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Benzene and Linearly Annelated Arenes as Dienophiles in DielsЦAlder Reactions with Inverse Electron Demand.

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age of the N-terminal amino acid as the tert-butylcarbamoyl amino acid isopropyl ester 3. After extraction of 3
with chloroform, the enantiomer proportions can be determined very exactly by enantioselective gas chromatography (a values 1.07-1.1 1 on a 25-m glass capillary with XE60-~-valine-(S)-a-phenylethylamide).
R
O
I
II
+ H2N-CH-C-NH-peptide
f Bu-N=C=O
1
R
0
O
II
I
II
f Bu-NH-C-NH-CH-C-NH-peptide
2
0
R
O
I/
I
I/
tBu-NH-C-NH-CH-C-0-iPr
+
thylaminopyridine-catalyzed reaction. The long reaction
times required for complete esterification may be responsible for the unusually high degree of racemization.
Comparison of the amounts of racemization after total
hydrolysis and after sequential degradation (Table 1) reveals that the hydrolysis of the peptide in 6 N HCl also
contributes to the racemization.
A further application of the procedure described here is
provided by the investigation of peptide antibiotics, in
which D- and L-amino acids are present in various positions.
For some amino acids (Lys, His, Arg, Trp), the carbamoyl derivatives are not sufficiently volatile for gas chromatographic investigation. In these cases, HPLC with chiral supports is a possible alternative. The first positive separation results were obtained with silica gel modified with
covalently bound glucose derivatives."]
Received: December 22, 1986 [Z 2019 IE]
German version: Angew. Chem. 99 (1987) 362
H2N-peptide
3
Scheme 1. For reaction conditions see text.
Under the given conditions, the use of isopropyl isocyanate and methanolic HCI results in the formation of Nisopropylhydantoins in addition to the isopropylcarbamoyl amino acid methyl esters. Although the former can
also be separated by gas chromatography, they are not
fully configurationally stable. In some cases, it proved to
be advantageous to esterify the peptide with HCl/isopropyl alcohol (1.0 N) before the reaction with isocyanate, because the solubility in pyridine and the conversion to the
carbamoyl derivative is often considerably improved.
Complete degradation of peptides containing 8-10 amino acids was achieved with 0.5-1 mg of starting material.
The method was used to investigate a synthetic octapeptide having the sequence H-Val-Ala-Leu-Ala-Lys-Lys-IleLeu-NH2, for which gas chromatographic analysis to determine the degree of racemization after hydrolysis gave an
unusually high value (8.7% D enantiomer) for Leu. Sequential degradation revealed a perfectly normal value (1.1%)
for the D-isomer content of Leu3 but a totally unexpected
value (10.2%) for the D-isomer content of the C-terminal
Leu. This finding is due to the synthesis of the peptide by
the procedure of Sheppard et al.[6.71using a polyacrylamide
resin as solid support. In this procedure, the C-terminal
Leu undergoes esterification with the polymer-bound anchor molecule 4-hydroxymethylbenzoic acid in a 4-dime-
Table I . Proportion of D enantiomers in the synthetic octapeptide 1. Gas
chromatographic investigation of the N-trifluoroacetyl amino acid isopropyl
esters after total hydrolysis and the ferf-butylcarbamoyl amino acid isopropyl
esters after sequential degradation.
1
2
3
4
5
6
7
8
H-Val-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2
1
Total hydrolysis
D enantiomer [Yo]
Sequential degradation
D enantiomer [%]
Z Ala 3.6
Ala2 0.8; Ala4 1.2
Val 1 0 . 3
Leu' 1.1; Leun 10.2
Ile 2.2
la1
Val 1.1
Z Leu 8.7
lie 2.2
Z Lys 3.8
[a] See text
332
0 VCH Veriagsgeselischafl mbH. 0.6940 Weinheim, 1987
[I] H. Frank, G. J. Nicholson, E. Bayer, Angew. Chem. 90 (1978) 396; Angew.
Chem. Inr. Ed. Engl. 17 (1978) 363.
