Stereoselective reduction of N-(3-arylcyclobutylidene)amines

Article abstract of DOI:10.1016/j.tetlet.2006.03.023

N-Alkylimines derived from cyclobutanones have not been evaluated in depth as building blocks for organic synthesis, although these compounds are, among others, good precursors for interesting 3-arylcyclobutylamines. The reduction of various N-alkyl-N-(3-

Full text of DOI:10.1016/j.tetlet.2006.03.023

Tetrahedron Letters 47 (2006) 3299–3302
Stereoselective reduction of N-(3-arylcyclobutylidene)amines
Guido Verniest, Sven Claessens and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Received 2 February 2006; revised 28 February 2006; accepted 3 March 2006
Available online 23 March 2006
Abstract—N-Alkylimines derived from cyclobutanones have not been evaluated in depth as building blocks for organic synthesis,
although these compounds are, among others, good precursors for interesting 3-arylcyclobutylamines. The reduction of various
N-alkyl-N-(3-arylcyclobutylidene)amines with LiAlH4 yielded cis-substituted cyclobutylamines as the only stereoisomers. When
borane was used as a reducing agent, an intermediate imine–borane complex could be isolated as a stable compound.
Ó 2006 Elsevier Ltd. All rights reserved.
Although cyclobutanones represent an important class
of compounds, which are widely used as building blocks
for the synthesis of a variety of natural products or (het-
erocyclic) bioactive compounds, the corresponding imi-
nes have not been studied in depth. It is surprising
that, until recently, no N-(3-arylcyclobutylidene)amines
had been described, despite the potential of such
compounds in organic synthesis.1 Imines derived from
3-arylcyclobutanones could lead directly to interesting
cyclobutylamines, which are compounds of considerable
physiological importance. In that respect, cyclobut-A
(1b) and -G (1c) can be mentioned, which are carbo-
cyclic analogues of the natural oxetanocin (1a), and
are potent antiviral agents exhibiting broadspectrum
activity against herpes viruses and HIV (see Fig. 1).2
N-Acylcyclobutylamine 2, isolated from Streptomyces
rochei strains, displays antimicrobial activity against
both G+- and GÀ-bacteria and also has herbicidal prop-
erties.3,4 From a medicinal point of view, 2-arylcyclo-
butylamines 3 were evaluated as conformationally
constrained analogues of dopamine to gain insight in
the conformational requirements of phenethylamines
to their respective receptors. Among others, this
research showed that in contrast to the trans-isomer
3b, no hallucinogenic effects were associated with the
cis-derivative 3a.5
N-Alkyl-3,3-diphenylcyclobutylamines 4 and 5 are anti-
depressants and inhibit urinary bladder contractions,
respectively (see Fig. 2).6 Derivatives 6 are lipoxygenase
R1
N
MeO
N
NH2
NH OH
HO
N
COOH
NH2
X
N
R2
MeO
O
OMe
HO
1a X = O, R1 = NH2, R2 = H (Oxetanocin)
1b X = CH2, R1 = NH2, R2 = H (Cyclobut-A)
1c X = CH2, R1 = OH, R2 = NH2 (Cyclobut-G)
3a cis
3b trans
2
Figure 1.
Keywords: Cyclobutanones; Cyclobutylamines; Reduction.
*
Corresponding author. Tel.: +32 (0)9 264 59 51; fax: +32 (0)9 264 62 43; e-mail: norbert.dekimpe@UGent.be
Postdoctoral Fellow of the Research Foundation—Flanders (FWO-Vlaanderen).
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.023

