A new convenient method for the preparation of enamides from N-allylamides

Article abstract of DOI:10.1055/s-2002-32962

Isomerization of various N-allylamides in the presence of Fe(CO)₅ smoothly afforded the corresponding enamides in yields up to 95%. The reported procedure is compatible with various functional groups including protected amino and hydroxy groups. The possible mechanism of transformation is discussed.

Full text of DOI:10.1055/s-2002-32962

LETTER
1313
A New Convenient Method for the Preparation of Enamides from
N-Allylamides
Convenient
M
e
ethodfor th
r
e
Prepar
g
ationof
E
nam
e
ide
s
y Sergeyev, Manfred Hesse*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
Fax +41(1)6356812; E-mail: mtbohley@oci.unizh.ch
Received 7 May 2002
cause it led to the equilibrium mixture of isomeric en-
amides with starting material, which was impossible to
separate. Stille and Becker reported in the above men-
tioned publication,15 that attempts to isomerize N-(3,3-
dimethylallyl)-acetamide resulted in the decomposition of
the starting material.
Abstract: Isomerization of various N-allylamides in the presence
of Fe(CO)5 smoothly afforded the corresponding enamides in yields
up to 95%. The reported procedure is compatible with various func-
tional groups including protected amino and hydroxy groups. The
possible mechanism of transformation is discussed.
Key words: enamides, N-allylamides, double bond shift, iron pen-
tacarbonyl
We have found, however, that the action of Fe(CO)5 on N-
(prop-2-enyl)-3-phenylpropanamide (1a) resulted in com-
plete conversion of the starting material to the mixture of
(Z)- and (E)-N-prop-1-enylamides 2a, 2a . Reaction con-
ditions were initially examined to optimize the yield of the
enamides. We were pleased to find that at 100 °C the
transformation of N-allylamide to N-prop-1-enylamide
can be performed in almost quantitative yield (Table 1,
entry 3). At lower temperatures complete conversion was
not achieved in reasonable time (entries 1, 2), while at
higher temperatures decomposition was essential and the
yield was lower (entries 4, 5).
Enamides (N-alken-1-ylamides) are the interesting sub-
strates for various transformations, including cyclopropa-
nation,1 Diels–Alder cycloaddition,2 hydroformylation,3
Paternò–Büchi photocycloaddition.4 The first example of
enamide-olefin ring-closing metathesis was recently pub-
lished.5 The simplest and most general method for the
synthesis of N-substituted enamides is the acylation of al-
do- or ketoimines with acyl halide or acid anhydride.6–8
Secondary enamides are not so trivially available as their
tertiary analogs. Several methods for their synthesis9–13
were reported, but the yield of enamides is often modest.
In addition, conditions used are in many cases quite harsh,
making such procedures hardly suitable for the synthesis
of the highly functionalized molecules.
Table 1 Isomerization of N-(Prop-2-enyl)-3-phenylpropanamide
a
(1a) in the Presence of Fe(CO)5
O
O
Fe(CO)5
Me
Ph
N
Ph
N
H
H
Isomerization of N-allylamides to enamides is very attrac-
tive because N-allyl amides are readily available via stan-
dard synthetic methods.14 Stille and Becker15 reported
isomerization of several simple N-allylamides to a mix-
ture of (Z)- and (E)-enamides in moderate to high yield in
the presence of hydridorhodium or -ruthenium complex-
es. However, a general catalyst could not be found, and it
was necessary to match the reaction conditions with a par-
ticular substrate to reach an acceptable yield of enamide.
In addition, catalysts used are not easily available and ex-
tremely air sensitive. In this paper we wish to report con-
venient and general procedure for the preparation of N-
alken-1-ylamides from N-allylamides upon the action of
commercially available, inexpensive, and stable
Fe(CO)5.16
2a (E), 2a' (Z)
1a
Entry
Temp (°C)
Yield (%)
E/Zb
Unreacted 1a
(%)
1
2
3
4
5
60
80
6
68
95
75
45
73:27
70:30
61:39
57:43
50:50
92
25
0
100
120
140
0
0
a All reactions without solvent, 0.2 equiv Fe(CO)5, 15 h.
b Determined by 1H NMR.
Little was hitherto known about the isomerization of allyl-
amides with this catalyst and the data are unpromising.
