One-pot synthesis of pyranocarbazoles by ethylenediamine diacetate catalyzed domino aldol-type reaction/6π-electrocyclization of hydroxycarbazoles to α,β-unsaturated aldehydes and conversion into other pyranocarbazoles

Article abstract of DOI:10.1055/s-0032-1316766

A new synthetic route for biologically interesting pyranocarbazoles was developed by reaction of 2- or 4-hydroxycarbazole with α,β- unsaturated aldehydes in the presence of ethylenediamine diacetate (EDDA). The key strategy of this methodology is a formal [3+3] cycloaddition via domino aldol-type/6π-electrocyclization. The synthesized pyranocarbazoles can be converted into derivatives bearing substituents on the carbazole and pyran rings. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316766

2910▌
PAPER
pOapnere-Pot Synthesis of Pyranocarbazoles by Ethylenediamine Diacetate Catalyzed
Domino Aldol-Type Reaction/6π-Electrocyclization of Hydroxycarbazoles to
α,β-Unsaturated Aldehydes and Conversion into Other Pyranocarbazoles
One-Pot Synthesis of Pyranocarbazoles
Rameshwar Prasad Pandit, Yong Rok Lee*
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Korea
Fax +82(53)8104631; E-mail: yrlee@yu.ac.kr
Received: 04.06.2012; Accepted after revision: 10.07.2012
R
Abstract: A new synthetic route for biologically interesting py-
ranocarbazoles was developed by reaction of 2- or 4-hydroxycarba-
zole with α,β-unsaturated aldehydes in the presence of
ethylenediamine diacetate (EDDA). The key strategy of this meth-
odology is a formal [3+3] cycloaddition via domino aldol-type/6π-
electrocyclization. The synthesized pyranocarbazoles can be con-
verted into derivatives bearing substituents on the carbazole and py-
ran rings.
O
O
N
R1
N
H
H
OH
HO
5 cis-dihydroxygirinimbine
1 R = Me, R1 = H girinimbine
2 R = CHO, R1 = H murrayacine
3 R = Me, R1 = OMe O-methylmurrayacine A
4 R = CHO, R1 = OMe 7-methoxymurrayacine
Key words: pyranocarbazoles, ethylenediamine diacetate, domino
reaction, heterocycles, cyclization
R2
R3
R4
O
O
Molecules with the pyranocarbazole moiety are found
widely in nature (Figure 1).1 These compounds have been
shown to have a range of significant biological and phar-
macological properties.2 Girinimbine (1), murrayacine
(2), and O-methylmurrayamine A (3) were isolated from
Murraya koenigii.3 The leaves of this plant are well-
known as curry leaves and have been used as one of the
important herbs of southern Indian cooking.4 This plant
has also been used as a folk medicine for increasing diges-
tive secretions and relieving nausea, indigestion, and
vomiting.5 Girinimbine (1) was also shown to exhibit an-
titumor activity.6 7-Methoxymurrayamine (4) was isolat-
ed from the roots of Murraya siamensis.7 The isolation of
cis-dihydroxygirinimbine (5) from Murraya koenigii as a
racemate was described,8 whereas that of trans-dihydro-
xygirinimbine (6) with an optical rotation of [α]D = –4.0
(MeOH) was accomplished from the root of Murraya eu-
chrestifolia.9 However, the absolute configuration of 6
has not been determined so far. Naturally occurring mah-
animbine (7), mahanine (8), and mahanimbicine (9) were
also isolated from Murraya koenigii.10–16 These com-
pounds have shown to possess anti-obesity,10 antidiabet-
ic,11 hypolipidemic,11 anti-trichomonal,12 antioxidant,13
antibiotic,14 antitumor,14 and acetylcholinesterase15 and
pancreatic lipase inhibitory activities.16 This wide range
of biological activities has stimulated interest in the syn-
thesis of pyranocarbazole derivatives.
N
N
H
H
HO
OH
7 R2 = Me, R3 = R4 = H mahanimbine
8 R2 = Me, R3 = H, R4 = OH mahanine
9 R2 = H, R3 = Me, R4 = H mahanimbicine
6 trans-dihydroxygirinimbine
Figure 1 Selected naturally occurring pyranocarbazole alkaloids
palladium-catalyzed intramolecular C–O and C–C cross-
coupling reaction of 1-hydroxy-7-methylcarbazole,18
iron-mediated oxidative cyclization,8 and reaction of 2-
cinnamoyl-1-hydroxycarbazoles under hydrogen perox-
ide/sodium hydroxide.19 These reactions are limited by
harsh reaction conditions, unsatisfactory yields, and use
of stoichiometric amounts of catalyst. Therefore, there is
still a demand for general methods that can efficiently
provide various substituents on the benzopyranyl ring.
Recently, a new methodology was developed for the prep-
aration of a variety of benzopyrans by ethylenediamine di-
acetate (EDDA) catalyzed reactions between cyclic 1,3-
dicarbonyl compounds or resorcinols and α,β-unsaturated
aldehydes.20 These reactions involve a formal [3+3] cy-
cloaddition through domino Knoevenagel/6π-electrocy-
clization or aldol-type/6π-electrocyclization.20 As part of
an ongoing study into the synthetic efficacy of this meth-
odology, we investigated other ethylenediamine diacetate
catalyzed reactions of 2-hydroxycarbazole or 4-hydroxy-
carbazole with α,β-unsaturated aldehydes. We report
herein a mild and facile methodology for preparing bio-
logically interesting pyranocarbazole derivatives. We also
report a new conversion of synthesized pyranocarbazoles
to other derivatives.
