Indium-mediated regio- and chemoselective synthesis of α-hydroxyalkyl allenic esters and gold-catalyzed cyclizations to ethyl 2-naphthoate derivatives

Article abstract of DOI:10.1021/ol801196g

(Chemical Equation Presented) The regio- and chemoselective synthetic method of functionalized α-hydroxyalkyl allenic esters was developed from the reactions of various aldehydes with organoindium reagent generated in situ from indium and ethyl 4-bromobut

Full text of DOI:10.1021/ol801196g

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3359-3362
Indium-Mediated Regio- and
Chemoselective Synthesis of
r-Hydroxyalkyl Allenic Esters and
Gold-Catalyzed Cyclizations to Ethyl
2-Naphthoate Derivatives
Chansoo Park and Phil Ho Lee*
National Research Laboratory for Catalytic Organic Reaction, Department of
Chemistry, and Institute for Molecular Science and Fusion Technology,
Kangwon National UniVersity, Chunchon 200-701, Republic of Korea
phlee@kangwon.ac.kr
Received May 26, 2008
ABSTRACT
The regio- and chemoselective synthetic method of functionalized r-hydroxyalkyl allenic esters was developed from the reactions of various
aldehydes with organoindium reagent generated in situ from indium and ethyl 4-bromobutynoate. The r-hydroxyalkyl allenic esters possessing
electron-donating groups were cyclized to ethyl 2-naphthoate derivatives through intramolecular C-alkylation catalyzed by gold salts.
The functionalized R-hydroxyalkyl allenic esters composed
of allenic alcohol and allenic ester play an important role in
organic chemistry, not only as key structural units in many
natural products and important pharmaceuticals but also as
useful building blocks in synthetic chemistry.1 For this
reason, the efficient synthesis of substituted R-hydroxyalkyl
allenic esters continues to attract the interest of synthetic
chemists. Recently, R-hydroxyalkyl allenic esters were
prepared in good yields (59-83%) from the modified
reactions of aldehydes with 3-(methoxycarbonyl)propargyl
bromide using SnCl2 and NaI in DMPU.1d However, these
reactions needed the toxic stannous chloride and a long
reaction time (14-36 h) in the absence of light. Aldol
reactions of allenic esters with aldehydes gave the R-hy-
droxyalkyl allenic esters, whereas functional group tolerance
and product yields were unsatisfactory due to the basic
reaction conditions.1b The allenic alcohols bearing an
ethoxycarbonyl group at the R-position were provided by
the 1,6-cuprate addition to acceptor-substituted enynes fol-
lowed by the oxidation of titanium enolates with dimethyl
dioxirane in a two pot process.2 Although the allenic alcohols
were obtained through the indium-mediated reactions of
trialkylsilylpropargyl bromide with aldehydes, the product
yields were moderate (45-71%) and the corresponding
(1) (a) Mukaiyama, T.; Harada, T. Chem. Lett. 1981, 621. (b) Tsuboi,
S.; Kuroda, H.; Takatsuka, S.; Fukawa, T.; Sakai, T.; Utaka, M. J. Org.
Chem. 1983, 58, 5952. (c) Winkler, J. D.; Quinn, K. J.; MacKinnon, C. H.;
Hiscock, S. D.; McLaughlin, E. C. Org. Lett. 2003, 5, 1805. (d) Deng, Y.;
Jin, X; Ma, S. J. Org. Chem. 2007, 72, 5901.
(2) (a) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. 1997, 36, 186.
(b) Krause, N.; Thorand, S. Inorg. Chim. Acta 1999, 296, 1. (c) Krause,
N.; Laux, M.; Hoffmann-Ro¨der, A. Tetrahedron Lett. 2000, 41, 9613. (d)
Krause, N., ; Zelder, C. In The Chemistry of Dienes and Polyenes;
Rappoport, Z., Ed.; Wiley: New York, 2000; Vol. 2, p 645.
