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Catalyzed Addition of Aldehydes to Activated Double BondsЧA New Synthetic Approach.

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Volume 15 - Number 11
1976
Pages 639
- 712
International Edition in English
Catalyzed Addition of Aldehydes to Activated Double Bonds
-A New Synthetic Approach
methods (17)
By Hermann Stetter[*l
In the presence of cyanide ions as catalyst, aromatic and heterocyclic aldehydes can be
smoothly added to ct,P-unsaturated ketones, esters, and nitriles in aprotic solvents to form
y-diketones, 4-0x0 carboxylic esters, and 4-ox0 nitriles. Thiazolium salts in the presence of
bases are also suitable catalysts; they permit not only addition of aromatic and heterocyclic
aldehydes but also the addition of aliphatic aldehydes.
1. General
One of the longest known reactions of organic chemistry
is the benzoin condensation, in which aromatic and heterocyclic aldehydes ( I ) are transformed into acyloins (u-hydroxy
ketones) (2). Cyanide ions serve as catalysts. The reaction
is reversible, and dependent upon the formation of a carbanion
stabilized by the nitrile group. We found that this carbanion
can be added to the double bond of cc,P-unsaturated ketones,
esters, and nitriles; an irreversible reaction then occurs to
give y-diketones, 4-0x0 carboxylic esters, and 4-0x0 nitriles"].
The mechanism is formulated for the addition of aldehydes
( I ) to cc,B-unsaturated carbonyl compounds (3). Formation
of benzoin (2) is reversible and kinetically controlled [eq.
(a) to Wl.
It is essential that the reaction be carried out in aprotic
solvents, general preference being given to dimethylformamide.
Being a fast reversible reaction, benzoin formation [eq. (b)]
precedes addition [eq. (c)]. Thus use of the respective benzoin
instead of the aldehyde gives the same products. Between
0.1 and 0.5 equivalent of sodium or potassium cyanide serves
as catalyst. The reaction time is generally 1 to 4 h at ca.
35 "C. Attempted reaction fails with aliphatic aldehydes
~
[*] Professor Dr. H. Stetter
Institut fur Organische Chemie der Technischen Hochschule
Prof.-Pirlet-Strasse I , D-5100 Aachen (Germany)
Anyrw. Clwm I n t . Ed. Engl.
1 Vol. 15 ( 1 9 7 6 ) N o . 1 1
R
PH
R-C:O
N
'
--
R'-C H=CH-C-R~
+
5
oa
R1-C0H-CH=;-R2
-
HP
8'
p"
R-C-CFi-CH=C-R*
I
CN
(4
route:
It is known from biochemistry that vitamin Bl (thiamine)
can convert aliphatic aldehydes into acyloins in buffered
639
aqueous solutions[’!
The catalytic activity is associated
with the thiazolium component of the vitamin. In the presence
of bases, quaternary thiazolium salts are transformed into
the ylide structure (4), the ylide being able to exert a catalytic
effect resembling that of the cyanide ion in benzoin condensation.
It is also known that thiazolium salts can in general assume
this catalytic function. And similar observations have also
been made with other azolium salts, e. g. benzimidazolium
salts and benzo- and naphtho[2,1-d]thiazolium salts[’. ’1. We
have successfully employed thiazolium salts in the presence
of bases as catalysts for addition of aliphatic, and also aromatic
and heterocyclic,aldehydes to a$-unsaturated ketones, esters,
and nitriles. Reactions yields y-diketones, %OX0 carboxylic
esters, and 4-OX0 nitriles, respectively [eq. (d)]C41.
may be considered. Working without solvent also has its
advantages in many cases. Under nitrogen, reaction times
of 6 to 15 h and temperatures of 60 to 80°C are necessary.
As in the case of cyanide catalysis, the benzoins can be used
instead of the aromatic and heterocyclic aldehydes, since
benzoin formation is once again the initial kinetically controlled reaction. Aliphatic aldehydes could not be replaced
by the acyloins.
2. Production of y-Diketones
2.1. By Addition of Aliphatic Aldehydes to a,P-Unsaturated
Ketones
As already mentioned, the addition of aliphatic aldehydes
to a$-unsaturated ketones can only proceed on catalysis by
azolium salts. The examples listed in Table 1 were carried
out exclusively with Cat. 1. A large number of aliphatic aldehydes could be converted into y-diketones by reaction with
aliphatic, aromatic, and heterocyclic a$-unsaturated ketones.
Working without solvent was frequently advantageous.
Table I . y-Diketones from aliphatic aldehydes and a$-unsaturated ketones.
Catalyst: Cat. 1.
R’
..a
&o:v:R2
R~?~&H-CH=C-X
PH
R
- 9 T2
R-CHO
5:
R-C-CH-CH~-C-X
__
+
14)
Extensive studies on quaternary thiazolium salts, e. g. 1,3thiazole, 4,5-dimethyl-I ,3-thiazole, and poly-4-methyl-5-vinyl1,3-thiazole, and corresponding salts of other heterocycles,
e. g. 1 -methylbenzimidazole and 4-p-chlorophenyl-l,2,4-triazole demonstrated catalytic activity in nearly all the salts
tested. However, since there seems to be no decisive advantage
over the use of quaternary salts of 5-(2-hydroxyethyl)-4-methyl1,3-thiazoleonly salts of this inexpensive, commercially available thiazole [Merck AG, Darmstadt (Germany)] were used.
With aliphatic aldehydes, N-benzylated salts such as 3-benzyl5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium
chloride (Cat. 1)
proved most suitable, while aromatic aldehydes responded
best to N-alkylated salts such as 3-ethyl-5-(2-hydroxyethyl)-4methyl-I ,3-thiazolium bromide (Cat. 2) or 5-(2-hydroxyethyl)3,4-dimethylthiazolium iodide (Cat. 3)[”]. Both kinds of catalyst were suitable for heterocyclic aldehydes. (Tested procedures for making the catalysts are to be found at the end of this
article.)
