Regioselective synthesis of tert-allylic ethers via gold(l)-catalyzed Lntermolecular hydroalkoxylation of allenes

Article abstract of DOI:10.1021/ol902675k

[Chemical equation presented] A highly regioselective method towards tertiary allylic ethers via gold(l)-catalyzed intermolecular hydroalkoxylation of alienes is disclosed. Preventing subsequent isomerizatlon of the tertiary allylic ether products to primary allylic ethers appears to be the key to achieving high regioselectivities.

Full text of DOI:10.1021/ol902675k

ORGANIC
LETTERS
2010
Vol. 12, No. 3
484-487
Regioselective Synthesis of tert-Allylic
Ethers via Gold(I)-Catalyzed Intermolecular
Hydroalkoxylation of Allenes
Maximillian S. Hadfield and Ai-Lan Lee*
School of Engineering and Physical Sciences, Heriot-Watt UniVersity,
Edinburgh EH14 4AS United Kingdom
a.lee@hw.ac.uk
Received November 20, 2009
ABSTRACT
A highly regioselective method towards tertiary allylic ethers via gold(I)-catalyzed intermolecular hydroalkoxylation of allenes is disclosed. Preventing
subsequent isomerization of the tertiary allylic ether products to primary allylic ethers appears to be the key to achieving high regioselectivities.
The preparation of ethers is one of the most fundamental
reactions in organic synthesis. For example, alkyl allylic
Scheme 1. Gold(I)-Catalyzed Hydroalkoxylation of Allenes
ethers are found in natural products and are versatile
substrates and building blocks in organic synthesis.1 The
most widely used method for formation of ethers, the
Williamson ether synthesis, is seldom useful for preparing
tertiary ethers, as elimination reactions tend to be favored
when tertiary alkoxides or tertiary halides are used.2
Despite recent advances, a mild, efficient, and general
method for the synthesis of alkyl tert-allylic ethers still
remains a challenging topic for synthetic chemists.3
An atom-economical solution to the problem would be to
develop a regioselective intermolecular hydroalkoxylation of
1,1-disubstituted allenes (1f3, Scheme 1). Stoichiometric
amounts of toxic mercury(II) salts have been known to
mediate such transformations,4 but no modern, catalytic
method exists.5 Gold(I) is a superb carbophilic Lewis acid6
and is thus an obvious candidate for catalyzing 1f3.
However, all reported procedures, notably by the groups
of Widenhoefer and Yamamoto, show that gold(I) catalyzes
the intermolecular hydroalkoxylation of 1 regioselectively
to provide primary allylic ethers 2 instead of tertiary allylic
ethers 3 (Scheme 1).7-9 While carrying out mechanistic
(1) For selected examples of biologically relevant molecules and natural
products with alkyl tert-allylic ether moieties, see: (a) Evidente, A.; Andolfi,
A.; Fiore, M.; Boari, A.; Vurro, M. Phytochemistry 2006, 67, 19. (b)
Matsumoto, F.; Idetsuki, H.; Harada, K.; Nohara, I.; Toyoda, Y. J. Essent.
Oil Res. 1993, 5, 123. (c) Bohlmann, F.; Singh, P.; Jakupovic, J.
Phytochemistry 1982, 21, 157. (d) Olagnier, D.; Costes, P.; Philippe; Berry,
A.; Linas, M.-D.; Urrutigoity, M.; Dechy-Cabaret, O.; Benoit-Vical, F.
Bioorg. Med. Chem. Lett. 2007, 17, 6075. (e) Giannouli, A. L.; Kintzios,
S. E. Med. Aromat. PlantssInd. Profiles 2000, 14, 69.
(3) For example, see: (a) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc.
2002, 124, 7882. (b) Trost, B. M.; McEachern, E. J.; Toste, F. D. J. Am.
Chem. Soc. 1998, 120, 12702. (c) Shintou, T.; Mukaiyama, T. J. Am. Chem.
Soc. 2004, 126, 7359. (d) Corma, A.; Renz, M. Angew. Chem. Int. Ed.
2007, 46, 298, and references cited therein.
(2) (a) Assabumrungrat, S.; Kiatkittipong, W.; Sevitoon, N.; Praserthdam,
P.; Goto, S. Int. J. Chem. Kinet. 2002, 34, 292. (b) Shi, B.; Davis, B. H. J.
Catal. 1995, 157, 359.
10.1021/ol902675k  2010 American Chemical Society
Published on Web 01/05/2010

