Au(I)- and Pt(II)-catalyzed cycloetherification of ω-hydroxy propargylic esters

Article abstract of DOI:10.1021/ol8008107

(Chemical Equation Presented) Depending on the nature of the metal catalyst, ω-hydroxy propargylic acetates choose between alternative cycloetherification manifolds to produce functionalized heterocycles in high yields. AuCl catalyzes the formation of oxacyclic enol acetates, whereas [Cl₂Pt(CH₂CH₂)]₂ (Zeise's dimer) will induce a propargylic substitution via an unprecedented S _N2′-type allenic substitution from within a chelated square planar cationic Pt(II) complex.

Full text of DOI:10.1021/ol8008107

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2533-2536
Au(I)- and Pt(II)-Catalyzed
Cycloetherification of ω-Hydroxy
Propargylic Esters
Jef K. De Brabander,* Bo Liu, and Mingxing Qian
Department of Biochemistry, The UniVersity of Texas Southwestern Medical
Center at Dallas, 5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
jef.debrabander@utsouthwestern.edu
Received April 9, 2008
ABSTRACT
Depending on the nature of the metal catalyst, ω-hydroxy propargylic acetates choose between alternative cycloetherification manifolds to
produce functionalized heterocycles in high yields. AuCl catalyzes the formation of oxacyclic enol acetates, whereas [Cl2Pt(CH2CH2)]2 (Zeise’s
dimer) will induce a propargylic substitution via an unprecedented SN2′-type allenic substitution from within a chelated square planar cationic
Pt(II) complex.
Recently, we reported a catalytic hydroalkoxylation of
alkynes as an attractive strategy to ketal/spiroketal substruc-
tures present in many natural products.1 This approach takes
advantage of the alkyne functionality as a nucleus for metal-
catalyzed reorganization of linear precursors into valuable
heterocycles. In an extension of these studies, we decided
to investigate the reactivity of ω-hydroxy propargylic esters
and uncovered two distinct modes of reactivity depending
on the nature of the metal catalyst that initiates electrophilic
activation of the triple bond.2 The studies reported herein
culminated in a practical mild method for the synthesis of
functionally diverse substituted oxygen-containing hetero-
cycles.3
We envisioned that a metal with dual alkynophilic/
allenophilic properties would be poised to catalyze a tandem
1,3-acyloxy migration/ cycloisomerization of ω-hydroxy
propargylic esters 1 to heterocyclic enolesters 2 (eq 1).4–6
In an initial screen with substrate 1a (R ) Me, R′ )
(4) For selected examples of reactions initiated by 1,3-acyloxy migration
not cited in the reviews listed in ref 2, see: (a) Correa, A.; Marion, N.;
Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo, L. Angew. Chem.,
Int. Ed. 2008, 47, 718. (b) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed.
2007, 46, 2750. (c) Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak,
D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868. (d) Barluenga, J.;
Riesgo, L.; Vicente, R.; Lo´pez, L. A.; Toma´s, M. J. Am. Chem. Soc. 2007,
129, 7772. (e) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147. (f)
Lemie`re, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A.-L.;
Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207. (g) Amijs, C. H. M.;
Lo´pez-Carrillo, V.; Echavarren, A. M. Org. Lett. 2007, 9, 4021. (h) Marion,
N.; Carlqvist, P.; Gealageas, R.; De Fre´mont, P.; Maseras, F.; Nolan, S. P.
(1) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4908.
(2) For selected reviews, see: (a) Fu¨rstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 3410. (b) Hashmi, A. S. K. Chem. ReV. 2007,
107, 3180. (c) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817. (d) Gorin,
D. J.; Toste, F. D. Nature 2007, 446, 395. (e) Hashmi, A. S. K.; Hutchings,
G. J. Angew. Chem., Int. Ed. 2006, 45, 7896. (f) Hoffmann-Ro¨der, A.;
Krause, N. Org. Biomol. Chem. 2005, 3, 387.
Chem. Eur. J. 2007, 13, 6437
(5) For a mechanistic study of Ag(I)-catalyzed propargyl/allenyl ester
isomerization, see: (a) Schlossarczyk, H.; Sieber, W.; Hesse, M.; Hansen,
.