10.1021/ol801196g CCC: $40.75
Published on Web 07/10/2008
2008 American Chemical Society

homopropargylic alcohols were produced as side products.3
In addition, the bulky groups, such as triisopropylsilyl and
tert-butyldiphenylsilyl groups, at the γ-position of propargyl
bromide were necessarily required. Despite recent progress,4,5
these results have led us to investigate the preparative
methods of functionalized R-hydroxyalkyl allenic esters. In
continuation of our studies directed toward the development
of efficient indium-mediated reactions,6 we described herein
an efficient synthetic method of functionalized R-hydroxy-
alkyl allenic esters. Also, treatment of R-hydroxyalkyl allenic
esters possessing electron-donating groups with gold catalyst
unexpectedly led to the formation of ethyl 2-naphthoate
derivatives through intramolecular C-alkylation (Scheme 1).
Table 1. Optimization for the Reaction of Benzaldehyde with
Metal and Ethyl 4-Bromobutynoatea
additive
(equiv)
temp time
yield
(%)b
entry metal
solvent
THF
(°C)
(h)
1
In
In
In
In
In
In
In
In
Mg
Zn
60
60
25
25
25
25
25
25
25
25
10
10
5
32c
2
3
4
5
6
7
DMF
THF
THF
THF/H2O
DMF/H2O
DMF
38c
LiI (3.0)
KI (3.0)
LiI (3.0)
LiI (3.0)
KI (3.0)
0d
45
6
4
4
6
58
29c
72
8
9
10
LiI (3.0) DMF
5
12
12
90 (86)e
0
Scheme 1
.
Preparation of R-Hydroxyalkyl Allenic Esters and
Their Cyclization to Naphthoates
THF
THF
38f
a Reactions were performed with benzaldehyde (1 equiv) and organo-
metallic reagent generated in situ from the reaction of metal (1 equiv) with
1 (1.5 equiv) under Grignard-type condition. b GC yields obtained on the
basis of 2-methoxynaphthalene as an internal standard. c Benzaldehyde was
mainly recovered. d TLC is messy. e Isolated yields. f Isolated yield of ethyl
5-hydroxy-5-phenyl-2-butynoate.
presence of lithium iodide (3 equiv) in DMF at 25 °C for
5 h under a nitrogen atmosphere, producing exclusively
allenic ester 5e in 86% yield with complete regioselectivity
(entry 8). Grignard-type addition reaction provided the better
results rather than one of Barbier type. DMF was the best
solvent among several reaction media (THF, DMF,
THF-H2O and DMF-H2O). Subjecting benzaldehyde to 1
and Mg in THF did not give 5e (entry 9). In the case of Zn,
propargylation product (ethyl 5-hydroxy-5-phenyl-2-bu-
tynoate) was only produced in 38% yield (entry 10). Ethyl
Reactions of benzaldehyde with indium and ethyl 4-bro-
mobutynoate (1)7 were initially examined (Table 1). Treat-
ment of benzaldehyde with organoindium reagent generated
in situ from indium and 1 selectively produced R-hydroxy-
benzyl allenic ester 5e in 32% (THF) and 38% (DMF) yields,
respectively (entries 1 and 2). The use of additives, such as
lithium iodide and potassium iodide, affected the reaction
time and product yields. Potassium iodide in DMF afforded
the allenic ester in 72% yield (entry 7). Of the reactions
screened, the best results were obtained with organoindium
reagent generated in situ from the reaction of indium (1
equiv) with ethyl 4-bromobutynoate (1.5 equiv) in the
1
4-iodobutynoate was detected in part in H NMR after
treatment with lithium iodide in DMF, indicating that iodide
replaced bromide in ethyl 4-bromobutynoate, and then the
corresponding iodide reacted smoothly with indium to
produce organoindium reagent.
1
The H NMR (400 MHz, DMF-d7, 25 °C) spectrum of
(3) Lin, M.-J.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 13042.
(4) (a) Hopf, H.; Bohm, I.; Kleinschroth, J. Org. Synth. 1982, 60, 41.
(b) Oehlsehlager, A. C.; Czyzewska, E. Tetrahedron Lett. 1983, 24, 5587.
