Gold(I)-catalyzed synthesis of benzoxocines by an 8-endo-dig cyclization

Article abstract of DOI:10.1002/anie.201103832

A golden dig! Gold-catalyzed direct access to functionalized 2H-1-benzoxocines, eight-membered-ring ethers, is described. This unprecedented synthesis of benzoxocines occurs by an 8-endo-dig cyclization of the 1,7-enyne substrates. Copyright

Full text of DOI:10.1002/anie.201103832

Communications
DOI: 10.1002/anie.201103832
Gold Catalysis
Gold(I)-Catalyzed Synthesis of Benzoxocines by an 8-endo-dig
Cyclization**
Kathrin Wittstein, Kamal Kumar,* and Herbert Waldmann*
The activation of alkynes by organogold catalysts has
emerged as a powerful method for the efficient synthesis of
carbo- and heterocycles, including scarcely accessible ring
systems.[1–9] Unsaturated benzoxocine ring systems occur in
numerous bioactive natural products, in particular the heli-
annane family of cyclic ethers,[10–15] (Scheme 1a) and have
been synthesized by different methods.[16–18] Given the strong
interest in this natural product class,[19,20] we envisioned that
an efficient and flexible synthetic route to 2H-1-benzoxocines
8 could be developed based on a gold-catalyzed 8-endo-dig
cyclization of readily accessible o-propargyloxy styrenes 6
(Scheme 1b).
We anticipated that for 1,7-enynes 6 the regiospecific
addition of the olefin to the alkyne, that is, an 8-endo-dig
cyclization, might be favored because of the formation of a
stable carbocationic intermediate 7. Alternatively, a seven-
membered benzoxepine ring could form through a 7-exo-dig
cyclization.[21]
Gold-catalyzed 8-endo-dig cyclizations have rarely been
observed. Echavarren and Ferrer reported a gold(III)-cata-
lyzed endo-dig hydroarylation of indole substrates 9 (Sche-
me 1c).[22] However, mechanistically these products most
likely arise from a 7-endo cyclization[23,24] with a subsequent
1,2-shift and isomerization.[25] The same group also reported
that 1,7-enynes, which can be considered analogous to
propargyl ethers 6, undergo cyclization by an exo pathway
followed by rearrangement of the cyclopropyl intermediate to
a diene.[26] Herein, we report the gold-catalyzed 8-endo-dig
cyclization of o-propargyloxy styrenes to yield functionalized
2H-1-benzo[b]oxocines, and the mechanism of this novel
catalytic cyclization.
Scheme 1. a) Natural products containing benzoxocine rings. b) Gold-
catalyzed synthesis of benzoxocines by an 8-endo-dig cyclization;
c) Gold(III)-catalyzed synthesis of indoles with annulated eight-mem-
bered rings.
In light of the successful 8-endo-dig hydroarylation
catalyzed by gold(III) (Scheme 1c),[22] we explored whether
such catalysts would also induce the formation of 2H-
benzo[b]oxocine 8a from propargyl ether 6a (Table 1).
Table 1:
[*] Dipl.-Chem. K. Wittstein, Dr. K. Kumar, Prof. Dr. H. Waldmann
Max-Planck-Institut fꢀr molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Entry Catalyst (mol%)
Solvent
t
Yield [%]
Technische Universitꢁt Dortmund
Fakultꢁt Chemie, Chemische Biologie
8a[a]
1
2
3
4
5
6
7
[Au(SMe2)Cl]/AgSbF6 (10) DCE
18 h
–
–
61
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
E-mail: kamal.kumar@mpi-dortmund.mpg.de
herbert.waldmann@mpi-dortmund.mpg.de
[Au(PPh3)Cl]/AgSbF6 (10) THF or MeCN 18 h
[Au(PPh3)Cl]/AgSbF6 (10) DCE 5 min
[Au(PPh3)Cl]/AgSbF6 (5) DCE
[Au(PMe3)Cl]/AgSbF6 (10) DCE
25 min 58
[**] This research leading to these results has received funding from
Max-Planck Gesellschaft and the European Research Council under
the European Union’s Seventh Framework Programme (FP7/2007-
2013)/ERC Grant agreement n8268309.
