was warmed to 0 ꢁC and a further equivalent of PTAD (60
ꢁ
(3aS*,5S*,10bS*)-5-((R*)-hydroxy(peruorophenyl)methyl)-7- mg, 0.34 mmol) was added. The reaction was stirred 0 C for 4
methoxy-2-methyl-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]- hours, resulting in the formation of a white precipitate. The
carbazole-1,3(2H,3aH)-dione (70%, 0.151 mg, 0.24 mmol) as a reaction mixture was ltered and 6-(3,5-dioxo-4-phenyl-1,2,4-tri-
white powder.
azolidin-1-yl)-2-phenyl-11-tosyl-5,6-dihydro-[1,2,4]triazolo[10,20:1,2]
Major diastereomer: Mp: 136.7–139.0 ꢁC; Rf: 0.40 (Pet(40/60)– pyridazino[3,4-b]indole-1,3(2H,11H)-dione (65%, 134 mg, 0.207
EA 2 : 1); 1H NMR (400 MHz, CDCl3): dH 7.76 (2H, d, J ¼ 8.3 Hz), mmol) was recovered as a white powder.
7.69 (1H, d, J ¼ 9.1 Hz), 7.22 (2H, d, J ¼ 8.3 Hz), 6.83 (1H, dd, J ¼
Mp: 227.8–230.6 ꢁC; 1H NMR (400 MHz, DMSO-d6): dH 10.76
9.1, 2.5 Hz), 6.72 (1H, d, J ¼ 2.5 Hz), 5.08 (1H, d, J ¼ 8.3 Hz), 4.87 (1H, s, NH), 7.91 (1H, d, J ¼ 7.8 Hz), 7.61 (2H, d, J ¼ 8.3 Hz),
(1H, d, J ¼ 7.4 Hz), 3.71 (3H, s), 3.58–3.47 (2H, m), 2.94 (3H, s), 7.48–7.24 (15H, m), 5.52 (1H, s), 4.76 (1H, d, J ¼ 13.8 Hz), 3.86
2.34 (3H, s), 2.11–2.04 (1H, m), 1.60 (1H, td, J ¼ 13.9, 5.3 Hz); 13
C
(1H, d, J ¼ 13.8 Hz), 2.24 (3H, s); 13C NMR (101 MHz, DMSO-d6):
NMR (101 MHz, CDCl3): dC 177.7, 173.2, 156.8, 145.2, 135.2, dC 154.3, 153.5, 150.6, 149.5, 146.0, 135.1, 133.3, 133.0, 131.7,
132.0, 130.9, 130.3, 129.8, 127.0, 120.6, 116.2, 114.0, 102.6, 70.2, 131.5, 130.4, 129.6, 129.5, 129.4, 128.8, 128.1, 127.6, 127.5,
55.6, 41.5, 39.0, 36.9, 28.6, 25.3, 21.7; IR (neat): nmax/cmꢀ1 2981, 126.9, 125.9, 125.4, 119.3, 116.8, 104.1, 48.8, 43.3, 21.6; IR
2884, 1709; MS (pAPCI): 157.0 (80%), 221.1 (92%), 281.1 (49%) (neat): nmax/cmꢀ1 2971, 2883, 1714; MS (pNSI): 263.0 (36%),
475.1 (94%), 635.1 (100%, (M + H)+); HRMS (pAPCI): calcd for 345.0 (51%), 371.1 (42%), 665.2 (89%, (M + NH4)+), 670.1 (100%,
C
30H24F5N2O6S [M + H]+: 635.1270; observed: 635.1266. Note: (M + Na)+); HRMS (pNSI): calcd for C33H25N7NaO6S [M + Na]+:
13C NMR missing peaks due to C–F coupling.
670.1479; observed: 670.1475.
3q – (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-
1-yl)-7-methoxy-10-tosyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]
carbazole-1,3(2H,3aH)-dione
3s – 6-(hydroxy(phenyl)amino)-2-phenyl-11-tosyl-5,6-dihydro-
[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-1,3(2H,11H)-
dione
To a stirred round bottomed ask was added 5-methoxy-1-tosyl- To a stirred round bottomed ask was added 1-tosyl-3-vinyl-
3-vinyl-1H-indole (112 mg, 0.34 mmol), DCM (5 mL) and 1H- 1H-indole (100 mg, 0.34 mmol) and DCM (5 mL) and the
pyrrole-2,5-dione (33 mg, 0.34 mmol). The reaction was heated solution was cooled to ꢀ78 ꢁC. To this solution PTAD (70 mg,
at reux for 48 hours. The reaction was cooled to 0 ꢁC and PTAD 0.34 mmol) was added and the reaction was stirred at ꢀ78 ꢁC
(60 mg, 0.34 mmol) was added. The reaction was stirred at 0 ꢁC for 3.5 hours. The reaction was warmed to room temperature
for 4 hours before the solvent was removed under reduced nitrosobenzene (44 mg, 0.34 mmol) was added and the
pressure to give the crude product as a pale red solid. The reaction was stirred for 18 hours. The solvent was removed
product was puried by column chromatography (column under reduced pressure to leave the crude product as a pale
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yellow oil. The product was puried by column chromatog- resulting solution was heated at reux for 48 hours. The reac-
raphy (column diameter ¼ 1 cm, silica ¼ 16 cm, eluent ¼ tion was cooled to room temperature and 2,6-dibromoni-
petrol (40/60)–ether–DCM 2 : 1 : 1) to give 6-(hydroxy(phenyl) trosobenzene (90 mg, 0.34 mmol) was added. The reaction was
amino)-2-phenyl-11-tosyl-5,6-dihydro-[1,2,4]triazolo[10,20:1,2] stirred at room temperature for 18 hours and the solvent was
pyridazino[3,4-b]indole-1,3(2H,11H)-dione (72%, 141 mg, removed under reduced pressure to give the crude product as a
0.24 mmol) as a white powder.
pale yellow solid. The product was puried by column chro-
1
ꢁ
Mp: 176.1–180.0 C; Rf: 0.48 (Pet(40/60)–Et2O 2 : 1); H NMR matography (petrol (40/60)–ethyl acetate 3 : 1, column diameter
(400 MHz, CDCl3): dH 8.03 (1H, d, J ¼ 8.3 Hz), 7.62 (2H, d, J ¼ 8.1 ¼ 2 cm, silica ¼ 17 cm) to give (3aS*,5S*,10bS*)-5-((2,6-dibro-
Hz), 7.56 (2H, d, J ¼ 7.6 Hz), 7.46 (2H, app t, J ¼ 7.7 Hz), 7.42–7.36 mophenyl) (hydroxy)amino)-N,N-dimethyl-1,3-dioxo-2-phenyl-
(1H, m), 7.23–7.07 (7H, m), 7.05–6.99 (2H, m), 6.59 (1H, d, J ¼ 7.4 2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-sulfon-
Hz), 5.81 (1H, br s), 5.18 (1H, d, J ¼ 13.5 Hz), 4.59 (1H, s), 3.23 amide (69%, 162 mg, 0.23 mmol) as a pale orange powder.
(1H, d, J ¼ 13.5 Hz), 2.30 (3H, s); 13C NMR (101 MHz, DMSO-d6):
Mp: 241–242 ꢁC; Rf: 0.43 (Pet(40/60)–Et2O 4 : 1); 1H NMR (400
dC 152.7, 152.2, 150.5, 146.0, 134.9, 132.9, 132.5, 131.8, 130.4, MHz, CDCl3): d 7.53 (2H, d, J ¼ 7.8 Hz), 7.46–7.30 (7H, m), 7.15
129.8, 129.3, 129.2, 128.5, 127.3, 127.3, 125.5, 125.4, 122.5, 119.8, (1H, app t, J ¼ 7.4 Hz), 7.02 (1H, app t, J ¼ 7.5 Hz), 6.71 (1H, app
117.6, 116.6, 108.6, 55.9, 44.6, 21.6; IR (neat): nmax/cmꢀ1 2981, td, J ¼ 8.0, 2.1 Hz), 6.05 (1H, s), 5.49–5.47 (1H, m), 5.17–5.12
2884, 1714; MS (pAPCI): 138.1 (100%), 157.0 (95%), 213.1 (50%), (1H, m), 4.35–4.27 (1H, m), 3.18–3.11 (1H, m), 2.92 (6H, s), 1.80
248.1 (86%), 279.1 (62%), 317.1 (33%), 333.1 (29%), 471.1 (31%), (1H, app t, J ¼ 13.1 Hz); 13C NMR (101 MHz, CD2Cl2): dC 177.9,
564.2 (11%), 580.2 (10%, (M + H)+); HRMS (pAPCI): calcd for 172.5, 144.6, 136.1, 134.3, 132.7, 132.1, 132.0, 129.5, 129.1,
C31H26N5O5S [M + H]+: 580.1649; observed: 580.1640.
128.6, 128.2, 126.6, 124.0, 122.8, 119.2, 115.1, 113.6, 77.6, 54.7,
42.7, 39.0, 38.0, 30.0; IR (neat): nmax/cmꢀ1 3431, 2927, 1780,
1715; MS (pNSI): 422.1 (25%, (M ꢀ N(OH)C6H3Br2)+), 689.0 (76%
3t – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-N,N,2-
trimethyl-1,3-dioxo-1,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]
carbazole-10(2H)-sulfonamide
(M + H)+), 711.0 (54%, (M + Na)+), HRMS (pNSI): calcd C28H25
Br2N4O5S [M + H]+: 688.9888; observed: 688.9886.
-
To a stirred bottomed ask was added N,N-dimethyl-3-vinyl-1H-
indole-1-sulfonamide (85 mg, 0.34 mmol), DCM (5 mL) and 1-
methyl-1H-pyrrole-2,5-dione (38 mg, 0.34 mmol). The solution
was heated at reux for 48 hours. The reaction was cooled to
room temperature and 1-methyl-2-nitrosobenzene (41 mg, 0.34
mmol) was added. The reaction was stirred for 3 hours at room
temperature before the solvent was removed under reduced
pressure to give the crude product. The crude product was puri-
ed by column chromatography (column diameter ¼ 2 cm,
silica ¼ 16 cm, eluent ¼ petrol (40/60)–ethyl acetate 2 : 1) to give
(3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-N,N,2-trimethyl-1,3-
dioxo-1,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(2H)-
sulfonamide (74%, 0.122 g, 0.25 mmol) as an off white solid.
3v – (3aS*,5S*,10bS*)-5-((S*)-hydroxy(peruorophenyl)
methyl)-N,N-dimethyl-1,3-dioxo-1,3,3a,4,5,10b-
hexahydropyrrolo[3,4-a]carbazole-10(2H)-sulfonamide
To a stirred round bottomed ask was added N,N-dimethyl-3-
vinyl-1H-indole-1-sulfonamide (85 mg, 0.34 mmol), DCM (5 mL)
and 1-methyl-1H-pyrrole-2,5-dione (38 mg, 0.34 mmol). The
reaction was heated at reux for 48 hours. The reaction was
cooled to ꢀ78 ꢁC and pentauorobenzaldehyde (66 mg, 0.34
mmol) and DMAC (1 M in hexane, 0.34 mL, 0.34 mmol) were
added and the reaction was stirred for 1 hour. The reaction was
poured into a solution of sodium bicarbonate (10 mL) and
extracted with DCM (3 ꢂ 10 mL). The combined organic extracts
were dried with MgSO4, ltered and the solvent was removed
under reduced pressure to leave the crude product as a pale
pink solid. The product was puried by column chromatog-
raphy (diameter ¼ 2 cm, silica ¼ 17 cm, eluent ¼ petrol (40/60)–
EA 2 : 1) to give (3aS*,5S*,10bS*)-5-((S*)-hydroxy(per-
uorophenyl)methyl)-N,N-dimethyl-1,3-dioxo-1,3,3a,4,5,10b-
1
Mp: 169.3–171.9 ꢁC; Rf: 0.32 (Pet(40/60)–EA 2 : 1); H NMR
(400 MHz, CDCl3): dH 7.84 (1H, d, J ¼ 8.4 Hz), 7.60 (1H, d, J ¼ 7.9
Hz), 7.50 (1H, d, J ¼ 8.0 Hz), 7.28 (1H, app t, J ¼ 7.8 Hz), 7.21–7.16
(2H, m), 7.13 (1H, d, J ¼ 8.1 Hz), 7.07–7.03 (1H, m), 4.98–4.96
(2H, m), 4.35–4.31 (1H, m), 3.69 (1H, app t, J ¼ 7.7 Hz), 2.93 (9H,
s), 2.60 (1H, app dt, J ¼ 13.1, 6.2 Hz), 2.33 (3H, s), 1.97 (1H, ddd, J
¼ 13.1, 7.7, 4.6 Hz); 13C NMR (101 MHz, CDCl3): dC 178.4, 173.8,
149.2, 137.4, 131.9, 131.1, 129.6, 128.4, 126.6, 125.3, 124.7, 123.7,
121.5, 120.4, 118.8, 115.0, 57.5, 40.5, 39.4, 38.4, 25.2, 24.7, 18.7;
IR (neat): nmax/cmꢀ1 3426, 2981, 1712; MS (pAPCI): 221.1 (9%),
251.1 (13%), 360.1 (100%, (M ꢀ (o-Tol)N(OH))+), 465.2 (15%, (M
ꢀ H2O)+), 483.2 (15%, (M + H)+); HRMS (pAPCI): calcd for
C24H27N4O5S1 [M + H]+: 483.1697; observed: 483.1685.
hexahydropyrrolo[3,4-a]carbazole-10(2H)-sulfonamide
(77%,
0.145 g, 0.26 mmol) as a pale pink solid.
