An open-and-shut strategy: Preparation of benzo-fused indanes by ring-opening of a vinylogous acyl triflate and metal-catalyzed Asao-Yamamoto benzannulation

Article abstract of DOI:10.1016/j.tet.2010.03.014

A two-step strategy for the synthesis of benzo-fused indanes is outlined herein. The strategy draws on two independent methodologies: the tandem addition/fragmentation of vinylogous acyl triflates (VATs) and the intramolecular benzannulation of o-alkynylp

Full text of DOI:10.1016/j.tet.2010.03.014

Tetrahedron 66 (2010) 4860–4866
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An open-and-shut strategy: preparation of benzo-fused indanes by ring-opening
of a vinylogous acyl triflate and metal-catalyzed Asao–Yamamoto benzannulation
*
David M. Jones, Gregory B. Dudley
Department of Chemistry and Biochemistry, Florida State University, Mail Code 4390, Tallahassee, FL 32306-4390, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step strategy for the synthesis of benzo-fused indanes is outlined herein. The strategy draws on
two independent methodologies: the tandem addition/fragmentation of vinylogous acyl triflates (VATs)
and the intramolecular benzannulation of o-alkynylphenyl ketones. Reduction of this strategy to practice
involves the use of aryltriazenes as masked aryl iodides; a synthetic equivalent of 2-iodophenyllithium is
featured. Benzo-fused indanes are prepared efficiently and in high yield.
Received 1 February 2010
Received in revised form 1 March 2010
Accepted 2 March 2010
Available online 9 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Vinylogous acyl triflates
Benzannulation
Indane
Fragmentation
2-Iodophenyllithium
1. Introduction
O
[4 + 2], then
The practical assembly of highly substituted aromatic rings is one
of the long-standing challenges in chemical synthesis.1 Stepwise
aromatic substitution processes will typically deliver the target
structures, but regio- and chemoselectivity issues and the problems
of cost associated with multi-step sequences ultimately limit the
appeal of these strategies. Convergent aromatic annulation methods
offer dramatic advantages for the preparation of specific systems;
many such methods have been developed over the years (Scheme 1).
The classic Alder–Rickert reaction of cyclohexadienes2 and the Di-
+
+
CO2 (1)
O
retro-[4 + 2]
alkyne
+
(2)
trimerization
els–Alder reaction of a
-pyrones3 (Eq.1) each provide aromatic rings
regioselectively by tandem [4þ2] and retro-[4þ2] pericyclic pro-
cesses. The Do¨tz4 and Danheiser5 benzannulations feature pericyclic
reactions of vinylketenes6 with alkynes to provide phenols. Alkyne
trimerization (Eq. 2) has frequently been exploited for the conver-
gent assembly of substituted arenes,7 perhaps most notably in the
classic Vollhardt synthesis of estrone.8 Of particular relevance to the
present study are the emerging gold- and copper-catalyzed ben-
AuX3 (X = Br, Cl) or
Cu(OTf)2, RCO2H
O
+
(3)
O
Scheme 1. Selected benzannulation reactions of alkynes.
zannulation reactions of b-alkynyl enones (and ortho-alkynylphenyl
ketones) described by Asao and Yamamoto (Eq. 3).9
processes and find many different applications in the synthesis of
complex aromatic systems.
The alkyne functionality is the common denominator in the
aforementioned convergent benzannulation reactions. Methods for
the synthesis of functionalized alkynes therefore enable these
1.1. Addition/fragmentation of vinylogous acyl triflates
We are developing a strategy for converting symmetric, cyclic
1,3-diones into differentially functionalized, acyclic alkynyl
ketones.10,11 The strategy hinges on the tandem nucleophilic
* Corresponding author. E-mail address: gdudley@chem.fsu.edu (G.B. Dudley).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.014

D.M. Jones, G.B. Dudley / Tetrahedron 66 (2010) 4860–4866
4861
1,2-addition and fragmentation of vinylogous acyl triflates
"Top-Down"
O
(VATs), which are readily available from cyclic 1,3-diones. Many
types of nucleophilic reagents trigger fragmentation of vinyl-
ogous acyl triflates, including aryllithiums,10 alkyl Grignards,12
lithium amides,11 enolates,13 and more, providing convenient
R
AuX3
n-3
(4)
n
n
3 and 4
=
R
access to alkynes tethered to ketones, amides, alcohols,14
b-keto
R
Ph, Bu, H, TMS
=
40 to 92%
Ph
esters, etc. Applications in synthesis12,15 and related methodol-
ogies16–18 are beginning to emerge.
O
Ph
"Bottom-Up"
O
We envisioned that our VAT fragmentation methodology
(Scheme 2), in conjunction with an intramolecular version of
chemistry featured in Eq. 3, could provide a useful entry into
highly substituted indane compounds, but such an endeavor
would require an extension of the gold- and/or copper-catalyzed
benzannulation reactions described previously. We set out to in-
vestigate the intramolecular benzannulation reaction in more
detail, as outlined below. The goals of this study were (a) to ex-
plore new applications for vinylogous acyl triflates in synthesis,
(b) to advance the ‘top-down’ intramolecular version19 of the
Asao–Yamamoto benzannulation, and (c) to merge the two
methodologies for the synthesis of benzo-fused indanes from
symmetrical cyclic diones.
R
AuX3
H
(5)
R
R = Bu, H, TIPS, Ph,
p-Tolyl, p-CF3C6H4,
(CH2)2OTIPS, I
O
3
66 to 91%
Scheme 3. Overview of intramolecular Asao–Yamamoto benzannulations.
featuring the use of vinylogous acyl triflate fragmentation re-
actions to provide the needed monocyclic benzannulation
precursors.
