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Radical cyclization via dichloromethyl radical. Stereoselective synthesis of cis-2,4-disubstituted pyrrolidine derivatives.
Tetrahedron Letters,Vol.28,No.34,pp Printed in Great Britain
3953-3956,1987
0040-4039/87 $3.00 + .OO Pergamon Journals Ltd.
RADICAL CYCLIZATION VIA DICHLOROMETHYL RADICAL.
STEREOSELECTIVE
SYNTHESIS OF CIS-2,4_DISUBSTITUTED PYRROLIDINE DERIVATIVES. Yoshihiko Watanabe*, Yoshio Ueno, Chie Tanaka, Makoto Okawara,and Takeshi Endo Research Laboratory of Resources Utilization, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 227 Abstract:
Allyl-2,2,2-trichloroethylamine
derivatives 3 were
cyclized via dichloromethyl radical to afford selectively cis2,4-disubstituted pyrrolidine derivatives -4 by the treatment with tributyltin hydride under radical conditions. Free-radical cyclization' is a quite attractive entry for ring construction via carbon-carbon bond forming process. Although a few methods utilizing 1,22 stereocontrol in cyclic systems have been reported, the still unsolved main problem seems to be the stereoselective radical cyclization. In continuation 3 of our studies on scope and limitation of radical process, we report here a new 1,3-stereoselective radical cyclization via dichloromethyl radical. The basis for these studies was our attempt to improve the quite poor stereoselectivity in the radical cyclization of tosylate 1 with tributyltin hydride and sodium iodide in the presence of a catalytic amount of AIBN at 80°C 4 In this case two stereoisomers 2a and -2b were in dimethoxyethane(Eq. 1). obtained in a ratio of 33 : 67 in accordance with the results reported in the literature. 5 In order to improve those stereoselectivity, we paid attention
NaI, Bu3SnH AIBN, 80°C
+ phAT"'cH3
'
T!s
S
2a -
1 to the cyclization transition state.
(')
2b -
Our new idea is to introduce sterically
demanding atoms on the radical center, which should enhance the stereoselectivity due to their steric hindering effect in the cyclization transition state, An A more rigid transition state may be stereolegulated to a larger extent. appropriate candidate is the trichloromethyl group, which advantageously generates dichloromethyl radical very easily, has the desired directing effect and Thus, allyl-2,2,2-trichloroethylcan be removed under very mild conditions amine -36 were cyclized exclusively to cis-2,4-disubstituted-3,3-dichloro pyrrolidine 4 in excellent yields by the treatment with tributyltin hydride 7 From nmr studies it was concluded under radical conditions(Eq. 2, Table). 3953
3954
that in any case only one diastereomer was found (nmr accuracy:>95%).S
C13C
A R
w
I’
The
Cl Bu?SnH
Cl
R'
>
AIBN
(2)
R II N H 4
cis geometry of pyrrolidine -4a was assured by its transformation to the dehalogenated analogue 5 with known stereochemistry as well as by comparison of the spectral and physical data. 9 Besides this high stereoselective ring formation
TsCl 4a Pyridine '
CH3
CH3
2 Bu3SnH AIBN
(3)
> Ph
this method also shows a very high regioselectivity since no six-membered cyclic products were detected. The wide range applicability of this method is demonstrated by the synthesis of the sterically pretentious Spiro compound 3, which was also obtained in good yield.
Furthermore, protection of hydroxy
group in the substrate, as in -3f was found to be not necessary, since they proved to be inert towards the intermediate radical species. The present method of enforcing stereocontrol by introduction of large, easily removable atoms at the radical site provides an attractive entry to highly stereoselective preparation of 2,4-disubstituted pyrrolidines. The high cis-selectivity may be explained by favouring the pseudo-chair conformation in the cyclization transition state(Fig. 1).
Increase of steric
repulsion by introduction of two chlorine atoms into the 2-position may be res10
ponsible for the observed high cis-selectivity.
Fig. 1
R sCl
.N
-4 H
H (a)
H Cl (b)
3955
Table.
