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Marked Increase in the Regioselectivity of Radical Substitution Minisci Reaction in a Two-Phase System.

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[41 H. Oschkinat, R. Freeman, J . Magn. Reson. 60 (1984) 164.
151 H. Kessler, A. Miiller, H. Oschkinat, Magn. Reson. Chem. 23 (1985), in
press.
[6] G . Quinkert, H. G. Schmalz, unpublished.
171 M. Rance, 0. W. Ssrensen, G . Bodenhausen, G. Wagner, R. R. Ernst, K.
Wuthrich, Biochem Biophy. Res. Commurr. 717 (1983) 479.
[8] D. Marion, K. Wuthrich, Biochem. Biophys. Res. Commun. 113 (1983)
967.
191 Suitable software has recently become available from Bruker.
[lo] D. J. States, R. A. Haberkorn, D. J. Ruben, J. M a p . Reson. 48 (1982)
286.
[ I I] Recorded via the TPPI method 181.
Table I . Product distribution [molLohjin the reaction of 1 with the ethoxycarbony1 radical (GLC analysis: 25 m 3% OV 17 WCOT, FID) For reaction conditions, see [7].
Mole ratio
1 :peroxide
Added CHzCll [mL]
3:l
1
81
14
3
3
1:3
~~
2
2 4, 5 , 6
unidentified products
24
36
38 [a]
2
1:3
1.3
1.10
30
150
150
6
80
6
9
49
42
3
6
~
85
4
II
[aj 4% 4, 24% 5 and 10% 6 [6]
Marked Increase in the Regioselectivity of Radical
Substitution:
Minisci Reaction in a Two-Phase System**
bonylation of protonated 1 in the presence of variable
amounts of dichloromethane. In each case, 2 was formed
as the main product. As shown in Table 1, it is possible to
react 1 practically quantitatively, so that analytically pure
2 can be obtained in > 80% yield.'']
By Gotrfried Heinisch* and Gerhard Lotsch
Dedicated to Professor Franz Viebock on the occasion
of his 85th birthday
Protonated Jc-electron-deficient N-heteroarenes are attacked by nucleophilic carbon radicals with pronounced
regioselectivity (Minisci reaction"'). This procedure is of
great preparative value if the heteroarene has only one free
position that can be attacked by radicals. Otherwise, unless
the first substituent introduced by radical reaction deactivates the ring system, polysubstitution occurs to a significant extent, as observed, for example, in homolytic acylations1*I and, especially, in alkoxycarb~nylations.~~~~~
We
have now found a simple method to significantly increase
the regioselectivity of radical ethoxycarbonylation which
thus provides an easy access to useful heteroaromatic synthetic building blocks.
According to Minisci et al.,I3l 4-pyridinecarbonitrile 1 is
attacked by ethoxycarbonyl radicals-employing a ratio of
1 :peroxide = 3 : 1-preferentially at the a-carbon atom; in
addition to ethyl 4-cyano-2-pyridinecarboxylate 2, 3 and
disubstitution products, which were not further identified,
were
Although, by reversing the ratio of 1 to
peroxide, the conversion could be increased from 19 to
76% (see Table l), disubstitution predominated as expected; this is shown by the increased formation of the pyridinetricarboxylic acid derivatives 4-6.16'
CN
CN
0
N
3-6
COOEt
2
1
3
4
5
6
R1
R?
R'
R4
H
COOEt
COOEt
COOEt
COOEt
H
COOEt
H
COOEt
H
H
H
H
COOEt
Since, in general, an alkoxycarbonylated heteroarene
should exhibit increased lipophilicity and reduced basicity, we investigated (cf. ref. [4]) the homolytic ethoxycar[*I Prof. Dr. G. Heinisch, Mag. pharm. G . Lotsch
[**I
692
7-10
11, 12
R'
R?
R'
7
8
9
10
H
COOEt
H
H
H
H
COOEt
H
H
H
H
COOEt
11
12
COOEt
H
Also in the case of 3-pyridinecarbonitrile 7 , it is possible
to suppress multiple substitution, even at high conversions,
by carrying out the reaction in a two-phase system.lxl The
resulting, expected mixture of the three esters 8,['l 9 , [ ' " ]
and 10r"' can be smoothly separated by chromatography.