O
O
Nu
2. Results and discussion
Tf2O
base
Nu–
R
O
R
O
R
The basic plan for preparing benzo-fused indanes involved the
use of ortho-alkynylphenyllithium 5 (or equivalent) as a nucleo-
philic trigger for the addition and fragmentation of vinylogous acyl
triflate 1, followed by benzannulation under conditions to be de-
termined (Scheme 4). However, we specifically wanted to study the
role of the ortho-alkyne substituent (6, R¼aryl, alkyl, etc.) on the
course of the intramolecular benzannulations. Therefore, it made
sense to introduce this substituent later in the sequence using
a Sonogashira coupling.22 ortho-Iodophenyl ketone 10 (vide infra)
became our initial target, requiring identification of an appropriate
surrogate to 2-iodophenyllithium (4) that does not break down into
benzyne.
OTf
Scheme 2. Overview of the synthesis and ring-opening fragmentation of vinylogous
acyl triflates.
In this article we describe the successful realization of these
three goals, and we introduce a new ortho-benzene ambiphile, N,N-
diethyl 2-lithiophenyltriazene (3). 2-Lithiophenyltriazene 3 serves
as a stable and convenient synthetic equivalent for 2-iodophe-
nyllithium (4), which itself would undergo rapid decomposition to
ortho-benzyne20 (Fig. 1).
Li
addition and C–C
Li
Li
I
+
is a stable
surrogate for
O
OTf
bond cleavage
N3Et2
R
1
5
vinylogous acyl
triflate (VAT)
3
4
benzo-fused
indanes
Figure 1. A synthetic equivalent for 2-iodophenyllithium.
Au and/or Cu-cat
benzannulation
O
1.2. Brief overview of the Asao–Yamamoto ‘top-down’
benzannulation
O
R
R
6
2
As part of on-going efforts into the preparation of highly func-
tionalized arenes (cf. Eq. 3, Scheme 1),9,19 Asao and Yamamoto
reported the synthesis of a series of polycyclic naphthalene de-
rivatives through the use of tethered (intramolecular) alkyne
dienophiles (Scheme 3). Two versions of the intramolecular ben-
zannulation were described:19 the ‘top-down’ approach, in which
the tethered alkyne is linked through the carbonyl group (Eq. 4),
and the ‘bottom-up approach’, in which the tethered alkyne is
linked through the aryl-alkyne group (Eq. 5).21 Gold and copper
salts are typically employed as catalysts in the broader methodol-
ogy, but only gold catalysts were developed for the intramolecular
benzannulations.
Scheme 4. The ‘‘open-and-shut’’ synthesis of benzo-fused indanes.
2.1. Vinylogous acyl triflate fragmentation using
2-lithiophenyltriazene 3, a new synthetic equivalent
of 2-iodophenyllithium
2-Lithiophenyltriazene 3 serves as a synthetic equivalent to 2-
iodophenyllithium (4). This new reagent is easily prepared from
2-iodoaniline (7, Scheme 5). Diazotization of 7 and trapping with
in nearly quantitative
8 with butyllithium at
ꢀ78 ꢁC gives rise to 2-lithiophenyltriazene 3, which does not
fragment into benzyne, molecular nitrogen, and lithium
diethylamide.
diethylamine provides iodotriazene
8
Combining our vinylogous acyl triflate fragmentation chemis-
try with the Asao–Yamamoto methodology gives rise to a new
approach to the synthesis of benzo-fused indanes from symmetric
1,3-diones. The following section describes new methodology
yield.23 Halogen–metal exchange of

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D.M. Jones, G.B. Dudley / Tetrahedron 66 (2010) 4860–4866
in high yields upon treatment with sodium iodide and sulfonic acid
cation exchange resins (Hþ form) in dry acetonitrile at 75 ꢁC; other
protic acids also provided aryl iodides in acceptable yields.28 Like-
wise, we completed the synthesis of our model benzannulation
substrates using camphorsulfonic acid (CSA) in warm acetonitrile to
convert aryltriazene 9 into aryl iodide 10 in 75% yield.
n-BuLi, THF, –78 °C
I
(6)
O
then
–78 °C
to rt
O
OMe
OMe
1
11
12
57%
JACS 2006, 128, 6499
TfO
2.2. New metal-catalyzed Asao–Yamamoto benzannulation
reactions
HCl,
NaNO2;
BuLi
I
I
Li
N
Aryl iodide 10 marked the divergence point in our synthesis of
substrates for the focused benzannulation methodology. Sonoga-
shira coupling with a series of alkyne partners is depicted in
Scheme 7. Coupling with phenylacetylene provided 6a in 68% yield;
two alkylacetylenesdone linear (6b, 85%) and one tertiary (6c,
52%)dand silylacetylene derivative 6d (80%) were likewise pre-
pared. Sonogashira coupling between 10 and the electron-rich
p-methoxyphenylacetylene provided 6e (60%), but our attempt to
install an electron-deficient aromatic substituent (R¼p-tri-
fluoromethylphenyl, 6f) under similar conditions failed. This
problem was overcome by a slight tactical adjustment: desilylation
of silylacetylene 6d with methanolic potassium carbonate provided
the terminal alkyne (6g), which was coupled with p-iodobenzo-
trifluoride (p-I–C6H4–CF3) to provide electron-deficient benzan-
nulation substrate 6f in good overall yield (Scheme 7).
3
then
Et2NH
97%
Et2O
N
NH2
N3Et2
NEt2
–78 °C
7
8
Li
I
N
LiNEt
2
+
+
2
4
Scheme 5. Preparation of 2-lithiophenyltriazene (3) for use as a synthetic equivalent
for 2-iodophenyllithium (4).
Consistent with our earlier reports,11 addition of vinylogous acyl
triflate 1 to a cold solution of 3 triggers fragmentation upon
warming to produce aryltriazene 9 (Scheme 6). Actually, this result
compares favorably to the closest precedent from our earlier work
(cf. Eq. 6). We originally employed THF as the solvent for the nu-
cleophilic addition and C–C bond cleaving fragmentation process.
Subsequently it has been determined that less polar solvents like
toluene offered better control over the reactivity of unstabilized
organolithium reagents.24 In this case, ether provided an ideal
solvent medium for the sequence of halogen–metal exchange,
nucleophilic addition, and fragmentation, which proceeded in ex-
cellent overall yield (85% based on VAT 1). We have also noticed
that stabilizing influences on the organolithium reagent are bene-
ficial,25 and the ortho-triazene may provide positive coordinative
stabilization of the aryllithium moiety.