121 W. A. Konig, I. Benecke, H. Bretting, Angew. Chem. 93 (1981) 688; Angew. Chem. Int. Ed. Engl. 20 (1981) 693.
[3] J. S. Davies, A. K. A. Mohammed. J. Chem. Soe. Perkin Trans. 2 1984.
1723.
141 J. S. Davies, E. Hakeem, Pept., Proc. Eur. Pep. Symp.. 18rh. 1984, 137.
151 W. A. Konig, I. Benecke, N. Lucht, E. Schmidt, J. Schulze, S. Sievers, J.
Chromatogr. 279 (1983) 555.
[6] E. Atherton, C. J. Logan, R. C. Sheppard, J. Chem. SOC.
Perkin Trans. I
1981. 538.
171 E. Brown, R. C. Sheppard, B. J. Williams, J. Chem. SOC.Perkin Trans. I
1983. 75.
[8] J. Schulze, W. A. Konig, J. Chromafogr. 355 (1986) 165.
Benzene and Linearly Annelated Arenes a s
Dienophiles in Diels-Alder Reactions with
Inverse Electron Demand
By Gunther Seitz,* Reinhard Hoferichter, and Rolf Mohr
As prototype aromatic 6n-electron systems, benzene and
its simple derivatives show little tendency to react as
dienes or dienophiles in [4 21 cycloadditions. Exceptions
were observed in the case of extremely reactive dienophiles, such as dehydrobenzene derivatives, hexafluoro-2butyne, dicyanoacetylene, and allenes, to which benzene
adds inter- and intramolecularly as a diene.".'] Diels-Alder
reactions in which benzene or simply substituted benzenes
react as dienophiles have been rare so far.[3.41
In bis(trifluoromethy1)tetrazine 1, an extremely electron-poor diene, the s-cis diazabutadiene system exhibits
the highest diene reactivity so far observed in Diels-Alder
reactions with inverse electron demand.['] We have now
found that 1 can be used especially well to show that benzene and simply substituted benzenes can also exhibit
dienophilic properties.
Whereas the [4 21 cycloaddition of benzene 2a to 1 requires 24 h of heating at 140°C in an autoclave, the donorsubstituted benzenes 2b-e react, in part, under somewhat
milder conditions (Table 1).
+
+
[*] Prof. Dr. G. Seitz, Apotheker R. Hoferichter, Dr. R. Mohr
Pharmazeutisch-chemisches lnstitut der Universitat
Marbacher Weg 6, D-3550 Marburg/Lahn (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
0570-0833/87/0404-0332 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 26 (1987) No. 4
I
Their constitution can be derived unequivocally from the
'H-NMR spectra (Table 2). The unusual reactivity is in accord with frontier orbital theory'" and can be predicted on
the basis of M N D O calculations.~'O1
Linearly annelated arenes such as naphthalene 8 and
anthracene 10 also exhibit pronounced dienophilicity,
which has hardly been exploited so far in [4+ 21 cycloadditions."."] Compound 1 reacts with 8 to give the benzophthalazine 9 and with 10 to give the naphthophthalazine
11. The constitutions of the new compounds 5, 9,and 11
are in accord with the analytical and spectroscopic findings ('H-NMR, I3C-NMR, IR, UV, and mass spectra, see
also Table 2).
cycloreversion
CF3
1
2a - e
[4 + 21
3a - 0
y 3
y 3
v*R
cycloreversion
oxidation
N\
y
p
N\
R
CF3
CF3
5a - e
40 - e
Table 2. 'H- and l3CC-NMRdata for the phthalazine derivatives 5a-e; in
CDCII with a 100-MHz NMR spectrometer if not given otherwise.
5a: 'H-NMR: 6=8.19 (mc, 2H; aryl H), 8.38 (mc, 2 H ; aryl H).-"C-NMR:
l o b
R
H
CH3
c
d
e
OCH,
N(CH3)2
SCH,
The Diels-Alder adduct 3a, which is possibly formed in
an equilibrium reaction, cannot be isolated. It undergoes
further reaction, in the sense of a [4 21 cycloreversion161
with elimination of nitrogen, to give 4a irreversibly. Compound 4a is sensitive to oxidation and is even oxidized by
atmospheric oxygen or excess 1 to give a good yield of the
phthalazine 5a. The constitution of 5a was confirmed by
independent synthesis from 1 and dehydrobenzene 7 (generated from 6,T H F = tetrahydrofuran)."'
