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Intramolecular Oxidative Cyclization of 3-Benzyl-1 2 3 4-tetrahydroisoquinolines.

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Chem. Int. Ed. Engl. 6,402 (1967); L. A. Paqueffe.J. P. Snyder in Nonbenzenoid Aromatics. Vol. 1. Academic Press. New York 1969, p. 249.
[2] Attempts to liberate (1) from ( 1 H-azepine)tricarbonyliron [E. 0. Fischer, H.
Ruhle, 2.Anorg. Allg. Chem. 341, 137 (1965)] with trimethylamine oxide
led only to difficultly identifiable mixtures of product ( J . - M . Drossard, N. T.
Allison, E. Yogel, unpublished); The reduction of N-tosyl-3-azaquadricyclane with sodium in liquid ammonia gave, even below -50°C. only 3Hazepine as isolable product [no physical data given. H. Prinrbach. H.
Babsch, Heterocycles I I , 1 I3 ( I978)].
131 According to most recent MIND0/3 calculations of the heats of formation,
( I ) is about 8.5 kcal/mol more stable than (2); corresponding calculations
for cycloheptatriene and norcaradiene and for oxepin and benzene oxide
gave a thermodynamic preference for the monocyclic valence tautomer of
12.2 and 1.7 kcal/mol, respectively ID.M. Hayes, S D Nelson, W. A . Gar[and, P. A. Koliman, J . Am Chem. SOC.102. 1255 (1980)]. For the substituent-determined shifts of the 1H-azepine-benzene imine equilibrium in favor of the benzene imine valence tautomer, see H . Prmzbach, H. Babsch, H.
Fritz, P. Hug, Tetrahedron Lett. 1977. 1355 (and references cited therein).
[4] E Yogel, U. Brocker, H . Junglas, Angew. Chem. 92. 1051 (1980); Angew.
Chem. Int. Ed. Engl. 19, 1015 (1980).
[5] The synthesis of (4) was accomplished analogously to that of 10-oxatricycl0[' ']deca-2,4-diene [E. Yogel, H. Gunther, Angew. Chem. Int. Ed.
Engl. 6, 385 (1967)] by dehydrohalogenation of 3,4-dibromo-lO-azatricyclo[4.3.1 .O'.']decane with potassium tert-butoxide in tetrahydrofuran; b. p.
28-3O0C/O.5 torr. The N-methoxycarbonyl derivative of (4) has been described by L. A . Paquerte er al. [lo].
161 M. E. Jung, M. A . Lyster, J. Chem. SOC.Chem. Commun. 1978, 315; G. A .
Olah, S. C. Narang, B. G. B. Cupra, R. Malhotra, Angew. Chem. 91, 648
(1979); Angew. Chem. Int. Ed. Engl. 18, 612 (1979).
171 a) (7a): 'H-NMR (CDC13. -60°C): 6=5.78 (m. H-3,6), 5.90 (m. H-2.7).
6.25 (m. H-4,5), 12.4 (COOH); "C-NMR (CDCI,. -60°C): 6=120.2 (C3,6), 129.6, 130.6 (C-2,4,5,7), 157 4 (C=O); b) (8): Short path distillation at
25 "C/O.l torr; 'H-NMR (CDCI,) S=2.42 (m. 2H-3). 5.25 (m, H-4). 6.206.70 (m. H-2.5.6). 7.55 (m. H-7); "C-NMR (CDCI,): 6=34.3 (C-3). 113.3,
117.5, 127.3, 136.4, 141.0 (C-2
7); c) (11): 'H-NMR (CDCI,): 6=0.13
( s , 3 C H ? ) , 4.78 (m. H-3.6)- 5.03 (m, H-2,7). 5.49 (m, H-4.5); ' C N M R
(CDCI,): 6=117.6 (C-3,6), 131.8 (C-4.5). 139.1 (C-2.7).
[S] For the synthesis of (I) on a preparative scale it proves convenient to decarboxylate 0.5 g of (7) in 12 ml of chloroform (also dichloromethane, acetone
or ether) according to the procedure given above. The longer reaction time
required (1-2 min) results in the formation of ca. 10% polymers besides ( I ) .
The solution of (I) is used immediately for chemical reactions.
