Unprecedented formation of benzo[d][1,2,3,6]oxatriazocine derivatives via diazo-oxygen bond formation and synthesis of enantiomerically pure 1-alkyl benzotriazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.04.049

A series of amino acid-derived enantiomerically pure substituted benzo[d][1,2,3,6]oxatriazocine derivatives and 1-alkyl substituted benzotriazoles has been prepared by the diazotization of amino acid-derived benzo-fused alicycles. The first unprecedented

Full text of DOI:10.1016/j.tetlet.2011.04.049

Tetrahedron Letters 52 (2011) 3234–3236
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Unprecedented formation of benzo[d][1,2,3,6]oxatriazocine derivatives
via diazo-oxygen bond formation and synthesis of enantiomerically pure
1-alkyl benzotriazole derivatives
⇑
Saurav Bera, Krishnananda Samanta, Gautam Panda
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow 226001, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 January 2011
Revised 1 April 2011
Accepted 12 April 2011
Available online 18 April 2011
A series of amino acid-derived enantiomerically pure substituted benzo[d][1,2,3,6]oxatriazocine deriva-
tives and 1-alkyl substituted benzotriazoles has been prepared by the diazotization of amino acid-derived
benzo-fused alicycles. The first unprecedented diazo-oxygen bond formation in acidic medium led to an
entirely new kind of substituted benzo[d][1,2,3,6]oxatriazocine heterocycles.
Ó 2011 Elsevier Ltd. All rights reserved.
Over the past decades, the design and synthesis of medium ring
heterocycles, having a ring size in the range of 7–11 with oxygen
and nitrogen atoms, have drawn a lot of attention as a consequence
of a wide variety of applications such as biologically active natural
products,1 drug candidates,2 materials,3 and for catalysis.4 For
example, the benzoxazocine ring is often present in many pharma-
ceutical agents.5 Nefopam hydrochloride,6 with a benzoxazocine
ring is a non-narcotic analgesicdrug having antidepressant activity.7
Benzotriazoles are also important structural motifs, having a
wide range of biological activities, including antifungal,8 antitu-
mor,9 anti-inflammatory,10 antimicrobial,11 and antidepressant.12
In particular, 1-alkyl-benzotriazole derivatives are highly selective
agonists for human orphan G-protein coupled receptor GPR109b.13
Further, benzotriazole was found to be an efficient ligand for the
Cu-catalyzed N-arylation of imidazoles.14
We have been working on the synthesis and biology of S-amino
acid-based chiral heterocyles and natural product-like mole-
cules.15 Recently, we have published a new series of amino acid-
derived benzoxazepine derivatives as an antitumor agent in breast
cancer.15c In continuation of our studies in finding out the effect of
ring size on antitumor activity, we decided to synthesize and eval-
uate a series of amino acid-derived benzoxazine derivatives. We
planned to synthesize benzoxazines via tandem diazotization fol-
lowed by intramolecular nucleophilic displacement of diazonium
sulphate with amino acid-derived primary carbinol (Scheme 2).
S-amino acids 3a–e were reacted with 1-flouro-2-nitrobenzene
derivatives 1 and 2 in the presence of K2CO3 and dry DMF at 80 °C
to furnish 2-nitro benzene protected amino acid derivatives which
were converted to their methyl esters 4a–e and 5 in the presence
of SOCl2 and MeOH (Scheme 1). Nucleophilic aromatic substitution
of 2-nitro-fluoro benzene with amino acids occurs without any
racemization.15e LiBH4 reduction of 4a–e and 5 gave carbinols
6a–e and 7 in 80–90% yield. The alcohol of 6a–e and 7 was pro-
tected with TBDMS group by using TBDMSiCl, imidazole in dry
DCM to afford 8a–e and 9 in good yield. Aromatic nitro group
was reduced to amine by hydrogenolysis to provide TBDMS pro-
tected carbinol 10a–e and 11 with 65–75% yield.
The final diazotization of the intermediates 10a–e, 11 gave
12a–e16 and 13 (Scheme 2) by one-pot three step sequence, (i)
diazotization of the aromatic amine (ii) TBDMS deprotection, and
(iii) cyclization through diazo-oxygen (N@N–O) bond formation.
Instead of benzoxazine, benzo[d][1,2,3,6]oxatriazocines were
isolated.
Since the secondary amine of A is in conjugation with diazo
group, it is less reactive than primary carbinol (Scheme 3). Thus,
formation of benzotriazole does not take place (path b) (Fig. 1).
Benzoxazines do not form through elimination of diazo group
followed by subsequent attack of primary carbinol of A (path
c). It is noted that the formation of benzo[d][1,2,3,6]oxatriazo-
cines takes place through nucleophilic attack of primary carbinol
on electrophilic diazo group (path a). To the best of our knowl-
edge amino acid-derived chiral heterocycles containing diazo-
oxygen bond are not reported in the literature.
With benzo[d][1,2,3,6]oxatriazocines in hand, synthesis of ben-
zoxazine was attempted through thermal elimination of molecular
nitrogen in 12a. Thus, heating at 120 °C gave only recovery of start-
ing materials perhaps due to strong double bond character in
C–N@N–O of 12a, (Scheme 4). After failure of thermal elimination
of N2, the free radical reaction of 12a with Cu powder was at-
tempted at 70 °C. Starting material was fully consumed without
isolation of desired product. Further, one-pot diazotization of 10a
followed by heating at 70 °C in the presence of Cu powder afforded
uncharacterized complex mixture.
⇑
Corresponding author. Tel.: +91 522 2612411–18x4385/4603; fax: +91 522
2623405.
E-mail addresses: gautam_panda@cdri.res.in, gautam.panda@gmail.com (G.
Panda).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.049

