Cobaloxime-mediated intramolecular radical addition onto oxime functions in the electrolysis media: Formation of mannich base analogues

Article abstract of DOI:10.1055/s-2001-11412

Addition of the carbon radical generated from α-bromoacetals onto the O-alkyloximes, affording Mannich base analogues, was achieved by the electrolysis in MeOH containing cobaloxime (catalytic) as a mediator at a Zn sacrificial electrode in an undivided cell. Cyclization proceeded stereoselectively in some cases to afford the 2-alkoxy-3-alkyl-4-aminotetrahydrofurans.

Full text of DOI:10.1055/s-2001-11412

LETTER
421
Cobaloxime-Mediated Intramolecular Radical Addition onto Oxime
Functions in the Electrolysis Media: Formation of Mannich Base Analogues
Tsutomu Inokuchi,*,a Hiroyuki Kawafuchib
aDepartment of Bioscience and Biotechnology, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan
Fax +81-86-251-8021; E-mail: inokuchi@biotech.okayama-u.ac.jp
bToyama National College of Technology, Department of Chemical and Biochemical Engineerings, 13, Hongo-machi, Toyama 939-8630,
Japan
Fax +81-76-492-3859; E-mail: kawafuti@toyama-nct.ac.jp
Received 13 November 2000
Br
NOMe
Co(I)
Abstract: Addition of the carbon radical generated from -bro-
moacetals onto the O-alkyloximes, affording Mannich base ana-
logues, was achieved by the electrolysis in MeOH containing
cobaloxime (catalytic) as a mediator at a Zn sacrificial electrode in
an undivided cell. Cyclization proceeded stereoselectively in some
cases to afford the 2-alkoxy-3-alkyl-4-aminotetrahydrofurans.
NHOMe
NOMe
NBS
+
CH2Cl2
electro-
reduction
O
O
O
O
O
HO
1
2
4
3
Scheme 1
Key words: acetals, amines, cyclization, ring closure, radical reac-
tions
As shown in general strategy in Scheme 1, the substrates
3 for radical cyclizations were easily prepared by bro-
moalkoxylation of readily available enol ethers 1 and
hydroxyacetone O-alkyloximes 2.11 2-Hydroxycyclo-
hexanone, accessible by acyloin condensation, was also
employed for the synthesis of a counterpart of the sub-
strate, e.g. 3f (Table). The electrochemical reactions were
carried out in the presence of cobaloxime (5-22 mol%)
and a small amount of 40% NaOH with two zinc foil elec-
trodes, one of which is used as a dissolving electrode, and
performed in a simple undivided cell. Thus, the passage of
4.3 F/mol of electricity for the electrolysis of compound
3b afforded the desired cyclization product 4b in 66%
yield as a single stereoisomer.12 In this case, trace of 1,2-
elimination, leaving 2, was found. On the other hand, the
reaction of the bromohydrin derivative from 2,3-dihydro-
pyran and -hydroxy ketone O-alkyloxime resulted in the
1,2-elimination of the starting bromoacetal, predominant-
ly.13
The carbon-nitrogen double bond of
O
-alkyloximes has
been used as
a
good radical acceptor in the
intramolecular1-4 and intermolecular5 radical couplings,
which may be accounted for by the stability of the result-
ing alkoxy aminyl radical by conjugation with a lone pair
on the adjacent oxygen atom. Furthermore, the method is
of value for assembly of amine function in the complex
natural products syntheses.1d Besides to
O
-alkyloximes,
hydrazones are also utilized in radical couplings.6 Al-
though radical cyclization of -alkyloximes has mainly
O
been examined for five- and six-membered carbocyclic
systems,2,3 few is known about radical cyclization for het-
erocyclic systems.4,5b Especially, addition of the radical
from -halo acetals onto the oxime double bonds would