investigations into gold(I)-catalyzed alcohol additions to cy-
clopropenes, we gathered compelling evidence that it is possible
to completely switch the regioselectivity of allene hydroalkoxy-
lations to provide the more challenging tert-allylic ethers 3.
Herein, we report our successful attempt at developing a
regioselective gold(I)-catalyzed method for hydroalkoxylation
of allenes to provide alkyl tert-allylic ethers 3.
Scheme 3. Gold(I)-Catalyzed Isomerization of tert-Allylic
Ethers to Primary Allylic Ethers: Excess Alcohol Retards
Isomerization
We recently disclosed a highly regioselective, facile, and
mild gold(I)-catalyzed addition of alcohols to cyclopropenes
4 to form alkyl tert-allylic ethers 5 (Scheme 2).10 An excess
Scheme 2
.
Previous Results: Regioselective Gold(I)-Catalyzed
Alcohol Additions to Cyclopropenes10
We were thus highly intrigued by a recent report on DFT
calculations regarding the intermolecular hydroalkoxylation of
allenes.12 Various groups have demonstrated that gold-catalyzed
hydroalkoxylation of 1,1-disubstituted allenes such as 8 pro-
duces the primary allyl ethers 10 regioselectively (Scheme 4).7
of alcohol is crucial to ensure high regioselectivity for the
tertiary (vs primary) ether. Suspecting isomerization between
ethers 3 and 2, tert-allylic ether 6 was subjected to gold(I)
catalysis11 in the absence and presence of excess alcohol
(Scheme 3). The tertiary ether 6 does indeed isomerize to
the primary ether 7 under gold(I) catalysis, but addition of
excess alcohol retards this isomerization. We postulated that
the latter observation is the key to the high regioselectivities
observed in Scheme 2.
Scheme 4. DFT Calculations by Paton and Maseras Suggest that
Facile Isomerization is Responsible for Selectivity of 1012
(4) Waters, W. L.; Kiefer, E. F. J. Am. Chem. Soc. 1967, 89, 6261.
(5) Intramolecular hydroalkoxylation of allenes, however, has been
realized using a variety of different metals, including Au(I) and Au(III).
For representative examples, see: (a) Winter, C.; Krause, N. Green Chem.
2009, 11, 1309. (b) Deutsch, C.; Gockel, B.; Hoffmann-Ro¨der, A.; Krause,
N. Synlett 2007, 1790. (c) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste,
F. D. Science 2007, 317, 496. (d) Volz, F.; Krause, N. Org. Biomol. Chem.
2007, 5, 1519. (e) Hashmi, A. S. K.; Blanco, M. C.; Fischer, D.; Bats,
J. W. Eur. J. Org. Chem. 2006, 1387. (f) Erdsak, J.; Krause, N. Synthesis
2007, 3741. (g) Alcaide, B.; Almendros, P.; Martinez del Compo, T. Angew.
Chem., Int. Ed. 2007, 46, 6684. (h) Zhang, A.; Liu, C.; Kinder, R. E.; Han,
X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128, 9066. (i)
Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283. (j)
Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
DFT calculations, however, suggest that the tertiary allyl ether
9 should be the kinetic product, and subsequent gold-catalyzed
isomerization possibly occurs to produce the observed (and
more stable) primary allylic ether 10.
Bearing in mind our discovery in Scheme 3, we became
excited at the possibility of switching the regioselectivity of
the gold-catalyzed hydroalkoxylation of allenes by simply
retarding the subsequent isomerization process, presumably
with excess alcohol. Such a switch in regioselectivity will
produce the much harder-to-access tert-allyl ethers 3 over
the primary allyl ethers 2. Our proof-of-concept study clearly
shows that an excess of alcohol changes the 2:3 selectivity
of the reaction (Scheme 5). Although a 3:1 ratio of 12:13 is
far from selective, the change in ratio nevertheless gave us
(6) For selected reviews on gold catalysis, see: (a) Gorin, D. J.; Toste,
F. D. Nature 2007, 446, 395. (b) Fu¨rstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3410. (c) Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008,
108, 3239. (d) Shen, H. C. Tetrahedron 2008, 64, 3885. (e) Shen, H. C.
Tetrahedron 2008, 64, 7847. (f) Hashmi, A. S. K. Chem. ReV. 2007, 107,
3180.
(7) (a) Zhang, Z.; Widenhoefer, R. Org. Lett. 2008, 10, 2079. (b) Nishina,
N.; Yamamoto, Y. Tetrahedron 2009, 65, 1799. (c) Nishina, N.; Yamamoto,
Y. Tetrahedron Lett. 2008, 49, 4908. (d) Cui, D.-M.; Yu, K. R.; Zhang, C.
Synlett 2009, 1103. (e) Cui, D.-M.; Zheng, Z.-L.; Zhang, C. J. Org. Chem.
2009, 74, 1426.
Scheme 5
. Initial Studies: Effect of Excess Alcohol on the
(8) The first report on Au(I)-catalyzed reaction of alcohols and allenes
involves the sequential addition of two molecules of methanol to the central
carbon of the allene: Schulz, M.; Teles, J. H. (BASF AG), WO-A1 9721648,
1997. Chem. Abstr. 1997, 127, 121499.
Gold(I)-Catalyzed Hydroalkoxylation of Allenes
(9) For a review on gold-catalyzed reaction of alcohols, see: Muzart, J.
Tetrahedron 2008, 64, 5815.
(10) Bauer, J. T.; Hadfield, M. S.; Lee, A.-L. Chem. Commun. 2008,
6405.
(11) For development of PPh3AuNTf2, see: Me´zailles, N.; Richard, L.;
Gagosz, F. Org. Lett. 2005, 7, 4133.
(12) Paton, R. S.; Maseras, F. Org. Lett. 2009, 11, 2237.
(13) For a review on applications of NHC-Au complexes, see: Marion,
N.; Nolan, S. P. Chem. Soc. ReV. 2008, 37, 1776.
Org. Lett., Vol. 12, No. 3, 2010
485