S. Bera et al. / Tetrahedron Letters 52 (2011) 3234–3236
3235
CO2CH3
R
i. anhy. K2CO3, dry DMF
80 °C, 4 h
NO2
F
HN
H2N
CO2H
+
O2N
R1
ii. SOCl2, MeOH
R
R1
60-70%
based on two steps
1 (R1 = H)
2 (R1 = CH3)
3a-e
3a
4a-e (R1 = H)
5 (R1 = CH3)
i. LiBH4 (2M),
dry THF, 1 h
80-90%
CH2OTBDMS
R
CH2OH
R
TBDMSiCl, imidazole,
DCM, 1 h
HN
HN
O2N
O2N
80-90%
R1
R1
8a-e (R1 = H)
9 (R1 = CH3)
6a-e (R1 = H)
1
7 (
R = CH3)
H2, Pd-C, MeOH,
50 Psi, 1 h
3a
, R = CH3
3b, R = CH(CH3)2
3c, R = CH2C6H5
65-75%
3d
, R = CH2CH(CH3)2
CH2OTBDMS
3e, R = CH(CH3)CH2CH3
HN
R
H2N
R1
1 = H)
10a-e (
R
1
11 (
R
= CH3)
Scheme 1. Preparation of intermediates 10a-e, 11.
CH2OTBDMS
R
+
NaNO2 (1 equiv) , 6 N H2SO4,
0-120 °C, 6 h
N
N
N
N
HN
x
O
b
c
x
a
H2N
R1
NH
R1
60-70%
N
H
OH
R1
R
R
A
12a-e
13
10 a-e (R1 = H)
11 (R1 = CH3)
Figure 1. Primary carbinol is more reactive than secondary amine.
NaNO2, 6 N H2SO4,
0-120 oC, 6 h
1
12a
12b
12c
, R = CH3, R = H
x
double bond character
-
, R = CH(CH3)2, R1 = H
, R = CH2C6H5, R1 = H
N
N
N
N
O
12d, R = CH2CH(CH3)2, R1 = H
O
O
12e, R = CH(CH3)CH2CH3,R1 = H
+
R = CH3, R1 = CH3
R1
N
H
R
13,
HN
N
H
CH3
CH3
12a
Scheme 2. Synthesis of benzo[d][1,2,3,6]oxatriazocines derivatives.
double bond character
-
N
N
N
N
+
N
N
N
+
N
-
+
-
+
O
+
O
O
N
N
N
N
-
+
NH
+
NH
HN
HN
N
H
R1
NH
R1
R1
CH3
CH3
CH3
OH
OH
12a
OH
R
R
R
A
B
C
Scheme 4. Double bond character of C–N@N–O bond.
Scheme 3. Resonance structure of A and resonance hybrid.
secondary amine attack, primary carbinols 6a–e, 7 were protected
with acid stable pivaloyl group in the presence of pivaloyl chloride,
triethyl amine in dry DCM to provide 14a–e and 15 in 70–80% yield
(Scheme 5). Aromatic nitro groups of 14a–e, 15 were converted to
The formation of 12a–e and 13 takes place through the reaction
of free primary carbinol on diazo group (Scheme 2). To prevent the
N@N–O bond formation as well as to facilitate the nucleophilic