Several synthetic approaches to pyranocarbozole deriva-
tives have been reported. These methods include sodium
carbonate catalyzed multicomponent reaction of 1-hy-
droxycarbazole with malononitrile and arylaldehyde,17
SYNTHESIS 2012, 44, 2910–2918
Advanced online publication: 08.08.2012
Firstly, various catalysts were investigated for the reaction
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
of 2-hydroxycarbazole (10a) with 3-methylbut-2-enal
DOI: 10.1055/s-0032-1316766; Art ID: SS-2012-F0487-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Pyranocarbazoles
2911
(Table 1). Neither indium(III) chloride (20 mol%) nor yt- amine diacetate (20 mol%) in refluxing xylene. The
terbium(III) triflate (20 mol%) as Lewis acid catalysts in results are shown in Table 2. The reaction of 2-hydroxy-
refluxing acetonitrile for 24 hours provided any adducts. carbazole (10a) with crotonaldehyde in refluxing xylene
The use of calcium hydroxide (20 mol%) under Shigema- for 15 hours produced the adduct 11b in 51% yield (entry
sa conditions21 did not produce any products either. The 1). The products were produced in higher yields when α,β-
use of ethylenediamine tetraacetic acid (20 mol%) as cat- unsaturated aldehydes with long chains were used. For ex-
alyst in refluxing xylene for 24 hours gave product 11a in ample, treatment of compound 10a with citral for 15 hours
only 10% yield. Further reactions with ethylenediamine gave 11c in 80% yield (entry 2), and the reaction with
diacetate (EDDA) (20 mol%) as catalyst were attempted. trans,trans-farnesal for 15 hours provided adduct 11d in
These reactions are solvent- and reaction temperature de- 83% yield (entry 3). In a related publication, reaction of
pendent. The best yield (72%) was obtained with reflux- 10a with citral in refluxing pyridine was reported to afford
ing xylene for 15 hours. Importantly, in this reaction, the 11c and its linear isomer in lower yield.22 The cycloaddi-
expected regioisomer was not detected. Compound 11a tion reaction was also successful with trans-cinnamalde-
was easily separated by column chromatography and hyde. Treatment of 10a with trans-cinnamaldehyde in
identified by the analysis of spectroscopic data. In the 1H refluxing xylene for 8 hours provided 11e in 61% yield
NMR spectrum of 11a, two aromatic protons on a benzo- (entry 4). The method was also successful in reactions
pyranyl ring appeared at δ = 7.77 (d, J = 8.4 Hz) and 6.72 with 4-hydroxycarbazole (10b). The reaction between 4-
(d, J = 8.4 Hz), whereas two vinylic protons on the py- hydroxycarbazole (10b) and 3-methylbut-2-enal in re-
ranyl ring appeared at δ = 6.61 (d, J = 9.9 Hz) and 5.69 (d, fluxing xylene for 12 hours afforded the adduct 11f in
J = 9.9 Hz).
64% yield (entry 5). Similarly, the reactions with croton-
aldehyde, citral, trans,trans-farnesal, and trans-cinnamal-
dehyde for 8–12 hours provided the desired products 11g–
j in 59–85% yield (entries 6–9). These reactions provide a
rapid route for the synthesis of biologically interesting py-
ranocarbazole derivatives with a variety of substituents on
the pyranyl rings.
Table 1 Catalyst Screening for the Reaction of 2-Hydroxycarbazole
(10a) with 3-Methylbut-2-enal
O
O
OH
H
catalyst
N
N
Although the precise mechanism of the reaction is un-
clear, a proposed mechanism is shown in Scheme 1. The
2-hydroxycarbazole (10a) first attacks the protonated enal
to yield intermediate 12 through an aldol-type reaction; 12
is directly dehydrated to give quinone methide 13. Such a
process where a phenol is deprotonated by acetate was al-
ready reported by another group.23 Intermediate 13 cycliz-
es by oxa-6π-electrocyclization to give the final product
11a.24
H
H
10a
11a
Catalyst
Conditions
Yield (%)
InCl3 (20 mol%)
MeCN, reflux, 24 h
MeCN, reflux, 24 h
MeOH, reflux, 24 h
xylene, reflux, 24 h
THF, reflux, 15 h
0
0
Yb(OTf)3 (20 mol%)
Ca(OH)2 (20 mol%)
EDTA (20 mol%)
EDDA (20 mol%)
EDDA (20 mol%)
EDDA (20 mol%)
0
10
0
As an application of this methodology, the synthesized
pyranocarbazoles 11a and 11f were converted into deriv-
atives with various substituents on the pyranyl rings
(Schemes 2 and 3). When 11a was treated with N-bromo-
succinimide in aqueous dioxane at room temperature for
three hours, trans-bromohydrin 14 was produced in 55%
yield (Scheme 2). The direct catalytic dihydroxylation of
11a with osmium tetroxide by using two equivalents N-
methylmorpholine N-oxide in tert-butyl alcohol–tetrahy-
drofuran–water (10:3:1) at room temperature for five
toluene, reflux, 15 h
xylene, reflux, 15 h
12
72
Additional reactions of 2-hydroxycarbazole (10a) or 4-
hydroxycarbazole (10b) with several α,β-unsaturated al-
dehydes were carried out in the presence of ethylenedi-
+
+
H3N
NH3
–OAc
–OAc
OH
O
H
H
+OH
O
O
O
– H2O
N
H
N
N
10a
N
H
12
H
HO
H
11a
13
Scheme 1
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2910–2918

2912
R. P. Pandit, Y. R. Lee
PAPER
hours gave the cis-diol 15 in 70% yield. Interestingly, ox- pound due to its instability. The stereochemical assign-
idation of 11a with dimethyldioxirane in undried acetone ments of the cis- and trans-diols were easily made on the
at room temperature for four hours provided cis-diol 15 basis of the coupling constants between the vicinal pro-
(52%) as the major product together with trans-diol 16 tons on the dihydropyranyl ring. For the vicinal coupling
(28%), without any isolation of the desired epoxide com- in the cis-diol 15, J = 4.8 Hz, while J = 8.1 Hz for the
Table 2 Reactions of 2-Hydroxycarbazole (10a) or 4-Hydroxycarbazole (10b) with α,β-Unsaturated Aldehydes in Refluxing Xylene Cata-
lyzed by Ethylenediamine Diacetate
Entry Starting material
α,β-Unsaturated
aldehyde
Time Product
(h)
Yield
(%)
OH
OH
O
O
O
H
1
2
10a
10a
15
15
11b
11c
51
80
N
H
N
H
citral
N
H
N
H
OH
OH
O
O
3
10a
trans,trans-farnesal
15
11d
83
N
H
N
H
O
H
4
5
10a
10b
8
11e
11f
61
64
N
H
N
H
O
O
OH
OH
O
H
12
HN
HN
HN
HN
O
H
6
7
10b
10b
12
12
11g
11h
59
79
OH
OH
OH
O
O
O
citral
HN
HN
HN
HN
HN
HN
8
9
10b
10b
trans,trans-farnesal
12
11i
11j
85
61
O
H
8
Synthesis 2012, 44, 2910–2918
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One-Pot Synthesis of Pyranocarbazoles
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O
N
H
OH
15
HO
O
OsO4, NMO
t-BuOH–THF–H2O
N
70%
H
OH
15 52%
HO
+
O
O
DMDO
NBS, H2O
acetone
(wet)
O
dioxane
55%
N
N
H
11a
H
14
Br
HO
N
H
OH
HO
MeI
DMF
95%
NaH
O
O
O
NBS, H2O
OsO4, NMO
dioxane
55%
t-BuOH–THF–H2O
N
N
N
Me
74%
OH
Me
Me
19
17
18
HO
Br
HO
Scheme 2
trans-diol 16. This result is very interesting when com- Further conversion of synthesized pyranocarbazole 11f
pared with a reported reaction where dimethyldioxirane- was also carried out as shown in Scheme 3. Reaction of
mediated oxidation of 2H-pyrans gave trans-diols exclu- 11f with N-bromosuccinimide in aqueous dioxane at room
sively.25 On the other hand, reaction of 11a with m-chlo- temperature for three hours afforded trans-bromohydrin
roperoxybenzoic acid provided complex mixtures 20 in 59% yield. Treatment of 11f with osmium tetroxide
containing the 3-chlorobenzoate group derived from ring by using two equivalents N-methylmorpholine N-oxide in
opening of epoxide. Methylation of 11a with methyl io- tert-butyl alcohol–tetrahydrofuran–water (10:3:1) at
dide in the presence of sodium hydride afforded com- room temperature for five hours provided the cis-diol 21
pound 17 in 95% yield. Reaction of 17 with N- in 67% yield, whereas the use of dimethyldioxirane in un-
bromosuccinimide in aqueous dioxane at room tempera- dried acetone at room temperature for four hours provided
ture for three hours gave trans-18 in 55% yield, whereas both cis-diol 21 (52%) and trans-diol 22 (26%). Methyla-
that with osmium tetroxide at room temperature for five tion of 11f with methyl iodide in base gave the desired
hours gave the cis-diol 19 in 74% yield.
