Bronsted acid-mediated nazarov cyclization of vinylallenes

Article abstract of DOI:10.1021/jo101112t

(Figure presented) Treatment of siloxy enynes with base leads to the corresponding vinylsiloxyallenes which undergo Nazarov cyclization in the presence of trifluoroacetic acid to provide the cyclized product as a mixture of regioisomers in moderate to goo

Full text of DOI:10.1021/jo101112t

pubs.acs.org/joc
SCHEME 1. Vinyl Allenes as Nazarov Precursors
Brønsted Acid-Mediated Nazarov Cyclization
of Vinylallenes
Yen-Ku Wu and F. G. West*
Department of Chemistry, University of Alberta,
E3-43 Gunning-Lemieux Chemistry Centre, Edmonton,
AB, Canada T6G 2G2
frederick.west@ualberta.ca
Received June 8, 2010
approaches.3f-j We envisioned another strategy, relying
on 3-oxygenated 1,2,4-trienes (vinyl allenes) as the pre-
cursors (Scheme 1).
The notion of activating a vinylallene via epoxidation has
been described previously4 and was recently applied using a
3-alkoxyvinylallene in an elegant and efficient synthesis of
(()-rocaglamide.5 Transition-metal-catalyzed methods have
also been reported.6 For example, Iwasawa (Pt(II))6a and
Toste (Au(I))6b have described cyclization of simple vinyl-
allenes, and Malacria and co-workers have also reported a
clever approach involving Au(I) activation of 3-acetoxy-
vinylallenes generated in situ from propargyl acetates.6c,d
We have sought to generalize the process of electrophilic
activation. In theory, addition of any electrophile would be
expected to occur at the allene central carbon to furnish directly
the desired pentadienyl intermediate A. Electrocyclization to
cyclopentenyl cation B and termination in the usual fashion
would then provide cyclopentenones, or alternatively, B could
be interecepted by a variety of traps in an “interrupted Nazarov”
reaction. Here, we describe the results of a preliminary study
using Brønsted acid activation, in which protonation of readily
prepared 3-silyloxyvinylallenes effects their conversion to
cyclopentenones under simple and mild conditions.
The proposed strategy required a reliable and efficient
method for preparation of the vinylallene substrates. We
settled on a straightforward approach employing base-
catalyzed isomerization7 of suitably protected allyl propargyl
alcohols 1, which should be readily available from acetylide
addition to enals (Table 1). In the event, a variety of unsatu-
rated aldehydes were subjected to 1,2-addition of lithium
acetylides to afford alcohols 1a-j in high yields. The alcohols
were then cleanly protected as triethylsilyl ethers8 2a-j by
Treatment of siloxy enynes with base leads to the corres-
ponding vinylsiloxyallenes which undergo Nazarov cycliza-
tion in the presence of trifluoroacetic acid to provide the
cyclized product as a mixture of regioisomers in moderate to
good overall yield.
The Nazarov reaction as conventionally practiced converts
cross-conjugated dienones into cyclopentenones with Brønsted
or Lewis acid activation.1 As a result of its unique mechanistic
features, the Nazarov reaction provides a versatile platform for
initiating domino processes;2 therefore, complex polycarbocycles
can be generated in an extremely efficient fashion. Recently,
there has been considerable interest in alternative precursors to
the key pentadienyl cation intermediate, potentially offering
access to unusual substitution patterns or milder conditions.3
Examples include allenyl vinyl ketones,3a,b R-diketones,3c
vinyldichlorocyclopropanes,3d cross-conjugated trienes,3e
and several transition-metal-catalyzed cycloisomerization
(1) For recent reviews, see: (a) Pellisier, H. Tetrahedron 2005, 61, 6479–
6517. (b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577–7606.
(c) Tius, M. A. Eur. J. Org. Chem. 2005, 2193–2206. (d) Nakanishi, W.; West,
F. G. Curr. Opin. Drug Discov. 2009, 12, 732–751.
(2) Recent examples: (a) Janka, M.; He, W.; Haedicke, I. E.; Fronczek,
F. R.; Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2006, 128, 5312–5313.
(b) Rostami, A.; Wang, Y.; Arif, A. M.; Mc Donald, R.; West, F. G. Org.
Lett. 2007, 9, 703–706. (c) Song, D.; Rostami, A.; West, F. G. J. Am. Chem.
Soc. 2007, 129, 12019–12022. (d) Rieder, C. J.; Fradette, R. J.; West, F. G.
Chem. Commun. 2008, 1572–1574. (e) Basak, A. K.; Tius, M. A. Org. Lett.
