Indium(III)-catalyzed hydrative cyclization of 1,7-diynyl ethers

Article abstract of DOI:10.1021/ol201624b

A new hydrative cyclization of 1,7- and 1,8-diynyl ethers is reported. Using catalytic InI₃ and p-TSA as a cocatalyst, several 2,2-disubstituted tetrahydrofurans with exocyclic enone appendages were prepared. Reaction optimization and scope, me

Full text of DOI:10.1021/ol201624b

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4280–4283
Indium(III)-Catalyzed Hydrative
Cyclization of 1,7-Diynyl Ethers
Amanda L. Gibeau and John K. Snyder*
Department of Chemistry and the Center for Chemical Methodology and Library
Development (CMLD-BU), Boston University, Boston, Massachusetts 02215,
United States
jsnyder@bu.edu
Received June 16, 2011
ABSTRACT
A new hydrative cyclization of 1,7- and 1,8-diynyl ethers is reported. Using catalytic InI3 and p-TSA as a cocatalyst, several 2,2-disubstituted
tetrahydrofurans with exocyclic enone appendages were prepared. Reaction optimization and scope, mechanistic insight, and further
transformation to a C-nucleoside analog are presented.
The preparation of functionalized cyclic structures from
simple acyclic precursors is of great value to the organic
chemist, since many biologically active compounds con-
tain carbo- and heterocyclic ring systems.1 One class of
substrates which has received attention is the nonconju-
gated 1,n-dialkynes.2ꢀ9 There are several reports of these
substrates being utilized in metal-catalyzed inter- and
intramolecular [2 þ 2 þ 2] cyclizations with a third 2π
component to produce six-membered rings.3 We have
reported the synthesis of fully substituted benzene rings4a
and tetrahydronaphthyridines4b,c in this manner. Danhei-
ser and co-workers have recently shown that without metal
catalysis and in the presence of a dienophile, 1,6-diynes can
undergo a tandem ene-[4 þ 2] cycloaddition sequence to
give cyclic systems bearing an exocyclic alkene.5 Simple
1,6-diynyl systems have also been shown to cyclize in the
absence of a third 2π partner using transition metal or
Lewis acid catalyzed processes.6 One recent example in-
volves the hydrative cyclization of 1,6-diynes to cyclohex-
enones using Au(I) catalysis.7,8
We became interested in the reactivity of tethered 1,7-
dialkynyl systems, which have received less attention in
the literature,9 with the hope that these substrates could
produce synthetically useful seven-membered rings. Upon
reaction of 1,7-diynyl ether 1a with stoichiometric InBr3
and p-TSA (0.5 equiv), an unexpected five-membered
(1) Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson,
D. H.; Savin, K. A.; Durst, G. L.; Hipskind, P. A. J. Med. Chem. 2004,
47, 224.
(2) For relevant examples, see: (a) Singidi, R. R.; Kutney, A. M.;
Galluci, J. C.; RajanBabu, T. V. J. Am. Chem. Soc. 2010, 132, 13078.
(b) Sohel, S. M. A.; Liu, R.-S. Chem. Soc. Rev. 2009, 38, 2269.
(3) For recent reviews of [2 þ 2 þ 2] cyclizations, see: (a) Varela, J. A.;
ꢀ
Saa, C. Synlett 2008, 2571. (b) Shibata, T.; Tsuchikama, K. Org. Biomol.
Chem. 2008, 6, 1317. (c) Chopade, P. R.; Louie, J. Adv. Synth. Catal.
2006, 348, 2307. (d) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org.
Chem. 2005, 4741.
(4) (a) Jones, A. L.; Snyder, J. K. J. Org. Chem. 2009, 74, 2907.
(b) Zhou, Y.; Beeler, A. B.; Cho, S.; Wang, Y.; Franzblau, S. G.; Snyder,
J. K. J. Comb. Chem. 2008, 10, 534. (c) Zhou, Y.; Porco, J. A., Jr.;
Snyder, J. K. Org. Lett. 2007, 9, 393.