(c) Brandsma, L.; Verkruijisse, H. In PreparatiVe Polar Organometallic
Chemistry I; Springer: Berlin, 1987; pp 61-64. (d) Isaac, M. B.; Chan,
T.-H. Chem. Commun. 1995, 1003. (e) Masuyama, Y.; Ito, A.; Fukuzawa,
M.; Terada, K.; Kurusu, Y. Chem. Commun. 1998, 2025. (f) Li, C.-J.; Chan,
T.-H. Tetrahedron 1999, 55, 11149. (g) Masuyama, Y.; Watabe, A.; Ito,
A.; Kurusu, Y. Chem. Commun. 2000, 2009. (h) Krause, N.; Hoffmann-
Ro¨der, A.; Cansius, J. Synthesis 2002, 1759. (i) Hoffmann-Ro¨der, A., ;
Krause, N. In Modern Allene Chemistry; Krause, N., ; Hashmi, A. S. K.,
organoindium reagents showed two signals (δ 4.01 and 3.88)
for the methylene group, indicating that two types of
propargylindium reagent (2, ratio ) 2.62:1 for 30 min, 2.40:1
for 45 min, 1.86:1 for 60 min) were produced and the
corresponding allenylindium reagents (3) were not formed
(Table 2).
To demonstrate the efficiency and scope of the present
method, we applied the organoindium reagent to a variety
of aldehydes (Table 3). Indium reagent was treated with
formaldehyde to selectively afford allenic ester 5a in 82%
yield (entry 1). In the case of butanal and cyclohexane-
carbaldehyde, the corresponding allenic esters 5b and 5d
were obtained in 83% and 82% yields, respectively (entries
2 and 4). Electronic variations on the aromatic substituents
did not diminish largely the efficiency and selectivity (entries
6-19). Reaction of 2,4,6-trimethylbenzaldehyde with the
organoindium reagent provided the corresponding product
Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1,pp 51-92 and 493-592
.
(5) For allenylmagnesium halide and allenyllithium, see: (a) Babudri,
F.; Florio, S. Synthesis 1986, 638. (b) Shinokubo, H.; Miki, H.; Yokoo, T.;
Oshima, K.; Utimoto, K. Tetrahedron 1995, 51, 11681. (c) Weyershausen,
B.; Nieger, M.; Do¨tz, K. H. Organometallics 1998, 17, 1602. (d) Hoffmann-
Ro¨der, A., ; Krause, N. In Modern Allene Chemistry, Vol. 1, (Eds.; Krause,
N., ; Hashmi, A. S. K., Eds.;Wiley-VCH: Weinheim, 2004; pp 497-499
and pp 509-510.
(6) (a) Lee, P. H.; Sung, S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201. (b)
Lee, K.; Seomoon, D.; Lee, P. H. Angew. Chem., Int. Ed. 2002, 41, 3901.
(c) Seomoon, D.; Lee, K.; Kim, H.; Lee, P. H. Chem.sEur. J. 2007, 13,
5197.
(7) MacInnes, I.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1987,
1077.
3360
Org. Lett., Vol. 10, No. 15, 2008

as demonstrated by the reaction of 3-hydroxylbenzaldehyde
(entry 13). Moreover, the present reaction proceeded to
furnish the allenic ester 5n in 68% yield despite the presence
of two hydroxyl groups on the aromatic ring (entry 14).
Aromatic aldehydes having electron-withdrawing groups,
such as 4-acetyl, 4-methoxycarbonyl, and 4-nitro groups,
reacted with organoindium reagents to result in the exclusive
formation of R-hydroxyalkyl allenic esters in excellent yields
under the optimum conditions (entries 15-17). A range of
4-chloro- and 2-iodobenzaldehyde readily participated in
these indium-mediated addition reactions (entries 18 and 19).
Surprisingly, no propargylic addition products are formed
in any reactions. The reactions of aldehydes, such as 4i, 4n,
and 4s, with 3-(methoxycarbonyl)propargyl bromide using
SnCl2 and NaI in DMPU for 24 h under the absence of light
produced 5i, 5n, and 5s, in 62%, 52%, and 50% yields,
respectively. These results indicate that the organoindium
reagent is more reactive than organotin reagent. However,
ketones have thus far failed.
