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Intramolecular Cycloadditions of C O and C N Multiple Bonds to ortho-Quinodimethanes.

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171 M. p. according to Ref. [2] : 190-191 "C
[8] W E . Bnchmann and W S . Struce, J. Arner. Chem. SOC.63, 2589
(1941).
[9] A . Horeau, C. R. Hebd. Seances Sci. ZZS, 2039 (1949); D.J. Cram
and H.Steinberg, J. Amer. Chem. SOC.76, 2735 (1954).
Intramolecular Cycloadditions of C,O and C,N
Multiple Bonds to ortho-Quinodimethanes"l
&FH3"Dem
N
76%
By WoEfgang Oppofzer"'
Recently the smooth intramolecular cycloadditions of
even nonactivated olefins and acetylenes to o-quinodihave been described. This communicamethane: (1
tion deals with the analogous reactions of weakly dienophilic carbonyl compounds, azomethines and nitriles
( I b ) t31.
O-NCHs
O-NCH?
82%
(1)
(a). Y
(b), Y
=
c
= 0, N
When a 1% solution of the aldehyde
was heated in
boiling bromobenzene under argon for 23 h a mixture of
the stereoisomeric benzopyranopyrroles (3) (m. p. 134 to
135°C; N M R : 6HA=8.1ppm) and (4) (rn.p. 218-219°C;
NMR : 6,,= 7.64 pprn) resulted in 25% yield.
+
I
On thermolysis in boiling bromobenzene the oxime ether
(15)["] gave a low yield of 3-phenyli~oquinoline['~~.
This
transformation obviously involves an electrocyclic reaction
of the intermediate o-quinodirnethane (16) sirniliar to the
cyclizations recently described by Schniid"." and Ka~netani['~!
The new compounds described here were characterized by
elemental analyses or high-resolution mass spectra as well
as by IR, UV and NMR spectra (CDCI,).
cis-2,3,3a,4,5,9 b-Hexahydro-4-nzethoxy-I H-pyrrdo(S,Cc]isoquinolin-I-one (7) .
OC H3
bCH3
Similarly the oxime ether (5)[61 rearranged in boiling bromobenzene to the stereoisomers (6) (m. p. 124-126°C;
NMR : tiHA=
8.1 ppm) and (7) (m. p. 231 -232 "C ; NMR :
?jHA=7.65ppm), in this case with a much better yield.
After addition of a catalytic amount of p-toluenesulfonic
acid, the trans-lactam (6) epimerized in boiling bromobenzene to the cis-lactam (7). This sequence thus opens an
efficient, stereo-controlled access to cis-pyrrolo[3,4-c]isoquinolines.
Surprisingly, even nitriles can add intramolecularly to
o-quinodimethanes under similiar conditions. Thus the
thermolysis of the nitriles[81(S), (10) and (12) gave a high
yield of the dihydroquinolines (9), (11) and (13), which
could be readily oxidized to the corresponding isoquinolines (e. g. ( 9 ) -+ (I4)).
[*] Dr. W. Oppolzer
Pharrnazeutisch-Chemische Forschungslaboratorien, Sandoz AG
CH-4002 Basel (Switzerland)
Angew. Chem. internal. Edit.1 Vol. ff (1972) No. I 1
A solution of the oxime ether (5)16' (99 g) in bromobenzene
(2.5 liters) is refluxed for 20 h under argon atmosphere. The
product (7) (57.2 g), which crystallizes from the cooled
solution, is collected, washed with pentane and dried. The
morher liquor (from which the isomer (6) can be isolated
by chromatography) is refluxed for 14 h with p-toluenesulfonic acid (0.5 g) and evaporated. The residue is then
purified by chromatography (silica gel) and crystallized
(ether/pentane) to give a further 10.0 g of the product (7)
(total yield 68%).