R
+
R~-CH=CH-CO-R~
--+
Rl
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
2-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
2-Fury1
2-Fury1
3-Pyridyl
3-Pyridyl
C6H5
C6H5
2-Fury1
CsH5
2-Fury1
Thiamine
Cat. 2 , R
Cat. 3, R
=
=
CzH5, X = B r
CH,, X = I
The most suitable bases are triethylamine and sodium acetate. The amount of catalyst is usually 0.1 equivalent but
can be reduced to 0.05 equivalent. Both protic solvents like
alcohol and aprotic ones like dimethylformamide and dioxane
640
R-CO-CHR’-CH,-CO-R~
.~
R*
Solvent
Yield
[”/.I
None
Ethanol
Ethanol
Ethanol
Ethanol
None
Ethanol
Ethanol
None
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
DMF
Ethanol
Ethanol
None
Ethanol
Ethanol
None
DMF
Ethanol
None
Ethanol
Ethanol
61
60
68
68
68
78
70
74
88
76
Ref.
61
38
41
20
35
70
46
65
65
75
95
92
88
84
67
91
89
84
77
88
Unsaturated and substituted aliphatic aldehydes can be
used with equal success in the reaction. o$-Unsaturated aldehydes could be transformed in satisfactory yields only on
working in solvents.The hardly known 6,eunsaturated y-diketones are obtained as products [eq. (e)].
If the double bond is not conjugated with a carbonyl group
then the addition can also be performed without solvent,
as illustrated by the example of the preparation of cis-8-undecene-2,5-dione from cis-4-heptenal and butenone [eq. (f)][51.
Anyen;. Chrm.
In<. Ed. Enyl. / Vvl. 1S (1976) No. I 1
H
H\
/
/C=c,
H
CHs-CH,
CH,-CH,-C=O
+ CHZ=CH-CO-CH,
-
The addition of numerous aliphatic aldehydes according to
eq. (h) has been accomplished in yields ranging around
80
Recent studies have shown that phthalimidoaldehydes can
be added to butenone in yields of 66-75 % [eq. (i)]I'41.
(f)
H\
/
H
/C=c
' Hz-C Hz-C 0-C H,-C H,-C 0 - C 11,
C H3-C Hz C
H
76%
0
A smooth reaction is also observed with aldehydes containing ether groups. Both ethers of glycolaldehyde and P-alkoxypropionaldehydes have been added to butenone. The &-['*I
and e-alkoxy y-diketoned"] could be obtained in 50-70 %
yield according to eq. (g).
H
R-O-CH,-C=O
+ CH2=CH-CO-CH,
+ CH,=CH-CO-CH,
+
n = 1, 2 , 3
n
In the last-mentioned examples butenone was most commonly employed as unsaturated ketone. All the reactions can
be performed with other unsaturated ketones, e.g. ethyl vinyl
ketones, benzylideneacetone, and benzylideneacetophenone.
--+
R-0-CHz-CO-CHz-CH2-CO-CH,
H
R-O-CHz-CHz-C=O
2.2. By Addition of Aromatic Aldehydes to a,p-Unsaturated
Ketones
(€9
+ CHZ-CH-CO-CH,
+
R-0-C Hz-C Hz-CO-C H2-C Hz-CO-C H,
The most suitable technique for addition of aromatic aldehydes to a,P-unsaturated ketones utilizes cyanide catalysis
in dimethylformamide as solvent. In practice, however, all
the additions can also be accomplished with thiazolium salts
as catalysts, preferably Cat. 2. Both unsubstituted aromatic
aldehydes and those bearing substituents in the ring can add
to aliphatic, aromatic, and heterocyclic cr,P-unsaturated
y-Diketones containing ether groups are also obtained by
addition of aldehydes to vinyl ketones bearing ether groups.
H
R-C=O
+ CH,=CH-CO-CH~-CH,-O-R~
-
R-CO-C Hz-CHz-CO-C
(h)
Hz-CH2-O-R'
-
Table 2. y-Diketones from aromatic aldehydes and rx,P-unsaturated ketones.
R-CHO
R
+
R'-CH=CH-C~R~
R'
R-CO-CHR'-CII,-C~-R~
R2
Catalyst
Solvent
Yield
Ref.
["/.I
H
H
H
C6H5
C6HS
C~HS
2-Fury1
2-Fury1
2-Fnryl
3-Pyridyl
3-Pyridyl
C6Hs
3-Pyridyl
C6H5
2-Pyrid y1
H
H
H
H
H
C6H5
C6H5
H
H
H
H
H
H
H
CNCat. 2
Cat. 2
CN
CN
Cat. 2
CN
Cat. 3
Cat. 3
Cat. 3
CNCat. 3
CNCNCat. 2
Cat. 2
Cat. 2
Cat. 2
Cat. 2
CNCN
CNCat. 2
Cat. 2
Cat. 2
Cat. 2
Cat. 2
Cat. 2
Cat. 2
~
~
~
~
DMF
None
DMF
DMF
DMF
Ethanol
DMF
Ethanol
Ethanol
Ethanol
DMF
Ethanol
DMF
DMF
Ethanol
None
DMF
DMF
DMF
DMF
DMF
DMF
Ethanol
DMF
DMF
None
DMF
DMF
DMF
82
65
62
80
93
84
13
86
82
65
x7
80
48
75
86
56
68
70
70
98
98
98
42
53
75
40
58
58
79
~.
Angrw. Chem. I n f . Ed. Engl.
