CAN-mediated tandem 5-exo-cyclisation of tertiary aminocyclopropanes: Novel accelerative effect of an N-benzyl group for oxidative ring-opening

Article abstract of DOI:10.1039/a800125a

Treatment of tertiary cyclopropylamines with cerium(IV) ammonium nitrate (CAN) gave ring-opened ketones and/or bicyclic secondary amines via an oxidative cyclopropane cleavage followed by a hydrogen abstraction or 5-exo radical cyclization: an N-benzyl gr

Full text of DOI:10.1039/a800125a

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CAN-mediated tandem 5-exo-cyclisation of tertiary aminocyclopropanes: novel
accelerative effect of an N-benzyl group for oxidative ring-opening
Yoshiji Takemoto, Saori Yamagata, Syun-ichirou Furuse, Hiroki Hayase, Tomoki Echigo and Chuzo Iwata*†
Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-Oka, Suita, Osaka 565, Japan
Treatment of tertiary cyclopropylamines with cerium(IV)
ammonium nitrate (CAN) gave ring-opened ketones and/or
bicyclic secondary amines via an oxidative cyclopropane
cleavage followed by a hydrogen abstraction or 5-exo radical
cyclization: an N-benzyl group plays a crucial role in these
reactions.
to clarify the mechanism for the inactivation of cytochrome
P-4506 and monoamine oxidase,7 and ethylene formation from
1-aminocyclopropane carboxylic acid8 have been examined. In
these studies, it has been proposed that the ring-opening
reaction proceeds via cyclopropylamine radical cations, whose
existence have been proven by an EPR study.9 Recently, we
developed an efficient synthetic method for cyclic ethers and
spirocyclic compounds by a single electron transfer (SET)
promoted ring-opening of cyclopropyl sulfides with cerium(iv)
ammonium nitrate (CAN).10 Our recent efforts have been
directed to the oxidative ring-opening of the tertiary cyclopro-
pylamines. Herein we report a convenient method for cleaving
a cyclopropyl bond‡ and an intramolecular [3 + 2]cycloaddition
with a tethered olefin.11
The ring-opening of N,N-dimethyl- and N-methyl-N-benzyl-
cyclopropylamines 1§ and 4§ was studied as a model reaction
(Scheme 1). The CAN-promoted oxidation of 1 proceeded
slowly (20 h) in DMF in the presence of NaHCO3 to give the
ring-opened ketone 2 and a,b-unsaturated ketone 3 in 11 and
20% yield, respectively. The use of MeOH as solvent in place of
DMF slowed the reaction rate, resulting in the recovery of
almost all the starting materials. On the other hand, the reaction
of 4 under the same reaction conditions proceeded smoothly (2
h), irrespective to the reaction solvent, to give the ring-opened
ketone 5 as the sole product in good yield. Although all products
seem to be produced by cleaving the most substituted
cyclopropyl bond of 1 and 4, two-electron oxidation occurred
simultaneously with single-electron oxidation in the former
case. In addition, the oxidation of 2-phenylcyclopropylamine 6
took place only through two electron oxidation, giving the
b-methoxy ketone 7 and the a,b-unsaturated ketone 8 in 32 and
45% yield, respectively. These results indicate that the CAN-
mediated oxidation of the tertiary cyclopropylamines is affected
by substituents on both the nitrogen and the cyclopropane ring.
The reaction pathway shown in Scheme 2 clearly explains these
phenomena. The SET oxidation of 1 and 4 generates the radical-
Cyclopropylamines have attracted considerable interest from
organic and biological chemists as conformationally con-
strained amino acids1 and mechanism-based inhibitors of
cytochrome P-450 and monoamine oxidase.2 Thus far many
facile preparations of cyclopropyl amines, such as the Sim-
mons–Smith cyclopropanation of enamines3 and the TiII-
mediated coupling of N,N-dialkylamides and monosubstituted
olefins,4 have been developed. However, compared with these
synthetic methods, few transformations of cyclopropylamines
into more versatile synthetic intermediates have been re-
ported.3,5 Only the enzymatic oxidation of cyclopropylamines
H
O
O
Me
i
TIPSO
+
R
i
R
NMe2
2 (11%)
3 (20%)
1
R = (CH2)4OTIPS
H
O
C5H11
MeNBn
TIPSO
R
C5H11
5 (38%)
4
OMe
OMe
O
O
ii
+
OMe
OMe
Ph
Ph
MeNBn
Ph
7 (32%)
8 (45%)
6
Scheme 1 Reagents and conditions: i, CAN, NaHCO3, DMF, room temp.;
ii, CAN, K2CO3, MeOH, 0 °C
R
R
R
Y
1,5-shift
of Ha
Hb
+H2O
+
2
Ha
N
R
Y
Y
Y
–e–
•CH2
C
Me
R
R
•
X = Me
+
+
N
NMeX
Me
N
X
•
Ha
Y
R
Y
X
–e–
+H2O
•
3
–Hb
1, 4, 6
+
A
B
N
N
Me
Me
Y
Me
Me
E
D
–Bn+
X = Bn
+H2O
R = alkyl
5
Hc N
•CH2
R
•
Y
Y
1,5-shift
of Hc
–e–
H
R
Hd
Me N •
N
Hc
Ph
Y
+H2O
+MeOH
7 and 8
+
R = Ph
F
G
+
or –Hd
N
Me
I
Scheme 2
Chem. Commun., 1998
651