compound 23 in 97% yield. Treatment of 23 with N-bro-
O
OH
OH
HN
21
O
OH
OsO4, NMO
67%
t-BuOH–THF–H2O
HN
HN
OH
21 52%
O
+
O
NBS, H2O
DMDO
Br
dioxane
59%
acetone
(wet)
HN
O
HN
OH
20
OH
OH
11f
MeI
DMF
97%
NaH
O
O
O
NBS, H2O
OsO4, NMO
Br
OH
OH
dioxane
46%
t-BuOH–THF–H2O
MeN
MeN
MeN
68%
OH
25
23
Scheme 3
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2910–2918

2914
R. P. Pandit, Y. R. Lee
PAPER
13C NMR (75 MHz, CDCl3): δ = 152.1, 139.2, 126.2, 125.7, 124.5,
123.7, 120.5, 119.6, 119.4, 118.5, 110.4, 109.2, 105.4, 71.3, 29.6,
20.7.
HRMS (EI): m/z [M+] calcd for C16H13NO: 235.0997; found:
235.0999.
mosuccinimide/water in dioxane at room temperature for
three hours afforded trans-bromohydrin 24 (46%), where-
as reaction with osmium tetroxide at room temperature for
five hours afforded cis-diol 25 in 68% yield.
In conclusion, a new synthetic route for a variety of bio-
logically interesting pyranocarbazole derivatives was de-
veloped starting from 2- or 4-hydroxycarbazole and α,β-
unsaturated aldehydes. The key strategy in these synthetic
routes is a formal [3+3] cycloaddition via domino aldol-
type/6π-electrocyclic ring closure. The conversion of thus
synthesized pyranocarbazoles to derivatives bearing sub-
stituents on the carbazole and pyranyl rings is also de-
scribed.
3-Methyl-3-(4-methylpent-3-enyl)-3,11-dihydropyrano[3,2-
a]carbazole (11c)
Reaction of 10a (182 mg, 1.0 mmol) with citral (304 mg, 2.0 mmol)
in refluxing p-xylene (10 mL) for 15 h afforded 11c.
Yield: 253 mg (80%); greenish oil.
IR (neat): 3353, 2921, 1708, 1627, 1443, 1355, 1216, 1092, 910,
811, 742 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.96 (br s, 1 H, NH), 7.91 (d,
J = 8.1 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.38–7.27 (m, 2 H),
7.20–7.15 (m, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 6.64 (d, J = 9.9 Hz, 1
H), 5.65 (d, J = 9.9 Hz, 1 H), 5.09 (t, J = 6.9 Hz, 1 H), 2.17–2.10 (m,
2 H), 1.79–1.70 (m, 2 H), 1.64 (s, 3 H), 1.56 (s, 3 H), 1.43 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 151.9, 139.7, 136.5, 131.8, 128.8,
124.6, 124.3, 124.1, 120.6, 119.8, 119.5, 117.6, 117.5, 110.6, 109.7,
104.7, 78.5, 40.9, 26.1, 25.8, 22.9, 17.8.
All the experiments were carried out under N2 atmosphere. Merck
precoated silica gel plates (Art. 5554) with fluorescent indicator
were used for analytical TLC. Flash column chromatography was
performed using silica gel 9385 (Merck).
1H NMR and 13C NMR spectra were recorded on a Varian VNS
(300 and 75 MHz, respectively) spectrometer; CDCl3, acetone-d6,
or DMSO-d6 were used as solvents. The IR spectra were recorded
on a Jasco FTIR 5300 spectrophotometer. The HRMS was carried
out at the Korea Basic Science Institute.
HRMS (EI): m/z [M+] calcd for C22H23NO: 317.1780; found:
317.1778.
3-(4,8-Dimethylnona-3,7-dienyl)-3-methyl-3,11-dihydropyra-
no[3,2-a]carbazole (11d)
Reaction of 10a (182 mg, 1.0 mmol) with trans,trans-farnesal (220
mg, 1.0 mmol) in refluxing p-xylene (10 mL) for 15 h afforded 11d.
Pyranocarbazoles 11a–j; General Procedure
EDDA (40 mg, 20 mol%) was added to a mixture of 10a or 10b (1.0
mmol) and an α,β-unsaturated aldehyde (2.0 mmol) in p-xylene (10
mL), and the reaction mixture was refluxed for 8–15 h under a N2
atmosphere. After completion of the reaction as indicated by TLC,
the solvent was removed under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane–EtOAc,
20:1) to give the product.
Yield: 566 mg (83%); yellowish oil.
IR (neat): 3415, 2920, 2346, 1707, 1633, 1447, 1323, 1216, 1091,
811, 743 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.89 (s, 1 H, NH), 7.86 (d, J = 7.8
Hz, 1 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.32–7.09 (m, 3 H), 6.66 (d,
J = 8.4 Hz, 1 H), 6.58 (d, J = 9.9 Hz, 1 H), 5.60 (d, J = 9.9 Hz, 1 H),
5.07–5.00 (m, 2 H), 2.11–2.06 (m, 2 H), 1.98–1.88 (m, 4 H), 1.74–
1.68 (m, 2 H), 1.59 (s, 3 H), 1.50 (s, 6 H), 1.39 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 151.9, 139.6, 136.4, 135.5, 131.5,
128.8, 124.6, 124.5, 124.1, 124.0, 120.6, 119.8, 119.5, 117.6, 117.4,
110.6, 109.7, 104.7, 78.5, 40.9, 39.8, 26.8, 26.1, 25.8, 22.8, 17.8,
16.1.