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G. Verniest et al. / Tetrahedron Letters 47 (2006) 3299–3302
R1
N
H
HO
N
N
N
NH2
R
R2
N
O
RO
7 R1 = COR, R2 = alkyl, aryl
4 R = Me
5 R = tBu
6 R = Me, aryl
Figure 2.
R2
inhibitors and thus inhibit the biosynthesis of leuko-
trienes (anti-inflammatory),7 while aminoimidazolyl
substituted cyclobutanes 7 are glycogen synthase kinase
(GSK-3) inhibitors.8
N
O
0.6 equiv. TiCl4
3.5 - 4 equiv. R2NH2
Et2O, 0 oC to r.t., 14h
R1
R1
The major synthetic pathways described in the literature
leading to cyclobutylamines make use of Curtius rear-
rangements of cyclobutanecarboxylic acids,9 substitu-
tion reactions on O-mesylated cyclobutanols, for
example, by NaN3,2d,10 [2+2]-cycloaddition reactions
using enamines11 or via reductions of cyclobutanone
oximes,10a,12 each method has its benefits and draw-
backs when specifically substituted cyclobutylamines
are envisaged. Although iminium salts of 3-arylcyclo-
butanones already yielded 3-arylcyclobutylamines after
reduction, this reaction resulted in mixtures of cis- and
trans-isomers (ratio cis:trans 3:2 to 13:1).13 The present
letter describes a stereoselective reduction of N-(cyclo-
butylidene)amines towards cis-3-arylcyclobutylamines
without the formation of the trans-isomers.
8
9 (73-90%)
1.2 equiv. LiAlH4
Et2O, r.t., 2h
H
R2
N
Ar
R2
H2O
N
H
AlH3
Li
R1
10
11a R1 = H, R2 = iPr (83%)
11b R1 = H, R2 = cHex (91%)
11c R1 = H, R2 = tBu (81%)
11d R1 = H, R2 = Bn (71%)
11e R1 = Cl, R2 = iPr (78%)
To establish a straightforward route towards 3-aryl-
cyclobutylamines, N-(cyclobutylidene)amines 9 were
prepared from readily available 3-arylcyclobutanones
using titanium(IV) chloride as an activating and dehy-
drating agent.1 The obtained imines 9 were reduced with
LiAlH4 in diethyl ether at room temperature giving rise
to the corresponding amines as single stereoisomers
(checked by GC-analysis). DIFNOE-experiments
revealed the cis-configuration for the substituents. This
result is most probably due to the combination of both
electronic and steric effects, where the preference of the
attack of the hydride to the imine happens to be pseu-
do-axial for stereoelectronic reasons (cf. analogous
results described in the literature concerning the
reduction of 4-substituted cyclohexanones).13 In addi-
tion, the steric hindrance of the aryl moiety also directs
most probably the hydride attack to the imine in a
pseudo-axial manner, which is in accordance to the
results obtained when 3-substituted cyclobutanones are
reduced.14 It should be mentioned that analogous reduc-
tions of iminium salts of cyclobutanones, as described in
Scheme 1.
the literature, resulted in mixtures of stereoisomers,
most probably because of the increased reactivity of
the iminium bond towards reduction.15 Using the syn-
thetic procedure as depicted in Scheme 1, cis-N-alkyl-
3-arylcyclobutylamines 11a–e were synthesized in good
yields.
During the course of a reactivity study of halogenated
N-(cyclobutylidene)amines, attempts were made to re-
duce imine 131 to obtain the corresponding cyclobutyl-
amine (Scheme 2). However, when standard reduction
procedures were performed using NaBH4 or LiAlH4
no reduction occurred, but reaction mixtures were
obtained containing the dehydrochlorinated N-(cyclo-
butenylidene)amine 12.
On the other hand, when borane was used as a reducing
agent, a clean reduction took place towards the tetra-
H
Cl
Cl
N
N
Cl
N
Cl
NaBH4 or Cl
LiAlH4
Cl
1 equiv. BH3 SMe2
Cl
Cl
THF, 0 oC to r.t., 3h
Cl
Cl
Cl
12 (15-21%)
14 (86%)
13
Scheme 2.

