Gold(i)-catalysed synthesis of conjugated trienes

Article abstract of DOI:10.1039/c0cc04217j

Gold(i)-catalysed reaction between cyclopropenes and furans produces functionalised conjugated trienes. The reaction is mild, facile and proceeds with very low catalyst loadings.

Full text of DOI:10.1039/c0cc04217j

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Gold(I)-catalysed synthesis of conjugated trienesw
Maximillian S. Hadfield and Ai-Lan Lee*
Received 4th October 2010, Accepted 4th November 2010
DOI: 10.1039/c0cc04217j
Gold(I)-catalysed reaction between cyclopropenes and furans
produces functionalised conjugated trienes. The reaction is mild,
facile and proceeds with very low catalyst loadings.
Table 1 Initial gold(I) catalyst screening on cyclopropene 1
Conjugated trienes are important structural units in many
biologically important polyene natural products such as
antifungal macrolides and anticancer retinoids,1 as well as
p-extended materials.2 As such, new synthetic methods
towards such building blocks are of great interest to synthetic
chemists.3 Current approaches towards functionalised, substituted
trienes, however, often require several iterative steps and/or
stoichiometric reagents.4 We recently initiated a programme to
explore the diverse chemistry of gold-catalysed5 transformations
with cyclopropenes.6–8 In this communication, we report an
unprecedented gold(I)-catalysed reaction of cyclopropenes
with furans to form a series of functionalised conjugated
trienes in a single step (Scheme 1). The reaction is very mild,
versatile, facile and proceeds with as little as 0.01 mol% of
catalyst to produce differentially substituted trienes. We thus
set out to explore the scope and selectivity of this novel,
one-pot catalytic approach towards conjugated trienes.
Entrya
Catalystb
Yieldc
1
2
3
4
PPh3AuNTf2
76%
72%
70%
78%
(IPr)AuCl/AgOTf
(IPr)AuCl/AgOTs
(IPr)AuCl/AgSbF6
5
91%
76%
6
(IMes)AuCl/AgOTf
a
Reaction conditions: cyclopropene 1 (1 equiv.), furan 2 (1.5 equiv.),
b
catalyst (5 mol%), 0.3 M in CH2Cl2. IPr = 1,3-bis(2,6-diisopropyl-
phenyl)imidazolylidene. IMes
c
Isolated yield of 3a+3b.
= 1,3-bis(mesityl)imidazolylidene.
We initiated our investigations with a catalyst screen on
cyclopropene 1 (Table 1). Every gold(I) catalyst screened in
Table 1 produced the conjugated triene in >70% yield
(Entries 1–6). Reaction monitoring indicated that the initial
gold(I)-catalysed ring-opening reaction is very fast (within
minutes), however, the immediate product is a complex
mixture of several E/Z isomer combinations of the triene product
3. Upon leaving the reaction for a further 24 h, the triene slowly
isomerises, mainly to 3a and 3b in B1 : 1 ratio. The cationic gold
catalyst 49 produces by far the best isolated yield of 3 (Entry 5)
and was thus adopted as the optimal catalyst.
A variety of alkyl substituted cyclopropenes also react
smoothly to produce the triene products in good yields
(Entries 2–5, 82–91% yields). In fact, we were pleased to find
that the (EEE)-triene can be isolated in good yields and
excellent stereoselectivities using the gold(I)/iodine one-pot
protocol when the substituents R1 and R2 are sterically or
electronically differentiated (Entries 5–9, Table 2).
Successful intermolecular reaction of the cyclopropenes
bearing aryl and/or ester functionalities is worthy of further
mention (Entries 6–9). Previous investigations have shown that
these cyclopropenes tend to undergo facile gold(I)-catalysed
intramolecular rearrangement to indenes and/or butenolides
and gold(I)-catalysed intermolecular reactions are, as a result,
highly challenging with such substrates.6a,8a,b It is thus very
pleasing that, for example, the intermolecular reaction of cyclo-
propene 15 with furan 2 predominates over the intramolecular
rearrangement in these reactions to produce the functionalised
conjugated triene 16a in good yield (75%) and high selectivity
(>95 : 5, Entry 7). Even the hindered trisubstituted cyclopropene
17 reacts smoothly to produce the (E,E,E) triene 18a in high
selectivity (>95 : 5, 77%), albeit requiring a higher reaction
temperature of 80 1C (Entry 8). When the phenyl substituents
in 17 are replaced with alkyl substituents (19), the desired triene
20a is still formed stereoselectively, but only in moderate yield
(37%, Entry 9). This is due to competition between the desired
reaction and a different rearrangement to produce the diene 22
(see ESI). Successful reaction with cyclopropene carboxylate
substrates such as 15, 17 and 19 is particularly pleasing as it
produces conjugated trienes with a handle for functionalisation
In an effort to expedite the isomerisation process, a crystal
of iodine was added to the reaction mixture after 15 min
(Table 2).3d Gratifyingly, this one-pot treatment with iodine
successfully isomerises the triene product to a presumably
thermodynamic ratio of stable isomers 3a and 3b, without
affecting the isolated yield of the product (Entry 1, Table 2).
