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2-amino-1,2,3,4-tetrahydropyridines
Tetrahedron Letters No. 4, pp 327 - 330, 1978.
Pergamon Press. Printed in Great Britain.
Z-AMINO-1,2,3,4-!CSTRARYDROPYRIDJS G. Fraenkel, J. Foos, C. C. Ho, Y. Liang, S.Q.A. Rizvi, H. Stucki, and F. Steel. Department of Chemistry, Ihe Ohio State University, 140 W. 18th Avenue, Columbus, Ohio 43210, U.S.A. (Received in USA 13 September 1977; received in UK for publication 5 December 1977) The traditional route to 1,4_dihydropyridinesand then to pyridines has been condensation of suitably substituted glutaraldehydeswith some amine function.1-3
C
CHO
(1)
CHO
-
=
-NR
oxidation
-CON
Now we wish to report that together with the expected 1,4_dihydropyridinesthis reaction sequence also gives 2-amino-1,2,3,4_tetrahydropyridines,
k
the result of two molecules of ammonia reacting with one of glutaraldehyde. While observable in solution by nmr, these materials were too unstable to purify. They were isolated as the corresponding diurethanes by treatment of the crude reaction mixture with ethyl chloroformate. In a typical procedure 3,3-dimethylcyclopentane-1,5-diol (7.8 g, 0.06 mole) was cleaved with sodium metaperiodate (115 g, 0.04 mole) in a mixture of water, 500 ml, and THF, 30 ml, at room temperature over 21 hours.
The ether extracts from the reaction mixture were dried
over MgSO+, concentrated and reacted with dry gaseous ammonia (slow bubbling) for six hours. lhen ethyl chloroformate (8 g, 0.074 mole) was added. Removal of solvent and distillation gave 2 g of6b, 1.5 g of 2,
and 0.3 g of%.
cyclopentane diols are listed in Table 1.
The result8 of similar procedures using other 327
No. 4
328
Scheme 1
R
OH H
Ra
3. C1C020Et
IvHCo~t 6
r
I
+
s
TABLE 1 PRODUCTS, Scheme 1
R 'C' R"
Ii
bp"/torrb
1
bp'/torr
8
bp'/torr
(mp")
%
(mp')
i-
(mp')
__
___
153-154/0.4
'C'
12
--
___
(84.5-85)
H"
CH3 'C' /\
152-155/0.66
13
14
1500152/0.66
2
loo-l20/0.1
(107~log)
-
---
a3
'/ C.c\ \ Cc' \ Cc’
___ 27 (106-107)
2
20
158-165/0.13
13
105~108/0.11
2
137.0.1
18
155-160/0.3
18
100-102/0.3
-
---
a Isolated yield
b
Uncorrected
329
No. 4
6
5 ,
proton, CDCl,
Nmr,
SHIF’IS,
2
Compound $
JB
3A
a
H,H
3.96
b
Me,Me
4.10
7.79
8.22
7.71
a.19
C
(CH)+
3.97
d
(CH.e)d
4.15
e
(CHr)e
4.27
7.9%m
8.lOm 8.44
7.74
TAU SCALE
4
5
6
NH
7.9%
5.08
3.20
3.93
8.93 8.82 3.7 m
5.12
3.2%
4.75
5.02
3.15
3.9
%.'29m
4.56
3.36
4.56
8.38m
5.08
3.42
4.86
COUFUNG CONSlYA'TS,Hz a
J(2,m)
7. o
J(5,6)
8.0
b
J(2,m) J(3&5)
7.0 1.7
J(2,JA) J(5,6)
3.5 7.3
J(2,JB)
4.0
J(343B)
-14
C
J(3B, 5)
2.0
J(5,6)
8.2
J(2,3B)
3.5
J(JA,3B)
-13.5
J(5,6)
8.5
J(2,3@ J(5,6)
ii.35 .
J(2,JB)
4.4
J(JA,SB)
-13.5
d
e
J(2,N@ J(JA, 5)
7.5 1.7
Nmr data, see Table 2 reveals the 2-amino-tetrahydropyridinesto exist in one form. Also of interest is the scalar coupling between He and &.
