Gold- Vs. platinum-catalyzed polycyclizations by O-acyl migration. solvent-free reactions

Article abstract of DOI:10.1002/adsc.200700356

Polycyclic derivatives incorporating a cyclopropyl group have been efficiently synthesized from propargyl acetates using platinum(II), gold(I) and gold(III) catalysis. These reactions which are also viable for the preparation of medium-sized rings, proceed with a complete diastereocontrol and can also be run in neat conditions.

Full text of DOI:10.1002/adsc.200700356

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DOI: 10.1002/adsc.200700356
Gold- vs. Platinum-Catalyzed Polycyclizations by O-Acyl
Migration. Solvent-Free Reactions
Xavier Moreau,a Jean-Philippe Goddard,a Matthieu Bernard,a Gilles Lemi›re,a
Juan Manuel López-Romero,a Emily Mainetti,a Nicolas Marion,a
Virginie Mouri›s,a Serge Thorimbert,a Louis Fensterbank,a,* and Max Malacriaa,*
a
UniversitØ Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie
MolØculaire (FR 2769), case 229, 4 place Jussieu, 75252 Paris cedex 05, France
Fax : (+33)-(0)1-4427-7360; e-mail: louis.fensterbank@upmc.fr or max.malacria@upmc.fr
Received: July 19, 2007; Published online: December 20, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Polycyclic derivatives incorporating a cy-
clopropyl group have been efficiently synthesized
from propargyl acetates using platinum(II), gold(I)
and gold(III) catalysis. These reactions which are
G
also viable for the preparation of medium-sized
rings, proceed with a complete diastereocontrol and
can also be run in neat conditions.
Scheme 1. General reaction.
Keywords: cyclopropanes; enynes; gold; platinum;
solvent-free reactions
zone enolates by using successively N,N-dimethylhy-
drazine, n-BuLi, an alkyl bromide and final hydroly-
sis.[7] The corresponding ketones B were alkylated by
the TMS-protected lithium acetylide and subsequent
For two decades now, enyne cycloisomerization reac- desilylation and acylation provided enyne 1 in good
tions have witnessed intense developments.[1] An in- overall yields (21 to 52%) as a mixture of diastereo-
teresting variant has emerged with the use of highly isomers (Scheme 2).[8]
electrophilic metal species,[2] such as PtCl2 as well as
We initially focused on allylic (m=1) precursors 1
gold(I) or (III) salts,[3] which have allowed various that should give birth to a central 6-membered ring
transformations. Importantly, charged intermediates on polycycles 2. Gratifyingly, we could validate our
are generally involved in these processes so that het- design with cyclohexyl substrate 1a which afforded
eroatomic functions can be involved. For instance, tricyclic compound 2a in 88% yield under platinum
we[4] and others[5] have shown that different acyl catalysis (Table 1, entry 1). No other product such as
groups at the propargylicposition of an enyne can mi-
an Alder-ene or metathesis-like substance was ob-
grate in a 1,2-fashion with concomitant intramolecular served in this reaction. Cyclobutyl precursor 1b
cyclopropanation onto the ene part of the substrate. proved to be also very reactive and afforded highly
This transformation has lent itself to versatile applica- strained product 2b in high yield with PtCl2 while Au-
tions such as natural product synthesis[6] as well as the
N
Pt(II), Au(I) and Au(III) catalysis is also underlined. PtCl2. Gold catalysis was not as efficient, and allenyl
A
Precursors 1 were readily prepared from the corre- ester 3c was formed in around 30% yield (entry 3).
sponding cyclic ketones A in a five-step sequence. Al- Extension to the cyclooctene series provided valuable
kylation of ketones A was achieved through hydra- information. When the reaction of 1d wasrun with
Adv. Synth. Catal. 2008, 350, 43 – 48
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43