(5) Robinson, J. M.; Sakai, T.; Okano, K.; Kitawaki, T.; Danheiser,
R. L. J. Am. Chem. Soc. 2010, 132, 11039.
(6) (a) Seo, S. Y.; Marks, T. J. Chem.;Eur. J. 2010, 16, 5148. (b) Yao,
L.-F.; Shi, M. Chem.;Eur. J. 2009, 15, 3875. (c) Trost, B. M.; Rudd,
M. T.; Costa, M. G.; Lee, P. I.; Pomerantz, A. E. Org. Lett. 2004, 6, 4235.
(d) Wang, X.; Chakrapani, H.; Madine, J. W.; Keyerleber, M. A.;
Widenhoefer, R. A. J. Org. Chem. 2002, 67, 2778.
(7) Zhang, C.; Cui, D.-M.; Yao, L.-Y.; Wang., B.-S.; Hu, Y.-Z.;
Hayashi, T. J. Org. Chem. 2008, 73, 7811.
(8) For other recent examples of Au-catalyzed reactions of diynes,
see: (a) Sperger, C.; Strand, L. H. S.; Fiksdahl, A. Tetrahedron 2010, 66,
7749. (b) Lian, J.-J.; Liu, R.-S. Chem. Commun. 2007, 1337. For a recent
review of Au- and Ag-catalyzed cycloisomerizations, see: (c) Belmont,
P.; Parker, E. Eur. J. Org. Chem. 2009, 6075.
(9) (a) Wender, P. A.; Christy, J. P. J. Am. Chem. Soc. 2007, 129,
13402. (b) Tanaka, K.; Otake, Y.; Hirano, M. Org. Lett. 2007, 9, 3953.
(c) Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 6478.
(10) (a) Phuwapraisirisan, P.; Surapinit, S.; Sombund, S.; Siripong,
P.; Tip-pyang, S. Tetrahedron Lett. 2006, 47, 3685. (b) Humphries, P. S.;
Almaden, J. V.; Barnum, S. J.; Carlson, T. J.; Do, Q.-Q. T.; Fraser, J. D.;
Hess, M.; Kim, Y. H.; Ogilvie, K. M.; Sun, S. Bioorg. Med. Chem. Lett.
2006, 16, 6116. (c) Inui, T.; Wang, Y.; Nikolic, D.; Smith, D. C.;
Franzblau, S. G.; Pauli, G. F. J. Nat. Prod. 2010, 73, 563.
r
10.1021/ol201624b
Published on Web 07/15/2011
2011 American Chemical Society

product, 2,2-disubstituted THF 2a, was produced in a
modest 37% yield (Table 1, entry 1). Substituted THF
rings are present in several bioactive molecules,10 and the
potential for further transformations of the enone function-
ality appended to the THF ring intrigued us to pursue this
chemistry. Furthermore, In(III) has shown potential as a π-
Lewis acid,11 and so additional screening with other
counterions was performed to see if the yield of 2a could
be improved. Using InI3 (entry 2), 53% of 2a was
isolated, while, with In(OTf)3 (entry 3), lower reactivity
was observed even after a prolonged reaction time. In the
absence of a protic acid, the reaction proceeded more
slowly and gave less product (entry 4). Any attempt to heat
the reaction mixture resulted in a lower yield and greater
amounts of decomposition (entry 5), and no reaction was
observed in the absence of indium (entry 6). Attempts to
4ꢀ8), the reaction had 90% conversion of the starting
dialkyne in 20 h, and the isolated yield could be increased
to 49% by reducing the amount of p-TSA to 0.05 equiv
(entry 7). Further reduction of the amount of metal to 0.1
equiv (entry 9) gave a comparable yield but required nearly
3 days to achieve useful conversion. In all trials, the modest
yields were attributed to the recovery of small amounts of
1b in addition to the formation of unidentified byproducts.