3,3-Dimethyl-3,11-dihydropyrano[3,2-a]carbazole (11a)
Reaction of 10a (182 mg, 1.0 mmol) with 3-methylbut-2-enal (168
mg, 2.0 mmol) in refluxing p-xylene (10 mL) for 15 h afforded 11a.
Yield: 179 mg (72%); reddish oil.
IR (neat): 3355, 3050, 2973, 1709, 1635, 1450, 1349, 1218, 1159,
743 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.95 (br s, 1 H, NH), 7.92 (d,
J = 7.8 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.38–7.15 (m, 3 H), 6.72
(d, J = 8.4 Hz, 1 H), 6.61 (d, J = 9.9 Hz, 1 H), 5.69 (d, J = 9.9 Hz, 1
H), 1.47 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 151.6, 139.8, 136.6, 129.5, 124.5,
123.9, 120.5, 119.6, 119.4, 117.7, 117.3, 110.7, 109.6, 104.9, 76.1,
27.7, 27.7.
HRMS (EI): m/z [M+] calcd for C27H31NO: 385.2406; found:
385.2403.
3-Phenyl-3,11-dihydropyrano[3,2-a]carbazole (11e)
Reaction of 10a (182 mg, 1.0 mmol) with trans-cinnamaldehyde
(132 mg, 1.0 mmol) in refluxing p-xylene (10 mL) for 8 h afforded
11e.
Yield: 181 mg (61%); blackish solid; mp 175–177 °C.
HRMS (EI): m/z [M+] calcd for C17H15NO: 249.1154; found:
IR (KBr): 3412, 3046, 2832, 1666, 1643, 1446, 1321, 1216, 1130,
1061, 743, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.01 (br s, 1 H, NH), 7.93 (d,
J = 7.8 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.50–7.48 (m, 1 H),
7.40–7.30 (m, 5 H), 7.21–7.16 (m, 2 H), 6.83 (d, J = 8.7 Hz, 1 H),
6.76 (d, J = 8.7 Hz, 1 H), 5.94–5.88 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 151.8, 140.8, 140.0, 136.7, 128.6,
128.6, 128.3, 127.1, 127.1, 124.6, 123.7, 123.3, 120.8, 119.5, 119.4,
118.0, 110.7, 108.9, 105.2.
249.1151.
3-Methyl-3,11-dihydropyrano[3,2-a]carbazole (11b)
Reaction of 10a (182 mg, 1.0 mmol) with trans-crotonaldehyde
(140 mg, 2.0 mmol) in refluxing p-xylene (10 mL) for 15 h afforded
11b.
Yield: 119 mg (51%); greenish solid; mp 120–122 °C.
IR (KBr): 3358, 3054, 2928, 1707, 1628, 1450, 1325, 1217, 1102,
744 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.99 (br s, 1 H, NH), 7.85 (d,
J = 7.8 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.32–7.21 (m, 2 H),
7.14–7.09 (m, 1 H), 6.67 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 9.3 Hz, 1
H), 5.67 (dd, J = 9.6, 3 Hz, 1 H), 4.98–4.94 (m, 1 H), 1.43 (d, J = 6.6
Hz, 3 H).
HRMS (EI): m/z [M+] calcd for C21H15NO: 297.1154; found:
297.1156.
2,2-Dimethyl-2,7-dihydropyrano[3,2-c]carbazole (11f)
Reaction of 10b (182 mg, 1.0 mmol) with 3-methylbut-2-enal (168
mg, 2.0 mmol) in refluxing p-xylene (10 mL) for 12 h afforded 11f.
Yield: 159 mg (64%); yellowish solid; mp 128–130 °C.
Synthesis 2012, 44, 2910–2918
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Pyranocarbazoles
2915
IR (KBr): 3388, 3044, 2768, 1611, 1448, 1389, 1324, 1207, 948,
790, 738, 647 cm–1.
112.2, 110.1, 102.4, 79.3, 41.7, 39.8, 26.9, 26.8, 25.8, 22.8, 17.8,
16.0.
1H NMR ((300 MHz, CDCl3): δ = 8.24 (d, J = 7.8 Hz, 1 H), 7.85 (br
s, 1 H, NH), 7.31–7.23 (m, 2 H), 7.16–7.11 (m, 1 H), 6.95 (d, J = 8.1
Hz, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 6.37 (d, J = 9.6 Hz, 1 H), 5.43
(d, J = 9.6 Hz, 1 H), 1.49 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 149.4, 141.3, 139.3, 126.5, 125.2,
124.6, 123.1, 122.9, 122.6, 119.6, 112.4, 112.3, 110.1, 102.5, 77.6,
28.5, 28.5.
HRMS (EI): m/z [M+] calcd for C27H31NO: 385.2406; found:
385.2403.
2-Phenyl-2,7-dihydropyrano[3,2-c]carbazole (11j)
Reaction of 10b (182 mg, 1.0 mmol) with cinnamaldehyde (132 mg,
1.0 mmol) in refluxing p-xylene (10 mL) for 8 h afforded 11j.
Yield: 181 mg (61%); brownish solid; mp 110–112 °C.
HRMS (EI): m/z [M+] calcd for C17H15NO: 249.1154; found:
249.1153.
IR (KBr): 3384, 3034, 2909, 1612, 1489, 1448, 1395, 1334, 1269,
1210, 1100, 956, 803, 742.
1H NMR (300 MHz, CDCl3): δ = 8.28 (d, J = 7.8 Hz, 1 H), 8.00 (br
s, 1 H, NH), 7.62 (d, J = 7.5 Hz, 2 H), 7.43–7.29 (m, 5 H), 7.24–7.19
(m, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 6.94 (d, J = 8.1 Hz, 1 H), 6.70
(d, J = Hz, 1 H 9.6 Hz), 6.23 (s, 1 H), 5.80 (dd, J = 9.9, 3.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 149.4, 141.7, 141.5, 139.3, 129.1,
128.7,128.7, 128.1, 126.7, 126.7, 125.3, 124.9, 124.6, 123.2,
122.3120.5, 119.8, 112.6, 111.9, 110.2, 103.1.
2-Methyl-2,7-dihydropyrano[3,2-c]carbazole (11g)
Reaction of 10b (182 mg, 1.0 mmol) with trans-crotonaldehyde
(140 mg, 2.0 mmol) in refluxing p-xylene (10 mL) for 12 h afforded
11g.
Yield: 139 mg (59%); greenish solid; mp 150–152 °C.
