Synthesis of cyclic hydrazines by ring-closing metathesis of dienes and enynes tethered by an N-N bond

Article abstract of DOI:10.1016/j.tetlet.2004.03.075

Ring-closing metathesis of dienes and enynes tethered by an N-N bond produced 6- to 10-membered cyclic 1,2-diaza compounds. The enyne RCM adducts were further transformed by Diels-Alder reaction into aromatic compounds.

Full text of DOI:10.1016/j.tetlet.2004.03.075

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3757–3760
Synthesis of cyclic hydrazines by ring-closing metathesis of dienes
and enynes tethered by an N–N bond
Jinsung Tae* and Dong-Woo Hahn
Center for Bioactive Molecular Hybrids (CBMH) and Department of Chemistry, Yonsei University, 134 Shinchon-Dong,
Seodaemum-Ku, Seoul 120-749, South Korea
Received 16 February 2004; revised 11 March 2004; accepted 15 March 2004
Abstract—Ring-closing metathesis of dienes and enynes tethered by an N–N bond produced 6- to 10-membered cyclic 1,2-diaza
compounds. The enyne RCM adducts were further transformed by Diels–Alder reaction into aromatic compounds.
Ó 2004 Elsevier Ltd. All rights reserved.
Several biologically active natural and unnatural com-
pounds consist of heterocycles containing an N–N bond.
Piperazic acid (1) and 1-azafagomine (2) are well-known
six-membered compounds with cyclic hydrazine skele-
ton (Fig. 1). Piperazic acid1 and substituted piperazic
acids are key amino acid components of several bio-
logically active natural peptides including novel cyclo-
philin-binding sanglifehrins.2 1-Azafagomine (2) and
related aza-sugar derivatives are known as potent gly-
cosidase inhibitors.3 A number of methods have been
reported to synthesize the six-membered cyclic hydra-
zine structures.4 In general, the hetero Diels–Alder
approach between dienes and azodicarboxylate esters
constitutes one of the earliest synthetic methods.5 More
recently, the electrophilic hydrazination of enolates
represent the most practical method to this class of
compounds, especially when asymmetric synthesis con-
cern.6 Unlike the six-membered cyclic hydrazines, only
limited synthetic methods are available to medium-size
(7- to 10-membered) congeners.7 Most of them utilize
alkylation method and therefore limited to simple sub-
strates. Developments of general synthetic methods for
the medium-size rings of this class of compounds are in
great demand.
Although the ring-closing metathesis (RCM)8;9 have
been extensively utilized in the synthesis of various
organic frameworks, to the best of our knowledge,
however, there is no literature precedent of the synthesis
of cyclic 1,2-diaza skeletons by RCM. As a part of our
research program directed toward the synthesis of het-
erocyclic compounds, we have recently reported the
synthesis of heterocycles by ring-closing metathesis.10
Herein, we report the synthesis of 6- to 10-membered
cyclic hydrazines by the RCM reaction (Scheme 1).
The starting dienes (5a–e) were prepared by double
alkylation reactions of the 1-tert-butoxycarbonyl-2-car-
bobenzyloxyhydrazine (3) with bromoalkenes under the
standard alkylation conditions (Scheme 2). Alkylation of
4 with propargyl bromide afforded the enynes (6a–c).11
OH
H
N
O
OH
NH
NH
NH
HO
OH
The ring-closing metathesis reactions of dienes were first
examined. The diene substrates (5a–e) were treated with
piperazic acid (1)
1-azafagomine (2)
Figure 1.
P
P
RCM
N
N
N
N
Keywords: Cyclizations; Cyclic hydrazines; Diels–Alder reaction; Ring-
closing metathesis; Ruthenium.
P'
P'
* Corresponding author. Tel.: +82-221232603; fax: +82-23647050;
e-mail: jstae@yonsei.ac.kr
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.075