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H
H
yield. More interestingly, the a,b-unsaturated ester 14 and the
a,b-acetylenic ester 16 cyclized more efficiently to give the
corresponding bicyclic products 15 and 17 without the ketones,
whereas the oxidation of the methyl enol ether 18 afforded 19 in
only moderate yield with several over-oxidation products. The
a,b-unsaturated lactone 20 was also investigated to examine
whether the chirality of the cyclopropylamine moiety influences
the diastereoselectivity of the products obtained by the tandem
cyclization. Because the CAN-mediated oxidation of 20
(diasteromeric mixture of 1.1:1) gave rise to the tricyclic
products 21a and 21b in a total yield of 74% as a single isomer,
the chirality of the cyclopropylamine moiety of 20 appears to
have no effect on the diastereoselectivity of the tandem [3 +
2]-type cycloaddition.12
C5H11
NHY
C5H11
O
i
C5H11
+
NMeBn
11 (19%)
9
10a Y = Me (42%)
b Y = H (17%)
H
OBn
OBn
ii
MeO
MeO
MeO
MeO
NHMe
NMeBn
H
13 (60%, 1:1)
12
CO2Et
H
CO2Et
C5H11
i
i
C5H11
In conclusion, we have developed a novel tandem [3 +
2]-type cycloaddition using the CAN-mediated ring-opening
reaction of the cyclopropylamines. This transformation allows
for the utilization of aminocyclopropanes as the synthetic
equivalents of g-imino radicals. In addition, the present research
demonstrates that the g-imino radicals possess a totally different
reactivity with g-keto radicals, which can be prepared from
cyclopropyl alcohols and a,b-unsaturated ketones by SET
NHMe
NMeBn
H
14
16
15 (77%, 6:1)
HO
HO
CO2Et
C5H11
CO2Et
C5H11
NHMe
NMeBn
H
oxidation and Bun SnH-mediated reduction, respectively.13
3
17 (67%, 2.7:2.3:1)
We thank the Research Foundation for Pharmaceutical
Sciences for financial support.
OMe
H
OMe
C5H11
iii
C5H11
Notes and References
NHMe
H
19 (43%, 5.2:2.3:1.3:1)
NMeBn
† E-mail: iwata@phs.osaka-u.ac.jp
‡ During our study, Cha reported the oxidative ring-opening of tertiary
cyclopropylamines by photooxidation to give the corresponding ring-
opened ketones (see ref. 11).
18
O
O
§ Syntheses of 1 and 4 were conducted according to the procedure of ref.
4.
O
NHZ
O
i
H
H
C5H11
C5H11
1 J. Salau¨n and M. S. Baird, Cur. Med. Chem., 1995, 2, 511; K. Burgess,
K.-K. Ho and D. Moye-Sherman, Synlett, 1994, 575; C. H. Stammer,
Tetrahedron, 1990, 46, 2231.
NMeBn
20
21a Z = Me (47%)
b Z = H (27%)
2 R. B. Silverman, Mechanism-Based Enzyme Inactivation: Chemistry
and Enzymology, CRC Press, Boca Raton, 1988, vol. 2, pp. 119–130;
C. J. Suckling, Angew. Chem., Int. Ed. Engl., 1988, 27, 537.
3 M. E. Kuehne and J. C. King, J. Org. Chem., 1973, 38, 304.
4 V. Chaplinski and A. de Meijere, Angew. Chem., Int. Ed. Engl., 1996,
35, 413; J. Lee and J. K. Cha, J. Org. Chem., 1997, 62, 1584.
5 T. Itoh, K. Kaneda and S. Teranishi, Tetrahedron Lett., 1975, 2801;
Y. S. Park and P. Beak, Tetrahedron, 1996, 52, 12 333.
6 M. R. Angelastro, M. E. Laughlin, G. L. Schatzman, P. Bey and
T. R. Blohm, Biochem. Biophys. Res. Commun., 1989, 162, 1571;
