Gold(I)-catalyzed intramolecular tandem addition/Friedel - Crafts reactions between acyclic enamides and 1-arylalkynes

Article abstract of DOI:10.1021/jo102036n

Electron-deficient acyclic enamine derivatives react with electron-rich 1-arylalkynes using cationic gold(I) species as catalysts in an intramolecular process to form annulated 1-amido-substituted indene derivatives as the major products. Yields for this

Full text of DOI:10.1021/jo102036n

pubs.acs.org/joc
Gold(I)-Catalyzed Intramolecular Tandem Addition/Friedel-Crafts
Reactions between Acyclic Enamides and 1-Arylalkynes
Jennifer A. Kozak, Brian O. Patrick,† and Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver, B.C., Canada,
V6T 1Z1. †Correspondence regarding crystal structures should be directed to Dr. Patrick, Manager,
UBC X-ray Crystallographic Facility
gdake@chem.ubc.ca
Received October 13, 2010
Electron-deficient acyclic enamine derivatives react with electron-rich 1-arylalkynes using cationic
gold(I) species as catalysts in an intramolecular process to form annulated 1-amido-substituted
indene derivatives as the major products. Yields for this process range between 21% and 98%. In
some cases, a two-step process that includes a subsequent alkene isomerization is needed.
Introduction
(enesulfonamides), N-carbamoyl enamines (enecarbamates), or
N-acyl enamines (enamides)] serving as nucleophiles in order to
form relatively complex nitrogen-containing ring systems.7 For
example, our group recently disclosed a cyclization in which
a cyclic enamine derivative of general structure 1 reacted to
produce largely compounds of type 2 within a mixture of
isomers (Scheme 1, path a).7a An important question that we
Additions of carbon nucleophiles to activated C-Cπsystems
are of fundamental importance in synthetic organic chemistry.
The use of catalytic amounts of electrophilic metal salts to
activate C-C π systems toward nucleophilic attack has been a
topic of much scholarly interest.1 Important examples of this
reactivity paradigm forming C-C bonds include the addition of
β-dicarbonyl compounds (Conia-ene),2 enol silyl ethers,3 allyl-
silanes or allylstannanes,4 functionalized indoles,5 and enamines
generated in situ.6 Our interest in this area stems from the use of
electron-deficient enamine derivatives [N-arylsulfonyl enamines
ꢀ
(4) (a) Porcel, S.; Lopez-Carrillo, V.; Garcıa-Yebra, C.; Echavarren,
´
A. M. Angew. Chem., Int. Ed. 2008, 47, 1883–1886. (b) Matsuda, T.;
Kadowaki, S.; Yamaguchi, Y.; Murakami, M. Chem. Commun. 2008,
ꢀ
2744–2746. (c) Mendez, M.; Echavarren, A. M. Eur. J. Org. Chem. 2002,
ꢀ
ꢀ
15–28. (d) Fernandez-Rivas, C.; Mendez, M.; Nieto-Oberhuber, C.; Echa-
varren, A. M. J. Org. Chem. 2002, 67, 5197–5201. (e) Martın-Matute, B.;
´
~
ꢀ
ꢀ
Bunuel, E.; Mendez, M.; Nieto-Oberhuber, C.; Cardenas, D. J.; Echavarren,
A. M. J. Organomet. Chem. 2003, 687, 410–419. (f) Asao, N.; Shimada, T.;
Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 10899–10902. (g)
Asao, N.; Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 3797–
3798. (h) Yoshikawa, E.; Gevorgyan, V.; Asao, N.; Yamamoto, Y. J. Am.
Chem. Soc. 1997, 119, 6781–6786. (i) Asao, N.; Yoshikawa, E.; Yamamoto,
Y. J. Org. Chem. 1996, 61, 4874–4875. (j) Asao, N.; Matsukawa, Y.;
Yamamoto, Y. Chem. Commun. 1996, 1513–1514. (k) Matsukawa, Y.; Asao,
N.; Kitahara, H.; Yamamoto, Y. Tetrahedron 1999, 55, 3779–3790.
