Ambient schmittel cyclization promoted by chemoselective triazole-gold catalyst

Article abstract of DOI:10.1021/ol300227a

The Schmittel cyclization was achieved at room temperature through triazole-gold (TA-Au) catalyzed propargyl vinyl ether rearrangement. Other tested [L-Au]⁺ catalysts gave complex reaction mixtures under identical conditions with no desired pro

Full text of DOI:10.1021/ol300227a

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1334–1337
Ambient Schmittel Cyclization Promoted
by Chemoselective Triazole-Gold Catalyst
Qiaoyi Wang, Siddhita Aparaj, Novruz G. Akhmedov, Jeffrey L. Petersen, and
Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown,
West Virginia 26506, United States
Xiaodong.Shi@mail.wvu.edu
Received January 27, 2012
ABSTRACT
The Schmittel cyclization was achieved at room temperature through triazoleꢀgold (TAꢀAu) catalyzed propargyl vinyl ether rearrangement.
Other tested [LꢀAu]þ catalysts gave complex reaction mixtures under identical conditions with no desired products observed. Importantly,
because of the employment of mild conditions, sterically hindered groups (such as t-Bu) on allene termini were no longer required, which allowed
successful synthesis of previously challenging substrates.
Over the past several decades, the thermal cyclo-
aromatizations of enediyne (Bergman and Pascal)1 and
enyneꢀallene (Myers-Saito and Schmittel)2 have attracted
considerable attention due to their fundamentally intri-
guing mechanisms and the crucial biological applications.3
Experimental and computational mechanistic investigations
suggested that these transformations proceed via diradical
intermediates.4 Two different cyclization paths have been
disclosed for the enyne-allene systems (Scheme 1): C2ꢀC7
and C2ꢀC6 cyclizations.
For the enyneꢀallene system, the formation of aroma-
ticity provides the driving force for the Myers-Saito
(C2ꢀC7) cyclization. The Schmittel (C2ꢀC6) path is also
energetically favored due to the carbon hybridization
conversion from sp to sp2. However, the C2ꢀC7 cycliza-
tionis generally preferredand appropriate substitutions on
alkyne termini are usually required for altering the regios-
electivity to C2ꢀC6 cyclization.5 Nevertheless, the ability
to construct 5-membered ring makes the Schmittel cycliza-
tion an interesting strategy for complex poly aromatic
structure construction.
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r
10.1021/ol300227a
Published on Web 02/22/2012
2012 American Chemical Society

First, the reaction conditions required high temperature
and the overall efficiency was low. Second, the sterically
hindered group was required to drive the equilibrium to
conformer B for effective aromatic cyclization, thereby
limiting the reaction scope. Herein, we report the triazoleꢀ
gold (TAꢀAu, 3 mol %) catalyzed propargyl vinyl ether
cascade rearrangement and cyclization to form the desired
benzannulated indenes at room temperature. The key
aspects for this work are: (a) the use of TAꢀAu catalysts
offered excellent chemoselectivity for selective formation
of allene intermediates with no further activation; (b) the
ability to form the highly reactive enyneꢀallene intermedi-
ates under mild conditions, allowing effective diradical
cyclization without the assistance from bulky substituted
group. As a result, the previously challenging non-tert-
butyl substituted enyneꢀallenes Schmittel cyclization
(Scheme 3) was successfully achieved for the first time.
Scheme 1. The Myers-Saito and the Schmittel Cyclizations
recently independently reported by Schmittel6 and Wang7
(Scheme 2).
Scheme 2. Enyne-Allene Cascade Cyclization
Scheme 3. The Challenging Non-tert-butyl Substrates
As shown in Scheme 3, the identical thermal conditions
did not work for phenyl-substituted alkyne 2a and 2b even
though they were derivatives of compounds shown in
Scheme 2B. This was caused either by the difficulty in
1,3-H-shift for the synthesis of allene (2a) or by the rapid
decomposition of the diradical. Considering that the prop-
er conformation of diradical intermediate C was required
for the cyclization between phenyl and vinyl radical and
the harsh conditions likely caused the decomposition prior
to the conformation equilibrium. We postulated that the
Schmittel cyclization of these challenging substrates might
be achieved by conducting the reaction under milder
conditions (such as room temperature) to avoid the dir-
adical decomposition. The key is then to identify strategies
that allow effective synthesis of enyneꢀallene under mild
conditions.
Because the thermal cyclizations require high tempera-
ture, efforts have been aimed at conducting diradical cycli-
zation under milder conditions. In 2005, Schmittel reported
the photochemical enyneꢀallene C2ꢀC6 cyclization6
(Scheme 2A). Cyclization products 1a and 1b were obtained
in modest yields (15%) with poor selectivity (1:1). It was
expected that the diradical conformers A and B were under
equilibrium (A as the energetically favored conformer with
minimized steric repulsion). To obtain the sequential cycli-
zation product 1a, Wang and co-workers reported an alter-
native thermal strategy7 (Scheme 2B), which used a bulky
tert-butyl group to push the diradical equilibrium toward B
conformer. Compound 1c was then successfully obtained
with improved yields. Later, Wang and co-workers demon-
strated the synthetic utility of this method for the prepara-
tion of heteroaromatic and polyaromatic structures.8
In the past several years, our group has been working on
the application of 1,2,3-triazoles as ligands in adjusting
transition metal catalyst reactivity.9 Several new 1,2,3-
triazole coordinated metal catalysts/reagents have been
(9) (a) Wang, D.; Zhang, Y.; Harris, A.; Gautam, L. N. S.; Shi, X.
Adv. Syn. Catal. 2011, 353, 2584–2588. (b) Wang, D.; Zhang, Y.; Cai, R.;
Shi, X.; Beilstein J. Org. Chem. 2011, 7, 1014–1020. (c) Wang, D.;
Gautam, L. N. S.; Bollinger, C.; Harris, A.; Li, M.; Shi, X. Org. Lett.
2011, 13, 2618–2621. (d) Duan, H.; Sengupta, S.; Petersen, J. L.;
Akhmedov, N.; Shi, X. J. Am. Chem. Soc. 2009, 131, 12100–12102. (e)
Duan, H.; Yan, W.; Sengupta, S.; Shi, X. Bioorg. Med. Chem. Lett. 2009,
3899–3902.
While the C2ꢀC6 cyclization was mechanistically inter-
esting and synthetically inspiring, there were limitations.
(8) (a) Wen, B.; Petersen, J. L.; Wang, K. K. Chem. Commun. 2010,
46, 1938–1940. (b) Cui, H.; Akhmedov, N. G.; Petersen, J. L.; Wang,
K. K. J. Org. Chem. 2010, 75, 2050–2056.
Org. Lett., Vol. 14, No. 5, 2012
1335

