Palladium-catalysed three component synthesis of α,β-unsaturated amidines and imidates

Article abstract of DOI:10.1016/j.tetlet.2004.07.150

Palladium-catalysed three component coupling of an alkenylbromide, isonitrile and an amine or alkoxide/phenoxide affords α,β- unsaturated-amidines and -imidates.

Full text of DOI:10.1016/j.tetlet.2004.07.150

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6991–6994
Palladium-catalysed three component synthesis of a,b-unsaturated
amidines and imidates
K. Kishore R. Tetala, Richard J. Whitby,* Mark E. Light and Michael B. Hurtshouse
School of Chemistry, University of Southampton, Highfield, Southampton, Hants, SO17 1BJ, UK
Received 15 July 2004; accepted 30 July 2004
Abstract—Palladium-catalysed three component coupling of an alkenylbromide, isonitrile and an amine or alkoxide/phenoxide
affords a,b-unsaturated-amidines and -imidates.
Ó 2004 Elsevier Ltd. All rights reserved.
But
We recently reported the palladium-catalysed three
component synthesis of aryl-amidines1 and -imidates2
from aryl bromides, isonitriles and amines or alcohols,
respectively (Scheme 1). We now report that the reaction
also works well with alkenyl bromides to afford a,b-
unsaturated-amidines and -imidates. The related palla-
dium catalysed carbonylation of alkenyl bromides to
afford esters and amides is known.3
NH
N
tBuNC,
Br
Ph
Ph
N
PdCl2 (5 mol%), dppf (10 mol%),
Cs2CO3, 65 °C, toluene
1a
Scheme 2.
line solid in good yield (Table 1, entry 1). Amidine 1a
was formed as a 99:1mixture of E:Z alkene stereoiso-
mers. When the commercial 85:15 E:Z mixture of
b-bromostyrene was used product 1a was formed
as a 90:10 alkene E:Z mixture. Only one isomer about
the C@N bond was observed.
We first tried the coupling reaction between b-bromostyr-
ene (>99% E),4 tert-butylisonitrile and pyrrolidine using
the same conditions developed for coupling of aryl bro-
mides (5mol% PdCl2, 10mol% dppf, Cs2CO3, toluene).1
Pleasingly the desired amidine 1a (Scheme 2) was
formed in excellent yield in less than 15min at 65°C, a
marked contrast to the 2h at 109°C needed for the
equivalent reaction of bromobenzene. On a preparative
scale extraction of the crude product into 2.5% aqueous
acetic acid, basification by addition of solid KOH,
extraction of the product into diethyl ether and removal
of solvent gave the amidine 1a as a pale yellow crystal-
X-ray crystallography of 1a (Fig. 1)5 showed that the
(E)-stereoisomer of the imine had been formed, the same
stereochemistry as observed in the formation of aryl
amidines (Scheme 1),6 and probably reflects thermody-
namic stability7,8 rather than the mechanism of forma-
tion. The barrier to rotation about the C–N single
bond in 1a was very low––no line broadening was
observed in carbon or proton NMR at 213K.9
PdCl2 (5 mol%),
A variety of primary and secondary amines were tried in
the reaction with the results given in Scheme 3 and Table
1. The amidines derived from primary amines (entries 5–
7) exist entirely in the tautomeric form 2 as judged from
the 1H NMR shifts of the tert-butyl groups at (dH 1.41–
1.43) compared to amidines 1 derived from secondary
amines (dH 1.23–1.26) in accordance with similar obser-
vations on aryl amidines.10 We have not proven the
imine stereochemistry in amidines 2, but that shown is
predicted by calculations.11
NR1
XR2
dppf (10 mol%)
ArBr + R1NC + R2XH
X = O, NR3
NaOtBu or Cs2CO3 Ar
Scheme 1.
Keywords: Isonitrile; Multi-component; Amidine; Imidate; Palladium
catalysed.
*
Corresponding author. Tel.: +44 (0)23 80592777; fax: +44 (0)23
80593781; e-mail: rjw1@soton.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.150