1 Vol. I5
(1976) No. 1 1
-
641
ketones. ortho-Substituted benzaldehydes, which do not react
on cyanide catalysis, represent an exception. In such cases
satisfactory results are obtained on catalysis with thiazolium
salts if vinyl ketones are co-reactants. For example, thiazolium
salt-catalyzed reaction of 2-chlorobenzaldehyde with butenone
affords the adduct in 56 % yield, while no reaction is observed
on cyanide catalyst [eq. (j)][”].
Catalysis by thiazolium salts also gives better results with
alkoxy aldehydes, whereas cyanide catalysis frequently fails
(Table 2).
2.3. By Addition of Heterocyclic Aldehydes to a,PUnsaturated
Ketones
As with aromatic aldehydes, addition of heterocyclic aldehydes can be catalyzed by cyanide or thiazolium salt (Table
which is stabilized by hydrogen bonding and therefore hinders
the reverse reaction required on cyanide catalysis [cf. eq.
(b)l.
With furfural too, thiazolium salt catalysis can often be
advantageous since the reaction products are obtained directly in high purity whereas formation of resinous products
can interfere with work-up in the case of cyanide catalysis
(Table 3).
2.4. By Addition of Aldehydes with Application of Mannich
Bases
In the Michael addition, Mannich bases can often be used
in place of a$-unsaturated ketones. The reaction then proceeds
uiu an elimination-addition mechanism. We found that the
cx,P-unsaturated ketones can also be replaced by Mannich
bases in the catalyzed addition of aldehydes. The aliphatic
aldehydes could react with Mannich bases on catalysis with
thiazolium salts. The best results were obtained on working
in dimethylformamide at 80 to 90°C. Examples are shown
in eq. (k)[”I.
CII,
3). Cyanide catalysis is generally preferable; however, in some
cases satisfactory results are obtained only on catalysis with
thiazolium salts. Thus 2-pyridinecarbaldehyde still undergoes
smooth addition to benzylideneacetophenone on cyanide catalysis, but good results are obtained only on thiazolium salt
catalysis with other unsaturated ketones such as butenone.
The reason probably lies in the specific structure of 2-pyridoin,
Aromatic and heterocyclic aldehydes can also be cleanly
added to Mannich bases in cyanide-catalyzed reaction to give
y-diketones on working at 35 to 100°C in dimethylformamide.
Table 4 surveys the reactions with benzaldehyde.
C~H,-CIIO
+
(CH,),N-CH,-CHR~-CO-R~
Table 3. -/-Diketonesfrom heterocyclicaldehydes and r.&unsaturated ketones.
R-CHO
R
+
R’-CH=CH-CO-R~
R’
R2
-,R-CO-CHR’-CH,-CO-R~
__
Catalyst
Solvent
Yield
642
H
CH3
C6Hs
C6Hs
C6Hs
C6Hs
2-Fury1
2-Fury1
H
C6HS
ChH5
C6Hs
H
H
H
C6Hs
C6Hs
H
H
C6HS
2-Fury1
2-Fury1
3-Pyridyl
3-Pyridyl
C6HS
C6HS
3-Pyridyl
H
CHI
CH3
CH3
CH3
C6H5
C6Hs
C6H3
2-Fury1
CH3
CH3
C6Hs
2-Thienyl
CH3
CzHs
C6Hs
CH3
C6Hs
CH3
C6Hs
2-Fury1
C6Hs
2-Fury1
2-Fury1
C6H3
3-Pyridyl
3-Pyridyl
3-Pyridyl
CH3
Cat. 1
Cat.2
Cat.2
CNCNCat.2
CNCNCNCNCNCNCat.3
Cat.3
Cat.3
Cat.3
CNCNCNCNCNCNCat.3
CNCat.3
CN
CNCN~
Ethanol
Ethanol
Ethanol
DMF
DMF
Ethanol
DMF
DMF
DMF
DMF
DMF
DMF
Dioxane
Dioxane
Dioxane
Dioxane
DMF
DMF
DMF
DMF
DMF
DMF
Ethanol
DMF
None
DMF
DMF
DMF
80
34
80
12
93
91
61
45
80
71
90
80
75
65
76
45
91
88
80
80
73
88
66
83
16
72
14
70
R’
R2
C 6H5-C O-CI-I,-CHR’-C
0-RZ
7-rmc1
Yield
[“/.I
Ref.
[”/.I
2-Fury1
2-Fury1
2-Fury1
2-Fury1
2-Fury1
2-Fury1
2-Fury1
2-Fury1
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
4-Pyridyl
-
Table 4 */-Diketones from benzaldehyde and Mannich bases [I91
PI
161
[61
51
[lS. 181
161
r91
191
[I 71
[ j 71
[ I 71
r171
191
191
191
191
[15. 1x1
1151
[I 51
191
191
c91
[91
191
c91
191
c91
51
P
47
60
10
40
70
40
35
100
40
40
64
49
58
63
The alkaloid gramin (6), which is readily accessible by
Mannich reaction from indole, formaldehyde, and dimethylamine, also reacts with benzaldehyde in the presence of a
cyanide catalyst to give a 5 2 % yield of w-(3-indolyl)acetophenone [eq.
Examples for the use of heterocyclic aldehydes are the reactions of 3-pyridinecarbaldehyde with 3-dimethylamino-I Angew. Chem. Ini. Ed. Engl.
/ Vol. 15
(1976) No. I 1
phenyl-l-propanone[181 (35y,),of furfural with 3-dimethylamino-I -(2-furyl)-l -propanone["', and of 2-thiophenecarbaldehyde with 3-dimethylamino-I-(2-thienyl)-l -propanone [eq.
(m)][171.
JIJ
+ (CII,),N-CII,-CII,-CO
QLHO
(60%), p-methoxybenzaldehyde (30%), furfural (50%), and
2-thiophenecarbaldehyde (51 %).
