An efficient preparation of 6-alkoxy-substituted benzocyclobutenones

Article abstract of DOI:10.1055/s-2001-12767

A short, efficient route to 3-alkoxybenzynes has been developed, starting from readily available compounds. This has enabled rapid access to 6-alkoxybenzocyclobutenones, which are valuable synthetic intermediates.

Full text of DOI:10.1055/s-2001-12767

PAPER
741
An Efficient Preparation of 6-Alkoxy-substituted Benzocyclobutenones
Christopher J. Bungard, Jonathan C. Morris*
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
Fax +64(3)3642110; E-mail: j.morris@chem.canterbury.ac.nz
Received 5 December 2000
6
O
Abstract: A short, efficient route to 3-alkoxybenzynes has been de-
5
veloped, starting from readily available compounds. This has en-
abled rapid access to 6-alkoxybenzocyclobutenones, which are
valuable synthetic intermediates.
R
4
3
1
Key words: benzynes, benzocyclobutenone derivatives, [2+2] cy-
cloadditions, metalations, protecting groups
R'
MgBr
MgBr
A key structural component of the naphthylisoquinoline
and michellamine alkaloids is the 1,8-dioxygenated naph-
thalene moiety and much synthetic effort has been ex-
pended on the development of efficient syntheses of such
compounds.1,2 Despite this, there is still a need for a flex-
ible and efficient route to the naphthalene core which
would enable functionality to be introduced at a variety of
positions around the ring. Benzocyclobutenones 1 are ver-
satile precursors to substituted tetralones and naphtha-
lenes. Addition of vinylic and acetylenic nucleophiles to
the carbonyl group, followed by thermolysis of these ad-
ducts provides a simple and efficient route to these ring
systems (Figure 1).3 It was envisaged that this strategy
could be adapted to allow for the development of a synthe-
OH
OH
R'
R
R
∆
∆
O
OH
R
R
R'
sis of 1,8-dioxygenated naphthalenes, which would meet Figure 1
our goal of a flexible, efficient route. To achieve this, ac-
cess to significant quantities of 6-alkoxybenzocy-
trapped with iodine in modest yield.8 In this paper, we
wish to report alternative benzyne precursors 5a,b,c,
(Scheme 2) which are readily generated in large quantities
from commercially available starting materials.
clobutenone derivatives 1 is necessary. However, while
there are many methods available for the synthesis of
functionalized benzocyclobutenones, the majority of
these require precursors that are only available from 3 to
5 step syntheses, thus limiting the utility of these ap-
proaches.4
As detailed in Scheme 2, benzyne precursor 5a is readily
obtained from 2-methoxyphenol (6). Bromination of 6 in
the presence of 2 equivalents of tert-butylamine selective-
ly produces the o-bromophenol 7 in excellent yield.9 Ini-
tially, the phenol group in bromide 7 was activated by
converting it to the tosylate 8 using TsCl and triethyl-
amine in dichloromethane. Halogen-metal exchange with
BuLi to generate an aryllithium species, followed by elim-
ination of the tosylate group was expected to generate the
3-methoxybenzyne (2). However, reaction of tosylate 8
with BuLi in the presence of 1,1-diethoxyethylene (9) af-
forded only minor quantities of the desired adduct, with
the main product isolated being the debrominated material
10.10
The most amenable approach to the 6-alkoxysubstituted
benzocyclobutenones is a two step procedure where 3-
methoxybenzyne (2) is reacted with either a dialkyl ketene
acetal5,6 or a silyl ketene acetal,7 then the resulting acetal
is hydrolyzed to give the ketone 3 (Scheme 1). However,
initial work on this route was plagued by the poor repro-
ducibility of the benzyne formation.6,7 This led Suzuki and
co-workers7 to develop a new benzyne precursor, the io-
dotriflate 4, which generates benzyne 2 in an efficient
manner upon treatment with butyllithium at –78°C.