[9] a) J. C. Pommeler, J. Chuche, Tetrahedron Lett. 1974. 3897; b) H. Giinther,
H.-H. Hinrichs. ibid. 1966, 787.
1101 L. A. Paquetfe, D. E. Kuhla, 1. H. Barrett, R. J. Haluska, J . Org. Chem. 34.
2866 (1969).
[ I l l A. L. Johnson, H. E. Simmons. J . Am. Chem. SOC.89, 3191 (1967).
[ 121 Unpublished experiments in collaboration with W Lange.
Intramolecular Oxidative Cyclization of 3-Benzyl1,2,3,4-tetrahydroisoq~inoIines[**~
By Johannes Hartenstein, The0 Heigl, and
Gerhard Satzinger"]
In view of the supreme importance of l-benzyl-I,2,3,4-tetrahydroisoquinolines for the biosynthesis of alkaloids['], it is
surprising that nature appears to have completely overlooked
the 3-benzyl isomers. In the search for such "unnatural" alkaloids we have found that the non-phenolic oxidative coupling of 3-benzyl-1,2,3,4-tetrahydroisoquinolines(la-c)[*]
with VOF3 in trifluoroacetic acid (TFA) at - 15 to 0 "C leads
smoothly and in high yields ( >80%) to the previously unreported 1,2,3,4-tetrahydro-2,8a-methanodibenzo[c,e]azocin-6ones (Z~-C)['.~~
(Table 1).
The cyclization products (2) are closely related to the natural morphinandienones, e. g. 0-methylflavinantine (3).
The alternative structure (5), the product of a para-coupling of the phenyl group with position 8a of the isoquinoline, could be ruled out by analysis of the 360-MHz 'H-NMR
spectra. Decoupling experiments with (2a) show that a re[*] Dr. J. Hartenstein [ * ], DipLPhys T. Heigl, Dr. G . Satzinger
Godecke Forschungsinstitut, Arzneimittelforschung
Mooswaldallee 1-9, D-7800 Freiburg (Germany)
[ ] Author to whom correspondence should be addressed
I**] We thank G. Pohlmann for valuable assistance with the experiments.
0 Verlag Chenue, GmbH, 6940 Weinheim. 1980
mote coupling of 1 Hz exists only between the vinyl proton
H-5 (6=6.09) and one of the aliphatic protons (H-4,
6= 3.39). Assuming structure (5), then the demonstrated relation between a vinyl proton and an aliphatic proton by remote coupling would require a n unusually large chemical
shift of 3.36 for the C-13 methylene group. Also the positions
of the signals at 1.91, 2.06 and 1.85 [Table 1, H-13B for (Za),
(Zb), and (Zc)], respectively, would hardly be compatible
with the chemical shift of protons of a n allylic CH,-group.
Besides the main products (2a-c), very small amounts
(< 5%) of products of over oxidation are formed, namely the
3,4-didehydro derivative of (2a) in the cyclization of (la),
( ( I ) , R'
CH3, R 2 = H
(h), R' = R 2 = CH,
(C), R' = CzH,, R 2 = CH3
and the I-hydroxy derivatives (46, c) in the cyclization of
(lb, c). The hydroxy compounds (4)are formed regio- and
diastereoselectively from (2) in analogy to the hydroxylation
of aporphined5'. Apart from the differences determined by
the substituents, the signals for H-2, H-4 and H-13 in (4)correspond to those in (2a-c). On the other hand, the ABX system of the H-I methylene group is absent; instead a somewhat broadened singlet is observed at 4.85. Compatible with
a dihedral angle of ca. 90" there is practically no coupling
between H-Is and H-2. Moreover, H-12 is shifted downfield
by ca. 0.2 ppm owing to the proximity of the hydroxy
Table I . Some data of the compounds (Za-c), 3.4-didehydro- (2a), and (4b)
[al(20). m.p. 186-187 "C (methanol/ether). MS (70 eV): m / e 327 ( M + ,12%), 178
(EI, 100). 150 (19); 299 (CI, 100); IR (KBr): 1655, 1633, 1610 cm I: 'H-NMR
[bl: S=3.70, 3.73, 3.89 (3 x OCH,), 5.93 (s, H-8). 6.09 (s, H-5), 6.50 (s, H-9). 6.74
(S. H-12); [Cl 1.91 (ddd, H-138. J A ~ = l 2 . 5 ,J E ~ , ~ = 1 . J5 E. ~2'4.0). 237 (dd,
H - ~ ~ A , J A B = ~ ~~.~~~, =J 1A. 8 ) , 3 . 0 2 ( b r . d , H - I ~ . J ~ H2<1),3.37(dd,
H-I,, JAB=^^, J A nz=6.5), 3.33 (d. H-4n. J ~ n = 1 4 Jo
, HSZO). 3.39(dd, H-4,.