Table 2. Optimization of the Reaction Conditions
7
perform the hydrative cyclization of 1a with MeAuPPh3
resulted only in uncyclized alkyne monohydration or ether
cleavage products.12
InI3
p-TSA
H2O
product
(% yield)a
entry
substrate
(equiv)
(equiv)
(equiv)
1b
2
1b
1c
1b
1b
1b
1b
1b
1b
1b
1.0
1.0
0.5
0.2
0.2
0.2
0.2
0.2
0.1
0.5
0.5
2b (9)c
N/A (0)
2b (41)
2b (15)
2b (34)
2b (38)
2b (49)
2b (14)
2b (46)
Table 1. Initial Optimization Studies with In(III)
0.5
0.5
3
0.25
0.5
0.75
0.5
4
5
0.2
0.8
6
0.1
0.9
7
0.05
0.01
0.05
0.95
0.99
0.95
8
9d
entry
X
time (h)
yield (%)a
a Isolated yield. b 1 h reaction time. c Significant decomposition. d 70
h reaction time.
1
Br
4
4
37
53
28
38
13d
0
2
I
3
OTf
24
22
5
4b
5c
6
I
The scope of the hydrative cyclization with the opti-
mized reaction conditions was investigated with a variety
of dialkynes bearing electron-rich aryl rings, leading to
the isolation of several 2,2-disubstituted THF derivatives
(Table 3). A donating group in the meta position of the aryl
ring resulted in significantly decreased levels of reactivity
(entries 4 and 5), while addition of a second methoxy group
in the ortho position gave many unidentified decomposi-
tion products with only 14% yield of the desired 2e (entry 6).
The 3,4,5-trimethoxy-bearing substrate 1h gave the highest
yield of cyclized product (61%, entry 9), with only a slightly
increased yield (66%) obtained after an additional 24 h of
reaction time (entry 10). An n-pentyl chain was also tolerated
in place of the methyl terminus (entry 11), while terminal
alkyne 1j (entry 12) and diyne 1k, with Me-capped internal
alkynes (entry 13), were unreactive.
Upon lengthening of the homopropargylic side chain to a
1,8-diynyl ether, the hydrative cyclization also proceeded
readily (Scheme 1). Although it was anticipated that the
additional methylene unit would result in a six-membered
ring, interestingly only the THF products were isolated.
For methyl-terminated 1,8-diynyl ether 1l, tetrahydrofuran
2l, which has an angular ethyl group, was produced in
33% yield along with small amounts of other unidenti-
fied products. Furthermore, terminal 1,8-diynyl ether
1m underwent cyclization, again providing access to 2h,
in 58% yield.
I
N/Ae
4
a Isolated yield. b H2O (1.0 equiv), no p-TSA . c 40 °C. d Significant
decomposition. e No metal used.
Two 1,7-diynes with substituents on the propargylic aryl
ringweresubjectedtothe reaction conditions toinvestigate
the electronic effects on the cyclization (Table 2). Substrate
1b, which has an electron-donating group on the aryl ring,
underwent complete conversion within 1 h to yield small
amounts of 2b (9%, entry 1) as well as significant decom-
position, while electron-deficient substrate 1c produced no
cyclized product (entry 2). Due to the high reactivity of
electron-rich diyne 1b, this substrate was chosen for addi-
tional optimization in an attempt to decrease the metal
loading and determine the optimal amount of acid coca-
talyst. By decreasing the amount of InI3 from 1.0 to 0.5
equiv (entry 3), the yield of 2b was increased 4-fold to 41%.
When the catalyst loading was reduced to0.2 equiv (entries
(11) (a) Montaignac, B.; Vitale, M. R.; Ratovelomanana-Vidal, V.;
Michelet, V. J. Org. Chem. 2010, 75, 8322. (b) Tsuji, H.; Tanaka, I.;
Yamagata, K.; Nakamura, M.; Nakamura, E. Org. Lett. 2009, 11, 1845.