+
Table 1. Characteristic data for the phthalazine derivatives 5a-e, 9 , and
11
Compound
5a
5b
5c
5d
5e
9
11
Yield
Reaction
conditions
[oh]
24 h,
24 h,
12 h,
12 h,
24 h,
12 h,
6 d,
87
40
68
57
56
59
30
140°C
140°C
140°C
I1O"C [b]
140°C
140°C
l l 0 " C [b]
M.p.
["C]
dmaX(lg&)
[nm] [a]
[cm-'1
166
146
114
196
278 (3.53)
280 (3.57)
325 (3.32)
403 (3.70)
358 (3.63)
360(3.12)
393 (3.79)
1580, 1570
1615
1605
1600
1590
1600
1610
150
170
210
The donor-substituted benzenes 2b-e react similarly
with 1, resulting in preferential formation['] of the 6-substituted phthalazines 5b-e in preparative yields (Table 1).
9
1)
c4+21
11
10
Angew. Chem
Ini.
Ed Engl. 26 (1987) No. 4
(4
5e: 'H-NMR (400 MHz): 6=2.69 (s, 3 H; SCH3), 7.91 (mc, 1 H; aryl H), 7.93
(dd, 1 H, 'J=9.0 Hz; 4 J = 1.8 Hz; aryl H), 8.22 (dm, I H, 'J=9.0 Hz; aryl
H).-"C-NMR: 6=14.5 (4). 116.4 (dm, 'JCb=3 Hz), 121.2 (m). 121.5 (q.
' J c ~ = 2 7 5Hz), 121.7 (q. 'Jc,=275 Hz), 124.0 (dm, 4 J C b = 3Hz), 124.5 (m),
132.9 (dm), 148.2 (q, ' J ~ . + = 3 3Hz), 148.4 (q, 'JcF=33 Hz), 150.2 (m)
CC-N
[a] Solvent CH2CI2;only the longest-wavelength maximum is given. [b] Temperature of boiling toluene.
8
6 = 121.5 (q. 'JcF=277 Hz; CF,), 124.0 (m), 124.6 (dq, *JCF=3.2 Hz), 134.7
(dd), 150.0 (q, *J0=34 Hz).
5b: 'H-NMR: 6=2.75 (s, 3 H ; CHI), 8.00 (d, 1 H, 'J=8.7 Hz; aryl H), 8.15
(br s, 1 H; aryl H), 8.32 (br d, 1 H, 'J=8.7 Hz; aryl H).--"C-NMR: 6=22.7
(q), 121.5 (q. 'JcF=277 Hz), 122.3 (m), 123.4 (dm, 4JcF=3 Hz), 124.3 (dm).
