Azide-mediated detosylation of N-tosylpyrroloiminoquinones and N-tosylindole-4,7-quinones

Article abstract of DOI:10.1055/s-0028-1083570

The utility of NaN₃ as a reagent for the detosylation of N-tosylpyrroloiminoquinones and N-tosylindole-4,7-quinones is described. The NaN₃-mediated detosylation is carried out in polar aprotic solvents such as DMF and DMSO. The reaction occurs under neutral, mild conditions and results in good to excellent yields of the detosylated quinones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083570

2864
LETTER
Azide-Mediated Detosylation of N-Tosylpyrroloiminoquinones and
N-Tosylindole-4,7-quinones
Detosylation
o
w
f
N
-Tosylpyrroloim
a
inoquinon
y
es and
N
-Tos
a
ylindole-4
m
,7-quinones prabha P. Patel, Dwayaja H. Nadkarni, Srinivasan Murugesan, Jason R. King, Sadanandan E. Velu*
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, AL 35294, USA
Fax +1(205)9342543; E-mail: svelu@uab.edu
Received 28 April 2008
atom of the quinone system. The tosyl group is one of the
most commonly used N-protecting groups used in the syn-
thesis of these alkaloids. A few such alkaloids are makalu-
Abstract: The utility of NaN3 as a reagent for the detosylation of N-
tosylpyrroloiminoquinones and N-tosylindole-4,7-quinones is de-
scribed. The NaN3-mediated detosylation is carried out in polar
aprotic solvents such as DMF and DMSO. The reaction occurs un-
vamine D,18 discorhabdin C,19 and secobatzelline B.20
A
der neutral, mild conditions and results in good to excellent yields few of N-tosylpyrroloiminoquinone and N-tosylindole-
of the detosylated quinones.
4,7-quinone intermediates reported in the synthesis of
these marine alkaloids are given in Figure 1.
Key words: sodium azide, detosylation, quinones, indoloquinone,
pyrroloiminoquinones.
O
Br
Br
N
HO
N
Protection and deprotection strategies of reactive func-
tional groups are extensively used in organic synthesis,
particularly in multistep organic synthesis of natural prod-
ucts. Amine is a common reactive functional group, which
often requires protection during an organic synthesis.
Common protecting groups used for amines are carbam-
ates and amides including sulfonamides.1 Indole is a
heterocyclic structural unit present in many biologically
important organic molecules and natural products. More
often, indole nitrogen needs to be protected during a syn-
thesis.2 The tosyl (p-toluene sulfonyl) group is a common-
ly used protecting group in the synthesis of indole and
related alkaloids.3,4 Removal of the tosyl group is often
accomplished by using strongly basic reagents such as
NaOH,5 NaOMe, and thioglycolate.6
N
R
N
H
N
R
N
H
O
O
R = H: makaluvamine D (1)
R = Ts: N-tosyl derivative (2)
R = H: discorhabdin C (3)
R = Ts: N-tosyl derivative (4)
HO
O
O
OH
Cl
N
H2N
R
R = H: secobatzelline B (5)
R = Ts: N-tosyl derivative (6)
Figure 1 N-Tosyl-protected derivatives of pyrroloiminoquinone
and indole-4,7-quinone alkaloids
The tosyl group is particularly useful in protecting the N
atom of present indoloquinones and pyrroloiminoquino-
nes that are useful intermediates in the synthesis of many
biologically active marine alkaloids.7,8 Recently, pyrro-
loiminoquinone alkaloids have received increased atten-
tion for their anticancer activities.9–12 A few important
members of this alkaloid family are discorhabdins,13 pria-
nosins,14 makaluvamines,15 and isobatzellines.16 This
class of alkaloids has a unique tricyclic pyrroloimino-
quinone ring structure.15 The interesting fused three-ring
structure coupled with potent biological properties such as
topoisomerase II inhibition and cytotoxicities have made
these alkaloids targets for a large number of synthetic
studies.17 Syntheses of these alkaloids involving several
steps are reported in the literature. Many of these synthe-
ses involve sensitive intermediates such as indole-4,7-
quinones and pyrroloiminoquinones.17 These synthetic in-
termediates almost always have a protection on the N
Removal of the tosyl group (detosylation) from these in-
termediates is a key step in the syntheses of these alka-
loids, which is often accomplished by the use of
traditional reagents such as NaOH, NaOMe, NH3, amines,
etc. In Cava’s synthesis of makaluvamine D detosylation
is carried out by using amines.18 In Heathcock’s synthesis
of discorhabdin C7 synthesis and in Velu’s synthesis of
secobatzelline B20 detosylation is carried out by using a
stronger base (NaOMe).