Since four bond couplings are
larger for the W planar arrangement4'7, this assigns HeA in $I_and &to be expected as the HeA shift is to lover field than for Hs.
be equatorial, to
In contrast, He, (higher field
than Hsl) in $c_also has to be equatorial. !Ihisreversal of the order of shifts for HeA and Hss in &must
result from the n structure in the S-membered ring.
!&at the vicinal coupling Ha, Hs is never larger than 5 it
implies that the
330
No. 4
carbethoxyamino substituent at C2 is sxia17,8, see $
The course of reaction which results in compound 6_can be envisaged to proceed via the imino aldehyde, g R 1
NH2
/N--H
R NH
=
!?%b R>c
Rx2 -
CHO
4 The preferred formation of the pseudo-axial substituted tetrahydropyridinemust be due to steric effects; the I,3 interactions in 4 would be less severe than 1,2 interactions in the corresponding pseudo equatorial p-amino isomer.
Aclmowledgment. This research was supported by grants from the National Science Foundation Grant No. cm76-109@
and the National tistitutes of Health, Grant No. CA-11820.
References 1.
U. Eisner and J. Kuthan, Chem. Rev., E,
1 (1972) and references contained therein.
2.
E. M. Kosower and T. S. Sorenson, J. Org. Chem., 3,
3.
G. Fraenkel, C. C. Ho, Y. Liang and S. Yu, J. Am. Chem. Sot., &,
4’732 (1972).
4.
D. R. Davis, R. P. Lutz and J. D. Roberts, J. Am. Chem. Sot., 5,
246 (1961).
5.
F. A. L. Anet, Can. J. Chem., 32, 789 (1961).
6.
A. A. Bothner-By and C. Naar-Colin, J. Am. Chem. Sot., 8&
7.
L. M. Jackumn and S. Sternhell, “Applicatians of Nmr Spectroscopy in Organic Chemistry," Pergamcm Press, New York, 1969, Chap. 4.
8.
R. U. Lemieux, R. K. Kullnig and R. Y. Moir, J. Am. Chem. Sot., &,
3764 (1962).
743 (1962).
2237 (1958).
Pergamon Press. Printed in Great Britain.
Z-AMINO-1,2,3,4-!CSTRARYDROPYRIDJS G. Fraenkel, J. Foos, C. C. Ho, Y. Liang, S.Q.A. Rizvi, H. Stucki, and F. Steel. Department of Chemistry, Ihe Ohio State University, 140 W. 18th Avenue, Columbus, Ohio 43210, U.S.A. (Received in USA 13 September 1977; received in UK for publication 5 December 1977) The traditional route to 1,4_dihydropyridinesand then to pyridines has been condensation of suitably substituted glutaraldehydeswith some amine function.1-3
C
CHO
(1)
CHO
-
=
-NR
oxidation
-CON
Now we wish to report that together with the expected 1,4_dihydropyridinesthis reaction sequence also gives 2-amino-1,2,3,4_tetrahydropyridines,
k
the result of two molecules of ammonia reacting with one of glutaraldehyde. While observable in solution by nmr, these materials were too unstable to purify. They were isolated as the corresponding diurethanes by treatment of the crude reaction mixture with ethyl chloroformate. In a typical procedure 3,3-dimethylcyclopentane-1,5-diol (7.8 g, 0.06 mole) was cleaved with sodium metaperiodate (115 g, 0.04 mole) in a mixture of water, 500 ml, and THF, 30 ml, at room temperature over 21 hours.
The ether extracts from the reaction mixture were dried
over MgSO+, concentrated and reacted with dry gaseous ammonia (slow bubbling) for six hours. lhen ethyl chloroformate (8 g, 0.074 mole) was added. Removal of solvent and distillation gave 2 g of6b, 1.5 g of 2,
and 0.3 g of%.
cyclopentane diols are listed in Table 1.
