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Experimental Evidence for a Novel Limiting Mechanism of Aliphatic Nucleophilic Substitutions.

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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
This result lends itself to the following alternative interpretations:
a) The substitution ( 1 ) + (3) proceeds with retentionc3],
whereas the others occur with i n v e r ~ i o n ~ ~ . ~ !
b) Compound ( 3 ) and its trans-isomer equilibrate, with the
equilibrium lying predominantly on the side of (3).
c) All substitutions, ( 1 ) (2), ( 1 ) + ( 3 ) and (2) + ( 3 ) , are
retentive.
Since all reactions have been carried out under the same
conditions and belong to the same substitution type[41,interpretation (a) is improbable[51.Interpretation (b) can be ruled
out because (3) is obtained in high purity, while, as a rule, in
the thermodynamic equilibrium of the cis- and trans-isomers
of 1,3-disubstituted cyclobutanederivatives, the cis-isomer predominates to the extent of 70-80 % I 6 ] .
Hence the conclusion is that all three substitutions proceed
according to (c) with retention.
Considering the reaction conditions, and the fact that the
S N reaction of the brosylate ( 1 ) in aqueous acetone leads
to 98% inversion, the above reaction cannot involve a
mechanism entailing ionic intermediates[’].
-+
The most reasonable explanation is offered by a recently
postulated type of bimolecular sub~titution[’~,
proceeding via
the penta-coordinated intermediates ( 4 ) and ( 5 ) , which are
interconverted by a turnstile rotation (TR)[*],or a resultwise
equivalent Berry pseudorotation (BPR)l8I;however, the latter
is less likely here because of the presence of the 4-membered
ring (Scheme 2 ) . The second order sN2 limiting mechanism
otherwise observed in aliphatic nucleophilic substitutions, with
pentacoordinated transition state (6) (or pentacoordinated
intermediate in the limiting case) having apical leaving and
entering groups, and a diequatorial 4-membered ring is at
an energetic disadvantage in contrast with ( 4 ) and ( 5 ) , because
of strain. An s N 1 nucleophilic substitution with “edge attack”
can be ruled out; all available experimental and theoretical
evidence indicates that in aliphatic second order nucleophilic
substitution the formation and decomposition of pentacoordinate transition states, or of intermediates takes place through
apical entry of the entering group and apical departure of
the leaving group[’].
philic substitutions (Scheme 3): A nucleophile, Y, enters a
“tetrahedral free face” of (7), a compound with a tetracoordinate central atom and four ligands L’, L2, L3, X one of
which, X, is a leaving group. The entering group Y becomes
thus an apical ligand of a pentacoordinate configuration ( 8 )
or (10).
If the nucleophile enters opposite to X, ( 8 ) results, with the
leaving group X in an apical position, from which it can
depart directly giving rise to a “normal” sN2. Otherwise pentacoordinate species (IOU), (lob), or (IOc), result, with the leaving group X in an equatorial position. In this case X can only
leave from an apical position after rearrangement (by TR, or
BPR)into ( I l a ) , ( I l b ) ,or (Ilc), respectively. The product is (g),
the enantiomer of (9). When there are no constraints that affect
the skeletal placement of the ligand set {L’, L2, L3,X, Y}, a “normal” S,2 according to (7) +(8)+(9) is observed-with (8) as
transition state, or intermediate-since (8) [or (lo)] loose X
much faster than they undergo the isomerization (10) + ( I l )
which would be required for a retentive S,. If, however, the attack on (7) by Y to form (8) is substantially retarded relative
to the formation of (10) by constraints originating with the
ligand set, then ( 7) + ( 1 0) + ( 11) + (9) prevails. Here ( 10)
and ( I I ) cannot be transition states, but must be intermediates,
because of the lifetime requirement for the permutation isomerization (10) + (11). Let L’ and L2, for example, belong to
a 3- or 4-membered ring, or maybe also a 5-membered
ring, then the species ( 8 ) , ( 1 0 c ) and ( 1 1a ) with a diequatorial
ring are too strained to be SN intermediates, and
(7) -+ (IOU) + ( I I b) + (9) and (7) ( l o b ) ( I 1 c) -+ (g) are
the fastest S, reactions.