2008, 10, 4073–4076. For a recent review, see: (f) Grant, T. N.; Rieder, C. J.;
West, F. G. Chem. Commun. 2009, 5676–5688.
(4) (a) Doutheau, A.; Gore, J.; Malacria, M. Tetrahedron 1977, 33, 2393–
2398. (b) Corey, E. J.; Ritter, K.; Yus, M.; Majera, C. Tetrahedron Lett. 1987,
28, 3547–3550. (c) Hess, B. A. J.; Smentek, L.; Brash, A. R.; Cha, J. K. J. Am.
Chem. Soc. 1999, 121, 5603–5604.
(5) Malona, J. A.; Cariou, K.; Frontier, A. J. J. Am. Chem. Soc. 2009, 131,
7560–7561.
(3) (a) Banaag, A. R.; Tius, M. A. J. Org. Chem. 2008, 73, 8133–8141.
(b) Marx, V. M.; Cameron, T. S.; Burnell, D. J. Tetrahedron Lett. 2009, 50,
7213–7216. (c) Bow, W. F.; Basak, A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A.
Org. Lett. 2010, 12, 440–443. (d) Grant, T. N.; West, F. G. J. Am. Chem. Soc.
2006, 128, 9348–9349. (e) Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am.
Chem. Soc. 2009, 131, 7504–7505. (f) Lin, G.-Y.; Yang, C.-Y.; Liu, R.-S.
J. Org. Chem. 2007, 72, 6753–6757. (g) Sans, R.; Miguel, D.; Rodriguez, F.
Angew. Chem., Int. Ed. 2008, 47, 7354–7357. (h) Zhang, L.; Wang, S. J. Am.
Chem. Soc. 2006, 128, 1442–1443. (i) Nakanishi, Y.; Miki, K.; Ohe, K.
Tetrahedron 2007, 63, 12138–12148. (j) Abu Sohel, S. M.; Lin, S.-H.; Liu,
R.-S. Synlett 2008, 745–750.
(6) (a) Funami, H.; Kusama, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2007,
46, 909–911. (b) Lee, J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 912–
914. (c) Lemiere, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A.-L.;
Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207–2209. (d) Lemiere, G.;
Gandon, V.; Cariou, K.; Hours, A.; Fukuyama, T.; Dhimane, A.-L.; Fenster-
bank, L.; Malacria, M. J. Am. Chem. Soc. 2009, 131, 2993–3006.
(7) (a) Mantione, R.; Leroux, Y. Tetrahedron Lett. 1971, 12, 591–592.
(b) Tius, M. A.; Stergiades, I. A. J. Org. Chem. 1999, 64, 7547–7551.
(8) The corresponding triisopropylsilyl ethers could also be prepared in
high yields, but the subsequent isomerization step failed to go to completion
with the bulkier protecting group.
5410 J. Org. Chem. 2010, 75, 5410–5413
Published on Web 07/14/2010
DOI: 10.1021/jo101112t
r
2010 American Chemical Society

Wu and West
JOCNote
TABLE 1. Preparation of Siloxy Enynes 2a
SCHEME 3. Possible Pentadienyl Intermediates
Perchloric acid in CH3CN did furnish small amounts of the
desired cyclopentenone 5a, but the optimal conditions were
trifluoroacetic acid (TFA) in CH2Cl2, which afforded a
nearly 1:1 mixture of 5a and methylidenecyclopentanone
4a in near-quantitative yield.
The trans relative stereochemistry was tentatively assigned to
the product 4a on the basis of 2D NMR analysis of a reduced
derivative.12 Assuming the usual conrotatory electrocyclization
pathway, a trans relationship for the phenyl groups demands
the intermediacy of (E,E)-pentadienyl cation D (Scheme 3). We
presume initial protonation of the allenol silyl ether occurs from
the less hindered side, affording (E,Z)-pentadienyl cation C. If
this is the case, an isomerization from C to D must take place
prior to electrocyclization.13
aGeneral procedures for the two steps are given in the Experimental
Section. bAll yields reported are for isolated material after purification.