(5) (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9533–
9537. (b) Han, X.; Lu, X. Org. Lett. 2009, 11, 2381–2384. (c) Kong, W.; Cui,
J.; Chen, G.; Fu, C.; Ma, S. Org. Lett. 2009, 11, 1213–1216. (d) Huang, H.;
Peters, R. Angew. Chem., Int. Ed. 2009, 48, 604–606. (e) Liu, C.;
Widenhoefer, R. A. Chem.;Eur. J. 2006, 12, 2371–2382. (f) Han, X.;
Widenhoefer, R. A. Org. Lett. 2006, 8, 3801–3804. (g) Liu, C.; Han, X.;
Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700–3701.
(h) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250–10251.
(6) (a) Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2008, 47, 5703–
5705. (b) Jensen, K. L.; Franke, P. T.; Arroniz, C.; Kobbelgaard, S.;
Jorgensen, K. A. Chem.;Eur. J. 2010, 16, 1750–1753.
(1) For recent reviews surveying the reactions promoted by electrophilic
€
Soriano, E.; Marco-Contelles, J. Acc. Chem. Res. 2009, 42, 1026–1036. (c) Li,
Z. G.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–3265. (d) Hashmi,
A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766–1775. (e) Arcadi, A.
metals, see: (a) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208–3221. (b)
€
Chem. Rev. 2008, 108, 3266–3325. (f) Furstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410–3449. (g) Chianese, A. R.; Lee, S. J.; Gagne,
ꢀ
M. R. Angew. Chem., Int. Ed. 2007, 46, 4042–4059. (h) Zhang, L.; Sun, J.;
Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271–2296. (i) Michelet, V.;
^
Toullec, P., Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–4315.
(2) (a) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J.
J. Am. Chem. Soc. 2009, 131, 9140–9141. (b) Corkey, B. K.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 17168–17169. (c) Gao, Q.; Zheng, B.-F.; Li,
J.-H.; Yang, D. Org. Lett. 2005, 7, 2185–2188. (d) Kuninobu, Y.; Kawata, A.;
Takai, K. Org. Lett. 2005, 7, 4823–4825. (e) Kennedy-Smith, J. J.; Staben,
S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526–4527. (f) Staben, S. T.;
Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350–
5352. (g) Yao, X.; Li, C. J. J. Am. Chem. Soc. 2004, 126, 6884–6885.
(3) (a) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
Lalonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991–5994. (b)
Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2007,
46, 7671–7673. (c) Lee, K.; Lee, P. H. Adv. Synth. Catal. 2007, 349, 2092–
2096. (d) Minnihan, E. C.; Colletti, S. L.; Toste, F. D.; Shen, H. C. J. Org.
Chem. 2007, 72, 6287–6289.
(7) (a) Kozak, J. A.; Dodd, J. M.; Harrison, T. J.; Jardine, K. J.; Patrick,
B. O.; Dake, G. R. J. Org. Chem. 2009, 74, 6929–6935. (b) Kozak, J. A.;
Dake, G. R. Angew. Chem., Int. Ed. 2008, 47, 4221–4223. (c) Harrison, T. J.;
Patrick, B. O.; Dake, G. R. Org. Lett. 2006, 9, 367–370. (d) Harrison, T. J.;
Dake, G. R. Org. Lett. 2004, 6, 5023–5026.
DOI: 10.1021/jo102036n
r
Published on Web 11/18/2010
J. Org. Chem. 2010, 75, 8585–8590 8585
2010 American Chemical Society

Kozak et al.
JOCArticle
SCHEME 1. Pt(II)-Catalyzed Cyclization of Cyclic Enamides
and Acyclic Enamides (Proposed)
SCHEME 3
SCHEME 4
SCHEME 2
have not yet addressed centers on the use of acyclic enamine
derivatives as nucleophiles (Scheme 1, path b). A number of
scientific questions would be addressed in such an investigation.