As a part of our work on analogues of marine natural prod-
ucts with potential pharmacological value, we have been
interested in studying the anticancer activity of makaluv-
amines and their analogues. We have synthesized makalu-
vamine analogues with substituents at the 7-position of
the pyrroloiminoquinone ring and studied their effects on
topoisomerase II inhibition and the anticancer activity.21,22
The synthesis of makaluvamine analogues makes use of a
reported18 N-tosylpyrroloiminoquinone as a key interme-
diate from which desired compounds were prepared by
SYNLETT 2008, No. 18, pp 2864–2868
1
4
.1
1
.2
0
0
8
Advanced online publication: 21.10.2008
DOI: 10.1055/s-0028-1083570; Art ID: S03608ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Detosylation of N-Tosylpyrroloiminoquinones and N-Tosylindole-4,7-quinones
2865
substitution with appropriate amines. After the introduc-
tion of substituents at the 7-position, we needed to detosy-
late the intermediates to obtain the final products of our
interest. Our detosylation reactions of these intermediates
using traditional reagents (NaOH, NaOMe, and NH4OH)
were complicated by the formation of side products and
always resulted in low yields. Similar difficulties in deto-
sylation of N-tosylpyrroloiminoquinones have been re-
ported in the past in the case of a pyrroloiminoquinone
alkaloid analogue synthesis.23 In this particular literature
report, the detosylation was carried out in 5–20% yields
using the reagent TBAF.23 To circumvent this problem,
we were interested in developing more effective methods
for detosylation that could work under milder reaction
conditions.
Table 1 Sodium Azide Mediated Detosylation of N-Tosylpyrro-
loiminoquinones in N,N-Dimethylformamide
N
N
NaN3, solvent
25 °C, 4 h
N
N
H
R
R
Ts
O
O
7a–d
8a–d
Entry 7, 8 R
Solvent Time Yielda
(h)
(%)
1
2
DMF
DMF
4
4
83
84
a
OMe
3
4
5
6
DMSO
MeOH
THF
4
48
48
4
64
25
b
NRb
98
NHCH2
F
While experimenting for milder reaction conditions for
detosylation of N-tosylpyrroloiminoquinones, we have
discovered that treatment of N-tosylpyrroloiminoquinone
7a with sodium azide in DMF effected this deprotection
very efficiently in good yields (83%) to afford the product
8a (Table 1). The byproduct, p-toluenesulfonyl azide,
formed in this reaction was also isolated and character-
ized.
DMF
7
8
9
DMSO
hexane
DMF
4
48
4
74
NHCH2CH2
NHCH2CH2
c
NRb
88
O
O
10
11
12
MeOH
THF
hexane
48
48
48
53
OMe
OMe
d
30
NRb
This detosylation reaction was very clean yielding only
the expected product. The reaction is carried out at room
temperature under mild conditions. It does not require
strongly basic reaction conditions as the commonly used
reagents. Sodium azide is a neutral reagent making it es-
pecially useful for the deprotection of N-tosylpyrroloimi-
noquinones containing base-sensitive groups. We also
have examined the detosylation of other 7-amino-substi-
tuted pyrroloiminoquinones 7b–d in a variety of polar
protic, polar aprotic, and nonpolar solvents. The deprotec-
tion proceeded well in highly polar aprotic solvents such
as DMF and DMSO (Table 1, entries 1–3, 6, 7, and 9, in
a Isolated yields.
b NR = no reaction.
resulting in the expected deprotection (entries 15 and 17).
We have also noticed that the reaction is not moisture sen-
sitive. It works in moist solvents just as well as in anhy-
drous solvents (entries 3, 4, and 12). Detosylation can be
carried out selectively in the presence of other protecting
groups such as N-Ac (entries 6 and 7) and N-Boc (entry
23) groups.
64–98% yield). The reaction did not work in a less polar This NaN3-mediated detosylation is selective to quinone
solvent such as THF in the case of a 4-fluorobenzyl deriv- systems described here. It does not work for the deprotec-
ative (entry 5). In the case of dimethoxyphenethyl deriva- tion of regular N-tosylindoles. For example, treatment of
tive the reaction in THF worked in poor yield taking
longer reaction time (entry 11, 30%, 48 h). In polar protic
solvent such as MeOH the reaction took longer time (48
h) yielding moderate yields (entries 4 and 10). Nonpolar
solvents such as hexane was not favored for this reaction
(entries 8 and 12).