SCHEME 2. Nazarov Cyclization of 2a
In order to examine the scope of this process, the remain-
ing substrates 2b-j were then subjected to the standard
conditions optimized for 2a (Table 2). In the event, conver-
sion of enynes 2b-j to the regioisomeric cyclized products 4/
5 progressed swiftly with moderate to good overall yield
(Table 2). In general, the substrate scope was broad with
respect to the nature of substituent (R) attached to the alkyne
moiety (alkyl, vinyl, or phenyl group). For most acyclic
substrates (entries 1-7), the termination of the Nazarov
process by proton loss predominantly led to cyclopentenone
5, in contrast to the preferential formation of exocyclic ole-
fins 4 for six-membered cyclic precursors (entries 8 and 9). In
the case of 2j (entry 10), the remote olefin within the resulting
cyclized product isomerized under the acidic reaction con-
ditions to give fully conjugated dienone 7 along with trace
amount of hydrolyzed product 6j. Moreover, 6j was un-
reactive under the reaction conditions, indicating that the
dienone is not an intermediate in the cyclization process.14
The relatively low yields of cyclized products seen in the more
highly conjugated cases (entries 3, 6, and 10) are consistent
with the observations of Tantillo, Sarpong, and co-workers,
who found a pronounced reduction in cyclization efficiency
of aryl dienyl ketones lacking a substituent at the R position.15
treatment with Et3SiOTf at low temperature in the presence of
2,6-lutidine.
Substrate 2a was chosen to examine the feasibility of the
desired process (Scheme 2). First, isomerization of the enyne
to vinylallene 3a was explored9 and found to proceed
smoothly upon treatment with 1.5 equiv of KO-t-Bu at
-78 °C, followed by warming to room temperature.10 While
the desired vinylallene 3a was present as the principal
component of the crude reaction mixture, it decomposed
during attempted chromatographic purification. Therefore,
conditions to effect the Nazarov reaction were evaluated
with the unpurified 3a. A number of Brønsted acids com-
monly applied to the Nazarov cyclization were tested.11
Stronger mineral acids such as H3PO4 or HCl at room
temperature resulted in destruction of 3a or simple hydro-
lysis to give dienone 6a, as was also the case with AcOH.
(12) Compound 4a was reduced under Luche conditions to give the
corresponding allylic alcohol as a single diastereomer. See the Supporting
Information for the stereochemical assignment based on 2D TROESY NMR
data.
(13) Isomerization of (Z)-dienones during Nazarov cyclization under
Lewis acid conditions has been observed: (a) Denmark, S. E.; Wallace,
M. A.; Walker, C. B. J. Org. Chem. 1990, 55, 5543–5545. (b) Giese, S.; West,
F. G. Tetrahedron 2000, 56, 10221–10228. (c) He, W.; Sun, X.; Frontier, A. J.
J. Am. Chem. Soc. 2003, 125, 12478–12479.
(9) Yoshizawa, K.; Shioiri, T. Tetrahedron 2007, 63, 6259–6286.
(10) Use of catalytic amounts (10 mol %) of KO-t-Bu resulted in poor
conversion and unacceptably slow reactions.
(14) Dienone 6a did furnish minor amounts of 4a þ 5a (6a:4a/5a=9:1)
under the standard reaction conditions (TFA/rt/4 h).
(15) Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.; Sarpong, R.
Angew. Chem., Int. Ed. 2008, 47, 6379–6383.
(11) Lewis acids BF3 OEt2 and TiCl4 failed to furnish any Nazarov
3
product.
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Wu and West
SCHEME 4. Fragmentation of Bridged Bicyclic Substrates
JOCNote
TABLE 2. Isomerization and Cyclization of Enynes 2a
aGeneral procedures for the two steps are given in the Experimental
Section. bAll yields reported are for isolated material after purification.
It is notable that all cyclopentenone products 5were formed with
complete regioselectivity in favor of the more substituted alkene
isomer. Moreover, no evidence was seen of trapping of the
cyclopentenyl cation by trifluoroacetate, in contrast to the recent
report by Marx and Burnell.16 A possible explanation for this
difference is a longer lived cyclopentenyl cation intermediate in
those cases due to the greater conjugative stabilization.
We also examined two cases in which the pentadienyl system
would be part of a rigid, bridged bicyclic system. Related
dienone systems had shown significant levels of diastereo-
selectivity in either silyl-directed Nazarov cyclizations17 or
halide-trapping processes.18 Enynes 2k and 2l were readily
prepared from (-)-myrtenal (8) via the usual protocol
(Scheme 4). In the event, when 2k was subjected to the typical
conditions, the normal cyclized product was not observed.
Instead, hydrindenone 9k was obtained in moderate yield as
a single diastereomer, with the relative configuration assigned
based upon the indicated TROESY correlations. Likewise,
substrate 2l also furnished hydrindenone 9l, albeit less effi-
ciently, along with greater amounts of compound 5l arising
from usual eliminative termination.
Products 9k,l are presumed to result from bond cleavage
of the strained cyclobutylcarbinyl cation G formed after
electrocyclization. The resulting isolated tertiary cation
would then undergo capture by trifluoroacetate.19 As with
the simpler monocyclic product 4a, the relative stereochem-
istry at the two centers in 9 derived from the former termini of
the pentadienyl indicates an isomerization of the initially
formed (E,Z)-isomer to the (E,E) isomer prior to cylization.
