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Non-Toxic Alternative for a Key Step in Porphyrin Synthesis.

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la: R = Me
l b : R = Et
IC: Rz = (CH2)4
3a: H
36: R
ceeds extraordinarily smoothly for vinylcyclopropane-cyclopentene or vinylcyclopropene-cyclopentadienerearrangements. Rearrangements of this type normally require
considerably higher temperatures[31(e.g. for triphenyl(viny1)cyclopropene: 180°C) or irradiation[']. The large number of amino substituents in 4 therefore effects a drastic
reduction in the activation barrier (in general, highly donor-substituted cyclopropenes very readily undergo ringopening reactions[']. However, the rate of the vinylcyclopropane-cyclopentene rearrangement is also markedly increased by the presence of donor rather than alkyl substituents on the three-membered
Upon acidification of the reaction solution, 2 is doubly
protonated. The resulting cyclic 1,2,3-triamino-substituted
vinamidinium salts 6 can be isolated as perchlorates[61.The
intermediate 5 has not yet been isolated, but its occurrence
(possibly mixed with isomers) in solution is implicated:
Addition of the weak proton donor tert-butyl alcohol to
the solution of 2 results in the disappearance of its NMR
signals and gives rise to a complicated spectrum; the characteristic signals of 6 appear only after addition of acids['].
2 can be re-formed from 6 by the addition of strong bases
such as potassium hydride.
2 is also attacked twice by methylating agents to form
4,5-dimethyl-substituted salts 316].Whereas dimethyl sulfate reacts smoothly (isolation of the perchlorate 3a starting from la), in reactions with methyl iodide large
amounts of by-products are formed (see also, the formation of the triiodide 3b instead of the normal iodide)"].
On the basis of preliminary results, the reaction of 1
with vinyllithium described here can be applied to its homologues (e.g. butenyllithium), but not to vinylmagnesium
Received: October 28, 1983;
revised: December 9, 1983 [Z 608 IE]
German version: Angew. Chem. 96 (1984) 224
CAS Registry numbers:
la, 36509-73-6; lb, 70674-11-2; lc, 61916-72-1 ; Za, 88968-35-8;Zb, 88968-369 ; Zc, 88968-37-0; 3a (isomer l), 88968-39-2; 3a (isomer 2), 88968-41-6; 3b,
88968-43-8;6a, 88968-45-0; 6b, 88968-47-2;6c, 88968-49-4;CH2=CHLi, 91757-7.
[I] M. Bernheim, C. Boche,Angew. Chem. 92 (1980) 1043;Angew. Chem. Int.
Ed. Engl. 19 (1980) 1010.
[2] Z. Yoshida, Y. Tawara, J . Am. Chem. SOC.93 (1971) 2573.
[3] a) Houhen-Weyl-Miiller: Methoden der organischen Chemie, Band IV/3,
Thieme, Stuttgart 1971, p. 597-604, 714-716; b) H. G. Richey, D. W.
Shull, Tetrahedron Lett. 1976, 575; c) B. M. Trost, P. H. Scudder, J. Org.
Chem. 46 (1981) 506, and literature cited therein.
[4] A. Padwa, Acc. Chem. Res. I2 (1979) 310.
151 a) M. T. Wu, D. Tauh, A. A. Patchett, Tetrahedron Left. 1976, 2405; b) R.
Gompper, K. Sch6nafinger, Chem. Ber. 112 (1979) 1514; c) R. Weiss, H.
Wolf, ibid. 113 (1980) 1746; d) H. Yoshida, M. Nakajima, T. Ogata, K
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
227-232 Advertisement
= M e , Y = C10,; 64"0
= Et, Y = 1,; 20%
Matsumoto, R. M. Acheson, J. D. Wallis, Chem. Lett. 1983, 155, and literature therein.
(0.7 g, 20.5 mmol) in 10
[6] Procedure: 3 and 6 : A solution of vinyllithi~m'~~
mL THF was added dropwise to a suspension of 1 (10 mmol) in 10 mL
THF at -78°C and the solution then slowly warmed until reaction commenced. When evolution of gas had ceased, the mixture was maintained
at 30-40°C for 1 h, and the electrophile (conc. perchloric acid, methyl
iodide, or dimethyl sulfate) added in excess (30-40 mmol) at -78°C.
After warming to RT (and for the methylation after additional stirring for
24 h at RT), the mixture is concentrated to ca. 5 mL in vacuo, the residue
treated with 20 mL water, and the aqueous phase extracted with dichloromethane (3 x 10 mL). The extracts were loaded onto a silica gel column,
and the product fraction eluted with acetone (3a, 6a, 6s) or THF (3b,
6b). The eluate was concentrated in vacuo and the residue recrystallized
from chloroform/ethyl acetate: colorless or violet-brown (3b) crystals;
3a: m.p.=112-117, 3b: 124, 6a: 131, 6b: 96-97,6c: 161°C; yields, see
Scheme 1. All compounds gave correct C,H,N-analysis values.