A drawback to this sequence is that a four step route is re-
quired to synthesize iodotriflate 4, with the key step in-
volving the generation of an aryllithium species that is
The lack of reactivity of the tosylate – whether due to in-
sufficient leaving group ability or competitive metallation
– directed our attention to the use of a triflate group. Tri-
flate 5a was obtained in near quantitative yield when phe-
nol 7 was reacted with triflic anhydride and pyridine. In
contrast to the tosylate 8, reaction of triflate 5a with BuLi
Synthesis 2001, No. 5, 12 04 2001. Article Identifier:
1437-210X,E;2001,0,05,0741,0744,ftx,en;P08100ss.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

742
C. J. Bungard, J. C. Morris
PAPER
OP
OP
a
OH
OH
Br
6 (P = Me)
7
(P = Me)
11 (P = i-Pr)
12 (P = MOM)
13 (P = i-Pr)
14 (P = MOM)
b
OP
OR
OMe
OTs
c
Br
10
5a (P = Me, R = Tf)
5b (P = i-Pr, R = Tf)
5c (P = MOM, R = Tf)
8
(R = Ts)
c
OP
O
Scheme 1
3
(P = Me)
15a (P = i-Pr)
15b (P = MOM)
in the presence of 1,1-diethoxyethylene (9) at –95°C pro-
ceeded smoothly and after an acidic workup, benzocy-
clobutenone 311 was isolated in 72% yield. The benzyne
reaction using bromotriflate 5a has been carried out on a
20 g scale, allowing access to significant quantities of 3.
Scheme 2
Reagents and conditions: (a) Br2/t-BuNH2 [7 (91%), 13
(85%), 14 (80%)]; (b) TsCl/Et3N/CH2Cl2 (99%) or Tf2O/pyridine [5a
(98%), 5b (88%), 5c (89%)] (c) BuLi/THF/1,1-diethoxyethylene (9),
–95°C, followed by 3% v/v H2SO4 [3 (72%), 15a (62%), 15b (55%)
In the total synthesis of the michellamine alkaloids, the
choice of protecting group on the naphthalenes is critical,
with the isopropyl and methoxymethyl (MOM) groups
having proven to be optimal.1 Thus, the preparation of
benzocyclobutenones 15 (where P = i-Pr or MOM) would
allow further flexibility in our proposed syntheses. While
benzocyclobutenone 3 could be readily deprotected with
hydrogen bromide in acetic acid at reflux, reaction of the
resulting phenol12 with either 2-bromopropane or chlo-
romethyl methyl ether led to complex mixtures, which
meant that the protecting group needed to be introduced
earlier in the synthesis. Thus, the bromotriflates 5b and 5c
thesis of 6-alkoxybenzocyclobutenones. These com-
pounds are useful synthetic intermediates which can be
readily functionalized to allow further synthetic elabora-
tion. Our current focus is on the utilization of these benzo-
cyclobutenones as intermediates in the preparation of 1,8-
dioxygenated naphthalenes.
All reactions were performed in dry glassware under oxygen-free
were prepared as detailed in Scheme 2. Using the earlier nitrogen. NMR spectra were recorded on either a Varian Unity 300
or Varian XL300 instrument. All chemical shifts are reported rela-
tive to residual CHCl3 (7.26 ppm) for proton, and CDCl3 (77.0 ppm)
for carbon NMR spectra. IR spectra were recorded on a Shimadzu
FTIR-8201PC spectrophotometer, either as KBr plates or films.
described ortho-bromination and triflate formation condi-
tions, the phenols 11 and 1213 were converted into the ben-
zyne precusors 5b and 5c, respectively, in excellent
overall yield. Generation of the 3-alkoxybenzyne with
Melting points were determined using an Electrothermal melting
BuLi at –95°C in the presence of 9 proceeded smoothly,
and after an acidic workup the benzocyclobutenones
15a,b were obtained in 62% and 55% yield, respectively.
The slightly lower yields for the benzyne addition reaction
are a reflection of how readily 15a,b sublime.
point apparatus and are uncorrected. HRMS were obtained on a
Kratos MS80RFA instrument operating in EI mode at 70 eV and 4
kV accelerating potential. Flash chromatography was performed us-
ing Merck60 silica gel (230–400 mesh). THF was distilled over so-
dium/benzophenone immediately before use. Toluene, tert-
butylamine, N,N-diisopropylethylamine, Et3N, pyridine and CH2Cl2
were distilled from CaH2 immediately before use. Phenols 6 and 11
In conclusion, a short route to precursors for 3-alkoxyben-
zynes has been developed, starting from readily available were purchased from Aldrich Chemical Company. Petroleum ether
used had bp 50–70 °C. Note: All organic extracts were washed with
brine and dried (Na2SO4).
compounds. This has allowed an efficient, large scale syn-
Synthesis 2001, No. 5, 741–744 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Preparation of 6-Alkoxy-substituted Benzocyclobutenones
743
ortho-Bromination of Phenols 6, 11 and 12; General Procedure
solution of anhyd tert-butylamine (2.0 equiv) in anhyd toluene
13C NMR (75 MHz, CDCl3): = 150.9, 137.5, 129.1, 124.5, 116.6,
118.5 (JC-F = 321 Hz), 113.5, 72.2, 21.3.