6992
K. K. R. Tetala et al. / Tetrahedron Letters 45 (2004) 6991–6994
But
N
R2
1a-d
2e-g
Ph
N
R1
PdCl2 (5 mol%),
dppf (10 mol%)
Br
Ph
R1
or
t
+ BuNC
+ R1R2NH
Cs2CO3
toluene, 65 °C
N
tBu
Ph
N
H
Scheme 3.
Table 1. Formation of 3-phenyl-2-alkenylamidines
Entry
R1, R2
Product
Yield (%)a
E:Zb
c
c
1–(CH
2)4–
1a
1b
1c
1d
2e
2f
77
6195:5 (91
62
>99:1(90:10)
c
c
2
3
4
5
6
7
Et, Et
:9)
(90:1
–(CH2)2O(CH2)2–
–(CH2)5–
Me, H
>98:1(93:7)
0)
71>98:1
71>99:1
71>99:1
25d
Cy, H
Ph, H
2g
>97:3
t
a Isolated yield. Reagents and conditions: b-bromostyrene (1.2mmol), amine (6mmol), BuNC (1.8mmol), Cs2CO3 (1.5mmol), PdCl2 (0.06mmol),
dppf (0.12mmol), toluene, 65°C, 15–30min.
b Alkene stereochemistry from >99% (E)-b-bromostyrene.
c Alkene stereochemistry from 85:15 mixture of E:Z-b-bromostyrene.
d Required heating at 109°C for 35h.
NtBu
n
Br
tBuNC,
NH
N
Ph
Ph
PdCl2 (5 mol%), dppf (10 mol%),
Cs2CO3, toluene, 109 °C
n
3a n = 1
3b n = 2
OH NtBu
NCy
tBu
N
N
H
Ph
Ph
n
4a n = 1
4b n = 2
5
Scheme 4.
sion, by GC, to the methylidine amidines 3a and 3b
(Scheme 4). Surprisingly our standard work-up by
extraction into aqueous acetic acid followed by basifica-
tion with solid KOH and extraction into ether gave sub-
stantial conversion into the b-hydroxyamidines 4a and
4b (40:60–25:75 3:4 by GC in various experiments).
Alcohols 4a and 4b could be isolated by column chro-
matography (5% triethylamine, 10% diethyl ether in
petrol as eluent) in 25% and 29% yields, respectively.
Amidine 3a was stable in the acid solution so hydration
must be occurring on addition of the base. The addition
of water could be avoided by vigorous stirring of the
acid solution with diethyl ether during addition of the
KOH to give 3a and 3b in 71% and 64% isolated yields,
respectively. We have not proven the stereochemistry of
the imine in 3 and 4, but it is expected to be (E) by com-
parison with similar systems (Schemes 1and 2 above),
and in accordance with calculations.11 The reaction
between a-bromostyrene, tert-butylisonitrile and cyclo-
Figure 1. Crystal structure of 1a. Thermal ellipsoids drawn at the 30%
˚
probability level. Selected measurements: C9–N2 = 1.363A; C9–
˚
˚ ˚
C9–C8 = 1.497A; C8–C7 = 1.32A; N2–C9–N1=
N1= 1.291A
;
117.5°; N1–C9–N2–C17 = 179.8°; N1–C9–C8–C7 = 105.6°; C8–C7–
C6–C1= 3.0 °.
When aniline was the amine source the reaction was
very slow with little conversion to products after 18h
stirring at 65°C. After 35h at 109°C the starting bro-
mide had all reacted, but only a low yield of the amidine
2g was isolated. Attempts to replace tert-butylisonitrile
with n-butyl-, cyclohexyl- or benzyl-isonitriles in the
synthesis of alkenylamidines were unsuccessful.
We next examined the reaction of a-bromostyrene with
tert-butylisonitrile and pyrrolidine and piperidine and
found that 2h at 109°C was needed to give good conver-