N-tosyl-4,6,7-trimethoxyindole (9) with NaN3 in DMF at
room temperature as well as at 100 °C for 12 hours did not
result in detosylation (Table 3).
In conclusion, a novel efficient protocol for the detosyla-
tion of N-tosylpyrroloiminoquinones and N-tosylindole-
4,7-quinones using a neutral reagent (NaN3) has been dis-
covered. The scope of this deprotection procedure is ex-
plored on a series of N-tosylpyrroloiminoquinone and N-
To examine the generality of this detosylation procedure,
we extended the study to a series of N-tosylindole-4,7-
quinones. The results of azide-mediated detosylation of tosylindole-4,7-quinone derivatives. The reaction is fa-
N-tosylindole-4,7-quinones are summarized in Table 2. vored in highly polar aprotic solvents such as DMF and
All detosylation reactions of N-tosylindole-4,7-quinones DMSO. It does not work or works in poor yields in polar
using NaN3 in polar aprotic solvents worked well with the protic or less polar solvents. The reaction does not work
purified yield of the products ranging from 82–98%. The in nonpolar solvents. The reaction is selective to N-tosyl-
reaction is favored in highly polar aprotic solvents such as indoloquinone systems. This detosylation procedure does
DMF and DMSO as shown in the cases of several exam- not work for N-tosylindoles, and may therefore be used
ples in Table 2. The reaction does not work in polar protic for the selective deprotection of N-tosylindoloquinone
solvents (MeOH, entries 5 and 16), less polar aprotic sol- groups in the presence of other N-tosyl protecting groups.
vents (THF, entries 8 and 14), or nonpolar solvents (hex-
anes, entry 20). Reactions in solvents such as MeOH and
THF were also attempted at reflux temperatures without
Further work is in progress to apply this methodology in
the synthesis of several other makaluvamine analogues.
Synlett 2008, No. 18, 2864–2868 © Thieme Stuttgart · New York

2866
S. P. Patel et al.
LETTER
Table 2 Sodium Azide Mediated Detosylation of N-Tosylindole-4,7-quinones
Entry
Substrate
Solvent
Time (h) Temp (°C) Product
Yield (%)a
O
O
O
1
2
3
4
5
DMF
DMSO
DMSO–H2O
DMF–H2O
MeOH
4
4
4
4
4
25
25
25
25
25
82
86
93
91
N
H
MeO
N
MeO
NRb
Ts
O
O
10
Ph
Ph
O
N
N
6
7
8
DMF
DMSO
THF
4
4
4
25
25
25
92
COMe
COMe
91
NRb
N
H
MeO
N
MeO
O
Ts
O
11
O
O
9
10
DMF
DMSO
4
4
25
25
94
83
Et
N
Et
N
N
N
H
H
O
Ts
H
O
O
12
11
12
13
14
15
16
17
4
4
4
4
12
4
25
25
25
25
65
25
64
88
91
94
DMF
O
O
DMF–H2O
DMSO
THF
THF
MeOH
MeOH
NRb
NRb
NRb
NRb
Bn
N
H
Bn
N
H
N
N
H
Ts
O
12
13
O
O
O
O
18
19
20
DMF
DMSO
hexanes
4
4
4
25
25
25
94
95
NRb
N
H
N
N
N
H
Ts
H
14
HO
O
HO
O
21
22
DMF
DMSO
4
4
25
25
84
82
N
H
N
H
N
N
O
Ts
H
O
15
O
O
O
NHBoc
NHBoc
23
DMF
4
25
93
N
MeO
N
MeO
H
O
Ts
16
a Yields reported are of isolated products characterized by 1H NMR and 13C NMR spectroscopy.
b NR = no reaction.
Synlett 2008, No. 18, 2864–2868 © Thieme Stuttgart · New York

LETTER
Detosylation of N-Tosylpyrroloiminoquinones and N-Tosylindole-4,7-quinones
2867
spot. Solvent was completely removed under high vacuum, and the
crude product was dissolved in CHCl3. The CHCl3 solution was
washed with H2O (3 × 10 mL) and brine (3 × 10 mL). Removal of
solvent from the dried (Na2SO4) extract afforded the crude product,
which was further purified by column chromatography over silica
gel to obtain the pure detosylated products 10–16.