-+
-+
+ x:
L3 L’
Y+,
Li 2
L2 L3
Y+Ll
X
L’ LZ
Y+
X
X
Scheme 2
x
+
x:
Scheme 3
Thus the reactions of Scheme 1 indicate that there exist SN
with pentacoordinate intermediates, whose lifetime is long
enough for permutational isomerization. This is in contrast
to the presently accepted belief of the transition state nature
of the pentacoordinate species via which S N processes proceed.
From the perspective of apical entry and departure of ligands
during the interconversion of tetra- and pentacoordinated
configurations, and with due consideration of the present
results, one is led to the following view of second order nucleo60
A mechanism analogous to that in Scheme 2 may also be
responsible for the observed preferential retention encountered in the reduction of gem. dihalocyclopropanes with
LiAIH, and LiAID,[’’’ and analogous reactions“ ‘I.
According to quantum mechanical calculations[’21 cyclopropane derivatives, with pentacoordinate carbon in a geometrical
arrangement resembling a TR barrier situation, are energetically more favorable than arrangements corresponding to (6).
The steric course of nucleophilic substitution at a tetracoordinate phosphorus center‘’ 31 incorporated in a 4-membered
Angew. Chem. inrernar. Edit. J Vol. 14 ( 1 9 7 5 )
/ No. I
ring proceeds analogously to the scheme ( I ) + ( 3 ) + (2).
Recently, however, a nucleophilic substitution at phosphorus
in a 4-membered ring was observed to involve i n v e r ~ i o n ~ ' ~ ' .
Perhaps in this case the permutational isomerization of the
pentacoordinate 'intermediate not only follows the TR
mechanism, but also an interconversion by TRz The retentive nucleophilic substitutions at silicon[''1 could also proceed
via interconverting pentacoordinate intermediates.
Received: August 12, 1974 [Z 114 IE]
German version: Angew. Chem. 87.66 (1975)
CAS Registry numbers:
(11, 27829-84-1 ; (21, 53778-40-8; (31, 53778-41-9; LiBr, 7550-35-8;
N a l , 7681-82-5
Asymmetrically Induced Four Component Condensation with Extremely High Stereoselectivityand Multiplication of § t e r e o s e I e c t i v i t y [ * * l
By Reinhard Urban and Ivar Ugi[*]
In the synthesis of peptide fragments by four component
condensations['] it is essential to form the new a-amino acid
unit in the desired configuration with maximum stereoselectivity.
The stereoselectivity of the asymmetrically induced model
four component condensation ( I ) (2) ( 3 ) ( 4 ) --t ( 5 )
reaches c(R.s)-(s,:
C ( K . R H S j 9 9 . 5 :0.5 under suitably chosen reaction conditions.
+ + +
[ I ] I. Lillien and L. Handloser, Tetrahedron Lett. 1970, 1213.
121 A. Streitwieser: Solvolytic Displacement Reactions. McGraw-Hill, New
York, 1962, pp. 1-34, and literature cited therein.
131 For the definition of 'retention' and 'inversion' see: a) J . Gasreiger,
P. Gillespie, D. Marquarding, and I . Ugi, Top. Curr. Chem. 48, 1 (1974);
b) J . Blair, J . Gasreiger. C . Gillespie, P. D . Gillespie, and 1. Ugi, Tetrahedron
30, 1845 ( 1 974).
1
R'
0
[4] L. Fowden, E . D . Hughes, and C . K . Ingold, J . Chem. Soc. 1955, 3187,
and literature cited therein.
[5] See Ref. [2], pp. 1 1 and 12.
[6] G. M . Lampman. G. D. Hager, and G. L. Couchan, J. Org. Chem. 35,
2398 ( 1 970).
[7] P . D . Gillespie and I . Ugi, Angew. Chem. 83,493 (1971): Angew. Chem.
internat. Edit. 10, 503 (1971). and literature cited therein.
[8] I. U g i . D. Marquarding, H. Klusacek, and P . Gillespie, Accounts Chem.
Res. 4, 288 (1971); P. Gillespie, P. Hofmann, H . Klusacek, D. Marquarding,
1
2
3
4
5
6
7 [d]
rac.
rac.
rac.
rac.