recently discovered.10 One particularly interesting triazole
complex was the triazoleꢀgold catalyst (TAꢀAu), which
exhibited unique reactivity toward alkyne activations.9e
For example, our group recently reported the asymmetric
synthesis of substituted allenes through propargyl ether
rearrangement at room temperature with TAꢀAu cata-
lyst. Unlike other conventional [LꢀAu]þ catalysts, the
TAꢀAu offered excellent chemoselectivity, selectively ac-
tivating alkynes over allenes.9b,c
significantly higher than both photoinitiation (15%) and
thermal condition (0%). Treatment of propargyl ester 4a0
with gold catalysts gave no reactions, which was likely
caused by the unfavored propargyl ester 3,3-migration.
The structure of 6a was confirmed by the X-ray diffrac-
This new catalyst provided the opportunity to investi-
gate our hypothesis, achieving selective C2ꢀC6 Schmittel
cyclization of the challenging 1,3-disubstituted allenes (no-
bulky substituted group on phenyl terminal) under milder
conditions. Totestour hypothesis, propargyl vinyl ether4a
and propargyl ester 4a0 were prepared and treated with
various gold catalysts as shown in Figure 1.
Figure 2. X-ray structure of 7a.
tion of the corresponding tosyl derivatives 7a as shown in
Figure 2. Overall, this result supported our hypothesis that
(A) enyneꢀallene cyclization was energetically favored
and could occur at room temperature, and (B) TAꢀAu
catalyst could selectively activate the propargyl ether,
generating the allene intermediates that allowed the subse-
quent aromatization. To the best of our knowledge, this is
the first example of an enyneꢀallene C2ꢀC6 cyclization at
room temperature without the aid from bulky substituents.
Table 1. Screening of the Reaction Conditionsa
1) 3 % TA ꢀ Au, DCM
4a
5a
f
2) NaBH4, MeOH
conv (%) yield (%)b
Figure 1. The Schmittel cyclization at room temperature.
entry concn (M) temp (°C)
time
1
2
3
4
5
5
6
0.075
0.075
0.075
0.1
rt
ꢀ10
0
15 min
24 h
6 h
>99
0
37
ND
44
48
32
20
12
Both propargyl vinyl ether and propargyl ester could
undergo 1,3-migration through gold catalyzed alkyne
activation.9b,c The concern was whether TAꢀAu could
selectively activate the propargyl alkyne other than the
other triple bond and allene intermediate. The screening of
catalysts revealed that common [LꢀAu]þ catalysts, includ-
ing [PPh3Au]þ, [iPrAu]þ, and [XPhosAu]þ, gave complex
reaction mixtures with no desired products observed, due
to the poor chemoselectivity. Using TAꢀAu catalyst, the
desired aldehyde 5a was successfully obtained (which was
subsequently reduced to alcohol 6a for easy isolation with
35% isolated yields over two steps). Notably, the reaction
with TAꢀAu catalyst was “clean” and the only cyclization
product observed was 6a. The major side reaction was the
polymerization. No C2ꢀC7 or other cyclization products
were identified. The overall yield, though modest, was
>99
>99
>99
>99
>99
0
6 h
0.2
0
4 h
0.01
0.005
0
48 h
48 h
0
a General reaction condition: 4a (0.2 mmol), catalyst (3 mol %) in
solvent (2 mL), the reactions were monitored by TLC, 0 °C to rt.
b Conversion and yields were determined by NMR with 1,3,5-trimethox-
ybenzene as internal standard.
Screening of solvents revealed dichloromethane as the
optimal solvent (see details in Supporting Information).
Considering that polymerization was the major side reac-
tion, different concentrations and reaction temperatures
were evaluated (Table 1). The TAꢀAu catalyst lost reac-
tivity atꢀ10°C. Loweringthe reaction temperature to0 °C
improved the overall reaction yield to 48%.
Some representative aromatic substituents at the allene
termini were prepared to evaluate the reaction substrate
scope. The results are summarized in Figure 3.
(10) (a) Ladouceur, S.; Fortin, D.; Zysman-Colman, E. Inorg. Chem.
2011, 50, 11514–11526. (b) Inomata, S.; Hiroki, Hi.; Terashima, T.;
Ogata, K.; Fukuzawa, S. Tetrahedron 2011, 67, 7263. (c) Uppal, B. S.;
Booth, R. K.; Ali, N.; Lockwood, C.; Rice, C. R.; Elliott, P. I. P. Dalton
Trans. 2011, 40, 7610–7616.
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Org. Lett., Vol. 14, No. 5, 2012

