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Hetero Cope Rearrangements in the Cyclization of Allyl and Propargyl Esters of N-Acyl Amino Acids to Oxazolin-5-ones.

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a-stannyl-organolithium compounds to have been prepared
by direct metalation (H/Li exchange)[5!
The sulfur-free carbonyl compounds (7), (S), and ( 9 ) have
been prepared by thioacetal hydrolysis or Raney nickel desulfurization oftheadducts ( 4 a ) . Yields: 71,66, and 60%,respectively; 'H-NMR (cc14):Si(CH3)3 singlets at 6=0.2, 0.23,
and 0.25, respectively; CH3 in ( 8 ) : 0.95 (d, 7 t h ) ; IR: 1710,
1640; 1745, 1635; and 1735, respectively.
H
R4
COCI2, pyridine
>
50 9:
R'-CH-COZ-CH,%~
I
>TICOR'
ill
J
Received: August 8. 1974 [Z 112 IE]
German version: Angew. Chem. 57, 37 (1975)
CAS Registry numbers:
( l a ) . R=CH,, 53369-90-7; ( I b ) , R = C H , , 53369-91-8;
O b i , R=n-C,H,, 53369-99-6; ( I b ) , R=C,H,, 53370-00-6;
(21, n=2,930-30-3; (Z), n=3, 930-68-7;
(2). n=4. 1121-66-0; (5), n = 3 , 53369-93-0; (6), n=3. E ' = E 2 = H ,
53369-94-1; ( 6 ) , n=3, E l = C H , , E 2 = H , 53369-95-2; (71, 53369-96-3;
(8). 53369-97-4; (9) 53369-98-5; ( 4 ) . M=Si, n=2, R=CH,, E = H ,
53370-01-7; ( 4 ) , M=Sn, n=2, R = C H , , E = H , 53370-02-8;
( 4 ) . M=Si. n=2, R = E = C H , , 53370-07-3; (41, M=Si, n = 2 . R = C H , ,
E=n-C,H,,, 53418-35-2; 141, M=Sn, n = 2 , R=CH,, E=n-C,H,,,
53370-10-8; (41, M = S i , n = 3 , R = C H , , E = H , 53370-03-9;
141, M =Sn. n=3, R=CH,, E = H , 53370-04-0; ( 4 ) , M=Sn, n=3,
R=n-C,H,,
E = H , 53370-05-1; ( 4 ) . M=Si, n=3, R = E = C H , ,
53370-08-4; (41, M = S n . n=3, R=C,H,, E = H , 53370-06-2;
( 4 ) , M=Si, n=4, R=CH,, E = H , 53370-09-5
[ I ] a) Cyanohydrin derivatives: H . Srerrrr and M . Schreckenberg, Angew.
Chem. 85.89 (1973); Angew. Chem. internat. Edit. I2,81 (1973); Tetrahedron
Lett. 1973, 1461; Chem. Ber. 107, 210 (1974): E . Leerr, M . R. Chedekd,
and G . B. Bodem, J. Org. Chem. 37. 4465 (1972). b) Cuprates of thioacetals:
7: Mukaij,ama, K. Narasaka, and M . Furusaro, J. Amer. Chem. Soc. 94,
8641 (1972). c) Anions of thioacetai monosulfoxides: R. H . Schlessinger et
af., Tetrahedron Lett. 1973,2595.2599, 2603, 3267, 3271, 3275. d ) Nitroalkane
anions: J . E . McMurry el a f . , J. Amer. Chem. Soc. 93, 5309 (1971); J. Org.
Chem. 38, 4367 (1973); 39, 258, 259 (1974). e) Carbonylnickel derivatives:
E . J. Core! and L. S. Hegedus, J. Amer. Chem. Soc. 91, 4926 (1969). f)
Anions of oxazolones: W Steglich ef a / . , Angew. Chem. 83, 725, 727 (1971);
Angew. Chem. internat. Edit. 10, 653, 655 (1971).
[2] In the Michael additions described in ref. [ l c]. further stabilized anions
derived from thioacetals are employed.