H–C C–R
≡
O
O
5 mol% PdCl2(PPh3)2
10 mol% CuI, Et3N, 50 °C
I
10
R
5
R = C6H5–
68% (6a)
85% (6b)
52% (6c)
80% (6d)
60% (6e)
0% (6f)
R = n-Bu–
R = t-Bu–
R = Me3Si–
R = p-MeO–C6H4–
R = p-CF3–C6H4–
1. K2CO3, MeOH, 92%
(R = H, 6g)
O
n-BuLi, Et2O, –78 °C
I
6d
O
2. 4-iodobenzotrifluoride
10 mol% CuI, Et3N, 50 °C
5 mol% PdCl2(PPh3)2, 85%
O
N
then
–78 °C
to rt
N
NEt2
N3Et2
8
9
6f
1
TfO
9
85%
CF3
Scheme 7. Preparation of benzannulation substrates.
10 equiv CSA, 2 equiv NaI
CH3CN, 75 °C, ca. 75% yield
O
With a series of appropriate substrates in hand, we began to
examine benzannulation reactions using both the AuCl3 and the
Cu(OTf)2/CF2HCO2H catalyst systems. Cyclization of substrates
similar to phenylacetylene derivative 6a (R¼Ph) using the gold
catalyst system has been reported previously.19 Our goals were to
understand better the scope, discern any reactivity trends with
respect to the alkyne substituent (R), and identify any advantages of
employing the copper catalyst system in the intramolecular
benzannulations.
Under the gold-catalyzed conditions, successful benzannulation
reaction was observed with the phenyl-derived substrate (Table 1,
entry 1): the target indane was isolated in ca. 80% yield (8 mg, small
scale), consistent with the previous reports.19 Alkylacetylene sub-
strates 6b (R¼n-Bu, entry 2) and 6c (R¼t-Bu, entry 3) underwent
similar cyclizations, as did the electron-deficient arylacetylene 6f
(entry 6, R¼p-CF3–C6H4–). In contrast, the electron-rich
I
10
Scheme 6. Synthesis of 2-iodophenyl ketone 10.
Aryltriazenes (i.e., 8) have been used extensively in the syn-
thesis of phenylacetylene-based systems.26 Conversion of aryl-
triazenes to the corresponding aryl iodides is typically
accomplished by heating in sealed tubes with iodomethane at
temperatures in excess of 100 ꢁC.27 In the case of electron-deficient
aryltriazenes, decomposition of the triazene in iodomethane re-
quires higher temperatures. The toxicity of iodomethane and the
high temperatures and pressures required for the decomposition of
aryltriazenes to iodoarenes prompted us to seek alternative
methods for this transformation. Electron-deficient aryltriazenes
have been reported to undergo decomposition to afford iodoarenes

D.M. Jones, G.B. Dudley / Tetrahedron 66 (2010) 4860–4866
4863
Table 1
Preliminary screening of benzannulation reactions of substrates 6a–fa
catalyst, DCE
80 °C, 1-1.5 h
O
+
H
R
O
R
6
2
13
Entry
R
Substrate
AuCl3 Catalystb
Cu(OTf)2/CF2HCO2H Systemc
2, Yieldd (%)
13, Yieldd (%)
2, Yieldd (%)
13, Yieldd (%)
1
2
3
4
5
6
Ph
n-Bu
t-Bu
Me3Si
p-MeO-C6H4
p-CF3-C6H4
6a
6b
6c
6d
6e
6f
2a, 80
2b, 70
2c, 50
2d, 0
2e, 0
2f, 80
0
0
0
2a, 70
2b, 10
2c, 0
20
70
70
0e
0e
0
0e
0e
0
2d, 0e
2e, 0e
2f, 80
a
Reactions performed on 10 mg scale for screening purposes.
5 mol % AuCl3.
5 mol % Cu(OTf)2, 1.0 equiv CF2HCO2H.
Isolated yields.
b
c
d
e
No reaction was detected by TLC after 15 h, substrates were recovered.
arylacetylene 6e (entry 5, R¼p-MeO–C6H4–) proved to be inert to
the reaction conditions: even after 15 h, only unreacted starting
material was recovered. Silylacetylenes also appear to be beyond
the current scope (entry 4).
diverging reactivity of alkyl and aryl substrates 6c and 6f under
copper-catalysis on a larger scale. Copper(II) triflate in conjunc-
tion with difluoroacetic acid efficiently converts t-Bu substrate 6c
to deacylated indane 13 in 88% yield (Eq. 7). The same protocol
effects the conversion of arylacetylene 6f to acylindane 2f in 89%
yield (Eq. 8).
The convergent fragmentation/annulation (‘open-and-shut’)
strategy for the synthesis of benzo-fused indanes is concisely il-
lustrated in the synthesis of indanes 17 and 18 (Scheme 8). Coupling
of aryl iodide 1430 with VAT 1531 using our addition/fragmentation
reaction provided dialkynyl ketone 16 in 61% yield. Mindful of our
observations described above (Table 1), we subjected ketone 16 to
the Asao–Yamamoto benzannulation conditions to provide either
17 or 18 (Scheme 8).
Similar reactivity trends were observed under the alternative
copper-catalyzed protocol, but in this series the deacylated indane
(13) was often produced. The ortho-acetylene substrates with
phenyl (entry 1), p-trifluoromethylphenyl (entry 6), and alkyl
substituents (entries 2 and 3) achieved full conversion to indanes,
whereas the electron-rich aryl (entry 5) and silyl (entry 4)
-substituted ynones were unreactive. Interestingly, the deacylated
indane 13 emerged as the major or exclusive product of the alky-
lacetylene substrates (entries 2 and 3), whereas none of this
product was produced in the reaction of the electron-deficient
trifluoromethylated substrate (entry 6).