Scheme 1 Gold(I)-catalysed synthesis of conjugated trienes.
School of Engineering and Physical Sciences,
Chemistry—William H. Perkin Building, Heriot-Watt University,
Edinburgh EH14 4AS, UK. E-mail: A.Lee@hw.ac.uk;
Tel: +44(0)131-4518030
w Electronic supplementary information (ESI) available: Experimental
details and analytical data for new compounds. See DOI: 10.1039/
c0cc04217j
c
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Table 2 Gold(I)-catalysed furan addition to a variety of cyclo-
propenes
Table 3 Gold(I)-catalysed addition of a variety of furan nucleophiles
to cyclopropene 11
Entrya R1
R2
R3
Product Yieldb
1
2
3
H
Me
OMe
H
H
H
H
H
H
24
12a
25
61%
85%
70%c
Ratio
of a : b Yieldb
Entrya Cyclopropene
Product
4
H
H
26
71%
5
6
CH2OCOCH3
tBu
(CH2)2CO2
H
H
H
H
27
28
78%
89%
1
3a
2.2 : 1
N/A
91%
83%
7
H
H
29
89%
i
(CH2)2 Pr
8
9
10
Me
Me
Me
H
Me
CO2Me
Me 30
H
H
82%
87%
75%d
31
32
2
6
Complex
mixture
11
Me
Me N/A
3
4
8a+8b
1.5 : 1
3.5 : 1
82%
91%
a
Reaction conditions: cyclopropene (1 equiv.), furan (1.5 equiv.),
catalyst 4 (5 mol%) in CH2Cl2 (0.3 M), 15 min, followed by a crystal
b
of I2, 1 h, RT., unless otherwise stated. Isolated yields; >95 : 5
10a+10b
c
selectivity of (E,E,E) isomer unless otherwise stated. Step ii): I2,
d
5 days, RT. Conditions: cyclopropene (1 equiv.), furan (1 equiv.),
catalyst 4 (3 mol%), 0.3 M in CH2Cl2. Ratio 1.5 : 1 Z/E around R2
substituent (see ESI).
5
6
7
12a
14a
16a
>95 : 5 85%
>95 : 5 64%
>95 : 5 75%c
Having explored the scope of the cyclopropene substrates,
we set out to explore the scope of the furan nucleophile
(Table 3). The substituent R1 on the furan 23 can be varied
(e.g. H, Me, OMe) to produce the aldehyde, ketone and ester
functionalised triene respectively (Entries 1–3). An acetal,
t
CH2OAc, bulky Bu and functionalised alkyl chain are also
tolerated at the R1 position, producing the corresponding
trienes in good yields and selectivities (Entries 4–7). Next, we
set out to investigate the reactivity and selectivity of
disubstituted furans. Methyl substituents at R1 and R3
(Entry 8) as well as R1 and R2 (Entry 9) are not detrimental
to the reactivity or selectivity, and is in fact a good way of
introducing further substituents into the triene product. An
electron withdrawing ester substituent is also tolerated at
position R2 (Entry 10). Trisubstituted furans, however, react
less well, presumably due to selectivity issues. For example, the
trisubstituted furan in Entry 11 provides a complex mixture of
products under the standard reaction conditions.
8
18a
>95 : 5 77%d
9
>95 : 5 37%e
a
Reaction conditions: cyclopropene (1 equiv.), furan 2 (1.5 equiv.),
catalyst 4 (5 mol%) in CH2Cl2 (0.3 M), 15 min, followed by a crystal of
Since the reaction appeared to be extremely facile, we were
keen to investigate if the catalyst loading could be lowered. We
were pleased to find that even with a 0.1 mol% loading of
Au(I) catalyst, the reaction (step i) was complete in o30 s with
no drop in isolated yield (90%, Table 4, Entry 1). Encouraged
by this result, the catalyst loading was lowered even further to
0.01 mol%. To our delight, the gold(I)-catalysed reaction was
still complete within 2 min to yield the triene products 3a+3b
in 89% yield (Table 4, Entry 2). This corresponds to an
impressive TON of 10 000.
b
I2, 1 h, RT., unless otherwise stated. Isolated yields. Step i left for
c
d
16 h. Reaction conditions for step (i): furan 2 (1.5 equiv.), catalyst 4
e
(15 mol%), DCE, 80 1C, 18 h. Reaction conditions for step (i): furan
2 (12 equiv.), catalyst 4 (10 mol%), 15 1C, 24 h. By-product is diene 22.
at both ends of the triene (16a, 18a, 20a), allowing for potential
incorporation of the triene unit into larger building blocks.
