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a-Substituted N-Formyl-S-benzylcysteines.

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C 0M M U N I CAT10 N S
Reaction of 1,l-Diphenylcyclopropane with
Tetracyanoethylener* *I
By Th. Martini and J . A . Kampmeier
Thermal reactions between electron-deficient ;r-systems and
C-C TI bonds have previously been encountered only with
highly strained cyclopropane compounds [I] such a s bicyclo12.1.O]pentanes, bicyclo[l.l .O]butanes, and quadricyclene [2,31.
A 1 : 1 cycloadduct of dispiro[2.4.2.0]decane and tetracyanoethylene was recently reported (41, hut the structure was
not clearly elucidated. We now report on the reaction of 1,ldiphenylcyclopropane ( I ) (51 with tetracyanoethylene (2).
When compound ( I ) (4.4 g, 0.023 mole) and compound (2)
(6.0 g, 0.047 mole) are heated together in benzene (100 ml)
in a n ampoule at 125 O C for 5 days, the color of the solution
changes from blood-red to brown. After removal of the solvent, the residue is heated t o boiling in CC14 (150 ml) and the
hot solution filtered to remove undissolved (2). The filtrate
is kept at O°C for several hours and then reheated and refiltered t o remove a final portion of (2).
A 10 ml portion of CHC13 is added to the filtrate which is
then allowed to stand at 0°C for 2 days t o give a brown
crystalline product (4.5 g, 65 % calculated for a 1 : 1 adduct).
The N M R spectrum o f the product shows it to consist of (3)
and (4) in the ratio 1 : 1.3. Careful N M R examination of all
work-up fractions failed to give evidence for other products.
NC.
cc
NN
ir
(41
The mixture could be separated by crystallization from absolute alcohol. The initial precipitate from alcohol is recrystallized from alcohol to give (3), m.p. 202-203°C. The
alcoholic mother liquor from the original separation is evaporated t o dryness and the residue taken up in cyclohexane.
The crystalline product, obtained after the solution has been
allowed t o stand for a day, is recrystallized from cyclohexane t o give (4 ) , m.p. 123-125 "C. Separation of 1.0 g of
crude reaction product gives 0.35 g of (3) and 0.3 g of ( 4 ) .
Both compounds give the expected C, H, N analyses and
molecular weight (mass spectrometry).
The N M R spectrum of ( 3 ) [in CDC13 a t 60 and 100 MHz:
2.70 (10 aromatic H/s); 6.88 (4 aliphatic H/s)] and the
U V spectrum [in CH3OH (Amax = 259 nm, E = 665)] support
structure (3). The symmetrical structure, 1,1,2,2-tetracyano4,4-diphenylcyclopentane,is ruled o u t by the NMR spectrum
[in C6D6 (60 MHz); T = 3.15 (10 aromatic Him); 7.97 (4 aliphatic Him 1691.
T =
The N M R spectrum of (4)[in CDC13 (60 MHz): T = 2.80
(10 aromatic Him); 4.02 (1 olefinic Hit), J = 7.1 Hz; 5.80
(1 aliphatic H/s) [71; 6.92 (2 allylic H/d), J = 7.1 Hz] shows an
unusually large solvent shift [81 [in C6D6 (60 MHz): T = 8.17
(1 aliphatic H/s) and 7.65 (2 allylic H/d)]. The UV spectrum
= 234 n m (sh), 259 nm, E = 13 600,
[in cyclohexane (A,
15500)][91 further supports structure (4). Reaction of 1,ldiphenyl-3-propene[lOJ with (2) in a n ene reaction 177 111,
under the conditions described above, gave a n independent
synthesis of (4)in 9 % yield (pure product, based on reacted
olefin). Neither the cycloadduct (3) nor rearrangement of the
olefin t o 1 , l -diphenyl-1-propene is observed.
236
Cyclopropane does not react with (2) under the conditions
described above. Heating compound ( I ) in benzene solution
for four days with maleic anhydride (at 140°C), fumaronitrile (at 175 "C), or 1,1-dichloro-2,2-difluoroethylene(at
130°C) gave only unreacted starting materials. (2) is thermally stable a t 130'C. The formation of (3) and (4) is most
simply explained in terms of a common, open-chain intermediate[2,11,121 ( 5 ) or ( 6 ) : cyclization leads to (3) and a
1,4 shift gives (4).
Received: January 9, 1970
[Z 142 IE]
German version: Angew. Chem. 82, 216 (1970)
[*I Dr. Th. Martini and Prof. Dr. J . A. Karnpmeier
University of Rochester, Department of Chemistry.
Rochester, N.Y. 14627 (USA)
[**I This work was supported by a Public Health Service Grant,
CA-06535, from the National Cancer Institute.
