A facile gold(I)-catalysed intramolecular alkyne hydroarylation approach to methyl 5-amino-2H-1-benzopyran-8-carboxylate derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.08.022

A high yielding and selective method for producing methyl 5-amino-2H-1-benzopyran-8-carboxylate derivatives via gold(I)-catalysed intramolecular alkyne hydroarylation has been developed.

Full text of DOI:10.1016/j.tetlet.2008.08.022

Tetrahedron Letters 49 (2008) 6279–6281
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Tetrahedron Letters
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A facile gold(I)-catalysed intramolecular alkyne hydroarylation approach
to methyl 5-amino-2H-1-benzopyran-8-carboxylate derivatives
*
Neil R. Curtis , Jeremy C. Prodger, Geracimos Rassias, Andrew J. Walker
Synthetic Chemistry, Chemical Development, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A high yielding and selective method for producing methyl 5-amino-2H-1-benzopyran-8-carboxylate
derivatives via gold(I)-catalysed intramolecular alkyne hydroarylation has been developed.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 July 2008
Revised 30 July 2008
Accepted 5 August 2008
Available online 9 August 2008
A key step in the initial synthesis of 5-HT4 agonist 1 is construc-
tion of methyl 5-acetamido-6-chloro-2H-1-benzopyran-8-carbox-
ylate (2a) via thermal cyclisation of aryl propargyl ether 3a.1
Such methodology has been used for related compounds from this
therapeutic class.2–4 However, the high temperature cyclisation of
3a to 2a proceeded in only moderate yield due to competing reac-
tion pathways4,5 and posed significant challenges on scale-up. As
part of an investigation into alternative routes6 to 1, we were intri-
gued by the potential utility of metal-catalysed intramolecular al-
kyne hydroarylation of 3.
of 2H-1-benzopyran 2b4,7 were limited by competing de-alkylation
to phenol 4b.7,10 A minor product identified was the methyl ketone
5b11 derived from hydration of the alkyne. Unlike the Sames
findings,8 platinum(II) chloride gave a higher yield of 2b than
platinum(IV) chloride. We postulated that dealkylation might be
promoted by the presence of chloride ions and considered addition
of a silver salt to sequester the chloride. However, platinum(II)
chloride with equimolar silver trifluoromethanesulfonate did not
significantly improve the yield of 2b. Interestingly, AgOTf
(5 mol %) alone catalysed the reaction (Table 1, entry 4) but gave
N
H
COOMe
O
COOMe
O
O
N
O
O
X
X
Br
NHCOR
NHCOR
NH2
1
2
3
a
b
c
d
R = Me, X = Cl
R = Me, X = H
R = CMe3, X = Cl
R = CMe3, X = H
Evaluation of the metal-catalysed cyclisation was carried out in
the first instance with platinum(IV) and platinum(II) chloride using
aryl propargyl ether 3b,4,7 based on the precedent from the groups
of Sames8 and Echavarren.9 The des-chloro substrate 3b was
chosen for synthetic expediency since in the initial synthesis of 1
the chlorine atom was introduced to facilitate the thermal
cyclisation and subsequently removed by hydrogenolysis. Whilst
promising results were obtained (Table 1, entries 1–3), the yields
additional products 6 and 7 characteristic of the high temperature
thermal process.4,12 Thus, benzopyran 2b was isolated in 46% yield
together with benzofuran 6 and indole 7, in 15% and 8% yields,
respectively. It appears that the silver trifluoromethanesulfonate-
catalysed reaction proceeded, at least in part, via the Claisen-like
[3,3] sigmatropic rearrangement postulated for the thermal
process4 rather than the electrophilic hydroarylation pathway
proposed by Sames for the platinum-mediated reaction.8b
In recent years, cationic phosphine–gold(I) complexes have
emerged as powerful homogeneous catalysts for electrophilic acti-
vation of alkynes.13 Indeed, several examples of 2H-1-benzopyran
* Corresponding author. Tel.: +44 01438 762756; fax: +44 01438 764869.