Xavier Moreau et al.
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Scheme 2. Synthesis of precursors.
Table1. Cycloisomerizations catalyzed by Pt(II), Au(I) and Au(III).
G
[a]
Au(I) refers to PPh3AuSbF6 generated in situ from an equimolar mixture of AgSbF6 and
AuClPPh3. Reactions were run at 808C in toluene with PtCl2 (5 mol%) for 2 h and at room
temperature in CH2Cl2 with gold catalysts (2 mol%) for 5–10 min.
Reactions with PtCl2 were run at room temperature for 24–48 h.
A minor diastereomer (<5%) was observed.
[b]
[c]
PtCl2 at 808C, a complex mixture was obtained the yields of 2d. A similar trend was observed with 5-
among which products 2d and 3d could be observed. membered ring precursor 1g. Interestingly, gold catal-
Running the reactions at room temperature optimized ysis gave mixed results and a net supremacy of plati-
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Gold- vs. Platinum-Catalyzed Polycyclizations by O-Acyl Migration
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Scheme 3. Mechanism proposal for the formation of cyclo-
propanes 2 and allenyl esters 3.
In the case of precursor 1i, no hydroarylation prod-
uct was observed,[13] instead allenyl ester 3i was
formed in 68% yield. As previously observed,[4b] the
introduction of an alkyl group on the alkyne favors
Figure1. X-ray view of 2dPNB.
num vs. gold was observed in the case of the 6-mem- the formation of the allenyl ester 3j. We also exam-
bered ring template 1d. In contrast, a very high yield ined the possibility to construct the bicyclo-
of 2g could be reached with Au
G
G
yields and highly diastereoselective reactions were ucts. Unfortunately, only traces of 2k were formed
also obtained with other 5-membered ring precursors upon PtCl2 as well as gold catalysis. Here also, the
1e and 1f (entries 5 and 6).
major product was allenyl ester 3k.
It is worthy of note that all tricyclic compounds 2
We were then attracted by the possibility to run
have been isolated as single diastereoisomers whose these reactions in solvent-free conditions.[14] In addi-
relative stereochemistry was deduced from NOE tion to the environmental benefits from such an ap-
measurements.[10] Further confirmation was obtained proach,[15] we anticipated that the concentration of
with a X-ray structure determination[11] of the parani- the reaction media could significantly influence the
trobenzoate derivative (2dPNB) of 2d (Figure 1) ob- ratio of tricyclic products 2 vs. allenyl esters 3 notably
tained in 62% yield upon PtCl2 catalysis at room tem- obtained in the case of gold-catalyzed reactions. Inter-
perature, accompanied by 14% of the corresponding estingly also, only a few reports describe gold-cata-
allene. In contrast, two diastereoisomers of allenyl lyzed reactions in neat conditions[16] and generally do
esters 3 have been generally isolated in a ratio close not compare diluted with solvent free reactions.
to 1:1. A mechanism rationale for these transforma-
We were pleased to find that PtCl2 in neat condi-
tions is under scrutinity, notably their diastereoselec- tions allowed in most cases the clean conversion of
tion. According to the proposed mechanism for the the starting propargylic acetate into the tricyclic prod-
intermolecular version of the reaction,[5j,12] a [2+1] uct 2 as the sole isolated product. Yields, which are
cyclopropanation would take place after [1,2] acetate usually high, are often in the same order as the ones
migration leading to the formation of polycyclic deriv- obtained in toluene (compare Table 1 and Table 3).
atives 2 (Scheme 3). A second [1,2] migration would Nevertheless, it has to be noted that dimericand
[17]
give the allenyl esters 3. The latter could alternatively other oligomericproducts
originate from a direct [1,3] migration.
were formed in the reac-
tions of 1e and 1f. Longer reaction times were needed
In this report, we focus on synthetic purposes and when the reaction was performed at room tempera-
in order to have a better insight into this reactivity, ture (20 h vs. 2 h).
we examined other precursors 1h–k of Table 2 using
Having established the possibility of running neat
PtCl2 which has proven to be the most versatile cata- reactions with PtCl2, we turned our attention to gold
lyst in most of these reactions. Introducing a gem-di- which gave us mixture of products in solution. Reac-
methyl group on 1h, compared to precursor 1c, result- tions of propargylicacetates with AuCl at room tem-
3
ed in a less effective formation of the tricyclic deriva- perature were generally very slow and poor conver-
tive and some allenyl ester 3h was also isolated.
sions were observed. For instance, after 1 h the 5,6,3-
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45