IR (KBr): 3360, 2958, 1704, 1620, 1446, 1358, 1223, 747 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.20 (d, J = 7.5 Hz, 1 H), 7.79 (br
s, 1 H, NH), 7.30- 7.19 (m, 2 H), 7.13 (dd, J = 7.2, 6.9 Hz, 1 H), 6.92
(d, J = 8.1 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 6.41 (d, J = 9.6 Hz, 1
H), 5.47 (dd, J = 9.9, 3 Hz, 1 H), 5.16–5.14 (m, 1 H), 1.49 (d, J = 6.3
Hz, 3 H).
13C NMR (75 MHz, CDCl3) δ = 149.7, 141.2, 139.1, 125.1, 124.6,
124.3, 123.0, 122.4, 122.3, 119.5, 112.9, 111.9, 109.9, 102.6, 71.9,
21.6.
HRMS (EI): m/z [M+] calcd for C21H15NO: 297.1154; found:
297.1151.
trans-2-Bromo-3,3-dimethyl-1,2,3,11-tetrahydropyrano[3,2-
a]carbazol-1-ol (14)
NBS (133 mg, 0.75 mmol) and H2O (0.5 mL) was added to a soln
of 11a (125 mg, 0.5 mmol) in dioxane (5 mL). After stirring of the
mixture at r.t. for 3 h, the excess solvent was removed in vacuo. The
mixture was extracted with EtOAc (3 × 10 mL) and washed with
brine (10 mL) and H2O (10 mL). The combined organic layer was
dried (Na2SO4). The solvent was removed in vacuo and the crude
product was purified by column chromatography (silica gel,
hexanes–EtOAc, 7:1) to give 14.
HRMS (EI): m/z [M+] calcd for C16H13NO: 235.0997; found:
235.0995.
2-Methyl-2-(4-methylpent-3-enyl)-2,7-dihydropyrano[3,2-
c]carbazole (11h)
Reaction of 10b (182 mg, 1.0 mmol) with citral (304 mg, 2.0 mmol)
in refluxing p-xylene (10 mL) for 12 h afforded 11h.
Yield: 95 mg (55%); off-white solid; mp 180–182 °C.
IR (KBr): 3457, 3416, 2986, 1776, 1696, 1606, 1459, 1386, 1163,
744 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 7.8 Hz, 1 H), 7.84 (d,
J = 8.4 Hz, 1 H), 7.80 (s, 1 H, NH), 7.36–7.27 (m, 2 H), 7.23–7.16
(m, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 5.83 (d, J = 9.6 Hz, 1 H), 5.26
(d, J = 9.6 Hz, 1 H), 2.92 (br s, 1 H, OH), 1.67 (s, 3 H), 1.42 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 151.5, 140.1, 136.6, 124.4,
122.7, 120.9, 119.4, 119.0, 117.3, 111.9, 109.9, 101.5, 77.9, 55.3,
50.6, 28.0, 19.5.
Yield: 250 mg (79%); reddish oil.
IR (neat): 3408, 2962, 2921, 1619, 1447, 1388, 1334, 1272, 1216,
1106, 913, 798, 744 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.22 (d, J = 7.8 Hz, 1 H), 7.90 (br
s, 1 H, NH), 7.29–7.27 (m, 2 H), 7.18–7.11 (m, 1 H), 6.94 (d, J = 7.8
Hz, 1 H), 6.77 (d, J = 8.1 Hz, 1 H), 6.40 (d, J = 10.2 Hz, 1 H), 5.39
(d, J = 9.9 Hz, 1 H), 5.06 (t, J = 7.2 Hz, 1 H), 2.20–2.14 (m, 2 H),
1.83–1.73 (m, 2 H), 1.54 (s, 3 H), 1.46 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 149.3, 141.1, 139.1, 131.5, 125.3,
124.9, 124.4, 124.1, 123.2, 122.9, 122.4, 119.3, 112.0, 111.9, 109.9,
102.2, 79.0, 41.5, 26.6, 25.5, 22.7, 17.4.
HRMS–FAB: m/z [M – H2O + H]+ calcd for C17H16BrNO2:
328.0337; found: 328.0334.
cis-3,3-Dimethyl-1,2,3,11-tetrahydropyrano[3,2-a]carbazole-
1,2-diol (15)
HRMS (EI): m/z [M+] calcd for C22H23NO: 317.1780; found:
Compound 11a (125 mg, 0.5 mmol) was added to stirred 4% aq soln
of OsO4 (0.31 mL, 10 mol%) and NMO (117 mg, 2.0 mmol) in t-
BuOH–THF–H2O (10:3:1, 10 mL) at 0 °C. The reaction mixture
was allowed to warm to r.t., and stirring was continued for 5 h. After
addition of a sat. aq soln of NaHSO3 (10 mL), the mixture was
stirred for an additional 1 h and then extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (30
mL), dried (Na2SO4), and evaporated under reduced pressure. The
crude product was purified by column chromatography (silica gel,
hexanes–EtOAc, 4:1) to give cis-diol 15.
317.1776.
2-(4,8-Dimethylnona-3,7-dienyl)-2-methyl-2,7-dihydropyra-
no[3,2-c]carbazole (11i)
Reaction of 10b (182 mg, 1.0 mmol) with trans,trans-farnesal (220
mg, 1.0 mmol) in refluxing p-xylene (10 mL) for 12 h afforded 11i.
Yield: 327 mg (85%); reddish oil.
IR (neat): 3405, 3039, 2957, 2920, 1709, 1618, 1444, 1347, 1218,
1099, 914, 798, 745, 658 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.30 (d, J = 7.8 Hz, 1 H), 7.92 (br
s, 1 H, NH), 7.36–7.32 (m, 2 H), 7.24–7.18 (m, 1 H), 7.01 (d, J = 7.8
Hz, 1 H), 6.84 (dd, J = 8.1, 1.5 Hz, 1 H), 6. 47 (d, J = 9.9 Hz, 1 H),
5.47 (d, J = 10.2 Hz, 1 H), 5.14 (t, J = 7.2 Hz, 1 H), 5.05 (t, J = 6.9
Hz, 1 H), 2.27 (t, J = 5.4 Hz, 2 H), 2.00 (t, J = 6.6 Hz, 2 H), 1.94–
1.83 (m, 4 H), 1.65 (s, 3 H), 1.56 (s, 3 H), 1.53 (s, 6 H).
Yield: 99 mg (70%); off-white solid; mp 160–162 °C.