provide a potential entry to synthetically valuable -amino
carbonyl derivatives, known as “Mannich base.” Howev-
er, to the best of our knowledge, the synthesis of Mannich
bases by radical reaction has little been attempted.7
Ring formation via radical cyclization is known to be ste-
reoselective in many cases.1c As shown in Table 1, the O-
alkyloximes of various structure were examined for the
radical cyclization. The radicals generated from primary,
secondary, and tertiary alkyl bromides added to the car-
bon-nitrogen double bonds without any difficulty and dif-
ference in their reactivity. The reaction of 3b, 3c, and 3d
afforded 4b, 4c, and 4d as a single isomer, respectively,
though relative stereochemistry of the methoxyamino
group is not determined at present. The configuration of
Prior to the present study, we have developed a conve-
nient procedure for generation of radicals from halo-
alkanes by using a combination of (chloropyridine)cob-
aloxime(III) and zinc foils as a sacrificial anode in an un-
divided electrolysis cell. The reaction can be achieved
with less than 5 mol% of the cobalt catalyst, which is re-
cycled by regenerating active low valence cobalt(I) spe-
cies on the cathode during the electrolysis.8 Since the
catalyst is recycled, the cobalt-induced radical reaction is
considered to be ecologically friendly, compared with bicyclic systems in the products 4b, 4c, 4d, and 4f were
assigned cis on the basis of precedent literature.2j
tributyltin hydride- and Sm(II)-based protocols.1 Recent-
ly, triethylborane was employed for radical reactions of
imine derivatives.5b In continuation of our research on in-
direct electrochemical reduction with cobaloxime as a
mediator,9 we examined the radical cyclization of O-
alkyloximes 3, giving functionalized 3-aminoacetals 410
(Scheme 1).
In order to obtain the 5-substituted acetals 6, we examined
the cyclization of 5, bearing an alkyl or a phenyl group at
the position to the oxime group. However, the reactions,
unfortunately, were not stereoselective and a mixture of
trans- and cis-6 was obtained as separable isomers14
(Scheme 2).
Synlett 2001 No. 3, 421–423 ISSN 0936-5214 © Thieme Stuttgart · New York

422
T. Inokuchi, H. Kawafuchi
LETTER
Table Cobaloxime-Mediated Radical Cyclization onto O-Alkyl-
oximes 3 in the Electrolysis Mediaa
Acknowledgement
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports and Culture, Japan
(T.I.). We are grateful to "SC-NMR Laboratory of Okayama Uni-
versity" for high-field NMR experiments.
Bromo Acetals
Yieldb
(Ratio)
Electricity, F/mol
(Cobaloxime, mol%)
Products
3
4
Br
NOMe
NHOMe
a
5.2
61
(15)
(5.6/1)
BuO
BuO
References and Notes
O
O
(1) (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986. (b)
Giese, B.; Kopping, B.; Goebel, T.; Dickhaut, J.; Thoma, G.;
Kulicke, K.; Trach, F. In Radical Cyclization Reactions; Vol.
48, Ch. 2; John Wiley & Sons: New York, 1996. (c) Curran,
D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: New York, 1996. (d) Jasperse, C. P.; Curran,
D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237.
Br
H
NHOMe
NHOMe
NOMe
NOMe
66c
65c
b
c
4.3
(10)
O
H
O
O
H
O
Br
5.8
(10)
O
O
O
O
H
(2) For five-membered carbocyclic syntheses: (a) Corey, E. J.;
Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821. (b) Enholm, E.
J.; Burroff, J. A.; Jaramillo, L. M. Tetrahedron Lett. 1990, 31,
3727. (c) Booth, S. B.; Jenkins, P. R.; Swain, C. J.; Sweeney,
J. B. J. Chem. Soc., Chem. Commun. 1991, 1248. (d)
Simpkins, N. S.; Stokes, S.; Whittle, A. J. Tetrahedron Lett.