[l] R. B. Turner, P . Goebel, B. J. Mallon, W . v. E . Doering, J. F.
Coburn, Jr., and M . Pomeranfz, J. Amer. chem. SOC.90, 4315
(1968).
[ 2 ] P. G. Gassmann, K . T. Mansfield, and Th. 1.Murphy, J. Amer.
chem. SOC.91, 1684 (1969), and literature cited therein.
[3] A . B. Evniri and D. R . Arnold, J . Amer. chem. SOC.,90, 5330
(1968).
[4] D. S. Magrill, J. Altman, and D. Cinsburg, Israel J. Chem. 7,
479 (1969).
[5] C. L. Bumgardner, J. Amer. chem. SOC.83, 4420 (1961).
[6] Symmetrical 12 line spectrum having AA'BB' character, cf.
F. A. Bovey: Nuclear Magnetic Resonance Spectroscopy. Academic Press, New York 1969, p. 119.
[7] A. M. Lautzenhieser and P. W. LeQuesne, Tetrahedron Letters 1969, 207, report a tetracyanoethane proton at 7 = 5.33.
[8] L. M. Jackinrrn and S . Sternhe// AppIication of Nuclear
Magnetic Resonance Spectroscopy in Organic Chemistry. Pergamon, Oxford 1969, 2nd Edition, p. 105.
[9] UV spectrum of 1,l-diphenylethylene (n-heptane): h = 235.4
(sh), 248 nm, E = 13 730; H . Suzuki, Bull. chem. SOC.Japan 33,
619 (1960).
[lo] C. L . Bumgardner, J. Amer. chern. SOC.83, 4423 (1961).
[ll] For ene reactions with compound ( 2 ) , see H. M . R . Hoffmann, Angew. Chem. 8/, 597 (1969); Angew. Chem. internat.
Edit. 8, 556 (1969).
[12] S. Proskow, H . E. Simmons, and T. L . Cairns, J . Amer.
chem. SOC. 88, 5254 (1966).
@-SubstitutedN-Formyl-S-benzylcysteinesI11
By UIrich Schollkopf and Dieter Hoppe [*I
$-Substituted N-formyl-S-benzylcysteines( 4 ) warrant attention as cysteine precursors on account of the ease with which
benzyl and formyl groups can be removed [2,31 and because
they appear amenable to optical resolution[31.
We have now found that these compounds can be prepared
in a "single-vessel'' process by treating metalated ethyl isocyanoacetate ( 1 ) (prepared from ethyl isocyanoacetate and
e.g. butyllithium, potassium tert-butoxide, or sodium hydride
in tetrahydrofuran) with carbonyl compounds (21, then
adding phenylmethanethiol, evaporating off the solvent,
adding water and potassium hydroxide to the residue, and
finally warming for a short period.
The synthesis probably proceeds via $-substituted ethyl CLformylaminoacrylates ( 3 ) 141 which add the thiol after the
Angew. Chem. internat. Edit.
/ Vol. 9 (1970)
NO.
3
manner of a Michael reaction to give ethyl N-formyl-Sbenzykysteindtes. Support for this reaction course comes
from the fact that N-formyl-S-benzyl-$-phenylcysteineis
formed in 85% yield on reaction of ethyl ix-formylaminocinnamate 141 with phenylmethanethiol in ethanol containing
sodium ethoxide and subsequent hydrolysis.
M@
..o
,c=c,
~N-CH-CO~CZH,
L
11'
NH-CHO
13)
(1)
1
J
111 Syntheses with ix-Metalated Isocyanides, Part 4.
-
Part 3:
Ref. [4].
[2] Cf. TIT. Wieland, R . Miiller, E . Niemnnn, L . Birkofer.
A . Schoberl, A . Wagner, and H . Sol1 in: Houben-Weyl-Miiller,
Vol. 11/2. Thieme, Stuttgart 1958, p. 269, particularly pp.452ff.
[3] See, e . g . , for penicillamine H . T. Clarke, J . R . Johnson, and
R. Robinson: The Chemistry o f Penicillin. Princeton University
Press, Princeton 1949, pp. 455ff.
141 Cf. U. Schollkopf, F. Gerhrt, and R. Schriidrr, Angew.
Chem. 81, 701 (1969); Angew. Chem. interitat. Edit. 8, 672
(1969).
[5] I . Ugi, U . Feizer, U . Eholzer, H . Knupfer, and K . Offerrnnnn, Angew. Chem. 77, 492 (1965); Angew. Chem. internat.
Edit. 4, 472 (1965).