Three specific intriguing entries are highlighted in Table 1. The t-
butylacetylene substrate (entry 3) undergoes selective conversion
to pivaloylindane 2c under the action of gold(III) chloride, whereas
the copper-catalyzed protocol converts the same substrate selec-
tively to deacylated indane 13. Thus, one can opt for either product
based on choice of catalyst system.29 A similar divergence can be
achieved within the copper-catalyzed series: by choosing the ap-
propriate acetylene substituentdelectron-deficient aryl vs hin-
dered alkyldone can gain access to either acylated or deacylated
indane product (entries 3 and 6).
n-BuLi, Et2O, –78 °C
I
O
O
then
–78 °C
to rt
15
14
16
61%
TfO
(>90% brsm)
5 mol%
5 mol%
AuCl3
Cu(OTf)2
16
5 mol% Cu(OTf)2
O
1.0 equiv
CF2HCO2H
DCE, 80 °C
83%
DCE, 80 °C
75%
1.0 equiv CF2HCO2H
(7)
DCE, 80 °C, 88%
H
O
18
H
17
6c
13
Scheme 8. Open-and-shut synthesis of benzo-fused indanes.
3. Conclusion
5 mol% Cu(OTf)2
A two-step strategy for the synthesis of benzo-fused indanes
arises from the sequential application of vinylogous acyl triflate
fragmentation and metal-catalyzed benzannulation. The new
benzannulation reactions described herein contribute to the
methodology reported previously made by Yamamoto and Asao
and expand the scope of their intramolecular reaction. The
ability to obtain either the ketone or decarbonylated benzannu-
lated products selectively through choice of catalyst or by alter-
ing the substrate provides synthetic versatility in the synthesis of
1.0 equiv CF2HCO2H
O
(8)
DCE, 80 °C, 89%
CF3
O
2f
6f
CF3
To follow up on this initial screening and establish more
precise estimation of reaction yields, we reexamined the

4864
D.M. Jones, G.B. Dudley / Tetrahedron 66 (2010) 4860–4866
substituted indanes, and the addition/fragmentation of vinyl-
ogous acyl triflates offers direct access to the benzannulation
substrates.
148.9, 135.1, 131.1, 128.0, 124.9, 118.1, 78.6, 76.0, 49.0, 43.5, 41.5, 23.8,
18.4,14.5, 11.3, 3.5; IR (neat) 1674, 1592, 1403, 1328, 1092, 757 cmꢀ1
;
HRMS (ESIþ) Calcd for C17H24N3O ([MþH]þ) 286.1919. Found
This approach to benzo-fused indanes incorporates the use of
aryltriazenes for the synthesis of useful intermediates and the
fragmentation of vinylogous acyl triflates. In addition to demon-
strating the utility of aryltriazene nucleophiles in our tandem ad-
dition and C–C bond cleavage reactions, in this study we have taken
the opportunity to highlight the use of ortho-lithiated phenyl-
triazene 3 as a synthetic equivalent of 2-iodophenyllithium.
The detailed benzannulation studies presented above provide
a firm foundation for future synthetic efforts. We demonstrate the
use of the Cu(OTf)2/CF2HCO2H catalyst system to promote intra-
molecular benzannulation reactions and document the advantage
of employing the alternative gold and copper protocols to control
product distribution. The application of the fragmentation/ben-
zannulation strategy to target-oriented chemical synthesis will be
reported in due course.
286.1915.
4.2.2. 1-(2-(2-tert-Butylethynyl)phenyl)-3,3-dimethyl-5-heptyn-1-
one (16). 1H NMR (300 MHz, CDCl3)
d
7.47 (dd, J¼7.4, 1.5 Hz, 1H),
7.43 (dd, J¼7.4, 1.5 Hz, 1H), 7.34 (dt, J¼7.4, 1.5 Hz, 1H), 7.29 (dt, J¼7.4,
1.5 Hz, 1H), 3.13 (s, 2H), 2.21 (q, J¼2.5 Hz, 2H), 1.75 (t, J¼2.5 Hz, 3H),
1.32 (s, 9H), 1.08 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 204.3, 143.6,
133.4, 130.2, 127.4, 121.4, 103.7, 79.0, 77.5, 76.8, 76.5, 51.4, 34.6, 32.4,
30.6, 28.2, 27.1, 3.5; IR (neat) 2359, 1684, 1472, 1362, 758 cmꢀ1
;
HRMS (EIþ) Calcd for C21H26O (Mþ) 294.1984. Found 294.1984.
4.3. Aryltriazene to aryl iodide conversion (9/10)
To a solution of camphor-10-sulfonic acid (2.44 g, 10.5 mmol)
and NaI (0.315 g, 2.1 mmol) in acetonitrile (25 mL) at 75 ꢁC was
added a solution of triazene 9 (300 mg, 1.05 mmol in 5 mL of ace-
tonitrile) dropwise. The evolution of nitrogen was complete after
5 min of stirring at 75 ꢁC. The mixture was cooled to rt and diluted
with 25 mL of hexane. The product was extracted five times with
hexane. The combined hexane layers were then dried with Na2SO4
and concentrated to provide a reddish oil. The crude material was
then purified by flash column chromatography using hexane. The
resulting red-brown oil (10) was used in the next step without
further purification (ca. 75% yield, >85% pure).
4. Experimental section
4.1. General information
1H NMR and 13C NMR spectra were recorded on a Varian 300
(300 MHz), Bruker 400 (400 MHz), or Bruker 600 (600 MHz)
spectrometer, using CDCl3 as the deuterated solvent. The chemical
shifts (d) are reported in parts per million (ppm) relative to the
residual chloroform peak (7.26 ppm for 1H NMR and 77.00 for 13C
NMR). Coupling constants (J) are reported in Hertz (Hz). IR spectra
were recorded on a Perkin-Elmer FTIR spectrometer with diamond
ATR accessory as thin film. Mass spectra were recorded on a JEOL
JMS600H spectrometer. Yields refer to isolated material judged to
be >95% pure by 1H NMR spectroscopy following silica gel chro-
matography (F-254 silica, 230–499 mesh particle size). All chem-
icals were used as received unless otherwise noted. Acetonitrile
(CH3CN) was distilled from calcium hydride (CaH2) and stored over
molecular sieves. Diethyl ether (Et2O) was dried through a solvent
purification system packed with alumina and molecular sieves
under an Ar atmosphere. Triethylamine and diethylamine were
distilled from CaH2 and stored over KOH pellets. The n-butyllithium
(n-BuLi) solutions were titrated with a known amount of menthol,
using 1,10-phenanthroline as an indicator, in a solution of ether. All
reactions were carried out under an inert argon atmosphere unless
otherwise stated.