K. K. R. Tetala et al. / Tetrahedron Letters 45 (2004) 6991–6994
6993
NR1
R1NC, R2ONa
Br
R2
Ph
Ph
O
PdCl2 (5 mol%), dppf (10 mol%)
109 °C, toluene, 1-2h
6a-e
NBu
O
OEt
tBu
Ph
Ph
N
H
NBu
8
7
Scheme 5.
Table 2. Formation of 3-phenyl-2-alkenylimidates
Entry
R1
R2
Time (h)
Product
Yield (%)a
1
2
3
4
5
tBu
tBu
nBu
nBu
Cy
Et
Ph
Et
Ph
Ph
1.5
0.5
1.0
0.5
1
6ab
6b
25
60
64c
72
55
6c + 8
6dd
.0 6ed
a Isolated yield. Reagents and conditions: PhCHCHBr (1mmol), R1NC (1.5mmol), PhONa or EtONa (5mL of 1M soln in THF or ethanol,
respectively), toluene (20mL), 109°C.
b 26% of 7 also isolated.
c 1:2 ratio 6c to 8.
d 65:35 mixture of imine stereoisomers.
hexylamine gave the tautomer 5 in 53% yield (Scheme 4)
and in this case hydration was not observed. Attempts
to replace tert-butylisonitrile with n-butyl- or cyclo-
hexyl-isonitriles were unsuccessful.
temperature.7,14 Phenoxyimidates 6d and 6e were each
a 65:35 mix of imine stereoisomers, whereas 6c was a
single isomer. Theoretical calculations15 are consistent
with these observations. For 6a, 6b and 6c the (E)-imine
stereoisomer is calculated to be 15, 7 and 20kJ/mol more
stable than the (Z). For 6d and 6e the energy difference
is <3kJ/mol (favouring the (Z)-stereoisomer) consistent
with the observed mixture.
We now turned to the synthesis of imidates. Initial
GC optimisation of the palladium-catalysed reaction
between b-bromostyrene, tert-butylisonitrile and sodium
ethoxide to afford 6a (Scheme 5) showed that 1h at
109°C was required for complete reaction. It is interest-
ing that the rate is much slower than amidine formation.
In the formation of aryl-amidines and -imidates the latter
was somewhat faster.1,2 The product 6a proved unstable
to both chromatography and distillation, substantial
amounts of amide 7 being formed, reducing the isolated
yield to 25% (Scheme 5, Table 2, entry 1). n-Butylisonit-
rile also worked well in the reaction, but the main prod-
uct was the a-iminoimidate 8 resulting from bis-insertion
of the isonitrile (Table 2, entry 3)––a similar result to the
analogous reaction starting with aryl bromides.12,13
Synthesis of imidates using a-bromostyrene was not suc-
cessful. Even after 18h at 125°C (pressure tube) the
starting bromide was largely unreacted.
In conclusion, we have shown that a,b-unsaturated ami-
dines and imidates are readily formed in a three compo-
nent palladium-catalysed reaction.
Acknowledgements
We thank Mrs. J. Street and Dr. N. Wells for variable
temperature NMR studies.
Palladium-catalysed reaction of b-bromostyrene and
sodium phenoxide with tert-butyl-, n-butyl- and cyclo-
hexyl-isonitriles afforded the desired imidates 6b, 6d
and 6e in good yield (Scheme 5, Table 2 entries 2, 4
and 5). No bis-insertion of isonitrile was observed and
the products were more stable to silica than the alk-
oxy-imidates. Although the b-bromostyrene used for
all the above reactions was a 99:1mixture of ( E)-:(Z)-
alkene stereoisomers, none of the (Z)-isomer of 6 was
observed by GC or NMR. Compounds 6a and b were
either single isomers at the imine double bond, or more
likely the isomers were rapidly interconverting at room
References and notes
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Int. Ed. 2000, 39, 4156–4158.
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4. Obtained from the commercial 85:15 E:Z mixture by
removal of the latter by treatment with NaOH under

6994
K. K. R. Tetala et al. / Tetrahedron Letters 45 (2004) 6991–6994
phase transfer conditions: Makosza, M.; Chesnokov, A.
A. Tetrahedron 2002, 58, 7295–7301.
10. Saluste, C. G. PhD Thesis, University of Southampton,
2002.
5. Crystallographic data (excluding structure factors) for 1a
has been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC
243515. Copies of the data may be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, U.K. (fax: +44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk).
6. Stereochemistry of arylamidines was erroneously drawn as
(Z) in Ref. 1. We later showed it to be (E) on the basis of
low temperature NMR studies and calculations (Whitby,
R. J., unpublished work).
7. Perrin, C. L. In The Chemistry of Amidines and Imidates;
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stable that the (Z) imine by DFT calculations.15 The
barrier to E/Z interconversion of MeCH@CHC-
(@ NPh)NMe2 is 109kJ/mol. Naulet, M.; Filleux, M. L.;
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dines 1 would be expected to be lower.
11. The (E)-imine isomers of 2e, f and g are calculated15 to be
15, 19 and 20kJ/mol, respectively, more stable than the
(Z)-forms. Likewise (E)-3a is calculated15 to be 40kJ/mol
more stable than (Z)-3a.
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PhCH@CHCOCONEt2 is known. Ozawa, F.; Soyama,
H.; Yamamoto, T.; Yamamoto, A. Tetrahedron Lett.
1982, 23, 3383–3386; Kobayashi, T.; Tanaka, M. J.
Organomet. Chem. 1982, 233, C64–C66; Double carbonyl-
ation of aryl iodides to afford a-keto-esters is also
known. Ozawa, F.; Kawasaki, N.; Okamoto, H.; Yama-
moto, T.; Yamamoto, A. Organometallics 1987, 6,
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480–483.
15. DFT calculations were carried out using the hybrid HF-
DFT B3LYP method and 6-31G basis set as implemented
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9. The low barrier to C–N rotation of 1a comes from
energetically favourable overlap of the C@C and C@N
bonds in the transition state B, which is not possible in the
ground state A
‡
tBu
tBu
N
N
H
N
N
Ph
Ph
B
A