Radical cyclization of 2-trichloromethyl derivatives Trichloromethyl compounds -3
Reaction a) conditions
Cyclization b, products 2
Yield (%)'I
a
70°C, 3h
79
b
7O“C, 4h
91
CH3 60°C, 5h
88 H
d
Ph
7O“C, 4h
95
H Cl e
70°C, 3h
T:xNy
Ts
93 S
H d)
f
g
CH3
Cl
70°C, 4h
d
&J
N H CH3 8ge) N H
df CIC
Cl3
N7 H
5O='C, 4h
N H
H3 75
a) All reactions were performed according to the general procedures . b) The stereochemistry of each compound was examined using 1H and 13C nmr. 4 cl The yields are given for the hydrochlorides of the products -* d) This compound was prepared by the reduction of y-ketoamine with NaBH4, erythro : threo = 72 : 27 (estimated by g.1.c. and 13C nmr.) e) Isolated as free amine by the column chlomatography, followed by recrystallization.
Acknowledgement;
We thank Dr. Thomas Miilenbernd for helpful discussions.
3956
References 1) J.M.Surzur, "Reactive intermediates"; Vo1.2. Abramobich. Ed; Plenum Press: New York, 1982; p121-295., B.Giese, "Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds"; J.E.Baldwin, Ed., Pergaman Press: London. 1986., B.Giese, Angew. Chem., Int. Ed. Engl., 553 (1985)., D.J.Hart, Science., 223, 4639 (1984). 2) G.Stork, R.Jr.Mook, S.A.Biller, S.D.Rychnovsky, J. Am. Chem. Sot., 105, 3741 (1983)., Y.Ueno, K.Chino, M.Watanabe, O.Moriya, M.Okawara, Ibid., 104, 5564 (1982)., H.Nishiyama, T.Kitajima, M.Matsumoto, K.Itoh, J. Org. Chem., 49, 2298 (1984)., G.Stork, M.Kahn, J. Am. Chem. Sot., 107, 500 (1985). 3) Y.Watanabe, Y.Ueno, T.Araki, M.Okawara, T.Endo, Tetrahedron Lett., 27, 215 (1986)., Y.Watanabe, Y.Ueno, T.Araki, T.Endo, Ibid., 27, 5385 (1986). 4) Tosylate -1 was obtained from phenylglycinol by usual method. Radical cyclization of l-unsubstituted tosylates was previously reported., Y.Ueno, The ratio of diastereomers
C.Tanaka, M.Okawara, Chem. Lett., 795 (1983).
2a and -2b was estimated to be 33 : 67 with 'H nmr. trans geometry was assigned to the major isomer.
From NOE measurements r67CH Ha
Increase of Ha signal intensity was observed by isomer, but no such increase occured in the case of the minor isomer.
3 13% NOE
irradiation of the methyl proton of the major p Ph
r Ts
5) A.L.J.Beckwith, A.K.Easton, A.K.Serelis, J. Chem. Sot., Chem. Comm. 484 2-Substituted 5-hexenyl radicals afforded predominantly trans-1,3(1980). disubstituted cyclopentane derivatives (cis : trans = 33 : 67) by radical cyclization. 20 1 and 1113 (1964). -3e and 3f; 6) -3a-3d and 3; A.Lukasiewicz, Tetrahedron., _, A.Takeda, S.Tsuboi, T.Moriwake, E.Hirata, Bull. Chem. Sot. Jpn., f?Z, 3685 (1972). 7) Typical experimental procedure is as follows. and AIBN (2 mol%) in dry benzene
To a mixture of 2 (10 mmol)
(40 ml) was added dropwise a solution Of
tributyltin hydride (11 mmol) in dry benzene (10 ml) over a period of 1 h and the mixture was stirred for 3 h at 70°C.
After removal of the solvent
and treatment with 35% HCl, (ca.3 equivalent in MeOH), isolation of the pure hydrochloride
(79%) was carried out by decantation with hexane and recrys-
tallized from CHC13-hexane. 8) For instance, 4a showed methyl proton signal at 6=1.33 ppm(d, J=6.3 Hz) and benzylic methine proton signal at 6=5.32 ppm(s) in 1H nmr (CDC13). 9) m.p. 91.5-92'C, 1H nmr (CDC13) 7.67(d, J=8 Hz), 7.23-7.28(m), 4.84(d,d J=8 Hz), 3.77, 3.70(d,d, J=9.3 Hz, J=9 Hz), 2.91, 2.82(d,d, J=9 Hz, J=9.3 Hz), 2.40(s), 2.13-2.51(m), 0.85(d, J=6.35 Hz). 10) In the equilibrium illustrated by Fig.1 the R group in the pseudo staggered conformation
(a) is interposed by two chlorine atoms, causing large SteriC
On the other hand, pseudo eclipsed form (b) shows only one steric repulsion between R and Cl. Therefore, reaction via the less hindered conformation (b) may easily explained the observed stereochemistry. (Received in Japan 30 April 1987) repulsion.