E-mail address: neil.r.curtis@gsk.com (N. R. Curtis).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.022

6280
N. R. Curtis et al. / Tetrahedron Letters 49 (2008) 6279–6281
Table 1
Metal-catalysed intramolecular hydroarylation of aryl propargyl ethers 3b and 3a
COOMe
O
COOMe
COOMe
OH
COOMe
O
O
O
X
X
X
X
NHCOMe
NHCOMe
NHCOMe
NHCOMe
3
2
4
5
Entry
Catalyst (mol %)
Conditions
HPLC product ratioa (%a/a)
Yieldb (%)
2
4
5
2
3b: X = H
1
2
3
4
5
6
PtCl4 (5)c
PtCl2 (5)
PtCl2 (5)
AgOTf (5)
(Ph3P)AuCl/AgOTf (5)
(Ph3P)AuCl/AgOTf (1)
Dioxane, 55 °C, O/N
Dioxane, 85 °C, O/N
2-MeTHF, 70 °C, 24 h
27.8
50.2d
53.4
47.0
74.8
83.6
49.1
25.9
23.5
8.0
7.5
9.6
4.1
2.0
1.8
2.7
5.0
5.2
26
50
53
46
75
73f
2-MeTHF, 75 °C, O/Ne
2-MeTHF, 70 °C, 1 h
2-MeTHF, 70 °C, 7 h
3a: X = Cl
7
(Ph3P)AuCl/AgOTf (2)
2-MeTHF, 70 °C, 6 hg
10.7
5.5
2.1h
—
a
HPLC peak areas at 220 nm as a percentage of total peaks area.
Isolated yield after silica chromatography, unless noted otherwise.
5 mol % for 3 h then a further 4 mol % added.
A minor product tentatively assigned as the isomeric 4H-benzopyran was also observed (3.5% a/a).
17.6% a/a of the benzofuran 6 (isolated yield 15%), 15.9% a/a of the indole 7 (isolated yield 8%).12
Isolated by crystallisation (with ca. 11% of 2b in the liquors by HPLC quantitation).
77.5% a/a 3a remained.
b
c
d
e
f
g
h
Methyl ketone product 5a tentatively assigned.
synthesis via cationic gold(I)-catalysed alkyne hydroarylation have
been reported,9b,14 although only for substrates bearing electron-
donating hydroxy or alkoxy substituents. Significantly, application
of the cationic gold(I) catalyst generated in situ from chloro(triphe-
nylphospine)gold(I) and silver trifluoromethanesulfonate gave a
striking improvement in the rate of reaction, the yield of benzo-
pyran 2b and the by-product profile due to reduced dealkylation
to phenol 4b (Table 1, entry 5).15 In addition, a slightly higher
amount of methyl ketone 5b was observed. The catalyst loading
was successfully reduced to 1 mol % in situ generated (Ph3P)AuOTf
(Table 1, entry 6). The benzopyran product 2b was isolated in 73%
yield (HPLC purity 98.5%) by crystallisation from 2-meth-
yltetrahydrofuran (2-MeTHF), which purged the by-products 4b
and 5b, leaving a further ca. 11% of 2b in the liquors. By compari-
son, the chloro analogue 3a7 was found to be a poor substrate for
the gold-catalysed hydroarylation, giving only ca. 10% of 2a (Table
1, entry 7), suggesting that the aryl group was rendered too elec-
tron-poor for facile cyclisation.
The moderate solubility of acetamide 2b in reaction solvents,
notably 2-MeTHF, meant that it crystallised prematurely during
the reaction. It was more desirable to have the product remain
soluble in hot solvent so that catalyst-derived material could be
removed by filtration at the end of the reaction prior to isolation.