Next, we tried to cyclize R-hydroxyalkyl allenic esters to
obtain a variety of dihydrofuran derivatives. In general,
allenic alcohols in the presence of gold salt catalysts provided
2,5-dihydrofuran derivatives.8 However, treatment of allenic
esters possessing electron-donating groups, such as methoxy
and hydroxyl group, on the aromatic ring with gold catalyst
unexpectedly produced ethyl 2-naphthoate derivatives (Table
4).9 Allenic ester 5h having 3-methoxyphenyl group was
treated with 5 mol % of (Ph3P)AuCl and 5 mol % of AgBF4
to give ethyl methoxy-2-naphthoate in 54% yield (6a:6b )
1:3.5) through C-alkylation and 2-(3-methoxyphenyl)-3-
ethoxycarbonyl-2,5-dihydrofuran in 33% yield through O-
alkylation (entry 1). This result implies that nucleophilicity
of aromatic ring bearing methoxy group is more strong than
one of hydroxy group at the benzylic position toward gold-
activated allene. As far as we are aware, there is no report
on the preparation of naphthalene derivatives through intra-
molecular C-alkylation of allenic alcohols catalyzed by gold
salts. When the cyclization of 5h was performed with 5 mol
% of AgOTf and AgBF4 in CH2Cl2, cyclization product did
not produce. These blank tests clearly indicate that
(Ph3P)AuCl is required for the cyclization to proceed. To
clarify the reaction course, the reaction of 5h with 5 mol %
of triflic acid and trifluoroacetic acid instead of (Ph3P)AuCl
and AgBF4 was investigated. However, no cyclization
product was obtained. Addition of organoindium reagent to
aldehydes and sequential treatment of allenic esters with gold
salt catalysts in one pot did not produce the naphthalene
derivatives due to lack of harmony of solvents (DMF and
CH2Cl2). Exposure of allenol 5j possessing dimethoxyphenyl
group to 5 mol % of (Ph3P)AuCl and 5 mol % of AgOTf
led to the formation of the naphthalene derivative 6c in 81%
yield (entry 2). Under the optimal conditions, allenic ester
5l having trimethoxyphenyl group gave ethyl 2-naphthoate
Table 2. NMR Study of the Reaction of Indium with Ethyl 4-
Bromo-2-butynoate in the Presence of LiI in DMF-d7
-CH2-
time (min)
ppm (δ)
ratio
30
45
60
4.01, 3.88
2.62:1
2.40:1
1.86:1
5g in 85% yield regardless of the steric effect (entry 7).
Although the reactions worked equally well with 3- and
4-methoxybenzaldehyde (entries 8 and 9) to give the desired
products (5h and 5i) in 80% and 89% yields, 3,5-dimethoxy-
and 3,4,5-trimethoxybenzaldehyde produced the allenic esters
(5j and 5l) in 70% and 71% yields due to the electronic
nature of methoxy groups (entries 10 and 12). 3,4-(Meth-
ylenedioxy)benzaldehyde also produced R-hydroxyalkyl al-
lenic esters in 93% yield (entry 11). It is noteworthy that
protection of hydroxyl group on substrates is not necessary
Table 3. Reactions of Various Aldehydes with Indium and
Ethyl 4-Bromobutynoatea
entry
R
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
H
n-Pr
PhCH2CH2
c-C6H11
Ph
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
10
7
7
7
5
82
83
79
82
86
88
85
80
89
70
93
71
65
68
84
87
80
84
69
4-Me-C6H4
5
2,4,6-Me3-C6H2
3-MeO-C6H4
4-MeO-C6H4
3,5-(MeO)2-C6H3
3,4-(OCH2O)-C6H3
3,4,5-(MeO)3-C6H2
3-HO-C6H4
3,5-(HO)2-C6H3
4-Ac-C6H4
10
10
20
12
14
12
5
8
2
2
3
9
10
11
12
13
14
15
16
17
18
19
4-MeO2C-C6H4
4-NO2-C6H4
4-Cl-C6H4
5
5
(8) (a) Hoffmann-Ro¨der, A.; Krause, N. Org. Lett. 2001, 3, 2537. (b)
Hoffmann-Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (c)
Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485. (d) Hashmi, A. S. K.;
Blanco, M. C.; Fischer, D.; Bats, J. W. Eur. J. Org. Chem. 2006, 1387. (e)
Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2006, 71, 8658. (f) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180.