J A E = ~ ~ J. A H S = 1). 3.62 (br., H-2); UV (hydrochloride, ethanol); h,,,(~)=238
(17200). 275 (6000) nm
l2b). m . p . 168.5-170°C (methanol); 'H-NMR [b]: 6=2.54 ( s . N-CH,). 3.72,
3.77, 3 88 (3 x OCH,). 5.94 (s, H-8), 6.15 (5, H-5), 6.50 (s, H-9). 6.77 (s, H-12); [c]
2.06(ddd,H-13B),2.26(dd. H-l3,),2.97(dd. H-ln).3.11 (s,2xH-4),3.20(d. H1,)- 3.35 (br.. H-2)
( 2 ~ )m.p.
158--159°C (methanol); 'H-NMR [bl: 6 = 1.4. 4.0 (m. 3 x OC2HS).
2.52 (N-CHd. 5.89 (s, H-8). 6.10 (s. H-5). 6 50 (s, H-9), 6.72 ( s , H-12)
3,4-Didehydro-(2a),m p. = 188--189°C (methanol/ether)
14b). m.p. 188-189 "C (methanol/ether): 'H-NMR [b]: 6 = 2.54 (N-CH3), 3.69,
3.74, 3.87 (3 x OCH,), 4.85 (br. s, H-I), 5.93 (s. H-8), 6.07 (s, H-5), 6.47 (s, H-9),
7.01 (S, H-12); [c] 1.85 (dd, H-l3B), 2.53 (dd, H-13,). 2.96 (d, H-4B). 3.03 (d, H4,). 3 24 (br., H-2)
[a] Mass, IR, and UV spectra are in agreement with the given structures. Satisfactory (kO.216) elemental analyses (C, H, C1, N) were obtained for the hydrochlorides of (2a-c). [b] 60 MHz. CDCI1. TMS int. [c] 360 MHz, CDCI,. TMS int.,
J in Hz.
Angew Chem. Int. Ed Engl. 19 (1980) No. 12
Et3P=CHMe (4) and (1); even in pure form, (5) is a noncrystallizable oil and can thus be measured NMR spectrosco( ? )-(2b): 2-Methyl-6,7-dimethoxy-3-veratryl-1,2,3,4-tepically''"!
trahydroisoquinoline (Ib) (5.63g, 15.74mmol) is dissolved in
TFA (60 ml) cooled with ice-water, and the stirred solution
treated dropwise within 5 min at - 15 to - 10 " C under Nz in
the absence of moisture with a solution of VOF3 (4.20g, 2.5
equivalents) in TFA (200 ml). Stirring is continued for a further l h and then the solvent is removed at 2O0C/1O0torr.
The residue is treated with water and extracted with chloroform. The combined chloroform extracts are washed with
semiconcentrated aqueous ammonia. Subsequent drying, removal of solvent, and crystallization of the residue from methanol furnishes 4.55 g (85%) of ( t ) - ( 2 b ) .
Received: March 17. 1980 [ Z 631 IE]
German version: Angew. Chem. 92, 1055 (1980)
[ I ] Cf. D. R Dalton: The Alkaloids. M. Dekker, New York 1979, pp. 216f.
[2] J . Knabe, J. Kubifz, Arch. Pharm. (Weinheim) 297, 129 (1964); 1. Knabe, N .
Ruppenthal, ibid. 297, 268 (1964); J. Knabe. H. Powilleit. ibid. 304, 52
131 J. Ifanenstern, G Satzinger, DOS 2849 472.6 (1978). Godecke AG.
141 The reactions were carried out with the racemic compounds. In the formulas
the second enantiomer has been omitted.
