Intramolecular [2+3]-addition of an azide to a C=C double bond as a novel approach to piperazines

Article abstract of DOI:10.1016/j.tetlet.2004.12.071

An intramolecular [2+3]-cycloaddition of an azide to a CC double bond was carried out to obtain hexahydro[1,2,3]triazolo[1,5-a]pyrazines. These compounds were used as intermediates to prepare 2-(halogenomethyl)piperazines that could serve as precursors fo

Full text of DOI:10.1016/j.tetlet.2004.12.071

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1205–1207
Intramolecular [2+3]-addition of an azide to a C@C double bond
as a novel approach to piperazines
Tatjana V. Lukina,a Sergey I. Sviridov,b,* Sergey V. Shorshnev,b
Grigory G. Alexandrovb and Aleksandr E. Stepanova
aM. V. Lomonosov Moscow State Academy of Fine Chemical Technology, Malaya Pirogovskaya 1,
119435 Moscow, Russian Federation
bChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russian Federation
Received 21 October 2004; revised 30 November 2004; accepted 10 December 2004
Available online 8 January 2005
Abstract—An intramolecular [2+3]-cycloaddition of an azide to a C@C double bond was carried out to obtain hexahydro-
[1,2,3]triazolo[1,5-a]pyrazines. These compounds were used as intermediates to prepare 2-(halogenomethyl)piperazines that could
serve as precursors for various condensed derivatives.
Ó 2004 Elsevier Ltd. All rights reserved.
It was shown recently that hydrogenated pyrazino-
[1,2-a]pyrazine derivatives 1 can serve as a new type of
b-turn mimetic.1 The shortest way to obtain the hetero-
cyclic system 1 is the transformation of 1,4-protected
piperazines 2 containing a functional group at one of
the carbon atoms2 (Scheme 1). However, methods for
the synthesis of these monocyclic derivatives 2 include
many steps and are extremely laborious, especially the
preparation of 2,5-disubstituted piperazines.
tion of various functional groups into the piperazine
ring by the action of electrophilic reagents.
In order to synthesize the key bicyclic system 6, we used
an intramolecular [2+3] cycloaddition of an azide group
to a C@C double bond (Scheme 2). Some examples of
this reaction can be found in the literature,3 however,
these cyclizations were often accompanied by nitrogen
evolution and in essence resulted in the formation of a
C–N bond. On the contrary, a distinctive feature of
our approach is the isolation of the hexahydro-
[1,2,3]triazolo[1,5-a]pyrazines 6, which can then be rea-
dily transformed into the target piperazines 7 by the
action of alkylating or acylating reagents.
In this letter we report a novel approach to the function-
alized piperazines 2, by formation of the hexahy-
dro[1,2,3]triazolo[1,5-a]pyrazine bicyclic system
6
(Scheme 2). As anticipated, the reactive 1,2,3-triazoline
ring in this system provides the means for the introduc-
In order to synthesize bicyclic intermediates 6, we used
the readily available amino alcohols 3 as starting com-
pounds. The transformation of the hydroxy group into
the azide (3!4) was carried out by the conventional
method after introducing an N-o-nitrobenzenesulfonyl
group, chosen for this purpose as the most convenient
for each step of the synthesis.4 The subsequent N-allyla-
tion of azides 4 was carried out under very mild condi-
tions using K2CO3/18–crown-6 as base. It is
noteworthy that N-allyl derivatives 5 turned out to be
unstable. Upon isolation, they underwent polymeriza-
tion within 1–2 h. We found that keeping N-allyl deriv-
atives 5 in dilute solutions was optimal for the
cyclization (5!6). The yields of triazolines 6 are shown
R3
R1
R2
Ns
N
Hal
COOMe
N
N
N
N
R1
1
2
Scheme 1. Formation of the hydrogenated pyrazino[1,2-a]pyrazines.
R1 = alkyl; R2, R3 = alkyl, aryl, etc.
Keywords: Piperazines; Azides; Intramolecular cycloaddition; 1,2,3-
Triazolines.