Cyclopropene carboxylates are also very easy to access, for
example, 17 and 19 are each synthesised in one step from
commercially available ethyl diazoacetate.10
In an effort to ascertain if catalysts other than gold(I) can
carry out the same reaction, a small screen of other transition
c
1334 Chem. Commun., 2011, 47, 1333–1335
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Table 4 Catalyst loading and further catalyst screening, and control
reactions
stereoselectively after treatment with iodine if the substituents
on the cyclopropene are sterically or electronically differentiated.
This novel reaction should be a useful addition to the toolkit
of synthetic methods for polyene targets.
We thank ScotChem, EPSRC and The Royal Society for
funding and the EPSRC Mass Spectrometry Services at
Swansea for analytical support. We thank Paul C. Young
for initial experiments with 5.
Ratio
of 3a : 3b Yieldb
Notes and references
Entrya Catalyst
Mol% Time
1 C. Thirsk and A. Whiting, J. Chem. Soc., Perkin Trans. 1, 2002, 999.
2 R. E. Martin and F. Diederich, Angew. Chem., Int. Ed., 1999, 38, 1350.
3 Selected examples: (a) S. J. Lee, K. C. Gray, J. S. Paek and
M. D. Burke, J. Am. Chem. Soc., 2008, 130, 466; (b) K. Miki,
M. Fujita, S. Uemura and K. Ohe, Org. Lett., 2006, 8, 1741;
(c) Y. Ikeda, M. Murai, T. Abo, K. Miki and K. Ohe, Tetrahedron
Lett., 2007, 48, 6651; (d) E. Wenkert, M. Guo, R. Lavilla,
B. Porter, K. Ramachandran and J. H. Sheu, J. Org. Chem.,
1990, 55, 6203; (e) P. Wipf and P. D. G. Coish, Tetrahedron Lett.,
1997, 38, 5073; (f) K. Hemming and R. J. K. Taylor, J. Chem. Soc.,
Chem. Commun., 1993, 1409; (g) D. Frederico, P. M. Donate,
M. G. Constantino, E. S. Bronze and M. I. Sairre, J. Org. Chem.,
2003, 68, 9126; (h) Y. J. Zhao and T. P. Loh, Tetrahedron, 2008, 64,
4972; (i) A. G. M. Barrett, D. Hamprecht and M. Ohkubo, J. Org.
Chem., 1997, 62, 9376; (j) B. H. Lipshutz and C. Lindsley, J. Am.
Chem. Soc., 1997, 119, 4555.
1
2
3
4
5
6
7
4
0.1
0.01
5
o30 s 2.2 : 1
90%
89%
77%
44%
Complex mixture
No reaction
No reaction
4
PtCl2
[Ru(CO)3Cl2]2 10
Rh2(OAc)4
No catalyst
I2 only
o2 min 2.2 : 1
6 h
2.2 : 1
2.2 : 1
N/A
N/A
N/A
24 h
24 h
24 h
24 h
5
N/A
N/A
a
Reaction conditions: cyclopropene 1 (1 equiv.), furan 2 (1.5 equiv.),
in CH2Cl2 (0.3 M), 15 min, followed by a crystal of I2, 1 h, RT., unless
b
otherwise stated. Isolated yields.
4 S. Koo, in Science of Synthesis, Georg Thieme Verlag, 2010, vol.
45b, p. 1349.
5 Selected reviews: (a) D. J. Gorin and F. D. Toste, Nature, 2007, 446,
395; (b) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180; (c) E. Jimenez-
Nunez and A. M. Echavarren, Chem. Commun., 2007, 333; (d) Z. G. Li,
C. Brouwer and C. He, Chem. Rev., 2008, 108, 3239; (e) N. Marion and
S. P. Nolan, Chem. Soc. Rev., 2008, 37, 1776; (f) A. Furstner and
¨
P. W. Davies, Angew. Chem., Int. Ed., 2007, 46, 3410;
(g) A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49, 5232.
6 (a) J. T. Bauer, M. S. Hadfield and A. L. Lee, Chem. Commun.,
2008, 6405; (b) M. S. Hadfield, J. T. Bauer, P. E. Glen and
A. L. Lee, Org. Biomol. Chem., 2010, 8, 4090; (c) M. S. Hadfield
and A. L. Lee, Org. Lett., 2010, 12, 484; (d) K. J. Kilpin,
U. S. D. Paul, A. L. Lee and J. D. Crowley, Chem. Commun.,
2010, DOI: 10.1039/c1030cc02185g.
