Au-containing all-carbon 1,3-dipoles: Generation and [3+2] cycloaddition reactions

Article abstract of DOI:10.1021/ja804690u

A novel approach to generate Au-containing all-carbon 1,3-dipoles is developed via an unprecedented migration-fragmentation of ketals/acetals. These in situ generated dipoles undergo rapid [3+2] cycloaddition under mild conditions with various enones/enal

Full text of DOI:10.1021/ja804690u

Published on Web 08/28/2008
Au-Containing All-Carbon 1,3-Dipoles: Generation and [3+2] Cycloaddition
Reactions
Guozhu Zhang and Liming Zhang*
Department of Chemistry/216, UniVersity of NeVada, Reno, 1664 North Virginia Street, Reno, NeVada 89557
Received June 19, 2008; E-mail: lzhang@ unr.edu
Table 1. Initial Results and Reaction Conditions Optimization
We have recently advanced a concept of “Au-containing all-carbon
1,n-dipole” and applied it in a versatile [4+2] annulation process.1
To further implement this concept and expand the scope of Au-
catalyzed2 annulation/cycloaddition reactions, we have developed and
herein report the generation of Au-containing all-carbon 1,3-dipoles
and their applications in [3+2] cycloadditions.
yield of
4 (2, 5) (%)b
entry
catalyst
conditionsa
1
2
3
4
5
6
7
8
9
5 mol % Ph3PAuNTf2 CH2Cl2 (0.2 M), rt, 15 min
5 mol % Ph3PAuNTf2 CH2Cl2 (0.05 M), rt, 15 min
5 mol % Ph3PAuNTf2 CH2Cl2 (0.05 M), 0 °C, 15 min 41 (40, <5)
5 mol % Ph3PAuNTf2 THF (0.05 M), rt, 15 min
5 mol % Ph3PAuNTf2 CH3CN (0.05 M), rt, 8 h
5 mol % Ph3PAuNTf2 CH3NO2 (0.05 M), rt, 15 min
55 (25, <5)
82 (12, <5)
c
2 (70, -)
5 (50, <5)
2 (80, -)
77 (10, -)
-
- (50, -)
- (95, -)
- (95, -)
The difficulty in studying a Au-containing all-carbon 1,3-dipole such
as A3 (eq 1) is to avoid the reactivities derived from its resonance
form, alkenyl Au carbenoid B. In fact, carbenoid B (X ) RCO2 or
RS), accessible via a 1,2-migration of acyloxy4a-d or alkylthio5 groups
in propargylic substrates, has been reported to undergo facile
inter-4a,c/intramolecular4b,d,e cyclopropanation reactions and cycliza-
tions,4 while no cycloaddition via its 1,3-dipole resonance form A has
ever been reported.6 However, we envision that the resonance form B
could be destabilized by direct substitution of an electron-withdrawing
group (EWG) at the carbene center and consequently reactivities of
1,3-dipole A may be harnessed (Scheme 1). In addition, such an EWG
can facilitate regioselective migration of acyloxy7 or alkylthio groups
due to electronic polarization of the C-C triple bond.
5 mol % IPrAuNTf2
5 mol % PtCl2
CH2Cl2 (0.05 M), rt, 15 min
toluene, 80 °C, 8 h
5 mol % AuCl3
CH2Cl2 (0.05 M), rt, 15 min
CH2Cl2 (0.05 M), rt, 15 min
CH2Cl2 (0.05 M), rt, 15 min
10 5 mol % TsOH
11 5 mol % BF3.Me2O
a Anhydrous solvent used. b Estimated by 1H NMR. c 75% isolated
yield.
that Ph3PAuNTf2 (entry 2) is a slightly better catalyst than IPrAuNTf29
(entry 7). The major side reaction was hydrolysis of 3 back to alcohol
2, which could not be prevented under various conditions. Interestingly,
dihydrofuran 5, formed via direct cyclization of D (R ) iPr; R1, R2,
R3 ) Me; EWG ) CO2Et), was also isolated in small amounts,
offering strong support for the initial alkoxy migration. No product 4
was observed when alcohol 2, MeOH, and anisaldehyde were treated
with Ph3PAuNTf2 for 1 h.10 Without anisaldehyde, treatment of 3 with
Ph3PAuNTf2, as expected, led to mostly hydrolysis and the formation
of <5% of 5.