1
Mp: 255.8–257.2 ꢁC; Rf: 0.30 (Pet(40/60)–EA 2 : 1); H NMR
(400 MHz, CDCl3): dH 7.77 (1H, d, J ¼ 8.3 Hz), 7.39 (1H, d, J ¼ 7.8
Hz), 7.33–7.28 (1H, m), 7.21 (1H, app t, J ¼ 7.8 Hz), 5.14 (1H, d, J
¼ 8.0 Hz), 4.80 (1H, d, J ¼ 7.3 Hz), 3.67–3.62 (1H, m), 3.48 (1H,
ddd, J ¼ 12.8, 7.2, 5.0 Hz), 2.98 (6H, s), 2.93 (3H, s), 2.49 (1H, br
s), 2.06 (1H, app dd, J ¼ 14.9, 4.1 Hz), 1.59 (1H, app dt, J ¼ 13.8,
6.9 Hz); 13C NMR (101 MHz, CDCl3): dC 177.8, 173.4, 137.2,
130.0, 129.3, 125.0, 123.5, 120.0, 118.2, 114.6, 70.3, 41.5, 39.2,
38.2, 36.7, 28.6, 25.2; IR (neat): nmax/cmꢀ1 3415, 2972, 2884,
3u – (3aS*,5S*,10bS*)-5-((2,6-dibromophenyl) (hydroxy)
amino)-N,N-dimethyl-1,3-dioxo-2-phenyl-1,3,3a,4,5,10b-
hexahydropyrrolo[3,4-a]carbazole-10(2H)-sulfonamide
To a stirred round bottomed ask was added N,N-dimethyl-3- 1713; MS (pNSI): 371.1 (22%), 558.1 (81% (M + H)+), 580.1
vinyl-1H-indole-1-sulfonamide (85 mg, 0.34 mmol), DCM (5 mL) (100%, (M + Na)+), HRMS (pNSI): calcd C24H20F5N3O5S [M + H]+:
and 1-phenyl-1H-pyrrole-2,5-dione (59 mg, 0.34 mmol) and the 558.1117; observed: 558.1118.
16142 | RSC Adv., 2015, 5, 16125–16152
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Note: 13C NMR missing peaks due to C–F coupling.
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(22%, (M + H)+); HRMS (pAPCI): calcd C23H25N4O5S [M + H]+:
469.1540; observed: 469.1537.
3w – 6-(hydroxy(o-tolyl)amino)-N,N-dimethyl-1,3-dioxo-2-
phenyl-2,3,5,6-tetrahydro-[1,2,4]triazolo[10,20:1,2]pyridazino
[3,4-b]indole-11(1H)-sulfonamide
3y – benzyl (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-2-
methyl-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]
carbazole-10(1H)-carboxylate
To a stirred round bottomed ask was added N,N-dimethyl-3-vinyl-
1H-indole-1-sulfonamide (85 mg, 0.34 mmol), DCM (5 mL) and To a stirred Schlenk ask was added benzyl 3-vinyl-1H-indole-1-
cooled to ꢀ78 ꢁC. To this solution PTAD (60 mg, 0.34 mmol) was carboxylate (94 mg, 0.34 mmol), DCM (5 mL) and 1-methyl-1H-
ꢁ
added and the reaction stirred at ꢀ78 C for 1 hour. 1-Methyl-2- pyrrole-2,5-dione (33 mg, 0.34 mmol). The resulting solution
nitrosobenzene (41 mg, 0.34 mmol) was added and the reaction was heated at reux for 24 hours. The reaction was allowed to
was stirred 4 hours before the solvent was removed under reduced cool to room temperature and to the stirred solution nitro-
pressure to give the crude product. The crude product was puried sobenzene (36 mg, 0.34 mmol) was added and the solution was
by column chromatography (column diameter ¼ 2 cm, silica ¼ 16 stirred for 18 hours. The solvent was removed under reduced
cm, eluent ¼ petrol (40/60)–ethyl acetate 2 : 1) to give 6-(hydroxy(o- pressure to leave the crude product as a pale yellow solid. The
tolyl)amino)-N,N-dimethyl-1,3-dioxo-2-phenyl-2,3,5,6-tetrahy- product was puried by column chromatography (petrol (40/
dro-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-11(1H)-
60)–ethyl acetate 3 : 1, column diameter ¼ 2 cm, silica ¼ 14 cm)
sulfonamide (76%, 0.141 g) as an off white solid.
to give benzyl (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-2-
1
Mp: 168.5–172.8 ꢁC; Rf: 0.25 (Pet(40/60)–EA 2 : 1); H NMR methyl-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carba-
(300 MHz, CDCl3): dH 7.87 (1H, d, J ¼ 8.3 Hz), 7.73 (1H, d, J ¼ 8.1 zole-10(1H)-carboxylate (74%, 124 mg, 0.25 mmol) as a yellow
Hz), 7.60 (2H, d, J ¼ 7.4 Hz), 7.51 (2H, t, J ¼ 7.6 Hz), 7.46–7.38 powder.
1
(1H, m), 7.30–7.18 (2H, m), 7.04 (2H, t, J ¼ 7.5 Hz), 6.90 (1H, d, J
Mp: 105.7–109.2 ꢁC; Rf: 0.34 (Pet(40/60)–EA 2 : 1); H NMR
¼ 7.6 Hz), 6.71 (1H, d, J ¼ 7.8 Hz), 5.76 (1H, s), 5.37 (1H, d, J ¼ (400 MHz, CD2Cl2): dH 8.10 (1H, br d, J ¼ 8.1 Hz), 7.70 (1H, br d, J
14.1 Hz), 4.66 (1H, s), 3.46 (1H, d, J ¼ 14.1 Hz), 2.90 (6H, s), 1.94 ¼ 7.3 Hz), 7.49 (2H, br d, J ¼ 6.6 Hz), 7.39 (3H, br app q, J ¼ 6.9,
(3H, s); 13C NMR (101 MHz, CDCl3): dC 153.5, 150.5, 148.7, 6.4 Hz), 7.35–7.25 (3H, br m), 7.22–7.13 (3H, br m), 7.01 (1H, br
135.1, 132.1, 131.9, 131.2, 130.6, 129.4, 128.7, 127.1, 126.9, app t, J ¼ 6.7 Hz), 5.55 (1H, d, J ¼ 11.8 Hz), 5.41 (1H, d, J ¼ 11.8
126.8, 125.9, 124.4, 124.2, 122.7, 118.1, 115.9, 104.7, 59.4, 44.7, Hz), 4.88 (1H, br d, J ¼ 6.8 Hz), 4.87 (1H, br s), 4.80–4.77 (1H, br
38.7, 17.9; IR (neat): nmax/cmꢀ1 3322, 2971, 1707; MS (pNSI): m), 3.54–3.41 (1H, br m), 2.85 (3H, s), 2.40–2.25 (1H, br m),
339.1 (33%), 424.1 (94%, (M ꢀ MeC6H4NOH)+), 547.2 (72%, (M + 2.08–1.93 (1H, br m); 13C NMR (101 MHz, CD2Cl2): dC 178.4,
H)+), 569.2 (100%, (M + Na)+); HRMS (pNSI): calcd C27H27N6O5S 174.6, 151.6, 151.0, 137.0, 135.0, 130.0, 129.0, 128.9, 128.8,
[M + H]+: 547.1758; observed: 547.1761.
128.8, 127.6, 125.0, 123.3, 122.3, 120.0, 118.3, 117.1, 115.1, 69.5,
57.7, 40.2, 39.2, 24.9, 22.6; IR (neat): nmax/cmꢀ1 3433, 2953,
1699; MS (pNSI): 387.1 (97%, (M ꢀ N(OH)Ph)+), 494.2 (100%, (M
ꢀ H)+), 518.2 (30%, (M + Na)+), 991.4 (15%, (2M + H)+), 1013.3
(10%, (2M + Na)+); HRMS (pNSI): calcd C29H25N3O5Na [M + Na]+:
518.1686; observed: 518.1676.
3x – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-N,N-dimethyl-
1,3-dioxo-1,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-
10(2H)-sulfonamide
To a round bottomed ask was added N,N-dimethyl-3-vinyl-1H-
indole-1-sulfonamide (85 mg, 0.34 mmol), DCM (5 mL) and 1H-
pyrrole-2,5-dione (33 mg, 0.34 mmol). The reaction was heated
at reux for 48 hours and then cooled to room temperature. 1-
Methyl-2-nitrosobenzene (41 mg, 0.34 mmol) was added and the
3z – benzyl (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-2-
methyl-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]
carbazole-10(1H)-carboxylate
reaction is stirred for 4.5 hours. The solvent was removed to give To a stirred Schlenk ask was added benzyl 3-vinyl-1H-
the crude product as pale yellow solid. The crude product was indole-1-carboxylate (94 mg, 0.34 mmol), DCM (5 mL) and 1-
puried by trituration from DCM to give (3aS*,5S*,10bS*)-5- methyl-1H-pyrrole-2,5-dione (33 mg, 0.34 mmol). The
(hydroxy(o-tolyl)amino)-N,N-dimethyl-1,3-dioxo-1,3,3a,4,5,10b- resulting solution was heated at reux for 24 hours. The
hexahydropyrrolo[3,4-a]carbazole-10(2H)-sulfonamide
123 mg, 0.26 mmol) as a white solid.
(77%, reaction was allowed to cool to room temperature and to the
stirred solution 1-methyl-2-nitrosobenzene (41 mg, 0.34
1
Mp: 199.9–201.0 ꢁC; Rf: 0.64 (Pet(40/60)–EA 3 : 1); H NMR mmol) was added and the solution was stirred for 18 hours.
(300 MHz, DMSO-d6): dH 11.15 (1H, s), 8.38 (1H, s), 7.88 (1H, d, J The solvent was removed under reduced pressure to leave the
¼ 8.4 Hz), 7.36 (1H, d, J ¼ 7.9 Hz), 7.31–7.20 (2H, m), 7.13 (3H, crude product as a pale yellow solid. The product was puried
app dt, J ¼ 14.3, 7.3 Hz), 7.01 (1H, d, J ¼ 7.3 Hz), 4.98 (1H, d, J ¼ by column chromatography (petrol (40/60)–ethyl acetate 3 : 1,
7.8 Hz), 4.38 (1H, app t, J ¼ 4.8 Hz), 3.73 (1H, app q, J ¼ 7.8 Hz), column diameter ¼ 2 cm, silica ¼ 16 cm) to give benzyl
2.70 (6H, s), 2.45–2.37 (1H, m), 2.36 (3H, s), 1.77–1.65, 1.77 (1H, (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-2-methyl-1,3-dioxo-
m); 13C NMR (101 MHz, DMSO-d6): dC 180.4, 175.5, 151.6, 137.2, 2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-carbox-
133.2, 131.1, 129.3, 129.1, 126.6, 124.4, 124.3, 123.4, 121.8, ylateas (78%, 135 mg, 0.26 mmol) as a yellow powder.
1
ꢁ
121.1, 118.6, 115.3, 56.5, 42.2, 41.1, 38.7, 26.6, 18.9; IR (neat):
Mp: 128.4–131.5 C; Rf: 0.45 (Pet(40/60)–EA 3 : 1); H NMR
nmax/cmꢀ1 3426, 2981, 1712; MS (pAPCI): 237.1 (60%), 346.1 (400 MHz, CDCl3): dH 8.11 (1H, d, J ¼ 8.3 Hz), 7.59 (1H, d, J ¼
(100%, (M ꢀ MeC6H4NOH)+), 451.1 (25%, (M ꢀ H2O)+), 469.2 7.8 Hz), 7.55 (1H, d, J ¼ 8.1 Hz), 7.50–7.48 (2H, m), 7.45–7.38
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(3H, m), 7.29–7.23 (1H, m), 7.20 (1H, app t, J ¼ 7.6 Hz), 7.14 (1H, 0.68 mmol) and DCM (10 mL). The resulting solution was
d, J ¼ 7.6 Hz), 7.10 (1H, d, J ¼ 7.8 Hz), 7.05 (1H, d, J ¼ 7.3 Hz), 5.56 heated at reux for 24 hours. The reaction was allowed to cool to
(1H, d, J ¼ 11.8 Hz), 5.46 (1H, d, J ¼ 11.8 Hz), 5.02 (1H, s), 4.93 room temperature and to the stirred solution nitrosobenzene
(1H, d, J ¼ 7.6 Hz), 4.38 (1H, t, J ¼ 5.2 Hz), 3.63 (1H, app q, J ¼ 6.9 (73 mg, 0.68 mmol) was added and the solution was stirred for
Hz), 2.91 (3H, s), 2.59 (1H, app dt, J ¼ 12.3, 6.0 Hz), 2.29 (3H, s), 18 hours. The solvent was removed under reduced pressure to
1.92 (1H, ddd, J ¼ 12.5, 7.5, 4.6 Hz); 13C NMR (101 MHz, CDCl3): leave the crude product as a yellow powder. The product was
dC 178.5, 174.6, 151.7, 149.2, 136.8, 134.8, 131.1, 129.9, 129.0, puried by column chromatography (petrol (40/60)–ethyl
129.0, 128.9, 128.9, 127.7, 126.6, 125.3, 125.0, 123.3, 121.5, 120.1, acetate 2 : 1, column diameter ¼ 2 cm, silica ¼ 20 cm) to give
118.1, 115.3, 69.6, 57.4, 40.4, 39.1, 25.2, 24.1, 18.6; IR (neat): nmax
/
benzyl(3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-1,3-dioxo-
cmꢀ1 3450, 2954, 1699; MS (pNSI): 343.1 (40%), 387.1 (82%, (M ꢀ 2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-carbox-
(N(OH)(o-Tol)))+), 508.2 (100%, (M ꢀ (H2) + H)+), 532.2 (59%, (M + ylate (70%, 230 mg, 0.48 mmol) as a yellow powder.
