only product observed when E is arylsulfonyl, alkoxycar-
bonyl, or phosphonyl is 13, due to 4-nitroimidazole acting
as the leaving group.
Scheme 3
The challenge in finding a 1,4-DNI replacement and the
fact that this route was nonstereoselective led us to formulate
an alternative synthesis. Previous work in our laboratory had
demonstrated that oxidation of alcohol 6 to cyclobutanone
15 followed by reductive amination with a secondary amine
afforded predominantly the cis-product 16 (>20:1) (Scheme
2).
Scheme 2
during the quenching step, some production of the undesired
imidazole N-3 alkylation isomer resulted. The order of
reagent addition was found to be critical as the addition of
DBU to a mixture of 4-nitroimidazole and 3-acetoxy-
cyclobutanone in acetonitrile at -40 °C gave variable yields,
possibly due to reaction of the DBU with 3-acetoxycyclobu-
tanone versus the poorly soluble 4-nitroimidazole. The
reaction of 3-benzyloxycyclobutanone12 or 3-phthalimidocy-
clobutanone13 with 4-nitroimidazole/DBU under various
conditions gave no product, indicating the importance of
having an appropriate leaving group at the cyclobutanone
3-position.
Access to 15, however, was restricted due to the require-
ment of using 1,4-DNI for the synthesis of 6 (Scheme 1).
An alternative synthesis of 15 would be via Michael addition
of 4-nitroimidazole 17 to cyclobutenone 18.7 The first
reported synthesis of cyclobutenone,8 from 3-chloro- or
3-bromocyclobutanone via elimination of HX, however,
indicates that this material polymerizes rapidly even at -78
°C. Nonetheless, the report does state that cyclobutenone
“probably can be formed and reacted in situ conveniently,”
and it was this strategy that we chose to explore.9
A solution of 3-acetoxycyclobutanone 1910 was added to
a solution of 4-nitroimidazole 17 and 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) in acetonitrile at -40 °C followed by
warming to 0 °C to provide the desired cyclobutanone 15 in
65% yield after silica gel chromatography (Scheme 3).11 We
presume that the 4-nitroimidazole anion (DBU salt) is
sufficiently basic to eliminate acetate, generating cyclobuten-
one, which reacts quickly with the excess 4-nitroimidazole
anion present in the reaction mixture. Direct SN2 displace-
ment of the acetate was ruled out based upon the poor
reactivity of 4-nitroimidazole anion with electrophiles such
as cyclobutyltosylate from room temperature to 150 °C.
When the reaction solution was warmed above 0 °C, was
allowed to sit for >2 h at 0 °C, or insufficient acid was added
The route was completed by introducing the cis-amine
group via reductive amination of 15 with bis(p-methoxy-
benzyl)amine which afforded 16a as a single stereoisomer.
Reductive amination with p-methoxybenzylamine was not
selective (2.5:1 cis/trans). Selective dealkylation of 16a with
1-chloroethyl chloroformate (ACE-Cl) in refluxing 1,2-
dichloroethane (DCE), removal of solvent, and then metha-
(11) 1-(3-Oxocyclobutyl)-4-nitroimidazole (15). A solution of 4-ni-
troimidazole 17 (520 mg, 4.6 mmol) and DBU (687 uL, 4.6 mmol) in
acetonitrile (23 mL) cooled to -40 °C was treated with a solution of
3-acetoxycyclobutanone 19 (300 mg, 2.34 mmol) in acetonitrile (2 mL).
The reaction temperature was increased to 0 °C for 45 min, and then HCl
(2.6 mmol, 1 M in methanol, freshly prepared) was added. The solvent
was removed in vacuo, and the solid was tritutrated with methylene chloride
and was filtered. The filtrate was concentrated in vacuo, and the residue
was purified by silica gel chromatography (30:1 chloroform-methanol) to
affored 65% yield (274 mg) of the title compound: 1H NMR (400 MHz,
DMSO-d6) δ 8.73 (d, J ) 1.7 Hz, 1H), 8.09 (d, J ) 1.2 Hz, 1H), 5.14 (m,
1H), 3.69 (m, 2H), 3.57 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 203.36,
137.68, 121.17, 55.89, 43.47; MS (AP/CI) 182.01 (M + H)+; HRMS calcd
182.0566 (M + H), obsd 182.0572 (M + H); FTIR (cm-1) 3123, 2357,
2331, 1790, 1544, 1488, 1290, 1144, 1107.
(7) For examples of the 1,4-addition of azoles to R,â-unsaturated systems,
see: (a) Horvath, A. Tetrahedron Lett. 1996, 37, 4423-4426. (b) Horvath,
A. Synthesis 1995, 17, 1183-1189.
(8) Sieja, J. B. J. Am. Chem. Soc. 1971, 93, 2481-2483.
(9) For two reports of the use of cyclobutenone in organic synthesis,
see: (a) Martin, H.-D.; Iden, R.; Mais, F.-J.; Kleefeld, G.; Steigel, A.; Fuhr,
B.; Rummele, O.; Oftring, A.; Schwichtenberg, E. Tetrahedron Lett. 1983,
24, 5469-5472. (b) Martin, H.-D.; Oftring, A.; Iden, R.; Schwichtenberg,
E.; Schiwek, H.-J. Tetrahedron Lett. 1982, 23, 841-844.
(12) Ogura, K.; Yamashita, M.; Suzuki, M.; Furukawa, S.; Tsuchihashi,
G. Bull. Chem. Soc. Jpn. 1984, 57, 1637-1642.
(13) Prepared via reaction between N-vinylphthalimide and N,N-di-
methylketeniminium triflate. See: Falmagne, J.-B.; Escudero, J.; Taleb-
Sahraoui, S.; Ghosez, L. Angew. Chem., Int. Ed. Engl. 1981, 20, 879-880.
(10) Prepared in two steps from vinyl acetate, see: Dehmlow, E. V.;
Buker, S. Chem. Ber. 1993, 126, 2759-2763.
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