124.4 (m), 136.7 (dm), 146.3 (m), 149.5 (q. 'JcF=34 Hz), 149.7 (q. 'JCF=34
HZ)
5 c . 'H-NMR: 6=4.08 (s, 3 H; OCH3), 7.55 (br s, I H ; aryl H), 7.66 (dd, 1 H,
1.7 Hz; aryl
'J=9.4 Hz, 'J=2.4 Hz; aryl H), 8.31 (dq, 1 H, 'J=9.4 Hz, 5JFn=
H).-"C-NMR: 6=56.1 (q), 102.6 (dm, "JcP=3 Hz), 119.4 (m), 122.4 (q,
' J c ~ = 2 7 6Hz), 122.5 (q. 'JcF=276 Hz), 126.5 (m), 126.5 (dm, 4JcF=3 Hz),
126.9 (dm), 139.1 (q, 'JcF=33 Hz), 149.1 (q. *JcF=33 Hz), 163.7 (m)
5d: 'H-NMR: 6=3.24 (s, 6 H ; N(CH3),), 7.11 (m, 1 H; aryl H), 7.50 (dd, 1 H,
1.7 Hz; aryl
'J=9.4 Hz, 4J=2.6 Hz; aryl H), 8.13 (dq, 1 H, 'J=9.4 Hz, *Jrn=
H).-"C-NMR
([D6]acetone): 6=40.2 (q), 99.5 (dm, 4Jcp=3.3 Hz), 116.3
(m), 123.2 (q, ' J ~ ~ = 2 7Hz),
6 123.3 (q, 'JC-,=276 Hz), 123.6 (dm), 126.2 (dm,
4 J c ~ = 2 . 6Hz), 127.1 (s), 148.4(q, 'Jc+=33 Hz), 148.8 (4, 'Jcr=33 Hz), 154.3
Received: September 29, 1986;
revised: January 7, 1987 [Z 1940 IE]
German version: Angew. Chem. 99 (1987) 345
[I] Reviews: J. Sauer, Angew. Chem. 78 (1966) 233; Angew. Cbem. Int. Ed.
Engl. 5 (1966) 21 1; H. Wollweber: Diels-Alder-Reakrion. Thieme, Stuttgart 1972; T. Wagner-Jauregg, Synthesis 1980. 165; J. Sauer, R. Sustmann, Angew. Chem. 92 (1980) 773; Angew. Chem. Int. Ed. Engl. 19
(1980) 779; recent publications: A. F. Murad, J. Kleinschroth, H. Hopf,
Angew. Chem. 92 (1980) 388; Angew. Chem. Int. Ed. Engl. 19 (1980) 389;
J. Kleinschroth, H. Hopf, Angew. Chem. 94 (1982) 485; Angew. Chem.
In(. Ed. Engl. 21 (1982) 469; K.-L. Noble, H. Hopf, L. Emst, Chem. Ber.
11 7 (1984) 474; K. Matsumoto, Chem. Lerr. 198s. 168 I.
[2] For the intramolecular Diels-Alder reaction of allenecarboxanilidene,
see G. Himbert, L. Henn, Angew. Chem. 94 (1982) 631; Angew. Chem.
I n l . Ed. Engl. 21 (1982) 620; Angew. Chem. Suppi. 1982. 1473; L. Henn,
G. Himbert, K. Diehl, M. Kaftory, Chem. Ber. 119 (1986) 1953.
131 Under an extremely high pressure of 10 kbar and at 22O-24O0C, benzene
reacts twice as a dienophile with hexachlorocyclopentadiene:W. Jarre,
D. Bieniek, F. Korte, Angew. Chem. 87 (1975) 201; Angew. Chem. h t .
Ed. Engl. 14 (1975) 181.
[4] G. Seitz, T. Kampchen, W. Overheu, U. Martin, Chem. Z f g . 105 (1981)
342; K. Saito, Y. Omura, E. Maekawa, P. G. Gassman, Tetrahedron Lett.
25 (1984) 2573.
[ S ] J. Sauer (Universitat Regensburg), private communication.
[6] Cf. R. Huisgen, Angew. Chem. 80 (1968) 329; Angew. Chem. Int. Ed.
Engl. 7 (1968) 321.
[7] Application of the reaction principle: J. Sauer, G. Heinrichs, Terrahedron Lett. 1966, 4980; J. Sauer, A. Mielert, D. Lang, D. Peter, Chem. Ber.
98 (1965) 1435.
[8] For example, reaction of 1 with 2c affords, in addition to 5c, a low yield
( < 2%) of 5a. Compound 5a is presumably formed by [4 + 21 cycloaddition of 1 to the 1 and 2 positions of Zc followed by elimination of ni-
0 VCH Verlagsgesellschaft mbH. 0-6940 Weinheim. 1987
0570-0833/87/0404-0333 S 02.50/0
333
trogen and methanol. In addition to Sa, traces ( < 1%) of E-1,2-bis[3,6bis(trifluoromethyl)pyridazin-4-yl]ethenewere also isolated (cf. 141).