3758
J. Tae, D.-W. Hahn / Tetrahedron Letters 45 (2004) 3757–3760
good yield (93%) under the conditions (Table 1, entry 1).
CbzN
BocN
b
a
m
CbzN
BocN
m
The next homologue 5b yielded the seven-membered cyclic
hydrazine 8b in 98% (Table 1, entry 2). Lower substrate
concentrations (0.008–0.005 M) were required for the effi-
cient cyclizations of the 8- to 10-membered rings. The
yields for the synthesis of medium-size rings were 74–70%
(Table 1, entries 3–5). Because the 1H and 13C NMR
spectra of cyclic hydrazine compounds (8a–e) were broad
and complicate, the Boc groups in 8a–e were deprotected
BocNHNHCbz
H
n
3
c
4
5a-e
m, n = 1, 2, 3
CbzN
BocN
m
6a-c
with 50% TFA in CH2Cl2 to give 9a–e where 1H and 13
C
Scheme 2. Reagents and conditions: (a) NaH (1.2 equiv), n-Bu4NI
(cat.), DMF, Br(CH2)mCH@CH2 (1.1 equiv), 25 °C, 33–67% (12–45%
of dialkylation products); (b) NaH (1.2 equiv), n-Bu4NI (cat.), DMF,
Br(CH2)nCH@CH2 (1.1 equiv), 25 °C, 87–89%; (c) NaH (1.2 equiv),
n-Bu4NI (cat.), DMF, BrCH2CCH (1.1 equiv), 25 °C, 94–99%.
Cbz ¼ carbobenzyloxy, Boc ¼ tert-butoxycarbonyl.
NMR spectra were clean. In the case of 10-membered ring
(8e), unlike the smaller rings (8a–d), only 40% of the
desired product (9e) was obtained under the same TFA
conditions. Thus, the Boc group in 8e was removed with
BF3ÆOEt2 to yield 9e in 84% (Table 1, entry 5).
10mol % Grubbs’ catalyst (7)12 under refluxing dichlo-
romethane solution (Table 1). The protected N,N0-diallyl-
hydrazine (5a) produced the 3,6-dihydropyridazine (8a) in
We then moved to the ring-closing enyne metathesis of
6a–c (Table 2). Yields for the synthesis of 6- to 8-
membered cyclic dienes were moderate to good (70–
99%). The Diels–Alder reactions between the enyne
metathesis adducts and dimethyl acetylenedicarboxylate
(DMAD) were studied as shown in Scheme 3.
Table 1. Ring-closing metathesis of 5 and deprotection of the Boc in 8
PCy3
Cl
Conjugated dienes (10a–c) were reacted with DMAD at
110 °C for 6 h to give the cycloaddition adducts (11a–c),
which were oxidized with DDQ to the bicyclic aromatic
compounds (12a–c). The two step overall yields were
uniformly good (Table 3). Again due to the broadenings of
the NMR spectra of 12a–c, the Boc groups in 12a–c were
removed to obtain 13a–c for the full characterizations.
Ru
7
Cl
Ph
PCy3
CbzN
BocN
m
n
CbzN
BocN
m
n
(10 mol %)
CH2Cl2
45 oC
8a-e
5a-e
TFA-CH2Cl2
(1:1)
1h, rt
(m, n = 1, 2, 3)
CbzN
HN
m
n
In conclusion, we have shown that small and medium-
size cyclic hydrazines can be synthesized by ring-closing
metathesis of dienes and enynes tethered by an N–N
9a-e
Entry
1
5
Condi-
tionsa
Yields (%)b
8
9
Table 2. Ring-closing enyne metathesis of 6
CbzN
HN
5a
m ¼ 1
8 h
0.02 M
8a (93)
8b (98)
7
CbzN
BocN
(10 mol%)
n ¼ 1
m
CbzN
BocN
9a (96)
m
CH2Cl2
45 o
C
6
10
2
3
4
5b
m ¼ 1
8 h
0.02 M
CbzN
HN
Entry Substrate Conditionsa
Product
Yield (%)b
99
n ¼ 2
9b (80)
1
6a
m ¼ 1
4 h
0.02 M
CbzN
BocN
10a
CbzN
HN
5c
m ¼ 2
16 h
0.008 M
8c (74)
8d (72)
n ¼ 2
9c (97)
CbzN
BocN
2
6b
m ¼ 2
8 h
0.02 M
CbzN
HN
70
5d
m ¼ 3
16 h
0.006 M
n ¼ 2
10b
9d (95)
CbzN
HN
5
5e
m ¼ 3
16 h
0.005 M
CbzN
BocN
3
6c
m ¼ 3
10 h
0.02 M
8e (70)
70
9e (84)c
n ¼ 3
10c
a Reaction time and concentration for the RCM.
b Isolated yields.
c
a Reaction time and concentration.
b Isolated yields.
ꢀ
Conditions for the deprotection of the Boc in 8e: BF3ÆOEt2, 4 A
molecular sieves, CH2Cl2.

