Metal-catalyzed regioselective oxy-functionalization of internal alkynes: An entry into ketones, acetals, and spiroketals

Article abstract of DOI:10.1021/ol0619819

(Chemical Equation Presented) Platinum(II) and an unusual cationic gold(I) complex were identified as mild catalysts for the room temperature cycloisomerization or tandem hydroalkoxylation/acetal formation of unactivated internal alkynols. Under the appro

Full text of DOI:10.1021/ol0619819

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4907-4910
Metal-Catalyzed Regioselective
Oxy-Functionalization of Internal
Alkynes: An Entry into Ketones,
Acetals, and Spiroketals
Bo Liu and Jef K. De Brabander*
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 August 9, 2006
ABSTRACT
Platinum(II) and an unusual cationic gold(I) complex were identified as mild catalysts for the room temperature cycloisomerization or tandem
hydroalkoxylation/acetal formation of unactivated internal alkynols. Under the appropriate conditions, 5-endo, 5-exo, 6-endo, and 6-exo
cycloisomerization modes are all available.
The oxy-functionalization of internal alkynes (hydration,
hydroalkoxylation)1 represents a potentially attractive strategy
for constructing ketone, acetal, or spiroketal substructures
found in many natural products (Figure 1). Alkynes are
Herein, we report efficient PtII- and AuI-catalyzed regiose-
lective oxy-functionalizations of unactivated internal alkynols.2,3
In contrast to the situation with terminal alkynes,1 the
addition of water or methanol to nonactivated and unbiased
internal alkynes suffers from low regioselectivity.4,5
A
potential solution to this problem emerged from pioneering
studies by Utimoto showing that PdII-catalyzed intramolecu-
lar hydroalkoxylation of internal alkynols provided cyclo-
isomerization products with high regioselectivity.6,7 The same
(2) For recent examples of intramolecular hydroalkoxylations with
terminal alkynols, see: (a) Barluenga, J.; Die´guez, A.; Ferna´ndez, A.;
Rodr´ıguez, F.; Fan˜ana´s, F. J. Angew. Chem., Int. Ed. 2006, 45, 2091. (b)
Genin, E.; Antoniotti, S.; Michelet, V.; Geneˆt, J.-P. Angew. Chem., Int.
Ed. 2005, 44, 4949. (c) Antoniotti, S.; Genin, E.; Michelet, V.; Geneˆt, J.-P.
J. Am. Chem. Soc. 2005, 127, 9976. (d) Elgafi, S.; Field, L. D.; Messerle,
B. A. J. Organomet. Chem. 2000, 607, 97. With electronically biased aryl
alkynols: (e) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett.
2005, 7, 5437. (f) Messerle, B. A.; Vuong, K. Q. Pure Appl. Chem. 2006,
78, 385. (g) Hashmi, A. S. K.; Schwartz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285. (h) Liu, Y.; Song, F.; Song, Z.; Liu, M.;
Yan, B. Org. Lett. 2005, 7, 5409.
Figure 1. Oxy-functionalization of internal alkynes.
relatively inert toward many reaction conditions, a charac-
teristic that can be leveraged to delay installation of valuable
but rather sensitive δ-hydroxyketone or acetal functionality
to later stages of the synthesis via C-O bond formation.
(1) For selected reviews, see: (a) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. ReV. 2004, 104, 3079. (b) Weyershausen, B.; Do¨tz, K. H. Eur. J.
Inorg. Chem. 1999, 1057. (c) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H.
Angew. Chem., Int. Ed. 2004, 43, 3368.
(3) For an attractive alkyne activation approach to the acetal/spiroketal
framework via a gold(I)-catalyzed tandem propargyl Claisen rearrangement/
heterocyclization, see: Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste,
D. F. J. Am. Chem. Soc. 2006, 128, 8132.
10.1021/ol0619819 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/20/2006