2,3,4,5-Tetrahydro-2-methyI-1H-pyrrofo[3,4-c] isoquinolinI-one (9) :
A solution of the nitrile ( 8 )[*I (46 g) in toluene (460 ml) is
transferred into a steel autoclave, flushed carefully with
argon and then heated at 180°C for 16 h. Evaporation of
the reaction mixture and crystallization from dichloromethane affords the product ( 9 ) (35.2 g, 76%).
2,3-Dihydro-2-methyZ-l H-pyrrolo[3,4-c] isoquinolin-I -one
(14) :
Oxygen is passed for 2 h through a solution of the compound ( 9 ) (12.5 g) in ethanol (500 ml) containing FeCI,
1031
(0.2 g) at 25 "C. The reaction mixture is evaporated and the
residue crystallized from dichloromethane/ether : 8.9 g,
71 %; m. p. 178-180°C.
Received: August 24,1972 [Z 713 IE]
German version: Angew. Chem. 84,1108 (1972)
[l] Part of a lecture: 13th National Medicinal Chemistry Symposium,
Iowa City (USA), June 1972.
[2] W Oppolrrr, J. Amer. Chem. SOC.93,3833.3834 (1971): W O p p o i x r
and K . Keller, ibid. 3836; Angew. Chem. 84,712 (1972); Angew. Chem.
internat. Edit. 11, 728 (1972).
[3] Carbonyl compounds, azomethines and nitriles in general act as
weak dienophiles, except for some derivatives that are activated by
electron-withdrawing substituents : J . Hamer: 1,CCycloaddition Reactions, Academic Press, New York 1967, p. 97, 128, 205; J . - M . Biehler.
J . Prrclutis, and J.-P. flrrrrj, Bull. Soc. Chim. Fr. / 9 7 / , 271 1 . M . f
Ansell and A . A . Charalambides, J. C. S. Chem. Comm. 1972, 739;
D. uor der Briick, R . Biihler, and H . Plieninger, Tetrahedron 28, 791
(1972).
[4] The oily aldehyde (2) was obtained by the following reaction
sequence : a) acylation of (methy1amino)acetaldehyde dimethylacetal
by benzocyclobutene-I-carbonylchloride [5] and 3 equiv. of pyridine
in dichloromethane; b) cleavage of the acetal by 1N HClO, in dioxane/
water (1S:l) for 6 h a t 25°C.
[S] J . A . Skorcz and J . E. Robertson, J. Med. Chem. 8, 255 (1965).
[6] The oxime ether ( 5 ) (m. p. 92-94°C) was prepared by reaction
of the N-formylmethyl-benzocyclobutene-I-carboxamide(cf. Ref. [4])
with 1 equiv. methoxyamine-hydrochloride in pyridine in the presence
of an excess of molecular sieves, 2 h, 25°C.
[ll] The oily oxime ether (IS) was prepared from l-benzoyl-benzocyclobutene [13]; cf. Ref. [6].
[I21 N . Vinot, Bull. SOC.Chim. Fr. 1960, 617.
[I31 R. Hug, H.-J. Hansen, and H . Schmid, Helv. Chim. Acta 55, 10
(1972).
[I41 7: Kametani, K . Ogasarawa, and 7: Takahashi, J. C. S. Chem.
Comm. 1972,675.
The Influence of Haloalkanes on the I3C-NMR
spectra of n-Alkanes
By Gerhard Bergmann and Joachim Dahm[*]
In contrast to the extensive study of solvent effects in
'H-NMR spectroscopy, little has hitherto been reported
about such effects on I3C-NMR spectra['-61. The observed
effects have mostly been interpreted as due to hydrogen
bond^[^,^] or the polar reaction field131.However, more
recent results15. with the apolar, isotropic tetramethylsilane indicate that other factors, perhaps van der Waals
forces, also have a marked influence on the chemical
shifts of 13C signals.
We have measured the solvent-dependence of all the
13C-NMR signals of a series of linear alkanes for infinite
dilution in the halomethanes CH,Cl,, CCI,, CH,Br, and
Table 1. 13C solvent shifts AG (ppm) [a].