confidence that following optimization studies, a complete
switch of regioselectivity could be achieved.
Table 2. Gold(I)-Catalyzed Intermolecular Hydroalkoxylation of
Following ligand, counterion, solvent, concentration, equiva-
lents of alcohol, and temperature screening (see Supporting
Information), we successfully developed conditions to pro-
duce alkyl tert-allylic ethers 3 through hydroalkoxylation of
allenes in excellent regioselectivity and good yields (Table
1). It is necessary to switch to the NHC gold catalyst
[(IPr)AuCl/AgOTf]13,14 in DMF and excess alcohol at 0 °C
to produce the desired regioselectivity.15 It is of interest to
note that of all the solvents screened only DMF produced
the desired regioselectivity and conversion (see Supporting
Information).16 Even running the reaction in neat alcohol
produced only a ∼1:1 ratio of 2:3.
a Range of Allenes
The intermolecular hydroalkoxylation of allene 14 with a
range of alcohols is presented in Table 1. A wide range of
Table 1. Gold(I)-Catalyzed Intermolecular Hydroalkoxylation of
14 with a Range of Alcohols
entry
R
product
3:2a
yield (%)b
1
2
3
4
5
6
7
8
9
Et
15a
15b
15c
15d
15e
15f
15g
15h
15i
99:1
99:1
99:1
99:1
99:1
99:1
99:1
3:1
83
86
74
85
85
81
82
20
0
-(CH2)4Ph
-(CH2)2CHdCH2
-(CH2)2Ph
-CH2CH(Ph)(Me)
-CH2C(CH3)3
-CH2CHdCHPh
iPr
tBu
N/A
a Determined by 1H NMR analysis of the crude mixture. b Isolated yield
of product 15.
primary alcohols add to allenes to produce the tert-allylic
ethers 15 in good to excellent selectivities and good isolated
yields (entries 1-7). In particular, even more sterically
encumbered primary alcohols such as 2-phenylpropan-1-ol
(entry 5) and neopentyl alcohol (entry 6) add with excellent
regioselectivities. Secondary and tertiary alcohols, however,
are not efficient nucleophiles under these conditions (entries
8 and 9). Isopropanol reacts rather sluggishly to produce only
20% of 15h after 24 h, with a 3:1 regioselectivity of the
tertiary and primary allylic ethers (entry 8). Unsurprisingly,
tert-butanol does not react at all even under prolonged
reaction times (entry 9).
a Determined by 1H NMR analysis of the crude mixture. b Isolated yield.
c This reaction was carried out with 15 mol % catalyst for 48 h.
hydroalkoxylation smoothly to provide the corresponding
tert-allylic ethers 17 and 18 regioselectively (99:1, entries 1
(14) A control with AgOTf as the catalyst resulted in no reaction.
(15) Under these optimized conditions, no isomerization of tertiary
ethers 3 to primary ethers 2 is observed, regardless of the presence of
excess alcohol. The excess alcohol, however, is still necessary to supress
the formation of other byproducts. See Supporting Information for more
details.
Next, we carried out scope and generality studies with a
range of allenes (Table 2). Allenes 16 and 11 undergo
486
Org. Lett., Vol. 12, No. 3, 2010