Furfural could be smoothly added to dibenzylideneacetone
and difurfirylideneacetone, giving the triketones [eq. ( ~ ) ] [ ~ ' l .
0
CHO
+ R-CII-CII-CO-CH-CII-JI
(P)
(m)
R
7570
Particular interest attaches to the use of Mannich bases
of unsaturated ketones, which leads to unsaturated y-diketones
ofthe same type as are obtained on addition of a,@-unsaturated
aldehydes when catalyzed by thiazolium salts [see eq. (e)].
In some cases it proved necessary to use the methylammonium
iodide instead of the simple Mannich base (Table 5).
= CsH,:
547;; R = 2-E'uryl: 44(y0
Interestingly, the addition of aliphatic aldehydes could only
be accomplished in the ratio 1 : 1 [eq. (q)], the products being
unsaturated y-diketones["!
R-CO-C H-CHZ-CO-CHI-C
Table 5. y-Diketones from aldehydes and Mannich bases. Catalyst. thiazolium
salts [19].
R-CHO
+
R2
Y-CH,-CH~-CO-CRLC'
\R3
-
R
2
CF13: 857'; R = CZH,: 7270; R =
II
-C4119: 6.5";
The addition of levulinaldehyde to a,@-unsaturatedketones
leads according to eq. (r) to 1,4,7-triket0nes[~'~.
-HY
R2
R-CO-C H,-CH,-CCFC
H-CBTTS
cBriS
R~=c:
CJI I
CI1,-CO-CH,-CTlz-CHO
+ CHZ=CH-CO-CH,
Dbll.
R3
(1.)
CF13-C 0-C 112-CH2-CO-C:
R
6 04:,
Y
If 2mol of levulinaldehyde is allowed to act upon I mol
of divinyl ketone then 2,5,8,11,I 4-pentadecanepentone is
obtained in 40 "/, yield [eq. (s)]"'~
23
53
16
55
45
41
48
2 CH3-CO-CHZ-CHz-CHO
+ CH,=CH-CO-CH=CFI,
CH3-( CG-CH,-CH,),-CO-C
3. Preparation of Tri- and Polyketones
Addition of formaldehyde to butenone catalyzed by thiazolium salts gives 2,5,8-nonanetrione in 27 %
c
2 CF12=CH-CO-CH3
Cat. I
DMI'
+
H3
In one case a heptaketone, 2,5,8,11,14,17,20-heneicosaneheptone, could be obtained according to eq. (t). The preparation
consisted in addition of 3-(5-methyl-2-furyl)propanal to divinyl
ketone in the ratio 2 : 1 followed by hydrolysis of the adduct[201.
2 H3
+
(s)
61
25
112'2-0
Hz-C HZ-CO-C'Ii3
0
n cH,-cH,-c Ho
+
c H,=CH-co-C
H=c:i,
(t)
(n!
C H3-C 0 - C H,-CIi,-C
0-C H2-C Hz-C 0-CIi,
Such 1,4,7-triketones can be obtained much more readily
by thiazolium salt-catalyzed addition of aldehydes to divinyl
ketone [eq. (o)].
2 R-CHO
+
62%
CH,=CH-CO-CH=CHz
(0)
R-CO-CHZ-CHz-C
O-CII~-CH~-CO-R
With aliphatic aldehydes the best results are achieved on
working without solvent, whereas working in dimethylformamide is preferred with aromatic and heterocyclic aldehydes.
The following aldehydes were transformed by divinyl ketone
into the triketones[*'I: acetaldehyde (70% yield), propanal
(60 %), n-butanal (65 %), i-butanal (62 %), n-pentanal (62 %),
n-hexanal (65 %), n-heptanal (64%), n-octanal (66 %), ndecanol (63 %), benzaldehyde (55 %), p-chlorobenzaldehyde
Anyew. Chem. Int. Ed. Enyl. f Val.
/5 ( 1 9 7 6 ) N o . 11
The thiazolium salt-catalyzed addition of aldehydes to alkylidene- or arylidene-P-diketones leads to branched triketones.
Thus, for example, addition of furfural to benzylideneacetylace-
643
+
R = E t h y l : 50:L; R = rz-Propyl: 52%; R = ti-Butyl: 610/0;
R = i f - P e n t y l : 57%; R = ti-Hexyl: 55%; R = ir-Heptyl: 54y0
Branched diketo carboxylic esters are obtained by thiazolium salt-catalyzed addition of aldehyde to alkylidene- or
arylidene-P-keto carboxylic esters. Thus addition of furfural
to the methyl ester of benzylideneacetoacetic acid in dioxane
as solvent yields 1-(2-furyl)-3-methoxycarbonyl-2-phenylpentane-1,Cdione in 75 yield[20a'.
-
2 CHz=CH-CO-CH,
C H3-CO-C 132-C Hz-CO-X-C
0-C Hz-C Hz-C 0-C H3
X
Catalyst
Solvent
4CHz)z-4CHz1.14CH214qcHZ)64CHz)sm-C6H4
P-C&
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 1
Cat. 3
Cat. 3
DMF
DMF
DMF
DMF
DMF
Ethanol
Ethanol
Yield
[ %*I
43
33
7
46
48
21
29
5. Production of 4 0 x 0 Nitriles
Aromatic and heterocyclic aldehydes can be added extremely smoothly to cl,P-unsaturated nitriles if the reaction is subjected to cyanide catalysis; high yields of %ox0 nitriles are
obtained [eq. (a) and (w)].
4. Production of Dioxo Carboxylic Esters
Succinaldehydic methyl ester could be added to a series
of vinyl ketones according to eq. (u), giving 4,7-dioxo carboxylic ester[211.