The efficiency of the reaction of cyclic substrates was affected to
a large extent by the substrate structure (i.e., ring size of enamine
derivative, nature of electron-withdrawing group). Would the
reactions of acyclic enamine derivatives in this study proceed as
predictably (or even occur to any extent) as they had with cyclic
enamine derivatives? A preference for an initial 6-endo cycliza-
tion event was observed previously;does the regioselectivity of
the reaction change for acyclic enamine substrates? This report
presents our initial work involving these questions.
It was subsequently found that the Sonogashira coupling
occurred smoothly in the presence of enamides. Conse-
quently the oxidation and condensation processes could be
carried out prior to the Sonogashira reaction (Scheme 3).
This sequence was used to build enamides 7-9.
A recently described Cu(I)-catalyzed coupling process
between alkenyl iodides and amides, carbamates, and sulfo-
namides was used in a third synthetic approach to substrates
10-13 (Scheme 4). The functionalized alkenyl iodide starting
materials were readily prepared. The copper(I)-catalyzed
process was generally high-yielding. Efforts to produce a
Z-configured enamide derivative by using a Z-alkenyl iodide
as starting material with either catalytic or stoichiometric
copper sources were uniformly unsuccessful due to extremely
poor yields (<15%).
Cyclization Experiments. As a starting point, enamide 3
was treated with 10 mol % of platinum(II) chloride
in toluene at 110 °C for 16 h (Scheme 5). Direct column
chromatography of the crude reaction mixture on silica gel
enabled the purification and isolation of cyclization products
14A and 14C in 67% yield in a 8:1 ratio. The major product
was characterized by using 1H, 13C, and 2D NMR spectros-
copy, specifically COSY and HMBC experiments. The major
product 14A apparently results from metal-catalyzed
cyclization followed by alkene migration under the reaction
conditions. Support for this conjecture derives from the
following experiments. When compound 3 was subjected to
the platinum catalyst at lower temperature (80 °C), an in situ
alkene migration did not occur such that two diastereomeric
compounds (1:1 ratio, represented as 14B) were produced
as well as 14C. Importantly, exposure of 14B either to
Results and Discussion
Substrate Construction. The substrates used in this study
were synthesized in a straightforward manner with use of
established synthetic technology. The key structural features
within the substrates were (a) a 1-aryl-substituted alkyne and
(b) an acyclic enamine functionalized by an electron-with-
drawing group. In the end, three strategies were employed.
Readily available 1,n-alkynyl alcohols could be converted
to substrates 3-6 by using a simple three-reaction sequence
incorporating a Sonogashira coupling of a terminal alkyne
function and a Swern oxidation followed by a carbonyl
condensation reaction utilizing 2-pyrrolidinone with cata-
lytic acetic acid in refluxing toluene (Scheme 2). Synthetically
useful yields (>75%) were typically observed in these
processes.8
(8) Substrates were constructed by using standard reactions with key
steps including Sonogashira coupling, aldehyde-amide condensations, Takai
olefination reactions, and copper(I)-catalyzed cross-coupling reactions be-
tween a vinyl iodide and amides. (a) Sonogashira coupling: Sonogashira, K.;
Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467–4470. (b) Takai
olefination: Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408–7410. (c) Copper(I)-catalyzed cross coupling: Pan, X.; Cai, Q.; Ma, D.
Org. Lett. 2004, 6, 1809–1812.