Figure 3. Substrate scope.
Figure 4. Mechanism investigations.
As indicated in Figure 3, the C2ꢀC6 cyclization could
occur for both electron donating and electron withdrawing
substituents on the aromatic rings. Electron withdrawing
groups gave significantly improved yields by reducing the
undesired diradical polymerization.11 Conjugation did not
show significant influence to the cyclization, which was
consistent with the proposed mechanism that involved a
highly reactive diradical intermediate. To further evaluate
the reaction mechanism, propargyl vinyl ether with “re-
versed” substitution pattern (8a) and TMS-substituted al-
kyne (8b) were prepared and reacted with TAꢀAu catalyst.
As shown in Figure 4A, propargyl ether 8a 1,3-rearrag-
nement would produce the trisubstituted allene. Under the
photocyclization condition shown in Scheme 2A, the
diradical intermediates proceeded through two different
reaction paths, which should lead to the formation of 9a
and 9a0. Interestingly, the TAꢀAu catalyzed conditions
gave exclusively 9a as the cyclization product. This might
be explained by the mild reaction conditions that favored
the aromatic cyclization instead of the elimination
(formation of 9a0), which highlighted the significantly
improved selectivity of this method over thermal and
photo conditions. Switching the alkyne termini substitu-
ents from Ph to TMS helped to successfully isolate the
proposed allene intermediate 9b (Figure 4B, decreasing
cyclization reaction rates), which provided another solid
evidence for the proposed mechanism and the unique
reactivity of TA-Au (activate alkyne over allene).
In conclusion, reported herein is a new catalytic version
of the Schmittel cyclization. The TAꢀAu catalyst offered
impressive chemoselectivity, activating the specific alkynes
only, which allowed the sequential cyclization to occur at
much milder conditions. Both the allene intermediate and
the final products were unambiguously confirmed. As a
result, an effective new strategy was uncovered under
much milder conditions and enhanced substrate scope
(substrates that could not be achieved with previously
reported thermal or photo conditions). Therefore, this
new method opens the possibility for mechanistic investi-
gation and new diradical based drug discovery by this
interesting enyne-allene cyclization process.
Acknowledgment. We thank the NSF (CHE-0844602),
WVU-PSCoR for financial support.
Supporting Information Available. Experimental de-
tails, characterization data, spectrographic data and CIF
file of compound 7a. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) (a) Xiao, Y.; Hu, A. Macromol. Rapid Commun. 2011, 32, 1688–
1698. (b) Ma, J.; Ma, X.; Deng, S.; Li, F.; Hu, A. J. Polym. Sci., Part A:
Polym. Chem. 2011, 49, 1368–1375.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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