H.-J.; Schmid, H. HelV. Chim. Acta 1973, 56, 875
.
(6) For a Ag(I)- and Au(I)-catalyzed endo-cycloisomerization for the
synthesis of dihydrofurans, see: (a) Shigemasa, Y.; Yasui, M.; Ohrai, S.-
I.; Sasaki, M.; Sashiwa, H.; Saimoto, H. J. Org. Chem. 1991, 56, 910. (b)
(3) For a recent review, see: (a) Larrosa, I.; Romea, P.; Urp´ı, F.
Tetrahedron 2008, 64, 2683.
Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957
.
10.1021/ol8008107 CCC: $40.75
Published on Web 05/28/2008
2008 American Chemical Society

hindered, less reactive isopropyl-substituted substrate 1j
required heating for 16 h.9
A mechanistic hypothesis consistent with the data is
-(CH2)2Ph, n ) 0), we found that AuCl (5 mol %) was the
optimal catalyst to perform the desired transformation to
enolester 2a (CH2Cl2, rt, 30 min, 93% yield).7 As will be
discussed later, [CH2CH2PtCl2]2 was unique among the
screened catalysts by initiating an alternative pathway leading
to propargylic substitution products 3 (eq 1).
provided in Figure 1. After initial AuCl-catalyzed [3,3]-
The AuCl-catalyzed cycloisomerisation represents a mild
and general method to access stereodefined enol acetates 2
in high yields (81-98%) and generally high Z-selectivity
(Table 1).8 Secondary alcohols 1h and 1i reacted with lower
Figure 1. Proposed mechanism for Au-catalyzed cyclizations.
rearrangement of propargylic acetate 1, the corresponding
allenyl gold complex 4 or 5 undergoes intramolecular
hydroalkoxylation to vinylgold species 6. Final proto-
deauration yields Z- or E-enol acetate 2. The selective
formation of Z-products indicates that cyclization from a
complex with gold coordinated cis to the R′-substituent (4)
is preferred over the alternative 5, possibly due to minimiza-
tion of A1,3 -strain. For secondary alcohols, the cycloisomer-
ization is subject to double diastereoselection. For example,
cyclization of 1-syn to Z-2 represents a matched case via an
all-equatorial chairlike TTS (4 f Z-6). For the corresponding
1-anti diastereomer, cyclization from the gold-allenoate
complex leading to the Z-isomer would occur via an
unfavorable TTS with axial R-substituent (not shown),
leading to the minor 2,6-trans-products (∼5%). Instead,
cycloisomerization proceeds through an all-equatorial TTS
leading to E-2. This represents a mismatched case, and
allene-epimerization5 (5 f 4) competes kinetically.10 Con-
sistent with this, syn/anti mixtures of substrates 1h,i yield
tetrahydropyrans 2h,i in Z/E ratios deviating from unity.
As noted in the introduction, Zeise’s dimer ([CH2CH2-
PtCl2]2) did not induce cycloisomerization according to eq
1 but instead catalyzed a propargylic substitution pathway.
As shown in Table 2, treatment of propargylic acetates 1
with 2.5 mol % of Zeise’s dimer (THF, 30 min, rt) efficiently
affords propargylic substitution products 3. Primary alcohols
gave monosubstituted ethers 3b-e,g or isochromans 3n,o
in yields ranging from 77-93%. Phenols also participate in
this transformation yielding dihydrobenzopyran 3m. Silyl
protecting groups (1c,d,k,l) survived the mild reaction
conditions, and ꢀ-hydroxy ester 1i cyclized (f 3i) without
competing ꢀ-elimination. Epimeric mixtures of δ-hydrox-
ypropargylic acetate 1p or 1q yield tetrahydrofurans 3p or
Table 1. AuCl-Catalyzed Synthesis of Oxacyclic Enolestersa
a Reaction conditions: propargyl acetate (0.1 M in THF), 5 mol % AuCl,
rt, 30 min. Substrate 1j was refluxed for 16 h. b Yields are for isolated
1
products. Ratios/stereochemistry determined by H NMR.
