Gold catalysed reactions with cyclopropenes

Article abstract of DOI:10.1039/b815891f

Gold(I) catalyses the ring-opening addition of cyclopropenes in a mild and regioselective manner. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b815891f

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Gold catalysed reactions with cyclopropenesw
Jurgen T. Bauer, Maximillian S. Hadfield and Ai-Lan Lee*
¨
Received (in Cambridge, UK) 10th September 2008, Accepted 8th October 2008
First published as an Advance Article on the web 5th November 2008
DOI: 10.1039/b815891f
Gold(I) catalyses the ring-opening addition of cyclopropenes in a
mild and regioselective manner.
Interest in organic transformations catalysed by Au(I) and
Au(III) complexes has undergone a marked increase in recent
years.1 The majority of homogenous Au catalysed reactions
draw on the superb Lewis acidity of gold for activation of
alkynes.1d More recently, gold carbenoid species have been
proposed to exist transiently in a number of gold-catalysed
reactions.1c,2 For example, gold carbenoid species are pro-
posed to be generated from a-diazocarbonyl compounds,3
rearrangement of propargylic carboxylates4 and alkynyl sulf-
oxides,5 or intermolecular cyclopropanation of enynes.6
Although there have been many examples1 of gold catalysed
activation of alkynes, allenes and alkenes, there have been no
reports to date on gold-catalysed reactions with highly
strained cyclopropenes. Cyclopropenes display a diverse range
of reactivities, thus presenting unique opportunities for or-
ganic synthesis.7 In this communication, we wish to report a
novel and remarkably regioselective transformation of
3,3-disubstituted cyclopropenes catalysed by gold(I) (Scheme 1).
We propose that gold(I) catalyses the ring opening of cyclo-
propenes to form intermediate gold vinyl carbenoid/cationic
species (I), which can be trapped by nucleophiles. As far as the
authors are aware, this constitutes the first report on gold-
catalysed reactions with cyclopropenes.
Scheme 1 The regioselective gold(I) catalysed ring-opening addition
of cyclopropene 1 to form tert-allylic ethers and the proposed inter-
mediate I.
Secondary alcohol i-PrOH also successfully undergoes the
regioselective ring-opening addition to cyclopropene 1 to
produce the corresponding sec-alkyl tert-allylic ether 2g in
70% yield (Entry 9). The regioselectivity is still excellent,
though very slightly diminished with a 97 : 3 ratio of 2 : 3,
reflecting the more sterically hindered nature of the secondary
alcohol.9 It is of interest to note that the employment of
Gagosz’s air-stable PPh3AuNTf2 catalyst10 (Entry 9) produces
superior activity, regioselectivity and yield in this case com-
pared to PPh3AuOTf (formed in situ with PPh3AuCl and
AgOTf, Entry 8). Reaction of 1 with t-BuOH, however,
provided only traces of the corresponding tert-alkyl tert-allylic
ether 2h with PPh3AuNTf2 as catalyst (Entry 10). The steric
bulk of the tertiary alcohol is very likely to blame for the
diminished activity as well as regioselectivity of the reaction.
The intermolecular gold(I) catalysed reaction of cyclo-
propene 1 with a range of alcohols is shown in Table 1. Entries
1–7 show that primary alcohols add exclusively and regio-
selectively at the C-3 position of the proposed intermediate I to
produce the tertiary ether 2 rather than the primary ether 3
(arising from reaction at C-1) under mild conditions (20 1C,
1–2 h, without the need for dried or distilled solvents).8 In
addition to simple primary alcohols MeOH and EtOH
(Entries 1–3), allyl alcohol and benzyl alcohol (Entries 4 and 5)
also smoothly undergo this regioselective addition on cyclo-
propene 1 to produce the corresponding allyl- and benzyl-
protected tertiary allylic alcohols 2c and 2d in good yields
(88% and 78%, respectively). The homoallylic alcohol
3-buten-1-ol and 2-phenylethanol also react smoothly to give
the corresponding products 2e and 2f in good yields (88% and
77% respectively).