4.4. General procedure for Sonogashira couplings (10/6)
To a solution of aryl iodide 10 (32 mg, 0.1 mmol) in triethyl-
amine (1 mL) was added dichlorobis(triphenylphosphine)palla-
dium (4 mg, 5 mmol) and copper(I) iodide (2 mg, 10 mmol). The
heterogeneous solution was degassed using the freeze-pump-thaw
method (five cycles) and warmed to room temperature. Hexyne
(30 mL, 0.22 mmol) was then added to the reaction mixture in one
shot. The solution was warmed to 50 ꢁC and stirred for 3 h. The
mixture was cooled to rt, diluted with ether, and filtered through
CeliteÔ. The filter cake was washed three times with ether and the
combined filtrates were concentrated. The crude product was then
purified by flash column chromatography using pure hexanes up to
1% EtOAc/Hex, providing 6b as a pale yellow oil in 85% yield
(22 mg).
4.4.1. 1-(2-(2-Phenylethynyl)phenyl)-5-heptyn-1-one (6a). 1H NMR
4.2. General procedure for the addition and fragmentation of
vinylogous acyl triflates 1 and 15
(300 MHz, CDCl3)
d
7.70 (dd, J¼7.5, 1.6 Hz, 1H), 7.63 (dd, J¼7.5, 1.5 Hz,
1H), 7.59–7.53 (m, 2H), 7.47 (dt, J¼7.5, 1.6 Hz, 1H), 7.40 (dt, J¼7.5,
1.5 Hz, 1H), 7.37–7.34 (m, 3H), 3.30 (t, J¼7.0 Hz), 2.26 (tq, J¼7.0,
2.5 Hz, 2H), 1.94 (quintet, J¼7.0, 2H), 1.69 (t, J¼2.5 Hz, 3H); 13C NMR
To a solution of iodotriazene 8 (2.0 g, 6.6 mmol) in diethyl ether
(180 mL) at ꢀ78 ꢁC was added n-BuLi (4.13 mL, 6.6 mmol, 1.6 M
solution in hexane) dropwise. The mixture was stirred at ꢀ78 ꢁC for
30 min. To the solution was added triflate 1 (1.87 g, 7.26 mmol) in
dry ether (50 mL), dropwise. The solution was stirred at ꢀ78 ꢁC for
(75 MHz, CDCl3) d 202.6, 141.0, 133.7, 131.5, 130.9, 128.6, 128.4, 128.2,
122.8, 121.2, 94.6, 88.2, 78.3, 76.4, 41.0, 23.6, 18.3, 3.3; IR (neat) 2215,
1678, 1493, 1217, 753, 689 cmꢀ1; HRMS (EIþ) Calcd for C21H18O (Mþ)
286.1358. Found 286.1353.
15 min, 0 ꢁC for 15 min, and at rt for 30 min. The reaction was then
1
quenched with
⁄
satd NH4Cl, extracted two times with Et2O,
4.4.2. 1-(2-(2-n-Butylethynyl)phenyl)-5-heptyn-1-one (6b). 1H NMR
2
washed with H2O and brine, and dried with MgSO4. The concen-
trated solution provided a crude oil, which was purified by flash
column chromatography using 1% EtOAc/Hex. The product (9) was
isolated as a yellowish-brown oil in 85% yield (1.59 g).
(300 MHz, CDCl3)
d
7.59 (dd, J¼7.6, 1.6 Hz, 1H), 7.47 (dd, J¼7.6, 1.5 Hz,
1H), 7.38, (dt, J¼7.6, 1.6 Hz, 1H), 7.32 (dt, J¼7.6, 1.5 Hz, 1H), 3.20 (t,
J¼7.3 Hz, 2H), 2.46 (t, J¼7.0, 2H), 2.31–2.16 (m, 2H), 1.89 (quintet,
J¼7.3 Hz, 2H), 1.76 (t, J¼2.5 Hz, 3H), 1.67–1.55 (m, 2H), 1.54 (m, 2H),
0.95 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 203.5, 141.4, 133.8,
4.2.1. 1-(2-(3,3-Diethyl-1-triazo)phenyl)-1-oxo-5-heptyne
NMR (300 MHz, CDCl3)
1.3 Hz, 1H), 7.37 (ddd, J¼8.2, 7.6, 1.5, 1H), 7.14 (dt, J¼7.6, 1.0 Hz, 1H),
3.77 (q, J¼7.0 Hz, 4H), 3.06 (t, J¼7.4 Hz, 2H), 2.19 (tq, J¼7.0, 2.5 Hz,
2H), 1.93–1.77 (app. quintet, J¼7.2 Hz, 2H), 1.74 (t, J¼2.5 Hz, 3H),
(9). 1H
127.8, 127.5, 121.9, 96.3, 79.4, 78.4, 76.1, 41.1, 30.5, 22.1, 18.3, 13.6, 3.4; IR
d
7.48 (dd, J¼8.2, 1.0 Hz, 1H), 7.43 (dd, J¼7.6,
(neat) 2228, 1679, 1440, 758 cmꢀ1; HRMS (EIþ) Calcd for C19H22
O
(Mþ) 266.1671. Found 266.1669.