Table 3 Attempted Detosylation of N-Tosyl-4,6,7-trimethoxy-
indole N-Tosylindole Using NaN3
OMe
OMe
OMe
NaN3
DMF
N
N
MeO
MeO
Ts
H
6-Methoxy-1H-indole-4,7-dione (10)
OMe
1H NMR (DMSO-d6): d = 3.77 (s, 3 H), 5.81 (s, 1 H), 6.47–6.49 (t,
1 H, J = 2.1 Hz), 7.25–7.27 (t, 1 H, J = 2.7 Hz), 12.75 (br s, 1 H).
13C NMR (DMSO-d6): d = 56.9, 107.6, 107.7, 126.7, 128.1, 129.7,
160.4, 171.3, 183.5. MS (ES+): m/z = 178 [M + H]. HRMS (EI, 70
ev): m/z calcd for C9H7NO3: 177.0425 [M+]; found: 177.0424.
9
Entry
Temp (°C)
25
Time (h)
Yield (%)
no reaction
no reaction
1
2
4
100
12
N-[(6-Methoxy-4,7-dioxo-4,7-dihydro-1H-indol-3-yl)methyl]-
N-phenylacetamide (11)
1H NMR (CD3OD): d = 1.78 (s, 3 H), 3.68 (s, 3 H), 5.00 (s, 2 H),
5.50 (s, 1 H), 7.02–7.07 (m, 3 H), 7.23–7.27 (m, 3 H). 13C NMR
(CD3OD): d = 21.2, 43.5, 55.7,106.8, 121.4, 126.9, 127.7, 127.8,
127.9, 129.2, 129.3 (2 C),142.4, 160.0, 171.5, 184.4. MS (ES+):
m/z = 325 [M + H].
General Methods for Synthesis
Solvent evaporations were carried out in vacuo on a rotary evapora-
tor. Thin layer chromatography (TLC) was performed on silica gel
plates with fluorescent indicator (Whatmann, silica gel, UV254, 25
mm plates). Spots were visualized by UV light (l = 254 and 365
nm). Purification by column and flash chromatography was carried
out using ‘BAKER’ silica gel (40 mm) in the solvent systems indi-
cated. Proton nuclear magnetic resonance (1H NMR) and carbon
nuclear magnetic resonance (13C NMR) spectra were recorded on a
Bruker DPX-300 spectrometer. The values of chemical shifts (d) are
given in ppm and coupling constants (J) in Hz. The chemical-shift
values are reported as parts per million (ppm) relative to tetrameth-
ylsilane (TMS) as internal standard. Mass spectra were recorded on
Micromass Platform LCC instrument. HRMS were recorded on
AutoSpec-UltimaTMNT instrument.
6-(Ethylamino)-1H-indole-4,7-dione (12)
1H NMR (DMSO-d6): d = 1.11–1.16 (t, 3 H, J = 7.2 Hz), 3.07–3.16
(p, 2 H, J = 7.2 Hz), 5.09 (s, 1 H), 6.38–6.39 (t, 1 H, J = 2.1 Hz),
7.06–7.10 (t, 1 H, J = 6 Hz), 7.21–7.23 (t, 1 H, J = 2.7 Hz), 12.59
(br s, 1 H). 13C NMR (DMSO-d6): d = 13.4, 37.3, 96.2, 107.9, 128.5
(2 C), 129.2, 148.9, 172.4, 182.2. MS (ES+): m/z = 191 [M + H].
HRMS (EI, 70 ev): m/z calcd for C10H10N2O2: 190.0742 [M+];
found: 190.0738.
6-(Benzylamino)-1H-indole-4,7-dione (13)
1H NMR (DMSO-d6): d = 4.35–4.37 (d, 2 H, J = 6.3 Hz), 5.00 (s,
1 H), 6.37 (s, 1 H), 7.22–7.33 (m, 6 H), 7.77–7.81 (t, 1 H, J = 6.3
Hz), 12.64 (br s, 1 H). 13C NMR (DMSO-d6): d = 45.9, 97.6, 107.9,
127.4, 127.5 (2 C), 128.5 (2 C), 128.9 (2 C), 138.2, 148.9, 172.5,
182.2. MS (ES+): m/z = 253 [M + H]. HRMS (EI, 70 ev): m/z calcd
for C15H12N2O2: 252.0899 [M+]; found: 252.0901.
Detosylation of N-Tosylpyrroloiminoquinones – General Proce-
dure
A solution of N-tosylpyrroloiminoquinone derivative (7a–d, 0.5
mmol) in DMF (2 mL) was stirred with NaN3 (0.6 mmol, 1.2 equiv)
at r.t. for 4 h. TLC examination (in 10% MeOH in CHCl3) at this
point revealed that the reaction is complete with the formation of
only one new product spot. Solvent was completely removed under
high vacuum, and the crude product was suspended in CH2Cl2. The
precipitated solid was filtered to obtain the crude product. The crude
product was further purified by column chromatography over silica
gel to obtain the pure detosylated product 8a–d in 83–98% yield. 1H
NMR, 13C NMR, and MS spectral data of 8b–d products were found
to be identical to previously reported data.22 Spectral data of com-
pound 8a are given below.