Hence, further development of the gold(I)-catalysed intramolecular
hydroarylation continued with the more soluble pivalamide 3d4,6
(Table 2). Aryl propargyl ether 3d gave a marginally faster reaction
Table 2
Gold(I)-catalysed intramolecular hydroarylation using (Ph3P)AuNTf2
COOMe
O
COOMe
O
COOMe
OH
COOMe
O
O
NHCOR
NHCOR
NHCOR
NHCOR
3
2
4
5
Entry
Catalyst (mol %)
Conditions
HPLC product ratioa (%a/a)
Yieldb (%)
2
4
5
2
3d: R = CMe3
1
2
3
4
(Ph3P)AuCl/AgOTf (1)
(Ph3P)AuNTf2 (0.5)
(Ph3P)AuNTf2 (0.5)
(Ph3P)AuNTf2 (0.5)
(Ph3P)AuNTf2 (0.1)
2-MeTHF, 70 °C, 3 h
2-MeTHF, 70 °C, 5 h
CF3C6H5, 85 °C, 1 h
Toluene, 85 °C, 1 h
Toluene, 85 °C, 2 h
79.1
84.1
90.5
91.9
94.0
11.6
7.9
2.8
2.5
2.3
6.0
3.7
2.2
1.5
0.9
80
87
88
92
80c
5
3b: R = Me
6
(Ph3P)AuNTf2 (0.5)
Toluene, 85 °C, 1 h
92.1
3.1
1.3
92d
a
HPLC peak areas at 220 nm as a percentage of total peaks area (corrected for solvent peak in the case of trifluorotoluene and toluene reactions).
Isolated yield after silica chromatography, unless otherwise noted.
b
c
Isolated by crystallisation from toluene, with ca. 10% of 2d in the liquors by HPLC quantitation.17
Isolated by direct crystallisation from the reaction mixture.
d

N. R. Curtis et al. / Tetrahedron Letters 49 (2008) 6279–6281
6281
in 2-MeTHF with the in situ generated catalyst than 3b, affording
References and notes
2d4 in 80% yield after flash chromatography (Table 2, entry 1).
De-alkylation to phenol 4d4 and alkyne hydration to methyl ketone
5d11 were again observed at similar levels. However, it should be
noted that the tabulated HPLC peak area data somewhat over
estimate the levels of 4d and 5d due to higher response factors
(2.3 and 1.5, respectively) relative to 2d (1.0) at 220 nm.
1. Ahmed, M.; Miller, N. D.; Moss, S. F.; Sanger, G. J. WO 2007096352; Chem. Abstr.
2007, 147, 300999.
2. Van Daele, G. H. P.; Van den Keybus, F. M. A. EP 389037; Chem. Abstr. 1990, 114,
164012.
3. King, F. D.; Gaster, L. M.; Joiner, G. F. WO 9316072; Chem. Abstr. 1994, 120,
106767.
4. Kakigami, T.; Baba, K.; Usui, T. Heterocycles 1998, 48, 2611–2619.
5. It should be noted that Kakigami et al.4 reported a modest yield of 2a from 3a
(29%) in refluxing N,N-diethylaniline, but saw a significant improvement with
the pivaloyl substrate 3c, giving 2c in 74% yield. They also found that the des-
chloro analogues 3b and 3d gave poor yields of 2b and 2d, respectively, with
formation of isomeric benzofurans as the major products. However, our
preliminary experiments on thermal cyclisation of 3c were less selective for 2c
than the literature precedent.
6. Rassias, G.; Curtis, N. R.; Gray, M.; Northall, J. M.; Prodger, J. C.; Stevenson, N. G.;
Walker, A. J.; Org. Process Res. Der., manuscript in preparation.
7. Kakigami, T.; Usui, T.; Tsukamoto, K.; Kataoka, T. Chem. Pharm. Bull. 1998, 46,
42–52.
8. (a) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055–1058; (b)
Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59, 8859–8868.
9. (a) Martin-Matute, B.; Nevado, C.; Cárdenas, D. J.; Echavarren, A. M. J. Am. Chem.
Soc. 2003, 125, 5757–5766; (b) Nevado, C.; Echavarren, A. M. Chem. Eur. J. 2005,
11, 3155–3164.
