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From 2 5-Dihydropyrazines to 2H-1 4-Diazepines and from Benzodihydroarenes to Benzocycloheptene Derivatives Structural Variants of the Antidepressant Protriptyline.

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[6] J. Lorberth, T. F. Berlitz, S.-H. Shin, U. Miiller, H. Sinning, Ahsrr. X / I / ' h
Int. Cunf: Organomet Chem., Torino 1988.
[7] J. Lorberth, S.-H. Shin, G. Baum, W. Massa, Angew. Chem. and Angea.
Chem. In/. Ed. EnxI., in press.
[8] S.-H. Shin, Disserrarion, UniversitIt Marburg 1989.
[Y] Crystallographic data of I : space group P I , Z = 4, u = 831.5(2),
h=1185.9(2), c = 1245.8(5)pm, x=91.80(2), ,B=101.24(2), 7 =
109.34(2)'. 2015 observed reflections with Fo > 4 u Fo were measured on
a four-circle diffractometer (CAD 4, Enrdf-Nonius) with Mo,, radiation
at 190 K ; empirical absorption correction (+ scan, p = 138 cm-'). The
structure was solved by Patterson methods. Refinement using anisotropic
temperature factors for all atoms except hydrogen atoms, which were
placed at calculated positions with common isotropic temperature factors
(218 parameters) led to R = 0.044 and M R = 0.038 [w = l/u2(F,)] [17].
Further details of the crystal structure investigation are available on request from the Fachinformationszentrum Energie. Physik, Mathematik
GmbH, D-7514 Eggenstein-Leopoldshafen2 (FRG), on quoting the depository number CSD-53710, the names of the authors. and the journal
citation.
[lo] N. A. Bell, M. Goldstein. T. Jones, I. W. Nowell, fnorx. Chim. Actu 48
(1981) 185.
[ l l ] E. Eitel, D. Oelkrug, W. Hiller, J. StrIhle. Z . Naturfiirsch. B35 (1980) 1247.
1121 M. Massaux, M. J. Bernard. M.-T. Le Bihan, Acfu Crurulhgr. Secf. 5 2 7
(1971) 2419.
[13] S. Vilminot, W. Granier, Z. AI Oraibi, L. Cot, Acta Cr,vsta/logr.Sect. B34
(1978) 143.
[14] K. D. Bos, E. J. Bulten, J. G. Noltes, J. Orgunomel. Chem. 99 (1975) 71.
[15] E. Keller: SCHAKAL-86B, A FORTRAN Programfur the Graphic Representation of Molecular and Crjsrailugraphir Models, Freiburg 1986.
1161 C. K. Johnson: ORTEP. Report ORNL-3794. Oak Ridge National Laboratory, Oak Ridge, TN 1965.
[17] G. M. Sheldrick: SHELX-76, Prugrum / o r Crjstul Slructure Determination, Cambridge 1976.
H R'
R'
I
2
3
1-4
R'
a
b
c
d
iPr
e
f
g
R4
Me0
5
R5
Y
R3
R2
a Me H
b Me D
5
f'kOMe
R2
R3
H
Me
rPr Me
Me Me
Bn
Bn
Ph Ph
H
P h
OMe Ph
D
H
H
H
H
H
R4 R 5
Me Me
Me M e
c M e H
H
H
d Bn H
Ph
H
*RZ
R3, 3 H
R
Scheme 1. Base-induced ring expansion of the bislactim ethers 1
Table 1. Reaction conditions of the ring expansion of 1 and yields of 4 and 5
PI.
1
Base/Solvent
I
Yield
[hl
4
From 2,5-Dihydropyrazines to 2H-1,4-Diazepines
and from Benzodihydroarenes to
Benzocycloheptene Derivatives, Structural Variants
of the Antidepressant Protriptyline
a
a
a
a
a
C
C
By Ulrich Scholikopf* and Joachirn Mittendorf
e
f
Dedicated to Sir Derek Barton
on the occasion of his 70th birthday
g
In our studies of the asymmetric synthesis of nonproteinogenic amino acids according to the bislactim method"' we have observed that bislactim ethers 1 with a nucleofugal leaving group on C-1' undergo a novel ring expansion
of the six-membered ring to a seven-membered ring in the
presence of bases such as potassium hydroxide or potassium
tert-butoxide in dimethyl sulfoxide (DMSO) or dimethylformamide (DMF) at room temperature, whereby diazepines 4
are formed (Scheme 1). If R' is a CHR, group, relatively
large amounts of dihydrodiazepines 5 are also formed, the
ratio 4:5 depending upon the reaction conditions (Table 1).
