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Cycloadditions of -Diazo Carbonyl Compounds to Enamines.

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Cycloadditions of a-Diazo Carbonyl Compounds to
Enamines
By Rolf Huisgen and Hans-Ulrich Reissig"]
Dedicated to Professor Horst Pommer on the occasion of his
60th birthday
Although diazomethane is inert towards enamines, wdiazo
carbonyl compounds can undergo 1,3-dipolar cycloadditions
with these compounds. Piozzi et al.['l refluxed ethyl diazoacetate with N-( 1 -cyclohexenyl)pyrrolidine, -piperidhe, or
-morpholine for 2 h in CHCIJ, evaporated the mixture, and
treated it for 15 min with 2 N HC1: they isolated the esters
(2), R=C2H5, in 55, 35, and 2 % yield, respectively. Does
cyclization of an open-chain precursor occur only after acid
treatment?
0 0
R02C-C-NH
J
,
N
Such doubts proved groundless: we obtained compound
(2), R=CH3 (82 %), on reaction of methyl diazoacetate with
N-(I-cyclohexeny1)pyrrolidine(3 weeks, 20°C) without acidification. The analogous reaction with p-nitrodiazoacetophenone
(1 h, 20°C) gave 85 % of ( 2 ) , p-N02C6H4C0 in place of
R 0 2 C ; pale yellow needles, m. p. 209-210°C.
Use of a P,P-disubstituted enamine suppresses release of the
secondary amine. Methyl diazoacetate combines with N-isobutenylpyrrolidine (8) (1 : 1, 8 h, boiling CHC13, 73 %) to give
the pyrazoline
Reaction in the ratio 1 :2 (4 weeks,
-5"C, neat) gave the 1 :2 adduct ( 1 1) (66% yield) which
was also formed from (10) with further (8). Just a little
silica gel was sufficient to bring about the transformation
( l I ) - + ( l o ) , whereas chromatography of (10) in ether over
a large amount of Si02 afforded 92% of the 3H-pyrazole
Table 1. Selected physical data of compounds ( 4 ) , ( l o ) , (111, and 112).
Cpd.
M.p. ["C]
vNH
[cm
While aromatization induces elimination of HNR; from ( I ),
this does not occur on reaction (4 d, 20"C, ether) of dimethyl
diazomalonate with N-(1-cyc1ohexenyl)pyrrolidine. The
adduct (73 % yield) was not (3) but its stable tautomer ( 4 )
(Table 1). The NH function of ( 4 ) is confirmed by reaction
with phenyl isocyanate to give the phenylurea (5). Compound
( 4 ) was transformed with HCI in boiling methanol into
(2), R=CH3. The appearance of the NH function also establishes that the reactants are oriented according to (3)
on cyclization; the primary product would not be able to
tautomerize to the 2-pyrazoline ( 4 ) if the opposite orientation
were to apply.
H3COzC-fNH
1
4+CH31".,IT(
(CH214N H
(6)
(7)
Addition of methyl diazoacetate to freshly prepared N-( 1propeny1)pyrrolidine (trans : cis = 4: 1, 3 d, 20°C) was also followed by pyrrolidine elimination to give the pyrazole (7)
(85 % yield), whose synthesis from diazoethane and methyl
propiolate served as structural proof. 3,5-Disubstitution left
no doubt as to the intermediacy of ( 6 ) .
[*] Prof. Dr. R. Huisgen, Dr. H.-U. Reissig
Institut fur Organische Chemie der Universitat
Karlstrasse 23, D-8000 Munchen 2 (Germany)
330
~
(4)
86-88
3360
(10)
64-66
3390
(11)
62-68
(12)
93.5-9s
'H-NMR (CDCII), 6 values
'1
6.15 (NH, disappears with D20), 3.74,
3.75 12\. 2 0 C H 3 )
6.36 I \ br.. NH), 3.83 (s, OCH,), 3.88
(s, 4-11), 1.15, 1.28 (Zs, 2CH3)
3.82 (s, 4-H), 3.50(s, OCH3),1.14, 0.70
(2s, 2 5-CH3), 1.03, 0.73 (Zd, 6H, isopropyl-CH,, J=6.0 Hz) [a]
7.79 (s, 4-H), 3.98 (s, OCH,), 1.52 (s,
2 CH3)
( 1 2 ) with liberation of pyrrolidine [(10)-(12), see Table
11. Synthesis of ( 1 2 ) from methyl propiolate and 2-diazopropanec3]is known.
On distillation of (12) (180-205"C/12 torr) or on reaction
with cold conc. sulfuric acid, van Alphen-Hiittel rearrangementE4I gave 63 and 57%, respectively, of the pyrazole (13).