-
::
R-CH
f
CNO
9"
R-CH
I
Caf 1
('H300C-CI-Iz-CH2-CH0
+ CHz=CH-CO-R
(v)
Hz-C Hz-C OOC H,
R-CO-C HZ-CHZ-CO-C
Table 6. Tetraketones from dialdehydes and butenone 1201.
OHC-X-CHO
-
+ CH~SH-CO-CHZ-CHZ-COOCH,
R-CHO
tone in ethanol as solvent affords 3-acetyl-l-(2-furyl)-2-phenylpentane-1,Cdione in 63%
A pathway to tetraketones leads via addition of dialdehydes
to =$-unsaturated ketones. Addition occurs only on catalysis
with thiazolium salts, both for aliphatic and for aromatic
and heterocyclic aldehydes. The yields of tetraketones generally remain below 50 % (Table 6).
CN
PIT
R-C:O
6N
(u)
DlOX*"C
R = i i - P e n t y l : 64%; R = ii-Hexyl: 69yb; R = rr-Heptyl: 7170;
R = rr-Octyl: 6970
Esters of this type are also obtained by adding aldehydes
according to eq. (v) under the same conditions to methyl
4-0xohexenoate[~~!
-
Table 7. 4-0x0 nitriles from aldehydes and a,p-unsaturated nitriles.
R-CHO
+ R'-CH=CR~-CN
R
R-CO-CHR'-CHR~-CN
R*
Rl
Catalyst
Solvent
Yield
Ref.
1x1
CHJ
(CH3)zC=CH
C6H5
CsHs
CsHs
GHs
CsH5
p-CICbH4
p-BrC6H4
m-CH3CsH4
p-CH,C.d4
m-CH30C6H4
p-CHjOC,jH&
2-Naphthyl
2-Fury1
2-Fury1
2-Fury1
2-Fury1
2-Fury1
2-Thienyl
2-Thienyl
2-Thienyl
5-Methyl-2-thienyl
3-Pyridyl
4-Pyridyl
H
H
H
H
H
H
CH3
C6Hs
H
H
H
H
H
H
H
H
H
CH3
H
C6Hs
H
CH3
C6Hs
H
H
H
n
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
Cat. 1
Cat. 1
CNCat. 1
CN
CNCN
CNCNCN CNCNCNCNCNCat. 1
CN
CN CN
CN
CNCNCNCN
CN
~
~
~
~
~
~
~
Ethanol
Ethanol
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Ethanol
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
30
34
80
52
73
71
80
91
81
47
43
83
39
81
65
49
73
62
68
85
76
71
60
89
71
~
644
Angew. Chrm. I n r . Ed.
Eiigl.
1 Vol. 15 ( 1 9 7 6 ) N o . I 1
Dimethylformamide was found to be the best solvent.
Sodium cyanide is required in amounts between 0.1 and 0.5 mol
per mol of aldehyde. Aliphatic aldehydes can only be added
to a,p-unsaturated nitriles on catalysis by thiazolium salts;
aromatic and heterocyclic aldehyde also reacts under those
conditions. In contrast to cyanide catalysis, however, satisfactory results are obtained only with acrylonitrile (Table 7).
Dialdehydes such as 2,5-thiophenedicarbaldehydecan also
be added to acrylonitrile in the presence of cyanide ions
[eq. (x)]“ ’1.
H 8 9 8 H + 2 CH,=CH-CN
CNO
7. Significance of the New Synthetic Approach
The synthetic approach described in this article is characterized by exceptional versatility, simplicity of operation, and
high yields. The procedure is superior to most reactions for
the synthesis of y-diketones, h X 0 nitriles, and h X 0 carboxylic esters by virtue of its purely catalytic nature. The compounds produced are highly important intermediates of synthetic organic chemistry.
Starting from y-diketones, it is very easy to prepare furans,
pyrroles, thiophenes, and pyridazines. Most of the newly prepared diketones were characterized as the N-phenylpyrroles.
The versatility of this simple procedure can be illustrated
for the synthesis of N-methyl-2,3,5-tri(3-pyridyl)pyrr0le[~I
[eq.
(Y)l.
gcHo
41%
+
QCH;CH-CO
0N
6. Production of 4 0 x 0 Carboxylic Esters
In the presence of cyanide ions as catalyst, aromatic and
heterocyclic aldehydes add to a$-unsaturated carboxylic
esters, forming 4-ox0 carboxylic esters. The most suitable
solvent is dimethylformamide, and the amount of catalyst
is generally 0.1-0.5 equivalent. High-boiling oils which were
not further characterized appeared as by-products. They are
probably esters of acyloins also present in equilibrium. It
is known that cyanide ions are excellent transesterification
catalysts.
This transesterification can be suppressed by variation of
the ester component. The yields admittedly increase on going
from the methyl, via the ethyl and the isopropyl, to the tertbutyl esters; however, even on use of teut-butyl esters it was
not possible to completely avoid side reactions. Overall, the
cyanide-catalyzed addition of aldehydes to a,p-unsaturated
esters is less favorable than the corresponding additions to
ct,p-unsaturated nitriles and ketones.
Both aliphatic and heterocyclic aldehydes undergo thiazohum-catalyzed addition to acrylic esters; however, the yields
are not entirely satisfactory (Table 8).
The possibility of obtained derivatives of cyclopentenone
starting from y-diketones by cyclizing aldol condensation is
of particular interest. Many of the y-diketones obtained were
converted into cyclopentenones. Since numerous natural products, such as jasmine odors, prostaglandins, and pyrethrolone contain the cyclopentenone ring as structural unit, or
can be derived therefrom, the reaction becomes particularly
important.
In order to prepare the odiferous substance dihydrojasmone,
2,5-undecanedione [accessible in 80 % yield by addition of
n-heptanal to butenone] was subjected to cyclizing aldol condensation [eq. (z)][’’.