Z/E-selectivity but good selectivity for the 2,6-cis-tetrahy-
dropyrans 2h and 2i. Diastereomerically pure alcohol 1k
cyclized with retention of configuration and excellent Z-
selectivity. Finally, silyl protecting groups (1c,d, 1k) were
compatible with the reaction conditions and ꢀ-hydroxy ester
1i cyclized without competing ꢀ-elimination. The more
(9) The enol acetate was not stable under the reaction conditions, and
ꢀ-ketone 2j was isolated instead. In all other cases presented in Table 1,
the enolic esters are stable to isolation and chromatography. If desired, they
can be transformed to the corresponding ꢀ-ketones under mild conditions
and in high yields; see Supporting Information.
(7) Other catalysts were inactive, resulted in low conversion (AgPF6),
or yielded complex mixtures (ClAuPPh3/AgPF6, MeAuPPh3/AgPF6, AuCl3,
NaAuCl4, PtCl2). In THF, NaAuCl4·2H2O (5 mol %) did catalyze the
formation of enol ester 2g (Z:E ) 8:1) from 1g in 90% yield.
(8) For a mechanistically distinct Au-catalyzed synthesis of heterocycles
from homopropargylic ethers, see: (a) Jung, H. H.; Floreancig, P. E. J.
Org. Chem. 2007, 72, 7359.
(10) The isomeric products do not equilibrate. However, AuCl and
[Cl2PtCH2CH2]2 catalyze the racemization of homochiral 3-acetoxy-2-Me-
7-Ph-4-heptyne (98% ee) at rates similar to those of the cyclizations in
Tables 1 and 2; see Supporting Information.
2534
Org. Lett., Vol. 10, No. 12, 2008

Table 2. Pt(II)-Catalyzed Synthesis of Cyclopropargyl Ethersa, b
Table 3. Influence of Ester and Solvent on Product Distribution
entry
substrate
conditions
3ga
8a
1
2
3
4
7a; R ) Me
7b; R ) Et
7c; R ) Ph
7c
THF, 30 min
THF, 1 h
THF, 1 h
2,4-Me2THF, 1 h 50%
CH2Cl2, 10 min 87%
93%
82%
50%
30%
5
7c
6
7
8
7d; R ) 4-MeOPh THF, 1 h
7e; R ) 4-tBuPh
THF, 1 h
7f; R ) 4-NO2Ph THF, 1 h
72%
73%
11%
9%
no reactionb
9
10
7f
CH2Cl2, 10 min 86%
THF, 1 h
7g; R ) 4-CNPh
no reactionb
11
7g
CH2Cl2, 10 min 83%
a Isolated product. b Starting material was recovered in >90%.
documented in Table 3 are illustrative. Compared to acetate
and propionate esters 7a and 7b, which yield exclusively
substitution product 3g (entries 1 and 2), the corresponding
benzoate 7c (entry 3) provided a mixture of substitution (3g,
50%) and cycloisomerization products (8c, 30%). Interest-
ingly, the preference for propargylic substitution increased
with electron-donating para-substituents (entries 6 and 7),
whereas electron-withdrawing p-nitro or p-CN substitution
shut the reaction down (entries 8 and 10). However, exclusive
propargylic substitution was observed when the solvent was
switched to CH2Cl2 (entries 5, 9, and 11).
In Figure 2, we formulate a mechanism initiated by Pt(II)-
catalyzed propargyl/allenyl isomerization. The resulting
allene engages the enolester double-bond face cis to the
smaller substituent (π-complex 10).13,14 In CH2Cl2, chloride
ionization leads to cationic square-planar bidentate complex
11.15 In this complex, activation of the ester leaving group
by Lewis acid type complexation2c to the cationic Pt(II)
center with concomitant LUMO-lowering olefin π* and ester
C-O σ* orbital alignment (coplanar) conspire to lower the
barrier for a concerted SN2′ cyclization (f 12).16,17 Elimina-
tion of acetic acid and ligand exchange (starting alkyne 7
for product alkyne 3) completes the catalytic cycle. In the
weakly coordinating solvent THF, cationic complexes 13 and
14 can compete with bidentate complex 11,18 thereby
enabling a bifurcating hydroalkoxylation manifold to eno-
lester 8 via activation of the olefin proximal to the alcohol
(14 f 15).19 This solvent effect conforms with the observa-
a Reaction conditions: propargyl acetate 1b-q (0.1 M in THF), 2.5
mol % [CH2CH2PtCl2]2, rt, 30 min. b Cis/trans ratio was determined by 1H
NMR (3j, 0% trans; 3h and 3i, 7.4% trans). c Isolated products.