7 Recent reviews on cyclopropene chemistry: (a) I. Marek, S. Simaan
and A. Masarwa, Angew. Chem., Int. Ed., 2007, 46, 7364; (b) M. Rubin,
M. Rubina and V. Gevorgyan, Synthesis, 2006, 1221; (c) M. Rubin,
M. Rubina and V. Gevorgyan, Chem. Rev., 2007, 107, 3117;
(d) J. M. Fox and N. Yan, Curr. Org. Chem., 2005, 9, 719.
8 For other reports on gold-catalysed reactions with cyclopropenes:
(a) Z. B. Zhu and M. Shi, Chem.–Eur. J., 2008, 14, 10219;
(b) C. K. Li, Y. Zeng and J. B. Wang, Tetrahedron Lett., 2009,
50, 2956; (c) C. K. Li, Y. Zeng, H. Zhang, J. Feng, Y. Zhang and
J. B. Wang, Angew. Chem., Int. Ed., 2010, 49, 6413; (d) F. Miege,
C. Meyer and J. Cossy, Org. Lett., 2010, 12, 4144.
Scheme 2 Plausible mechanism for the gold(I)-catalysed synthesis of
conjugated trienes.
metal catalysts was carried out (Table 4). PtCl2, a p-Lewis
acid,5f successfully catalyses the reaction, but in a much slower
reaction time and with a lower isolated yield (6 h, 77% yield,
Entry 3).12 [Ru(CO)3Cl2]2 requires even longer reaction
3b
times (24 h) and produces the trienes in much lower yields
(44%, Entry 4). Rh2(OAc)4 on the other hand, produced a
complex mixture of products (Entry 5). By comparison,
several different gold(I) catalysts shown in Table 1 successfully
formed triene products within minutes. Finally, control
reactions without catalyst (Entry 6) and with iodine
(Entry 7) resulted in no reaction, thus confirming that the
triene forming reaction in Entries 1 and 2 is indeed gold(I)-
catalysed. It is also noteworthy that the gold(I)-catalysed
reaction is not sensitive to air or moisture.
9 C. Nieto-Oberhuber, S. Lopez, M. P. Munoz, D. J. Cardenas,
E. Bunuel, C. Nevado and A. M. Echavarren, Angew. Chem., Int.
Ed., 2005, 44, 6146.
10 C. Li, H. Zhang, J. Feng, Y. Zhang and J. Wang, Org. Lett., 2010,
12, 3082.
A plausible mechanism for the reaction is shown in
Scheme 2. Gold(I) activates the ring opening of the cyclo-
propene to form intermediate I, which possesses both cation
and carbene character.11 Furan then reacts as a nucleo-
phile13,14 and subsequent ring opening produces a mixture of
triene isomers, which isomerises to the most stable triene (path
A). A second possible pathway involves cyclopropanation of
furan, followed by ring opening of II to form the triene
(path B).
11 (a) D. Benitez, N. D. Shapiro, E. Tkatchouk, Y. M. Wang,
W. A. Goddard and F. D. Toste, Nat. Chem., 2009, 1, 482;
(b) G. Seidel, R. Mynott and A. Furstner, Angew. Chem., Int. Ed.,
¨
2009, 48, 2510; (c) A. M. Echavarren, Nat. Chem., 2009, 1, 431.
12 For a comparison of gold, Pt and Rh-catalysts for the synthesis of
phenols from alkynes and furans, see: A. S. K. Hashmi,
T. M. Frost and J. W. Bats, Org. Lett., 2001, 3, 3769.
13 For examples of carbene trigerred ring opening of furans, see
ref. 3b–d.
14 For examples of gold-catalysed reactions of furans with alkynes to
form phenols, see: (a) A. S. K. Hashmi, M. Rudolph, H.-U. Siehl,
M. Tanaka, J. W. Bats and W. Frey, Chem.–Eur. J., 2008, 14, 3703;
(b) A. S. K. Hashmi, T. M. Frost and J. W. Bats, J. Am. Chem. Soc.,
2000, 122, 11553; (c) A. S. K. Hashmi, M. C. Blanco, E. Kurpejovic,
W. Frey and J. W. Bats, Adv. Synth. Catal., 2006, 348, 709.
In conclusion, we have developed a mild and facile
gold(I)-catalysed reaction of cyclopropenes and furans to form
a series of functionalised trienes in high yields. As little as
0.01 mol% catalyst can be used and the trienes are formed
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 1333–1335 1335