3953-3956,1987
0040-4039/87 $3.00 + .OO Pergamon Journals Ltd.
RADICAL CYCLIZATION VIA DICHLOROMETHYL RADICAL.
STEREOSELECTIVE
SYNTHESIS OF CIS-2,4_DISUBSTITUTED PYRROLIDINE DERIVATIVES. Yoshihiko Watanabe*, Yoshio Ueno, Chie Tanaka, Makoto Okawara,and Takeshi Endo Research Laboratory of Resources Utilization, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 227 Abstract:
Allyl-2,2,2-trichloroethylamine
derivatives 3 were
cyclized via dichloromethyl radical to afford selectively cis2,4-disubstituted pyrrolidine derivatives -4 by the treatment with tributyltin hydride under radical conditions. Free-radical cyclization' is a quite attractive entry for ring construction via carbon-carbon bond forming process. Although a few methods utilizing 1,22 stereocontrol in cyclic systems have been reported, the still unsolved main problem seems to be the stereoselective radical cyclization. In continuation 3 of our studies on scope and limitation of radical process, we report here a new 1,3-stereoselective radical cyclization via dichloromethyl radical. The basis for these studies was our attempt to improve the quite poor stereoselectivity in the radical cyclization of tosylate 1 with tributyltin hydride and sodium iodide in the presence of a catalytic amount of AIBN at 80°C 4 In this case two stereoisomers 2a and -2b were in dimethoxyethane(Eq. 1). obtained in a ratio of 33 : 67 in accordance with the results reported in the literature. 5 In order to improve those stereoselectivity, we paid attention
NaI, Bu3SnH AIBN, 80°C
+ phAT"'cH3
'
T!s
S
2a -
1 to the cyclization transition state.
(')
2b -
Our new idea is to introduce sterically
demanding atoms on the radical center, which should enhance the stereoselectivity due to their steric hindering effect in the cyclization transition state, An A more rigid transition state may be stereolegulated to a larger extent. appropriate candidate is the trichloromethyl group, which advantageously generates dichloromethyl radical very easily, has the desired directing effect and Thus, allyl-2,2,2-trichloroethylcan be removed under very mild conditions amine -36 were cyclized exclusively to cis-2,4-disubstituted-3,3-dichloro pyrrolidine 4 in excellent yields by the treatment with tributyltin hydride 7 From nmr studies it was concluded under radical conditions(Eq. 2, Table). 3953
3954
that in any case only one diastereomer was found (nmr accuracy:>95%).S
C13C
A R
w
I’
The
Cl Bu?SnH
Cl
R'
>
AIBN
(2)
R II N H 4
cis geometry of pyrrolidine -4a was assured by its transformation to the dehalogenated analogue 5 with known stereochemistry as well as by comparison of the spectral and physical data. 9 Besides this high stereoselective ring formation
TsCl 4a Pyridine '
CH3
CH3
2 Bu3SnH AIBN
(3)
> Ph
this method also shows a very high regioselectivity since no six-membered cyclic products were detected. The wide range applicability of this method is demonstrated by the synthesis of the sterically pretentious Spiro compound 3, which was also obtained in good yield.
Furthermore, protection of hydroxy
group in the substrate, as in -3f was found to be not necessary, since they proved to be inert towards the intermediate radical species. The present method of enforcing stereocontrol by introduction of large, easily removable atoms at the radical site provides an attractive entry to highly stereoselective preparation of 2,4-disubstituted pyrrolidines. The high cis-selectivity may be explained by favouring the pseudo-chair conformation in the cyclization transition state(Fig. 1).
Increase of steric
repulsion by introduction of two chlorine atoms into the 2-position may be res10
ponsible for the observed high cis-selectivity.
Fig. 1
R sCl
.N
-4 H
H (a)
H Cl (b)
3955
Table.
Radical cyclization of 2-trichloromethyl derivatives Trichloromethyl compounds -3
Reaction a) conditions
Cyclization b, products 2
Yield (%)'I
a
70°C, 3h
79
b
7O“C, 4h
91
CH3 60°C, 5h
88 H
d
Ph
7O“C, 4h
95
H Cl e
70°C, 3h
T:xNy
Ts
93 S
H d)
f
g
CH3
Cl
70°C, 4h
d
&J
N H CH3 8ge) N H
df CIC
Cl3
N7 H
5O='C, 4h
N H
H3 75
a) All reactions were performed according to the general procedures . b) The stereochemistry of each compound was examined using 1H and 13C nmr. 4 cl The yields are given for the hydrochlorides of the products -* d) This compound was prepared by the reduction of y-ketoamine with NaBH4, erythro : threo = 72 : 27 (estimated by g.1.c. and 13C nmr.) e) Isolated as free amine by the column chlomatography, followed by recrystallization.