4.4.3. 1-(2-(2-tert-Butylethynyl)phenyl)-5-heptyn-1-one
NMR (300 MHz, CDCl3)
7.60 (dd, J¼7.5, 1.5 Hz, 1H), 7.46 (dd, J¼7.5,
(6c). 1H
1.40–1.14 (broad multiplet, 6H); 13C NMR (100 MHz, CDCl3)
d
206.4,
d

D.M. Jones, G.B. Dudley / Tetrahedron 66 (2010) 4860–4866
4865
1.5 Hz), 7.38 (dt, J¼7.5, 1.5 Hz, 1H), 7.31 (dt, J¼7.5, 1.5 Hz, 1H), 3.24
(t, J¼7.2 Hz, 2H), 2.24 (tq, J¼6.0, 2.5 Hz, 2H), 1.89 (quintet, J¼7.2 Hz,
2H), 1.76 (t, J¼2.5 Hz, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3)
4.6.1. (4-Methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene-5-yl)-
phenyl-methanone (2a). 1H NMR (300 MHz, CDCl3)
7.85–7.80 (m,
2H), 7.61–7.53 (m, 1H), 7.50–7.38 (m, 3H), 7.34–7.26 (m, 1H), 3.35 (t,
d
d
203.5, 141.3, 133.6, 127.8, 127.5, 104.1, 78.4, 78.2, 76.1, 41.4, 30.6,
J¼7.5 Hz, 2H), 3.08 (t, J¼7.5 Hz, 2H), 2.30 (quintet, J¼7.5 Hz, 2H),
28.2, 23.6, 18.3, 3.4; IR (neat) 2235, 1679, 1362, 1273, 757 cmꢀ1
;
2.22 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 200.9, 141.0, 140.4, 138.0,
HRMS (EIþ) Calcd for C19H22O (Mþ) 266.1671. Found 266.1669.
134.7, 133.6, 130.3, 129.8, 129.6, 128.7, 125.5, 125.4, 125.3, 124.5;
32.6, 31.6, 23.9, 17.2; IR (neat) 1664, 1448, 1219, 884, 756, 717 cmꢀ1
;
4.4.4. 1-(2-(2-(p-Methoxyphenyl)ethynyl)phenyl)-5-heptyn-1-one
(6d). 1H NMR (300 MHz, CDCl3)
HRMS (EIþ) Calcd for C21H18O (Mþ) 286.1358. Found 286.1353.
d
7.69 (dd, J¼7.5, 1.2 Hz, 1H), 7.59
(dd, J¼7.5, 1.1 Hz, 1H), 7.50 (d, J¼8.7 Hz, 2H), 7.44 (dt, J¼7.5, 1.2 Hz,
1H), 7.36 (dt, J¼7.5, 1.1 Hz, 1H), 6.88 (d, J¼8.7 Hz, 2H), 3.82 (s, 3H),
3.29 (t, J¼7.3 Hz, 2H), 2.32–2.18 (m, 2H),1.93 (app. quintet, J¼7.0 Hz,
4.6.2. n-Butyl-(4-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene-
5-yl)-methanone (2b). 1H NMR (300 MHz, CDCl3)
d
7.78 (dd, J¼7.8,
1.8 Hz, 1H), 7.55 (dd, J¼7.2, 1.8 Hz, 1H), 7.43–7.37 (m, 2H), 3.29 (t,
J¼7.2 Hz, 2H), 3.04 (t, J¼7.8 Hz, 2H), 2.87 (t, J¼7.8 Hz, 2H), 2.31 (s,
3H), 2.26 (quintet, J¼7.8 Hz, 2H), 1.78 (quintet, J¼7.8 Hz), 1.44 (app.
sextet, J¼7.6 Hz, 2H), 0.953 (t, J¼7.2 Hz, 3H); 13C NMR (150 MHz,
2H), 1.69 (t, J¼2.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 203.0, 159.9,
140.8, 133.6, 133.0, 130.9, 128.2, 127.8, 121.6, 115.0, 114.0, 94.8, 87.1,
78.4, 76.4, 55.3, 41.0, 23.7, 18.3, 3.4; IR (neat) 2212, 1678, 1605, 151,
1247, 1028, 831, 758 cmꢀ1; HRMS (EIþ) Calcd for C22H20O2 (Mþ)
316.1463. Found 316.1462.
CDCl3)
d 211.2, 141.0, 140.0, 137.8, 128.9, 128.9, 127.5, 125.6, 125.3,
124.7, 124.6, 45.6, 32.6, 31.6, 25.8, 23.9, 22.5, 16.9, 13.9; IR (neat)
1697, 1130, 751 cmꢀ1; HRMS (EIþ) Calcd for C19H22O (Mþ) 266.1671.
Found 266.1670.
4.4.5. 1-(2-(2-Trimethylsilylethynyl)phenyl)-5-heptyn-1-one
(6e). 1H NMR (300 MHz, CDCl3)
d 7.64–7.59 (m, 1H), 7.57–7.52 (m,
1H), 7.41 (dt, J¼7.4, 1.9 Hz, 1H), 7.37 (dt, J¼7.4, 1.7 Hz, 1H), 3.23 (t,
J¼7.3 Hz, 2H), 2.42 (tq, J¼7.1, 2.5 Hz, 2H), 1.90 (quintet, J¼7.1 Hz,
2H), 1.76 (t, J¼2.5 Hz, 3H), 0.26 (s, 9H); 13C NMR (75 MHz, CDCl3)
4 . 6 . 3 . t e r t - B u t y l - ( 4 - m e t h y l - 2 , 3 - d i h y d r o - 1 H - c y c l o -
penta[a]naphthalene-5-yl)-methanone (2c). 1H NMR (300 MHz,
CDCl3)
d
7.77 (dd, J¼7.6, 1.1 Hz, 1H), 7.53–7.33 (m, 3H), 3.29 (app.
d
203.0, 141.8, 134.0, 130.6, 128.5, 127.9, 120.8, 103.5, 100.4, 78.3,
triplet, J¼7.8 Hz, 2H), 3.13–2.94 (m, 2H), 2.29 (s, 3H), 2.26 (app.