Na)+); HRMS (pNSI): calcd C30H27N3O5Na [M + Na]+: 532.1843;
observed: 532.1834.
Mp: 177.1–177.8 ꢁC; Rf: 0.38 (Pet(40/60)–EA 2 : 1); H NMR
(500 MHz, CD2Cl2): dH 8.20 (1H, s), 8.11 (1H, d, J ¼ 8.3 Hz), 7.66
(1H, d, J ¼ 7.8 Hz), 7.50 (2H, dd, J ¼ 7.9, 1.6 Hz), 7.43–7.36 (3H,
m), 7.33 (2H, app t, J ¼ 7.8 Hz), 7.28 (1H, app t, J ¼ 7.8 Hz), 7.22
(2H, d, J ¼ 8.0 Hz), 7.16 (1H, app t, J ¼ 7.5 Hz), 7.02 (1H, app t, J
¼ 7.3 Hz), 5.55 (1H, d, J ¼ 11.9 Hz), 5.40 (1H, d, J ¼ 11.9 Hz), 5.19
(1H, s), 4.96 (1H, br d, J ¼ 8.1 Hz), 4.82 (1H, app t, J ¼ 5.7 Hz),
3.56 (1H, br app q, J ¼ 7.4 Hz), 2.35 (1H, br app dd, J ¼ 13.4, 6.7
Hz), 2.00–1.92 (1H, br m); 13C NMR (101 MHz, CD2Cl2): dC 178.5,
174.5, 151.6, 150.7, 136.9, 134.9, 129.7, 129.0, 128.9, 128.9,
128.8, 127.6, 125.1, 123.3, 122.6, 119.8, 118.0, 117.3, 115.2, 69.5,
57.7, 41.4, 40.6, 23.0; IR (neat): nmax/cmꢀ1 ¼ 3418, 3329, 2970,
1705; MS (pNSI): 199.2 (87%), 373.1 (68%, (M ꢀ (N(OH)Ph))+),
1
3aa – (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-
1-yl)-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-
a]carbazole-10(1H)-carboxylate
To a stirred Schlenk ask was added benzyl 3-vinyl-1H-indole-
1-carboxylate (189 mg, 0.68 mmol), 1-methyl-1H-pyrrole-2,5-
dione (76 mg, 0.68 mmol) and DCM (10 mL). The reaction
mixture was heated at reux for 24 hours. The reaction was
cooled to 0 ꢁC and then 4-phenyl-1,2,4-triazolidine-3,5-dione
(120 mg, 0.68 mmol) was added. The reaction was stirred at
ꢁ
0 C for 1 hour then at room temperature for 18 hours. The
480.2 (100%, (M
C
ꢀ
(H2) +
H)+); HRMS (pNSI): calcd
solvent was removed under reduced pressure to leave the
crude product as an orange powder. The product was puried
by column chromatography (petrol (40/60)–ethyl acetate 1 : 1,
28H23N3O5Na [M + Na]+: 504.1530; observed: 504.1522.
column diameter
¼
2
cm, silica
¼
20 cm) to give
(3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-
2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]-
carbazole-10(1H)-carboxylate (54%, 207 mg, 0.37 mmol) as an
off-white powder and (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-
1,2,4-triazolidin-1-yl)-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexahy-
dropyrrolo[3,4-a]carbazole-10(1H)-carboxylate (27%, 76 mg,
0.19 mmol) as a white powder.
3cc – benzyl (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-1,3-
dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-
10(1H)-carboxylate
To a stirred Schlenk ask was added benzyl 3-vinyl-1H-indole-1-
carboxylate (94 mg, 0.34 mmol), DCM (5 mL) and 1H-pyrrole-
2,5-dione (33 mg, 0.34 mmol). The resulting solution was
heated at reux for 24 hours. The reaction was allowed to cool to
room temperature and to the stirred solution 1-methyl-2-
nitrosobenzene (41 mg, 0.34 mmol) was added and the solu-
tion was stirred for 4 hours. The solvent was removed under
reduced pressure to leave the crude product as a pale yellow
solid. The product was puried by column chromatography
(petrol (40/60)–ethyl acetate 3 : 2, column diameter ¼ 2 cm,
silica ¼ 16 cm) to give benzyl-(3aS*,5S*,10bS*)-5-(hydroxy(o-
tolyl)amino)-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]-
carbazole-10(1H)-carboxylate (83%, 140 mg, 0.28 mmol) as a
yellow powder.
Mp: 202.3–203.9 ꢁC; Rf: 0.15 (Pet(40/60)–EA 1 : 1); 1H NMR
(400 MHz, CDCl3): dH 8.38 (1H, s), 8.07 (1H, d, J ¼ 8.4 Hz), 7.51
(1H, app dt, J ¼ 7.6, 0.9 Hz), 7.49–7.37 (4H, m), 7.39–7.33 (6H, m),
7.30 (1H, ddd, J ¼ 8.6, 7.3, 1.3 Hz), 7.21 (1H, app td, J ¼ 7.5, 1.0
Hz), 5.53 (1H, app t, J ¼ 5.2 Hz), 5.44 (1H, d, J ¼ 11.8 Hz), 5.38
(1H, d, J ¼ 11.8 Hz), 4.89 (1H, d, J ¼ 8.0 Hz), 3.50 (1H, ddd, J ¼ 9.6,
8.0, 5.5 Hz), 2.87 (3H, s), 2.41 (1H, app dt, J ¼ 14.2, 5.5 Hz), 2.14
(1H, ddd, J ¼ 14.2, 9.5, 5.5 Hz); 13C NMR (101 MHz, CDCl3): dC
177.4, 173.6, 153.6, 152.2, 151.3, 136.9, 134.5, 130.9, 130.8, 129.3,
129.1, 128.9, 128.9, 128.4, 126.1, 125.8, 125.3, 123.8, 118.8, 115.7,
113.8, 69.8, 47.5, 40.0, 38.4, 27.5, 25.2; IR (neat): nmax cmꢀ1 3462,
2969, 1699; MS (pNSI): 199.2 (16%), 387.1 (19%, (M ꢀ PTAD)+),
564.2 (59%, (M + H)+), 581.2 (100%, (M + NH4)+), 643.2 (15%),
1144.4 (39%, (2M + NH4)+); HRMS (pNSI): calcd C31H26N5O6 [M +
H]+: 564.1878; observed: 564.1873.
1
Mp: 181.4–183.9 ꢁC; Rf: 0.48 (Pet(40/60)–EA 3 : 2); H NMR
(400 MHz, DMSO-d6): dH 11.26 (1H, s), 8.41 (1H, s), 7.93 (1H, d, J
¼ 8.3 Hz), 7.51 (2H, d, J ¼ 7.0 Hz), 7.45–7.33 (4H, m), 7.18–7.08
(3H, m), 7.03–6.91 (3H, m), 5.56 (1H, d, J ¼ 12.1 Hz), 5.32 (1H, d,
J ¼ 12.1 Hz), 4.96 (1H, d, J ¼ 8.0 Hz), 4.34 (1H, app t, J ¼ 3.7 Hz),
3.73 (1H, app q, J ¼ 8.7 Hz), 2.50–2.44 (1H, m), 2.17 (3H, s), 1.74–
1.64 (1H, m); 13C NMR (101 MHz, DMSO-d6): dC 180.6, 176.5,
151.6, 136.2, 135.7, 131.1, 130.8, 130.0, 129.2, 129.1, 129.1,
128.2, 126.6, 124.7, 124.5, 122.9, 122.2, 120.6, 117.5, 114.4, 69.2,
3bb – benzyl (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-1,3-
dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-
10(1H)-carboxylate
To a stirred Schlenk ask was added benzyl 3-vinyl-1H-indole-1- 57.1, 41.8, 40.2, 26.7, 18.6; IR (neat): nmax/cmꢀ1 3495, 3325,
carboxylate (189 mg, 0.68 mmol), 1H-pyrrole-2,5-dione (66 mg, 2953, 1711; MS (pNSI): 373.1 (51%, (M ꢀ (N(OH)(o-Tol)))+), 494.2
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(16%, (M ꢀ (H2) + H)+), 518.2 (21%, (M + Na)+); HRMS (pNSI): Hz), 5.22 (1H, dd, J ¼ 14.0, 1.7 Hz), 4.97–4.89 (1H, m), 3.66
calcd C29H25N3O5Na [M + Na]+: 518.1686; observed: 518.1681.
(1H, dd, J ¼ 14.0, 3.4 Hz); 13C NMR (101 MHz, CD2Cl2): dC
147.2, 147.0, 146.6, 145.6, 131.0, 130.1, 127.3, 126.2, 125.4,
125.2, 124.9, 124.9, 124.9, 124.8, 124.8, 122.4, 122.3, 120.7,
120.5119.7, 115.8, 114.5, 110.5, 97.2, 66.2, 55.1, 39.6; IR
(neat): nmax/cmꢀ1 ¼ 3337, 3063, 1716; MS (pAPCI): 395.1
(100%), 451.1 (59%, (M ꢀ (N(OH)Ph))+), 542.2 (5%, (M ꢀ
(H2O) + H)+), 558.2 (1%, (M ꢀ H)+), 560.2 (1%, (M + H)+);
HRMS (pAPCI): calcd C32H26N5O5 [M + H]+: 560.1928;
observed: 560.1913.
3dd – benzyl (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-
triazolidin-1-yl)-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo
[3,4-a]carbazole-10(1H)-carboxylate
To a stirred Schlenk ask was added benzyl 3-vinyl-1H-indole-1-
carboxylate (189 mg, 0.68 mmol), DCM (10 mL) and 1H-pyrrole-
2,5-dione (66 mg, 0.68 mmol). The resulting solution was
ꢁ
heated at reux for 24 hours. The reaction was cooled to 0 C
and 4-phenyl-1,2,4-triazolidine-3,5-dione (120 mg, 0.68 mmol)
was added. The solution was stirred at 0 ꢁC for 1 hour. The
solvent was removed under reduced pressure to leave the crude
product as an off white solid. The product was puried by
3ff – benzyl (R*)-6-(hydroxy(o-tolyl)amino)-1,3-dioxo-2-phenyl-
2,3,5,6-tetrahydro-1H,11H-[1,2,4]triazolo[10,20:1,2]pyridazino
[3,4-b]indole-11-carboxylate
column chromatography (petrol (40/60)–ethyl acetate 1 : 1, To a stirred Schlenk ask was added benzyl 3-vinyl-1H-
column diameter ¼ 2 cm, silica ¼ 13 cm) to give benzyl indole-1-carboxylate (94 mg, 0.34 mmol) and DCM (10 ml).
(3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl)- The reaction mixture was cooled to ꢀ78 ꢁC and 4-phenyl-
1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole- 1,2,4-triazolidine-3,5-dione (60 mg, 0.34 mmol) was added.
10(1H)-carboxylate (58%, 216 mg, 0.39 mmol) as a pale pink The reaction mixture was stirred at ꢀ78 ꢁC for 5 hours, 1-
powder.
methyl-2-nitrosobenzene was added (41 mg, 0.34 mmol) and
1
Mp: 174.6–177.1 ꢁC; Rf: 0.06 (Pet(40/60)–EA 1 : 1); H NMR the reaction stirred at room temperature for 18 hours. The
(400 MHz, CD2Cl2): dH 8.78 (1H, s), 8.05 (1H, d, J ¼ 8.3 Hz), 7.54 solvent was removed under reduced pressure to leave the
(1H, d, J ¼ 7.7 Hz), 7.44–7.38 (6H, m), 7.38–7.30 (4H, m), 7.30– crude product as a yellow powder. The product was puried
7.24 (1H, m), 7.20 (1H, app t, J ¼ 7.5 Hz), 5.51 (1H, app t, J ¼ 5.3 by column chromatography (petrol (40/60)–ethyl acetate 3 : 1,
Hz), 5.45 (1H, d, J ¼ 11.9 Hz), 5.31 (1H, d, J ¼ 11.9 Hz), 4.98 (1H, column diameter ¼ 2 cm, silica ¼ 20 cm) to give benzyl (R*)-6-
d, J ¼ 7.9 Hz), 3.46 (1H, app q, J ¼ 8.1 Hz), 2.36–2.30 (1H, m), 2.18 (hydroxy(o-tolyl)amino)-1,3-dioxo-2-phenyl-2,3,5,6-tetrahydro-
(1H, ddd, J ¼ 13.9, 8.6, 5.3 Hz); 13C NMR (101 MHz, CD2Cl2): dC 1H,11H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-11-car
178.1, 173.8, 153.7, 152.4, 151.4, 136.8, 134.7, 131.1, 130.6, 129.1, boxylate (68%, 132 mg, 0.23 mmol) as an off white powder.