Similarly, this reaction principle enables the product ratio
in the homolytic ethoxycarbonylation of pyrazine 11 (cf.
ref. [3]) to be decisively influenced in favor of the monosubstitution; ethyl 2-pyrazinecarboxylate 12[12]is formed
in 80% yield.['I Furthermore, the reaction of 4-phenethylpyridazine to give ethyl 5-phenethyl-4-pyridazinecarboxylate, which proceeds smoothly under these conditions (70%
yield) is noteworthy.l4I
Received: April 9, 1985;
supplemented: May 31, 1985 (Z 1253 IE]
German version: Angew. Chem. 97 (1985) 694
R'
H
H
R2
lnstitut fur Pharmazeutische Chemie der Universitat
Wihringerstrasse 10, A-1090 Vienna (Austria)
This work was supported by the Hochschuljubilaumsstiftung der Stadt
Wien. We thank Mr. C . Zinsherger for the gas chromatographic analyses.
0 VCH Verlagsgesell.~chaftmbH. 0-6940 Weinheim. 1985
CAS Registry numbers:
1, 100-48-1; 2, 97316-50-2: 3, 97316-51-3; 4, 97316-52-4; 5, 97316-53-5; 6 ,
97316-54-6; 7, 100-54-9; 8, 97316-55-7; 9, 91 192-30-2; 10, 41051-03-0: 11,
290-37-9; 12, 6924-68- I ; ethoxycarbonyl, 14541-20-9; ethyl pyruvate, 617-356.
[I] a) F. Minisci, Synthesis 1973. I ; b) F. Minisci, 0. Porta, Adu. Hererucycl.
Chem. 1974, 123: c) F. Minisci, Tup. Curr. Chem. 62 (1976) I .
[2j a) T. Caronna, G . Gardini, F. Minisci, Chem. Commun. 1969. 201; b) T.
Caronna, G. Fronza, F. Minisci, 0. Porta, J . Chem. Soc. Perkin Trans. 2
1972, 1477: c) G. Heinisch, A. Jentzsch, M. Pailer, Monatsh. Chem. 10s
(1974) 648; d) M. Braun, G. Hanel, G. Heinisch, ibid. 109 (1978) 63.
[3] R. Bernardi, T. Caronna, R. Galli, F. Minisci, M. Perchinunno, Tetrahedron Lett. 1973. 645.
141 G. Heinisch, G. Lotsch, Tetrahedron 41 (1985) 1199.
151 We were able to largely confirm these results (Table I ) ; G C / M S analysis, however, provided no evidence of 3 .
(61 G. Heinisch, G. Lotsch, unpublished results.
0570-0833/85/0808-692 $ 02.50/0
Angew Chem. Int. Ed. Engl. 24 (19851 No. 8
Experimental procedure: 2 : 30% H 2 0 2 (11.3 g, I00 mmol) was added
with stirring to ethyl pyruvate (17.3 g, 150 mmol) at - 10 to 0°C [3]. This
solution was then added with stirring and cooling ( - 5 t o 0°C) to a mixture of I (10 mmol), conc. H S O J (3 g), H 2 0 (8g), F e S 0 4 . 7 H 2 0 (28 g,
100mmol), and CH?CIZ(150mL). After 15 min of further stirring, the
resulting mixture was poured into ice water, the phases were separated,
and the aqueous phase was exhaustively extracted with CH2C12. After
drying over anhydrous Na2S0,, the solvent and excess ethyl pyruvate
were removed in vacuo. The spontaneously crystallizing, colorless needles were recrystallized from diethyl ether: Yield: 1.4g (81Yo) 2 ;
mp=X%93"; correct C,H,N analyses. IR (KBr): 1715 (v(.="), 2250 c m - '
(vCsN): MS: m/z 176 (2%, M + ) , 104 (100%): 'H-NMR (CDCI,, 90
MHz): 6=9.00 (d, 1 H, J = 5 Hz, H-6), 8.39 (d, 1 H, J = 2 Hz, H-3), 7.75
(dd, I H, J = 5 Hz, 2 Hz, H-S), 4.53 (4, 2 H , J = 7 Hz, CHI), 1.48 (t. 3 H ,
J = 7 Hz, CHI).
8-10. 12: 30% HIOI (3.4 g, 30 mmol) was added with stirring to ethyl
pyruvate (5.2 g, 45 mmol) at - 10 to 0°C (31. This solution was then added with stirring and cooling ( - 5 to 0°C) to a mixture of 7 o r I 1 (10
mmol). conc. H?SO, ( 3 g), H 2 0 (8 g), FeS04.7 H 2 0 (8.3 g, 30 mmol), and
CHZC12(30 mL).-8-10: After a work-up similar to that for 2, the residue is separated by medium pressure chromatography (LobaP size B,
LiChroprepm Si60, Merck; dichloromethane/ethyI acetate 5 : I). Fraction I : 394 mg 10 [ I l l (22%); fraction 11: 580 mg 9 [lo] (33%); fraction
111: 366 mg 8 [9] (21%).-1Z: After washing the spontaneously crystallizing, pale yellow needles with diisopropyl ether, 1.2 g (80%) of the product is obtained, whose spectroscopic data are identical with those of authentic material [12].