F. P. Guengerich, R. J. Willard, J. P. Shea, L. E. Richards and
T. L. Macdonald, J. Am. Chem. Soc., 1984, 106, 6446.
7 R. B. Silverman and X. Lu, J. Am. Chem. Soc., 1994, 116, 4129;
J.-M. Kim, S. E. Hoegy and P. S. Mariano, J. Am. Chem. Soc., 1995,
117, 100.
8 M. C. Pirrung, J. Cao and J. Chen, J. Org. Chem., 1995, 60, 5790;
J. E. Baldwin, R. M. Adlington, G. A. Lajoie and B. J. Rawlings,
J. Chem. Soc., Chem. Commun., 1985, 1496; R. K. Hill, S. R. Prakash,
R. Wiesendanger, W. Angst, B. Martinoni, D. Arigoni, H.-W. Liu and
C. T. Walsh, J. Am. Chem. Soc., 1984, 106, 795.
Scheme 3 Reagents and conditions: i, CAN, NaHCO3, DMF, room temp.;
ii, CAN, NaHCO3, MeOH–THF (5:1), room temp.; iii, CAN, NaHCO3,
DMF, 0 °C
cation A, which is equilibrated to the ring-opened iminium
radical B. In the case of 1 (X
= Me), the following
1,5-hydrogen shift (B ? C) and successive deprotonation and
second SET oxidation (B ? D ? E) might proceed slowly
because the equilibrium lies so far to A. On the other hand, in
the case of 4 (X = Bn), the benzyl group of the radical-cation
species A and B was rapidly lost from the nitrogen atom, giving
the aminyl radical F and/or iminyl radical G. Because the
aminyl radical F undergoes a very rapid ring-opening to G,12
the next 1,5-hydrogen shift (G ? H) occurs at a reasonable rate
to afford 5. However, in the case of 6 (R = Ph), another SET
oxidation of G takes place at a rate faster than the 1,5-hydrogen
shift due to the stability of the radical, producing 7 and 8 via the
cation intermediate I.
To achieve an intramolecular trapping of the presumed
radical G by a tethered olefin, we next examined the CAN
oxidation of N-benzyl-N-methylcyclopropylamines bearing a
suitably situated radical acceptor, typically a double or triple
bond (Scheme 3). The oxidation of 9 bearing a terminal olefin
was carried out with 5 equiv. of CAN in DMF at room
temperature. The reaction was completed in 2 h and gave the
bicyclic products 10a and 10b in a total yield of 59% along with
the ketone 11 as a minor product, while no monocyclic products
were obtained.¶ The cyclization of 12 was not influenced by the
substituent on the tether, giving the desired products 13 in 60%
9 X.-Z. Qin and F. Williams, J. Am. Chem. Soc., 1987, 109, 595.
10 Y. Takemoto, T. Ohra, S. Furuse, H. Koike and C. Iwata, J. Chem. Soc.,
Chem. Commun., 1994, 1529; Y. Takemoto, T. Ohra, H. Koike,
S. Furuse, C. Iwata and H. Ohishi, J. Org. Chem., 1994, 59, 4727.
11 J. Lee, J. S. U. S. C. Blackstock and J. K. Cha, J. Am. Chem. Soc., 1997,
119, 10 241.
12 Y. Takemoto, S. Furuse, H. Koike, T. Ohra, C. Iwata and H. Ohishi,
Tetrahedron Lett., 1995, 36, 4085.
13 K. I. Booker-Milburn, B. Cox and T. E. Mansley, Chem. Commun.,
1996, 2577; N. Iwasawa, S. Hayakawa, M. Funahashi, K. Isobe and
K. Narasaka, Bull. Chem. Soc. Jpn., 1993, 66, 819; E. J. Enholm and
K. S. Kinter, J.Org. Chem., 1995, 60, 4850; G. Pandey, S. Hajra and
M. K. Ghorai, Tetrahedron Lett., 1994, 35, 7837.
Received in Cambridge, UK, 5th December 1997; 8/00125A
652
Chem. Commun., 1998