However, no [3+2] cycloaddition between substrate 1 (X ) OAc
n
or SPh, EWG ) CO2Me, R ) Pr) and anisaldehyde was observed
under various reaction conditions. We speculated that this lack of
reactivity might be due to the decreased nucleophilicity of the
alkenylgold moiety in dipole C in the presence of an EWG group and
reasoned that it could be overcome by replacing known migrating
groups (i.e., X ) RCO24 or RS5) with a more electron-donating alkoxy
group. However, substrate 1 with X ) OMe again did not work, as
MeO 1,2-migration appeared difficult. We envisioned that a novel
migration-fragmentation sequence of a ketal substrate8 could deliver
such a 1,3-dipole [i.e., intermediate C (X ) OR), Scheme 1]. Notable
in this design is the fragmentation of the ketal moiety into a migrated
alkoxy group and a ketone which behaves as a good leaving group.
To our delight, the expected 4-methoxy-2,5-dihydrofuran 4 was
indeed formed when a mixture of ketal ester 3 and anisaldehyde was
treated with Ph3PAuNTf2 (5 mol %) in 15 min (entry 1, Table 1).
Moreover, this annulation is highly diastereoselective as only cis-4
was observed. Optimization of reaction conditions (Table 1) revealed
The success of this reaction is worth commenting on: (a) the terminal
carboxylate group was important as ketal 6 with a terminal alkyne
reacted rather poorly and with a low diastereoselectivity (eq 2); (b)
there is a facile exchange of the leaving acetone and anisaldehyde likely
via 1,3-dipole intermediate C, and the highly selective formation of 4
can not be explained simply by sterics (Vide infra) but rather by
stereoelectronic considerations (eq 3): 5-endo-trig cyclization11 of E
is disfavored according to the Baldwin’s rule,12 but for anisaldehyde-
substituted intermediate F, its significant quinone methide resonance
form can undergo favored and facile 5-exo-trig cyclization.11
Scheme 1. Design
The reaction scope study is shown in Table 2. First, we examined
the dipolarophiles.13 Both enals (entries 1, 2, and 5) and electron-rich
aromatic aldehydes (entries 3 and 4) reacted well. In all these cases,
excellent diastereoselectivities were again observed as only the cis-
isomers were isolated. Particularly noteworthy is the case of cyclohex-
1-enecarbaldehyde (entry 5), indicating that a simple double bond is
sufficient to facilitate the 5-exo-trig cyclization (eq 3). Not surprisingly,
hexanal or cyclohexanone did not react well, and the corresponding
9
12598 J. AM. CHEM. SOC. 2008, 130, 12598–12599
10.1021/ja804690u CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Further Scope Study
cycloadducts were formed in 8% and 15% yield, respectively. To our
surprise, benzaldehyde reacted poorly (<5% yield). In addition,
electron-rich furan and thiophene rings did not notably interfere with
the cycloaddition. In contrast to acetone, simple enones (entries 6 and
8) and aryl enones (entries 7 and 9) underwent this cycloaddition
smoothly, and dihydrofurans with quaternary carbon centers were
obtained in moderate to good yields. Asymmetric ketones with large
steric biases showed good to excellent diastereoselectivity (entries 8
and 9). In the case of 2-benzylidenecyclopentanone (entry 9), spiro-9i
was isolated as a single diastereomer in 63% yield along with 25% of
the enone recovered. For the Au-containing 1,3-dipole precursor,
besides 3, esters with R1 ) n-propyl (entry 10) or siloxymethyl (entry
11) reacted smoothly although the latter case displayed surprisingly
low and opposite diastereoselectivity. In most cases except entries 2,
10, and 11, Ph3PAuNTf2 worked better than IPrAuNTf2, and hydrolysis
was a notable side reaction for some cases.