The result8 of similar procedures using other 327
No. 4
328
Scheme 1
R
OH H
Ra
3. C1C020Et
IvHCo~t 6
r
I
+
s
TABLE 1 PRODUCTS, Scheme 1
R 'C' R"
Ii
bp"/torrb
1
bp'/torr
8
bp'/torr
(mp")
%
(mp')
i-
(mp')
__
___
153-154/0.4
'C'
12
--
___
(84.5-85)
H"
CH3 'C' /\
152-155/0.66
13
14
1500152/0.66
2
loo-l20/0.1
(107~log)
-
---
a3
'/ C.c\ \ Cc' \ Cc’
___ 27 (106-107)
2
20
158-165/0.13
13
105~108/0.11
2
137.0.1
18
155-160/0.3
18
100-102/0.3
-
---
a Isolated yield
b
Uncorrected
329
No. 4
6
5 ,
proton, CDCl,
Nmr,
SHIF’IS,
2
Compound $
JB
3A
a
H,H
3.96
b
Me,Me
4.10
7.79
8.22
7.71
a.19
C
(CH)+
3.97
d
(CH.e)d
4.15
e
(CHr)e
4.27
7.9%m
8.lOm 8.44
7.74
TAU SCALE
4
5
6
NH
7.9%
5.08
3.20
3.93
8.93 8.82 3.7 m
5.12
3.2%
4.75
5.02
3.15
3.9
%.'29m
4.56
3.36
4.56
8.38m
5.08
3.42
4.86
COUFUNG CONSlYA'TS,Hz a
J(2,m)
7. o
J(5,6)
8.0
b
J(2,m) J(3&5)
7.0 1.7
J(2,JA) J(5,6)
3.5 7.3
J(2,JB)
4.0
J(343B)
-14
C
J(3B, 5)
2.0
J(5,6)
8.2
J(2,3B)
3.5
J(JA,3B)
-13.5
J(5,6)
8.5
J(2,3@ J(5,6)
ii.35 .
J(2,JB)
4.4
J(JA,SB)
-13.5
d
e
J(2,N@ J(JA, 5)
7.5 1.7
Nmr data, see Table 2 reveals the 2-amino-tetrahydropyridinesto exist in one form. Also of interest is the scalar coupling between He and &.
Since four bond couplings are
larger for the W planar arrangement4'7, this assigns HeA in $I_and &to be expected as the HeA shift is to lover field than for Hs.
be equatorial, to
In contrast, He, (higher field
than Hsl) in $c_also has to be equatorial. !Ihisreversal of the order of shifts for HeA and Hss in &must
result from the n structure in the S-membered ring.
!&at the vicinal coupling Ha, Hs is never larger than 5 it
implies that the
330
No. 4
carbethoxyamino substituent at C2 is sxia17,8, see $
The course of reaction which results in compound 6_can be envisaged to proceed via the imino aldehyde, g R 1
NH2
/N--H
R NH
=
!?%b R>c
Rx2 -
CHO
4 The preferred formation of the pseudo-axial substituted tetrahydropyridinemust be due to steric effects; the I,3 interactions in 4 would be less severe than 1,2 interactions in the corresponding pseudo equatorial p-amino isomer.
Aclmowledgment. This research was supported by grants from the National Science Foundation Grant No. cm76-109@
and the National tistitutes of Health, Grant No. CA-11820.
References 1.
U. Eisner and J. Kuthan, Chem. Rev., E,
1 (1972) and references contained therein.
2.
E. M. Kosower and T. S. Sorenson, J. Org. Chem., 3,
3.
G. Fraenkel, C. C. Ho, Y. Liang and S. Yu, J. Am. Chem. Sot., &,
4’732 (1972).
4.
D. R. Davis, R. P. Lutz and J. D. Roberts, J. Am. Chem. Sot., 5,
246 (1961).
5.
F. A. L. Anet, Can. J. Chem., 32, 789 (1961).
6.
A. A. Bothner-By and C. Naar-Colin, J. Am. Chem. Sot., 8&
7.
L. M. Jackumn and S. Sternhell, “Applicatians of Nmr Spectroscopy in Organic Chemistry," Pergamcm Press, New York, 1969, Chap. 4.
8.
R. U. Lemieux, R. K. Kullnig and R. Y. Moir, J. Am. Chem. Sot., &,
3764 (1962).
743 (1962).
2237 (1958).