[ 5 ] J. Harrenslein, C Solzinger, Angew. Chem. 89, 739 (1977). Angew. Chem.
Int Ed. Engl. 10. 730 (1977).
Total Reversibility of the Addition and
Transylidation of Trialkyl(alky1idene)phosphoranes
to Metal-Coordinated Carbon Monoxide["]
By Herbert Blau and Wolfgang Malischi'i
Dedicated to Professor Arfed Roedig on the occasion of
his 70th birthday
Nucleophilic phosphorus ylides add to the carbonyl carbon of carbonylmetal compounds that do not contain any
ligands other than CO"]. However, when trialkyl(alky1idene)phosphoranes[21are used the reaction does not stop at
the stage of the 1 : 1 adduct; instead, a rapid transylidation
(with further phosphorane) takes place to give phosphorus
ylide-substituted phosphoniummetal a ~ y l a t e s ' ~ ~ .
We have now found for the first time that reaction of a carbonyl(cyclopentadieny1)metal compound, MeC5H4Mn(C0)3
( I ) , with trimethyl(methy1ene)phosphorane (2) in the molar
ratio 1 : 2 leads, as with carbonylmetal compounds, in a twostep reaction to formation of phosphorus ylide substituted
phosphoniummetal acylates, having quite novel and unusual
properties. Thus, the product (36)-an egg-yellow, extremely
pyrophoric substance-obtained from (1) and (2) in pentane
by addition and transylidation, completely regenerates the
educts ( I ) and (2) on dissolution in tetrahydrofuran, or an
ample amount of benzene, or pentane.
Consequently, (3b) can only be identified by IR spectroscopy (by two low-wavelength v C 0 bands, indicating the anionic character of the metal acylate), by analysis, and by secondary reactions[5!
Decisive evidence for the structure of (3b) is obtained from
the product (5), formed in the same fashion from
Prof Dr. W. Malisch, Dipl.-Chem. H. Blau
lnstitut fur Anorganische Chemie der Universitat
Am Hubland. D-8700 Wiirzburg (Germany)
[**I Presented in part at the Chemiedozententagung 1919 (Darmstadt), Referateband B47, and the 1X.International Conference on Organometallic Chemistry
1979 (Dijon), Abstracts of Papers P32T. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
Angew. Chem. lnr. Ed. Engl. 19 (1980) No 12
0 0
(2) M e 3 P C H Z
Dissociation (on dissolution) and regeneration (on concentration of the solution) of (3b) and (5) can be repeated unlimitedly. Addition of the phosphorus ylide (2) to the carbonyl
carbon of (1) (step A) and deprotonation of the adduct (3a)
at the CH2-bndgeby further ylide (2) (step B) are accordingly completely reversible processes.
2 Et3P=CHMe
M n -C(O)-MeC=PEt,]
= q5-MeC5h(CO)zMn
Decisive for an understanding of this unusual phenomenon is the fact that in step B a transylidation equilibrium['] is
established between the corresponding acid/base pairs:
[Me,P]@ (acid @)/Me3PCH2 (2) (base
-0(3a) (acid @)/[Me,PCHC(O)-
@ ] (base
The shift of equilibrium to the left on dissolution of (3b) beins with the deprotonation of the cation @) by the anion
b2 and is strongly favored, because the regenerated ylide
a duct (3a) is extremely labile and is already spontaneously
cleaved into (1) and (2) by the solvent. Since the reversibility
of addition and transylidation is not observed in the case of
metal systems bearing only CO11.3]ligands, it has to be ascribed chiefly to the higher a-donor/.rr-acceptor ratio of the
methylcyclopentadienyl ligand in comparison to CO. It
causes a) a lower electrophilicity of the carbonyl carbon and
hence a lower stability of the primary product (3a), b) a high
electron density on the manganese, which increases the basicity of the ylide function in the metal acylate to such an extent that it can deprotonate the [Me4P]@counterion''].
0 Verlag Chemie. GmbH, 6940 Weinheim, 1980
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benzyl, intramolecular, tetrahydroisoquinoline, cyclization, oxidative
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