The cost of a gold catalyst was likely to be significant on scale up
so a major driver was to minimise the catalyst loading. To do this
conveniently on a small scale during process development, the iso-
lable catalyst triphenylphosphine gold(I) bis(trifluoromethanesul-
fonyl)imidate [(Ph3P)AuNTf2] reported by Gagosz was used.14,16
This triflimide catalyst (0.5 mol %) gave a slightly higher yield of
2d (Table 2, entry 2) than the in situ generated (Ph3P)AuOTf
(1 mol %). This may be rationalised by the combination of less deal-
kylation to phenol 4d, perhaps due to the absence of any nucleo-
philic anion or any effect due to a silver salt, and lower alkyne
hydration. However, attempts to reduce the catalyst loading to
0.1 or 0.25 mol % in 2-MeTHF resulted in incomplete reactions. A
solvent screen was carried out using (Ph3P)AuNTf2 with the dual
aim of reducing the level of minor products and providing scope
10. MacKenzie, A. R.; Moody, C. J.; Rees, C. W. Tetrahedron 1986, 42, 3259–
3268.
11. Authentic samples of methyl ketones 5b and 5d were prepared in poor yields
(ca. 20%) by alkylation of phenols 4b and 4d, respectively, with chloroacetone
in the presence of potassium carbonate in NMP. Compound 5b: 1H NMR
(400 MHz, CDCl3) d 2.19 (3H, s), 2.38 (3H, s), 3.89 (3H, s), 4.60 (2H, s), 6.90 (1H,
dd, J 8.5, 1.7 Hz), 7.47 (2H, m), 7.85 (1H, d, J 8.5 Hz); 13C NMR (100 MHz, CDCl3)
d 24.9, 27.0, 52.0, 73.6, 104.2, 111.3, 115.3, 133.3, 143.1, 158.5, 165.7, 168.6,
205.4; m/z (ES+) 234 ([M+H]+-CH3OH); HRMS (APCI) calcd for C13H16NO5
([M+H]+) 266.1023, found 266.1023. Compound 5d: 1H NMR (400 MHz, CDCl3)
d 1.32 (9H, s), 2.39 (3H, s), 3.89 (3H, s), 4.61 (2H, s), 6.89 (1H, dd, J 8.5, 1.9 Hz),
7.49 (1H, br s), 7.62 (1H, d, J 1.9 Hz), 7.87 (1H, d, J 8.5 Hz); 13C NMR (100 MHz,
CDCl3) d 27.0, 27.5, 39.9, 51.9, 73.5, 104.5, 111.7, 115.0, 133.1, 143.5, 158.6,
165.7, 177.3, 205.3; m/z (ES+) 308 ([M+H]+), 276 ([M+H]+-CH3OH); HRMS
(APCI) calcd for C16H22NO5 ([M+H]+) 308.1492, found 308.1495.
12. The structures of benzofuran 6 and indole 7 were assigned on the basis of 1H
NMR comparison with the literature data.7
for reducing catalyst loading. This highlighted a,a,a-trifluorotolu-
ene and toluene as the most promising solvents, giving both a
reduction in de-alkylation to 4d and formation of methyl ketone
5d. Thus, 2d was obtained in ca. 90% yield after column chromatog-
raphy using 0.5 mol % (Ph3P)AuNTf2 at 85 °C (Table 2, entries 3 and
4). Pleasingly, a lower loading of 0.1 mol % (Ph3P)AuNTf2 in toluene
now gave complete turnover of 3d to 2d (Table 2, entry 5). In this
case, the benzopyran 2d was isolated by crystallisation following
hot filtration to remove catalyst-derived material.17 The isolated
2d contained some residual gold (220 ppm). At this early stage of
development metal scavenging was not investigated, although it
was anticipated that the gold content would be substantially re-
duced in the remaining steps required to convert 2d to the target
substance 1. The acetate 3b also gave an improved yield of 2b and
less side products with (Ph3P)AuNTf2 in toluene (Table 2, entry 6).