Hubert et al.17 reported the attempted photochemical
isomerization of N-allylacetamide in the presence of
Fe(CO)5. Synthetic value of this method is limited, be-
Two mechanisms may be responsible for the metal-cata-
lyzed conversion of N-allylamides to N-prop-1-enyl-
amides. Mechanism suggested by Hubert et al.17
(Scheme 1) includes hydrido- -complex 3. However, hy-
dride transfer to the terminal methylene group should give
exclusively (Z)-isomer 2 , which was not observed. More-
over, (E)-isomer 2 is normally the major one (Table 1). In
the control experiment with (Z)-enamide, no E/Z isomer-
ization took place under the reaction conditions. In addi-
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1313,1317,ftx,en;G12302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1314
S. Sergeyev, M. Hesse
LETTER
O
O
O
Fe(CO)5
–2 CO
H
N
R
N
R
R
N
H
H
HFe(CO)3
Fe
(CO)3
1
3
O
R
O
O
O
H
N
H
N
H
R
N
R
+
R
N
H
Me
Me
Fe
(CO)3
Fe
(CO)3
2'
Scheme 1
tion, we observed decreasing of E/Z ratio with raising the
temperature (Table 1), indicating that this transformation
is kinetically controlled.
O
R3
R3
iii)
R2
Ph
N
H
R2
X
R1
R1
Another mechanism was suggested by Stille and Becker15
for the isomerization of N-allylamides upon the action of
Ru or Rh hydrides. We assumed, that the similar mech-
anism occurs in the catalysis with Fe(CO)5. In this case,
some iron species like -complex 3 may be involved as a
donor of hydride (Scheme 2). cis-Elimination from metal-
lacycle 4 should lead to (Z)-enamide 2 , whereas interme-
diate 5 gives (E)-isomer 2. Intermediate 4 with a methyl
group in the axial position is certainly the less favorable
one, therefore the (Z)-isomer is the minor reaction prod-
uct. At elevated temperatures the selectivity of the reac-
tion decreases and both isomers are formed in nearly
equal amounts (Table 1).
9a–d
6a,b X = Cl; 6c,d X = Br
7a–d X = NBoc2
a R1= Me, R2=R3= H
b R1=R3= H, R2= Me
c R1=R3= H, R2= Ph
d R1= H, R2=R3= Me
i)
ii)
8a–d X = NH2
Scheme 3 Reagents and conditions: (i) Boc2NH, Cs2CO3, DMF, r.t.,
12 h. (ii) TFA, CH2Cl2, r.t., 4 h. (iii) PhCH2CH2COCl, Et3N, CH2Cl2,
0 °C, 1 h.
of the latter with 3-phenylpropanoyl chloride in the pres-
ence of Et3N delivered the substituted allylamides 9.20
A number of N-allylamides was subjected to the isomer-
ization in the presence of Fe(CO)5 (Table 2).21 Usually, a
mixture of (E)- and (Z)-isomers was obtained, which was
in some cases separated by crystallization or column chro-
matography. Otherwise the E/Z ratio was determined by
1H NMR spectroscopy.22 The double bond in the acyl
moiety of crotonoyl amide 1b underwent no change under
the reaction conditions (Table 2, entry 2). The presence of
ether or ester groups has no remarkable influence on the
migration of the double bond (entries 3, 4). The amino
group, protected by Ts or CF3CO, did not affect the trans-
formation as well (entries 6, 7). In the case of the N-Boc
group, very widely used in peptide chemistry, the yield
was, however, moderate (entry 8). The attempt to perform
the isomerization of N-(prop-2-enyl)-3-bromopropan-
amide (1e) failed: only recovery of the starting material
was observed (entry 5).
H
H
R
R
ML H
H
H
N
H
H
N
1
+
M
L
M
L
Me
H
O
O
H
Me
4
5
H
H
L
L
H
H
M
Me
M
O
O
N
H
N
H
H
Me
H
R
R
–
cis-elimination
ML H
–
ML H
2'
2
Scheme 2
Next, we checked the utility of the method for the isomer-
ization of N-allylamides containig various functional Data on isomerization of substituted 3-phenyl-N-allyl-
groups in the acyl residue. Starting N-allylamides 1a–h amides 9a–d are summarized in Table 3. Compounds
were prepared by acylation of allylamine using standard 9a,b demonstrated only partial conversion at 100 °C
protocols. Amides 9a–d, bearing additional substituents (entries 1, 3). Hence, further experiments were conducted
in allyl moiety, were synthesized in a three-step sequence at 120 °C. Some decomposition of material was observed
starting from the corresponding commercially available at this temperature, but the conversion was complete and
allylhalides 6 (Scheme 3). Alkylation of 6 with Boc2NH18
the yield was still good (entries 2, 4). In the case of the
in the presence of Cs2CO319 afforded the N,N-di-Boc der- phenylsubstituted allylamide 9c and the dimethylsubsti-
ivatives 7, which were smoothly and quantitatively hydro- tuted allylamide 9d the conversion remained incomplete
lyzed with TFA to the corresponding amines 8. Acylation and the yield was relatively low. However, essential
amounts of the starting material was recovered and the
Synlett 2002, No. 8, 1313–1317 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Convenient Method for the Preparation of Enamides
1315
ment, supporting the suggested mechanism for migration
of double bond. Indeed, intermediate complex 13 is steri-
cally more hindered compared to 4, which has an H-atom
instead of Me group at the N-atom (Scheme 2, Scheme 4).