1992, 33, 793. (e) Hatem, J.; Henriet-Bernard, C.; Grimaldi,
J.; Maurin, R. Tetrahedron Lett. 1992, 33, 1057. (f) Simpkins,
N. S.; Stokes, S.; Whittle, A. J. J. Chem. Soc., Perkin Trans. 1
1992, 2471. (g) Marco-Contelles, J.; Pozuelo, C.; Jimeno, M.
L.; Martinez, L.; Martinez-Grau J. J. Org. Chem. 1992, 57,
2625. (h) Marco-Contelles, J.; Ruiz, P.; Martinez, L.;
Martinez-Grau, A. Tetrahedron 1993, 49, 6669. (i) Ingall, A.
H.; Moore, P. R.; Roberts, S. M. J. Chem. Soc., Chem.
Commun. 1994, 83. (j) Booth, S. E.; Jenkins, P. R.; Swain, C.
J.; Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1 1994, 3499.
(k) Chiara, J. L.; Marco-Contelles, J.; Khiar, N.; Gallego, P.;
Destabel, C.; Bernabé, M. J. Org. Chem. 1995, 60, 6010. (l)
Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J. Org. Chem. 1998,
63, 5877.
(3) For six-membered carbocyclic syntheses: (a) Bartlett, P.A.;
McLaren, K. L.; Ting, P. C. J. Am. Chem. Soc. 1988, 110,
1633. (b) Parker, K. A.; Spero, D. M.; Van Epp, J. J. Org.
Chem. 1988, 53, 4628. (c) Marco-Contelles, J.; Martinez-
Grau, A.; Bernabé, M.; Martin, N.; Seoane, C. Synlett 1991,
165. (d) Marco-Contelles, J.; Pozuelo, C.; Jimeno, M. L.;
Martinez, L.; Martinez-Grau, A. J. Org. Chem. 1992, 57,
2625. (e) Pattenden, G.; Schulz, D. J. Tetrahedron Lett. 1993,
34, 6787.
Br
H
NHOBn
NOBn
76c,d
d
7.8
(5)
O
O
MeO
MeO
OMe
OMe
O
O
e
f
73
(3/1)
7.8
(13)
Br
NOMe
NHOMe
MeON
Br
NHOMe
OEt
47e
10.4
(22)
OEt
O
O
(1/1)
H
a
Electrochemical reactions were carried out by using 3 (0.8-2.0
mmol), cobaloxime (5-22 mol%) in an MeOH (7 mL)-NaOH (40%,
3 drops)-Et4NOTs (400 mg)-(Zn)-(Zn) system under an applied
voltage of 3 V at room temperature for passage of 4.3-10.4 F/mol of
electricity. b Isolated yields by column chromatography (SiO2) and
isomers are ascribed to the stereoisomers at the acetal carbon whose
ratios are based on isolated products. c One stereoisomer was formed,
exclusively. d Yield was improved to 82% using 25 mol% of cobalo-
xime (from 76% with 5 mol% of cobaloxime). e Carried out without
adding 40% NaOH.
(4) For heterocyclic syntheses: (a) Booth, S. E.; Jenkins, P. R.;
Swain, C. J. J. Chem. Soc., Chem. Commun. 1991, 1248. (b)
Naito, T.; Tajiri, K.; Harimoto, T.; Ninomiya, I.; Kiguchi, T.
Tetrahedron Lett. 1994, 35, 2205.
(5) (a) Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631.
(b) Miyabe, H; Ueda, M.; Naito, T. J. Org. Chem. 2000, 65,
5043.
(6) For radical addition to hydrazones: (a) Kim, S.; Kee, I. S.
Tetrahedron Lett. 1993, 34, 4213. (b) Bowman, W. R.;
Stephenson, P. T.; Terrett, N. K.; Young, A. R. Tetrahedron
Lett. 1994, 35, 6369. (c) Sturino, C. F.; Fallis, A. G. J. Am.
Chem. Soc. 1994, 116, 7447.