Surprisingly, the relationship between the tertiary trifluoro-
acetate side chain and the bridgehead proton indicates that
cyclization of this cation occurs from the same face as the
geminal dimethyl bridge. The exclusive counterclockwise
torquoselectivity of the electrocyclization from that face is
presumably preferred over the alternate clockwise rotation,
as the latter would move the phenyl substituent into steric
conflict with the hindered quaternary carbon of the bridge.
We have found that silyl-protected allyl propargyl alco-
hols can serve as convenient substrates for Nazarov cycliza-
tion, via sequential base-catalyzed isomerization to siloxy
vinyl allenes, followed by mild activation with trifluoracetic
acid. The modular nature of the substrate synthesis allows
for substantial diversity in substitution. Notably, two cases
possessing remote stereocenters displayed high levels of
diastereoselectivity, as well as an intriguing fragmentation/
trapping pathway. Other approaches for electrophilic acti-
vation of vinyl allenes, and methods for intercepting the
cyclized intermediate, are under current investigation and
will be described in due course.
Experimental Section
Representative Acetylide Addition Procedure: (E)-2-Methyl-
1,5-diphenylpent-1-en-4-yn-3-ol (1a). To a flame-dried round-
bottom flask containing a magnetic stirring bar were added phenyl-
acetylene (3.98 mmol, 406 mg) and ether (8 mL) under Ar. The
temperature of the solution was dropped to -78 °C. n-BuLi (1.60 M
solution in hexane, 3.98 mmol, 2.48 mL) was added dropwise, and
the reaction mixture was stirred at the same temperature for 30 min.
The R-methyl-trans-cinnamaldehyde (3.98 mmol, 581 mg) was
(16) Marx, V. M.; Burnell, D. J. Org. Lett. 2009, 11, 1229–1231.
(17) Mazzola, R. D., Jr.; White, T. D.; Vollmer-Snarr, H. R.; West, F. G.
Org. Lett. 2005, 7, 2799–2801.
(18) White, T. D.; West, F. G. Tetrahedron Lett. 2005, 46, 5629–5632.
(19) Analogous halide trapping of a fragmented intermediate was ob-
served in the TiX4-mediated Nazarov cyclization of myrtenal-derived di-
enones (see ref 18).
5412 J. Org. Chem. Vol. 75, No. 15, 2010

Wu and West
JOCNote
added, and the resulting solution was allowed to warm to room
temperature. The reaction was quenched with saturated aqueous
NH4Cl and diluted with ether. The separated organic layer was
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated to provide pure compound 1a (850 mg, yield 86%):
Rf 0.28 (hexane/EtOAc 4:1); IR (film) 3341 (br), 3081, 3056, 3024,
2981, 2917, 2859, 2201, 1664, 1598, 1573, 1489, 1442, 1381, 1361,
1281, 1070, 1008, 998, 756, 691 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.52-7.50 (m, 2H), 7.39-7.30 (m, 7H), 7.29-7.27 (m, 1H), 6.81
cooling bath. Upon consumption of 2a as determined by thin-
layer chromatography, the reaction was quenched with 15%
aqueous NH4Cl and diluted with ether. The separated organic
layer was washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated to give the crude siloxyallene 3a which
was used for the next step without further purification. The
unpurified 3a thus obtained was dissolved in CH2Cl2 (2 mL)
and treated with trifluoroacetic acid (3.0 equiv based on 2a,
0.13 mmol, 10 μL) at room temperature. After the mixture
was stirred for 4 h, the reaction was quenched with saturated
aqueous NaHCO3 and diluted with CH2Cl2. The separated
organic layer was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated. The crude mixture was
purified by flash column chromatography (silica gel, 10%
EtOAc/hexane) to provide the desired products 4a (5.6 mg,
yield 51%) and 5a (5.1 mg, yield 47%). 4a: Rf 0.61 (hexane/
EtOAc 4:1); IR (film) 3085, 3061, 3028, 2925, 2854, 1718, 1601,
(s, 1H), 5.20 (s, 1H), 2.31 (br s, 1H), 2.11 (d, J=1.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 137.0, 136.7, 131.7, 129.0, 128.5, 128.2,
128.1, 127.2, 126.7, 122.4, 88.0, 86.3, 68.7, 14.1; HRMS (EI, Mþ) for
C18H16O calcd 248.1201, found:m/z 248.1196.