[3] a) For production of ( l a ) , see ref. [4a]. For preparation of ( I b ) ,
(CH ,S)KHLi [4] is reacted with chlorostannanes and the resulting
( C H I S ) I C H S ~ RisI metalated with lithium diisopropylamide in THFiHMPA
at -78 t o -30°C. b) Prior to transmetalation of (3) t o (5) (CH3Li at
- 100°C) the diisopropylamine is distilled off with the major portion of
the T H F (replaced later) at 0°C bath temperature and 0.001 torr pressure.
[4] a) Lithiated silylthioacetals: D. Seebach, M . Kolb, and B.-7h. GrBhel.
Chem. Ber. 106, 2277 (1973). b) Lithiated stannyldithianes: I. Wiflerr and
B.-Th. GrBbef, Universitat Giessen, 1973 (hitherto unpublished).
[S] For (R,Sn),CCI, +RLi+(R,Sn)CCI,Li, see: D. Seyferrh, F . M . Armbrechr
jr., and E. M . Hanson, J. Organometal. Chem. 10, P-25 (1967);
(R,Sn)CBr,+RLi+(R ,Sn)CBrILi: D. Sryferrh rr af., ibirl. 44, 299 (1973).
(31
(41
minutes' stirring at 20°C to 50-70°C for 1-3 hl2]. P205
in chloroform proved to be less satisfactory as reagent since
acid-sensitive allyl residues are liberated (see Table 1).
From the 'H-NMR spectra of ( 3 e ) and ( 3 f ) it is evident
that only one diastereoisomer is formed in each of these
cases; this is in agreement with the stereospecific course of the
CIaisen rearrangementl51.
On prolonged heating, the 2-oxazolin-5-ones (3), R ',R4 H,
obtained from 3,3-disubstituted ally1 esters are converted by
further hetero Cope rearrangement into 2-allyl-3-oxazolin-5ones ( 4 ) . For the preparative synthesis of (4) it is recommended that esters ( 1 ) be used as starting material, without
isolating ( 3 ) (Table 1).
The ease of the secondary reaction ( 3 ) + ( 4 ) depends on
the spatial requirements of the groups R', R3, R4. Thus ( 3 f )
rearranges completely into ( 4f ) on boiling in chloroform
for 3 h, while 12 hours' boiling in benzene is necessary for
the rearrangement ( 3 e ) + ( 4 e ) . Under the conditions used
for cyclization (COC12/pyridine, 1.5 h, SOT), N-isobutyryl-2phenylglycine geranyl ester affords (4h) directly-as a result
of additional stabilization of the 3-oxazolinone form by conjugation of the C=N double bond with a phenyl residue.
4-Allenyl-2-oxazolin-5-ones( 6 ) are accessible in the same
way as ( 3 ) if the propargyl esters of N-acyl amino acids
(5) are cyclized instead of ( 1 ) (Table 2).
+
R2
R1-CH-C02-C-C~
I
I
C,H,COHN
A3
CH
-
Hc0
R'
N v O
I
C6H5
Hetero CopeRearrangements in the Cyclization of Ally1
and Propargyl Esters of N-Acyl Amino Acids to Oxazolin-5-ones["l
By Borries Kiibel, Gerhard HoJe, and Wolfgang Steglich"]
Alkyl esters of N-acyl amino acids are converted on treatment
with dehydrating agent into 5-alkoxyoxazoles['~'I. We have
found that 5-allyloxyoxazoles ( 2 ) , formed from the N-acylamino acid allyl esters
rearrange directly under the reaction conditions to 4-allyloxazolin-5-ones ( 3 ) . Cyclization is
accomplished by dropwise addition of a solution of phosgene
(1.5 mol) in toluene to a solution of the ester ( I ) and pyridine
(3-6 mol) in chloroform and warning the mixture after 30
[*] Dr. B. Kubel, Dr. G. Hofle, and Prof. Dr. W. Steglich
Organisch-Chemisches Institut der Technischen Universitat
1 Berlin 12, Strasse des 17. Juni I35 (Germany)
[**I The work was supported by the ERP Special Fund. We thank BASF
Ludwigshafen for supplying the starting materials.