128.9, 128.8, 128.8, 128.4, 126.2, 125.7, 125.6, 123.7, 119.0, 115.5,
Mp: 163.8–165.1 ꢁC; Rf: 0.49 (Pet(40/60)–EA 3 : 1); 1H NMR (400
114.2, 69.7, 47.7, 41.0, 39.5, 26.8; IR (neat): nmax/cmꢀ1 ¼ 3169, MHz, CD2Cl2): dH 8.01 (1H, d, J ¼ 8.3 Hz), 7.65 (1H, dd, J ¼ 8.1, 1.3
2975, 1699; MS (pNSI): 279.1 (38%), 373.1 (13%, (M ꢀ PTAD)+), Hz), 7.54–7.38 (7H, m), 7.35 (3H, dd, J ¼ 5.0, 2.1 Hz), 7.19 (2H, app
550.2 (21%, (M + H)+), 567.2 (100% (M + NH4)+), 1116.4 (39%, dtd, J ¼ 8.5, 7.2, 6.7, 1.4 Hz), 6.99 (2H, app tdd, J ¼ 7.5, 3.4, 1.2
(2M + NH4)+), 1666.5 (6%, (3M + NH4)+); HRMS (pNSI): calcd Hz), 6.90 (1H, dd, J ¼ 7.7, 1.4 Hz), 6.75 (1H, d, J ¼ 7.8 Hz), 5.87
C30H24N5O6 [M + H]+: 550.1721; observed: 550.1719.
(1H, s, OH), 5.48 (1H, d, J ¼ 11.9 Hz), 5.34 (1H, d, J ¼ 11.9 Hz),
5.19 (1H, dd, J ¼ 14.1, 2.3 Hz), 4.63 (1H, app t, J ¼ 2.3 Hz), 3.52
(1H, dd, J ¼ 14.1, 2.3 Hz), 1.94 (3H, s); 13C NMR (101 MHz, CDCl3):
dC 151.9, 150.3, 150.0, 148.8, 134.6, 133.6, 131.6, 131.1, 130.6,
130.0, 129.4, 128.9, 128.9, 128.8, 128.8, 127.0, 126.6, 126.0, 125.7,
124.4, 123.6, 122.7, 117.9, 114.6, 101.7, 70.1, 58.6, 43.5, 17.7; IR
(neat): nmax/cmꢀ1 ¼ 3291, 2981, 1782, 1737, 1699; MS (pNSI):
199.2 (100%), 407.2 (79%), 451.1 (81%, (M ꢀ (N(OH)(o-Tol)))+),
572.2 (25%, (M ꢀ H)+), 596.2 (65%, (M + Na)+); HRMS (pNSI):
calcd C33H27N5O5Na [M + Na]+: 596.1904; observed: 596.1898.
3ee – benzyl (R*)-6-(hydroxy(phenyl)amino)-1,3-dioxo-2-
phenyl-2,3,5,6-tetrahydro-1H,11H-[1,2,4]triazolo[10,20:1,2]
pyridazino[3,4-b]indole-11-carboxylate
To a stirred Schlenk ask was added benzyl 3-vinyl-1H-indole-1-
carboxylate (189 mg, 0.68 mmol) and DCM (10 mL). The solu-
tion was cooled to ꢀ78 ꢁC and 4-phenyl-1,2,4-triazolidine-3,5-
dione (120 mg, 0.68 mmol) was added. The reaction was stirred
at ꢀ78 ꢁC for 5 hours. The reaction was warmed to room
temperature, nitrosobenzene (73 mg, 0.68 mmol) was added and
the reaction was stirred for 3 hours. The solvent was removed
under reduced pressure to leave the crude product as a pale
yellow oil. The product was puried by column chromatography
3gg – benzyl (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-7-
methoxy-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo
[3,4-a]carbazole-10(1H)-carboxylate
(petrol (40/60)–ethyl acetate 2 : 1, column diameter ¼ 1 cm, To a stirred Schlenk ask was added benzyl 5-methoxy-3-vinyl-
silica ¼ 16 cm) to give benzyl (R*)-6-(hydroxy(phenyl)amino)-1,3- 1H-indole-1-carboxylate (209 mg, 0.68 mmol), DCM (10 mL) and
dioxo-2-phenyl-2,3,5,6-tetrahydro-1H,11H-[1,2,4]triazolo[10,20:1,2] 1-methyl-1H-pyrrole-2,5-dione (76 mg, 0.68 mmol). The result-
pyridazino[3,4-b]indole-11-carboxylate (72%, 274 mg, 0.49 ing solution was heated at reux for 18 hours. The reaction was
mmol) as a white powder.
cooled to room temperature and nitrosobenzene (72 mg, 0.68
Mp: 101.2–103.1 ꢁC; Rf: 0.53 (Pet(40/60)–EA 2 : 1); 1H NMR mmol) was added and the reaction was stirred for 1.5 hours. The
(400 MHz, CD2Cl2): dH 8.09 (1H, d, J ¼ 8.2 Hz), 7.51–7.38 (8H, solvent was removed under reduced pressure to leave the crude
m), 7.38–7.24 (5H, m), 7.23–7.07 (4H, m), 6.87 (1H, d, J ¼ 7.9 product as a pale orange oil. The product was puried by
Hz), 6.36 (1H, s), 5.52 (1H, d, J ¼ 12.1 Hz), 5.39 (1H, d, J ¼ 12.1 column chromatography (petrol (40/60)–ethyl acetate 2 : 1,
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column diameter ¼ 1 cm, silica ¼ 16 cm) to give benzyl 1H-pyrrole-2,5-dione (66 mg, 0.68 mmol). The resulting solution
(3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-7-methoxy-2-methyl-1, was heated at reux for 18 hours. The reaction was cooled to
3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)- room temperature and nitrosobenzene (72 mg, 0.68 mmol) was
carboxylate (73%, 218 mg, 0.44 mmol) as an orange powder.
added and the reaction was stirred for 2.5 hours. The solvent
Mp: 106.8–110.2 ꢁC; Rf: 0.65 (Pet(40/60)–EA 2 : 1); 1H NMR (400 was removed under reduced pressure to leave the crude product
MHz, CD2Cl2): dH 7.97 (1H, br d, J ¼ 8.3 Hz), 7.49–7.47 (2H, m), as a pale orange oil. The product was puried by column
7.41–7.37 (3H, m), 7.33–7.30 (2H, m), 7.21–7.19 (2H, m), 7.05–7.00 chromatography (petrol (40/60)–ethyl acetate 2 : 1, column
(2H, m), 6.85 (1H, br d, J ¼ 8.4 Hz), 5.53 (1H, d, J ¼ 11.9 Hz), 5.39 diameter
¼
1
cm, silica
¼
16 cm) to give benzyl
(1H, d, J ¼ 11.9 Hz), 5.02 (1H, br s), 4.91–4.87 (1H, m), 4.75 (1H, br (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-7-methoxy-1,3-
s), 3.68 (3H, s), 3.50 (1H, br s), 2.86 (3H, s), 2.36 (1H, br s), 2.01 (1H, dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-
br s); 13C NMR (101 MHz, CD2Cl2): dC 178.3, 174.5, 156.3, 151.5, carboxylate (79%, 317 mg, 0.54 mmol) as a pale orange powder.
1
151.1, 135.0, 131.5, 130.7, 129.0, 128.9, 128.8, 128.8, 128.4, 122.4,
Mp: 134.2–136.9 ꢁC; Rf: 0.34 (Pet(40/60)–EA 3 : 2); H NMR
117.7, 117.2, 115.9, 113.4, 102.4, 69.4, 57.9, 55.6, 40.3, 39.2, 24.9, (400 MHz, CD2Cl2): dH 8.42 (1H, br s), 7.94 (1H, d, J ¼ 9.0 Hz),
23.4; IR (neat): nmax/cmꢀ1 ¼ 3408, 2969, 2890, 1699; MS (pNSI): 7.47–7.44 (2H, m), 7.40–7.34 (3H, m), 7.30–7.27 (2H, m), 7.19–
417.1 (100%, (M ꢀ (N(OH)Ph))+), 524.2 (68%, (M ꢀ (H2) + H)+), 7.17 (2H, m), 7.01–6.98 (1H, m), 6.93 (1H, br s), 6.81 (1H, d, J ¼
548.2 (16%, (M + Na)+), 1073.4 (4%, (2M + Na)+); HRMS (pNSI): 9.0 Hz), 5.49 (1H, d, J ¼ 11.9 Hz), 5.39 (1H, br s), 5.34 (1H, d, J ¼
calcd C30H27N3O6Na [M + Na]+: 548.1792; observed: 548.1785.
11.9 Hz), 4.92 (1H, br d, J ¼ 6.2 Hz), 4.74 (1H, br s), 3.64 (3H, s),
3.57–3.51 (1H, br m), 2.39–2.35 (1H, br m), 1.91–1.89 (1H, br m);
13C NMR (101 MHz, CD2Cl2): dC 178.6, 174.4, 156.2, 151.5, 151.0,
135.0, 131.4, 130.3, 129.0, 128.9, 128.8, 128.8, 128.4, 122.6,
117.5, 117.4, 116.0, 113.5, 102.3, 69.4, 57.9, 55.6, 41.5, 40.5, 24.0;
IR (neat): nmax/cmꢀ1 ¼ 3233, 2952, 1708; MS (pNSI): 403.1 (37%,
(M ꢀ (N(OH)Ph))+), 510.2 (100%, (M ꢀ (H2) + H)+), 532.1 (26%,
(M ꢀ (H2) + Na)+); HRMS (pNSI): calcd C29H24N3O6 [M ꢀ (H2) +
H]+: 510.1654; observed: 510.1660.
3hh – benzyl (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-7-
methoxy-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo
[3,4-a]carbazole-10(1H)-carboxylate
To a stirred Schlenk ask was added benzyl 5-methoxy-3-vinyl-
1H-indole-1-carboxylate (209 mg, 0.68 mmol), DCM (10 mL) and
1-methyl-1H-pyrrole-2,5-dione (76 mg, 0.68 mmol). The result-
ing solution was heated at reux for 18 hours. The reaction was
cooled to room temperature and 1-methyl-2-nitrosobenzene (82
mg, 0.68 mmol) was added. The solution was stirred at room
temperature for 3 hours. The solvent was removed under
reduced pressure to leave the crude product as a pale yellow
solid. The product was puried by column chromatography
(petrol (40/60)–ethyl acetate 2 : 1, column diameter ¼ 2 cm,
silica ¼ 15 cm) to give benzyl (3aS*,5S*,10bS*)-5-(hydroxy(o-
tolyl)amino)-7-methoxy-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexa-
hydropyrrolo[3,4-a]carbazole-10(1H)-carboxylate (74%, 279 mg,
0.50 mmol) as a pale yellow powder.
3jj – benzyl (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-7-
methoxy-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]
carbazole-10(1H)-carboxylate
To a stirred Schlenk ask was added benzyl 5-methoxy-3-vinyl-
1H-indole-1-carboxylate (209 mg, 0.68 mmol), DCM (10 mL) and
1H-pyrrole-2,5-dione (66 mg, 0.68 mmol). The resulting solution
was heated at reux for 18 hours. The reaction was cooled to
room temperature and 1-methyl-2-nitrosobenzene (82 mg, 0.68
mmol) was added. The solution was stirred at room temperature
for 3.5 hours. The solvent was removed under reduced pressure
to leave the crude product as a pale yellow solid. The product was
puried by column chromatography (petrol (40/60)–ethyl acetate
2 : 1, column diameter ¼ 2 cm, silica ¼ 14 cm) to give benzyl
(3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-7-methoxy-1,3-dioxo-
2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-carboxy-
late (76%, 255 mg, 0.52 mmol) as a pale yellow powder.
Mp: 107.6–110.1 ꢁC; Rf: 0.29 (Pet(40/60)–EA 2 : 1); 1H NMR (400
MHz, CD2Cl2): dH 7.93 (1H, d, J ¼ 9.1 Hz), 7.54 (1H, dd, J ¼ 8.1, 1.3
Hz), 7.49–7.45 (2H, m), 7.43–7.35 (3H, m), 7.19 (1H, ddd, J ¼ 7.6,
6.9, 1.9 Hz), 7.10–7.01 (2H, m), 6.88 (1H, d, J ¼ 2.6 Hz), 6.80 (1H, dd,
J ¼ 9.1, 2.6 Hz), 5.52 (1H, d, J ¼ 11.9 Hz), 5.37 (1H, d, J ¼ 11.9 Hz),
5.18 (1H, s), 4.87 (1H, d, J ¼ 8.1 Hz), 4.33–4.29 (1H, m), 3.65 (3H, s),
3.67–3.61 (1H, m), 2.86 (3H, s), 2.61 (1H, app dt, J ¼ 13.4, 5.9 Hz),
2.22 (3H, s), 1.86 (1H, ddd, J ¼ 13.4, 8.5, 4.3 Hz); 13C NMR (101
MHz, CD2Cl2): dC 178.4, 174.4, 156.1, 151.6, 149.8, 135.0, 134.9,
131.2, 130.8, 130.6, 130.4, 128.8, 128.8, 128.5, 126.4, 125.3, 121.7,
117.5, 115.7, 113.6, 102.0, 69.3, 57.8, 55.4, 40.5, 38.9, 25.0, 24.9,
18.2; IR (neat): nmax/cmꢀ1 ¼ 3370, 2965, 2887, 1699; MS (pNSI):
207.1 (39%), 417.1 (34%, (M ꢀ (N(OH)(o-Tol)))+), 438.2 (100%, (M ꢀ
(H2) + H)+), 1075.4 (15%, (2(M ꢀ (H2) + H)+)); HRMS (pNSI): calcd
C31H28N3O6 [M ꢀ (H2) + H]+: 538.1976; observed: 538.1973.