*
Corresponding author. Fax: +7 095 956 4948; e-mail: sviridov@
chembridge.ru
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.071

1206
T. V. Lukina et al. / Tetrahedron Letters 46 (2005) 1205–1207
Ns
HN
Ns
N
Ns
N
R1
R1
R1
H2N
HO
R1
i
ii
iii
N3
N3
N
N
4a-d
5a-d
6a-d
3a-d
N
Ns
N
Ns
N
R1
R1
iv
+
X
N
N
-N2
R2
7aa-dc
R2
8aa-dc
Ns- -nitrobenzensulphonyl
o
Scheme 2. Reagents and conditions: (i) (a) NsCl, aq NaHCO3, EtOAc; (b) MsCl, TEA, CH2Cl2; (c) NaN3, DMF; (ii) allyl bromide, K2CO3,
18-crown-6, MeCN; (iii) MeCN, 1–14 days rt; (iv) R2Hal, MeCN.
Table 1. Preparation of triazolines 6a–d
The target 2-(halogenomethyl)piperazines 7 were suc-
R1
Time, days
6 Yield (%)
cessfully synthesized from intermediates 6 in reactions
with acyl chlorides, carbamoyl chlorides, and alkyl
halides. It should be noted that while the reactions with
acyl chlorides proceed almost instantly, alkyl halides
reacted much more slowly. Thus, we succeeded in
obtaining positive results only for the most reactive
compounds, such as methyl iodide,8 benzyl bromide,9
allyl bromide, and ethyl bromoacetate. No reactions
were observed with benzyl chloride, n-butyl bromide,
and cyclopropylmethyl bromide. The best yield of com-
pounds 7 was obtained using CbzCl as electrophile
(Table 2). In most cases, tetrahydropyrazines 8 (which
6a
6b
6c
6d
H
4–5
10–14
1–2
43
35
77
34
Me
iPr
Bn
6–9
in Table 1. It appears that bulky substituents R1
facilitate the cyclization, and the best results were
obtained with valinol as a starting amino alcohol
(3, R1 = i-Pr).
Triazolines 6 are crystalline compounds stable at 0 °C
for several months. They can also be stored for a long
time as solutions in aprotic solvents such as MeCN or
CH2Cl2. The structures of compounds 6 were confirmed
by 1H NMR and 13C NMR spectroscopic analysis.5
The assignment of the 1H and 13C NMR spectra
Table 2. Preparation of halides 7aa–dc
No. R1
R2
X
Yield (%) Yield 8aa–dc (%)
1
1
1
7aa
7ba
7ca
7da
7ab
7bb
7cb
7db
7ac
7bc
7cc
7dc
H
CH2Ph
Me CH2Ph
Br 87
Br 78
Br 93
Br 89
5
6
involved H–1H COSY, H–13C HMBC, and H–13C
HSQC experiments. In addition, X-ray crystallographic
analysis unambiguously confirmed the structures
of compounds 6a and 6d (Fig. 1).6 In all cases, a stereo-
specific cyclization reaction occurred resulting in cis-2,5-
disubstituted piperazine derivatives. The triazolines 6
turned out to be unstable in the presence of acids, even
as weak as alcohols.7 Contact with silica gel gave rise to
decomposition of 6 accompanied by violent nitrogen
evolution, as has been reported for analogous
triazolines.3a
iPr
Bn
H
CH2Ph
CH2Ph
7
11
11
14
0
COOCH2Ph Cl 89
Me COOCH2Ph Cl 76
iPr
Bn
H
COOCH2Ph Cl 95
COOCH2Ph Cl 88
0
COPh
Cl 57
Cl 45
Cl 87
Cl 62
10
13
0
Me COPh
iPr
Bn
COPh
COPh
0
6a
6d
Figure 1. ORTEP drawings of triazolines 6a and 6d.

T. V. Lukina et al. / Tetrahedron Letters 46 (2005) 1205–1207
1207
67.88 (C-3), 124.66, 130.95, 132.07, 133.74, 136.71, 147.42
(carbons of Ns), 126.88, 128.58, 129.47, 133.35 (Ph).