Therefore, difference in energies between 13 and 14
(Scheme 4) is even bigger than between 4 and 5
(Scheme 2).
Table 2 Isomerization of N-Allylamides 1a–h Upon the Action of
Fe(CO)5
a
O
O
Fe(CO)5
Me
R
N
H
R
N
H
2a–h (E), 2a'–h' (Z)
1a–h
Entry Starting
material
R
Total yield E/Z
In addition, we demonstrated that by suggested method N-
allylimides can be converted to N-(prop-1-enyl)imides in
high yield.25 Attempts to extend this transformation to N-
sulfonamides were unsuccessful.26
(%)
95
88
72
86
0f
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
PhCH2CH2
61:39c
71:29d
70:30c
55:45d
–
(E)-MeCH=CH
MeOCH2
O
O
Fe(CO)5
Me
MeOOC(CH2)4
BrCH2CH2
Ph
N
Ph
N
Me
Me
11
12
H
H
CF3CONH(Ph)CHCH2 89b,e
75:25d
64:34d
50:50d
L
L
H
H
M
Me
M
O
O
1g
1h
TsNH(Ph)CH
90b
44b
N
H
N
Me
H
R
R
Me
Me
BocNH(PhCH2)CH
14
13
a Reaction without solvent, 0.2 equiv Fe(CO)5, 100°C, 15 h.
b Reaction in PhCl.
cis-elimination
– MLH
– MLH
c Products were separated by column chromatography.
d Determined by 1H NMR.
O
O
Me
e Products were separated by crystallization.
f Starting 1e (71%) was recovered.
N
R
N
R
Me
Me
Me
Scheme 4
yield respective to the reacted material was acceptable
(entries 5, 6).23
In summary, we have found a convenient and general
method for the conversion of N-allylamides to N-prop-1-
enylamides. The reported procedure has an advantage of
inexpensive catalyst and is compatible with various func-
tional groups including protected hydroxy and amino
groups. It allows to perform conversion of amides, vari-
ously substituted in allyl moiety, with appreciable yields.
We have shown that the method found could be extended
to the tertiary enamides. Isomerization of N-methyl-3-
phenyl-N-(prop-2-enyl)-propanamide 1124 afforded the
corresponding enamide 12 in good yield. Interestingly,
only the (E)-isomer was obtained. This is a further argu-
a
Table 3 Isomerization of Substituted N-Allylamides 9a–d Upon the Action of Fe(CO)5
R3
O
R3
O
Fe(CO)5
R2
Ph
N
R2
Ph
N
H
H
R1
R1
9a–d
10a–d (E), 10a'–d' (Z)
Entry
Starting
material
Temp (°C)
R1
R2
R3
Yield (%)
E/Z ratio
Recovery of 9
(%)
1
2
3
4
5
6
9a
9a
9b
9b
9c
9d
100
120
100
120
120
120
Me
Me
H
H
H
75
–
11
0
H
H
86
–
Me
Me
Ph
Me
H
63
69:31
74:26
68:32
83:17
30
0
H
H
59
H
H
28 (58)b
22 (76)b
52
71
H
Me
a All reactions without solvent, 0.2 equiv Fe(CO)5, 15 h.
b Yields respective to the reacted 9 are given in parenthesis.
Synlett 2002, No. 8, 1313–1317 ISSN 0936-5214 © Thieme Stuttgart · New York

1316
S. Sergeyev, M. Hesse
LETTER
CH2Cl2 (75 mL) and H2O (50 mL), the organic phase was
separated and washed with H2O (2 50 mL), dried (MgSO4),
and concentrated to afford crude 7a. It was dissolved in
CH2Cl2 (20 mL) and treated with TFA (6.1 mL, 80 mmol) in
one portion. After 4 h stirring at r.t. the mixture was
concentrated and the residue was dried in vacuo to give
crude 8a as TFA salt. It was dissolved in the mixture of
CH2Cl2 (75 mL) and Et3N (8.3 mL, 60 mmol) and treated
dropwise at 0 °C with 3-phenylpropanoyl chloride (2.83 mL,
19 mmol). The mixture was stirred for 1 h at 0 °C, then
allowed to reach r.t., washed with H2O (25 mL), 10% aq
citric acid (25 mL), again H2O (2 25 mL), and dried
(MgSO4). Evaporation of the solvent in vacuo and
crystallization of the residue from hexane/EtOAc afforded
9a (3.82 g, 94% total yield after 3 steps). Slightly yellow
solid, mp 51–52 °C.