R( -1 [a]
Rl - ) [a]
S(+) [a]
- 30
0
20
- 78
- 78
0
- 78
H3C'
0.02
0.02
0.02
0.02
0.05
0.05
0.05
'CH3
26.4 : 73.6
38.7 :61.3
51.5 :48.5
0.5 : 99.5
0.94: 99.06 [c]
40.9 : 59. I [c]
20.0 : 80.0
(6)
32
40
45
26
97
77
61
PI
[a] [?I$,'= k79.8" ( c = I, benzene). Preparation and configurational assignment of (2): H . Klusacek, D. Marquarding,
I . Ugi, and R. Urban, unpublished.
[b] Concentration of all starting materials, except in experiment 5 where a 10% excess of ( I ) , ( 2 ) and ( 3 ) was
used.
[c] Gravimetric determination.
[d] Addition of 0.02 mol/l triethylammonium benzoate.
S . Pfohl, F . Ramirez, E . A. Tsolis, and I . Ugi, Angew. Chem. 83, 691 (1971);
Angew. Chem. internat. Edit. 10, 687 (1971).
[9] a ) D. Marquarding, F . Ramirez, I . Ugi, and P. D. Gillespie, Angew.
Chem. 85,99 (1973); Angew. Chem. internat. Edit. 12, 91 (1973); b) L. Tenud,
S. Farooq, J . Seibl, and A. Eschenmoser, Helv. Chim. Acta 53, 2059 (1970).
[lo] H. Yamanaka, 7: Yagi, K . Teramura, and 7: Ando, Chem. Commun.
1971,380; C. w Jeford, u. Burger, M . H . Lafler, and 7: Kabengele, Tetrahedron Lett. 1973, 2483.
[ l l ] J . 7: Grows and K . M! Ma, Tetrahedron Lett. 1974, 909.
[12] a) Pentacoordinate C-anions: A. M . Wooley and M . S. Child, Mol.
Phys. 19, 625 (1970); A. Dedien and A. Veillard, J. Amer. Chem. SOC. 94,
6730 (1972): R. F. Bader, A. J. Duke, and R. R . Messrr, ibid. 95, 7715
(1973); b) Pentacoordinate cyclopropane derivatives: W D. Srohrer, Chem.
Ber. 107. 1795 (1974); CNDOI2 and ab initio calculations concerning the
He-adduct of 1.1-difluorocyclopropane were carried out at our institute
by J. Gasreiger, W Schubert, and R. Kopp.
[I31 See Ref. [9a]: references [34], [49], [51-54], 1571; C . R. Hall and
D. J . H . Smith, Tetrahedron Lett. 1974, 1696.
[14] J . Emsley, 7: B. Middleton, and J . K . Williams, J. C. S . Dalton 1974,
633.
[15] L. H . Sommer: Stereochemistry, Mechanism and Silicon, McGraw-Hill,
New York 1965; B. G. McKinnie, N . S. Bhacca, F . K . Cartledge, and J .
Fapsonx, J. Amer. Chem. SOC.96, 2537 (1974).
Angew. Chem. internat. Edit. 1 Vol. 14 (1975) 1 No. I
The unusually high degree of stereoselectivity is due to the
fact that under the conditions of reaction 4 (Table
the
rather bulky optically active amine component (2) leads to
an almost uniform reaction mechanism, a pair of corresponding reactions involving solvent separated immonium ions and
nitrilium ions" - 31; the decrease in stereoselectivity on the
addition of triethylammonium benzoate is evidence for thisIzb1.
The latter pair o f corresponding reactions has high intrinsic
stereoselectivityl'c], because the bulky groups reduce the
number of participating conformations in the selectivity determining pair of transition states, and effect thus the high degree
of selectivity which is characteristic for rigid systemsl3'.
The ratio of the isomers formed, Qpn= C ( R . R H S ) : C ( K . S H S ) , was
determined by high pressure liquid chromatography (Hupe
[*I Dipl.-Chem. R. Urban and Prof. Dr. 1. Ugi
Organisch-Chemisches Laboratorium der Technischen Universitat
8 Munchen 2, Arcisstr. 21 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
61
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