Mp: 193.0–195.6 ꢁC; Rf: 0.20 (Pet(40/60)–EA 2 : 1); 1H NMR (400
MHz, CD2Cl2): dH 7.92 (1H, d, J ¼ 9.7 Hz), 7.81 (1H, s), 7.53 (1H, d,
J ¼ 7.8 Hz), 7.46 (2H, dd, J ¼ 7.8, 1.6 Hz), 7.42–7.33 (3H, m), 7.21–
7.15 (1H, m), 7.09–7.00 (2H, m), 6.84–6.75 (2H, m), 5.50 (1H, d, J ¼
11.9 Hz), 5.35 (1H, d, J ¼ 11.9 Hz), 5.16 (1H, s), 4.96 (1H, d, J ¼ 7.6
Hz), 4.37 (1H, app t, J ¼ 4.9 Hz), 3.71 (1H, app td, J ¼ 8.7, 5.6 Hz),
3.64 (3H, s), 2.64 (1H, app dt, J ¼ 13.6, 5.6 Hz), 2.21 (3H, s), 1.88
(1H, ddd, J ¼ 13.6, 9.3, 4.3 Hz); 13C NMR (101 MHz, DMSO-d6): dC
180.6, 176.4, 155.6, 151.8, 151.7, 135.8, 131.6, 130.8, 130.7, 130.2,
129.1, 129.1, 129.0, 126.7, 124.8, 122.3, 117.2, 115.2, 113.5, 102.7,
69.1, 57.3, 55.5, 41.9, 40.3, 27.2, 18.5; IR (neat): nmax/cmꢀ1 ¼ 3457,
3ii – benzyl (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-7-
methoxy-1,3-dioxo-2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]
carbazole-10(1H)-carboxylate
To a stirred Schlenk ask was added benzyl 5-methoxy-3-vinyl- 3367, 2981, 2886, 1712; MS (pNSI): 403.1 (100%, (M ꢀ (N(OH)(o-
1H-indole-1-carboxylate (209 mg, 0.68 mmol), DCM (10 mL) and Tol)))+), 524.1 (75%, (M ꢀ (H2) + H)+), 548.2 (16%, (M + Na)+),
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1073.4 (5%, (2M + Na)+); HRMS (pNSI): calcd C30H27N3O6Na [M + 7.55–7.48 (2H, m), 7.46–7.41 (3H, m), 7.41–7.33 (4H, m), 7.33–
Na]+: 548.1792; observed: 548.1785.
7.29 (2H, m), 7.13–7.03 (2H, m), 6.97 (1H, app td, J ¼ 7.4, 1.3
Hz), 6.83 (1H, dd, J ¼ 9.1, 2.6 Hz). 6.38 (1H, s), 5.43 (1H, d, J ¼
12.1 Hz), 5.33 (1H, d, J ¼ 12.1 Hz), 4.80 (1H, dd, J ¼ 13.7, 1.8 Hz),
4.71 (1H, dd, J ¼ 3.3, 1.8 Hz), 3.68–3.61 (1H, dd, J ¼ 13.7, 3.3 Hz),
3.58 (s, 3H), 2.30 (s, 3H); 13C NMR (101 MHz, CD2Cl2): dC 156.3,
151.6, 150.8, 150.3, 149.8, 135.3, 131.6, 130.9, 130.3, 130.0,
129.7, 129.2, 129.1, 129.1, 128.9, 128.0, 127.4, 127.1, 126.8,
125.2, 121.8, 115.3, 113.2, 103.1, 101.9, 69.9, 55.9, 55.6, 43.9,
18.2; IR (neat): nmax/cmꢀ1 ¼ 3212, 2939, 1720; MS (pNSI): 481.2
(100%, (M ꢀ N(OH)(o-Tol))+), 602.2 (34%, (M ꢀ (H2) + H)+), 626.2
(100%, (M + Na)+); HRMS (pNSI): calcd C34H29N5O6Na [M + Na]+:
626.2010; observed: 626.2006.
3kk – benzyl (R*)-6-(hydroxy(phenyl)amino)-8-methoxy-1,3-
dioxo-2-phenyl-2,3,5,6-tetrahydro-1H,11H-[1,2,4]triazolo
[10,20:1,2]pyridazino[3,4-b]indole-11-carboxylate
To a stirred Schlenk ask was added benzyl 5-methoxy-3-vinyl-
1H-indole-1-carboxylate (209 mg, 0.68 mmol) and DCM (10
mL). The solution was cooled to ꢀ78 ꢁC and 4-phenyl-1,2,4-
triazolidine-3,5-dione (120 mg, 0.68 mmol) was added. The
reaction was stirred at ꢀ78 ꢁC for 1.5 hours. The reaction was
warmed to room temperature, nitrosobenzene (73 mg, 0.68
mmol) was added and the reaction was stirred for 20 hours.
The solvent was removed under reduced pressure to leave the
crude product as a pale yellow oil. The product was puried by
column chromatography (petrol (40/60)–ethyl acetate 2 : 1,
4a – (3aS*,5S*,10bS*)-5-methoxy-2-methyl-4,5,10,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione
column diameter ¼ 1 cm, silica ¼ 16 cm) to give benzyl (R*)-6- To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
(hydroxy(phenyl)amino)-8-methoxy-1,3-dioxo-2-phenyl-2,3,5,6- (hydroxy(o-tolyl)amino)-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexa-
tetrahydro-1H,11H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]- hydropyrrolo[3,4-a]carbazole-10(1H)-carboxylate (120 mg, 0.24
indole-11-carboxylate (78%, 312 mg, 0.53 mmol) as a white mmol), platinum(IV) oxide (53 mg, 0.24 mmol) and methanol (5
powder.
mL). The resulting suspension was placed under an atmosphere
1
Mp: 110.4–113.2 ꢁC; Rf: 0.20 (Pet(40/60)–EA 2 : 1); H NMR of H2 and stirred at room temperature for 18 hours. The
(400 MHz, CD2Cl2): dH 7.88 (1H, d, J ¼ 9.1 Hz), 7.42–7.38 (5H, suspension was ltered through celite and the solvent was
m), 7.36–7.32 (3H, m), 7.29–7.26 (2H, m), 7.24–7.20 (2H, m), removed under reduced pressure to leave the crude product as
7.13 (2H, d, J ¼ 8.1 Hz), 7.05 (1H, app t, J ¼ 7.3 Hz). 6.76 (1H, dd, an orange solid, The crude product was puried by column
J ¼ 9.1, 2.6 Hz), 6.24 (1H, s), 6.10 (1H, d, J ¼ 2.5 Hz), 5.43 (1H, d, chromatography (petrol (40/60)–ethyl acetate 1 : 1, column
J ¼ 12.0 Hz), 5.32–5.29 (1H, m), 5.25–5.18 (1H, m), 4.84–4.80 diameter ¼ 2 cm, silica ¼ 13 cm) to give (3aS*,5S*,10bS*)-5-
(1H, m), 3.64 (1H, dd, J ¼ 14.0, 3.3 Hz), 3.55 (3H, s); 13C NMR methoxy-2-methyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carba-
(101 MHz, CD2Cl2): dC 156.5, 151.1, 150.3, 149.4, 134.8, 131.2, zole-1,3(2H,3aH)-dione (60%, 41 mg, 0.14 mmol) as a pale
130.3, 129.2, 129.0, 129.0, 128.70, 128.7, 128.7, 128.6, 128.2, yellow powder.
126.9, 126.2, 124.6, 119.7, 115.3, 113.2, 101.0, 100.5, 69.9, 59.1,
Mp: 139.4–142.7 ꢁC; Rf: 0.25 (Pet(40/60)–EA 1 : 1); 1H NMR
55.5, 44.0; IR (neat): nmax/cmꢀ1 ¼ 3336, 2935, 1716; MS (pNSI): (400 MHz, CD2Cl2): dH 8.91 (1H, s), 7.56 (1H, d, J ¼ 7.8 Hz),
481.1 (17%, (M ꢀ (N(OH)Ph))+), 588.2 (100%, (M ꢀ (H2) + H)+), 7.34 (1H, d, J ¼ 7.7 Hz), 7.14 (1H, app t, J ¼ 7.5 Hz), 7.09 (1H,
612.2 (15%, (M + Na)+); HRMS (pNSI): calcd C33H27N5O6Na [M + app t, J ¼ 7.4 Hz), 4.73 (1H, app t, J ¼ 2.7 Hz), 4.14 (1H, d, J ¼
Na]+: 612.1854; observed: 612.1838.
8.8 Hz), 3.31–3.25 (1H, m), 3.22 (3H, s), 2.94 (1H, app t, J ¼ 2.4
Hz), 2.90 (3H, s), 1.88 (1H, ddd, J ¼ 14.2, 6.9, 2.2 Hz); 13C
NMR (101 MHz, CD2Cl2): dC 178.9, 176.1, 136.4, 128.8, 126.6,
122.3, 120.1, 118.2, 111.9, 111.3, 69.4, 56.1, 39.5, 37.3, 27.4,
25.1; IR (neat): nmax/cmꢀ1 3398, 2931, 2870, 1689; MS (pNSI):
285.0 (29%), 355.1 (100%), 371.1 (57%), 560.0 (21%); HRMS
(pNSI): calcd C15H13N2O2 [M ꢀ OMe]+: 253.0972; observed:
253.0974.
3ll – benzyl (R*)-6-(hydroxy(o-tolyl)amino)-8-methoxy-1,3-
dioxo-2-phenyl-2,3,5,6-tetrahydro-1H,11H-[1,2,4]triazolo
[10,20:1,2]pyridazino[3,4-b]indole-11-carboxylate
To a stirred Schlenk ask was added benzyl 5-methoxy-3-vinyl-
1H-indole-1-carboxylate (209 mg, 0.68 mmol) and DCM (10 mL).
The solution was cooled to ꢀ78 ꢁC and 4-phenyl-1,2,4-
triazolidine-3,5-dione (120 mg, 0.68 mmol) was added. The
4b – (3aS*,5S*,10bS*)-5-ethoxy-2-methyl-4,5,10,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione
ꢁ
reaction was stirred at ꢀ78 C for 1.5 hours. The reaction was
warmed to room temperature, 1-methyl-2-nitrosobenzene (73
mg, 0.68 mmol) was added and the reaction was stirred for 24 To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
hours. The solvent was removed under reduced pressure to (hydroxy(o-tolyl)amino)-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexa-
leave the crude product as a pale orange oil. The product was hydropyrrolo[3,4-a]carbazole-10(1H)-carboxylate (100 mg, 0.20
puried by column chromatography (petrol (40/60)–ethyl mmol), platinum(IV) oxide (45 mg, 0.20 mmol) and ethanol (5
acetate 2 : 1, column diameter ¼ 2 cm, silica ¼ 17 cm) to give mL). The resulting suspension was placed under an atmosphere
benzyl
(R*)-6-(hydroxy(o-tolyl)amino)-8-methoxy-1,3-dioxo-2- of H2 and stirred at room temperature for 18 hours. The
phenyl-2,3,5,6-tetrahydro-1H,11H-[1,2,4]triazolo[10,20:1,2]pyr- suspension was ltered through celite and the solvent was
idazino[3,4-b]indole-11-carboxylate (82%, 338 mg, 0.56 mmol) removed under reduced pressure to leave the crude product as
as an off white powder.
an yellow solid, The crude product was puried by column
1
Mp: 181.1–183.0 ꢁC; Rf: 0.55 (Pet(40/60)–EA 2 : 1); H NMR chromatography (petrol (40/60)–ethyl acetate 2 : 1, column
(400 MHz, DMSO-d6): dH 8.70 (1H, s), 7.84 (1H, d, J ¼ 9.0 Hz), diameter ¼ 2 cm, silica ¼ 15 cm) to give (3aS*,5S*,10bS*)-5-
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ethoxy-2-methyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole- was ltered through celite and the solvent was removed under
1,3(2H,3aH)-dione (24%, 20 mg, 0.04 mmol) as a brown reduced pressure to leave the crude product as a yellow solid.
powder.
The crude product was puried by column chromatography
1
ꢁ
Mp: 100.6–102.8 C; Rf: 0.16 (Pet(40/60)–EA 2 : 1); H NMR (petrol (40/60)–ethyl acetate 1 : 1, column diameter ¼ 2 cm,
(400 MHz, CD2Cl2): dH 8.78 (1H, s), 7.54 (1H, d, J ¼ 7.7 Hz), 7.35 silica ¼ 16 cm) to give (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)
(1H, d, J ¼ 7.7 Hz), 7.17–7.12 (1H, m), 7.09 (1H, app t, J ¼ 7.0 amino)-2-methyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
Hz), 4.83 (1H, app t, J ¼ 2.8 Hz), 4.16 (1H, d, J ¼ 8.8 Hz), 3.55 1,3(2H,3aH)-dione (87%, 65 mg, 0.17 mmol) as a pale orange
(1H, app td, J ¼ 6.9, 1.8 Hz), 3.32–3.26 (2H, m), 2.93–2.91 (1H, powder.
m), 2.90 (3H, s), 1.88 (1H, ddd, J ¼ 14.3, 7.1, 2.7 Hz), 0.97 (1H, t,
Mp: 179.3–181.0 ꢁC; Rf: 0.60 (Pet(40/60)–EA 1 : 1); 1H NMR
J ¼ 7.0 Hz); 13C NMR (101 MHz, CD2Cl2): dC 178.9, 176.0, 136.3, (400 MHz, DMSO-d6): dH 11.08 (1H, s), 8.28 (1H, s), 7.50 (1H, d, J
128.8, 126.5, 122.3, 120.1, 118.1, 112.5, 111.3, 67.4, 63.5, 39.5, ¼ 8.0 Hz), 7.29 (1H, d, J ¼ 8.1 Hz), 7.14–7.10 (1H, m), 6.91–6.87
37.3, 27.9, 25.0, 15.2; IR (neat): nmax/cmꢀ1 3300, 2969, 1690; MS (4H, m), 6.67 (1H, app t, J ¼ 7.4 Hz), 4.29 (1H, d, J ¼ 8.2 Hz), 4.27
(pAPCI): 108.1 (24%), 298.1 (6%, (M)+), 299.1 (5%, (M + H)+); (1H, app t, J ¼ 3.9 Hz), 3.83–3.74 (1H, m), 2.81 (3H, s), 2.65–2.56
HRMS (pAPCI): calcd
observed: 299.1387.