3236
S. Bera et al. / Tetrahedron Letters 52 (2011) 3234–3236
CH2OH
R
References and notes
CH2OPiv
R
PivCl, Et3N, dry DCM,
6 h
HN
HN
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O2N
70-80%
R1
R1
6a-e
7
1
14a-e
(R = H)
1
15
(R = CH3)
6a, R = CH3, R1 = H
1
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6c
6d
, R = CH(CH3)2, R = H
, R = CH2C6H5, R1 = H
, R = CH2CH(CH3)2, R1 = H
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0 -120 °C, 5 h
N
N
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HN
R
R1
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H2N
60-70%
R
R1
1
18 a-e
(R = H)
1
1
19
(R = CH3)
16a-e
17
(R = H)
1
(R = CH3)
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and 17 were diazotised in the presence of NaNO2 (1 equiv),
6 NÁH2SO4 to provide amino acid-derived 1-alkyl substituted enan-
tiomerically pure benzotriazole derivatives 18a–e and 19 with
good yield through formation of (N–N@N) bond.
In conclusion, we have reported an unprecedented diazo-oxy-
gen (N@N–O) bond formation which led to an entirely new kind
of benzo[d][1,2,3,6]oxatriazocines via one-pot three step sequence,
(i) diazotisation (ii) TBDMS deprotection, and (iii) cyclization. We
have also synthesized amino acid-derived 1-alkyl benzotriazole
derivatives via diazotization of 16a–e and 17 through diazo-
nitrogen (N@N–N) bond formation. Although diazo-nitrogen bond
formation is known,17 diazo-oxygen bond formation in acidic
medium is not reported in the literature.
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16. General experimental procedure for the synthesis of 12a–e and 13: The
compounds 10a–e and 11 were dissolved in 5 mL 6 NÁH2SO4, then the
solution was cooled at 0 °C, followed by addition of ice-cooled aq solution of
NaNO2 (1 equiv.). It was refluxed for 6 h at 120 °C and was neutralized with aq
NaHCO3. The aqueous layer was extracted with ethyl acetate (3 Â 50 mL) and
dried over anhydrous sodium sulphate. The solvent was removed under
vacuum and the crude product was then purified by chromatography over
silica gel with eluent chloroform/methanol (9.2:0.8) to afford the title
compound 12a–e and 13. Spectra of 12a: IR (neat, cmÀ1): 3420, 3021, 2366,
1216, 768; 1H NMR (300 MHz, CDCl3) d 7.76 (d, 1H, J = 8.4 Hz), 7.50 (d, 1H,
J = 8.3 Hz), 7.41–7.36 (m, 1H), 7.23–7.18 (m, 1H), 4.91–4.85 (m, 1H), 4.26–4.19
(m, 1H), 4.08–4.04 (m, 1H), 3.21 (bs, 1H), 1.61 (d, 3H, J = 6.9 Hz) ppm; 13C NMR
Acknowledgements
Authors thank the Department of Science and Technology
(DST), New Delhi, India for financial support. KS and SB thank CSIR
for the fellowships.
(50 MHz, CDCl3):
d 145.5, 133.2, 127.2, 124.0, 119.6, 109.7, 65.8, 57.3,
16.8 ppm; MS (ESI): m/z 178 [M+H]+; Anal. Calcd for C9H11N3O: C, 61.00; H,
6.26; N, 23.71%; Found: C, 61.11; H, 6.20; N, 23.63%.
17. Kale, R. R.; Prasad, V.; Hussain, H. A.; Tiwari, V. K. Tetrahedron Lett. 2010, 51,
5740–5743.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.04.049.