76.1, 41.2, 23.7, 18.3, 3.4, 0.4; IR (neat) 2157, 1682, 1249, 863, 840,
quintet, J¼7.8 Hz, 2H), 1.27 (s, 9H); 13C NMR (150 MHz, CDCl3)
758 cmꢀ1
305.1338. Found 305.1333.
;
HRMS (ESIþ) Calcd for C18H22OSiNa ([MþNa]þ)
d 219.1, 141.0, 139.4, 137.1, 129.3, 128.8, 127.5, 125.7, 129.2, 125.1,
124.7, 45.7, 32.7, 31.5, 28.1, 23.8,18.3; IR (neat) 1688,1276,1261, 764,
749 cmꢀ1; HRMS (EIþ) Calcd for C19H22O (Mþ) 266.1671. Found
266.1668.
4.5. Synthesis of 1-(2-(2-(p-trifluoromethylphenyl)-
ethynyl)phenyl)-5-heptyn-1-one (6d/6f)
4.6.4. (4-Methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene-5-yl)-p-
To a methanolic solution (2 mL) of trimethylsilylacetylene (2d)
(136 mg, 0.48 mmol) was added potassium carbonate (100 mg,
0.72 mmol) at room temperature. The reaction mixture was stirred
at room temperature until the starting material was no longer
detected by TLC (ca. 30 min). The mixture was diluted with ether
and water. The reaction was quenched with 1 N HCl and stirred
until CO2 evolution was no longer observed. The product was
extracted twice with EtOAc. The combine organics were washed
with water and brine, dried with Na2SO4, filtered, and concen-
trated. The resulting crude oil was purified by flash column chro-
matography using gradient elution of 0–1% EtOAc/Hex, providing
6g as a clear oil in 94% yield (94 mg). A Sonogashira reaction was
then carried out between 6g and 4-iodobenzotrifluoride following
the general procedure outlined in Section 4.4 to provide 135 mg of
trifluoromethylphenyl-methanone (2f). 1H NMR (300 MHz, CDCl3)
d
7.95 (d, J¼8.1 Hz, 2H), 7.84 (d, J¼8.1 Hz, 1H), 7.69 (d, J¼8.1 Hz, 2H),
7.52–7.39 (m, 2H), 7.36–7.28 (m, 1H), 3.37 (t, J¼7.5 Hz, 2H), 3.10 (t,
J¼7.5 Hz, 2H), 2.32 (quintet, J¼7.5 Hz, 2H), 2.22 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d
199.8, 141.0, 140.5, 134.7 (q, J¼32.5 Hz), 133.8,
130.1, 130.0, 129.8, 128.8, 125.8 (q, J¼3.7 Hz), 125.7, 125.2, 124.7,
123.6 (q, J¼272.9 Hz), 32.6, 31.7, 23.8, 17.3; IR (neat) 1673, 1409,
1322, 1168, 1128, 1069 cmꢀ1; HRMS (ESIþ) Calcd for C22H17F3ONa
([MþNa]þ) 377.1129. Found 377.1135.
4.6.5. tert-Butyl-(3,3,4-trimethyl-2,3-dihydro-1H-cyclo-
penta[a]naphthalene-5-yl)-methanone (18). 1H NMR (300 MHz,
CDCl3)
d
7.71 (dd, J¼7.8, 1.4 Hz, 1H), 7.47 (dd, J¼7.8, 1.3 Hz, 1H), 7.42
(dt, J¼7.8, 1.4 Hz, 1H), 7.36 (dt, J¼7.8, 1.4 Hz), 3.09 (s, 2H), 2.89 (d,
6f as a pale yellow oil (85% yield). 1H NMR (300 MHz, CDCl3)
d 7.74
J¼16.0 Hz,1H), 2.80 (d, J¼16 Hz,1H), 2.25 (s, 2H),1.29 (s, 3H),1.27 (s,
(dd, J¼7.4, 1.5 Hz, 1H), 7.67 (d, J¼8.3 Hz, 2H), 7.65–7.58 (m, 3H), 7.50
(dt, J¼7.4, 1.6 Hz, 1H), 7.44 (dt, J¼7.4, 1.5 Hz, 1H), 3.24 (t, J¼7.3 Hz,
2H), 2.26 (tq, J¼7.0, 2.5 Hz, 2H), 1.94 (quintet, J¼7.0 Hz, 2H), 1.70 (t,
9H), 1.23 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 219.2, 140.1, 128.6,
137.1, 129.3, 129.1, 127.7, 125.7, 125.1, 125.0, 124.5, 47.7, 46.4, 45.7,
39.2, 29.8, 29.8, 28.1,18.2; IR (neat) 1685,1463,1102, 903, 738 cmꢀ1
;
J¼2.5 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d
202.2, 141.1, 134.8, 131.0,
HRMS (EIþ) Calcd for C21H26O (Mþ) 294.1984. Found 294.1984.
130.3 (q, 32.7 Hz), 128.8, 125.3 (q, 3.9 Hz), 123.9 (q, 270.9 Hz), 120.6,
92.7, 90.6, 78.3, 76.5, 40.8, 23.6, 18.3, 3.5; IR (neat) 1683, 1614, 1320,
1126, 1065, 824 cmꢀ1; HRMS (EIþ) Calcd for C22H17OF3 (Mþ)
354.1232. Found 354.1230.
4.7. General procedure for copper-catalyzed benzannulations
(6/13)
To a solution of Cu(OTf)2 (4 mg, 11
mmol) and difluoroacetic acid
4.6. General procedure for gold-catalyzed benzannulations
(6/2)
(14 mL, 0.22 mmol) in DCE, was added a solution of diyne 6c (58 mg,
0.22 mmol in 1 mL of DCE). The solution was heated to 80 ꢁC and
stirred for 40 min. The reaction mixture was cooled to rt and fil-
tered through silica gel. The filtrate was concentrated; the resulting
oil was purified by flash column chromatography using hexanes,
providing naphthalene derivative 13 in 88% yield (35 mg).
To
chloroethane (DCE), obtained from a stock solution (6 mg/mL), was
added an additional 200 L of DCE and diyne 6b (10 mg, 37 mol, in
200
L of DCE). The solution was then heated to 80 ꢁC for 1.5 h. The
a solution of AuCl3 (0.6 mg, 1.8 mmol) in 100 mL di-
m
m
m
mixture was cooled to rt and filtered through a plug of silica gel. The
filtrate was concentrated and purified by flash column chroma-
tography using 1% EtOAc/Hex, providing naphthyl ketone 2b in 70%
yield (7 mg) as a clear oil.