This approach, obviously, provides also a competitive al-
ternative to the known methods for the preparation of ter-
tiary enamides. In addition, it can be of value as a method
for removal of N-allyl protecting group from amides
(isomerization to enamide followed by acidic hydrolysis).
Acknowledgement
We thank the Swiss National Science Foundation for financial sup-
port of this work.
References
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(7) (a) Lenz, G. R. Synthesis 1978, 489. (b) Campbell, A. L.;
Lenz, G. R. Synthesis 1987, 421.
(8) Meth-Cohn, O.; Westwood, K. T. J. Chem. Soc., Perkin
Trans. 1 1984, 1173.
1H NMR (CDCl3): = 1.65 (s, 3 H, Me), 2.51 (t, 2 H, J = 7.7
Hz, CH2CO), 2.96 (t, 2 H, J = 7.7 Hz, CH2Ph), 3.75 (d, 2 H,
J = 6.0 Hz, CH2N), 4.68, 4.76 (2 s-like m, 2 H, CH2=C), 5.80
(br s, NH), 7.15–7.28 (m, 5 H, Ph). 13C NMR (CDCl3):
20.1 (Me), 31.6 (CH2Ph), 38.3 (CH2CO), 44.9 (CH2N),
110.7 (CH2=C), 126.1 (arom. CH), 128.2 (2 arom. CH),
=
128.4 (2 arom. CH), 140.7 (C), 141.8 (C), 172.0 (C=O). CI-
MS (NH3): m/z (%) = 407(29) [2 M + 1]+, 221(25) [M +
NH4]+, 204(100) [2 M + 1]+.
(21) Preparation of 2a/2a (Typical Procedure for the
Isomerization of N-Allylamides to N-Prop-1-
enylamides). A mixture of 1a (945 mg, 5 mmol) and
Fe(CO)5 (0.2 mL, 1 mmol) was stirred under Ar for 16 h at
100 °C. The mixture was allowed to reach r.t., then the
catalyst was removed in vacuo and collected in a trap, cooled
by liquid N2. Content of the trap was treated with 5%
alcoholic FeCl3 solution to destroy toxic Fe(CO)5. The
residue in the reaction flask was dissolved in CHCl3 and
filtered through Celite. Evaporation of the solvent in vacuo
and column chromatography of the residue on silica gel
(CH2Cl2/EtOAc 10:1) afforded 2a (548 mg, 58%) and 2a
(350 mg, 37%), total yield of 2a/2a 95%.
(9) (a) Suen, Y. H.; Horeau, A.; Kagan, H. B. Bull. Soc. Chim.
Fr. 1965, 1454. (b) Kagan, H. B.; Horeau, A.; Suen, Y. H.
Bull. Soc. Chim. Fr. 1965, 1457.
(10) (a) Eiden, F.; Nagar, B. S. Arch. Pharm. (Weinheim, Ger.)
1964, 297, 367. (b) Eiden, F.; Nagar, B. S. Arch. Pharm.
(Weinheim, Ger.) 1963, 296, 458. (c) Eiden, F.; Nagar, B. S.
Arch. Pharm. (Weinheim, Ger.) 1963, 296, 445.
(11) Ben-Ishai, D.; Giger, R. Tetrahedron. Lett. 1965, 4523.
(12) (a) Kurtz, P.; Disselnkötter, H. Liebigs Ann. Chem. 1972,
764, 69. (b) Brettle, R.; Shibib, S. M.; Wheeler, K. J. J.
Chem. Soc., Perkin Trans. 1 1985, 831.
(13) (a) Fürstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G.
Chem.–Eur. J. 2001, 7, 5286. (b) Stefanuti, I.; Smith, S. A.;
Taylor, R. J. K. Tetrahedron Lett. 2000, 41, 3735. (c) Shen,
R.; Porco, J. A. Org. Lett. 2000, 2, 1333.
(14) Larock, R. C. Comprehensive Organic Transformations;
Wiley: New York, 1999.
(15) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139.
(16) This work is a part of the Ph.D. Thesis of S. Sergeyev,
University of Zürich, 2002.