and 2). Gratifyingly, even trisubstituted allene 19 produces
tert-allylic ether 20 regioselectively and stereoselectively
(99:1, E-selectivity, entry 3). Entries 4-6 investigate the
effect of bringing the Ph ring progressively closer to the
reactive center. While reaction with allene 14 proceeds
smoothly (entry 4), allene 21 with a benzyl substituent
produces slightly lower regioselectivity (90:10, entry 5). The
regioselectivity drops again with bulkier allene 23 (85:15, entry
6). Nevertheless, the tert-allylic ether product is still favored
over the primary in all of the cases studied. Finally, reaction
with exocyclic allene 25 produces 26 regioselectively, and the
acetal moiety is tolerated under these conditions (entry 7).
Since the hydroalkoxylation of allene 21 produced only a
9:1 ratio of 3:2, we were intrigued to compare this reaction
with the gold(I)-catalyzed addition of alcohol to the corre-
sponding cyclopropene 27 (Scheme 6). To our delight, tert-
Scheme 7. Further Functionalizations
(Scheme 7).17,18 The iodoalkene is a good handle for further
functionalization at the alkene. For example, Sonogashira
coupling with phenylacetylene successfully produces 30 in
95% yield (Scheme 7).
Scheme 6. Preparation of tert-Allylic Ether 22 through
Gold(I)-Catalyzed Alcohol Addition to Cyclopropene 27
In summary, we present a method for regioselective
formation of alkyl tert-allylic ethers via gold-catalyzed
hydroalkoxylation of allenes. It is thus now possible to
achieve either regioselective formation of primary allylic
ethers 27 or tertiary allylic ethers 3 via gold-catalyzed
hydroalkoxylation of allenes simply by switching the reaction
conditions. The method presented in this communication is
complementary to our previous approach involving gold-
catalyzed additions of alcohols to cyclopropenes.10 Future
work will focus on the extension of these reactions to
enantioselective methods.
allylic ether 22 is formed regioselectively (>99:1) and in good
yield (86%) from cyclopropene 27. We believe that this
example exemplifies the complementarity of the two ap-
proaches toward tert-allylic ethers.
Finally, it is possible to trap the putative vinylgold
intermediate (e.g., 28) with NIS to produce iodoalkene 29
Acknowledgment. We thank ScotChem, EPSRC (EP/
G006695/1) and the EPSRC National Mass Spectrometry
Service Centre at Swansea.
(16) For a review on DMF: much more than a solvent, see: Muzart, J.
Tetrahedron 2009, 65, 8313.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) For examples of capture of vinylgold intermediates with iodine,
see: (a) Schuler, M.; Silva, F.; Bobbio, C.; Tessier, A.; Gouverneur, V.
Angew. Chem., Int. Ed. 2008, 47, 7927. (b) Kirsch, S. F.; Binder, J. T.;
Crone, B.; Duschek, A.; Haug, T. T.; Lie´bert, C.; Menz, H. Angew. Chem.,
Int. Ed. 2007, 46, 2310. (c) Buzas, A.; Gagosz, F. Synlett 2006, 2727. (d)
Buzas, A.; Gagosz, F. Org. Lett. 2006, 8, 515. (e) Yu, M.; Zhang, L. Org.
Lett. 2007, 9, 2147. (f) Alcaide, B.; Almendros, P.; del Campo, T. M. Angew.
Chem., Int. Ed. 2007, 46, 6684. (g) Liu, L.-P.; Hammond, J. B. Chem. Asian
J. 2009, 4, 1230.
OL902675K
(18) A control reaction with NIS as the reagent (without any gold
catalyst) results in <5% of 29 being formed.
Org. Lett., Vol. 12, No. 3, 2010
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