G. Verniest et al. / Tetrahedron Letters 47 (2006) 3299–3302
3301
H3B
N
N
H
N
1 equiv. BH3 SMe2
THF, 0 oC to r.t., 3h
heating (70 oC)
aq. workup
9a
15 (76%)
11a (80%)
aq. HCl 2M
Δ, 2h
aq. NaOH 2M
Δ, 2h
O
OH
8a (40%)
16 (50%)
Scheme 3.
chlorinated cyclobutylamine 14, probably because of the
less alkaline properties of borane as compared to ionic
reducing agents, such as LiAlH4 or NaBH4 and thus
promoting a reduction over a dehydrochlorination
reaction. Also in this case only the cis-substituted
cyclobutylamine 14 was obtained, which was confirmed
by DIFNOE analysis. To verify whether the use of
borane could further increase the yield of the reduction
of 2,2,4,4-unsubstituted N-(cyclobutylidene)amines 9,
imine 9a (R1 = H, R2 = i-Pr) was treated with borane-
dimethylsulfide in THF analogous to the reduction of
imine 13. However, in this case no reduction product
was formed, but a stable complex between the imine
9a (R1 = H, R2 = i-Pr) and borane was formed as evi-
denced by IR- and NMR-spectroscopy (including 11B
NMR) and by the fact that the heating (melting,
mp = 68 °C) of the obtained crystals indeed resulted in
cyclobutylamine 11a (Scheme 3). The complex 15 was
stable at room temperature and could even be purified
by flash chromatography on silica gel. Treatment of
the complex 15 with aqueous HCl or aqueous NaOH
yielded 3-phenylcyclobutanone 8a and cis-3-phenyl-
cyclobutanol 16, respectively. The latter cyclobutanol
16 could arise from the reduction of the formed cyclo-
butanone (due to hydrolysis of the activated imine bond
of complex 15) by a borane isopropylamine complex,
which is also formed during hydrolysis. Although the
reduction of imine 9a using borane also results in
cyclobutylamine 11a, no increase in yield could be estab-
lished as compared to the reduction with LiAlH4.
nological Research in Industry) and Ghent University
(GOA) for financial support.
Supplementary data
Supplementary data (experimental procedures and full
characterization data for new compounds 9d, 11a–e,
14 and 15) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2006.03.023.
References and notes
1. Verniest, G.; Colpaert, J.; To¨rnroos, K. W.; De Kimpe, N.
J. Org. Chem. 2005, 70, 4549.
2. (a) Jacobs, G. A.; Tino, J. A.; Zahler, R. Tetrahedron Lett.
1989, 30, 6955; (b) Honjo, M.; Maruyama, T.; Sato, Y.;
Horii, T. Chem. Pharm. Bull. 1989, 37, 1413; (c) Ichikawa,
Y.-I.; Narita, A.; Shiozawa, A.; Hayashi, Y.; Narasaka, K.
J. Chem. Soc., Chem. Commun. 1989, 1919; (d) Cotterill, I.
C.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1992,
2585; (e) Jung, M. E.; Sledeski, A. W. J. Chem. Soc., Chem.
Commun. 1993, 589; (f) Brown, B.; Hegedus, L. S. J. Org.
Chem. 1998, 63, 8012; (g) Panda, J.; Ghosh, S.; Ghosh, S.
J. Chem. Soc., Perkin Trans. 1 2001, 3013.
3. (a) Baldwin, J. E.; Adlington, R. M.; Parisi, M. F.; Ting,
H.-H. Tetrahedron 1986, 42, 2575; (b) Adlington, R. M.;
Baldwin, J. E.; Jones, R. H.; Murphy, J. A.; Parisi, M. F.
J. Chem. Soc., Chem. Commun. 1983, 1479.
4. Ayer, S. W.; Isaac, B. G.; Luchsinger, K.; Makkar, N.;
Tran, M.; Stonard, R. J. J. Antibiot. 1991, 44, 1460.
5. (a) Miller, D. D.; Bossart, J. F.; Chelekis, K. J. Org.
Chem. 1979, 44, 4449; (b) Nichols, D. E.; Jadhav, K. P.;
Oberlender, R. A.; Zabik, J. E.; Bossart, J. F.; Hamada,
A.; Miller, D. D. J. Med. Chem. 1984, 27, 1108.
6. (a) Periasamy, M.; Jayakumar, K. N.; Bharathi, P. J. Org.
Chem. 2005, 70, 5420, and references cited therein; (b)
Taniguchi, K.; Okumura, K.; Take, K.; Tsubaki, K.;
Terai, T.; Nakanishi, I.; Shiokawa, Y. Chem. Pharm.
Bull. 1995, 43, 71; Chem. Abstr. 1995, 123, 555438; (c)
Carnmalm, B.; Ramsby, S.; Renyi, A. L.; Ross, S. B.;
Ogren, S. O.; Stjernstrom, N. E. J. Med. Chem. 1977, 21,
78.
7. (a) Hodgson, S. T.; Wates, P. J.; Blackwell, G. J.; Craig,
C.; Yeadon, M.; Boughton-Smith, N. Bioorg. Med. Chem.
Lett. 1993, 3, 2565; (b) Nakao, K.; Kawai, A.; Stevens, R.
W. PCT Int. Appl., Coden: PIXXD2 WO 9321149 A1
In conclusion it can be stated that a stereoselective
reduction was accomplished by reaction of N-(cyclo-
butylidene)amines with LiAlH4 leading to cis-3-arylcyclo-
butylamines, which are of interest in pharmaceutical and
medicinal chemistry. The use of borane as reducing
agent gave rise to a stable imine–borane complex, which
yielded the corresponding cyclobutylamine when
heated.
Acknowledgements
The authors are indebted to the FWO-Flanders, IWT
(Flemish Institute for the Promotion of Scientific-Tech-

