2
Tetrahedron
seemed to be more effective because it had less influence on
structure of azodicarboxylates. In the above-mentioned study,
although styrylboronic acid was added to azodicarboxylate by a
copper salt catalyst in a moderate yield, alkylboronic acid did not
give the corresponding hydrazine under the same conditions.
These observations led us to hypothesize that it would be
possible to add cyclopropylboronic acid to the azo group of
azodicarboxylate under the same catalytic conditions to give the
protected cyclopropylhydrazine because of the olefin-like nature
of cyclopropane rings.9
Based on the proposed reaction mechanisms of the copper
salt-catalyzed addition of arylboronic acid to azodicarboxylate,8 a
possible reaction mechanism would be that shown in Scheme 3.
Indeed, addition of cyclopropylboronic acid to the azo group
of 2 proceeded smoothly with a catalytic amount of copper(II)
acetate in DMF to give the desired N,N’-di-Boc-protected
cyclopropylhydrazine 3 in 98% yield (run 1, Table 1).11 The
reaction was incomplete when a shorter reaction time (runs 2 and
3) or equimolar amounts of cyclopropylboronic acid were used
(run 6). A higher reaction temperature tended to reduce the
Scheme 3. Possible Reaction Mechanism
reaction time (runs 4 and 7). In contrast to Chatani’s report,8a
a
clear difference was observed between the use of DMF and THF
as solvents under our reaction conditions. THF failed to generate
the desired 3 in a high yield (run 8). Furthermore, methanol,
which Mäeorg reported was a suitable solvent for the addition of
arylboronic acid to azodicarboxylate,8b was not for the production
of 3 using our reaction (runs 9 and 10). In this case, a small
amount of 4 was the sole detectable product. Among the solvents
we investigated as shown in Table 1, DMF gave the best result.
These incompatibilities observed about reaction solvents,
temperature and time on the addition to the azo group between
cyclopropylboronic acid and arylboronic acids would depend on
stability and reactivity of cyclopropylboronic acid.10
Deprotection of 3 under acidic conditions cleanly provided
cyclopropylhydrazine salts in high yields (Scheme 4).11 We
identified the deprotected cyclopropylhydrazine as a ditosylate
salt instead of the known hydrochloride due to its hygroscopicity
and poor crystallinity. The ditosylate salt of 1 could be stored and
was easy to handle.
Table 1. Copper Catalytic Addition of Cyclopropylboronic
Acid to 2
a: TsOH H2O, CH3CN, 60 °C, 5h. b: 4M HCl-dioxane. c: TFA-
DCM.
H
H
Boc
N
conditionsa
B(OH)2
N
Boc
Boc
Boc
N
N
N
Boc
N
H
Boc
Scheme 4. Deprotection of 3 to Ditosylate of 1
2
3
4
In conclusion, we have developed a highly efficient method to
synthesize cyclopropylhydrazine salts. The method includes the
copper-catalyzed addition of cyclopropylboronic acid to the azo
group of azodicarboxylate. Our procedure features
cyclopropylhydrazine salts as useful building blocks for the
construction of N-cyclopropyl group-containing heterocycles.
run
catalyst
solvent
temp
(°C)
Time
(h)
yield
4
(re SM) (%)
(%)
1
2
Cu(OAc)2
Cu(OAc)2
DMF
DMF
rt
rt
96
48
48
2
98
69 (27)
68
References and notes
3
Cu(OAc)2·H2O
Cu(OAc)2
DMF
rt
4
DMF
50
50
50
80
rt
90
1. Almansa, C.; Go´mez, L. A.; Cavalcanti, F. L.; de Arriba, A. F.;
Garcı´a-Rafanell, J.; Forn, J. J. Med. Chem. 1997, 40, 547–558.
(b) Ghahremanzadeh, R.; Ahadi, S.; Bazgir, A. Tetrahedron Lett.
2009, 50, 7379–7381. (c) Park, S. O.; Kim, J.; Koh, M.; Park, S.
B. J. Comb. Chem. 2009, 11, 315–326. (d) Jones, C. D.; Luke, R.
W. A.; McCoull, W. WO2005060970 A1.
b
5
Cu(OAc)2
DMF
4
90
6c
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2·H2O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMF
3
47(41)
78
7
DMF
1
11
2. (a) Carruthers, N. L.; Chai, W.; Deng, X.; Dvorak, C. A.; Kwok,
A. K.; Liang, J. T.; Mani, N.; Rudolph, D. A.; Wong, V. D.
WO2005040169 A1. (b) Cogan, D.; Hao, M.-H.; Kamhi, V. M.;
Miller, C. A.; Nether-T., M. R.; Swinamer, A. D. WO2005090333
A1. (c) Anderson, K. W.; Fotouhi, N.; Gillespie, P.; Goodnow, R.
A. Jr.; Guertin, K. R.; Haynes, N.-E.; Myers, M. P.; Pietran-Ico-
Cole, S. L.; Qi, L.; Rossman, P. L.; Scott, N. R.; Thakkar, K. C.;
Tilley, J. W.; Zhang, Q. WO2007107470 A1. (d) Martin, S. W.;
Bergstrom, C. P.; Ding, M.; Zheng, X.; Gentles, R. G.
8
THF
48
24
24
48
48
48
4 (88)
N.D.d
N.D.
8 (61)
N.D.
N.D.
9
MeOH
MeOH
CH3CN
DCE
rt
21
20
10
11
12
13
rt
rt
rt
toluene
rt
WO2009137454 A1. (e) Lemieux, R. M.; Brunette, S. R.; Horan,
J. C.; Kowalski, J. A.; Lawlor, M. D.; Mckibben, B.; Miller, C. A.;
Barbosa, A. J. M. WO2010141273 A1.
aStandard conditions: 2 (0.5 mmol), cyclopropylboronic acid
b
(1 mmol), catalyst (10 mol%) and solvents (1 mL). 5 mol%.
cCyclopropylboronic acid (0.5 mmol). dNot detected by TLC.
3. Tsukamoto, S.; Fujii, M.; Igarashi, S.; Yasunaga, T.; Usuda, S.;
Hidaka, K.; Tamura, T. JP04018092 A.