6. Crystallographic data for compound 6a: C11H13N5O4S,
Mr = 311.32, monoclinic space group P2(1)/n, a =
can be obtained from halides 7 by exposure to various
bases) were obtained as side products along with the tar-
get compounds 7.
˚
8.4690(17), b = 8.4690(17), c = 9.806(2) A, a = 90, b =
Thus, quite stable triazolopiperazines 6 can be obtained
by intramolecular [2+3] cycloaddition of the azide
group in 5 to the C@C bond. The reaction proceeds
stereoselectively in acceptable yields. We showed that
the halogenomethyl derivatives 7 as precursors for the
hydrogenated pyrazino[1,2-a]pyrazines can be obtained
by a previously unknown reaction of triazolines 6 with
alkyl and acyl halides.
3
˚
110.56(3), c = 90°, V = 1339.3(5) A , Z = 4, T = 293(2) K,
F(000) = 648, l = 0.267 mmꢀ1, hmax = 27.79°, 2588 reflec-
tions measured and 2362 unique (Rint = 0.0171) reflections,
full matrix least-squares refinement on F2, R1
(obsd) = 0.0930, and wR2 (all data) = 0.1090. Crystallo-
graphic data for compound 6d: C18H19N5O4S, Mr = 401.44,
monoclinic space group P2(1)/n, a = 8.026(2), b =
˚
11.449(4), c = 10.376(4) A a = 90, b = 97.08(2), c = 90°,
V = 946.2(5) A , Z = 2, T = 293(2) K, F(000) = 420,
3
˚
l = 0.207 mmꢀ1. hmax = 29.97°, 3066 reflections measured
and 2856 unique (Rint = 0.0171) reflections, full matrix
least-squares refinement on F2,R1 (obsd) = 0.0932, and
wR2 (all data) = 0.1804. Supplementary data in the
form of CIFs have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 249283 and 249284).
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44(0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
References and notes
1. (a) Kim, H.-O.; Nakanishi, H.; Lee, M. S.; Kahn, M. Org.
Lett. 2000, 2, 301–302; (b) Golebiowski, A.; Klopfenstein,
S. R.; Chen, J. J.; Shao, X. Tetrahedron Lett. 2000, 41,
4841–4844; (c) Golebiowski, A.; Klopfenstein, S. R.; Shao,
X.; Chen, J. J.; Colson, A.-O.; Grieb, A. L.; Russell, A. F.
Org. Lett. 2000, 2, 2615–2617.
2. (a) Gubert, S.; Braojos, C.; Sacristan, A.; Ortiz, J. A.
Synthesis 1991, 318–320; (b) Sturm, P. A.; Cory, M.; Henry,
D. W.; McCall, J. W.; Ziegler, J. B. J. Med. Chem. 1977, 20,
1327–1333.
7. If dissolved in MeOH, the triazolines 6 transform within 3–
4 h into complicated mixtures, from which compounds 7
(X = OMe, R2 = H) can be isolated sometimes in ꢁ15%
yield.
3. (a) Keshava Murthy, K. S.; Hassner, A. Tetrahedron Lett.
1987, 28, 97–100; (b) Hassner, A.; Amarasekara, A. S.;
Andisik, D. J. Org. Chem. 1988, 53, 27–30; (c) Rai, K. M.
L.; Hassner, A. Heterocycles 1990, 30, 817–830.
8. Iodomethylates 7 (R2 = Me; X = I) were isolated when an
excess of methyl iodide was used. In other cases, no
quaternization was observed.
