Palladium catalysed synthesis of cyclic amidines and imidates

Article abstract of DOI:10.1016/j.tetlet.2004.07.151

The palladium catalysed insertion of isonitriles into aryl bromides carrying pendant amine or alcohol groups on the ortho position affords cyclic amidines or imidates in good yield.

Full text of DOI:10.1016/j.tetlet.2004.07.151

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6995–6996
Palladium catalysed synthesis of cyclic amidines and imidates
C. Gustaf Saluste,a Simon Crumpler,a Mark Furberb and Richard J. Whitbya,
*
aSchool of Chemistry, University of Southampton, Southampton, HANTS, SO17 1BJ, UK
bAstraZeneca Charnwood, Department of Medicinal Chemistry, Bakewell Road, Loughborough, Leics, LE11 5RH, UK
Received 15 July 2004; accepted 30 July 2004
Available online 13 August 2004
Abstract—The palladium catalysed insertion of isonitriles into aryl bromides carrying pendant amine or alcohol groups on the ortho
position affords cyclic amidines or imidates in good yield.
Ó 2004 Elsevier Ltd. All rights reserved.
We recently reported the palladium catalysed three com-
t
HN Bu
PdCl2 (5 mol%),
dppf (10 mol%)
ponent synthesis of aryl-amidines or -imidates from aryl
bromides, isonitriles, and amines or alcohols respec-
tively (Scheme 1).1 We now report that the reactions
work well in an intramolecular fashion to afford cyclic
amidines and imidates.
Br
+ tBuNC
NH2
N
n
Cs2CO3 (1.2 equiv.),
toluene, 1 h, 109 ˚C.
n
1a n = 1
1b n = 2
2a n = 1, 64%
2b n = 2, 64%
The formation of cyclic lactones and lactams by intra-
molecular cyclisation of aryl halides on to alcohols or
amines with incorporation of carbon monoxide is
known.2 The stoichiometric insertion of isonitriles into
1-palladaisoindolines to afford isoindolinium salts has
also been reported.3
Scheme 2.
judged from the proton chemical shift of the tert-butyl
groups of 1.54 and 1.49ppm, respectively. In a variety
of amidines ArC(@NtBu)NR2 and ArC(@NR)NHtBu
the proton shift of the tert-butyl group was 1.0 in the
former, 1.41–1.45 in the latter.4
Treatment of 2-bromobenzylamine 1a and 2-(2-bromo-
phenyl)ethanamine
1b
with
tert-butylisonitrile
(1.5equiv), dry Cs2CO3 (1.2equiv), 5mol% PdCl2 and
10mol% 1,10-diphenylphosphinoferrocene (dppf) in tol-
uene at 109°C for 1h gave quantitative (by GC) conver-
sion into the cyclic amidines 2 (Scheme 2). Work-up by
extraction into 2.5% acetic acid in water, basification,
extraction into ether and Kugelrohr distillation afforded
2a and 2b as white crystalline solids, each in 64% yield.
Only the endocyclic imine tautomers were observed, as
Unfortunately, the cyclisation has the same limitation to
tert-alkylisonitriles that we observed for the analogous
intermolecular process––both cyclohexyl- and n-butyl-
isonitriles gave low yields. Surprisingly, the reaction also
failed when cyclisation of secondary amines was tried.
We then turned our attention to the formation of cyclic
imidates, and found a much more versatile process
(Scheme 3, Table 1). Treatment of the appropriate
bromoalcohol 3 or 4 with an isonitrile (1.5equiv), so-
dium tert-butoxide (1.3equiv), PdCl2 (5mol%) and
dppf (10mol%) in toluene at 109°C for 4–16h gave
clean conversion into the desired imidates 5 and 6.
The best work-up method was found to be to dilute
the cold reaction mixture with diethyl ether and filter
through a pad of silica eluting with 5% triethylamine
in diethylether. After removal of solvent the crude prod-
uct was chromatographed on silica eluting with 5%
PdCl2 (5 mol%),
dppf (10 mol%)
NR1
ArBr + R1NC + R2XH
NaOtBu or Cs2CO3 Ar
XR2
X = O, NR3
Scheme 1.
Keywords: Amidine; Imidate; Palladium catalysed; Isonitrile.
*
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.2004.07.151