30 min 52
50 min 75
25 min 76
[AuIPrCl]/AgSbF6 (5)
[AuIPrCl]/AgSbF6 (10)
DCE
DCE
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103832.
[a] Yields determined by GC analysis using n-octadecane as internal
standard. DCE=1,2-dichloroethane, THF=tetrahydrofuran.
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Angew. Chem. Int. Ed. 2011, 50, 9076 –9080

However, neither in the presence of AuBr3, AuBr3/AgBF4,
nor AuCl3/AgSbF6 in dichloromethane or dichloroethane was
any product formation observed.
In several cases the newly formed E- and Z-configured
olefins could be isolated and separated. In the reactions
employing terminal acetylene, the two diastereomeric forms
could be easily identified by their corresponding olefinic cis
and trans coupling constants, as depicted for benzoxocine 8m
in Scheme 2.[30,31] The nOe interactions observed in the two
Accordingly, we turned to gold(I) salts. While [Au-
(SMe)2Cl]/AgSbF6 did not induce product formation
(Table 1, entry 1), the cationic complexes generated in situ
from [Au(PR3)Cl] and AgSbF4 in dichloroethane (but not in
acetonitrile) led to the smooth formation of the desired ether
with an eight-membered ring, at room temperature (Table 1,
entries 2–5). The use of the more nucleophilic PMe3 instead of
PPh3 did not increase the yield (Table 1, entries 3 and 5).
AgSbF6 alone and Lewis acids BF3·OEt2 and TiCl4, in up to
equimolar amounts, did not catalyze the cyclization, thus
indicating a gold-specific catalysis. Finally, the use of a
cationic gold complex 11 ([AuIPrCl]/AgSbF6) with an N-
heterocyclic carbene ligand with relatively low electrophilic-
ity gave the best results and gave the benzoxocines in yields
up to 76% (Table 1, entries 6 and 7).[27,28]
Scheme 2. Structural assignment of (Z)- and (E)-benzoxocine 8m.
With these reaction conditions established the scope of
the gold-catalyzed synthesis of functionalized benzoxocines,
eight-membered-ring ethers, was explored and the substitu-
ents on the alkyne, the olefin, and the aromatic ring were
varied (Table 2). Different substituents on the terminal
carbon atom of the alkyne were well tolerated and the
benzoxocines were obtained in moderate to high yield
(Table 2, entries 1–4). Similarly substituents R1 and R2 on
the aromatic ring could be changed considerably (Table 2,
entries 3–7).
isomers further supported the structural assignments
(Scheme 2, for detailed analysis see the Supporting Informa-
tion). Palladium-catalyzed hydrogenation of the different
diastereomers resulted in identical tetrahydro-2H-benzo[b]-
oxocines (see Scheme 5 and the Supporting Information).
With the assumption that the decisive step of the
cyclization might include nucleophilic attack of the olefin
on the alkyne activated by the gold catalyst, the substituent on
the alkene was varied (Table 2, entries 7–12). Introduction of
aryl groups with electron-withdrawing substituents led to
product formation in respectable yields (Table 2, entries 8 and
9), whereas introduction of electron-donating methoxy
groups induced the formation of a different product (see
Scheme 4).
Table 2:
Introduction of a terminal methyl group or, even more
pronounced, an electron-withdrawing ester on the olefin led
to a reduced reaction rate (Table 2, entries 10 and 12). In the
absence of any substituent on the olefin (6k), an additional
product was formed (Scheme 3b).
To mimic the substitution pattern of naturally occurring
heliannanes, dimethyl-substituted o-propargyloxy-b-phenyl-
styrene 6m was employed in the gold-catalyzed cyclization to
yield the benzoxocine 8m in 31% yield (Table 2, entry 13).
The formation of several minor products and unexpected
cyclization products, as well as the investigation of additional
custom-made potential cyclization precursors allowed us to
gain insight into the mechanism of the gold-catalyzed
cyclization reaction. Cyclopropane-fused benzoxocines 12
(Scheme 3a) were isolated from the reaction mixtures, and, in
addition, the formation of cyclopropanes was routinely
detected in the crude reaction mixtures by means of NMR
spectroscopy. Attempts to convert cyclopropane 12b into the
corresponding benzoxocine (8b) did not result in product
formation even after prolonged treatment with gold(I)
complexes.