A
(1 M) was cooled to –30°C. Br2 (1.0 equiv) was added dropwise and
the resulting solution stirred at –30°C for 30 min. The turbid solu-
tion was cooled to –78°C and a solution of the appropriate phenol
6, 11 or 12 (1.0 equiv) in anhyd CH2Cl2 (6 M) was added slowly.
The reaction was allowed to warm to r.t. over a period of 5 h. After
this time Et2O and H2O were added and the aqueous layer was acid-
ified to pH 1 with 1 M aq HCl solution. The aqueous layer was ex-
tracted with a further portion of Et2O and the combined organic
extracts were washed in turn with 1 M aq HCl solution and satd
Na2S2O3 solution. After removing the solvent in vacuo, the residue
was purified by bulb to bulb distillation.
HRMS: m/z Calcd for C10H1079BrF332SO4 (M+) 361.9436, found
361.9433.
2-Bromo-6-methoxymethyloxyphenyl Trifluoromethanesulfonate
(5c)
Yield: 89%; bp 135°C/11 Torr.
1H NMR (300 MHz, CDCl3): = 7.24–7.29 (m, 2 H), 7.15 (dd,
J = 8.3, 7.8 Hz, 1 H), 5.25 (s, 2 H), 3.52 (s, 3 H).
13C NMR (75 MHz, CDCl3): = 150.4, 137.3, 129.3, 126.2, 118.5
(JC-F = 321 Hz), 116.4, 115.2, 95.3, 56.6.
HRMS: m/z Calcd for C9H879BrF332SO5 (M+) 363.9228, found
363.9226.
2-Bromo-6-methoxyphenol (7)
Yield: 91%.9
6-Alkoxybenocyclobutenones 3, 15a,b; General Procedure
2-Bromo-6-isopropoxyphenol (13)
Yield: 85%; bp 113°C/11 Torr.
1H NMR (300 MHz, CDCl3): = 7.07 (dd, J = 8.3, 1.5 Hz, 1 H), 6.81
(dd, J = 7.8, 1.5 Hz, 1 H), 6.71 (dd, J = 8.3, 8.3 Hz, 1 H), 6.04 (br s,
1 H), 4.58 (m, 1 H), 1.37 (d, J = 6.4 Hz, 6 H).
13C NMR (75 MHz, CDCl3): = 145.1, 143.9, 124.6, 120.3, 112.2,
108.0, 72.1, 21.8.
IR (film): = 3508 cm–1.
A
stirred solution of triflate 5a–c (1.0 equiv) and 1,1-
diethoxyethylene14 (2.0 equiv) in anhyd THF (0.2 M) was cooled to
–95°C. A solution of BuLi in hexanes (1.74 M, 2.0 equiv) was add-
ed dropwise via syringe and the resulting mixture stirred at -95°C
for 30 min, and then allowed to warm to r.t. overnight. The resulting
acetal was hydrolyzed in situ by the addition of aq H2SO4 solution
(3% v/v, 0.83 M), followed by stirring at r.t. for 3 h. The resulting
solution was poured into H2O, and extracted with Et2O (4 20 mL).
The combined organic extracts were washed in turn with sat aq
NaHCO3 solution and H2O. The solvent was removed in vacuo to
give an oily residue, which was purified by flash chromatography
on silica gel using the solvents indicated.
HRMS: m/z Calcd for C9H1179BrO2 (M+) 229.9943, found
229.9940.
2-Bromo-6-methoxymethyloxyphenol (14)
Yield: 80%; bp 135°C/11 Torr.
6-Methoxybenzocyclobutenone (3)
10% EtOAc/petroleum ether; white solid (72%); mp 34–35°C
1H NMR (300 MHz, CDCl3): = 7.16 (m, 1 H), 7.05 (m, 1 H), 6.72
(t, J = 8.3 Hz, 1 H), 6.25 (br s, 1 H), 5.21 (s, 2 H), 3.52 (s, 1 H).