Acknowledgement;
We thank Dr. Thomas Miilenbernd for helpful discussions.
3956
References 1) J.M.Surzur, "Reactive intermediates"; Vo1.2. Abramobich. Ed; Plenum Press: New York, 1982; p121-295., B.Giese, "Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds"; J.E.Baldwin, Ed., Pergaman Press: London. 1986., B.Giese, Angew. Chem., Int. Ed. Engl., 553 (1985)., D.J.Hart, Science., 223, 4639 (1984). 2) G.Stork, R.Jr.Mook, S.A.Biller, S.D.Rychnovsky, J. Am. Chem. Sot., 105, 3741 (1983)., Y.Ueno, K.Chino, M.Watanabe, O.Moriya, M.Okawara, Ibid., 104, 5564 (1982)., H.Nishiyama, T.Kitajima, M.Matsumoto, K.Itoh, J. Org. Chem., 49, 2298 (1984)., G.Stork, M.Kahn, J. Am. Chem. Sot., 107, 500 (1985). 3) Y.Watanabe, Y.Ueno, T.Araki, M.Okawara, T.Endo, Tetrahedron Lett., 27, 215 (1986)., Y.Watanabe, Y.Ueno, T.Araki, T.Endo, Ibid., 27, 5385 (1986). 4) Tosylate -1 was obtained from phenylglycinol by usual method. Radical cyclization of l-unsubstituted tosylates was previously reported., Y.Ueno, The ratio of diastereomers
C.Tanaka, M.Okawara, Chem. Lett., 795 (1983).
2a and -2b was estimated to be 33 : 67 with 'H nmr. trans geometry was assigned to the major isomer.
From NOE measurements r67CH Ha
Increase of Ha signal intensity was observed by isomer, but no such increase occured in the case of the minor isomer.
3 13% NOE
irradiation of the methyl proton of the major p Ph
r Ts
5) A.L.J.Beckwith, A.K.Easton, A.K.Serelis, J. Chem. Sot., Chem. Comm. 484 2-Substituted 5-hexenyl radicals afforded predominantly trans-1,3(1980). disubstituted cyclopentane derivatives (cis : trans = 33 : 67) by radical cyclization. 20 1 and 1113 (1964). -3e and 3f; 6) -3a-3d and 3; A.Lukasiewicz, Tetrahedron., _, A.Takeda, S.Tsuboi, T.Moriwake, E.Hirata, Bull. Chem. Sot. Jpn., f?Z, 3685 (1972). 7) Typical experimental procedure is as follows. and AIBN (2 mol%) in dry benzene
To a mixture of 2 (10 mmol)
(40 ml) was added dropwise a solution Of
tributyltin hydride (11 mmol) in dry benzene (10 ml) over a period of 1 h and the mixture was stirred for 3 h at 70°C.
After removal of the solvent
and treatment with 35% HCl, (ca.3 equivalent in MeOH), isolation of the pure hydrochloride
(79%) was carried out by decantation with hexane and recrys-
tallized from CHC13-hexane. 8) For instance, 4a showed methyl proton signal at 6=1.33 ppm(d, J=6.3 Hz) and benzylic methine proton signal at 6=5.32 ppm(s) in 1H nmr (CDC13). 9) m.p. 91.5-92'C, 1H nmr (CDC13) 7.67(d, J=8 Hz), 7.23-7.28(m), 4.84(d,d J=8 Hz), 3.77, 3.70(d,d, J=9.3 Hz, J=9 Hz), 2.91, 2.82(d,d, J=9 Hz, J=9.3 Hz), 2.40(s), 2.13-2.51(m), 0.85(d, J=6.35 Hz). 10) In the equilibrium illustrated by Fig.1 the R group in the pseudo staggered conformation
(a) is interposed by two chlorine atoms, causing large SteriC
On the other hand, pseudo eclipsed form (b) shows only one steric repulsion between R and Cl. Therefore, reaction via the less hindered conformation (b) may easily explained the observed stereochemistry. (Received in Japan 30 April 1987) repulsion.