Entry R1 R2
R3
R4
R5
t
8
Yield
[%][a]
1
2
3
4
H
H
H
H
H
Me
Me
Me
Br
Ph
Ph
Ph
Ph
Me
H
Ph
Et
H
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
30 min 8a
30 min 8b
1 h
50 min 8d
2 h
60
72[b]
47[b]
55
8c
5
OMe Ph
8e
8 f
8g
56
62
55
69
6
Cl Me
Ph
Ph
1 h
1.5 h
7
8
9
10
11
12
13
H
H
H
H
H
H
H
Br
Me
Me
Me
Me
Me
Me
4-NO2C6H4
4-CO2MeC6H4
Me
H
CO2Et
Ph
50 min 8h
50 min 8i
2 h
50 min 8k
28 h 8l
H
53
Me
Et
H
8j
47[b]
41[c]
29
H
Me 1 h
8m 31[b]
Cyclization substrate 6k having a terminal olefin yielded
benzoxepine 13k in addition to the desired benzoxocine
(Scheme 3b), and bromo-substituted cyclization precursor 6g
delivered the side product benzoxocine 14g with an allene
incorporated in the eight-membered ring (Scheme 3c). The
[a] Yields of the isolated products. [b] Z and E diastereomers were
formed in the ratio 2:3 to 3:4; for details of the isolation and
characterization of these isomers see the Supporting Information.
[c] Yield determined by GC analysis using n-octadecane as internal
standard.[29]
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Communications
intermediate 17 may be generated and upon
protodeauration this intermediate can yield ben-
zoxepines 12.
In this scenario, the electron-donating influence
of the ether oxygen plays an important role, and in
agreement with this hypothesis, CH2-substituted
analogue 21 and ester analogue 22 (Scheme 3d) did
not cyclize, even in the presence of up to four-fold
excess of gold(I) complex.
These mechanistic observations are in agree-
ment with the results obtained by Toste and co-
workers, who had shown that propargylvinyl ethers
cyclize in the presence of gold catalysts and
external nucleophiles by a 6-endo-dig process to
yield tetrahydropyrans.[34–36] This mechanistic
rationale is also supported by the observation that
the overall process follows a different pathway if,
instead of formation of the benzylic cation at the
C1-position, formation of a carbocation at the C2-
position of the olefin of the cyclization precursors
predominates (Scheme 4).[34] Thus, whereas aryl
rings with electron-withdrawing substituents at C2
lead to formation of the eight-membered ethers
(Table 2, entries 8 and 9), introduction of electron-
donating substituents onto the aryl ring, or double
substitution of the olefin, which stabilizes the
carbocation formation at C2, induces the formation
of six-membered ethers with an exocyclic allene
(Scheme 4).
As shown in Scheme 4, compound 6n, which
has a methyl and a phenyl substituent on the olefin
terminal carbon atom, led to the formation of
exocyclic allene 23a and benzoxocine 24, the latter
presumably arising from a migration of the methyl
group in the intermediate benzylic cation, which is
analogous to 16 (Scheme 3a). By analogy, the
highly electron-rich dimethoxyphenyl-substituted
cyclization precursor 6o gives rise to allene 23b in
quantitative yield. Formation of this allene may
involve the nucleophilic attack of the olefin on the
alkyne to form benzopyran intermediate 25 and
then possibly 26 (Scheme 4).
Scheme 3. a) Mechanistic proposal for the formation of benzoxocines 8 and cyclo-
propyl oxepenes 12 and b,c) other side products. d) Substrates that do not yield
any benzoxocine or other rings under gold catalysis. [a] Yield determined by GC
analysis.
cyclic allene structure was corroborated by the characteristic
Finally, support for the proposed mechanism was obtained
allenic carbon signals in the 13C NMR spectrum (d = 208.7,
90.4, 90.0 ppm) and a highly characteristic IR signal at
1954 cmÀ1 for allene stretching.[32,33] To obtain 14g an
apparent 1,2-shift of the aryl group has occurred.
by the selective deuteration of cyclization precursor [D1]-6b
(Scheme 5a). Thus, as expected, exposure of [D1]-6b to the
reaction conditions detailed above yielded medium-sized
cyclic ether [D1]-8b. The analogous C-ethyl-substituted
propargyl ether [D1]-6 f reacted similarly. Hydrogenation of
the deuterated 2H-1-benzoxocines yielded the analogous
saturated cyclic ethers, which were fully characterized by
NMR spectroscopy (see Scheme 5 and the Supporting
information).