3302
G. Verniest et al. / Tetrahedron Letters 47 (2006) 3299–3302
19931028, 1993; Chem. Abstr. 1993, 120, 19131; (c)
11. (a) Scholz, K.-H.; Heine, H.-G.; Hartmann, W. Tetra-
hedron Lett. 1978, 17, 1467; (b) Aitken, D. J.; Gauzy, C.;
Pereira, E. Tetrahedron Lett. 2002, 43, 6177; (c) Saito, S.;
Ishikawa, T.; Moriwake, T. J. Org. Chem. 1994, 59, 4375;
(d) Brannock, K. C.; Burpitt, R. D.; Goodlett, V. W.;
Thweatt, J. G. J. Org. Chem. 1964, 29, 813; (e) Cagnon, J.
R.; Le Bideau, F.; Marchand-Brynaert, J.; Ghosez, L.
Tetrahedron Lett. 1997, 38, 2291.
12. (a) Hanrahan, J. R.; Taylor, P. C.; Errington, W. J. Chem.
Soc., Perkin Trans. 1 1997, 493; (b) Fuchs, R. PCT Int.
Appl., Coden: PIXXD2 WO 2000069806 A1 200001123,
2000; Chem. Abstr. 2000, 133, 362573.
13. (a) Carey, F. A.; Sundberg, R. J. Advanced Organic
Chemistry, 3rd ed.; Plenum Press: New York, London,
1990; pp 167–173; (b) Clayden, J.; Greeves, N.; Warren,
S.; Wothers, P. Organic Chemistry, 1st ed.; Oxford
University Press: Oxford, New York, 2001; p 472.
Brooks, D. W.; Rodriques, K. E. US Patent, Coden:
USXXAM US 5187192 A 19930216, 1993; Chem. Abstr.
1993, 119, 27749.
8. (a) Ahlijanian, M. K.; Cooper, C. B.; Helal, C. J.; Lau,
L.-F.; Menniti, F. S.; Sanner, M. A.; Seymour, P. A.;
Villalobos, A. PCT Int. Appl., Coden: PIXXD2 WO
2002010141 A1 20020207, 2002; Chem. Abstr. 2002, 136,
151165; (b) Helal, C. J. US Patent Appl. Publ., Coden:
USXXCO US 2003083352, 2003; Chem. Abstr. 2003, 138,
353987; (c) Chen, Y. L.; Zhang, L. US Patent Appl. Publ.,
Coden: USXXCO US 2005222239, 2005; Chem. Abstr.
2005, 143, 367296.
9. (a) Beard, C.; Burger, A. J. Org. Chem. 1961, 26, 2335; (b)
Martin-Vila, M.; Muray, E.; Aguado, G. P.; Alvarez-
Larena, A.; Branchadell, V.; Minguillon, C.; Giralt, E.;
Ortuno, R. M. Tetrahedron: Asymmetry 2000, 11, 3569; (c)
Meinwald, J.; Labana, L. L.; Wheeler, T. N. J. Am. Chem.
Soc. 1970, 92, 1006.
14. (a) Verniest, G.; Bombeke, F.; Kulinkovich, O. G.; De
Kimpe, N. Tetrahedron Lett. 2002, 43, 599; (b) Dehmlow,
10. (a) Beard, C.; Burger, A. J. Org. Chem. 1962, 27, 1647; (b)
Slusarchyk, W. A.; Young, M. G.; Bisacchi, D. R.;
Hockstein, D. R.; Zahler, R. Tetrahedron Lett. 1989, 30,
6453.
E. V.; Buker, S. Chem. Ber. 1993, 126, 2759.
¨
15. (a) Brown, R. C. D.; Keily, J.; Karim, R. Tetrahedron
Lett. 2000, 41, 3247; (b) Urch, C. J.; Walter, G. C.
Tetrahedron Lett. 1988, 29, 4309.