6-(Phenethylamino)-1H-indole-4,7-dione (14)
1H NMR (DMSO-d6): d = 2.87 (t, 2 H, J = 7.8 Hz), 3.33 (m, 2 H),
5.18 (s, 1 H), 6.40 (d, 1 H, J = 2.4 Hz), 7.11 (t, 1 H, J = 6.0 Hz),
7.20–7.31 (m, 7 H), 12.6 (br s, 1 H). 13C NMR (DMSO-d6): d = 33.8,
44.0, 96.6, 107.9, 126.7, 128.4, 128.6, 128.9, 129.1, 129.2, 139.5,
148.8, 172.3, 182.2. MS (ES+): m/z = 267 [M + H]. HRMS (EI, 70
ev): m/z calcd for C16H14N2O2: 266.1055 [M+]; found: 266.1060.
6-(4-Hydroxyphenethylamino)-1H-indole-4,7-dione (15)
1H NMR (CD3OD): d = 2.74 (t, 2 H, J = 7.8 Hz), 3.26 (t, 2 H, J = 7.0
Hz), 5.12 (s, 1 H), 6.40 (d, 1 H, J = 1.2 Hz), 6.63 (d, 2 H, J = 8.7
Hz), 6.97 (d, 2 H, J = 8.4 Hz), 7.03 (d, 1 H, J = 3.0 Hz). 13C NMR
(DMSO-d6): d = 32.8, 44.1, 95.1, 107.5, 115.0, 127.2, 128.2, 128.8,
129.2, 129.3, 149.6, 155.8, 171.2,184.4. MS (ES+): m/z = 283 [M +
H].
3,4-Dihydro-7-methoxypyrrolo[4,3,2-de]quinolin-8(1H)-one
(8a)
1H NMR (CD3OD): d = 3.05 (t, 2 H, J = 6.9 Hz), 3.22 (t, 2 H, J = 6.9
Hz), 3.83 (s, 3 H), 5.78 (s, 1 H), 7.10 (s, 1 H) ppm. 13C NMR
(CD3OD): d = 24.9, 40.7, 57.2, 108.4, 121.4, 124.7, 127.9, 131.7,
161.5, 172.6, 186.3 ppm. MS (ES+): m/z = 204 [M + H]. HRMS (EI,
70 ev): m/z calcd for C11H10N2O2: 202.0742 [M+]; found: 202.0741.
tert-Butyl 2-(4,7-Dihydro-6-methoxy-4,7-dioxo-1H-indol-3-yl)-
ethylcarbamate (16)
1H NMR (DMSO-d6): d = 1.32 (s, 9 H), 2.75 (t, 2 H, J = 7.1 Hz),
3.12 (t, 2 H, J = 6.0 Hz), 3.75 (s, 3 H), 5.75 (s, 1 H), 6.83 (br s, 1 H),
7.06 (d, 1 H, J = 2.4 Hz), 12.57 (br s, 1 H). 13C NMR (DMSO-d6):
d = 26.1, 28.6 (3 C), 56.8, 77.8, 79.7, 107.9, 123.3 (2 C), 126.6,
129.8, 155.9, 160.0, 171.0, 184.5. MS (ES+): m/z = 305 [M + H].
HRMS (EI, 70 ev): m/z calcd for C16H14N2O2: 247.0719 [M –
C4H9O]+; found: 247.0717.
Detosylation of N-Tosylindole-4,7-quinones – General Proce-
dure
A solution of N-tosylindole-4,7-quinone derivative (0.5 mmol) in
DMF (2 mL) was stirred with NaN3 (0.6 mmol, 1.2 equiv) at the
temperature and solvent for a period indicated in Table 2. TLC ex-
amination (in 10% MeOH in CHCl3) at this point revealed that the
reaction is complete with the formation of only one new product
Synlett 2008, No. 18, 2864–2868 © Thieme Stuttgart · New York

2868
S. P. Patel et al.
LETTER
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Acknowledgment
The authors wish to acknowledge the financial support by Breast
Spore pilot grant from the University of Alabama at Birmingham
(UAB). SEV also wishes to acknowledge the financial support by
UAB Faculty Development grant from (FDGP) and a translational
research grant from UAB Council of University-Wide Interdiscipli-
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