A New Spirocyclobutanone Synthesis
in the Steroid Series[**]
By Rudolf Wiechert1'1
'')
Reaction of 17-halogeno-16x-niethyl-20-oxasteroids( l a ) ,
( l b ) , and ( 3 ) "1 with a 2.4-fold excess bf dimethyloxosulfonium methylidel21 over a period of 90 minutes at 4OoC
leads t o formation of a product, which, after working-up,
acetylation, and separation by column chromatography, affords the symmetrical spirocyclobutanone ( 2 ) [m.p. 190 t o
192 "C (isopropyl ether), [a]',' = - -1 26 (CHCI,, c =: 0.5)j in
yields of 35- -55 "/I.
-
I
I R'
R'
nietalated
at ( ' C )
with [a]
yield
KOtBu
KOtBu
BuLi
NaH
BuLi
BuLi
BuLi
KOtBu
KOtBu
NaH
KOtBu
KOtBu
9
33
1
(%)
I
H
CH3
H
H
H
H
H
H
15
10
--70
35
-70
--70
-70
I5
30
35
30
30
61
30
21
1
1
3
Ibl
5333
67
C=O
70
54
32
,
39
59
[a] I n tetrahydrofuran. KOtBu = K tert-butoxide; BuLi
lithium.
[bl The ester IS only partially hydrolyzed.
HO
=
butyl-
( l a ) , X = C1
(lb), X = Br
N-Formyl-S-benzylpenicillamine (4b)
Butyllithium (0.04 mole as a 2.0 N solution in pentane) is
added dropwise to a vigorously stirred solution of ethyl isocyanoacetate [51 (4.53 g, 0.04 mole) in tetrahydrofuran
(30 ml) at -70 "C in such a way that the drops fall directly
into the reaction mixture. A solution of acetone (2.35 g, 0.04
mole) in tetrahydrofuran (10 ml) is then also added dropwise,
the mixture allowed t o warm up t o room temperature, and
phenylmethanethiol added (5.0 g, 0.04 mole). After removal
of solvent under vacuum, water (25 ml) is added t o the residue and the mixture is stirred for 5 min before addition of
potassium hydroxide (2.5 g, 0.045 mole). Stirring is continued
until a homogeneous solution is obtained (cn. 15 min)
which is then cooled t o room temperature before addition of
concentrated hydrochloric acid and subsequent ice-cooling.
When crystallization starts, ether is added and the mixture is
stirred for a short time. After 12 h (ca. -5 "C), 6.56 g (61 %)
of (46) precipitated, m.p. 157 "C (from ethanoli'water, 1 : 2).
N- Formyl-S-benzyl-B-phenylcysteine (4e)
A solution of ethyl isocyanoacetate (4.52 g, 0.04 mole) and
benzaldehyde (4.26 g, 0.04 mole) in tetrahydrofuran (10 ml)
is added dropwise t o a vigorously stirred suspension of 80%
potassium rert-butoxide (tert-butanol as crystal solvent) in
tetrahydrofuran (30 ml) at 150 "C. After 15 min, phenylmethanethiol (5.0 g, 0.04 mole) is added and the mixture is
treated as described above. (4e) (8.9 g, 70%) is obtained as a
mixture of diastereomers. Recrystallization from ethanol
affords a diastereomer having m.p. 170 O C .
(3)
The vC=O band of the four-ring ketone (2) appears at
1790 cm-1. A multiplet occurring at 6 = 2.75 ppm in the
N M R spectrum (CDC13, Varian A60) can be assigned t o the
two CHz groups of the four-membered ring. On measuring
the circular dichroism in dioxane a weak, negative Cotton
effect can be detected (Amax = 297 nm, LIE = -0.43). The
molecular weight (measured mass spectrometrically) is 384.
The analogous reaction of ketone ( 4 ) [31 (without methyl
group on C-16) leads t o formation of the symmetrical cyclobutanone ( 5 ) [yield 8%, m.p. 200.5-201.5 "C (isopropyl
ether); IR: vC0
1790cm-1; N M R : 6 - 2.2-3.25 pprn
(4H); CD: Amax = 296 nm, LIE = --0.411 and the ketone (6)
(yield 17 y:, m.p. 1 6 2 ~ 1 6 "C).
4
Signals due t o the two protons adjacent to the keto group
give rise t o a triplet in the N M R spectrum of ( 6 ) [A2 part of
:
CH
Received: January 7. 1970
[Z144 IE]
German version: Angew. Chem. 82, 253 (1970)
._
["I Prof. Dr.
U. Schollkopf and Dip].-Chem. D. Hoppe
Organisch-Chemisches Institut der Universitat
34 Gottingen, Windausweg 2 (Germany)
Angew. Chem. internat. Edit.
1 Vol. 9 (1970) No. 3
i
23 7
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