Representative Silyl Protection: ((E)-2-Methyl-1,5-diphenyl-
pent-1-en-4-yn-3-yloxy)triethylsilane (2a). To a flame-dried
round-bottom flask containing a magnetic stirring bar were
sequentially added hydroxyenyne 1a (1.06 mmol, 264 mg),
CH2Cl2 (5 mL), and 2,6-lutidine (3.18 mmol, 0.37 mL) under
Ar. The temperature of the solution was dropped to -78 °C.
Triethylsilyl trifluoromethanesulfonate (1.59 mmol, 0.36 mL)
was added dropwise, and the resulting solution was stirred at the
same temperature for 30 min. The reaction mixture was
quenched with H2O and diluted with CH2Cl2. The separated
organic layer was washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated. The crude mixture thus
obtained was purified by flash column chromatography (silica
gel, 2% EtOAc/hexane) to give pure siloxyenyne 2a (369 mg,
yield 96%): Rf 0.80 (hexane/EtOAc 4:1); IR (film) 3081, 3060,
3026, 2956, 2912, 2876, 2203, 1691, 1665, 1490, 1450, 1238, 1060,
1003, 754, 690 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53-7.50
(m, 2H), 7.43-7.35 (m, 7H), 7.29-7.27 (m, 1H), 6.80 (br s, 1H),
5.21 (s, 1H), 2.11 (d, J = 1.2 Hz, 3H), 1.16-1.06 (m, 9H),
0.86-0.80 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 137.5,
137.5, 131.6, 129.0, 128.2, 128.0, 126.5, 125.7, 123.0, 89.2,
85.0, 68.7, 14.1, 6.8, 4.9 (one sp2 carbon signal is missing due
to peak overlap); HRMS (EI, Mþ) for C24H30OSi calcd
362.2066, found: m/z 362.2063.
1
1495, 1453, 1119, 1075, 785, 698 cm-1; H NMR (400 MHz,
CDCl3) δ 7.29-7.17 (m, 6H), 7.12-7.07 (m, 4H), 6.22 (dd, J =
3.3, 0.9 Hz, 1H), 5.04 (dd, J = 3.0, 0.8 Hz, 1H), 3.96 (ddd, J =
10.6, 3.0, 3.0 Hz, 1H), 3.41 (ddd, J = 11.2, 11.2, 7.2 Hz, 1H), 2.91
(ddd, J = 18.2, 7.6, 0.8 Hz, 1H), 2.71 (dd, J = 18.0, 12.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 204.7, 149.6, 141.1, 140.9,
128.9, 128.8, 128.8, 127.4, 127.3, 127.2, 120.0, 56.7, 48.9, 45.8;
HRMS (EI, Mþ) for C18H16O calcd 248.1201, found m/z
248.1201. 5a: Rf 0.50 (hexane/EtOAc 4:1); IR (film) 3060,
3027, 2923, 2853, 1698, 1624,1495, 1454, 1443, 1378, 1342,
1076, 761, 698 cm-1
;
1H NMR (400 MHz, CDCl3) δ
7.27-7.02 (m, 10H), 4.43 (ddq, J = 7.1, 2.0, 2.0 Hz, 1H), 3.05
(dd, J = 19.0, 7.2 Hz, 1H), 2.44 (dd, J = 19.0, 2.2 Hz, 1H), 1.97
(d, J=2.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.9, 169.1,
142.4, 137.7, 135.3, 128.9, 128.7, 128.3, 128.0, 127.3, 126.7, 47.1,
45.1, 9.9; HRMS (EI, Mþ) for C18H16O calcd 248.1201, found
m/z 248.1198.
Acknowledgment. We thank NSERC for support of this
work, and Y.K.W. gratefully thanks the Alberta Ingenuity
Foundation for a PhD graduate scholarship.
Representative Alkyne-Allene Isomerization and Nazarov
Cyclization: 2-Methylene-3,4-diphenylcyclopentanone (4a) and
2-Methyl-3,4-diphenylcyclopent-2-enone (5a). To a flame-dried
round-bottom flask containing a magnetic stirring bar were
added siloxy enyne 2a (0.044 mmol, 16 mg) and ether (4 mL)
under Ar. The temperature of the solution was dropped to
-78 °C (acetone/dry ice bath). KO-t-Bu (0.07 mmol, 7 mg)
was added in one portion, and the resulting suspension was
stirred vigorously followed by the immediate removal of the
Supporting Information Available: Characterization data
for 1b-l, 2b-l, 4d,g-i, 5b-i,l, 6j, 7, and 9k,l, stereochemical
assignment of 4a via reduction and derivatization, and copies of
NMR spectra for all products and synthetic intermediates. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5413