IR (KBr): 3309, 3056, 2924, 1706, 1609, 1451, 1346, 1255, 1146,
1087, 922, 793, 738 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 9.89 (s, 1 H, NH), 7.95 (d,
J = 7.8 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 8.1 Hz, 1 H),
7.29–7.24 (m, 1 H), 7.13–7.08 (m, 1 H), 6.61 (d, J = 8.1 Hz, 1 H),
5.20 (dd, J = 8.1, 4.8 Hz, 1 H), 4.23 (d, J = 6.3 Hz, 1 H, OH), 4.14
(d, J = 8.4 Hz, 1 H, OH), 3.83 (dd, J = 5.4, 5.1 Hz, 1 H), 1.48 (s, 3
H), 1.32 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 149.6, 141.3, 139.3, 135.4, 131.4,
125.6, 125.2, 124.7, 124.5, 124.2, 123.4, 123.1, 122.6, 119.7, 112.3,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2910–2918

2916
R. P. Pandit, Y. R. Lee
PAPER
13C NMR (75 MHz, actone-d6): δ = 152.6, 141.0, 124.8, 124.8,
124.3, 121.0, 119.8, 119.7, 117.5, 111.8, 110.2, 106.1, 78.5, 72.0,
65.1, 24.5, 24.3.
HRMS (EI): m/z [M+] calcd for C17H17NO3: 283.1208; found:
283.1207.
uct was purified by column chromatography (silica gel, hexanes–
EtOAc, 7:1) to give 18.
Yield: 99 mg (55%); off-white solid; mp 228–230 °C.
IR (KBr): 3469, 2982, 2935, 1710, 1591, 1452, 1354, 1212, 1154,
1007, 815, 752 cm–1.
cis-3,3-Dimethyl-1,2,3,11-tetrahydropyrano[3,2-a]carbazole-
1,2-diol (15) and trans-3,3-Dimethyl-1,2,3,11-tetrahydropyra-
no[3,2-a]carbazole-1,2-diol (16)
A 0.052 M soln of DMDO in acetone (2.8 mL, 1.0 mmol) was added
to a soln of 11a (125 mg, 0.5 mmol) in wet acetone (5 mL) at r.t.
The mixture was stirred at r.t. for 4 h and concentrated under re-
duced pressure. The resulting residue was purified by flash column
chromatography (silica gel, hexanes–EtOAc, 3:1) to give cis-diol
15 and trans-diol 16 .
1H NMR (300 MHz, acetone-d6): δ = 7.97–7.92 (m, 2 H), 7.38–7.33
(m, 2 H), 7.14–7.20 (m, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 6.26 (d,
J = 9.3 Hz, 1 H), 4.70 (d, J = 9.3 Hz, 1 H), 3.72(s, 3 H), 2.80 (br s,
1 H, OH), 1.62 (s, 3 H), 1.58 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 177.6, 154.8, 144.1, 125.4,
121.9, 121.0, 120.6, 120.0, 119.7, 119.5, 111.4, 110.6, 103.9, 78.5,
57.6, 53.0, 34.5, 18.3, 18.1.
HRMS–FAB: m/z [M – H2O + H]+ calcd for C18H18BrNO2:
342.0494; found: 342.0493.
Yield (cis-diol 15): 73 mg (52%); yield (trans-diol 16): 40 mg,
(28%).
cis-3,3,11-Trimethyl-1,2,3,11-tetrahydropyrano[3,2-a]carba-
zole-1,2-diol (19)
trans-Diol 16
Off-white solid; mp 70–72 °C.
Compound 17 (132 mg, 0.5 mmol) was added to stirred 4% aq soln
of OsO4 (0.31 mL, 10 mol%) and NMO (117 mg, 2.0 mmol) in t-
BuOH–THF–H2O (10:3:1, 10 mL) at 0 °C. The reaction mixture
was allowed to warm at r.t., and stirring was continued for 5 h. After
addition of a sat. aq soln of NaHSO3 (10 mL), the mixture was
stirred for an additional 1 h and then extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (30
mL), dried (Na2SO4), and evaporated under reduced pressure. The
crude product was purified by column chromatography (silica gel,
hexanes–EtOAc, 4:1) to give cis-diol 19.
IR (KBr): 3436, 2961, 2926, 1711, 1613, 1459, 1308, 1221, 1021,
745 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 9.77 (s, 1 H, NH), 7.82 (d,
J = 7.8 Hz, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H),
7.13 (t, J = 8.1 Hz, 1 H, 1 H), 6.97 (dd, J = 8.1, 7.8 Hz, 1 H), 6.49
(d, J = 8.4 Hz, 1 H), 4.79 (d, J = 8.1 Hz, 1 H), 4.60 (br s, 1 H, OH),
4.34 (br s, 1 H, OH), 3.63 (d, J = 8.1 Hz, 1 H), 1.34 (s, 3 H), 1.10 (s,
3 H).
13C NMR (75 MHz, acetone-d6): δ = 152.2, 141.0, 140.5, 124.8,
124.1, 121.1, 119.8, 119.7, 117.6, 111.8, 110.1, 107.5, 79.6, 77.4,
69.8, 27.2, 19.2.
HRMS (EI): m/z [M+] calcd for C17H17NO3: 283.1208; found:
283.1205.
Yield: 110 mg (74%); off-white solid; mp 178–180 °C.
IR (KBr): 3424, 2930, 2882, 1590, 1452, 1336, 1217, 1114, 1070,
997, 739 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 7.97 (d, J = 7.5 Hz, 1 H), 7.92
(d, J = 8.4 Hz, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 7.35 (dd, J = 8.1, 7.2
Hz, 1 H), 7.15 (dd, J = 7.8, 7.2 Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H),
5.39 (t, J = 4.5 Hz, 1 H), 4.66 (d, J = 6.3 Hz, 1 H), 4.24 (s, 3 H), 4.21
(d, J = 4.2 Hz, 1 H), 3.94 (dd, J = 6.0, 5.1 Hz, 1 H), 1.46 (s, 3 H),
1.45 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 153.4, 142.9, 125.3, 125.3,
124.2, 122.0, 120.2, 119.8, 119.7, 118.3, 111.3, 109.9, 77.7, 73.3,
63.7, 32.0, 27.5, 21.9, 21.9.
3,3,11-Trimethyl-3,11-dihydropyrano[3,2-a]carbazole (17)
NaH (60% dispersion in mineral oil, 300 mg, 7.5 mmol) was added
portionwise to a stirred soln of 11a (1.245 g, 5.0 mmol) in DMF (30
mL) at 0 °C, and the mixture was then stirred for 30 min; dropwise
addition of MeI (0.34 mL, 5.5 mmol) followed. The reaction mix-
ture was stirred for an additional 30 min, and then quenched with ice
water (30 mL). The mixture was extracted with EtOAc (3 × 30 mL)
and washed with a sat. aq soln of NH4Cl (50 mL) and H2O (30 mL).