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SCHEME 5. Initial Experiments
SCHEME 6. Four Distinct Products Could Be Formed
the original reaction conditions (10 mol % PtCl2, toluene,
110 °C) or to rhodium(III) catalysis (10 mol % RhCl3 3H2O,
3
EtOH, 100 °C) generated 14A. Further optimization experi-
ments demonstrated that the catalyzed reaction of 3 with 5
mol % each of triphenylphosphine gold(I) chloride and silver
hexafluoroantimonate in 1,2-dichloroethane at 80 °C pro-
vided 14A and 14C in 86% yield in a 13:1 ratio in only 1 h. As
the cyclorearrangement of acyclic enamides using gold(I)
catalysis proceeded with better selectivity at lower tempera-
tures in less time compared to platinum(II) catalysis, catalyst
systems based on gold(I) became the focus of further inves-
tigation. The standard catalyst conditions were the combina-
tion of triphenylphosphine gold(I) chloride and silver
hexafluoroantimonate at 5 mol % load each in 1,2-dichlor-
oethane. Compounds that were not particularly reactive with
these catalyst conditions were reacted with [(2-biphenylbis-
those from the reactions of cyclic enamides (Scheme 6).
Putative coordination of the cationic metal catalyst to the
alkyne initiates either a 6-endo (major pathway) or 5-exo
(minor pathway) cyclization event to form intermediary
azacarbenium ions I or II, and each of these undergoes
subsequent Friedel-Crafts reaction.10 After this cyclization,
the initially formed product(s) of catalyst-induced 6-endo
closure (possibly generated as a diastereomeric mixture,
represented as B) can undergo alkene migration to form a
1-amidoindene derivative A. The product(s) C that derive
from an initial 5-exo cyclization (again, the formation of
diastereomers are possible) can also eliminate to give a
substituted napthalene derivative D (vide infra). The diag-
nostic signals used in the NMR spectroscopic analysis of the
product mixtures are presented later.
tert-butylphosphine)Au(I) NCCH3]þ SbF6- (15), a catalyst
3
demonstrated to be particularly efficient in the activation of
cycloisomerization reactions.9
Each of the substrates 3-13 share the structural feature of
electron-donating oxygen substituents on the aromatic ring,
as these compounds were observed to undergo the tandem
addition-Friedel-Crafts process with both reasonable effi-
ciency and good regioselectivity (initial 6-endo vs 5-exo
cyclization). These observations were in line with our pre-
vious results in which electron-rich aromatic systems were
optimal in the cyclizations of cyclic enamides;reactions
were both high-yielding and occurred with a good margin
of 6-endo cyclization selectivity. Our experiments within the
acyclic series using compounds having electron-withdrawing
substituents on the aromatic ring (e.g., p-CF3, p-NO2) pro-
ceeded sluggishly or not at all. Electron-donating substituents
on the aromatic ring would increase the electron density of the
alkyne function, providing a rationale explaining the sluggish or
nonreactivity of substrates having arene rings substituted by
electron-withdrawing groups. A 1-aryl-substituted alkyne where
the arene ring is substituted with electron-donating groups may
also have electron density specifically localized on the carbon
Clearly, the product mixtures resulting from the reactions
of acyclic enamide substrates are more complicated than
ꢀ
(9) (a) Nieto-Oberhuber, C.; Lopez, S.; Munoz, M. P.; Cardenas, D. J.;
Bunuel, E.; Nevado, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2005, 44,
~
ꢀ
~
ꢀ
6146–6148. (b) Herrero-Gomez, E.; Nieto-Oberhuber, C.; Lopez, S.; Benet-
Buchholz, J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5455–5459.
ꢀ
~
ꢀ
ꢀ
~
(c) Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jimenez-Nunez, E.;
Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren, A. M.
ꢀ
Chem.;Eur. J. 2006, 12, 1677–1693.
(10) For other examples of “coinage-metal”-catalyzed reactions that are
sequenced with a Friedel-Crafts reaction, see: (a) Gourdet, B.; Lam, H. W.