[7] B. Bogdanovic, B. Wermeckes, Angew. Chem. 93 (1981) 691; Angew.
Chem. I n f . Ed. Engl. 20 (1981) 684.
[8] 'H-NMR (CDCI,): 6a (R=Me): S=2.54 (s, 6H), 2.75 (s, 4H), 3.29 (s,
12H); 6b (R=Et): 1.01 (t, 6H), 1.28 (t, 12H), 2.83 (q, 4H), 2.90 (s, 4H),
3.66 (4,8H); 6s (RZ=(CH2)4):1.75-2.25 (m, 12H), 2.82 (s, 4H), 2.99
(mc, 4 H), 3.65 (mc, 8 H).
191 38 crystallizes as a mixture of cis- and frans-isomers; 3b appears to consist largely of the pure trans-isomer. 'H-NMR (CDCI,): 3a: 6 = 1.24/1.28
(2d, together 6H), 2.54/2.55 (2s, together 6H), 2.65 (mc, 2H), 3.30/3.33
(2%together 12H); 3b: 1.05 (t, 6H), 1.34 (d, 6H), 1.36 (t, 12H), 2.78 (4,
2H), 2.90 (mc, 4H), 3.77 (mc, 8H).
Non-Toxic Alternative for a
Key Step in Porphyrin Synthesis**
By The0 Wollmann and Burchard Franck*
The oxidative rearrangement of acetylpyrroles such as 1
to pyrrolacetic acids 4 is a key step in the synthesis of porphyrins with "natural" acetic acid side-chains. Until now
this rearrangement, whose result is analogous to the Willgerodt reaction, was performed using thallium(II1) nitrate"'. The toxity of this reagent, however, restricts the
usefulness of the method and also the application of the
synthesized products for medicinal purposes. Here, we describe an efficient, generally applicable method for the
rearrangement of acetylpyrroles in the presence of silver
nitrate (Scheme 1).
The pyrroleacetic acids 4a and 4b are of preparative importance because they permit the biomimetic syntheses of
medicinally used porphyrins in a few steps[*].For example,
[*] Prof. Dr. B. Franck, Dip1.-Chem. T. Wollmann
Organiscb-chemisches fnstitut der UniversitBt
OrlCans-Ring 23, D-4400 Miinster (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
0570-0833/84/0303-0226 $ 02.50/0
Angew. Chem. I n f . Ed. Engl. 23 (1984) No. 3
The silver can be fully recovered from the silver halide precipitates.
Received: November 25, 1983 [Z 633 IE]
German version: Angew. Chem. 96 (1984) 227
CAS Registry numbers:
la, 73869-95-1; lb, 62916-29-4;3a, 88915-86-0;3b, 88915-87-1; 4a, 73869-962; 4b, 50622-64-5; (MeO),CH, 149-73-5; 12, 7553-56-2; AgN03, 7761-88-8.
C,H zC 1
K' =
b, R' =
CH2-COzMe; R2 = C 0 2 M e
CH2-CH2-COzMe; RZ = C 0 2 C H 2 P h
Scheme 1. Intermediates
4a can be converted in three steps into the porphyrinoctaacetic acid 6,which differs only slightly from the biologically active naturally occurring porphyrin~[~].
4b can be
converted in five steps into the porphobilinogen 7,a building block in the biosynthesis of red blood pigmentr4];7 can
be condensed biomimetically to afford porphyrins.
Investigations of the mechanism of the oxidative rearrangement of simple aryl ketones indicated that the system
thallium(m) nitrate in MeOH/HClO, can be replaced by
I2/AgNO3l5].The reaction sequence involves a-halogenation of the ketone, ketalization, and rearrangement of the
a-haloketal to the acetate induced by silver ions
(1 + 2 + 5 +4).
By fulfilling certain restrictive reaction conditions, we
found that using this method the acetylpyrrole l b can be
converted into the triester 4b. Because of the formation of
side products, which necessitate chromatographic separation the method is still too troublesome for preparative
purposes. Furthermore, studies indicated that side products arise because of the instability of the intermediate iodoacetylpyrroles 2. These problems could be solved by
trapping 2 by conversion into the chloroacetylpyrroles 3.
The chloroacetylpyrroles 3a and 3b, obtained in high
yield, are readily isolable and form good crystals@].
For the rearrangement, 3a and 3b are converted into the
ketals 5a and Sb, respectively, which are refluxed in the
presence of silver nitrate. The yield of the rearrangement
step to afford 4a and 4b, respectively, is so high that the
overall yield starting from l a or l b is 68-69%. The yields
obtained using the new method correspond to those
achieved in the rearrangement with thallium(II1) nitrate,
but the former is preferable because of its non-toxicity.