In summary, a high yielding method for producing methyl 5-
amino-2H-1-benzopyran-8-carboxylate derivatives 2b and 2d via
gold(I)-catalysed intramolecular alkyne hydroarylation has been
developed. This method provides access to the benzopyran moiety
which is a common substructure in pharmaceutical agents. Of the
metal catalysts evaluated, cationic gold(I) species were superior
and appear to operate via an electrophilic substitution mechanism
rather than the Claisen rearrangement manifold of the thermal
process.8b Low catalyst loading (0.1 mol %) was demonstrated, sug-
gesting that an economic process could be achieved. Further opti-
misation of solvent, temperature and catalyst loading has yet to be
carried out. In addition, other cationic gold(I) catalysts remain to
be evaluated.18,19 The gold-catalysed method avoids the harsh
conditions of the corresponding thermal process, which typically
requires temperatures of 180–240 °C,1,4 and in the case of forma-
tion of 2b is much cleaner and higher yielding. A chloro substituent
provided selectivity for benzopyran products over alternative iso-
meric benzofurans for the thermal process,4 whereas des-chloro
substrates proved advantageous in our gold-catalysed benzopyran
synthesis, demonstrating some complementarity between the
methods.
COOMe
O
COOMe
OH
N
NHCOMe
O
7
6
13. (a) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Commun. 2007, 333–346; (b)
Fürstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449; (c) Gorin,
D. J.; Toste, F. D. Nature 2007, 446, 395–403; (d) Hashmi, A. S. K. Chem. Rev.
2007, 107, 3180–3211; (e) Shen, H. C. Tetrahedron 2008, 64, 3885–3903.
14. Mézailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133–4136.
15. Chloro(triphenylphospine)gold(I) (5 mol %) alone gave no reaction in 2-MeTHF
after 1 h at 70 °C.
16. Commercially
(Ph3P)AuNTf2Á0.5C7H8 cat. no. 677922.
typical experimental procedure for the preparation of 2d with an
available
from
Aldrich
as
a
toluene
solvate,
17.
A
unoptimised isolation via crystallisation (cf. Table 2, entry 5) is given. A
mixture of aryl propargyl ether 3d (731.2 mg, 2.53 mmol) and
(Ph3P)AuNTf2Á0.5C7H8 (2.0 mg, 2.5
lmol) in toluene (14.6 ml) was stirred at
85 3 °C under nitrogen for 2 h. The reaction mixture was allowed to cool to
55 °C and filtered, washing the filter paper with toluene (3.6 ml). The filtrate
was concentrated in vacuo and the residual solid dissolved in hot toluene
(2.9 ml). The solution was allowed to cool and stirred at room temperature
overnight. The crystalline solid was collected under suction, washed with
toluene (1.5 ml) and dried in vacuo at 45 °C to afford 2d (584.0 mg, 80%) as an
off-white solid; mp 153–155 °C (dec); 1H NMR (400 MHz, CDCl3) d 1.35 (9H, s),
3.87 (3H, s), 4.83 (2H, m), 5.96 (1H, dt, J 9.8, 3.9 Hz), 6.38 (1H, m), 7.37 (1H, br
s), 7.42 (1H, d, J 8.8 Hz), 7.69 (1H, d, J 8.8 Hz); 13C NMR (100 MHz, CDCl3) d 27.6,
39.8, 51.9, 64.9, 115.3, 115.6, 115.9, 118.9, 122.7, 131.4, 136.7, 155.0, 165.8,
176.8; m/z (ES+) 290 ([M+H]+); HRMS (APCI) calcd for C16H20NO4 ([M+H]+)
290.1387, found 290.1392. Compound 2d contained ca. 220 ppm Au and 6 ppm
P by ICP. HPLC analysis of the combined filtrate and wash indicated a ca. 10%
yield of 2d was present by comparison with a standard solution.
Acknowledgements
We thank Dr. Klaus Laue (Carbogen Amcis) for initial studies
using substrate 3a. We are grateful to Simon Hayes and Kate Ross
for performing screening experiments and Alec Simpson for accu-
rate mass determinations. Dr. Matthew Gray is acknowledged for
helpful discussions.
18. Nieto-Oberhuber, C.; Pérez-Galán, P.; Herrero-Gómez, E.; Lauterbach, T.;
Rodríguez, C.; López, S.; Bour, C.; Rosellón, A.; Cárdenas, D. J.; Echavarren, A.
M. J. Am. Chem. Soc. 2008, 130, 269–279 and references cited therein.
19. (a) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614–12615; (b) Buzas, A.
K.; Istrate, F. M.; Gagosz, F. Angew. Chem., Int. Ed. 2007, 46, 1141.