As has been shown by a mechanistic study with deuterium-labeled compounds (e.g. 1 b),[31the ring expansion begins with the deprotonation of 1 at C-5 and formation of
the heteronorcaradiene 2. This rearranges electrocyclically
to SH-1,4-diazepine 3. So far we have only been able to isolate 3g; the 1,4-diazepines 3a-f undergo further rapid reaction involving a [l,S]-sigmatropic shift to give 4. When
R' = CHR, a deprotonation-reprotonation reaction is possible at the stage of 3 in the presence of a base, leading to the
dihydrodiazepines 5 .
As already mentioned, when R ' = OMe (1 g) the "cycloheptatriene intermediate" 3g is isolable, since the additional
imino ether group strongly stabilizes the ground state. With
[*I
Prof. Dr. U. Schollkopf, Dipl.-Chem. J. Mittendorf
Institut fur Organische Chemie der Universitiit
Tammannstrasse 2, D-3400 Gottingen (FRG)
Angew. Chem. Inr. Ed. Engl. 28 (1989J Nu. 5
d
:c
KOtBu/DMSO
DMSOO Lie/DMSO
KOHIDMSO
KOHIDMSO
KOHIDMF
KOHIDMSO
KOrBu/DMSO
KOHIDMSO
KOH/DMSO:DMF ( 1 : l )
KOHIDMSO
KOtBuiDMSO
50
25
25
50
25
25
50
25
0
25
25
1
10
24
5
24
96
1
24
4
2
0.2
[%I
5
75
62
6
< 0.5
1
44
~
8
73
93
62
14
I1
~
73
~
87
59
7[a]
-
[a] Initially 3g is obtained, which upon heating for 1 h at 90 T completely
rearranges to 4g.
3g the (irreversible) transannular 1,s-hydrogen shift to give
4g can be kinetically monitored. The rate constants are
k = (4.385 i 0.033) x
s-' at 70 "C and (1.023 f
0.013) x
s - ' at SS OC.14] In contrast, the rate constants
for the isomerization 6 -+ 7, the prototype of the transannu-
6
7
'
lar [I ,S]-hydrogen shift are k = 4.8 x lo-* s- at 98 "C,
s-' at 140°C.r51
6.6 x lo-' s-' at 121 "C and 3.2 x
Hence, the isomerization 3g -+ 4g at 70 "C is ca. lo5 times
faster than the reaction 6 + 7. If one sets a lower limit of
96 kJmol-' of the activation barrier of the [l,S]-hydrogen
shifts 3 + 4, in which 3 is not isolable, then it can be estimated that this rearrangement is at least 10' times faster than the
rearrangement 6 -+ 7.[']
As expected, the ring expansion is not limited to the 2,5-dihydropyrazines, but can also be extended to analogous allcarbon compounds. Thus, reaction of the 1,4-dihydronaphthalene 8['' with potassium tert-butoxide affords the
norcaradiene derivative 9, which, on heating, is converted
VCH Verlux.~ge,sells~haft
mhH, 0-6940 Weinheim, 19N9
0570-0833~~9/0S05-0613
3 02.50jO
613
via the “cycloheptatriene intermediate” 10 into a mixture of
the benzocycloheptenes 11 and 12 (Scheme 2).
moMe
Me CH,-OTos
+
a) &OMe
\
/
b)
_ j
\
&
21 (Scheme 3). Compound 22 warrants attention as 10-methy1 analogue of the antidepressant protriptyline. Since the
substituent in position 10 of 22 is variable within wide limits,
the ring expansion method described here opens up a simple
and productive entry to structural variants of protriptyline.
OMe
\
Received: October 31, 1988 [Z 3033 IE]
German version: Angew. Chem. 101 (1989) 633
H H
8
CAS Registry numbers:
l a , 119945-28-7; l c , 119909-37-4; I d , 119909-38-5; l e , 119909-39-6; I f ,
119909-40-9; Ig, 119909-41-0;4a, 119909-18-1;4c, 119909.19-2; 4e, 11990934-1; 4f, 119909-35-2;4g, 119909-36-3;5a, 119909-17-0;Sc, 119909-20-5;5d.
119909-21-6; 6, 1541-12-4; 7, 65007-13-8; 8, 119909-22-7;9, 119909-23-8; 10,
119909-24-9; 11, 119909-25-0; 12, 119909-26-1: 13, 613-31-0; 14, 119909-27-2;
15,119909-28-3; 16,119909-29-4; 17,119909-30-7; 18,119909-31-8;19,1620428-7; 20, 119909-32-9; 21, 521-80-2; 22, 119909-33-0.
10
9
11
12
Scheme 2. Reaction conditions: a) KOtBu, DMSO, 25 “C; 93%. b) 250°C in
n-icosane; 85% [Sl.