The combined organic layer was dried (Na2SO4). The solvent was
removed in vacuo and the crude product was purified by column
chromatography (silica gel, hexanes–EtOAc, 20:1) to give 17.
HRMS (EI): m/z [M+] calcd for C18H19NO3: 297.1365; found:
297.1361.
trans-3-Bromo-2,2-dimethyl-2,3,4,7-tetrahydropyrano[3,2-
c]carbazol-4-ol (20)
Yield: 1.249 g (95%); off-white solid; mp 160–162 °C.
NBS (133 mg, 0.75 mmol) and H2O (0.5 mL) was added to a soln
of 11f (125 mg, 0.5 mmol) in dioxane (5 mL). After the mixture had
stirred at r.t. for 3 h, the excess solvent was removed in vacuo. The
mixture was extracted with EtOAc (3 × 10 mL) and washed with
brine (10 mL) and H2O (10 mL). The combined organic layer was
dried (Na2SO4). The solvent was removed in vacuo and the crude
product was purified by column chromatography (silica gel,
hexanes–EtOAc, 7:1) to give 20.
IR (KBr): 3051, 2970, 2928, 1632, 1584, 1463, 1401, 1342, 1213,
1114, 1012, 820, 736 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.92 (d, J = 7.5 Hz, 1 H), 7.80 (d,
J = 8.4 Hz, 1 H), 7.39–7.29 (m, 2 H), 7.20–7.12 (m, 2 H), 6.74 (d,
J = 8.1 Hz, 1 H), 5.66 (d, J = 9.9 Hz, 1 H), 4.01 (s, 3 H), 1.48 (s, 6
H).
13C NMR (75 MHz, CDCl3): δ = 152.7, 141.8, 137.6, 128.7, 124.6,
123.2, 120.6, 119.4, 119.2, 118.7, 118.1, 109.8, 108.4, 106.3, 75.1,
33.0, 27.2, 27.2.
Yield: 102 mg (59%); off-white solid; mp 172–174 °C.
IR (KBr): 3402, 2982, 1776, 1705, 1612, 1497, 1450, 1374, 1157,
733 cm–1.
HRMS (EI): m/z [M+] calcd for C18H17NO: 263.1310; found:
1H NMR (300 MHz, CDCl3): δ = 8.11 (d, J = 7.8 Hz, 1 H), 7.99 (s,
1 H, NH), 7.25–7.22 (m, 2 H), 7.14–7.08 (m, 1 H), 6.76 (d, J = 8.1
Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 5.63 (d, J = 10.8 Hz, 1 H), 5.14
(d, J = 10.8 Hz, 1 H), 2.80 (br s, 1 H, OH), 1.73 (s, 3 H), 1.44 (s, 3
H).
13C NMR (75 MHz, CDCl3): δ = 148.9, 140.5, 138.9, 125.2, 122.9,
122.6, 122.1, 119.6, 112.3, 110.0, 108.4, 104.0, 79.5, 53.4, 53.0,
29.1, 19.1.
263.1309.
trans-2-Bromo-3,3,11-trimethyl-1,2,3,11-tetrahydropyra-
no[3,2-a]carbazol-1-ol (18)
NBS (133 mg, 0.75 mmol) and H2O (0.5 mL) was added to a soln
of 17 (132 mg, 0.5 mmol) in dioxane (5 mL). After the mixture had
stirred at r.t. for 3 h, the excess solvent was removed in vacuo. The
mixture was extracted with EtOAc (3 × 10 mL) and washed with
brine (10 mL) and H2O (10 mL). The combined organic layer was
dried (Na2SO4). The solvent was removed in vacuo and crude prod-
Synthesis 2012, 44, 2910–2918
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Pyranocarbazoles
2917
HRMS–FAB: m/z [M – H2O + H]+ calcd for C17H16BrNO2:
328.0337; found: 328.0334.
was dried (Na2SO4). The solvent was removed in vacuo and the
crude product was purified by column chromatography (silica gel,
hexanes–EtOAc, 20:1) to give 23.
cis-2,2-Dimethyl-2,3,4,7-tetrahydropyrano[3,2-c]carbazole-3,4-
diol (21)
Yield: 1.279 g (97%); off-white solid; mp 50–52 °C.
1H NMR (300 MHz, CDCl3): δ = 8.24 (d, J = 7.5 Hz, 1 H), 7.30 (t,
J = 8.4 Hz, 1 H), 7.19–7.07 (m, 2 H), 6.96 (d, J = 8.1 Hz, 1 H), 6.70
(d, J = 8.1 Hz, 1 H), 6.35 (d, J = 9.9 Hz, 1 H), 5.39 (d, J = 9.9 Hz, 1
H), 3.60 (s, 3 H), 1.46 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 149.8, 143.1, 141.1, 126.7, 125.3,
124.7, 123.4, 123.3, 122.5, 119.4, 112.4, 111.9, 108.2, 100.7, 77.8,
29.5, 28.8, 28.8.
Compound 11f (125 mg, 0.5 mmol) was added to a stirred 4% aq
soln of OsO4 (0.31 mL, 10 mol%) and NMO (117 mg, 2.0 mmol) in
t-BuOH–THF–H2O (10:3:1, 10 mL) at 0 °C. The reaction mixture
was allowed to warm to r.t., and stirring was continued for 5 h. After
addition of a sat. aq soln of NaHSO3 (10 mL), the mixture was
stirred for an additional 1 h and then extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (30
mL), dried (Na2SO4), and evaporated under reduced pressure. The
crude product was purified by column chromatography (silica gel,
hexanes–EtOAc, 4:1) to give cis-diol 21.
HRMS (EI): m/z [M+] calcd for C18H17NO: 263.1310; found:
263.1308.
Yield: 95 mg (67%); brownish solid; mp 100–112 °C.
3-Bromo-2,2,7-trimethyl-2,3,4,7-tetrahydropyrano[3,2-c]car-
bazol-4-ol (24)
IR (KBr): 3429, 2979, 1694, 1468, 1338, 1253, 1145, 1109, 750
cm–1.
NBS (133 mg, 0.75 mmol) and H2O (0.5 mL) was added to a soln
of 23 (132 mg, 0.5 mmol) in dioxane (5 mL). After the mixture had
stirred at r.t. for 3 h, the excess solvent was removed in vacuo. The
mixture was extracted with EtOAc (3 × 10 mL) and washed with
brine (10 mL) and H2O (10 mL). The combined organic layer was
dried (Na2SO4). The solvent was removed in vacuo and the crude
product was purified by column chromatography (silica gel,
hexanes–EtOAc, 7:1) to give 24.