4.7.1. 4-Methyl-2,3-dihydro-1H-cyclopenta[a]naphthalene (13). 1H
NMR (300 MHz, CDCl3)
d
7.78 (d, J¼7.3 Hz, 1H), 7.75 (d, J¼7.3 Hz,
1H), 7.47 (s, 1H), 7.46–7.35 (m, 2H), 3.28 (t, J¼7.5 Hz, 2H), 3.04 (t,
J¼7.5 Hz, 2H), 2.43 (s, 3H), 2.26 (quintet, J¼7.5 Hz, 2H); 13C NMR

4866
D.M. Jones, G.B. Dudley / Tetrahedron 66 (2010) 4860–4866
7. Grotjahn, D. B. Transition Metal Alkyne Complexes: Transition Metal-Catalyzed
(150 MHz, CDCl3)
d
199.80, 141.03, 140.47, 134.73 (q, J¼32.5 Hz),
Cyclotrimerization In. Comprehensive Organometallic Chemistry II; Abel, E. W.,
Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 741–770.
8. Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1979, 101, 215–217.
9. (a) Asao, N.; Takahashi, K.; Lee, S.; Kashahara, T.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 12650–12651; (b) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 10921–10925.
10. Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028–5029.
11. Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128, 6499–6507.
12. Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006, 936–938.
13. Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175–177.
133.8, 130.1, 130.0, 129.8, 128.8, 125.8 (q, J¼3.7 Hz), 125.7, 125.2,
124.7, 123.6 (q, J¼272.9 Hz), 32.6, 31.7, 23.8, 17.3. 141.3, 139.1, 133.2,
132.9, 129.0, 127.6, 125.6, 124.9, 124.7, 124.2, 32.4, 31.3, 24.1, 19.8; IR
(neat) 1595, 1382, 1020, 872, 766, 743 cmꢀ1; HRMS (ESIþ) Calcd for
C14H14 (Mþ) 182.1096. Found 182.1094.
4.7.2. 3,3,4-Trimethyl-2,3-dihydro-1H-cyclopenta[a]naphthalene
(17). 1H NMR (300 MHz, CDCl3)
d
7.76 (dd, J¼6.8, 2.5 Hz, 1H), 7.70
(dd, J¼6.6, 2.5 Hz, 1H), 7.46 (s, 1H), 7.44–7.34 (m, 2H), 3.08 (s, 2H),
2.86 (s, 2H), 1.26 (s, 6H); 13C NMR (75 MHz, CDCl3)
144.6, 142.5,
14. Kamijo, S.; Dudley, G. B. Tetrahedron Lett. 2006, 47, 5629–5632.
15. Jones, D. M.; Dudley, G. B. Synlett 2010, 223–226.
16. Tummatorn, J.; Dudley, G. B. J. Am. Chem. Soc. 2008, 130, 5050–5051.
17. Kolakowski, R. V.; Manpadi, M.; Zhang, Y.; Emge, T. J.; Williams, L. J. J. Am. Chem.
Soc. 2009, 131, 12910–12911.
d
137.5, 137.4, 133.6, 132.0, 130.0, 129.1, 128.9, 128.4, 51.8, 50.6, 43.6,
34.2, 24.0; IR (neat) 1364, 872, 843, 743 cmꢀ1; HRMS (EIþ) Calcd for
C16H18 (Mþ) 210.1408. Found 210.1404.
18. (a) Draghici, C.; Brewer, M. J. Am. Chem. Soc. 2008, 130, 3766–3767; (b) Bayir, A.;
Draghici, C.; Brewer, M. J. Org. Chem. 2010, 75, 296–302.
19. Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682–
3685.
Acknowledgements
20. Gilchrist, T. L.; Rees, C. W. Carbenes, Nitrenes and Arynes; Nelson: London, 1969.
21. Sato, K.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2005, 70, 8977–8981.
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Org. Lett. 2000, 2, 969–972.
24. It is our current hypothesis that the higher aggregation of organolithium re-
agents in less polar solvents leads to better selectivity for the desired 1,2-ad-
dition reaction by attenuating their reactivity in electron-transfer reduction
processes, which promote decomposition of the VAT substrates.
25. For example, the addition/fragmentation reaction of VAT 1 with TMS–meth-
yllithium provides a higher yield of the corresponding methyl ketone (after
hydrolysis of the TMS group) than does direct addition of methyllithium, which
is a more reactive nucleophile. See Ref. 11.
26. Kimball, D. B.; Haley, M. M. Angew. Chem., Int. Ed. 2002, 41, 3338–3351.
27. Moore, J. S.; Weinstein, E. J.; Wu, Z. Tetrahedron Lett. 1991, 22, 2465–2466.
28. Satyamurthy, N.; Barrio, J. R. J. Org. Chem. 1983, 48, 4394–4396.
29. A similar phenomenon was documented in the intermolecular benzannulation
reactions; see Ref. 9.
30. Prepared in two steps from iodotriazene 8: Sonogashira coupling and tri-
azene/iodide conversion using NaI and CSA (cf. 9/10, Scheme 6).
31. Prepared by triflation of 2-methyldimedone according to our standard condi-
tions (Ref. 11). For the synthesis of 2-methyldimedone, see Lertpibulpanya, D.;
Marsden, S. P. Org. Biomol. Chem. 2006, 4, 3498–3504.
This research was supported by a grant from the National Sci-
ence Foundation (NSF CHE 0749918). We thank Dr. Tom Gedris and
Steven Freitag for support and administration of the NMR facilities,
Dr. Umesh Goli for providing the mass spectrometry data.
References and notes
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Bamfield, P.; Gordon, P. F. Chem. Soc. Rev. 1984, 13, 441–488.
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references cited.
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Science of Synthesis: Houben–Weyl Methods of Molecular Transformation; Bellus, D.,
Danheiser, R. L., Eds.; Thieme: Stuttgart, 2006; Vol. 23; Chapter 13, pp 492–568.