We have discovered a novel 8-endo-dig cyclization of o-
propargyloxy styrenes catalyzed by cationic gold(I) com-
plexes. The transformation is broad in scope and provides
rapid and efficient access to cyclic eight-membered-ring
ethers, characteristic of a large group of biologically relevant
natural products. Functionalized benzoxocines have been
made available with limited success so far. The cyclization
The formation of compounds 12 suggests a cationic
intermediate may have been formed and that this intermedi-
ate can either lead to the formation of the desired 8-
membered cyclic ethers, or undergo ring closure to give a
cyclopropane ring, and then undergo protodeauration (Sche-
me 3a). In this case, gold(I) could coordinate to the alkyne,
thus promoting cyclization and inducing the formation of
benzylic cation 15. The cation is stabilized by the electron-
donating influence of the ether oxygen atom which also
promotes the cyclization. Cation 16 can then either collapse to
benzoxocine 8 or alternatively cyclopropane-substituted gold
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Angew. Chem. Int. Ed. 2011, 50, 9076 –9080

Experimental Section
(1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene)gold
chloride
(12.5 mg, 0.02 mmol, 0.05 equiv) and silver hexafluoroantimonate
(7 mg, 0.02 mmol, 0.05 equiv) were dried in a 25 mL two-neck round-
bottom flask for 1.5 h under high vacuum. 6b (99 mg, 0.4 mmol) and
n-octadecane (29.7 mg, 0.12 mmol, 30 weight%), as internal standard,
were dissolved in dry DCE (4 mL) under argon. This solution was
added to the catalyst and the resulting mixture was stirred at room
temperature. After 30 min the starting material had been consumed
and the mixture was filtered through a short pad of silica gel with
CH2Cl2 and Et2O as eluents. The solvents were evaporated under
reduced pressure and purification of the crude residue by preparative
TLC (silica gel) with 0.5% Et2O/petroleum ether (5 runs) provided
8b in 72% yield (Z isomer: 61%, 60.5 mg, 0.24 mmol; E isomer:
11%, 10.9 mg, 0.04 mmol) as a colorless oil.
Z isomer; Rf = 0.4 (1% Et2O/petroleum ether); 1H NMR
(400 MHz, CDCl3): d = 7.36–7.27 (m, 3H), 7.26–7.23 (m, 2H), 6.97
(d, J = 7.6 Hz, 1H), 6.87 (dd, J = 7.5, 1.4 Hz, 1H), 6.79 (dd, J = 7.5 Hz,
1H), 6.61 (d, J = 12.0 Hz, 1H), 6.52 (s, 1H), 6.27 (d, J = 12.1 Hz, 1H),
4.47 (s, 1H), 2.14 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d =
151.75, 138.36, 131.06, 130.63, 130.58, 128.65, 128.34, 128.11, 127.37,
126.02, 124.84, 124.45, 122.73, 120.89, 66.96, 15.46 ppm.
E isomer; Rf = 0.38 (1% Et2O/petroleum ether); 1H NMR
(400 MHz, CDCl3): d = 7.45 (d, J = 7.2 Hz, 2H), 7.34 (dd, J =
7.6 Hz, 2H), 7.27–7.23 (m, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.89 (dd,
J = 7.2, 1.4 Hz, 1H), 6.87 (d, J = 16.5 Hz, 1H), 6.79 (dd, J = 7.4 Hz,
1H), 6.51 (s, 1H), 6.45 (d, J = 16.4 Hz, 1H), 5.11 (s, 2H), 2.22 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d = 151.70, 137.02, 130.73, 130.39,
128.72, 127.76, 127.69, 126.69, 126.38, 124.84, 124.67, 124.36, 122.19,
120.88, 65.58, 15.52 ppm; HRMS (EI): m/z: calcd
Scheme 4. Synthesis of exocyclic allenic pyrans and a proposed
mechanism.
for C18H16O: 248.11957 [M]+, found: 248.11991.
Received: June 6, 2011
Revised: July 27, 2011
Published online: August 22, 2011
Keywords: alkynes · benzoxocines · cyclization ·
.
gold · homogeneous catalysis
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