4. (a) Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53,
15787–15798; (b) Skerlj, R. T.; Nan, S.; Zhou, Y.; Bridger,
G. J. Tetrahedron Lett. 2002, 43, 7569–7572.
9. Preparation of 7da (R2 = Bn; X = Br): A solution of benzyl
bromide (0.2 g, 1.1 mmol) in acetonitrile (10 mL) was
added dropwise to a solution of 6d (0.5 g, 1 mmol) in
acetonitrile (7 mL) under argon. After standing overnight,
the acetonitrile was evaporated, and the residue was
purified by chromatography on silica gel (hexane/dichloro-
methane in gradient 95:5 to 0:100 then dichloromethane/
chloroform in gradient 95:5 to 0:100) to afford 7da (0.6 g,
89%). 1H NMR (CDCl3, 400 MHz): d 2.15 (1H, dd,
J = 11.8 Hz, J = 3.6 Hz, 6-HA), 2.54 (1H, m, 2-H), 2.69
(1H, dd, J = 11.8 Hz, J = 1.8 Hz, 6-HB), 2.87 (1H, dd,
J = 12.9 Hz, J = 5.2 Hz, 5-CH2Ph), 2.90 (1H,
d, J = 12.5 Hz, 1-CH2Ph), 3.10 (1H, dd, J = 12.9 Hz,
J = 9.4 Hz, 5-CH2Ph), 3.54 (1H, m, 3-HA), 3.56 (1H, m,
2-CH2Br), 3.76 (1H, m, 2-CH2Br), 3.80 (1H, m, 3-HB), 3.94
(1H, m, 5-H), 4.16 (1H, d, J = 12.5 Hz, 1-CH2Ph), 6.79–
6.82 and 6.97–7.00 (2H and 3H, m, 1-CH2Ph), 7.30–7.40
(5H, m, 5-CH2Ph), 7.60–7.65 and 7.88–7.91 (3H and 1H, m,
4-Ns). 13C NMR (CDCl3, 100 MHz) d 32.85 (2-CH2Br),
36.04 (5-CH2Ph), 45.27 (C-3), 52.16 (C-6), 56.40 (C-5),
56.87 (1-CH2Ph), 59.23 (C-2), 124.41, 130.91, 131.86,
133.36, 133.77, 147.54 (carbons of Ns), 126.24, 128.36,
129.24, 137.99 (1-CH2Ph), 127.39, 128.20, 129.59, 137.67
(5-CH2Ph).
5. Typical procedure for 6b: Azide 4d (3.0 g, 8 mmol) was
dissolved in acetonitrile (50 mL) and K2CO3 (2.3 g,
16 mmol), allyl bromide (1.4 g, 10 mmol) and then 18-
crown-6 (0.4 g, 2 mmol) were added to the mixture, which
was then stirred for 3 h at room temperature. The solvent
was evaporated, and the residue was purified by chroma-
tography (alumina, hexane/dichloromethane 1:1). Com-
pound 5d was obtained and kept as a solution in
acetonitrile (200 mL) until complete cyclization to triazo-
line 6d, which was crystallized from hexane/ethyl acetate
1
mixture (2:1) to afford 6d (1.1 g, 34%). H NMR (CDCl3,
400 MHz): d 2.73 (1H, dd, J = 13.3 Hz, J = 5.6 Hz, 6-
CH2Ph), 2.83 (1H, dd, J = 13.3 Hz, J = 9.6 Hz, 6-CH2Ph),
3.05 (1H, dd, J = 14.1 Hz, J = 11.6 Hz, 4Hax), 3.52 (1H, dd,
J = 14.1 Hz, J = 5.0 Hz, 4-Heq), 3.65 (1H, m, 7-Hax), 3.77
(1H, m, 3a-H), 4.01 (1H, dd, J = 16.1 Hz, J = 9.8 Hz,
3-HA), 4.08 (1H, m, 6-H), 4.17 (1H, dd, J = 16.1 Hz,
J = 3.2 Hz, 3-HB), 4.25 (1H, d, J = 14.4 Hz, 7-Heq), 7.10–
7.22 (5H, m, 6-CH2Ph), 7.60–7.70 and 7.92–7.94 (3H and
1H, m, 5-Ns). 13C NMR (CDCl3, 100 MHz) d 35.48 (6-
CH2Ph), 40.81 (C-4), 46.42 (C-7), 52.44 (C-3a), 56.45 (C-6),