Table 1 The regioselective gold(I) catalysed ring-opening addition of
cyclopropene 1 with a variety of alcohols to form tert-allylic ethers
Yield
Ratio
Entrya ROH
Method of 2b (%) Product 2/3c
1
2
3
4
5
6
7
8
MeOH
EtOH
EtOH
Allyl alcohol
Benzyl alcohol
HOCH2CH2CHQCH2
HOCH2CH2Ph
i-PrOH
B
A
B
B
A
B
B
A
B
B
B
86
64
83
88
78
88
2a
2b
2b
2c
2d
2e
2f
2g
2g
2h
2i
499%
499%
499%
499%
499%
499%
499%
2.5 : 1
97 : 3
77
N/Ad
70
9
10
i-PrOH
t-BuOH
H2O
Traces
34
N/A
499%
11e
a
All reactions were carried out at 20 1C in CH2Cl2 for 1–2 h unless
otherwise stated. Isolated yield, unless otherwise stated. Deter-
b
c
School of Engineering and Physical Sciences, Heriot-Watt University,
Edinburgh, UK EH14 4AS. E-mail: A.Lee@hw.ac.uk;
Tel: +44(0)131 451 8030
w Electronic supplementary information (ESI) available: Experimental
details and analytical data for new compounds. See DOI:
10.1039/b815891f
mined by 1H NMR analysis of the crude mixture. Reaction was
d
allowed to stir for 4 days, after which B50% conversion was observed
e
to 2g and 3g (B30%), 4 and 5 (B20%). 15 eq. of t-BuOH was added
as a co-solvent and the reaction was allowed to stir for 24 h.
ꢀc
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Even water can successfully act as a nucleophile to produce the
corresponding tertiary alcohol 2i, albeit in low conversion and
yield (34%, Entry 11).11 Upon repeating the reaction shown in
Entry 3 with a reduced Au(I) catalyst loading (1 mol%),
complete conversion to 2b (499% regioselectivity) is still
observed within 1.5 h. Indeed, reactions with primary alcohol
nucleophiles such as EtOH (Entry 3) are facile and often
complete in o10 min (see ESIw).
In an effort to ascertain whether the reaction is truly gold-
catalysed, we carried out some control reactions (Table 2). The
gold(I) catalyst PPh3AuOTf is formed in situ from PPh3AuCl
and the hygroscopic AgOTf, resulting in the possibility of
there being slight traces of TfOH present during the reaction
(64% 2b, Entry 1).12 Reaction with the air stable
PPh3AuNTf2, which does not require any hygroscopic co-
catalyst, produces an even better yield of the product 2b (83%,
Entry 2). The control reaction employing 5 mol% of TfOH as
catalyst results in no reaction, suggesting that traces of acid
are not catalytically active (Entry 3). Reaction with Ag(OTf)
as catalyst is also greatly inferior to gold(I), resulting in
incomplete consumption of the starting material, along with
a complex mixture of products (Entry 4). We also wanted to
ascertain if (Rh(OAc)2)2, which is believed to ring-open related
cyclopropenes to form the corresponding rhodium carbenoid
intermediates, could also catalyse this reaction.13 In stark
contrast to Au(I), employment of (Rh(OAc)2)2 as catalyst,
produces a mixture of 4 and 5, along with traces of both 2b
and 3c. Interestingly, employment of Au(III) instead of Au(I) as
catalyst also completely changes the outcome of the reaction,
with the aldehydes 4 and 5 being the major products (Entry 6).