58
(61
If cyclization of the esters (1 c ) and ( 5 i ) is carried out with
P4S in 1,2-dichloroethane (24 h, reflux)[61,the 2-thiazolin-5ones (m.p. 53 and 59°C resp.)I4l corresponding to ( 3 c ) and
(6 i ) are formed in 40 % yield.
4- Isopropyl-4-linalyl-2-phenyl-2-oxazolin-5-one
( 3 f ) and 2-geranyl-4-isopropyl-2-phenyl-3-oxazolin-5-one
( 4f )
But yllithium (2.5 mmol) followed by 4-isopropyl-2-phenyl-2oxazolin-5-one (4.0g, 20mmol) are added with stirring to
a solution of geraniol (3.1 g, 20mmol) in benzene (30ml).
The mixture is stirred for one day, washed with 0.5 N HCI,
dried over M g S 0 4 and finally concentrated by evaporation
under vacuum [yield 6.1 g (86 %) ( I f ) , pale yellow oil].-A
solution of COCl2 (10.3mmol) in toluene (3 ml) is now added
slowly with stirring to a solution of the ester ( I f ) (2.5g,
AngeMs. Chem. inrernar. Edit. / Vol. 14 (1975) 1 No. I
Table 1. 4-Allyl-2-oxazolin-5-ones
( 3 ) [4] and 2-allyl-3-oxarolin-5-ones ( 4 ) 141.
R'
RZ
R3
Cyclization
conditions
R4
(31
Yield [ %]
Work up
(41
B.p. ["C/torr]
(M.p. [TI)
Reaction
conditions
Yield
[ X]
99-10010.03
2.5 h [a]
55°C
3h [a1
70°C
[bl
9910.2
PI
2h [a1
55°C
1.5h [a]
55 "C
1.5 h [a]
50°C
1.5h [a]
50°C
oil
oil
[q
[q
[gl
oil
[q
12h [h]
100 b] oil
(6547)
3h P I
2.5 h [i]
1.5h [i]
50 "C
1.5h [i]
50 "C
100 oil
41 [d] oil
12 [d, e] oil
(67)
41 [d] oil
67 [d] oil
[a] COCI,-pyridine method. [b] P,O, method. [c] Distillation. [d] Chromatography on silica1 gel, eluent CCI,. [el Crude yield 63%; according to NMR a
mixture of 60% ( 3 9 ) and 40% ( 4 9 ) . [q Decomposition on distillation. [g] From ( l a ) , COCI, and pyridine (2.5h. 55°C). then 16 hours' heating in benzene.
[h] From ( 3 ) by heating in benzene. [i] From ( I ) , COCI,, and pyridine. b3 Crude product, not analyzed.
Table 2. 4-Allenyl-2-oxazolin-5-ones(6) [4]
R'
(6i)
(6i)
(6k)
(61)
CH(CH,),
C6H,
CH(CH,),
CH(CH,),
R2
H
H
H
CH,
R3
H
H
CH,
CH,
Cyclization
conditions
Yield
PA]
6 h [a]
43
68
30
78
65
PI
15 h[a]
[c]
[c]
[a] P,O,-method (chloroform, reflux). [b] P,O,
[c] COC1,-pyridine method, 3 h, 65 "C.
9.p. ['C/torr]
(M.p. [TI)
88-89/0.03
[4] All compounds gave correct elemental analyses. The 'H-NMR and IR
spectra are consistent with the given structures.
[ 5 ] The stereochemistry of formula ( 3 ) follows from assumption of a chair
form in the transition state, as has been quoted for other examples: P.
Virrorelli, 7: Winkler, H . 4 . Hansen, and H . Schmid. Helv. Chim. Acta 51,
1457 (1968).
[6] L. Wilschowitz, Dissertation, Technische Universitat Miinchen 1973.
(56)
103-106/0.04
123/0.1
in DMF, 4h, 125°C.
Experimental Evidence for a Novel Limiting
Mechanism of Aliphatic Nucleophilic Substitutions[**]
By Tarek ElGomati, Dieter Lenoir, and Ivar Ugi"
7mmol) and pyridine (4ml, 40mmol) in CHCl3 (30ml). The
mixture is stirred for 30min at 20°C, for a further 1.5h at
5 0 T , and finally washed with 0.5 N HCI, dried, and evaporated
down under vacuum at 35 "C. Filtration of the residue through
a short column of silica gel with CC14as eluent and recrystallization from petroleum ether affords 0.65g (27 %) (3f), m.p.