8 : Structure determination on the basis of the 'H-NMR spectrum
[CDCI,. 90 MHz: 6=9.10-8.90 (m, 1 H, H-6). 8.38-8.18 (m, 1 H, H-4),
7.83~7.60(m,1H,H-5),4.58(q,2H,J=7Hz,CH2),1.49(t,3H,J=7Hz,
CH,)] as well as the hydrolysis in 2~ Na2C03solution to 3-cyano-2-pyridinecarhoxylic acid 1131.
L. Noracek, K. Palat, M. Celadnik, E. Matuskova, Cesk. Form. I 1 (1962)
1 6 ; Chrm. Abstr. 57(1962) 15067i.
H. Watanabe, Y. Kikugawa, S. Yamada, Chem. Pharm. Bull. 21 (1973)
465.
H. Shindo, Chem. Pharm. Bull 8 (1960) 33.
S. Fallab, H. Erlenmeyer, Helu. Chim. Acra 34 (1951) 488.
Proton Exchange between Arenium Ions and Arenes
in the Gas Phase**
By Diefmar Kuck,* Steen Ingemann, Leo J . de Koning,
Hans-Friedrich Grutzmacher. and Nico M . M . Nibbering
Proton transfer reactions are known to be extremely fast
in general."] In the gas phase, they can be studied by modern, time-resolved mass spectrometry. Thus, MIKE spectrometry of metastable ionsL2](time scale l o - ' to
s) is
used for the investigation of intramoleculai hydrogen migration reactions, e.g., the proton exchange in protonated
a,o-diphenylalkanes [Eq. (la)],131while, for intermolecular
exchange reaction^,'^] Fourier transform ion cyclotron resonance (FT-ICR) s p e c t r ~ m e t r y ' is
~ ]becoming increasingly
important (time scale l o p 3 to l o + ' s). We report here on
the intermolecular proton exchange [Eq. (lb)] between
simple arenium ions and arenesl4'I in the cell of a FT-ICR
mass spectrometer[6' (Ar, Ar'= aryl).
Fig. I. a ) t 7 - I C K mdss spectrum of rl tiiikture of C H I , C,,H,,, .ind C'<,Il,, [7a];
b) after ejection of all ions except C,,H': (m/z 79) at the time r , = O ; c) after
I,= 190 ms, and d) after f,=6290 ms.
We generated the benzenium ions C6HY and C,HDz by
electron-impact ionization of a mixture of benzene,
[D,]benzene, and methane at lo-' Pa (Fig. la).[7"'All ions
except C6@ (m/z 79) were then removed from the ICR
cell by "notch ejection"[x1 (Fig. Ib); subsequently, the ionmolecule reactions of the benzenium ions isolated in this
way with the C6H6/ChD6mixture were followed as a function of time (fr). Figures Ic and Id show all ions present in
the cell at t , = 190 and 6290 ms, respectively; Figure 2 displays the dependence of the relative abundance of the
product ions c,(H,D)': on t,.
m lz
20
86
86
80
ArH @-(CH2),,-Ar' e Ar-(CH,),21n520
ArH?
+ Ar'H
@
ArH
10
Ar'H@
+ Ar'H?
(lb)
[*] Dr. D. Kuck, Prof. Dr. H.-F. Grutzmacher
Fakultgt fur Chemie der Universitat
Posrfach 8640, D-4800 Bielefeld 1 (FRG)
Prof. D r . N. M. M. Nibbering, Dr. S. Ingemann, L. J . d e Koning
Laboratorium voor Organische Scheikunde, Universiteit van Amsterdam
Nieuwe Achtergracht 129, NL-1018 WS Amsterdam (The Netherlands)
[**I
D. K . thanks the Deutscher Akademischer Austauschdienst, Bonn, and
the Ministerie voor Onderwijs en Wetenschappen, The Hague, for a
grant.
Anyew C'liern. Inr. Ed. Engl. 24 (1985) No. 8
rnI2
83
81
82
0
0
1000
2000
3000
LOO0
-
5000
6000
t,Irnsl
Fig. 2. Relative abundances of the product tons in the system C , , H 7 ) C ,,H,,
C,D, as a function of the reaction time f, given relative to the sum of all
product ions and corrected for naturally occurring "C.
The measurements allow two conclusions to be drawn:
1. The proton exchange between benzenium ions and
benzene is a surprisingly slow process (cf., for example, the
system D,0e/C&[4"1). For short reaction times 1, (under
0 VC'H Verlagsqe.sellschafi mbH, 0-6940 Weinheim. 1985
0570-0X33/85/0808-693 $ 02.50/0
693
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