This difference in reactivity further exemplifies the differences
between Au(I) and Au(III) catalysts.14,15
Scheme 2 Gold(I) catalysed ring-opening oxidation and ring-opening
cyclopropanation of 1.
across C-1, C-3 and Au (Ia 2 Ib 2 Ic, Scheme 1).17 The
regioselectivity of the reaction with nucleophiles, however, is
highly dependent on the identity of the nucleophile. When the
nucleophilic oxidant Ph2SO is employed,4b exclusive attack at
C-1 occurs, producing the Z and E isomers 4 and 5 in 66%
yield (Scheme 2). In addition, I can also undergo inter-
molecular olefin cyclopropanation with styrene to form the
cyclopropane 6, albeit in low stereoselectivity (Scheme 2). The
success of these reactions lends some support for the carbenoid
nature of intermediate I.4a,b
Our proposed mechanism for the regioselective gold(I)
catalysed ring-opening addition of cyclopropene 1 with alco-
hols is shown in Scheme 3. Activation of the strained cyclo-
propene double bond by gold(I) results in ring-opening to
produce the proposed intermediate I (only one resonance
structure shown). Attack of the alcohol at the C-3 position
followed by protodemetallation thus furnishes the tert-allylic
ether 2. In order to probe the validity of our proposed
mechanism, the reaction was carried out with CD3OD as the
nucleophilic alcohol (Scheme 4). Deuterium is indeed incor-
porated at the C-1 position (90%), lending support to our
proposed mechanism.
The remarkable regioselectivity with gold(I) is rather sur-
prising, since these species (vide infra) usually involve attack at
the C-1 position next to gold, rather than at C-3.16 We propose
that the intermediate I can have its positive charge delocalised
The reason for this intriguing switch of regioselectivity from
C-1 to C-3 when alcohol nucleophiles are employed is cur-
rently unclear and will be the subject of future investigation in
our laboratory. However, it is interesting to note that an
excess of alcohol is necessary to ensure good regioselectivity.
When the reaction in Entry 2, Table 2 is repeated with only
1.5 eq. (instead of 6 eq.) of EtOH, the regioselectivity is
diminished: a 4 : 1 ratio of 2b : 3b is observed. However, when
the reaction is carried out with 1 eq. of EtOH and 5 eq. of
t-BuOH, as an additive, the regioselectivity is retained (499%
2b, 64% yield). The presence of the unreactive t-BuOH as a
Table 2 Transition metal-catalysed reaction of 1 with EtOH
Entry Catalyst
t/h
Result
1
2
3
4
PPh3AuCl/AgOTf 1.5a 64% 2bb
PPh3AuNTf2
HOTf
AgOTf
1.5 83% 2bb
24
No reactionc
7 : 4 ratio of 1 : 2b along with
traces of 3b, 4 and 5 and other
unidentified by-productsc
24
24
24
Scheme 3 Proposed mechanism for the regioselective gold(I)-cata-
lysed ring-opening addition of 1 with alcohols.
5
6
(Rh(OAc)2)2
AuCl3
Major products: 4 and 5 (with
traces of 2b and 3b and other
unidentified by-products)c
Complex mixture of products:
4 and 5 (with traces of 2b and 3b
and other unidentified by-products)c
a
No change in yield or selectivity is observed if the reaction is allowed
b
to stir for 24 h. Isolated yield; 3b, 4 and 5 were not detected by
1H NMR analysis of the crude mixture. By 1H NMR analysis of the
crude mixture.
c
Scheme 4 The regioselective gold(I) catalysed ring-opening addition
of 1 with CD3OD.
ꢀc
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and F. D. Toste, Nature, 2007, 446, 395; (d) A. Furstner and
¨
P. W. Davies, Angew. Chem., Int. Ed., 2007, 46, 3410;
(e) E. Jimenez-Nu´ nez and A. M. Echavarren, Chem. Commun.,
´
2007, 333; (f) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180.
2 The existence of gold carbenoid vs. cationic intermediates is still a
matter of debate, see: A. S. K. Hashmi, Angew. Chem., Int. Ed.,
2008, 47, 6754 and references cited therein.