+e—
YONH
R
YONH
R
YON
R
Br
Co(I)
+
OEt
OEt
OEt
O
O
O
6, trans
(a: 22%, b: 38%)
6, cis
(a: 27%, b: 20%)
5
a, R = Me, Y = Bn
b, R = Ph, Y = Me
Scheme 2
(7) Kleinman, E. F. In Comprehensive Organic Synthesis, Vol 2;
Pergamon Press: N.Y., 1991, p 893.
(8) Inokuchi, T.; Kawafuchi, H.; Aoki, K.; Yoshida, A.; Torii, S.
Bull. Chem. Soc. Jpn 1994, 67, 595.
(9) Inokuchi, T.; Tsuji, M.; Kawafuchi, H.; Torii, S. J. Org.
Chem. 1991, 56, 5945.
In conclusion, radical addition onto O-alkyloximes, pro-
viding a new entry to synthetically useful -aminocarbo-
nyl derivatives, was achieved by electrochemical
reduction with cobaloxime as a recyclable catalyst. Stere-
oselective ring formation, giving 3-aminoacetals, is also
achieved.
Synlett 2001, No. 3, 421–423 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Cobaloxime-Mediated Intramolecular Radical Addition
423
(10) This class of compounds constitutes the backbone of
nucleoside analogues, such as 3’-azido-3’-deoxythymidine
(AZT), a useful antiviral agent for human immunodeficiency
viruses: McLeod, G. X.; Hammer, S. M. Ann. Int. Med. 1992,
117, 487.
polar component) IR (film) 3247, 2807, 1446, 1375, 1334,
1110, 1049, 1000 cm-1; 1H NMR (300 MHz) 1.20 (t, J = 7.1
Hz, 3H), 1.32-1.79 (m, 8H), 1.93 (dd, J = 13.6, 3.0 Hz, 1H),
2.08 (dd, J = 13.6, 5.8 Hz, 1H), 3.39-3.49 (m, 1H), 3.53 (s,
3H), 3.72-3.82 (m, 1H), 3.99 (t, J = 5.0 Hz, 1H), 5.09 (dd,
J = 5.8, 3.0 Hz, 1H), 5.82 (br, 1H); 13C NMR (75.5 MHz)
15.3, 20.4, 21.0, 27.6, 29.8, 41.9, 63.0, 63.3, 65.0, 76.5, 102.3.
(polar component): IR (film) 3243, 2807, 1375, 1112, 993,
941 cm-1; 1H NMR (300 MHz) 1.20 (t, J = 7.1 Hz, 3H), 1.30-
1.45 (m, 1H), 1.55-1.75 (m, 5H), 1.83-1.95 (m, 2H), 1.92 (dd,
J = 14.1, 4.4 Hz, 1H), 2.13 (dd, J = 14.1, 6.3 Hz, 1H), 3.38-
3.50 (m, 1H), 3.53 (s, 3H), 3.74-3.86 (m, 1H), 3.87 (dd,
J = 9.1, 6.0 Hz, 1H), 5.18 (dd, J = 6.3, 4.4 Hz, 1H), 5.42 (br,
1H); 13C NMR (75.5 MHz) 15.3, 21.9, 22.5, 29.8, 30.0, 39.3,
63.1, 63.6, 67.2, 78.6, 103.6.
HO
B
O
H
H
AZT (B: thymine)
H
H
N3
H
(11) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M.