Table 8. y-0x0 carboxylic esters from aldehydes and a,P-unsaturated esters.
R-CHO
+
R1-CH=CR2-COOR3
R
R‘
R’
-+
U3
R-CO-CHR’-CHR2-COOR3
Catalyst
Yield
Ref.
Ixl
n-C,H,
C6HS
CtFS
C6H5
C6H5
p-CIC,H
p-CIC,H,
P-CI,H,
p-CIC,H,
p-CIC,H,
p-CIC6H,
p-CIC6H,
p-C I C, H
2-Fury1
2-Thienyl
2-Thienyl
3-Pyridyl
Anqrw. Chem. I n t . Ed. Enyl.
Cat. 1
CN
CNCNCNCN
CNCNCNCN
CNCNCN
Cat. 1
CN
CN
CN
~
~
~
~
~
~
~
Vol. 15 ( 1 9 7 6 ) N o . 1 1
29
55
33
40
52
68
35
42
49
64
54
60
34
31
50
54
37
[22]
1281
[l, 281
[28]
[28]
1281
[ZX]
[l, 281
__+
U C H ,
cis-Jasmone, which is also an odiferous substance, was produced according to eq. (aa)from cis-3-hexen-1-01 (leaf alcohol),
which was converted into 1 -bromo-cis-3-hexene and its
Grignard compound. On treatment with diethyl phenylorthoformate the Grignard compound gave 7,7-diethoxy-cis-3-hep-
/7=/--
HO
v+
Br
1281
1281
[28]
1281
[28]
14, 61
[28]
I281
[28]
645
tene which could be converted into cis-Cheptenal with formic
acid. The cis-8-undecene-2,5-dione resulting from addition of
butenone furnished natural cis-jasmone by cyclizing aldol cond e n ~ a t i o n [ ~The
] . key step is addition of the aldehyde which
can also be prepared by another pathway.
The y-diketones readily accessible by addition of 2-pyridinecarbaldehyde to a$-unsaturated ketones open up a facile
entry to quinolizidines. Thus 4-methyl-I -quinolizidinol could
be prepared in 75 % yield from 1 -(2-pyridyl)-l,4-pentanedione
by hydrogenation with platinum oxide in glacial acetic acidl91.
desulfurizing ring cleavage into aliphatic r-diketones and 40x0 carboxylic acids. The best results were obtained on desulfuration by Raney nickel in ethyl methyl ketone (Table 9)["l.
Table 9. y-Diketones and 4-OXO carboxylic acids from thiophene derivatives
[ I 71.
H
H
H
H
H
CH3
CH3
CbHs
2-Thienyl [a]
2-Thienyl [a]
H
CH,
Analogous hydrogenation of 1-phenyl-3-(2-pyridyl)-i ,4-hexanedione likewise accessible via our reaction, which gives
1 -(3-phenyl-1-indolizidinyl)-l
-propano1 according to eq. (ac)
in 87 % yieldlg1, leads into the indolizidine series.
OH
OH
OH
OH
H
H
CHs
II
CH300C-CHZ-CHz-C-C
Hz-CH-CH-CN
81
HCIIHzO
A
R
HOOC-CH~-CHz-C-CH~-CH-CH-COOH
8
1
17
x3
78
19
4,9-Dioxododecanedioic acid was prepared from 2,5-thiophenedicarbaldehyde according to eq. (af) [see eq. (x)][' 'I.
417'
The brief selection of examples presented above should
provide an indication of the suitability of the compounds
obtained as starting materials for other reactions. However,
in view of the sheer volume of possibilities all such indications
can only remain fragmentary.
8. Experimental
3-Benzyl-S-(2-h~dro.uyethyl)-Cmethyl-1,3-thiuzolium chloride
(Cut. l)[51
5-(2-Hydroxyethyl)-4-methyi-l,3-thiazole
(143.2 g, 1 mol; commercial product, e x . Merck AG. Darmstadt), freshly distilled benryl chloride (126.6 g,
1 mol), and dry acetonitrile (500 ml) are mixed together in a 1000-ml threenecked flask fitted with a stirrer, a renux condenser, and a stopper. The
mixture is heated for 24 h under reflux and then allowed to cool to room
temperature with constant stirring. (The product precipitates from the boiling
solution on seeding after 12h.) The product is isolated by vacuum filtration,
washed colorless, subjected to preliminary drying, and then dried with gentle
turning in a water-pump vacuum (bath temperature 90°C). Yield 220.8g
(82%), m.p. 14&140.5"C.
3-Ethyl-S-(2-h~drox~~ethyl)-4-methyl-l,3-thiuzoliumbromide
(Cat. 2)161
8 2
R' = R2 = H; R' = CH,, R2 = H; R' = H, R2 = CH,;
R' = CsH,, R2 = H
The y-diketones and 4-OX0 nitriles readily accessible by
addition of thiophenecarbaldehydes could be converted by
646
51
[a] After reaction R 2=n-butyl
Numerous 4-OX0 nitriles and their reaction products are
also accessible by the aldehyde addition described. Catalytic
hydrogenation to give pyrrolidines [eq. (ad)] is an important
reaction.
Among the numerous ring c l o s ~ r e s ' ~ special
~J,
mention
should be made of the facile nicotine synthesis utilizing the
4-ox0 nitrile readily obtained in 80% yield by addition of
3-pyridinecarbaldehyde to a c r y l ~ n i t r i l e [ ~ ~ ] .
The 4-0x0 nitriles easily produced by addition of furfural
to a$-unsaturated nitriles according to eq. (ae) can be reduced
by sodium tetrahydridoborate to form 4-hydroxy nitriles,
which can be converted by Marckwald cleavage and hydrolysis
into 4-oxooctanedioic acids. It is not necessary to isolate the
intermediate~[~'l.