3q in a cis:trans ratio of 1:2 (80-84% yield), whereas
epimeric mixtures of 1,5-disubstituted substrates 1h-j
converge to 2,6-cis-tetrahydropyrans 3h-j (65-81% yield,
0-8% trans-isomer). Finally, substrates with a ꢀ-silyloxy
substituent retain some degree of stereochemical memory;
1,3-syn substrate 1k afforded 3k in a cis:trans ratio of 1:2,
whereas anti-isomer 1l yielded 3l in a 1.5:1 ratio.10
Although propargylic substitution can be achieved with
the Nicholas reaction,11 the overall transformation is not
catalytic and necessitates a multistep sequence including
dicobalt complex formation, (Lewis) acid-mediated ioniza-
tion, and final reductive metal decomplexation. Alternatively,
propargylic substitution can be catalyzed by transition metals,
although the scope remains somewhat limited to substrates
bearing terminal alkynes or carbocation-stabilizing substit-
uents.12 Various control experiments rule out a mechanism
involving propargylic carbocation intermediates. For ex-
ample, stirring alkyne 1g with strong Lewis acids (cat. or
equiv TiCl4, BF3·OEt2, FeCl3) invariably returned starting
material (>90%). Also, substrates that sterically prevent
coordination to the alkyne but not the ester are inert (e.g.,
1f).
(12) For selected examples not involving allenylidene intermediates, see:
(a) Matsuda, I.; Komori, K.; Itoh, K. J. Am. Chem. Soc. 2002, 124, 9072.
(b) Sherry, B. D.; Radosevich, A. T.; Toste, F. D. J. Am. Chem. Soc. 2003,
125, 6076. (c) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem.
Soc. 2005, 127, 14180. (d) Nishibayashi, Y.; Shinoda, A.; Miyake, Y.;
Matsuzawa, H.; Sato, M. Angew. Chem., Int. Ed. 2006, 45, 4835. (e) Zhan,
Z.; Yu, J.; Liu, H.; Cui, Y.; Yang, R.; Yang, W.; Li, J. J. Org. Chem.
2006, 71, 8298. (f) Evans, P. A.; Lawler, M. J. Angew. Chem., Int. Ed.
2006, 45, 4970. (g) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2007, 46, 409. (h) Mahrwald, R.; Quint, S.; Scholtis,
To gain some mechanistic insight, the effects of the ester
leaving group and solvents were studied, and the results
(11) For selected reviews, see: (a) Green, J. R. Curr. Org. Chem. 2001,
5, 809. (b) Teobald, B. J. Tetrahedron 2002, 58, 4133. (c) D´ıaz, D. D.;
Betancort, J. M.; Mart´ın, V. S. Synlett 2007, 343.
S. Tetrahedron 2002, 58, 9847
.
Org. Lett., Vol. 10, No. 12, 2008
2535

Figure 2. Mechanistic proposal for the platinum(II)-catalyzed cycloetherification of ω-hydroxypropargylic esters.
tion that reaction of benzoate 7c in 2,4-Me2THF (a nonco-
ordinating substitute for THF) exclusively yields substitution
product 3g through bidentate complex 11 (compare entries
3 and 4, Table 3).18 Our model also explains the observed
correlation between ester donor-strength and product distri-
bution in THF (Table 3). Electron-rich esters compete more
efficiently with THF for coordination to the platinum center,
augmenting propargylic substitution (via 11) in going from
benzoate to p-MeO- or p-tBu-benzoate to acetate and
propionate esters.20 On the other hand, THF is not as strong
an ionizing solvent as CH2Cl2 to allow the charge buildup
required for the formation of any cationic complex with the
electron-withdrawing allenic p-NO2Bz and p-CNBz esters,
thereby shutting down both modes of reactivity (compare
entries 8, 10 with 9, 11). Finally, other Cl2ML2 complexes
that can accommodate bidentate allenyl ester coordination
catalyze the propargylic substitution. For example, reaction
of 7a with 5 mol % of Cl2Pd(MeCN)2 in THF yielded 3g
(12% at 40% conversion, 2 h) via 11i (box Figure 2). Also,
Cl2Pt(PPh3)2 (5 mol %) catalyzed the reaction when activated
by AgBF4 (5 mol %) to yield 52% of substitution product
3g via 11ii and 34% of enolester 8 via 14i (CH2Cl2, 1 h, rt).