J. Am. Chem. Soc. 1982, 104, 5564.
(12) The typical electrochemical procedure: A solution of the
bromide 3b (504 mg, 2.00 mmol) and
(chloropyridine)cobaloxime(III) (80 mg, 0.20 mmol) in
MeOH (7 mL) containing 40% NaOH (3 drops) and Et4NOTs
(400 mg) as an electrolyte was electrolyzed with two zinc foils
(1.0 2.0 0.5 cm3) as a cathode and an anode under a
constant applied voltage of 3 V (current: 35-70 mA). The
reaction was monitored by TLC and the electrolysis was
continued until almost all of the starting material had been
consumed (340 min). The mixture was filtered on a celite pad
and the resulting solution was concentrated and the residue
was worked up in the usual manner to yield 4b (229 mg, 66%)
as a single stereoisomer after column chromatography (SiO2,
hexane-AcOEt = 3:1). Spectroscopic data of the electrolysis
products 4 in Table 1 are as follows: 4a: IR (film) 3255, 2809,
1457, 1155, 1095, 1031, 918 cm-1; 1H NMR (300 MHz) 0.92
(t, J = 7.4 Hz, 3H), 1.33-1.42 (m, 2H), 1.33 (s, 3H), 1.50-1.58
(m, 2H), 1.81 (dd, J = 13.6, 5.2 Hz, 1H), 2.02 (d, J = 13.6 Hz,
1H), 3.31-3.39 (m, 1H), 3.54 (s, 3H), 3.60 (d, J = 9.3 Hz, 1H),
3.62-3.70 (m, 1H), 3.98 (d, J = 9.3 Hz, 1H), 5.08 (d, J = 5.2
Hz, 1H), 6.13 (brs, 1H); 13C NMR (75.5 MHz) 13.8, 19.3,
22.5, 31.7, 42.7, 62.9, 64.9, 67.2, 75.3, 104.1. 4b: IR (film)
3248, 2810, 1373, 1099 cm-1; 1H NMR (400 MHz) 1.34 (s,
3H), 1.76-1.86 (m, 1H), 2.03-2.10 (m, 1H), 2.46-2.51 (m, 1H),
3.46 (s, 3H), 3.53 (d, J = 8.4 Hz, 1H), 3.59 (d, J = 8.4 Hz, 1H),
3.82-3.87 (m, 2H), 5.50 (brs, 1H), 5.67 (d, J = 5.2 Hz, 1H);
13C NMR (100 MHz) 24.8, 25.6, 51.8, 62.7, 65.8, 69.1, 75.2,
109.6. 4c: IR (film) 3261, 2809, 1448, 1216, 1043 cm-1; 1H
NMR (300 MHz) 1.28 (s, 3H), 1.32-1.44 (m, 1H), 1.63-1.94
(m, 4H), 3.37-3.45 (m, 1H), 3.49 (s, 3H), 3.52 (d, J = 8.9 Hz,
1H), 3.81-3.89 (m, 1H), 4.23 (d, J = 8.9 Hz, 1H), 5.03 (d,
J = 3.6 Hz, 1H), 6.20 (brs, 1H); 13C NMR (75.5 MHz) 19.6,
20.4, 22.6, 45.2, 62.9, 63.4, 66.1, 75.7, 102.5. 4d: IR (film)
3274, 1454, 1361, 1085, 1025, 887, 698 cm-1;1H NMR (300
MHz) 1.20-1.42 (m, 3H), 1.52 (s, 3H), 1.55-1.73 (m, 3H),
1.75-2.00 (m, 3H), 3.21 (s, 3H), 3.57 (d, J = 9.5 Hz, 1H), 3.77
(d, J = 9.5 Hz, 1H), 4.69 (ABq, J = 11.5 Hz, 2H), 5.59 (br,
1H), 7.33 (m, 5H); 13C NMR (75.5 MHz) 21.1, 22.87, 22.91,
24.1, 29.9, 47.5, 52.7, 67.7, 74.3, 76.9, 108.5, 127.6, 128.0
(2C), 128.2 (2C), 137.8. 4e: (less polar component and major
product) IR (KBr) 3266, 2850, 2804, 1380, 1220, 1020, 962,
927 cm-1; 1H NMR (300 MHz) 1.10 (s, 3H), 1.12-1.20 (m,