60
77
75
58
5-(2-Hydroxyethylj-4-methyl-1,3-thiazole
(143.2 g, I mol), bromoethane
(109.0 g, f mol). and dry acetonitrile (500 ml) are mixed in a 1000-mi roundbottom flask with a reflux condenser (potassium hydroxide drying tube) and
heated under reflux for 24 h. After cooling, the acetonitrile IS removed and
the residue treated with isopropyl alcohol (200 mlj. Ether is then added until
the solution retains a very slight turbidity and then seeded or rubbed. After
crystallization is complete the precipitate is filtered off under suction. washed
Aiigrw.
Chem. Inr. Ed. Engl. i Vil. 1 5 ( 1 9 7 6 ) N o . I I
with ether. and the ether-moist product dried in a water-pump vacuum. The
product is hygroscopic. Yield 192.2 g (76'%,),m.p. 85.0 86.5"C.
2,s-U n d e c u n e d i ~ n e [ ~ ~
Heptanal (57.1 g, 0.5 mol). butenone (35.1 g. 0.5 mol). and Cat. 1 (13.5 g.
0.05 mol) are united in a 250-ml three-necked flask fitted with stirrer, reflux
condenscr (with drying tube). dropping funnel. and gas entry tube. Triethylamine (30.3 g. 0.3 mol) is rapidly added from the dropping funnel: the mixture
is stirred with hcating under nitrogen for 8 h. Work-up is by pouring into
1 ''(, sulfuric acid (500 ml), thorough shaking, and extraction with chloroform
(4 x 100 ml). Thc chloroform phase is s a s h e d with watcr, sodium hydrogen
carbonate solution. and once again with water. After removal of chloroform
the mixture is distilled over a 30-cm Vigreux column. Yield 71.8 g (78:,),
b.p. 128 C/X torr. m.p. 33 -34 C (from pentane, -18 ' C ) .
I f the reaction is performed in ethanol (500 ml) with the same quantitie\
of starting materials then 12 hours' refluxing are required. Alter removal of
thc ethanol by distillation. the mixture is worked up in the same way: yield
cu. 72:,,,.
I -Phenj,l-I ,4-pentanedione"
A solution of freshly distilled benzaldehyde (10.6 g, 100 mmol) and anhydrous I I M F (50 ml) is added dropwise within 10 min t o a stirred mixture
of sodiiiin cyanide (049g, I0mmol) and D M F (50ml) at 35'C. After 5 minutes' stirring, a solution of freshly distilled methyl vinyl ketone (5.3g, 75mmol)
in D M F (100 ml) is added at 35 C over 20 min. Stirring is continued for 1 11
at the same temperature and the reaction mixture theii treated with twice
the amount of water. After repeated extraction with chloroform the combined extracts are washcd with dilute hydrochloric acid (pH 2). then with
sodium hydrogcii carbonate solution, and finally with water. Aftcr removal
of solvent. the residue is vacuum distilled. Yield 1 0 8 g (82'ii), b.p. 93-94 C:
0.1 torr. m.p. 28--29 C (from isopropyl alcohol)
2,4- Di(2juryl) -I-ph~~nyl-1,4-butanedione~~~
Benzaldehyde (6.9 g, 0 06 mol). 1,3-di(2-furyI)-2-propen-l-one
(9.3 g. 0 05
mol), Cat. 2 (2.5 g, 0 0 1 mol). triethylamine (10.1 g, 0.1 mol), and dry ethanol
(25 ml) arc united in a 100-ml three-necked flask fitted with a stirrer, a gas
tube. and a rellux condenser with a potassium hydroxide drying tube. The
mixture is stirred for 15 h at 70 C in a slow stream of nitrogen. After cooling
thc volatile components are distilled off in a water-pump vacuum. The residue
is taken in water (200 ml) and dilute H,SO, (25 ml). thoroughly shaken. and
d several tinics with CHCI, The combined organic phases are washed
with sodium hydrogen carbonate solution and a little water and then dried
with MgSO,. After filtration thc solwnt is distilled off and the residue recrystallized from isopropyl alcohol. Yield 12.0 g (82"/<;). m.p. 79-80 C.
I-0x0-2- (2-oxopentyI)tetralin"
91
2-(DimethylaminomethyI)-l-oxotetralin(40.4 g, 0.2 mol). Cat. 1 (10.75 g.
0.04 mol), and anhydrous D M F (200 ml) are transferred into 500-mi threenecked flask fitted with a stirrer, reflux condenser with drying tube ( K O H ) ,
and a pressure-equalizing dropping funnel with nitrogen entry tube. After
warming to 80-90 (', triethylamine (16.2 g. 0.16 mol) is added: butyraldehydc
(28.84 g. 0.4 moll 15 subsequently added dropwise over 1.5 h. The reaction
mixture I\ stirred for another 2 h. The solvent is then distilled off and the
oily residue added to water (500 i d ) . The aqueous phase is acidified with
dilute hydrochloric acid and extracted uith ether (4 x 100 ml). The combined
ether extracts ai-e neutralized with dilute N a H C O , solution. washed with
water. and then dried over Na,SO, Removal of ether is followed by vacuum
distillation of the residue. Yield 32.8 g ( 7 2 7 3 h.p. 134 Ci0.2 torr.
1,4-Di(2-thienyl)-I,4-but~nedione~'~~
A solution of freshly distilled 2-thiophenecarbaldehyde (14 g, 125 mmol)
in anhydrous D M F (40 ml) is added to a mixture ofsodium cyanide (10 mmol)
and D M F (40 i d ) . After addition or 3-dimcthylamino-l-~2-thienyl)-1-propanone (18.3g, 100 mmol: from 22.5 g of hydrochloride) in D M F (I00 ml),
stirring is continued for another 2 h prior to addition of twice the amount
of water. After repeated extraction with chloroform the combined extracts
arc washed neutral. r h e solvent is distilled off and the residue recrystallized
from ethanol. Yield 18.8 g (75%). m.p. 130-131 C.