3 (a) M. R. Fructos, T. R. Belderrain, P. de Fre
´
S. P Nolan, M. M. Dıaz-Requejo and P. J. Pe
mont, N. M. Scott,
rez, Angew. Chem.,
´
´
Int. Ed., 2005, 44, 5284; (b) M. R. Fructos, P. de Fre
Nolan, M. M. Diaz-Requejo and P. J. Perez, Organometallics,
2006, 25, 2237.
´
mont, S. P
´
Scheme 5 Gold(I) catalysed rearrangement of cyclopropenes 7 and
10a–d.
4 (a) M. J. Johansson, D. J. Gorin, S. T. Staben and F. D. Toste,
J. Am. Chem. Soc., 2005, 127, 18002; (b) C. A. Witham,
P. Mauleon, N. D. Shapiro, B. D. Sherry and F. D. Toste,
´
J. Am. Chem. Soc., 2007, 129, 5838; (c) P. W. Davies and
S. J.-C. Albrecht, Chem. Commun., 2008, 238.
protic co-solvent, seems to enhance the regioselectivity of the
reaction. Thus the alcohol nucleophile need not be in excess, as
long as t-BuOH is present as an additive.
5 (a) N. D. Shapiro and F. D. Toste, J. Am. Chem. Soc., 2007,
129, 4160; (b) G. Li and L. Zhang, Angew. Chem., Int. Ed., 2007,
46, 5156.
Finally, we varied the cyclopropene by replacing the two
alkyl substituents in 1 with carbonyl and phenyl substituents
to ascertain if intramolecular attack of the proposed vinyl
cationic/carbenoid intermediate could occur under gold(I)
catalysis. Indeed, cyclopropene 7 rearranges to the furanone
8 (52%), with indene 9 (20%) formed as the major by-
product.18 Furanone 8 can be envisaged to result from the
C-1 intramolecular attack of the ester carbonyl oxygen moiety
followed by hydrolysis, whereas the indene 9 results from
intramolecular attack of the Ph substituent, thus further
supporting our proposed vinyl carbenoid/cationic intermedi-
ate.19 Several substituted cyclopropenes 10a–d also undergo
gold(I)-catalysed rearrangements to the corresponding fura-
nones and a mixture of regioisomeric indenes under milder
conditions (Scheme 5).18 Upon subjecting cyclopropene 7 to
15 eq. of EtOH under Au(I) catalysis, the intramolecular
rearrangement to 8 and 9 still predominates (52% and 19%,
respectively) with only traces of intermolecular addition pro-
ducts being observed. When substituted cyclopropene 10c is
used, however, the intermolecular addition of EtOH becomes
competitive with the intramolecular rearrangement (B1 : 1,
see ESIw for further details).
In summary, we have described the first examples of gold-
catalysed ring-opening addition of cyclopropenes. The reac-
tion of alkyl-disubstituted cyclopropene 1 with a series of
alcohols is mild and highly regioselective, yielding the corre-
sponding tert-allylic ethers. Gold(I) catalysts were found to be
unique and superior in terms of reactivity and regioselectivity.
Upon introduction of ester and Ph substituents on the cyclo-
propene (7, 10), gold(I) catalysed rearrangement to furanones
and indenes is observed. Further exploration of the scope,
reactivity and utility of the gold vinyl carbenoid/cation inter-
mediates formed from cyclopropenes, as well as further in-
vestigations into the mechanism of the process is under way
and will be reported in a full article in due course.
6 S. Lopez, E. Herrero-Gomez, P. Perez-Galan, C. Nieto-Oberhuber
´ ´ ´ ´
and A. M. Echavarren, Angew. Chem., Int. Ed., 2006, 45, 6029.
7 For recent reviews on cyclopropenes, see: (a) M. Rubin,
M. Rubina and V. Gevorgyan, Synthesis, 2006, 1221;
(b) M. Rubin, M. Rubina and V. Gevorgyan, Chem. Rev., 2007,
107, 3117; (c) I. Marek, S. Simaan and A. Masarwa, Angew.