(c) Itoh, Y.; Tsuji, H.; Yamagata, K.; Endo, K.; Tanaka, I.; Nakamura,
M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 17161. (d) Yanada, R.;
Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2006, 45,
3822.
(12) See Supporting Information for experimental details.
Org. Lett., Vol. 13, No. 16, 2011
4281

products 2. After hydration, the 7-exo-dig-derived inter-
mediate III can rejoin this pathway through either isomer-
ization to an endocyclic alkene or protonation following
the elimination to the enone. Alternatively, in pathway B,
an In(III)-assisted hydration of the aryl-terminated alkyne
gives hydrated alkyne VIII, which can react through the
enol tautomer IX via an intramolecular 7-endo-dig closure
onto the second alkyne. Zhang has shown that unactivated
alkynesundergo hydrativecyclization using π-Lewisacidic
metal catalysis,7 so this aryl ketone pathway must be
considered.
Table 3. Scope of the Hydrative Cyclizationa
Scheme 2. Proposed Mechanistic Pathways
a See Supporting Information for specific reaction times. b Isolated
yield. c 48 h reaction time. d InI3 (1.0 equiv), p-TSA.H2O (0.5 equiv) used.
e Significant decomposition.
Scheme 1. Hydrative Cyclizations of 1,8-Diynyl Ethers
To test the mechanistic hypothesis involving initial
alkyne hydration (pathway B), monoalkyne 5, a putative
intermediate on this pathway, was prepared via an oxy-
Michael addition13 of commercial 3-pentyn-1-ol with en-
one 414 (Scheme 3). However, when 5 was subjected to the
In(III)-catalyzed hydrative cyclization, no reaction to 2a
was observed. This lack of reactivity disproves pathway B.
After observing the requirements necessary for success-
ful cyclization, we envisioned two mechanistic possibilities
(Scheme 2). The first (pathway A) begins with activation of
the homopropargylic alkyne through an indium chela-
tion11c with the ether oxygen, which promotes the initial
7-endo-dig cyclization with the required nucleophilic aryl
alkyne. With the 1,8-diynes1l and 1m (n = 2), initial 7-exo-
dig closure would furnish vinyl carbocation III (inset).
Subsequent trapping of II by water generates enol IV,
which can undergo elimination to generate acyclic cross-
conjugated dienone V. Protonation of V yields tertiary
carbocation VI, and then ring closure gives the THF
Scheme 3. Initial Mechanistic Study
PathwayA (Scheme2) accounts forseveral experimental
observations. First, the propargylic substituent must be
electron-rich in order for the reaction to proceed. In
particular, sufficient nucleophilicity would be required to
4282
Org. Lett., Vol. 13, No. 16, 2011

promote the initial ring closure, stabilize vinyl carbocation
II, and may also assist in the elimination to enone V. The
absence of a sufficiently electron-rich propargylic group
explains the inability of 1,7-diynyl ethers 1c (Table 2) and 1j
and 1k (Table 3) to produce THF products. Additionally,
the failure of dialkynyl amides 6 and 7 (Figure 1) to give
cyclized products may be due to either inability to eliminate
the amide group to the acyclic intermediate analogous to V
or inability to form the appropriate In(III) chelate complex
analogous to I in the first place.
Suzuki coupling,16 giving exocyclic alkene 10 in 36% over
2 steps. Presumably, angle strain prohibits formation of
the initial In(III) complex with the ether oxygen and one of
the alkyne units of 8, leading to the alternative reaction
pathway.