In summary, we have developed a novel approach to generate Au-
containing all-carbon 1,3-dipoles via an unprecedented migration-
fragmentation of ketals/acetals. These in situ generated dipoles undergo
facile [3+2] cycloaddition with various enones/enals, electron-rich
aromatic aldehydes, and N-benzylindole at room temperature, leading
to rapid formation of highly functionalized 2,5-dihydrofurans17 and
cyclopentenes with good efficiencies.
Acknowledgment. Generous financial support from ACS PRF
(43905-G1), ORAU, and Merck are appreciated. The NMR spectrom-
eters are funded by NSF CHE-0521191.
Ester substrates with fully substituted γ-positions also underwent
smooth cycloadditions, yielding highly substituted 9l and 9m efficiently
(Scheme 2). In these substrates, ethyl acetals were employed for the
migration-fragmentation process as the corresponding ketal derivatives
were difficult to prepare due to steric congestion. Besides carbonyl
compounds, N-benzylindole reacted as dipolarophile as well, forming
the cyclopentene ring in 9n and allowing expedient functionalization
of indole. Moreover, the ester group can be readily replaced with other
EWGs14,15 including acetyl, mesyl, benzoyl, and 2,6-dichlorobenze-
nesulfinyl groups,16 yielding products (i.e., 9o-9r) with diverse
functionalizations at the dihydrofuran 3-position in fair to good yields.17
Interestingly, the last example could allow chiral sulfoxide-controlled
stereoselective construction of dihydrofurans.
Supporting Information Available: Experimental procedures, com-
pound characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
(1) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130,
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(2) For selected reviews on Au/Pt catalysis, see: (a) Hashmi, A. S. K. Chem.
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(3) For other Au-containing all-carbon 1,3-dipoles, see: (a) Huang, X.; Zhang,
L. J. Am. Chem. Soc. 2007, 129, 6398–6399. (b) Schelweis, M.; Dempwolff,
A. L.; Rominger, F.; Helmchen, G. Angew. Chem., Int. Ed. 2007, 46, 5598–
5601.
Table 2. Efficient Formation of Functionalized 2,5-Dihydrofuransa
(4) For selected examples, see: (a) Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem.
2003, 68, 8505–8513. (b) Mamane, V.; Gress, T.; Krause, H.; Fürstner, A.
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(10) <5% of 4 was formed if the reaction was stirred overnight at rt.
(11) This step likely proceeds via cyclization of the π electrons to the electron-
deficient center with concurrent Au-C bond fragmentation.
(12) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b) Baldwin,
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3846–3852.
(13) Preliminary studies using imines, styrene, and ethyl vinyl ether as
dipolarophile did not yield desired [3+2] cycloadducts.
(14) Using H instead of an EWG led to rather poor cycloaddition (26% yield,
60% conv.). For details, please see the Supporting Information.
(15) Other EWG groups such as Br, Cl, and CN led to no product.
(16) Using benzenesulfinyl instead led to signficant acetal hydrolysis.
(17) For substrates not fully substituted at the γ-positions, replacing CO2R with
these EWGs led to significant hydrolysis and <50% yields.
a The amounts of alcohols and 5 were estimated by 1H NMR and
shown in parentheses, respectively. b Entry number. c IPrAuNTf2 (5 mol
%) was used. d The major isomer is shown. e 3 was used in excess
instead (2 equiv), and two batches of 5 mol % of Ph3PAuNTf2 were
added; time, 1 h; 25% of the enone was recovered. f The corresponding
2,2-dimethyldihydrofuran was not identified.
JA804690U
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J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008 12599