2-I-C6H4
s
a Reactions were performed with aldehyde (1 equiv) and organoindium
generated in situ from the reaction of indium (1 equiv) with 1 (1.5 equiv)
in the presence of lithium iodide (3.0 equiv) in DMF. b Isolated yields.
(9) Skouta, R.; Li, C.-J. Can. J. Chem. 2008, 86, 616.
Org. Lett., Vol. 10, No. 15, 2008
3361

Table 4. Synthesis of Naphthalene Derivatives via
Scheme 2
.
Plausible Mechanism of Synthesis of Naphthalene
Derivatives
Gold-Catalyzed Cyclization of Allenic Estera
6c and releases the gold catalyst into the catalytic cycle. At
present, the exact nature of the catalytically active gold
species is unknown.
a Isolated yields. b 5 mol % of (Ph3P)AuCl and 5 mol % of AgBF4
were used in CH2Cl2 at 25 °C for 1 h. c Ratio of 6a (5-MeO) and 6b
(7-MeO). d 2-(3-Methoxyphenyl)-3-ethoxycarbonyl-2,5-dihydrofuran. e 5
mol % of (Ph3P)AuCl and 5 mol % of AgOTf were used in CH2Cl2 at 25
°C for 1 h. f Ratio of 6e (5-OH) and 6f (7-OH). g 2-(3-Hydroxyphenyl)-3-
ethoxycarbonyl-2,5-dihydrofuran.
In summary, we have developed a regio- and chemo-
selective synthetic method of functionalized R-hydroxyalkyl
allenic ester derivatives from the reaction of various alde-
hydes with organoindium reagent generated in situ from
indium and ethyl 4-bromobutynoate. The functionalized
R-hydroxyalkyl allenic esters possessing electron-donating
groups were cyclized to naphthalene derivatives through
intramolecular C-alkylation catalyzed by gold salts.
in 38% yield due to the methoxy group at the 4-position
(entry 3). In the case of allenol 5m, ethyl hydroxy-2-
naphthoate was produced in 76% yield (6e:6f ) 1: 3.2)
together with 2-(3-hydroxyphenyl)-3-ethoxycarbonyl-2,5-
dihydrofuran in 21% yield with 5 mol % of (Ph3P) AuCl
and 5 mol % of AgOTf (entry 4). Allenic ester 5n was treated
with gold catalyst, producing exclusively ethyl 5,7-dihy-
droxy-2-naphthoate (6g) in 64% yield (entry 5). Although
the mechanism of 2,5-dihydrofuran formation from allenic
alcohols has been reported,8 the mechanism of the cyclization
to naphthalene derivatives has not been established. A
plausible reaction pathway is described in Scheme 2. Thus,
coordination of the gold catalyst to terminal double bond in
allene 5j results in the formation of the intermediate A which,
upon nucleophilic attack of the carbon on aromatic ring, is
cyclized to the σ-gold complex B. Dehydration of C followed
by protodeauration of E affords the naphthalene derivative
Acknowledgment. This work was supported by the Korea
Science and Engineering Foundation (KOSEF) through the
National Research Laboratory. The program funded by the
Ministry of Science and Technology (No. M10600000203-
06J0000-20310) and by KOSEF (R01-2006-000-11283-0).
The NMR data were obtained from the central instrumental
facility in Kangwon National University. Dr. Sung Hong Kim
at the KBSI (Daegu) is thanked for obtaining the MS data.
Supporting Information Available: Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL801196G
3362
Org. Lett., Vol. 10, No. 15, 2008