Chem., Int. Ed., 2007, 46, 7364.
8 Effective methods for the synthesis of alkyl tert-allylic ethers are
limited. See: Z. Zhang and R. A. Widenhoefer, Org. Lett., 2008, 10,
2079 and references cited therein.
9 When the reaction was repeated at a higher temperature of 60 1C in
DCE, the selectivity plummeted (1 : 1 of 2g : 3g). Indeed, all the
reactions shown in Table 1 should be run at r20 1C to ensure good
selectivities.
10 N. Mezailles, L. Richard and F. Gagosz, Org. Lett., 2005, 7, 4133.
´
11 Formation of tert-allylic alcohol from 3,3-dimethylcyclopropene-
1,2-dicarboxylate and water is known with Pd(0), albeit in low
selectivity. See: A. S. K. Hashmi, M. A. Grundl and J. W. Bats,
Organometallics, 2000, 19, 4217.
12 (a) D. C. Rosenfeld, S. Shekhar, A. Takemiya, M. Utsonomiya
and J. F. Hartwig, Org. Lett., 2006, 8, 4179; (b) Z. Li, J. Zhang,
C. Brouwer, C.-G. Yang, N. W. Reich and C. He, Org. Lett., 2006,
8, 4175.
13 For example, see: A. Padwa, J. M. Kassir and S. L. Xu, J. Org.
Chem., 1991, 56, 6971.
14 (a) For other examples, see: A. S. K. Hashmi, R. Salathe
´
and
re,
W. Frey, Chem.–Eur. J., 2006, 12, 6991; (b) G. Lemie
´
V. Gandom, N. Agenet, J.-P. Goddard, A. de Kozak,
C. Aubert, L. Fensterbank and M. Malacria, Angew. Chem., Int.
Ed., 2006, 45, 7596; (c) A. W. Sromek, M. Rubina and
V. Gevorgyan, J. Am. Chem. Soc., 2005, 127, 10500 and ref. 3b.
15 For oxidative potential of gold(III), see: A. S. K. Hashmi,
M. C. Blanco, D. Fischer and J. W. Bats, Eur. J. Org. Chem.,
2006, 1387.
´
16 For an exception, see: C. H. M. Amijs, V. Lopez-Carrillo and
A. M. Echavarren, Org. Lett., 2007, 9, 4021.
17 DFT studies on a related gold vinyl carbenoid species have shown
that the C1–C2 and C2–C3 bonds are almost equally long,
suggesting that the positive charge is highly delocalized in p
orbitals of the conjugated system involving the Au, C1, C2 and
C3 atoms; see: A. Correa, N. Marion, L. Fensterbank,
M. Malacria, S. P. Nolan and L. Cavallo, Angew. Chem., Int.
Ed., 2008, 47, 718.
We thank Erasmus (JTB), ScotChem (MSH) and Heriot-Watt
University for their financial support.
18 Similar rearrangements have been reported with rhodium(II) cata-
lysts, although with much lower yields. See: (a) P. Muller and
¨
C. Granicher, Helv. Chim. Acta, 1995, 78, 129; Pd catalysed indene
formation from related cyclopropenes have been proposed to occur
via p-allylic complexes, see: (b) R. A. Fiato, P. Mushak and
M. A. Battiste, J. Chem. Soc., Chem. Commun., 1975, 869.
19 See ESIw for full mechanistic proposal and further details.
Notes and references
1 For selected reviews on gold catalysis, see: (a) Z. Li, C. Brouwer
and C. He, Chem. Rev., 2008, 108, 3239; (b) N. Bongers and
N. Krause, Angew. Chem., Int. Ed., 2008, 47, 2178; (c) D. J. Gorin
ꢀc
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Chem. Commun., 2008, 6405–6407 | 6407