Overall, this mechanistically noVel platinum-catalyzed pro-
pargylic substitution represents an operationally simple
alternatiVe that functions with internal alkynes lacking a
carbocation-stabilizing substituent.
In conclusion, we have developed novel catalytic cyclo-
etherifications of ω-hydroxy propargylic esters initiated by
a common propargyl/allenyl ester rearrangement. Particularly
noteworthy is the observation that the incipient metal-
complexed allenyl esters will partition between a hy-
droalkoxylation manifold and an SN2′-type allenic substitu-
tion depending on the catalyst and solvent conditions.21 Thus,
catalysis by AuCl will lead exclusively to stereodefined
oxacyclic enol acetates, whereas square planar platinum(II)
chlorides catalyze the formation of propargylic substitution
products. A mechanistic rationale reconciling this divergent
behavior in the context of metal coordination chemistry was
developed and we will continue to test this model experi-
mentally. Finally, it is worth emphasizing that our methodol-
ogy is defined by mild reaction conditions and broad substrate
scope. The corresponding substituted cyclic ethers are
valuable intermediates for the synthesis of biologically active
polyketide natural products.
(13) For a crystal structure of dichloro(tetramethylallene)platinum(II)
dimer, see: (a) Hewitt, T. G.; De Boer, J. J. J. Chem. Soc. A 1971, 817.
(14) π-Bonded allenes oscillate between the orthogonal π-systems: Ben-
Shosan, R.; Pettit, R. J. Am. Chem. Soc. 1967, 89, 2231.
(15) The addition of LiCl or Bu4NCl inhibits the reaction.
(16) For SN′ substitutions of allenyl halides involving allenyl/propargyl
cation or carbene intermediates, see: (a) Kitamura, T.; Miyake, S.;
Kobayashi, S. Chem. Lett. 1985, 929. (b) Shiner, V. J.; Humphrey, J. S.,
Jr. J. Am. Chem. Soc. 1967, 89, 622. (c) Toda, F.; Higashi, M.; Akagi, K.
Bull. Chem. Soc. Jpn. 1969, 829. For a proposed SN2′ hydrolysis of
propargylic acetates, see ref 4h. For a propargylic substitution via a proposed
SN2′ addition of alcohols to a rhenium(V)-oxo allenolate intermediate, see
ref 12b.
Acknowledgment. This work was supported by the Robert
A. Welch Foundation and Merck Research Laboratories.
(17) For a Au-catalyzed cyclization of monoallylic diols proceeding via
a proposed SN2′ allylic substitution, see: (a) Aponick, A.; Li, C.-Y.; Biannic,
B. Org. Lett. 2008, 10, 669.
Supporting Information Available: General procedures,
characterization data, and copies of NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) No reaction is observed in 1,4-dioxane. This solvent has a lower
donor strength than THF and is less polar than THF and CH2Cl2, thus
preventing solvent-mediated stabilization of cationic intermediates.
(19) Control experiments indicate that enol ester products do not arise
from subsequent Pt(II)-catalyzed hydroacetoxylation of propargylic substitu-
tion product 3.
OL8008107
(20) Alternative pathways invoking a role for ester Brønsted base
strength (H+-transfer or H-bonding) on product distribution cannot explain
the results in Table 3. Also, addition of 2,6-tBu2-pyridine (1 equiv) to the
reaction in entry 1 (Table 3) did not prevent the propargylic substitution,
and product 3g was obtained in 88% yield.
(21) For a recent example of divergent cycloisomerization of a common
alleneyne substrate depending on whether the reaction was catalyzed by
gold or platinum, see: (a) Zriba, R.; Gandon, V.; Aubert, C.; Fensterbank,
L.; Malacria, M. Chem. Eur. J. 2008, 14, 1482.
2536
Org. Lett., Vol. 10, No. 12, 2008