In an analogous way 9,10-dihydroanthracene 13 furnishes
10-methyl-5 H-dibenzo[a,d]cycloheptene19 via the intermediates 14 to 18 (Scheme 3). After introduction of a 3dimethylaminopropyl group at position 10 of 15, the compound 22 is formed analogously via the intermediates 20 and
-4
14
13
15
& dM )e &
CH,O,SMe
+
\
/
d
\
/
/
17
16
&
\
\
/
18
Total Enantiospecific Synthesis of
(9s)- and (9R)-9-Hydroxyeicosatetraenoic Acid
(PHETE) Methyl Ester
Me.
By MichPle Saniere, Yves Le Merrer, Brigitte Barbe, Thierry
Koscielniak, Jacques Dumas, Dominique Micas-Languin, and
Jean-Claude Depezay *
19
It has recently been demonstrated that leukotrienes
(LTC,, LTD, and LTE,) are formed in the central nervous
system. [‘I Furthermore, 9-hydroxyeicosatetraenoic acid (9HETE) was isolated from incubations of sliced rat brain
tissue,[*]thus pointing to a direct lipoxygenase activity in the
brain. The formation of 9-HETE had previously never been
observed in mammalian tissues.
Two syntheses of (&)9-HETE and (9S)-HETE have already been published. [31 In the interest of fully evaluating the
biological properties of 9-HETE it was desirable to obtain
adequate supplies of both enantiomers. We report here on
the synthesis of the enantiomeric 9-HETE methyl esters from
Me.
(CH,),NHMe. HCl
Scheme 3. Reaction conditions: a) 1. nBuLi, THF, -78°C; 2. Dropwise addition to ClC0,Et (fourfold excess) in THF, -78°C; 3. KOtBu, THF, 0°C; 4.
MeI. 0 ° C ; 85%. b) LiAlH,, ther; 96%. c) MeSO,Cl, NEt,; 93%. d) KOtBu,
DMSO,2S0C;94%.e)1. 2equiv.nBuLi,THF,0°C;2. CICH,CH,CH,NMe,,
0 -C; 81%. f)I.MeSO,CI, NEt,; 2.KOtBu, DMSO, 25°C; 79%.
g) 1. CICO,Ph, CH,CI,, 25°C; 2. NaOH, 5 0 % aqueous ethanol, reflux;
3. HCI; 67% IS].
614
[I] Reviews of the bislactim ether method for the asymmetric synthesis of
amino acids: U. Schollkopf in J. Streith, H. Prinzbach, G. Schill (Ed.):
Organic Synthesis: An InterdisciplinaryChallenge, Blackwell. Oxford 1985,
p. 101; U. Schollkopf, Pure Appl. Chem. 55 (1983) 1799: Chem. Scr. 25
(1985) 105.
[2] U. Froth, U. Schollkopf, Synthesis 1983, 37.
[3] J. Mittendorf, Diplomarbeit, Universitdt Gottingen 1987, and unpublished
results.
[4] The mole fraction of 3 was determined ‘H NMR spectroscopically as a
function of time.
[5] A. P. ter Borg, H. Kloosterziel, N. van Meurs. Recl. Tray. Chim. Pays-Jas
84 (1965) 717.
[6] H . Kessler, Angew. Chem. 82 (1970) 237; Angew. Chem. Int. Ed. Engl. 9
(1970) 219.
171 This easier [1,5]-hydrogen shift is said to be due to a change in the orbital
energies and orbital coefficients (see also C. B. Argo, J. T. Sharp, J. Chem.
Soc. Perkin Trans. 1 1984, 1581; N. Hoshi, H. Hagiwara, H. Uda. Chem.
Leu. 1979, 1291, 1295, N. Hoshi, H. Uda. J. Chem. Soc. Chem. Commun.
1981, 1163). In the transition state of the rearrangement 3 + 4 the imino
ether group has a relatively strong electron-withdrawing effect on both ends
of the azapentadiene system. The energy of the HOMO of the azapentadienyl radical should be lowered thereby and the transition state should be
stabilized compared to that in the cycloheptatriene system 6 (I. Fleming:
Frontier Orbitals and Organic Reactions. Wiley, Chichester 1978, p. 27).
[S] Correct C , H analyses and ‘H and 13C NMR and mass spectra were obtained for all the described compounds.
8 VCH Verlagsgesellsrhaji mbH. 0-6940 Weinheim, 1989
[*I Prof. Dr. J . C . Depezay, Dr. M. Saniere, Dr. Y. Le Merrer. B. Barbe,
T. Koscielniak, J. Dumas, Dr. D. Micas-Languin
Universitk Rene Descartes,
Laboratoire de Chimie et Biochimie Pharmacologiques
et Toxicologiques (UA 400 CNRS)
45 rue des Saints P&s, F-75270 Paris Cedex 06 (France)
0570-0833j89jOSOS-0614$02.50/0
Angew. Chem. I n l . Ed. Engl. 28 (1989) N o . 5
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diazepin, benzodihydroarenes, structure, dihydropyrazines, variant, benzocycloheptene, derivatives, protriptyline, antidepressants
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