J. Am. Chem. Soc. 2009, 131, 3802–3803. (b) Leseurre, L.; Chao, C.-M.; Seki,
^
T.; Genin, E.; Toullec, P. Y.; Genet, J.-P.; Michelet, V. Tetrahedron 2009, 65,
1911–1918. (c) Odabachian, Y.; Gagosz, F. Adv. Synth. Catal. 2009, 351,
^
379–386. (d) Toullec, P. Y.; Chao, C.-M.; Chen, Q.; Gladiali, S.; Genet, J.-P.;
Michelet, V. Adv. Synth. Catal. 2008, 350, 2401–2408. (e) Nieto-Oberhuber,
ꢀ
ꢀ
ꢀ
C.; Perez-Galan, P.; Herrero-Gomez, E.; Lauterbach, T.; Rodrıguez, C.;
´
ꢀ
ꢀ
ꢀ
Lopez, S.; Bour, C.; Rosellon, A.; Cardenas, D. J.; Echavarren, A. M. J. Am.
Chem. Soc. 2008, 130, 269–279. (f) Toullec, P. Y.; Genin, E.; Leseurre, L.;
^
Genet, J.-P.; Michelet, V. Angew. Chem., Int. Ed. 2006, 45, 7427–7430. (g)
Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005,
ꢀ
127, 6178–6179. (h) For an early example, see: Snider, B. B.; Kwon, T. J. Org.
Chem. 1992, 57, 2399–2410.
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SCHEME 7
distal (i.e., carbon 2) of the alkyne (Scheme 7). This electronic
polarization may explain the preference for initial 6-endo cycli-
zation rather than reaction through a 5-exo mode. The subse-
quent Friedel-Crafts process should also occur more readily
with use of arene traps having electron-donating substituents.
Despite the potential for the formation of a variety of products
as outlined in Scheme 6, the outcomes of treatment of these
substrates to gold(I) catalysis typically followed one of two
scenarios.
The first cyclization scenario involves the production of
compounds exemplified as products A and C in Scheme 6.
The major isomer in the product mixture results from initial
6-endo cyclization followed by an alkene isomerization to
produce a 1-substituted indene derivative (i.e., compound A).
Products resulting from this cyclization path are presented in
Figure 1. Some points merit comment. A minimum of one
electron-donating alkoxy group was needed for adequate
reactivity (entry 1). Indene derivative 17A resulting from 5-endo
cyclization of 6 could be obtained, although the yield was poor
(entry 2). The yield could be improved to a less mediocre 34%
by using catalyst 15 (5 mol % loading). Substrate 7 that
contains a 1,3-dioxolane function was surprisingly sensitive to
the presence of the gold(I) catalyst systems as it readily
decomposed, revealing no indication that a useful reaction
occurred (entry 3). However, the treatment of 7 with platinum-
(II) chloride in refluxing toluene did induce cyclization to
produce 1-pyrrolidinoyl indene derivative 18A as the major
product in 69% yield. The regioselectivity of the initial alkyne
addition reaction was typically high (12:1 to >95:5), although
diester 11 was exceptional as it produced a mixture of products
in a 2:1 isomeric ratio favoring initial 6-endo cyclization (entry
4). The reactions could also be run by using valerolactam or
carbamate enamine derivatives, producing functionalized in-
denes 20A and 21A as the exclusive products (entries 5 and 6). A
small amount (9%) of naphthalene derivative 21D was isolated
in the reaction forming 21A (entry 6).
FIGURE 1. Acyclic enamide cyclizations producing indene deriva-
tives as major products.
not take place at this lower temperature (entries 1 and 4). A
small amount (4%) of naphthalene derivative 22D was observed
in the cyclization reaction of 5 to 22 (entry 1).
Importantly, a subsequent alkene isomerization of the pro-
ducts of Figure 2 could be smoothly promoted by using
rhodium(III) catalysis in ethanol at 80-100 °C. In this manner,
a construction of 1-substituted indene derivatives could be
performed (eq 1). This isomerization process also assisted with
the ultimate characterization of the reaction mixtures; it con-
firms that the substituted indene products are derived from a
product of cyclization/Friedel-Crafts process.