13C NMR (75 MHz, CDCl3): = 144.9, 143.7, 126.2, 120.6, 114.6,
108.8, 95.7, 56.3.
IR (film): = 3501 cm–1.
(Lit.11 mp 32–33°C).
1H NMR (300 MHz, CDCl3): = 7.43 (dd, J = 8.3, 6.8 Hz, 1 H), 7.03
(d, J = 6.8 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 4.12 (s, 3 H), 3.93 (s,
2 H).
HRMS: m/z Calcd for C8H979BrO3 (M+) 231.9735, found 231.9733.
6-Isopropoxybenzocyclobutenone (15a)
5 % Et2O/petroleum ether; white solid (62%); mp: 34–35°C.
1H NMR (300 MHz, CDCl3): = 7.41 (dd, J = 8.3, 7.3 Hz, 1 H), 6.97
(d, J = 7.3 Hz, 1 H), 6.77 (d, J = 8.3 Hz, 1 H), 5.09 (m, 1 H), 3.89 (s,
2 H), 1.34 (d, J = 5.9 Hz, 6 H).
13C NMR (75 MHz, CDCl3): = 184.7, 151.8, 150.3, 137.6, 131.7,
116.7, 114.2, 74.4, 50.7, 22.0.
IR (KBr): = 1765 cm–1.
HRMS: m/z Calcd for C11H12O2 (M+) 176.0837, found 176.0837.
Triflates 5a-c; General Procedure
Triflic anhydride (1.5 equiv) was added dropwise via syringe to a
solution of phenol 6, 11 or 12 (1.0 equiv) in anhyd pyridine (1.8 mL)
at 0°C. The reaction was stirred at this temperature for 5 min, then
allowed to warm to r.t. overnight. The resulting solution was poured
into H2O and extracted with Et2O (4 20 mL). The combined or-
ganic extracts were washed in turn with 10% HCl solution (v/v) and
H2O. The solvent was removed in vacuo to afford an oil, which was
purified by bulb to bulb distillation.
6-Methoxymethyloxybenzocyclobutenone (15b)
5 % Et2O/petroleum ether; white solid (55%); mp 37–40°C.
2-Bromo-6-methoxyphenyl Trifluoromethanesulfonate (5a)
Yield: 98%; bp 95°C/3 Torr.
1H NMR (300 MHz, CDCl3): = 7.23 (dd, J = 8.3, 2.0 Hz, 1 H), 7.18
(dd, J = 8.3, 7.8 Hz, 1 H), 6.98 (dd, J = 7.8, 2.0 Hz, 1 H), 3.92 (s, 3
H).
13C NMR (75 MHz, CDCl3): = 152.6, 136.9, 129.3, 125.1, 118.6
(q, JC-F = 321 Hz), 116.5, 112.0, 56.3.
HRMS: m/z Calcd for C8H679BrF3O432S (M+) 333.9123, found
333.9122.
1H NMR (300 MHz, CDCl3): = 7.46 (dd, J = 8.3, 7.3 Hz, 1 H), 7.08
(d, J = 7.3 Hz, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 5.48 (s, 2 H), 3.92 (s,
2 H), 3.48 (s, 3 H).
13C NMR (75 MHz, CDCl3): = 184.6, 150.5, 149.4, 137.7, 132.8,
116.4, 115.8, 96.2, 56.6, 51.1.
IR (KBr): = 1761 cm–1.
HRMS: m/z Calcd for C10H10O3 (M+) 178.0630, found 178.0630.
2-Bromo-6-isopropoxyphenyl Trifluoromethanesulfonate (5b)
Acknowledgement
Yield: 88%; bp 130 oC/11 Torr.
1H NMR (300 MHz, CDCl3): = 7.11–7.19 (m, 2 H), 6.95 (m, 1 H),
4.69 (m, 1 H), 1.39 (d, J = 6.0 Hz, 6 H).
We thank the University of Canterbury for financial assistance
(Ph.D. scholarship to C.J.B.) and Mr Bruce Clark for mass spectro-
metry experiments.
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C. J. Bungard, J. C. Morris
PAPER
(6) Liebeskind, L. S.; Lescosky, L. J.; McSwain, C. M. Jr. J.
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Synthesis 2001, No. 5, 741–744 ISSN 0039-7881 © Thieme Stuttgart · New York