C
17H19N2O3 [M
+
H]+: 299.1390; (1H, m), 1.98 (3H, s), 1.67 (1H, ddd, J ¼ 13.6, 10.5, 3.9 Hz); 13C
NMR (101 MHz, DMSO-d6): dC 180.0, 176.3, 152.2, 136.7, 130.7,
130.5, 130.3, 126.5, 126.5, 124.5, 122.4, 121.2, 119.3, 118.9, 111.7,
109.7, 58.3, 40.0, 38.6, 27.3, 25.1, 18.3; IR (neat): nmax/cmꢀ1 3379,
4c – (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-2-methyl-
4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-
dione
2955, 2873, 1691; MS (pAPCI): 108.1 (98%), 251.1 (100%), 253.1
(61%, (M ꢀ (N(OH)(o-Tol)) + H)+), 271.1 (6%, (M ꢀ (N(OH)(o-Tol))
+ OH2)+), 358.2 (13%, (M ꢀ OH)+); HRMS (pAPCI): calcd
C22H22N3O3 [M + H]+: 376.1656; observed: 376.1658.
To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-
5-(hydroxy(phenyl)amino)-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-
hexahydropyrrolo[3,4-a]carbazole-10(1H)-carboxylate (120 mg,
0.25 mmol), platinum(IV) oxide (57 mg, 0.25 mmol) and THF (5
mL). The resulting suspension was placed under an atmosphere
of H2 and stirred at room temperature for 5 hours. The
4e – (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-
1-yl)-2-methyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione
suspension was ltered through celite and the solvent was To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
removed under reduced pressure to leave the crude product as a (3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-2-methyl-1,3-dioxo-
yellow solid, The crude product was puried by trituration from 2,3,3a,4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-carbox-
DCM to give (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-2- ylate (110 mg, 0.20 mmol), platinum(IV) oxide (46 mg, 0.20
methyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)- mmol) and THF (5 mL). The resulting suspension was placed
dione (75%, 68 mg, 0.19 mmol) as a pale yellow powder.
under an atmosphere of H2 and stirred at room temperature for
1
Mp: 157.2–161.9 ꢁC; Rf: 0.17 (Pet(40/60)–EA 1 : 1); H NMR 5 hours. The suspension was ltered through celite and the
(400 MHz, DMSO-d6): dH 11.06 (1H, s), 8.20 (1H, s), 7.35 (1H, d, J solvent was removed under reduced pressure to leave the crude
¼ 8.0 Hz), 7.26 (1H, d, J ¼ 8.0 Hz), 7.24–7.19 (2H, m), 7.17–7.08 product as a yellow solid. The product was puried by tritura-
(2H, m), 6.98 (1H, app ddd, J ¼ 8.2, 7.0, 1.2 Hz), 6.91–6.81 (1H, tion from DCM to give (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-
m), 6.81 (1H, app ddd, J ¼ 8.0, 6.9, 1.0 Hz), 4.88 (1H app t, J ¼ 4.9 1,2,4-triazolidin-1-yl)-2-methyl-4,5,10,10b-tetrahydropyrrolo-
Hz), 4.27 (1H, d, J ¼ 8.8 Hz), 3.64 (1H, app td, J ¼ 8.8, 6.1 Hz), [3,4-a]carbazole-1,3(2H,3aH)-dione (91%, 79 mg, 0.18 mmol) as
2.81 (3H, s), 2.33 (1H, app dt, J ¼ 13.7, 6.1 Hz), 1.84 (1H, ddd, J ¼ an off-white solid.
13.7, 8.8, 4.9 Hz); 13C NMR (101 MHz, DMSO-d6): dC 179.8,
Mp: 262.4–264.0 ꢁC; 1H NMR (400 MHz, DMSO-d6): dH 11.43
176.3, 153.3, 137.0, 130.0, 129.0, 126.3, 121.5, 121.2, 119.9, (1H, s), 10.67 (1H, br s), 7.52–7.42 (4H, m), 7.39–7.37 (2H, m),
119.0, 117.2, 111.7, 110.0, 57.4, 39.6, 39.3, 25.8, 25.1; IR (neat): 7.21 (1H, d, J ¼ 7.9 Hz), 7.06 (1H, app t, J ¼ 7.6 Hz), 6.94 (1H, app
nmax/cmꢀ1 3374, 3306, 2919, 1683; MS (pAPCI): 108.0 (28%), t, J ¼ 7.5 Hz), 5.39 (1H, app t, J ¼ 6.1 Hz), 4.33 (1H, d, J ¼ 8.0 Hz),
251.1 (100%), 253.1 (68%, (M ꢀ (N(OH)Ph) + H)+), 344.1 (13%, 3.72 (1H, app q, J ¼ 6.8 Hz), 2.81 (3H, s), 2.35–2.31 (2H, m); 13
C
(M ꢀ (OH) + H)+), 361.1 (3%, (M + H)+); HRMS (pAPCI): calcd NMR (101 MHz, DMSO-d6): dC 178.9, 175.8, 152.7, 152.7, 137.2,
C
21H20N3O3 [M + H]+: 362.1499; observed: 362.1501.
132.3, 130.7, 129.5, 128.5, 126.7, 125.3, 122.2, 119.9, 118.4,
112.3, 107.3, 48.1, 39.5, 38.3, 27.7, 25.3; IR (neat): nmax/cmꢀ1
3229, 1693; MS (pAPCI): 178.1 (35%), 253.1 (100%, (M ꢀ (PTAD)
+ H)+); HRMS (ASAP) calcd C15H13N2O2 [M ꢀ PTAD + H]+:
253.0972; observed: 253.0969.
1
ꢁ
Note: H NMR ran at 40 C.
4d – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-2-methyl-
4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-
dione
4f – (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-4,5,10,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione
To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
(hydroxy(o-tolyl)amino)-2-methyl-1,3-dioxo-2,3,3a,4,5,10b-hexa-
hydropyrrolo[3,4-a]carbazole-10(1H)-carboxylate (100 mg, 0.20 To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
mmol), platinum(IV) oxide (45 mg, 0.20 mmol) and THF (5 mL). (hydroxy(phenyl)amino)-1,3-dioxo-2,3,3a,4,5,10b-hexahydro-
The resulting suspension was placed under an atmosphere of pyrrolo[3,4-a]carbazole-10(1H)-carboxylate (90 mg, 0.18 mmol),
H2 and stirred at room temperature for 7 hours. The suspension platinum(IV) oxide (41 mg, 0.18 mmol) and THF (5 mL). The
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resulting suspension was placed under an atmosphere of H2 10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-carboxylate (110
and stirred at room temperature for 10 hours. The suspension mg, 0.20 mmol), platinum(IV) oxide (46 mg, 0.20 mmol) and
was ltered through celite and the solvent was removed under THF (5 mL). The resulting suspension was placed under an
reduced pressure to leave the crude product as an yellow solid, atmosphere of H2 and stirred at room temperature for 5 hours.
The crude product was puried by column chromatography The suspension was ltered through celite and the solvent was
(petrol (40/60)–ethyl acetate 1 : 1, column diameter ¼ 2 cm, removed under reduced pressure to leave the crude product as a
silica ¼ 14 cm) to give (3aS*,5S*,10bS*)-5-(hydroxy(phenyl) white solid. The crude product was puried by trituration from
amino)-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
DCM to give (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-tri-
1,3(2H,3aH)-dione (41%, 26 mg, 0.07 mmol) as a yellow powder. azolidin-1-yl)-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
Mp: 150.0–153.1 ꢁC; Rf: 0.33 (Pet(40/60)–EA 1 : 1); 1H NMR (400 1,3(2H,3aH)-dione (64%, 53 mg, 0.13 mmol) as a white powder.
MHz, DMSO-d6): dH 11.22 (1H, s), 11.09 (1H, s), 8.24 (1H, s), 7.33
Mp: 212.6–213.9 ꢁC; 1H NMR (400 MHz, DMSO-d6): dH 11.39
(1H, d, J ¼ 8.1 Hz), 7.27–7.23 (1H, m), 7.20 (2H, app d, J ¼ 7.3 Hz), (1H, s), 11.36 (1H, s), 10.66 (1H, s), 7.51–7.44 (4H, m), 7.41–7.37
7.12 (2H, d, J ¼ 7.7 Hz), 7.00–6.95 (1H, m), 6.85 (1H, app t, J ¼ 7.2 (2H, m), 7.23 (1H, d, J ¼ 7.8 Hz), 7.07 (1H, app t, J ¼ 7.5 Hz), 6.96
Hz), 6.80 (1H app t, J ¼ 7.3 Hz), 4.89 (1H, app t, J ¼ 4.9 Hz), 4.25 (1H, app t, J ¼ 7.5 Hz), 5.42 (1H, app t, J ¼ 6.0 Hz), 4.29 (1H, d, J
(1H, d, J ¼ 8.1 Hz), 3.63–3.52 (1H, m), 2.27 (1H, app dt, J ¼ 13.6, ¼ 8.0 Hz), 3.69 (1H, app q, J ¼ 6.8 Hz), 2.37–2.21 (2H, m); 13C
5.6 Hz), 1.80 (1H, ddd, J ¼ 13.6, 9.2, 4.8 Hz); 13C NMR (101 MHz, NMR (101 MHz, DMSO-d6): dC 180.3, 177.1, 152.7, 152.6, 137.2,
DMSO-d6): dC 181.2, 177.6, 153.3, 137.0, 130.3, 129.0, 126.3, 121.4, 132.3, 131.0, 129.5, 128.5, 126.7, 125.3, 122.2, 119.9, 118.4,
121.1, 119.9, 118.9, 117.2, 111.7, 109.9, 57.4, 40.9, 40.6, 25.7; IR 112.3, 107.1, 55.5, 48.1, 40.9, 27.5; IR (neat): nmax/cmꢀ1 ¼ 3310,
(neat): nmax/cmꢀ1 3302, 2924, 1706; MS (pAPCI): 108.1 (18%), 237.1 3155, 3077, 1719, 1674; MS (pAPCI): 239.1 (100%, (M ꢀ (PTAD) +
(100), 239.1 (46%, (M ꢀ (N(OH)Ph) + H)+); HRMS (pAPCI): calcd H)+), 414.1 (2%, (M ꢀ H)+); HRMS (pAPCI): calcd C22H16N5O4 [M
C14H11N2O2 [M ꢀ (N(OH)Ph) + H]+: 239.0815; observed: 239.0810. ꢀ H]+: 414.1197; observed: 414.1185.
4g – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-4,5,10,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione
4i – (R*)-6-(hydroxy(phenyl)amino)-2-phenyl-6,11-dihydro-
1H,5H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-
1,3(2H)-dione
To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
(hydroxy(o-tolyl)amino)-1,3-dioxo-2,3,3a,4,5,10b-hexahydro- To a stirred Schlenk ask was added benzyl (R*)-6-(hydroxy-
pyrrolo[3,4-a]carbazole-10(1H)-carboxylate (120 mg, 0.24 (phenyl)amino)-1,3-dioxo-2-phenyl-2,3,5,6-tetrahydro-1H,11H-
mmol), platinum(IV) oxide (54 mg, 0.24 mmol) and THF (5 mL). [1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-11-carboxylate
The resulting suspension was placed under an atmosphere of (110 mg, 0.20 mmol), platinum(IV) oxide (46 mg, 0.20 mmol) and
H2 and stirred at room temperature for 6 hours. The suspension THF (5 mL). The resulting suspension was placed under an
was ltered through celite and the solvent was removed under atmosphere of H2 and stirred at room temperature for 5 hours.
reduced pressure to leave the crude product as a yellow solid, The suspension was ltered through celite and the solvent was
The crude product was puried by column chromatography removed under reduced pressure to leave the crude product as a
(petrol (40/60)–ethyl acetate 2 : 3, column diameter ¼ 2 cm, yellow solid. The product was puried by trituration from DCM
silica ¼ 17 cm) to give (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl) to give (R*)-6-(hydroxy(phenyl)amino)-2-phenyl-6,11-dihydro-
amino)-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)- 1H,5H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-1,3(2H)-
dione- (70%, 61 mg, 0.17 mmol) as an off white solid.
dione (65%, 55 mg, 0.13 mmol) as an off-white solid.