Solvent
n-Alkane
Position of
I
2
3
-0.46
-0.46
-0.47
-0.44
-0.87
-0.85
-0.87
-0.89
- 1.48
1.47
- 1.46
- 1.45
-0.19
-0.19
-0.19
-0.19
-0.25
-024
-0.24
-0.25
-0.63
-0.63
-0.63
-0.62
-0.1 I
-0.12
-0.12
-0 14
-0.18
-0.18
-0.18
-0.19
-0.43
-0.46
-0.44
-0.46
-1.59
- 1.58
- 1.59
- 1.60
-0.80
-0.80
-0.80
-0.79
-0.54
-0.60
-0.58
-0.60
4
5
6-8
-0.12
-0.16
-0.13
-0.14
-0.13
-0.13
-0.20
-0.20
-0.21
-0.20
-0.20
-0.20
-0.47
-0.46
-0.49
-0.46
-0.48
-0.49
-0.64
-0.62
-0.64
-0.63
-0.62
-0.63
...
CH,Cl,
CCI,
CH,Br,
CHJ
CsHr2
CIIHI H
C,r,H22
CisH~i
C4H12
CHHIH
CioH22
CisH~i
CsHiz
CxHix
CIOH~L
CIHJZ
CsHii
CNHIX
CioHi,
ClSH32
-
[a] Resonance frequencies v for infinite dilution in haloalkanes minus v for infinite dilution in cyclohexane
and susceptibility correction ; negative values towards lower field. Infinite dilution shifts were extrapolated from
measurements at six different concentrations with a least squares parabola. Assignment of the signals by Grant
and Paul's method [8] ;the assignment for C-5 to C-8 of n-pentadecane is uncertain ;this has, however, no influence
on the interpretation because of the almost equal solvent shifts of these signals.
[7] After heating a 2% solution of methyl benzocyclobutene-l-carboxylate in acetonitrile for 16 h at 200", only dimethyl trans-5,6,11,12tetrahydrodibenzo[a,e]cyclooctene-5,6-dicarboxylate (m. p. 154 to
156°C) could be isolated. This shows how strongly the course of the
reaction depends on the steric proximity of the nitrile group and the
o-quinodimethane moiety.
[S] The nitriles ( 8 ) (m.p. 70-72"C), (10) (mixture of diastereoisomers, m. p. 9O-11O0C) and (12) (m. p. 138--140°C) were obtained
by treating henzocyclobutene-1-carbonyl chloride [S] with (methylamino)acetonitrile, 2-piperidenecarhonitrile [9], or ethyl 4-cyano-4(methylamino)-1-piperidinecarboxylate[lo] respectively, in the presence of 3 equiv. of pyridine in dichloromethane for 1 h at -15°C.
[9] C.A . Grob, H . P . Fischer, H . Link, and E. Renk, Helv. Chim. Acta
46,1190 (1963).
[lo] The ethyl 4-cyano-4-(methylamino)-l-piperidinecarboxylate
(b. p.
125-139"C/0.5 torr) is accessible by a Strecker synthesis: ethyl 4-0x01-piperidinecarboxylate (1 mol), NaCN (0.9 mol), methylamine hydrochloride (0.9 mol), methanol/water (I :I), 16 h, 25°C.
1032
CHJ. The changes of the chemical shifts Ao in halomethanes, referred to the shift at infinite dilution in
cyclohexane, are listed in Table 1,from which the following
facts can be recognized.
1.With cyclohexane as reference solvent, all the haloalkanes
studied shift the signals to lower field. A systematic relation
exists between the shift of the 13Csignal and the position of
the C atom: the methyl group is the most sensitive to
solvent effects. Within any one alkane, IAol decreases
rapidly with increase in the distance from the end of the
chain and reaches, beginning with C-4, an approximately
[*I Prof. Dr. G. Bergmann and Dip1.-Chem. J. Dahm
Lehrstuhl f i r Analytische Chemie der Universitat
463 Bochum-Querenburg, Buscheystr. NC 4/72 (Germany)
Angew. Chem. internat. Edit. I Vol. I1 (1972) 1 No. I1
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