The second cyclization scenario involved the production of
compounds exemplified as B and C in Scheme 6 (Figure 2). The
alkene migration process did not take place in situ for five
substrates that were examined, although the product derived via
an initial 6-endo cyclization event was the major product.
Interestingly;and fortunately in consideration of the practical
difficulties of the analysis of the reaction mixture;the products
of type B from 6-endo addition were observed as single diaster-
eomers. In two instances a lower reaction temperature (25 °C)
was used to prevent decomposition;alkene isomerization did
The reaction of 2-alkynyl indole 26 is interesting as the
substrate in this case does not feature an oxygen-substituted
aromatic ring, but rather a relatively electron-rich indole
fragment (eq 2). The reactions of 26 with PtCl2 were
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FIGURE 3. Diagnostic Spectral Characteristics of Products.
and 25C formed a cocrystal suitable for analysis. This technique
helped to establish the relative configuration of the stereogenic
carbon atoms in the products. Single diastereomeric compounds
in the B and C product series were observed. This observation is
consistent with the original E-configuration in the enamide
starting materials being relayed into the products. Unfortu-
nately, a Z-configured enamide could not be synthesized in a
practically useful yield, so the stereoselectivity of the gold-
catalyzed process was not unequivocally determined.
In summary, the intramolecular reactions of acyclic en-
amine derivatives tethered to electron-rich aromatic rings to
form 1-aza-substituted indene derivatives using a gold-cata-
lyzed tandem alkyne addition/Friedel-Crafts process has
been presented. Our understanding of the process at the
present time does not enable prediction whether or not a
subsequent alkene isomerization takes place during the
course of the reaction. Future work will incorporate mod-
ification of the metal catalyst to generate products with a
high level of enantiopurity and the further synthetic manip-
ulation of these reaction products to generate compounds of
interest in synthesis or biological studies. Efforts toward
these goals will continue in our laboratory.
FIGURE 2. Acyclic enamide cyclizations producing tricycles as
major products.
unsuccessful, but a cationic gold system initiated a tandem
addition-Friedel-Crafts process to generate pentacycle
27B as the major component in a product mixture obtained
in 85% yield. Interestingly, products resulting from an initial
5-exo cyclization were not observed in the product mixture.
The product mixture in this unusual case was composed of 27B
and 27A, the 6-endo cyclization product that did not undergo
alkene migration.11
Experimental Section
Diagnostic signals for the spectroscopic analysis of two
exemplary product mixtures are given in Figure 3. The key
signal for products of type A (cyclization-isomerization) is a
singlet between 5.6 and 5.8 ppm. For the products of 6-endo
and 5-exo cyclization prior to alkene migration, key differ-
ences in the spectra are observed. The vinyl protons of 22C
and 23C are found downfield relative to that of the major
isomers, 22B and 23B. In addition, the coupling constants of
the benzylic protons in each system are also diagnostic. The
NMR spectra of products of 5-exo cyclization (C-series)
have a diagnostic doublet with a relatively large (∼14 Hz)
coupling constant, while the 6-endo regioisomers (B-series)
are doublets having a smaller (∼7 Hz) J value.
Representative Procedure of an Enamide Condensation. (E)-1-(7-
(3,5-Dimethoxyphenyl)hept-1-en-6-ynyl)pyrrolidin-2-one (5). A solu-
tion of 0.29 g of 7-(3,5-dimethoxyphenyl)hept-6-ynal (1.2 mmol),
0.4 mL of 2-pyrrolidinone (4.8 mmol), and 1.2 mL of acetic acid in 5
mL of toluene was heated to reflux within a Dean-Stark apparatus.
The reaction mixture was stirred at reflux for 3 h before being cooled
to rt. The solution was diluted with diethyl ether and washed
carefully twice with a saturated solution of sodium bicarbonate.