1
Mp: 149.9–153.2 ꢁC; Rf: 0.52 (Pet(40/60)–EA 2 : 3); 1H NMR
Mp: 174.3–175.2 C; H NMR (400 MHz, DMSO-d6): dH 11.63
ꢁ
(400 MHz, CD2Cl2): dH 8.81 (1H, s), 8.21 (1H, s), 7.56 (1H, d, J ¼ (1H, s), 8.61 (1H, s), 7.54–7.38 (6H, m), 7.18 (2H, app t, J ¼ 7.8 Hz),
8.0 Hz), 7.30 (1H, d, J ¼ 7.9 Hz), 7.18 (2H, d, J ¼ 6.9 Hz), 7.06 (1H, 7.10 (2H, app d, J ¼ 7.8 Hz), 7.00–6.96 (2H, m), 6.91–6.83 (2H, m),
app t, J ¼ 7.6 Hz), 7.03–6.99 (2H, m), 6.91–6.85 (1H, m), 5.36 (1H, 5.18–5.15 (1H, m), 4.48 (1H, dd, J ¼ 13.0, 2.0 Hz), 3.77 (1H, dd, J ¼
s), 4.51 (1H, app t, J ¼ 4.5 Hz), 4.19 (1H, d, J ¼ 8.6 Hz), 3.80 (1H, 13.0, 4.2 Hz); 13C NMR (101 MHz, DMSO-d6): dC 152.6, 149.6,
app td, J ¼ 9.3, 6.4 Hz), 2.74 (1H, app dt, J ¼ 13.6, 5.5 Hz), 2.15 146.6, 134.2, 131.7, 129.8, 129.6, 128.9, 128.9, 127.0, 125.8, 122.3,
(3H, s), 1.83 (1H, ddd, J ¼ 13.6, 10.1, 4.1 Hz); 13C NMR (101 MHz, 121.1, 120.2, 118.5, 118.3, 112.3, 92.4, 57.4, 43.4; IR (neat): nmax
/
DMSO-d6): dC 181.5, 177.6, 152.2, 136.7, 130.6, 130.5, 130.5, 126.5, cmꢀ1 3431, 3054, 1698; MS (pAPCI): 317.1 (100%, (M ꢀ (N(OH)
126.5, 124.5, 122.4, 121.1, 119.3, 118.9, 111.6, 109.5, 58.3, 55.5, Ph) + H)+), 407.1 (5%, (M ꢀ H2O)+); HRMS (pAPCI) calcd
40.9, 27.3, 18.3; IR (neat): nmax/cmꢀ1 3372, 3298, 1683; MS (nNSI) C24H19N5O3 [M ꢀ H]+: 424.1404; observed: 424.1398.
¼ 186.0 (100%), 237.1 (97%, (M ꢀ (N(OH)(o-Tol)) ꢀ H)ꢀ), 358.1
(35%, (M ꢀ H2)ꢀ), 394.1 (23%); HRMS (nNSI): calcd C21H18N3O3
4j – (R*)-6-(hydroxy(o-tolyl)amino)-2-phenyl-6,11-dihydro-
[M ꢀ H]ꢀ: 360.1354; observed: 360.1348.
1H,5H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-
1,3(2H)-dione
4h – (3aS*,5S*,10bS*)-5-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-
1-yl)-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione
To a stirred Schlenk ask was added benzyl (R*)-6-(hydroxy(o-
tolyl)amino)-1,3-dioxo-2-phenyl-2,3,5,6-tetrahydro-1H,11H-[1,2,4]-
triazolo[10,20:1,2]pyridazino[3,4-b]indole-11-carboxylate
(140
To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5- mg, 0.24 mmol), platinum(IV) oxide (55 mg, 0.24 mmol) and
(3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-1,3-dioxo-2,3,3a,4,5, THF (5 mL). The resulting suspension was placed under an
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atmosphere of H2 and stirred at room temperature for 5 hours. 4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-carboxylate
The suspension was ltered through celite and the solvent was (108 mg, 0.20 mmol), platinum(IV) oxide (46 mg, 0.20 mmol) and
removed under reduced pressure to leave the crude product as a THF (5 mL). The resulting suspension was placed under
white solid. The crude product was puried by trituration from an atmosphere of H2 and stirred at room temperature for
DCM to give (R*)-6-(hydroxy(o-tolyl)amino)-2-phenyl-6,11- 5 hours. The suspension was ltered through celite and
dihydro-1H,5H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole- the solvent was removed under reduced pressure to leave the
1,3(2H)-dione (44%, 46 mg, 0.11 mmol) as a white powder.
crude product as a white solid. The crude product was
Mp: 188.1–189.6 ꢁC; 1H NMR (400 MHz, DMSO-d6): dH 11.65 puried by column chromatography (petrol (40/60)–ethyl
(1H, s), 8.58 (1H, s), 7.59–7.51 (5H, m), 7.47–7.42 (1H, m), 7.36 acetate 1 : 1, column diameter ¼ 2 cm, silica ¼ 15 cm) to
(1H, d, J ¼ 8.0 Hz), 7.17–7.13 (1H, m), 6.96–6.91 (3H, m), 6.79– give
(3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-7-methoxy-2-
6.69 (2H, m), 4.69 (1H, d, J ¼ 12.8 Hz), 4.58 (1H, br s), 3.62 (1H, methyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,
dd, J ¼ 12.8, 3.3 Hz), 2.06 (3H, s); 13C NMR (101 MHz, DMSO-d6): 3aH)-dione (70%, 57 mg, 0.14 mmol) as an off white powder.
1
dC 151.4, 150.4, 146.8, 134.0, 131.8, 131.2, 130.6, 129.8, 129.7,
Mp: 139.7–142.5 ꢁC; Rf: 0.36 (Pet(40/60)–EA 1 : 1); H NMR
128.9, 127.0, 126.7, 126.0, 125.1, 122.6, 121.0, 120.1, 118.1, (400 MHz, DMSO-d6): dH 10.89 (1H, s), 8.36 (1H, s), 7.52 (1H, d, J
112.2, 92.3, 57.8, 43.5, 18.2; IR (neat): nmax/cmꢀ1 ¼ 3426, 3380, ¼ 8.0 Hz), 7.15–7.11 (2H, d, J ¼ 8.7 Hz), 6.93–6.85 (2H, m), 6.49
2950, 1712; MS (pAPCI): 108.1 (100%), 317.1 (37%, (M ꢀ (1H, dd, J ¼ 8.7, 2.4 Hz), 6.23–6.17 (1H, m), 4.28 (1H, d, J ¼ 8.2
(N(OH)(o-Tol)) + H)+), 422.2 (4%, (M ꢀ (H2O) + H)+), 438.2 (6%, Hz), 4.22 (1H, app t, J ¼ 3.8 Hz), 3.78 (1H, ddd, J ¼ 10.8, 8.2, 6.1
(M ꢀ H)+); HRMS (pAPCI): calcd C25H20N5O3 [M ꢀ H]+: Hz), 3.45 (3H, s), 2.81 (3H, s), 2.70–2.63 (1H, m), 1.89 (3H, s),
438.1561; observed: 438.1553.
1.66 (1H, ddd, J ¼ 14.1, 10.8, 3.8 Hz); 13C NMR (101 MHz,
DMSO-d6): dC 180.1, 176.3, 153.2, 152.5, 131.6, 131.1, 130.7,
130.4, 126.8, 126.5, 124.7, 122.7, 112.2, 111.4, 109.2, 100.6, 58.8,
55.3, 39.6, 38.4, 28.3, 25.1, 18.1; IR (neat): nmax/cmꢀ1 ¼ 3384,
2954, 2866, 1693; MS (pAPCI): 283.1 (100%, (M ꢀ (N(OH)(o-Tol))
+ H)+), 388.2 (34%, (M ꢀ (H2O) + H)+), 404.2 (13%, (M ꢀ H)+),
406.2 (11%, (M + H)+); HRMS (pAPCI): calcd C23H24N3O4 [M +
H]+: 406.1761; observed: 406.1750.
4k – (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-7-methoxy-2-
methyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione
To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
(hydroxy(phenyl)amino)-7-methoxy-2-methyl-1,3-dioxo-2,3,3a,
4,5,10b-hexahydropyrrolo[3,4-a]carbazole-10(1H)-carboxylate
(130 mg, 0.25 mmol), platinum(IV) oxide (57 mg, 0.25 mmol) and
THF (5 mL). The resulting suspension was placed under an
atmosphere of H2 and stirred at room temperature for 5 hours.
The suspension was ltered through celite and the solvent was
removed under reduced pressure to leave the crude product as
an orange solid. The crude product was puried by column
chromatography (petrol (40/60)–ethyl acetate 3 : 2, column
diameter ¼ 2 cm, silica ¼ 14 cm) to give (3aS*,5S*,10bS*)-5-
(hydroxy(phenyl)amino)-7-methoxy-2-methyl-4,5,10,10b-tetra-
hydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione (70%, 69 mg,
0.18 mmol) as a pale yellow powder.
4m – (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)amino)-4,5,10,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione
To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
(hydroxy(phenyl)amino)-1,3-dioxo-2,3,3a,4,5,10b-hexahydro-
pyrrolo[3,4-a]carbazole-10(1H)-carboxylate (90 mg, 0.18 mmol),
platinum(IV) oxide (41 mg, 0.18 mmol) and THF (5 mL). The
resulting suspension was placed under an atmosphere of H2
and stirred at room temperature for 10 hours. The suspension
was ltered through celite and the solvent was removed under
reduced pressure to leave the crude product as an yellow solid,
The crude product was puried by column chromatography
(petrol (40/60)–ethyl acetate 1 : 1, column diameter ¼ 2 cm,
silica ¼ 14 cm) to give (3aS*,5S*,10bS*)-5-(hydroxy(phenyl)
amino)-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,
3aH)-dione (41%, 26 mg, 0.07 mmol) as a yellow powder.
Mp: 150.0–153.1 ꢁC; Rf: 0.33 (Pet(40/60)–EA 1 : 1); 1H NMR
(400 MHz, DMSO-d6): dH 11.22 (1H, s), 11.09 (1H, s), 8.24 (1H, s),
7.33 (1H, d, J ¼ 8.1 Hz), 7.27–7.23 (1H, m), 7.20 (2H, app d, J ¼ 7.3
Hz), 7.12 (2H, d, J ¼ 7.7 Hz), 7.00–6.95 (1H, m), 6.85 (1H, app t, J ¼
7.2 Hz), 6.80 (1H app t, J ¼ 7.3 Hz), 4.89 (1H, app t, J ¼ 4.9 Hz),
4.25 (1H, d, J ¼ 8.1 Hz), 3.63–3.52 (1H, m), 2.27 (1H, app dt, J ¼
13.6, 5.6 Hz), 1.80 (1H, ddd, J ¼ 13.6, 9.2, 4.8 Hz); 13C NMR (101
MHz, DMSO-d6): dC 181.2, 177.6, 153.3, 137.0, 130.3, 129.0, 126.3,
121.4, 121.1, 119.9, 118.9, 117.2, 111.7, 109.9, 57.4, 40.9, 40.6,
25.7; IR (neat): nmax/cmꢀ1 3302, 2924, 1706; MS (pAPCI): 108.1
(18%), 237.1 (100), 239.1 (46%, (M ꢀ (N(OH)Ph) + H)+); HRMS
Mp: 149.1–151.2 ꢁC; Rf: 0.19 (Pet(40/60)–EA 3 : 2); 1H NMR (400
MHz, DMSO-d6): dH 10.95 (1H, s), 8.29 (1H, s), 7.23–7.19 (2H, m),
7.18 (1H, d, J ¼ 2.8 Hz), 7.14–7.10 (2H, m), 6.87–6.83 (1H, m), 6.57
(1H, dd, J ¼ 8.7, 2.5 Hz), 6.51 (1H, d, J ¼ 2.5 Hz), 4.83 (1H, app t, J
¼ 4.8 Hz), 4.24 (1H, d, J ¼ 8.2 Hz), 3.64 (1H, app td, J ¼ 9.1, 6.1 Hz),
3.48 (3H, s), 2.80 (3H, s), 2.35 (1H, ddd, J ¼ 13.7, 6.1, 4.8 Hz), 1.83
(1H, ddd, J ¼ 13.7, 9.1, 4.8 Hz); 13C NMR (101 MHz, DMSO-d6): dC
179.9, 176.3, 153.6C1, 153.4, 132.0, 130.6, 129.0, 126.6, 121.2,
117.4, 112.3, 111.5, 109.5, 101.7, 57.7, 55.5, 39.5, 39.1, 27.1, 25.1;
IR (neat): nmax/cmꢀ1 ¼ 3394, 2937, 2833, 1690; MS (pAPCI): 283.1
(100%, (M ꢀ (N(OH)Ph) + H)+), 374.1 (18%, (M ꢀ (H2O) + H)+),
390.1 (2%, (M ꢀ H)+), 392.2 (1%, (M + H)+); HRMS (pAPCI): calcd
C22H22N3O4 [M + H]+: 392.1605; observed: 392.1597.
4l – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-7-methoxy-2-
methyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-
1,3(2H,3aH)-dione
To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5- (pAPCI): calcd C14H11N2O2 [M ꢀ (N(OH)Ph) + H]+: 239.0815;
(hydroxy(o-tolyl)amino)-7-methoxy-2-methyl-1,3-dioxo-2,3,3a, observed: 239.0810.
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(100%, (M ꢀ (N(OH)Ph) + H)+); HRMS (pAPCI): calcd C25H20N5O4
[M ꢀ H]+: 454.1510; observed: 454.1502.
4n – (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)amino)-4,5,10,10b-
tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,3aH)-dione
To a stirred Schlenk ask was added benzyl (3aS*,5S*,10bS*)-5-
(hydroxy(o-tolyl)amino)-1,3-dioxo-2,3,3a,4,5,10b-hexahydro-
pyrrolo[3,4-a]carbazole-10(1H)-carboxylate (120 mg, 0.24
mmol), platinum(IV) oxide (54 mg, 0.24 mmol) and THF (5 mL).