6996
C. G. Saluste et al. / Tetrahedron Letters 45 (2004) 6995–6996
R3
Acknowledgements
N
PdCl2 (5 mol%),
dppf (10 mol%),
Br
We thank AstraZeneca and the University of South-
ampton for funding this work.
OH
R1
R2
O
+ R3NC
R1
R2
NaOtBu (1.3 equiv.),
toluene, 2-20 h, 109 ˚C.
n
n
3 n = 0
4 n = 1
5 n = 0
6 n = 1
References and notes
1. Saluste, C. G.; Whitby, R. J.; Furber, M. Angew. Chem.,
Int. Ed. 2000, 39, 4156–4158; Saluste, C. G.; Whitby, R. J.;
Furber, M. Tetrahedron Lett. 2001, 42, 6191–6194.
2. Mori, M.; Washioka, Y.; Urayama, T.; Yoshiura, K.;
Chiba, K.; Ban, Y. J. Org. Chem. 1983, 48, 4058–4067;
Martin, L. D.; Stille, J. K. J. Org. Chem. 1982, 47,
3630–3633; Pandey, G. D.; Tiwari, K. P. Tetrahedron 1981,
37, 1213–1214; Orito, K.; Mityazawa, M.; Suginome, H.
Synlett 1994, 245–246.
Scheme 3.
Table 1. Palladium catalysed synthesis of imidates 5 and 6
R1
R2
R3
Product
Yield %a
H
H
tBu
nBu
5a
5b
5c
5d
5e
5f
76
61
75
44
82
63
60
38
50
84
H
H
H
H
c-C6H11
CH2Ph
tBu
3. Vicente, J.; Llamas, I. S.; Grunwald, C.; Alcaraz, C.; Jones,
¨
H
H
P. G.; Bautista, D. Organometallics 2002, 21, 3587–3595;
OÕSullivan, R. D.; Parkins, A. W. J. Chem. Soc., Chem.
Commun. 1984, 1165–1166.
H
Me
Me
H
Me
H
tBu
tBu
6a
6b
5c
6d
4. Saluste, C. G. Ph.D. Thesis, University of Southampton,
2002.
H
H
nBu
H
Me
H
Me
c-C6H11
tBu
5. The (E)-isomer of 5/6 was more stable than the (Z)- by
between 24 (5b) and 72 (6d) kJ/mol according DFT
(B3YLP/6-31G*) calculations. Calculations were carried
out using Spartan04, Wavefuntion Inc. In the case of N-
tert-butyl-substituted imidates E/Z isomerisation would be
expected to be fast at room temperature: Gallis, D. E.;
Crist, D. R. Magn. Reson. Chem. 1987, 25, 480–483.
6. (Z)-N-(Isobenzofuran-1(3H)-ylidene)-2-methylpropan-2-
amine 5a. Dry sodium tert-butoxide (0.25g, 2.6mmol),
dppf (0.111g, 0.20mmol) and 2-bromobenzyl alcohol
(0.374g, 2mmol) were added to a 20mL tube equipped
with a reflux condenser and the vessel flushed with argon.
Dry degassed toluene (10mL), tert-butylisonitrile (0.25g,
3.0mmol in 1mL toluene) were added by syringe before
solid palladium dichloride (17.4mg, 0.1mmol) was added
against a flow of argon. The tube was then heated at 109°C
with stirring in a thermostatically controlled block under an
argon atmosphere for 8h. After cooling to room temper-
ature the reaction mixture was filtered through a 1–2cm bed
of silica on a sinter funnel washing through with a solution
of 5% triethylamine in diethyl ether. After removal of
solvent the residue was chromatographed on silica eluting
with 3% triethylamine in petrol (bp 40–60°C) to afford the
title compound 5a as a pale yellow oil, which solidified on
storage. Recrystallisation from hexane gave very pale
yellow crystals of the title imidate mp 61–63°C. Anal.
C12H15NO requires: C, 76.16; H, 7.99; N, 7.40%. Found: C,
a Isolated yield.
triethylamine in petrol to afford the pure cyclic imidates.
Aqueous work-up, or chromatography without the
presence of base gave partial hydrolysis to the corre-
sponding lactones.
It is notable that both 5- and 6-membered ring imidates
could be formed, the isonitrile could be primary, second-
ary or tertiary, and the alcohol could be primary, sec-
ondary or tertiary. The conversions to 5a, 5f and 6a
after 1h were 37%, 51% and 21%, respectively, indicat-
ing that neither the size of ring formed, nor steric hin-
drance of the alcohol has a big effect on the rates of
reaction and suggesting that the rate of attack of the
alcohol on the supposed iminoacylpalladium intermedi-
ate is not rate limiting.
Although we have not proven the shown (Z)-stereo-
chemistry of the imidates 5 and 6 formed, calculations
indicate it to be substantially more stable than the (E)-
form.5 Exposure of the imidates to acid––conditions ex-
pected to equilibriate the geometric isomers––caused
only slow hydrolysis to afford the expected lactones.
1
75.80; H, 8.02; N, 7.33%. H NMR (400MHz, CDCl3) dH
7.81 (1H, br d, J = 7.4Hz), 7.46 (1H, br t, J = 7.4Hz), 7.39
(1H, br t, J = 7.5Hz), 7.32 (1H, br d, J = 7.6Hz), 5.30 (2H,
s), 1.40 (9H, s) ppm. 13C NMR (75MHz, CDCl3) dC 157.0
(C), 142.6 (C), 132.2 (C), 131.0 (CH), 128.4 (CH), 123.9
(CH), 121.3 (CH), 72.2 (CH2), 53.7 (C), 30.3 (CH3) ppm.
MS (ES+) m/z 204 (M+H+, 100%). IR (neat) 1691 (br s),
In conclusion we have shown that benzo-fused cyclic
amidines and imidates are readily obtained by a palla-
dium catalysed coupling, and the latter, in particular is
a versatile process.6
1467 (m), 1352 (s), 1215 (s), 1035 (s), 994 (s), 723 (s) cmꢀ1
.