It is also formed from diazoethane and methyl 2-butynoate.
The invariant orientation of the diazocarbonyl compound
and enamines in the 1,3-dipolar cycloaddition is remarkable:
4-Aminopyrazolines [ ( l ) , ( 3 ) , (6), ( 9 ) ] are the primary
adducts. Addition to acrylic ester occurs in the opposite
orientation, i.e. the ester group is located in position 3 of
the a d d ~ c t [ ~If]cycloaddition
.
were to proceed via a diradical
intermediateL61, then the mentioned substituents on the dipolarophile should effect the same orientation in the adduct
because theester group, like alkyl or amino groups, can stabilize
carbon radicals.
In concerted reactions, M O perturbation theory accounts
for the observed bidirectional behavior. The second-order perturbation term gives the greatest bonding interaction for an
orientation in which the atomic orbital coefficients are combined according to large-times-large and small-times-small.
Only frontier-orbital interactions are considered in Scheme
1'81.
Angew. Chem.
0 Vrrlag Chemie, GmbH, 6940 Weinheim,1979
lilt.
Ed. Engl. 18 (1979) No. 4
0570-0833/79~0404-0330 $ 02.50/0
H
LUMO
\
0.63
r
0.44
HZC-C-COzH
H
+
- 0.3
LUMO
S
0.31
I
0.40
1
- 10.7
HO~C-C-CHZ
HOMO
=N
LUMO
H
group (a=3290 cm-'). Mild hydrolysis on silica gel transformed (#) into an 0x0 hydrazone with intramolecular NH
bridge.
Scheme 1.
For diazoacetic acid + acrylic acid the two HOMO-LUMO
interactions determine the opposite directions of addition;
owing to the small energy difference HOMO(diazoacetic acid)LUMO(acry1icacid) prevails, i. e. the 3,5-pyrazolinedicarboxylic ester is formed. With diazoacetic acid + N-isobutenylamine
two HOMO-LUMO interactions cooperate in formation of
the 4-amino compound.
Received: February 6, 1979 [Z 174a IE]
German version: Angew. Chem. 91, 346 (1979)
CAS Registry numbers:
(21, R =CH3, 32286-98-9; (21, R O ~ C = P - N O ~ C ~ H , C 69668-68-4;
O,
(41,
69668-69-5; (51, 69668-70-8; ( 7 ) , 25016-17-5; ( 8 ) , 2403-57-8; ( l o ) , 6966871-9; ( I I j, 69668-72-0; (12), 21603-19-0; ( 1 3 1 , 60858-33-5; methyl diazoacetate, 6832-16-2; N-(I -cyclohexenyl)pyrrolidine, 1125-99-1; p-nitrodiazoacetophenone, 4203-31-0; dimethyl diazomalonate, 6773-29-1 ; trans-N-(1propenyl)pyrrolidine, 13044-42-3; cis-N-(I -propenyl)pyrrolidine, 13098-67-4
[l] F. Piozzi, A . Umani-Ronchi, L. Merlini, Gazz. Chim. Ital. 95, 814 (1965).
[2] E. Wenkert, C . A . McPherson, J. Am. Chem. SOC.94,8084 (1972), described
the oily impure ethyl ester of type (10).
[3] A . f.Day, R . N . inwood, J. Chem. SOC.C1969, 1066.
[4] J . van Alphen, Rec. Trav. Chim. Pays-Bas 62, 485, 491 (1943); R . Hiirtel,
J . Rirdl. H . Martin, K . Franke, Chem. Ber. 93, 1425, 1433 (1960).
[5] E. Buckner, Ber. Dtsch. Chem. Ges. 21, 2637 (1888); 23, 701 (1890).