The resulting suspension was placed under an atmosphere of
H2 and stirred at room temperature for 6 hours. The suspension
was ltered through celite and the solvent was removed under
reduced pressure to leave the crude product as a yellow solid,
The crude product was puried by column chromatography
(petrol (40/60)–ethyl acetate 2 : 3, column diameter ¼ 2 cm,
silica ¼ 17 cm) to give (3aS*,5S*,10bS*)-5-(hydroxy(o-tolyl)
amino)-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-1,3(2H,
3aH)-dione (70%, 61 mg, 0.17 mmol) as an off white solid.
4p – (R*)-6-(hydroxy(o-tolyl)amino)-8-methoxy-2-phenyl-6,11-
dihydro-1H,5H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]
indole-1,3(2H)-dione
To a stirred Schlenk ask was added benzyl (R*)-6-(hydroxy(o-
tolyl)amino)-8-methoxy-1,3-dioxo-2-phenyl-2,3,5,6-tetrahydro-
1H,11H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4 b]indole-11-carbo-
xylate (120 mg, 0.20 mmol), platinum(IV) oxide (46 mg, 0.20
mmol) and THF (5 mL). The resulting suspension was placed
under an atmosphere of H2 and stirred at room temperature for
5 hours. The suspension was ltered through celite and the
solvent was removed under reduced pressure to leave the crude
product as a white solid. The crude product was puried by
trituration from DCM to (R*)-6-(hydroxy(o-tolyl)amino)-8-
methoxy-2-phenyl-6,11-dihydro-1H,5H-[1,2,4]triazolo[10,20:1,2]-
pyridazino[3,4 b]indole-1,3(2H)-dione (64%, 53 mg, 0.13 mmol)
as a white powder.
1
Mp: 149.9–153.2 ꢁC; Rf: 0.52 (Pet(40/60)–EA 2 : 3); H NMR
(400 MHz, CD2Cl2): dH 8.81 (1H, s), 8.21 (1H, s), 7.56 (1H, d, J ¼
8.0 Hz), 7.30 (1H, d, J ¼ 7.9 Hz), 7.18 (2H, d, J ¼ 6.9 Hz), 7.06
(1H, app t, J ¼ 7.6 Hz), 7.03–6.99 (2H, m), 6.91–6.85 (1H, m), 5.36
(1H, s), 4.51 (1H, app t, J ¼ 4.5 Hz), 4.19 (1H, d, J ¼ 8.6 Hz), 3.80
(1H, app td, J ¼ 9.3, 6.4 Hz), 2.74 (1H, app dt, J ¼ 13.6, 5.5 Hz),
2.15 (3H, s), 1.83 (1H, ddd, J ¼ 13.6, 10.1, 4.1 Hz); 13C NMR (101
MHz, DMSO-d6): dC 181.5, 177.6, 152.2, 136.7, 130.6, 130.5,
130.5, 126.5, 126.5, 124.5, 122.4, 121.1, 119.3, 118.9, 111.6,
109.5, 58.3, 55.5, 40.9, 27.3, 18.3; IR (neat): nmax/cmꢀ1 3372,
3298, 1683; MS (nNSI) ¼ 186.0 (100%), 237.1 (97%, (M ꢀ
(N(OH)(o-Tol)) ꢀ H)ꢀ), 358.1 (35%, (M ꢀ H2)ꢀ), 394.1 (23%);
HRMS (nNSI): calcd C21H18N3O3 [M ꢀ H]ꢀ: 360.1354; observed:
360.1348.
1
ꢁ
Mp: 171.9–173.8 C; H NMR (400 MHz, DMSO-d6): dH 11.44
(1H, s), 8.64 (1H, s), 7.59 (1H, d, J ¼ 8.1 Hz), 7.54–7.50 (4H, m),
7.46–7.43 (1H, m), 7.19 (1H, d, J ¼ 8.5 Hz), 7.15 (1H, d, J ¼ 7.5 Hz),
6.97–6.91 (2H, m), 6.50 (1H, dd, J ¼ 8.7, 2.2 Hz), 6.01 (1H, s), 4.73
(1H, d, J ¼ 12.8 Hz), 4.52 (1H, s), 3.67–3.61 (1H, m), 3.47 (3H, s),
1.96 (3H, s); 13C NMR (101 MHz, DMSO-d6): dC 154.1, 151.8, 150.5,
146.4, 131.8, 131.6, 130.6, 130.0, 129.7, 128.9, 128.7, 127.0, 126.7,
126.5, 125.3, 122.8, 112.7, 110.7, 100.0, 91.8, 58.3, 55.4, 44.3, 18.0;
IR (neat): nmax/cmꢀ1 ¼ 3442, 3394, 2939, 1699; MS (pAPCI): 347.1
(68%, (M ꢀ (N(OH)(o-Tol) + H)+)), 391.1 (100%), 452.2 (4%, (M ꢀ
(H2O) + H)+), 468.2 (2%, (M ꢀ H)+); HRMS (pAPCI): calcd
C26H22N5O4 [M ꢀ H]+: 468.1666; observed: 468.1658.
4o – (R*)-6-(hydroxy(phenyl)amino)-8-methoxy-2-phenyl-6,11-
dihydro-1H,5H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]
indole-1,3(2H)-dione
Acknowledgements
The authors thank Newcastle University and EPSRC (EP/
I033959/1) for funding, MA thanks the Ministry of Higher
Education of Saudi Arabia for a PhD scholarship, EPSRC for X-
ray crystallography facilities at Newcastle (EP/F03637X/1), Prof.
W. McFarlane and Dr C. Wills (Newcastle) for NMR support, L.
Watson and S. Thompson (Newcastle) for preliminary studies.
Mass spectrometry data was acquired at the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
To a stirred Schlenk ask was added benzyl (R*)-6-(hydroxy
(phenyl)amino)-8-methoxy-1,3-dioxo-2-phenyl-2,3,5,6-tetra-
hydro-1H,11H-[1,2,4]triazolo[10,20:1,2]pyridazino[3,4-b]indole-
11-carboxylate (118 mg, 0.20 mmol), platinum(IV) oxide (46 mg,
0.20 mmol) and THF (5 mL). The resulting suspension was
placed under an atmosphere of H2 and stirred at room
temperature for 5 hours. The suspension was ltered through
celite and the solvent was removed under reduced pressure to
leave the crude product as a yellow solid. The product was
puried by trituration from DCM to give (R*)-6-(hydroxy(phenyl)
amino)-8-methoxy-2-phenyl-6,11-dihydro-1H,5H-[1,2,4]triazolo
[10,20:1,2]pyridazino[3,4-b]indole-1,3(2H)-dione (38%, 35 mg,
0.08 mmol) as an off-white solid.
References
1 S. Omura, Y. Iwai, A. Hirano, A. Nakagawa, J. Awaya,
H. Tsuchiya, Y. Takahashi and R. Asuma, J. Antibiot., 1977,
30, 275–282.
Mp: 173.7–176.4 ꢁC; Rf: 0.18 (Pet–EA 3 : 1); 1H NMR (400 MHz,
DMSO-d6): dH 11.44 (1H, s) 8.62 (1H, s), 7.54–7.47 (4H, m), 7.44–
7.41 (1H, m) 7.25–7.18 (3H, m), 7.12 (2H, d, J ¼ 7.7 Hz), 6.90 (1H,
app t, J ¼ 6.8 Hz), 6.56 (1H, d, J ¼ 8.7 Hz), 6.26 (1H, s), 5.12 (1H, br
s), 4.51 (1H, d, J ¼ 13.0 Hz), 3.81 (1H, dd, J ¼ 13.0, 3.3 Hz), 3.49
(3H, s); 13C NMR (101 MHz, DMSO-d6): dC 154.3, 152.9, 149.7,
146.4, 131.8, 130.1, 129.6, 129.6, 128.9, 128.9, 127.0, 126.3, 122.3,
2 N. Funato, H. Takayanagi, Y. Konda, Y. Toda, Y. Harigaya,
¯
Y. Iwai and S. Omura, Tetrahedron Lett., 1994, 35, 1251–1254.
3 O. A. B. S. M. Gani and R. A. Engh, Nat. Prod. Rep., 2010, 27,
489–498.
4 M. S. Lopez, J. W. Choy, U. Peters, M. L. Sos, D. O. Morgan
and K. M. Shokat, J. Am. Chem. Soc., 2013, 135, 18153–18159.
´
118.4, 112.9, 110.7, 100.8, 92.3, 57.7, 55.5, 44.3; IR (neat): nmax
/
5 E. Conchon, F. Anizon, R. M. Golsteyn, S. Leonce, B. Pfeiffer
cmꢀ1 3362, 3000, 1758, 1700; MS (pAPCI): 213.1 (70%), 347.1
and M. Prudhomme, Tetrahedron, 2006, 62, 11136–11144.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 16125–16152 | 16151

View Article Online
RSC Advances
Paper
6 A. Voldoire, M. Sancelme, M. Prudhomme, P. Colson, 23 L. J. Watson, R. W. Harrington, W. Clegg and M. J. Hall, Org.
´
C. Houssier, C. Bailly, S. Leonce and S. Lambel, Bioorg.
Biomol. Chem., 2012, 10, 6649–6655.
Med. Chem., 2001, 9, 357–365.
7 N. Ty, G. Dupeyre, G. G. Chabot, J. Seguin, L. Quentin,
24 L. J. Cotterill, R. W. Harrington, W. Clegg and M. J. Hall, J.
Org. Chem., 2010, 75, 4604–4607.
A. Chiaroni, F. Tillequin, D. Scherman, S. Michel and 25 L. Pfeuffer and U. Pindur, Helv. Chim. Acta, 1988, 71, 467–
X. Cachet, Eur. J. Med. Chem., 2010, 45, 3726–3739. 471.
8 E. Conchon, F. Anizon, B. Aboab, R. M. Golsteyn, S. Leonce, 26 K. Suzuki, K. Inomata and Y. Endo, Org. Lett., 2004, 6, 409–
´
B. Pfeiffer and M. Prudhomme, Eur. J. Med. Chem., 2008, 43,
282–292.
411.
27 G. A. Kraus and J. Kim, Org. Lett., 2004, 6, 3115–3117.
9 E. Pereira, A. Youssef, M. El-Ghozzi, D. Avignant, J. Bain, 28 R. B. Ruggeri, M. M. Hansen and C. H. Heathcock, J. Am.
M. Prudhomme, F. Anizon and P. Moreau, Tetrahedron
Lett., 2014, 55, 834–837.
Chem. Soc., 1988, 110, 8734–8736.
29 D. Li, Y. Cao, A. Shi and Z. Xi, Chem.–Asian J., 2011, 6, 392–
10 M. Eitel and U. Pindur, J. Org. Chem., 1990, 55, 5368–5374.
395.
11 W. E. Noland, W. C. Kuryla and R. F. Lange, J. Am. Chem. Soc., 30 D. G. Hingane, S. K. Goswami, V. Puranik and R. S. Kusurkar,
1959, 81, 6010–6017. Synth. Commun., 2011, 42, 1786–1795.
12 W. E. Noland and S. R. Wann, J. Org. Chem., 1979, 44, 4402– 31 B. t. Joseph, M. Facompre, H. Da Costa, S. Routier,
´
´
4410.
J.-Y. Merour, P. Colson, C. Houssier and C. Bailly, Bioorg.
13 M. Bleile, T. Wagner and H.-H. Otto, Helv. Chim. Acta, 2005,
Med. Chem., 2001, 9, 1533–1541.
88, 2879–2891.
32 B. Saroja and P. C. Srinivasan, Synthesis, 1986, 1986, 748–
749.
14 U. Pindur and M.-H. Kim, Tetrahedron Lett., 1988, 29, 3927–
3928.
33 X. Zhang, S. I. Khan and C. S. Foote, J. Org. Chem., 1993, 58,
7839–7847.
34 P. R. Schreiner, Chem. Soc. Rev., 2003, 32, 289–296.
35 J. Robertson, M. J. Hall, P. M. Stafford and S. P. Green, Org.
Biomol. Chem., 2003, 1, 3758–3767.
15 M. Medion-Simon and U. Pindur, Helv. Chim. Acta, 1991, 74,
430–437.
16 U. Pindur and C. Otto, Tetrahedron, 1992, 48, 3515–3526.
17 R. Bergamasco, Q. N. Porter and C. Yap, Aust. J. Chem., 1977,
30, 1531–1544.
36 L. F. Tietze, Chem. Rev., 1996, 96, 115–136.
18 J. D. Lambert and Q. N. Porter, Aust. J. Chem., 1981, 34, 1483– 37 C. J. Lovely, H. Du, Y. He and H. V. Rasika Dias, Org. Lett.,
1490. 2004, 6, 735–738.
19 C. Gioia, A. Hauville, L. Bernardi, F. Fini and A. Ricci, Angew. 38 N. Uludag and S. Patir, J. Heterocycl. Chem., 2007, 44, 1317–
Chem., Int. Ed., 2008, 47, 9236–9239. 1322.
20 C. Gioia, L. Bernardi and A. Ricci, Synthesis, 2010, 2010, 161– 39 P. Magnus, N. L. Sear, C. S. Kim and N. Vicker, J. Org. Chem.,
170. 1992, 57, 70–78.
21 B. Tan, G. Hernandez-Torres and C. F. Barbas, J. Am. Chem. 40 R. Yang and F. G. Qiu, Angew. Chem., Int. Ed., 2013, 52, 6015–
´
Soc., 2011, 133, 12354–12357.
6018.
22 U. Pindur, M. H. Kim, M. Rogge, W. Massa and M. Molinier,
J. Org. Chem., 1992, 57, 910–915.
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