[91 Review: 1. Fleming: Frontier Orbitals and Organic Chemicat Reactions.
Wiley, New York 1976, Chap. 4, p. 86ff; Grenrorbitale und Reaklionen
organischer Verbindungen. Verlag Chemie, Weinheim 1979, Chap. 4, p.
133 ff, and references cited therein.
[lo] Dr. A. Heidenreich, Prof. Dr. A. Schweig (Universitat Marburg), private
communication.
[ I I] G. Seitz, R. Mohr, W. Overheu, R. Allmann, M. Nagel, Angew. Chem. 96
(1984)885;Angew. Chem. Ini. Ed. Engl. 23 (1984)890.
Herein we report on the synthesis of oxazolidinone and
oxazinanone derivatives by reaction of allylamines and homoallylamines, respectively, with carbon dioxide and iodine via intramolecular cyclization under extremely mild
conditions."01
Treatment of allyl- or homoallylamines with carbon
dioxide in MeOH, followed by treatment with I2 at ambient temperature for 20 h, gave iodoalkyloxazolidinones
[Eq. (e)] o r iodoalkyloxazinanones [Eq. (f)], respectively, in
Formation of Oxazolidinones and Oxazinanones by
Reaction of Allylamines and of Homoallylamines
with Carbon Dioxide and Iodine via Intramolecular
Cyclization**
n
By Takashi Toda' and Yoshinori Kitagawa
Recently, much attention has been focused on the utilization of carbon dioxide in organic synthesis."] However,
almost all reactions of these types are carried out in the
presence of biotin (or its analogues),[21metal complexes,[3*
large amounts of phosphorus compounds,[41strong bases
under high pressure,[51 or combinations of these methods.['.'] Furthermore, the reaction conditions are often
rather severe.
We have been interested in carbon dioxide fixation via
ammonium carbamates under mild conditions: without a
catalyst, at atmospheric pressure, and, if possible, at ambient temperature. Since several aliphatic amines form stable carbamates 1 [Eq. (a)],['] these salts were expected to
R
0
R
Table I . Yields and some physical properties of the oxazolidinones and
oxazinanones. The yields in parentheses are those obtained after prolonged
reaction in the presence of Cs2C0, (see text).
Reac- Amine
tion
Product
Yield
IN1
M.p.
1"CI
vco
(in KBr)
[cm - '1
n
I
R
&..AH,
1
= alkyl; R' = alkyl, H
61 (70) 117-118.5
1730
60 (90) 83-84
1730
s
e
offer certain advantages in carbon dioxide fixation. We
have indeed reported several such reactions.['l For example, intermolecular reactions between ammonium carbamates and oxiranes (or their synthons) give carbamate derivatives including cyclic carbamates [Eqs. (b)-(d)].
0
3
~
N
hP'
H OKNAPh
*I
Me
0
R' R2 0
0
HO R2
0
R' = R2 = alkyl, a r y l
R' = alkyl; R2 = H
R
a,
+
/"\
R = alkyl
R'= H
R = R'
+
OCON,
alkyl
5
Ph-NH
OKNnPh
52(80) 134.5-136[a] 1735
hP'
OH
1
=
R'
.ITR2
OCON,/ R
Ph
0
6
-NH,
OKNH
41 (60) 142.5-144[a] 1680
L.Jd
R'
+ 1
CH2Cl
[a] Decomposition.
[*I Prof. Dr. T. Toda, Dr. Y. Kitagawa
Department of Industrial Chemistry,
Faculty of Engineering, Utsunomiya University
Utsunomiya 321 (Japan)
[**IUtilization of Carbon Dioxide in Organic Synthesis via Ammonium
Carbamates, Part 8.
334
0 VCH Verlagsgesellschaft m b f f . E)-6940 Weinheim, 1987
fairly good yields (40-709'0). The results and some physical
properties of the products are summarized in Table 1. Pro-
OS70-0833/87/0404-0334 $ 02.50/0
Angew. Chem. Int. Ed. Engl. 26 (1987) No. 4
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