The aqueous fractions were then extracted twice with diethyl ether.
The combined organic fractions were dried over sodium sulfate,
filtered, and concentrated in vacuo to afford a brown oil. The crude
oil was purified by column chromatography on triethyla-
mine washed silica gel (3:1 to 1:1 to 1:3 hexanes:ethyl acetate) to
afford 0.34 g (91%) of the title compound 5 as a pale yellow oil.
In addition, the product characterization process was facili-
tated by X-ray crystallography. Specifically, compounds 25B
IR (neat): 2938, 2245, 1694, 1597, 835, 732 cm-1. H NMR
1
(400 MHz, CDCl3): δ 6.92 (d, J=14.7 Hz, 1H), 6.54 (d, J =
2.4 Hz, 2H), 6.38 (t, J = 2.4 Hz, 1H), 4.93 (dt, J = 14.3, 7.2 Hz,
1H), 3.75 (s, 6H), 3.47 (t, J = 7.2 Hz, 2H), 2.47-2.43 (m, 2H),
(11) Attempts to isomerize this mixture to 27A by using rhodium(III)
chloride at 100 °C resulted in decomposition.
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Kozak et al.
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2.40 (t, J = 7.2 Hz, 2H), 2.23 (q, J = 6.8 Hz, 2H), 2.06 (qt, J =
7.6 Hz, 2H), 1.68 (qt, J = 7.3 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 172.9, 160.6, 125.4, 124.5, 111.2, 109.5, 101.3, 89.6,
81.1, 55.5, 45.4, 31.4, 29.4, 29.2, 18.9, 17.6. HRMS (ESI) calcd
for C19H23NO3Na (M þ Na)þ 336.1576, found 336.1584.
Representative Procedure for a Copper(I)-Catalyzed Coupling.
(E)-1-(3-(3-(3,4-Dimethoxyphenyl)prop-2-ynyloxy)prop-1-enyl)pyr-
rolidin-2-one (10). A solution of 0.23 g of iodide, 0.058 mL of
2-pyrrolidinone (0.76 mmol), 0.018 g of copper(I) iodide (0.095
mmol), 0.027 g of N,N-dimethylglycine hydrochloride (0.19 mmol),
and 0.41 g of cesium carbonate (1.3 mmol) in 1.5 mL of dioxane was
prepared in a large test tube reaction flask in the absence of light.
The reaction mixture was heated to 80 °C for 45 h. The resulting
blue suspension was cooled to rt and filtered through a pipet of
triethylamine washed silica gel. The solution was concentrated to
afford a yellow oil. The crude oil was purified by column chroma-
tography on triethylamine washed silica gel (3:1 to 1:1 to 0:1
hexanes:ethyl acetate) to afford 0.16 g (82%) of the title compound
10 as a clear, pale yellow oil.
Isomerization of Alkene with Rhodium(III) Catalysis. A solu-
tion of 0.088 g of compound 22B (0.28 mmol), 7.4 mg of rhodium-
(III) chloride trihydrate (0.028 mmol), and 1 mL of ethanol was
stirred in a sealed tube at 100 °C for 16 h. The reaction mixture was
cooled to rt and directly purified by column chromatography on
triethylamine washed silica gel (1:1 to 1:3 hexanes:ethyl acetate) to
afford 0.047 g (53%) of the title compound 22A as a clear oil, along
with 0.020 g (31%) of the elimination product 5,7-dimethoxy-2,3-
dihydro-1H-cyclopenta[b]naphthalene (22D) as a off-white solid
(mp 85-88 °C).