[6] R . 4 . Firestone, J. Org. Chem. 37, 2181 (1972).
[7] We are grateful to Prof. R . Susrmann, Essen, for the CNDOj2 calculations.
[8] The orbital energies were estimated from experimental data; H:U. Reissig, Dissertation, Universitat Miinchen 1978, Section 8.6.
Azo Coupling of a-Diazo Carbonyl Compounds with
N-(1-Cyclopenteny1)amines
By Rorf Huisgen, Werner Bihlmaier, and Hans-Cilrich Reissig"]
Dedicated to Professor Horst Pommer on the occasion of his
60th birthday
Combination of methyl diazoacetate with N-(I-cyclopenteny1)morpholine ( I ) (1 week, 20°C) gave a yellow crystalline
1 : 1 adduct, uiz. enamine hydrazone ( 4 ) , in 51 % yield ['HNMR (CDC13):6=4.2 (s, br. NH, vanishes with DzO), 5.4 (t,
J=2.2Hz, vinylic H, disappears with D30@),3.95 (s, CH2
of side chain) 3.70 (s, OCH,)]. Compound ( 4 ) was accompanied by only 1-2% of the cycloadduct ( 3 ) ; ( 4 ) could
not be converted into (3). The I ,3-dipolar cycloaddition[']
which dominates reaction of N-(1-cyclohexenyl)dialkylamines
is suppressed by an azo coupling-presumably via the zwitterion ( 2 ) .
The enamine system of ( 4 ) added 4-nitrophenyl azide to
give a triazoline (92% yield), which still contains the NH
p] Prof. R. Huisgen, DipLChem.
W. Bihlmaier, Dr. H.-U. Reissig
Institut fur Organische Chemie der Universitat
Karlstrasse 23, D-8000 Miinchen 2 (Germany)
( 5 ) ) R = COzCH,
Dimethyl diazomalonate reacted with ( 1 ) even at - 30°C
in ether; an orange-yellow 65:35 mixture of crystalline enamine hydrazones syn-(5) and anti-(5), respectively, (66%
yield) could be precipitated with hexane. According to the
'H- and I3C-NMR spectra, the ester groups are equivalent
['H-NMR (nitrobenzene): syn-(5) and anti-(5), respectively,
6=5.70 and 5.55 (NH), 5.12 and 4.98 (malonic ester H), 5.33
(vinylic H); all these protons exchange with D,O@]. The UV
maximum at 355 nm (log E = 2.6, dioxane) reflects the conjugation of the enamine and the hydrazone system.
Are zwitterions of type (2) likely candidates as primary
products? The zwitterion (7) obtained from the more nucleophilic species N-( 1-cyclopentenyl)pyrrolidine (6) and diazomalonic ester is isolable. (7) was formed in ether or cyclohexane at 25°C in 93 % yield; brick-red needles m. p. 89°C (dec.),
which can be stored at -30°C; IR (KBr): V"C=N+ 1694,
\;C=O 1650cm-'. The color is due to intramolecular charge
transfer interaction; i
,
,
,
(CHC13) 477 nm (loge=4.3). The
weak diazomalonate absorption at 2135 cm- (in CHCl3) indicated a dissociation equilibrium of (7) with the reactants.
Distillation of (7) at S0-90°C/0.001 torr proceeded via retrocleavage and recombination; (6) was trapped by triazoline
formation with 4-nitrophenyl azide placed in the receiver.
'
The IR solution spectra and the ' H- and ,C-NMR spectra
of (7) also indicate equilibration with the syn,anti isomeric
enamine hydrazones ( 8 ) and ( 9 ) . Their structural resemblance
to the stereoisomers of ( 5 ) permitted assignment of the NMR
signals to the zwitterion (7). In pyridine at 3 2 T , 43 % of
(7) was present with 57 % of ( 8 ) + ( 9 ) (in the ratio 1.4: 1);
the equilibrium is temperature dependent [in CDC13: 40%
of (7) at -49"C, and 15 % of (7) at +28"C]. The occurrence
331
-
0 Verlag Chemre, GmbH, 6940 Wernkerm, 1979
0570-0833/79i0404-033S $ 02 5010
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