Xavier Moreau et al.
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Table2. Scope and limitations of the cycloisomerization process.
[a]
Reactions were run at 808C in toluene.
tricyclic compound 2e was isolated in 38% yield as
well as 46% of the starting material (Table 3,
entry 2). Increasing the reaction time or the tempera-
ture was not productive nor was the addition of more
catalyst. Starting from the homoallylic cyclopentane
1f (Table 3, entry 3), we isolated the 5,7,3-tricyclic
enol ester 2f in 15% yield after 2 h at room tempera-
Scheme 4. 1,5-Enynol cycloisomerization in neat conditions.
[17]
ture. Dimericand trimeric
products were also ob-
served in this reaction. Using NaAuCl4 as catalyst al-
lowed to isolate 2f in 53% yield as well as 9% of 1f. low loading of catalyst: only 0.5 mol% was intro-
Precursor 1c gave an interesting example of com- duced!
pletely altered reactivity between platinum and gold
catalysis (Table 3, entry 5), the former giving 2c in
high yield and the latter with Echavarren gold(I) cata-
Experimental Section
lyst[18] only allenyl ester 3c.
In conclusion, this study shows that the platin-
um(II)- or the gold(I)- and gold (III)-catalyzed cyclo-
Typical Procedure for Metal-Catalyzed Reactions
isomerization of propargyl acetates is a versatile pro- PtCl2 (5.3 mg, 5 mol%), AuCl3 (2.4 mg, 2 mol%) or
AuClPPh3 (4 mg, 2 mol%) and AgSbF6 (2.7 mg, 2 mol%)
were introduced in a round-bottom flask under an argon at-
mosphere. Anhydrous toluene or CH2Cl2 (16 mL, 0.025M)
was then added. Enyne 1e (77 mg, 0.4 mmol) was introduced
and the reaction mixture was stirred at the appropriate tem-
perature (for 2–3 h at 808C with PtCl2, 5–10 min at room
temperature with gold catalysts) and was monitored by
TLC. After completion, the solution was filtered through a
pad of silica and the pad was washed with diethyl ether. The
solvent was removed under reduced pressure and the crude
cess for the expedient and stereoselective preparation
of various polycyclic products. Despite their lack of
generality, preliminary results in solvent-free condi-
tions are encouraging and strongly suggest that these
conditions should always be considered when running
this type of reactions. A confirmation of this is given
by the efficient and clean transformation of enynol 4
into bicyclic ketone 5 isolated in 76% yield after dis-
tillation (see Scheme 4). This reaction could be run
on a 4.5 mmol scale and we could use a particularly mixture was purified by flash chromatography on silica gel
46
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Gold- vs. Platinum-Catalyzed Polycyclizations by O-Acyl Migration
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Table3. Cycloisomerizations catalyzed by PtCl2, AuCl3 and Au(I) in neat conditions.
[a]
Reactions were run at 808C in toluene.[a] Oligomericstructures were observed.
Dimericand trimericproducts were isolated.
[b]
[c]
[17]
Au(I)=
.
(petroleum ether/Et2O, 98/2) to give 2e as a single diastereo-
isomer. H NMR (CDCl3, 400 MHz): d=2.68 (m, 1H), 2.35
Procedure for PtCl2-Catalyzed Enynol
Cycloisomerization
1
(m, 1H), 2.10 (s, 3H), 2.08 (m, 2H), 1.83 (m, 1H), 1.64 (m,
1H), 1.46 (m, 1H), 1.24 (m, 2H), 0.92–0.78 (m, 3H,), 0.37
(q, J=4.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz): d=169.1,
141.1, 133.3, 42.6, 34.1, 33.8, 26.8, 25.1, 21.1, 20.9, 13.0, 12.8;
IR (neat): n=2998, 2930, 1752, 1710, 1451 cmÀ1; anal. calcd.
for C12H16O2: C 74.97, H 8.39; found: C 74.98, H 8.45.
To a catalytic amount of PtCl2 (6 mg, 0.5 mol%) was added
5-methyl-hex-5-en-1-yn-3-ol 4 (500 mg, 4.54 mmol). The re-
action mixture was stirred 2 h at 808C and distilled with a
Kugelrohr apparatus (758C, 30 mm Hg) to provide 5;[12a]
yield: 380 mg (76%).
Acknowledgements
Typical Procedure for Solvent-Free Reaction
This work was supported by CNRS, MRES, IUF, and ANR
To a catalytic amount of PtCl2 (5.3 mg, 5 mol%) or AuCl3
(2.4 mg, 2 mol%) was added enyne 1e (77 mg, 0.4 mmol)
under an argon atmosphere. The reaction mixture was
stirred at the appropriate temperature (for 30 min at 808C
with PtCl2, 5–10 min at room temperature with AuCl3) and
monitored by TLC. After completion, the crude mixture
was directly purified by flash chromatography on silica gel
(petroleum ether/Et2O, 98/2) to give 2e as a single diastereo-
isomer.
BLAN 06–2 159258 “All›nes”. JMLR acknowledges
MECyD fellowship from the “Programa de Movilidad de
Profesorado 2002”.
a
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47

Xavier Moreau et al.
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