J. Tae, D.-W. Hahn / Tetrahedron Letters 45 (2004) 3757–3760
3759
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CO2Me
a
CbzN
BocN
CbzN
BocN
b
m
m
11a-c
10a-c
CO2Me
CO2Me
CO2Me
CO2Me
c
CbzN
BocN
CbzN
HN
m
m
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13a-c
Scheme 3. Reagents and conditions: (a) DMAD (1.2 equiv), toluene,
110 °C, 6 h; (b) DDQ (2.0 equiv), toluene, 110 °C; (c) 50% TFA–
CH2Cl2, rt, 1 h. DMAD ¼ dimethyl acetylenedicarboxylate,
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acetic acid.
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Table 3. Conversion of 10 to 13
Entry
10
Yield (%)a
12
11
13
1
10a
11a (88)
12a (82)
13a (75)
m ¼ 1
10b
2
11a (97)
11a (92)
12b (87)
12c (92)
13b (75)
13c (50)
m ¼ 2
10c
3
m ¼ 3
a Isolated yields.
bond. The enyne RCM adducts were converted to
bicyclic aromatic heterocycles by the Diels–Alder reac-
tion/oxidation sequence.
General procedures for RCM/deprotection of Boc group:
A solution of 5a (88 mg, 0.25 mmol) and Grubbs’ cata-
lyst 7 (22 mg, 0.025 mmol) in CH2Cl2 (13 mL) was ref-
luxed at 45 °C for 8 h under N2. The solvent was
removed under reduced pressure and the residue mixture
was column chromatographed on silica gel (hexane/
EtOAc ¼ 20:1) to give 75 mg (93%) of 8a. A solution of
8a in 50% TFA–CH2Cl2 (4 mL) was stirred for 1 h at
room temperature. The solvent was removed under
reduced pressure and the residue mixture was column
chromatographed on silica gel (hexane/EtOAc ¼ 5:1) to
give 49 mg (96%) of 9a.13
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Acknowledgements
This work was supported by a grant from the Korea
Research Foundation (KRF-2003-015-C00360).
References and notes
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11. The first alkylation sites were the nitrogens protected by
Cbz, which was confirmed by comparisons of the 1H

3760
J. Tae, D.-W. Hahn / Tetrahedron Letters 45 (2004) 3757–3760
NMR chemical shifts of the propargylic and allylic
methylene protons of 6 and those of their derivatives
where the Boc groups were deprotected.
12. The use of the second generation Grubbs’ catalyst did not
improve the yields.
13. Spectral data, for 9a: colorless oil; Rf ¼ 0:2 (silica gel,
hexane/EtOAc ¼ 2:1); 1H NMR (250 MHz, CDCl3): d
7.50–7.20 (m, 5H), 6.00–5.85 (m, 1H), 5.85–5.70 (m, 1H),
5.20 (s, 2H), 4.07 (s, 2H), 3.48 (s, 2H); 13C NMR
(62.5 MHz, CDCl3): d 156.0, 136.6, 128.6, 128.3, 125.8,
123.6, 67.6, 46.3, 44.1; IR (film, cmꢀ1); 3273, 2939, 2848,
1701, 1409, 1347, 1224, 1117; HRMS: m=z calcd for
C12H14N2O2 (Mþ): 218.1055; found: 218.1057.
For 13c: colorless solids; Rf ¼ 0:1 (silica gel, hexane/
EtOAc 1:1); mp ¼ 116–118 °C; 1H NMR (250 MHz,
CDCl3): d 7.88 (d, J ¼ 7:7 Hz, 1H), 7.34 (s, 6H), 5.16
(s, 2H), 4.06 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.33 (br
s, 2H), 2.85–2.65 (m, 2H), 1.99 (br s, 2H); 13C NMR
(62.9 MHz, CDCl3): d 170.0, 166.0, 156.1, 143.8, 137.5,
136.4, 131.9, 128.7, 128.6, 128.3, 127.9, 127.5, 67.8, 54.3,
52.7, 52.6, 49.2, 29.0, 26.4; IR (film, cmꢀ1
2950, 1726, 1696, 1445, 1399, 1276, 1199, 1117; HRMS:
m=z calcd for C22H24N2O6 (Mþ): 412.1634; found:
412.1634.
) 3298,