(17) Hubert, J.; Moniotte, P.; Goebbels, G.; Warin, R.; Teyssié,
P. J. Chem. Soc., Perkin Trans. 2 1973, 1954.
(18) Boc2NH represents an exellent alternative to the classical
Gabriel method for preparation of amines from halides:
(a) Grehn, L.; Ragnarson, U. Synthesis 1987, 285.
(b) Grehn, L.; Ragnarson, U. Acc. Chem. Res. 1991, 24, 285;
and references cited therein.
(19) We have shown that the use of Cs2CO3 as the phase-transfer
catalyst allows to avoid the preparation of Na or K salt of
Boc2NH, see ref.18a
(20) Preparation of N-(2-Methylprop-2-enyl)-3-
phenylpropanamide 9a (Typical Procedure for the
Preparation of Substituted N-Allylamides 9a–d). A
mixture of 6a (4.0 mL, 40 mmol), Boc2NH (4.34 g, 20
mmol), Cs2CO3 (6.52 g, 20 mmol), and DMF (20 mL) was
stirred for 12 h at r.t., then the volatile materials were
removed in vacuo. The residue was partitioned between
(E)-3-Phenyl-N-prop-1-enyl-propanamide(2a). Colorless
solid, mp 113–114.5 °C.
1H NMR (CDCl3): = 1.62 (dd, 3 H, J = 1.7, 6.7 Hz, Me),
2.49 (t, 2 H, J = 7.8 Hz, CH2CO), 2.95 (t, 2 H, J = 7.8 Hz,
CH2Ph), 5.09 (qd, 1 H, J = 6.7, 14.2 Hz, CH=CHN), 6.71–
6.78 (m, 1 H, CH=CHN), 7.15–7.28 (m, 5 H, Ph), 7.40 (br d,
NH). 13C NMR (CDCl3): = 14.7 (Me), 31.4 (CH2Ph), 38.1
(CH2CO), 107.8 (CH=CHN), 123.1 (CH=CHN), 126.2
(arom. CH), 128.2 (2 arom. CH), 128.4 (2 arom. CH), 140.6
(arom. C), 169.2 (C=O). CI-MS (NH3): m/z (%) =
207(37)[M + NH4]+), 190(100) [M + 1]+).
(Z)-3-Phenyl-N-prop-1-enyl-propanamide (2a ).
Colorless solid, mp 53.5–55 °C.
1H NMR (CDCl3): = 1.49 (dd, 3 H, J = 1.5, 7.0 Hz, Me),
2.57 (t, 2 H, J = 7.7 Hz, CH2CO), 2.96 (t, 2 H, J = 7.7 Hz,
CH2Ph), 4.73 (qd, 1 H, J = 7.0, 8.9 Hz, CH=CHN), 6.64–
6.71 (m, 1 H, CH=CHN), 7.16–7.28 (m, 6 H, Ph, NH). 13
C
NMR (CDCl3): = 10.7 (Me), 31.4 (CH2Ph), 38.0 (CH2CO),
105.3 (CH=CHN), 121.8 (CH=CHN), 126.2 (arom. CH),
128.2 (2 arom. CH), 128.5 (2 arom. CH), 140.5 (arom. C),
169.5 (C=O). CI-MS (NH3): m/z (%) = 207(48) [M + NH4]+,
190(100) [M + 1]+).
(22) E/Z ratio was determined from the integral intensities of the
signals of CH=CHN, (E)- or (Z)-configuration of double
bond was assigned based on the value of coupling constants
(typically 13.5–14.2 Hz for (E)- and 8.5–9.0 Hz for (Z)-
enamides).
(23) It should be noted, that our findings are in contrast with those
of Stille and Becker, reported decomposition of N-(3,3-
Synlett 2002, No. 8, 1313–1317 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Convenient Method for the Preparation of Enamides
1317
dimethylallyl)acetamide upon the action of Fe(CO)5, see
our results were in disagreement with those of Rossi and
Barola, reporting only partial conversion of some N-
allylimides with Fe(CO)5: Rossi, P.; Barola, P. F. Ann. Chim.
1969, 59, 762.
ref.15
(24) Prepared by alkylation of 1a with MeI in DMF in the
presence of NaH.
(25) N-Allylphthalimide afforded N-(prop-1-enyl)-phthalimide
(E/Z 10: 1) in 99% yield after 15 h at 100 °C. Interestingly,
(26) N-Tosylallylamine remained unchanged upon the action of
Fe(CO)5.
Synlett 2002, No. 8, 1313–1317 ISSN 0936-5214 © Thieme Stuttgart · New York