1H NMR (300 MHz, acetone-d6): δ = 10.2 (s, 1 H, NH), 8.24 (d,
J = 7.5 Hz, 1 H), 7.47–7.42 (m, 2 H), 7.33–7.27 (m, 1 H), 7.16–7.10
(m, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 4.96 (dd, J = 6.6, 4.5 Hz, 1 H),
4.15 (d, J = 7.5 Hz, 1 H, OH), 4.00 (d, J = 5.7 Hz, 1 H, OH), 3.85
(dd, J = 5.7, 4.5 Hz, 1 H), 1.61 (s, 3 H), 1.45 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 149.8, 142.0, 140.4, 127.6,
125.2, 123.6, 123.6, 119.5, 113.5, 112.2, 111.0, 104.1, 78.8, 72.4,
65.8, 25.3, 24.5.
Yield: 83 mg (46%); off-white solid; mp 205–207 °C.
IR (KBr): 3471, 2979, 1711, 1601, 1488, 1368, 1283, 1155, 998,
801, 746 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 8.26 (d, J = 7.8 Hz, 1 H),
7.51–7.40 (m, 2 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.07–7.02 (m, 2 H),
5.71 (d, J = 10.8 Hz, 1 H), 5.31 (d, J = 10.8 Hz, 1 H), 3.85 (s, 3 H),
2.95 (br s, 1 H, OH), 1.86 (s, 3 H), 1.58 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ = 149.9, 143.3, 141.9, 126.2,
124.4, 123.8, 122.7, 120.2, 112.4, 110.1, 109.6, 103.5, 80.5, 54.6,
54.0, 29.0, 29.0, 19.6.
HRMS (EI): m/z [M+] calcd for C17H17NO3: 283.1208; found:
283.1205.
cis-2,2-Dimethyl-2,3,4,7-tetrahydropyrano[3,2-c]carbazole-3,4-
diol (21) and trans-2,2-Dimethyl-2,3,4,7-tetrahydropyrano[3,2-
c]carbazole-3,4-diol (22)
A 0.052 M soln of DMDO in acetone (2.8 mL, 1.0 mmol) was added
to a soln of 11f (125 mg, 0.5 mmol) in wet acetone (5 mL) at r.t. The
mixture was stirred at r.t. for 4 h and concentrated under reduced
pressure. The resulting residue was purified by flash column chro-
matography (silica gel, hexanes–EtOAc, 3:1) to give cis-diol 21 and
trans-diol 22.
HRMS–FAB: m/z [M – H2O + H]+ calcd for C18H18BrNO2:
342.0494; found: 342.0492.
Yield (cis-diol 21): 73 mg (52%); yield (trans-diol 22): 36 mg
(26%).
2,2,7-Trimethyl-2,3,4,7-tetrahydropyrano[3,2-c]carbazole-3,4-
diol (25)
Compound 23 (132 mg, 0.5 mmol) was added to a stirred 4% aq
soln of OsO4 (0.31 mL, 10 mol%) and NMO (117 mg, 2.0 mmol) in
t-BuOH–THF–H2O (10:3:1, 10 mL) at 0 °C. The reaction mixture
was allowed to warm to r.t., and stirring was continued for 5 h. After
addition of a sat. aq soln of NaHSO3 (10 mL), the mixture was
stirred for an additional 1 h and then extracted with EtOAc (3 × 10
mL). The combined organic layers were washed with brine (30
mL), dried (Na2SO4), and evaporated under reduced pressure. The
crude product was purified by column chromatography (silica gel,
hexanes–EtOAc, 4:1) to give cis-diol 25.
trans-Diol 22
Off-white solid; mp 122–125 °C.
IR (KBr): 3042, 2971, 2927, 1711, 1626, 1465, 1331, 1292, 1125,
995, 789, 744 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 10.24 (s, 1 H, NH), 8.24 (d,
J = 7.8 Hz, 1 H), 7.50–7.43 (m, 2 H), 7.31 (dd, J = 9.3, 7.2 Hz, 1 H),
7.13 (t, J = 8.1 Hz, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 4.68 (d, J = 7.8
Hz, 1 H), 4.56 (br s, 1 H, OH), 4.36 (br s, 1 H, OH), 3.70 (d, J = 8.1
Hz, 1 H), 1.64 (s, 3 H), 1.34 (s, 3 H).
13C NMR (75 MHz, actone-d6): δ =149.2, 141.9, 140.4, 126.5,
125.2, 123.4, 123.4, 119.4, 115.1, 112.1, 111.0, 104.0, 79.7, 77.1,
70.1, 27.4, 19.9.
HRMS (EI): m/z [M+] calcd for C17H17NO3: 283.1208; found:
283.1207.
Yield: 101 mg (68%); off-white solid; mp 140–142 °C.
IR (KBr): 3429, 2979, 2930, 1694, 1633, 1605, 1468, 1338, 1253,
1145, 1109, 1041, 788, 750 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.28 (d, J = 7.8 Hz, 1 H), 7.55 (d,
J = 8.4 Hz, 1 H), 7.47–7.36 (m, 2 H), 7.20–7.14 (m, 1 H), 4.98 (d,
J = 3.3 Hz, 1 H), 4.23 (br s, 1 H, OH), 4.05 (br s, 1 H, OH), 3.85 (s,
3 H), 3.84 (d, J = 3.3 Hz, 1 H), 1.62 (s, 3 H), 1.44 (s, 3 H).
13C NMR (75 MHz, acetone-d6): δ =149.9, 143.1, 141.4, 127.7,
125.3, 123.6, 123.2, 119.6, 113.8, 111.5, 109.0, 102.0, 78.9, 72.4,
65.8, 25.3, 25.3, 24.4.
2,2,7-Trimethyl-2,7-dihydropyrano[3,2-c]carbazole (23)
NaH (60% dispersion in mineral oil, 300 mg, 7.5 mmol) was added
portionwise to a stirred soln of 11f (1.245 g, 5.0 mmol) in DMF (30
mL) at 0 °C, and the mixture was stirred for 30 min before dropwise
addition of MeI (0.34 mL, 5.5 mmol). The reaction mixture was
stirred for an additional 30 min, and then quenched with ice water
(30 mL). The mixture was extracted with EtOAc (3 × 30 mL), sat.
aq NH4Cl (50 mL), and H2O (30 mL). The combined organic layer
HRMS (EI): m/z [M+] calcd for C18H19NO3: 297.1365; found:
297.1363.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2910–2918

2918
R. P. Pandit, Y. R. Lee
PAPER
(12) Adebajo, A. C.; Ayoola, O. F.; Iwalewa, E. O.; Akindahunsi,
A. A.; Omisore, N. O. A.; Adewunmi, C. O. Adenowo T. K.
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Acknowledgment
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2012009620).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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Synthesis 2012, 44, 2910–2918
© Georg Thieme Verlag Stuttgart · New York