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 3
[l] G. W. Kenner, K. M. Smith, J. F. Unsworth, J. Chem. SOC.Chem. Commun. 1973,43; J. H. Fuhrhop in K. M. Smith: Porphyrins and Metalloporphyrins, Elsevier, Amsterdam 1975, p. 759; J. B. Paine in D. Dolphin: The
Porphyrins, Vol. 1, Academic Press, New York 1978, p. 127.
[21 The porphyrins obtained from 4a and 4b have been used for metabolic
studies and for studies of the phototoxic activity of porphyrins: cf. M.
Doss: Diagnosis and Therapy of Porphyrias and Lead Intoxication, Springer, Berlin 1978; B. Franck, M. Dust, A. Stange, P. Hoppe, Naturwissenschaften 69 (1982) 401.
[31 B. Franck, G. Bringmann, C. Wegner, U. Spiegel, Liebigs Ann. Chem.
1980, 263.
[4] B. Franck, Angew. Chem. 94 (1982) 327; Angew. Chem. Int. Ed. Engl. 21
(1982) 343.
[5] S. D. Higgins, C. B. Thomas, J. Chem. Soc. Perkin Trans. 1 1982, 235; C.
Giordani, G . Castaldi, F. Casagrande, A. Belli, ibid. 1982, 2575.
[6] Preparation of chloroacetylpyrroles 3 : AgNO, (17 g, 100 mmol) and 1 (50
mmol) are added to anhydrous CaCI, (25 g, 225 mmol) in 150 mL anhydrous methanol. A solution of iodine (12.7 g, 50 mmol) in 100 mL anhydrous MeOH is added dropwise into the refluxing solution over 2 h, the
mixture heated for 1 h longer, the solution filtered while hot, and the precipitate washed with hot MeOH. After the filtrate has been diluted with a
threefold volume of water, the solution is saturated with NaCl, extracted
with CHC13, the extract concentrated, and the residue recrystallized from
MeOH/HZO. 91% 3a, colorless needles, m.p. = 149--150°C; 3b, colorless needles, m. p. = 109- 110°C.
[7] Rearrangement of 3 into the pyrroleacetic acids 4: p-Toluenesulfonic acid
(200 mg) was added to a solution of 3 (45 mmol) in 175 mL anhydrous
MeOH and 50 mL (460 mmol) trimethylorthoformate, the mixture
warmed to 50°C, and stirred for 1- 2 h under an inert gas atmosphere.
After conversion of the starting material into the ketal 5 (TLC monitoring
with ether (3a) or toluene/acetic actd=4: 1 (3b) on silica gel), AgNO,
(1 1.8 g, 67.5 mmol) is added. The mixture is refluxed for 5-7 h until 5 has
been fully converted into 4 (TLC monitoring). After addition of KI (4 g)
and cooling, the solution is filtered off, the filtrate diluted with a threefold volume of water, saturated with NaCl, extracted with CHCl,, concentrated, and the oily residue recrystallized from ethedpetroleum ether
(b.p. 30-60°C). 75% 4a, m.p.=92"C; 76% 4b, m.p.=78'C.
3-Trimethylsilylacrylic Acid as an Acetylene
Equivalent in Diels-Alder Reactions ;Olefins via
Anodic Decarboxylation-Desilylation**
By Dieter Hermeling and Hans J. Schafer*
Synthetic equivalents for acetylene which have a greater
dienophilicity and lower pressure sensitivity are desirable
for the preparation of 1,4-cyclohexadienes by [4 21-c~cloaddition. In this connection, (E)-l-benzenesulfonyl-2trimethylsilylethylene['l and maleic acid anhydride have
proved to be particularly useful. The maleic acid cycloadducts undergo facile anodic bisdecarboxylation to afford
However, low yields and electrode passivation
frequently limit the range of application and the scale of
the electrolysis. We have now investigated 3-trimethylsilylacrylic acid 1 as an acetylene equivalent. The trimethylsilyl moiety lowers the dienophilicity only marginally['1,and
the P-trimethylsilylcarboxylic acid obtained can be converted anodically into an olefinL3].
[*I Prof. Dr. H. J. SchPfer, DipLChem. D. Hermeling
Organisch-chemisches Institut der Universitat
OrlCans-Ring 23, D-4400 Miinster (FRG)
[**I Anodic Oxidation, Part 31. This work was supported by the Fonds der
Chemischen 1ndustrie.-Part 30: G. Schlegel, H. J. Schafer, Chem. Ber.,
in press.
0 Verlag Chemie GmbH, 0-6940 Weinheim, 1984
0570-0833/84/0303-0233 $ 02.50/0
777-717 Adnprtirpmpnt
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step, synthesis, key, porphyrio, non, alternative, toxic
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