3H), 1.30-1.45 (m, 3H), 1.60-1.72 (m, 3H), 1.77-1.83 (m, 1H),
3.40 (s, 3H), 3.48 (s, 3H), 3.54 (d, J = 9.2 Hz, 1H), 4.28 (d,
J = 9.2 Hz, 1H), 4.86 (s, 1H), 6.61 (brs, 1H); 13C NMR (75.5
MHz) 15.2, 23.1, 23.2, 25.3, 25.9, 30.3, 50.5, 55.3, 63.0,
68.2, 73.6, 107.7. (polar component and minor product): IR
(film) 3274, 2861, 1456, 1373, 1106, 1031, 929 cm-1; 1H NMR
(500 MHz) 1.16-1.20 (m, 2H), 1.26-1.34 (m, 1H), 1.36-1.48
(m, 1H), 1.38 (s, 3H), 1.48-1.56 (m, 2H), 1.58-1.67 (m, 2H),
1.68-1.73 (m, 1H), 1.90-1.95 (m, 1H), 3.34 (s, 3H), 3.47 (s,
3H), 3.62 (d, J = 9.0 Hz, 1H), 3.70 (d, J = 9.0 Hz, 1H), 4.83 (s,
1H), 5.76 (brs, 1H); 13C NMR (75.5 MHz) 21.0, 23.4, 23.9,
25.7, 28.1, 28.9, 50.4, 55.1, 62.9, 67.6, 76.1, 109.2. 4f: (less
(13) This reaction seems to be influenced by some steric factor in
the cyclization process. For example, the compound i bearing
an additional methyl group, compared with 3c, produced the
radical cyclized ii (24%), along with uncyclized iii (15%) and
the 1,2-elimination product iv (53%).
Br
+e—
NOR
NHOR
NHOR
Co(I)
+
O
O
O
O
O
O
R = Bn
i
iii
ii
NOR
iv
+
OH
(14) The formations of trans- and cis-isomers 6 are explained by
the transition states TS-I and TS-II, in both of which the
ethoxy group prefers axial orientation due to anomeric effect
and the alkyl or aryl group will take equatorial direction due
to steric reasons. In this case, orientation of the C=NOY
terminuses is considered to be crucial to the stereochemical
outcome of the products. Stereochemistry of 6b is assigned
based on 1H NMR data of a proton on the C-5 carbon: trans
isomer showed coupling constant of 6.4 Hz and cis isomer 2.8
Hz. Stereochemistry of 6a was decided by analogy with 6b. 1H
NMR (500 MHz) of 6b, trans-isomer (less polar component):
1.26 (t, J = 7.0 Hz, 3H), 2.17-2.20 (m, 2H), 3.52-3.58 (m,
1H), 3.55 (s, 3H), 3.75-3.79 (m, 1H), 3.88-3.95 (m, 1H), 4.94
(d, J = 6.4 Hz, 1H), 5.26 (dd, J = 4.6, 3.1 Hz, 1H), 5.30-5.70
(br, 1H), 7.30-7.45 (m, 5H). cis-isomer (polar component):
1.24 (t, J = 7.0 Hz, 3H), 1.93 (dd, J = 13.7, 1.2 Hz, 1H), 2.17-
2.23 (m, 1H), 3.49-3.52 (m, 1H), 3.54-3.59 (m, 1H), 3.56 (s,
3H), 3.80-3.87 (m, 1H), 5.18 (d, J = 2.8 Hz, 1H), 5.36 (d,
J = 4.9 Hz, 1H), 6.05 (brs, 1H), 7.24-7.47 (m, 5H).
EtO
EtO
+e—
H
H
H
H
H
H
H
Co(I)
+
+
5
O
N
O
OY
TS-I
H
H
H
R
N
R
H
OY
TS-II
H
EtO
EtO
H
H
H
H
H
2
H
O
NHOY
O
5
H
R
NHOY
R
H
6, cis
6, trans
Article Identifier:
1437-2096,E;2001,0,03,0421,0423,ftx,en;Y17800ST.pdf
Synlett 2001, No. 3, 421–423 ISSN 0936-5214 © Thieme Stuttgart · New York