IR (film): 2932, 1682, 821 cm-1. 1H NMR (400 MHz, CDCl3):
δ 6.38 (d, J = 1.7 Hz, 1H), 6.26 (d, J = 2.1 Hz, 1H), 5.66 (s, 1H),
3.83 (s, 3H), 3.78 (s, 3H), 2.78 (t, J = 7.0 Hz, 2H), 2.46 (t, J = 8.0
Hz, 2H), 2.36 (br s, 2H), 2.28-2.23 (m, 1H), 2.09-2.04 (m, 1H),
1.96-1.87 (m, 2H), 1.81-1..66 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ 175.6, 162.2, 156.2, 147.9, 142.1, 137.8, 119.1, 96.8,
95.4, 57.8, 55.7, 55.6, 42.9, 31.3, 23.4, 22.9, 22.6, 22.3, 18.2.
HRMS (ESI) calcd for C19H24NO3 (M þ H)þ 314.1756, found
314.1749.
IR (neat): 2937, 2247, 1702, 1662, 1514, 731 cm-1. 1H NMR (400
MHz, CDCl3):δ7.14 (d, J=14.3Hz,1H),7.03(d,J=8.2Hz,1H),
6.94 (s, 1H), 6.77 (d, J = 8.5 Hz, 1H), 5.04 (dt, J = 14.3, 7.0 Hz,
1H), 4.31 (s, 2H), 4.13 (d, J = 7.2 Hz, 2H), 3.84 (s, 6H), 3.50 (t, J =
5,7-Dimethoxy-2,3-dihydro-1H-cyclopenta[b]naphthalene
1
(22D): IR (film): 2956, 2843, 2252, 1615, 825 cm-1. H NMR
(400 MHz, CDCl3): δ 7.98 (s, 1H), 7.52 (s, 1H), 6.69 (d, J = 2.1
Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.03
(t, J=7.3 Hz, 4H), 2.13 (qt, J = 7.3 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 157.6, 156.5, 144.7, 140.6, 134.6, 121.1, 121.0,
116.5, 98.1, 96.9, 55.6, 55.4, 32.8, 32.7, 26.3. HRMS (ESI) calcd
for C15H17O2 (M þ H)þ 229.1229, found 229.1231
7.0 Hz, 2H), 2.45 (t, J = 8.2 Hz, 2H), 2.07 (qt, J = 7.6 Hz, 2H). 13
C
NMR (100 MHz, CDCl3): δ 173.5, 149.7, 148.7, 128.1, 125.2, 114.9,
114.7, 111.1, 106.7, 86.5, 83.7, 68.7, 57.6, 56.0, 55.9, 45.2, 31.3, 17.6.
HRMS (ESI) calcd for C18H21NO4Na (M þ Na)þ 338.1368, found
338.1364.
Representative Procedure for Cycloisomerization with Ph3PAuCl
and AgSbF6. 1-(6,8-Dimethoxy-1,2,3,4,9-pentahydro-4H-fluoren-9-yl)-
pyrrolidin-2-one (22A). A solution of 0.050 g of enamide 5 (0.16
mmol), 3.9 mg of [Ph3PAuCl] complex (0.0079 mmol), and 2.7 mg
of silver hexafluoroantimonate(V) (0.0079 mmol) in 0.75 mL of 1,2-
dichloroethane was stirred in a large test tube reaction flask at rt for
8.5 h. The reaction mixture was cooled to rt and directly purified by
column chromatography on triethylamine washed silica gel (1:1 to
1:3 hexanes:ethyl acetate) to afford 0.043 g (87%) of compound 22B
as a clear oil, along with 1.4 mg (4%) of elimination product
7-dimethoxy-2,3-dihydro-1H-cyclopenta[b]naphthalene (22D) as a
off-white solid.
Acknowledgment. The authors thank the University of
British Columbia, the Natural Science and Engineering
Research Council (NSERC) of Canada, and the Canada
Foundation for Innovation (CFI) for the financial support
of our programs. J.A.K. thanks NSERC for PGS M and
PGS D graduate fellowships.
Supporting Information Available: Experimental proce-
dures and characterization data for all previously unreported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
8590 J. Org. Chem. Vol. 75, No. 24, 2010