The 2,2-disubstituted tetrahydrofuran products 2 with
the enone substituent are intriguing substrates for scaffold
postmodifications in library synthesis. Attempts to use the
parent enone 2a in reactions with traditional condensation
partners such as urea and hydrazine failed, so preparation
of the R-keto epoxide as a handle for reactivity was
considered (Scheme 5). Treatment of racemic 2a with
excess t-BuOOH led to the isolation of separable diaster-
eomeric epoxides 11a and 11b in a 4:1 ratio (eq 1).17 The
major isomer was further subjected to a condensation with
excess hydrazine18 followed by aromatization under acidic
conditions19 and tosylation to produce pyrazole 12 in 53%
yield over 3 steps (eq 2). This structural motif mimics a
C-nucleoside, which typically are potent antiviral agents.20
Figure 1. Unsuccessful N-tethered cyclization substrates.
After observing the formation of THF products 2 from
1,7- and 1,8-diynyl ethers, the reactivity of dipropargyl
ethers in this hydrative cyclization was examined. Inter-
estingly, when 1,6-diyne 8 was subjected to stoichiometric
InBr3, a new product, vinyl bromide 9, was isolated as a
mixture of stereoisomers by NMR (12:1, Scheme 4).15
Scheme 5. Postmodifications of THF Products
Scheme 4. Hydrobromination of 1,6-Diynyl Ether 8
In conclusion, a novel hydrative cyclization of 1,7- and
1,8-dialkynyl ethers was achieved using InI3 and p-TSA
cocatalysis. The resulting 2,2-disubstituted THF systems
contain an exocyclic enone, and the highest yields were
obtained for substrates bearing propargylic termini with
nucleophilic aryl groups. Current work is focused on
additional optimization, a more extensive mechanistic
study, and investigation of an enantioselective variant.
Since 9 was unstable after storage at ambient conditions,
the crude product was subjected to a TlOEt-promoted
(13) Tofi, M.; Koltsida, K.; Vassilikogiannakis, G. Org. Lett. 2009,
11, 313.
(14) Bartoszewicz, A.; Livendahl, M.; Martin-Matute, B. Chem.;
Eur. J. 2008, 14, 10547.
(15) Reaction of 8 with InI3 (0.2 equiv), p-TSA (0.05 equiv), and H2O
(0.95 equiv) gave a 20% NMR yield of the vinyl iodide.
(16) Frank, S. A; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.;
Roush, W. R. Org. Lett. 2000, 2, 2691.
Acknowledgment. We thank the NIGMS CMLD in-
itiative (P50 GM067041) for financial support and NSF
for supporting the purchase of the NMR (CHE
0619339) and HRMS (CHE 0443618) spectrometers.
A.L.G. thanks the Henry Luce Foundation for a Clare
Boothe Luce graduate fellowship and Kenneth Moy
(Boston University) for assistance in preparation of the
starting materials.
(17) Nicolaou, K. C.; Becker, J.; Lim, Y. H.; Lemire, A.; Neubauer,
T.; Montero, A. J. Am. Chem. Soc. 2009, 131, 14812.
(18) Lange, J. H. M.; Coolen, H. A. K. C.; van Stuivenberg, H. H.;
Dijksman, J. A. R.; Herremans, A. H. J.; Ronken, E.; Keizer, H. G.;
Tipker, K.; McCreary, A. C.; Veerman, W.; Wals, H. C.; Stork, B.;
Verveer, P. C.; den Hartog, A. P.; de Jong, N. M. J.; Adolfs, T. J. P.;
Hoogendoorn, J.; Kruse, C. G. J. Med. Chem. 2004, 47, 627.
(19) Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel,
M.; Qazi, G. N. Bioorg. Med. Chem. Lett. 2005, 15, 3177.
Supporting Information Available. Full experimental
procedures, characterization data, and copies of 1H and
13C spectra of 1aꢀi,l,m, 2a,b,dꢀi,l, 5, 8, 10, 11aꢀb, 12.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ꢁ
ꢀ
(20) For a recent review of C-nucleosides, see: Stambasky, J.; Hocek,
ꢁ
ꢀ
M.; Kocovsky, P. Chem. Rev. 2009, 109, 6729.
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