5,8,1I - P e n t a d e c ~ n e t r i o n e [ ~ ~ l
Cat. 1 (7 g, 0.025 mol), triethylamine (30 g. 0.3 mol), divinyl ketone ( 1 1 g.
0.135 mol), and pentanal (26.4 g, 0.30) are successively introduced into il
250-ml three-necked flask fitted with a reflux condenser carrying a K O H
drying tube, a stirrer, and a gas inlet tube. The mixture is heated under
nitrogen up to an oil-bath temperature of 65 C. After distilling off the 1 1 1 ethylamine. the residue is dissolved in chloroform and the chloroform phase
washed with sodium hydrogen carbonate and common salt solution. The
aqueous phase is again extracted with chloroform and the combined chloroform phases conccntrated in I Y K U O . The residuc is recrystallized from methanol
Yield 20.5 g (62u/,), m.p. 8 4 ' C .
4-O.uo-4-phen,vlh~tyronitrile[~"~
A solufion of freshly distilled henzaldehyde (10.6 g, 0.1 mol) in anhydrous
dimethylformamide (50 ml) is added w e r 10 min to a stirred mixture of
sodium cyanide (2.45 g. 0.05 mol) and dimethylformamide (50 ml) at 35 C
Stirring is continued for another 5 min and then freshly distilled acrylonitrile (4.0 g, 0.075 mol) in dimethylformamide (100 ml) is added dropwise
over 20 min at 35 C. The mixture is stirred for 3 h at the same temperaturc
and then treated with twice the amount of water. Aftcr repeated extraction
with chloroform the combined extracts are washed with dilute sulfuric acid
( p H 2), then with aodium hydrogen carbonate solution, and finally with
water. The solvent is removed and the residue vacuum distilled. Yield 9.5 g
(80",,), b.p. 114 C , 0 3 torr, m.p 70 C.
Received: May 7, 1976 [ A 133 IT:]
German version: Angew. Chem. XX. 695 (1976)
~~
-~
H . Srerrer and .M. S c i i r t ~ c I ~ e i i h i ~Angew.
rg.
Chem. XS. 89 (1973): Angeu
Chem Int. Ed. Engl. 12,81 (1973); H . Slelfer and M. Schreckcnhrrg. DOS
2262343 (1972). Bayer AG.
R. B r ~ d o w ,J . Am. Chem. SOC. XO. 3719 (1958); N . 7 ~ p hand 11
Hura, J. Chem. Soc., Chem. Commun. 1973, 891.
B. Lackmum, H . Steinmuus. and H . W Wuiizlick. Tetrahedron 27, 40x5
(19711.
H . Sretrer and If. Kuhlriioiiii. Ansen Chem. X6. 589 11974): Angc\\.
Chem. Int. Ed Engl. 13, 539 (1974): H . Sfertpr and H K u h h i u n n . DOS
2437219 (1971), Bayer A G
H . Srerru and H. Kidiliiiuiiii. Synthcsis IY75. 379
H . Sfe//er and H . Kuhlinanri, Chcm. Ber. I O Y , 28YO (1976).
H . Srerter and H . Ki~/i/iiiuiiii,
Tetrahedron Lett. 1974. 4505
H . Sterrer and If Kidilimriiii. Chem. Ber., i n press.
H . Stetrer and J . Kras.se//..I Hetcrocycl. Chem.. in press.
H . Sfefrer and G . Hilholl, unpublished.
If. Kuh/niuriii, Dissertation. Technische Hochschule Aachen I 975.
H . Stetter and W Schleiilrrr. unpublished.
H . S f e t f e r and J . Nienhous. unpublished.
H . Stetrer and P. Luppe. unpublished.
H . S r e f t e r and M . Schreckeitherg, Chem. Ber. 107, 2453 (1971)
H . Srcltrr and H . - D . Jiige, unpublished.
If. Stetter and B. Rujh, Chem. Ber. 109. 534 (1976).
H . SIetter and M . Sclirec/~eiiherg,Tetrahedron Lett. 1Y73, 1461.
H . S r r t t n and 1'. H . ScAinirz. Chem. Ber., in press.
H. Srerter. M! B"x,. H . K l ~ h / m o i l r l .4.Luiid,whridf, and W Sdiliwker.
Chem. Ber., i n press.
[20a] H . Stefter and H Kuhltiiunn, unpublished.
[21] H . Srefrer and W. Basse, unpublished.
[22] H . Stetler and K . Wieinoiiit, unpublished.
[23] H. Stetrer and C. Hilboll, unpublished.
1241 H . Srerrer and M . Schreckenherg. Chem. Ber. 107. 210 (1974).
[25] H . Sretter and J . Kracselr. unpublished.
[26] M. S<hreckenberg,Dissertation, Technische Hochschule Aachen 1974.
1271 H . S r e t f e r and H . Kuhlinuiiri, Tetrahedron, in press.
[2X] H . Srerrer, M. Schreckeiihrrg. and K. Wiemaiiii, Chem. Ber. IOY, 541
(1976).
[29] F . Murlacchi, I.! Losucco, and K E v t o r e l l u , Gazz. Chim. Ital. 105,
349 (1975); F . Morlucchi and I.! LO.VJCCO.
J. Heterocycl. Chem. IY76,
165.
[30] CI., ' . g . E. Leere. M. R. Chetlrkel. and C . B. B o d m , J. Org. Cheni
37.4465 (1972).
647
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