65--67"C, IR (CCI4): 1815, 1660cm-'.-A
solution of (3f)
(0.5 g) in benzene (5ml) is boiled under reflux for 3 h. Evaporation under vacuum affords analytically pure (4f) as a light
yellow oil, IR (CC14): 1780, 1645cm-'.
Received: August 30, 1974 [Z 113 IE]
German version: Angew. Chem. 97.64 (1975)
Reaction of cis-3-ethoxycyclobutyl brosylate
(7.00g,
21mmol) with sodium iodide (11.2Og, 75mmol) in refluxing
acetone (70 ml), i. e. under typical S Nconditions['',
~
leads to
the formation of a stereochemically uniform iodide ( 3 ) ;
according to a 'H-NMR comparison with ( I ) , ( 3 ) is the
cis-isomer.
Exchange of the brosylate by iodide via a two-step sequence
of reactions, including isolation of the bromide (2), affords
a product which according to its IR and NMR spectra and
refractive index, is identical with the directly formed iodide
( 3 ) . The yields of the products (2) and (3) (Scheme 1) were
60-80 % after destillation.
CAS Registry numbers:
( l a ) . 53777-87-0; ( I b ) , 53777-88-1 ; ( I c), 53777-89-2; ( l d ) , 53777-90-5;
( I e ) , 53777-91-6;( I f ) , 53777-92-7; ( l g ) , 53777-93-8; ( 3 a ) , 53777-94-9; ( 3 b ) ,
53171-95-0; ( 3 ~ ) 53777-96-1
.
; ( 3 d ) , 53777-97-2; ( 3 e ) , 53777-98-3; ( 3 f ) ,
53777-99-4; ( 3 s ) . 53778-00-0; ( 4 d ) . 53778-01-1; ( 4 ~ ) 53778-02-2;
.
(4f).
53778-03-3; ( 4 k ) , 53778-04-4; (5 i ) , 53778-05-5; ( S j ) , 53778-06-6; (5 k ) ,
53778-07-7;(51), 53778-08-8;(6i),53778-09-9; (6j), 53778-10-2; ( 6 k ) , 53778geranyl ester, 53778-1311-3; (61), 53778-12-4; N-isobutyryl-2-phenylglycine
5.
[l]J . W Cornforth in H. 7: Clarke, J. R . Johnson, and R . Robinson: The
Chemistry of Penicillin, Princeton University Press 1949, p. 695, 708; cf. also
R . A. Firesrone, E . E . Harris, and W: Reuter, Tetrahedron 23. 943 (1967).
121 J . Maeda, M . Takehara, K . Togo, S . Asai, and R. Yoskida, Bull. Chem.
SOC. Jap. 42, 1435 (1969).
[3] The esters are formed in high yield by reaction of the oxazolin-5-ones
with alcohols in benzene and addition of 0.1 mol butyllithium [in the case
of ( I d ) , (Ifl, (19) ( S l ) ] , acid catalyzed esterilkation ofthe N-acyl amino acids
[in the case of ( l a ) , ( I b ) , ( I c ) , ( S i ) , ( S j ) , ( S k j ] , or alkylation of the
N-acyl amino acid sodium salt in HMPT with ally1 halides [in the case
of ( I t ) , ( I h l ] .
Angew. Chem. inrernar. Edir.
/ Vol. 14 ( 1 9 7 5 ) 1 No.
1
Scheme 1
[*I T. EIGomati, Dr. D. Lenoir, and
Prof. Dr. 1. Ugi
lnstitut fur Organische Chemie der Technischen Universitat
8 Miinchen 2, Arcisstrasse 21 (Germany)
[**I We thank Dr. Herbert Eck of Wacker-Chemie, Burghausen, for 3-ethoxycyc1obutanone.-Support
is acknowledged from the National Science
Foundation, Grant G. P. 28927 X, the Deutsche Forschungsgemeinschaft,
and the Fonds der Chemischen Industrie.
59
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