report also discloses the PdCl2-catalyzed cycloisomerization
of 4-nonyne-1,9-diol (1a) to yield selectively [4.6] spiroketal
3 in 60% yield (Scheme 1).8 In our hands, however, a 2.5:1
AuCl3 (entry 4) afforded rather low yields of endo/exo
mixtures in ratios ranging from 1.3:1 to 2.2:1.11 Gratifyingly,
we found that PtII salts were effective and 6-exo selective
hydroalkoxylation catalysts (entries 5 and 6). Although
Zeise’s dimer was slightly less selective than PtCl2 (30:1 vs
116:1), it was a more efficient catalyst consuming starting
material in less than 30 min at room temperature and 1 mol
% catalyst loading.
Scheme 1
Compared to substrate 1b, TBS-protected variant 1c
yielded spiroketal 210 with only a slight reduction in
selectivity (20:1 vs 30:1, entries 1 and 2, Table 2) but higher
mixture of [4.6] and [5.5] spiroketals 3 and 2 was consistently
obtained.9 We did not find this surprising considering that
reduced selectivity could stem from the fact that both primary
alcohols could react at comparable rates (i.e., a chemose-
lectivity issue) and with their own inherent endo-dig or exo-
dig preference (i.e., a regioselectivity issue). We therefore
decided to use mono-hydroxyalkynes as substrates in a screen
to identify regioselective hydroalkoxylation catalysts.
In Table 1, we present our results with alkynol 1b.10 Con-
trary to expectation, we found that most catalysts delivered
Table 2. Pt(II)-Catalyzed 6-exo Selective Hydroalkoxylation
product
(ratio)b
yield
(%)b
entry
R
derivatizationa
1
2
3
4
5
6
OTHP (1b) CSA, MeCN/H2O; MgSO4 2:3 (30:1)
OTBS (1c) CSA, MeCN/H2O; MgSO4 2:3 (20:1)
75
83
Table 1. Catalyst Screening for the Hydroalkoxylation of 1b
OTBS (1c) THF/H2O, 23 °C, 5 min
4c:5c (30:1) 84
OAc (1d)
n-Pr (1e)
n-Pr (1e)
PPTS, MeOH, HC(OMe)3 6d:7d (13:1) 94
PPTS, MeOH, HC(OMe)3 6e:7e (7:1)
THF/H2O, 23 °C, 5 min 4e:5e (7:1)
92
87
a See the Supporting Information for details. b Total yield and endo:exo
ratio (2:3, 4:5, or 6:7) determined by GC with an external standard (entries
1 and 2), NMR (entries 4-6), or isolated yield (entry 3).
entry
mol % catalyst
1% PdCl2
1% MeAuPPh3, 10% TfOH
5% ClAuPPh3/AgOTf (1:1)
5% AuCl3
time (h) yielda (%) ratioa
1b
2
3
4
5
1.5
0.5
0.5
0.5
52
40
36
41
64
75
2:1
1.3:1
2:1
2.2:1
116:1
30:1
overall yield (83% vs 75%). Alternatively, the addition of
moist THF upon completion of the PtII-catalyzed cyclo-
isomerization of 1c yielded δ-hydroxyketone 4c in 84% yield
(30:1; entry 3), demonstrating the stability of the TBS-
protecting group to the reaction conditions. Similar conditions
yielded δ-hydroxyketone 4e from 4-dodecynol (1e) (entry
6). Entries 4 and 5 show that methylacetals are also accessible
in high yields by the addition of an acidic MeOH/HC(OMe)3
solution after completion of the cycloisomerization.
2% PtCl2
1% [Cl2Pt(CH2dCH2)]2
24c
0.5
6
a Yields (at >95% conversion) and ratios (6-exo:7-endo) determined by
GC with an external standard. b MeCN was used instead of Et2O. c <5%
conversion at 30 min.
mixtures resulting from 6-exo-dig and 7-endo-dig cyclization.
Having found a solution for the 6-exo selective hydro-
alkoxylation, we next examined the more intricate 5-exo/6-
endo problem associated with the hydroalkoxylation of
4-alkynols. As shown in Table 3, PtII-catalyzed hydroalkoxy-
lation of 8b-g followed by derivatization as before10
furnished the corresponding spiroketals 2, 3 and methylac-
etals 6d-g, 9d-g favoring the 6-endo derived products
(entries 1-7). Interestingly, δ-tetrahydropyranyloxy substitu-
tion has a beneficial impact on endo-selectivity (9-11:1;
entries 1 and 2), followed to a lesser extent by silyloxy
substitution (entry 3, 3.7:1). Acetoxy, methoxy, and (meth-
Thus, PdCl2 (entry 1), cationic gold(I) (entries 2 and 3) and
(4) For examples catalyzed by gold(I): (a) Teles, J. H.; Brode, S.;
Chabanas, M. Angew. Chem., Int. Ed. 1998, 37, 1415. (b) Mizushima, E.;
Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed. 2002, 41, 4563.
(c) Roembke, P.; Schmidbaur, H.; Cronje, S.; Raubenheimer, H. J. Mol.
Catal. 2004, 212, 35. By gold(III): (d) Fukuda, Y.; Utimoto, K. J. Org.
Chem. 1991, 56, 3729. By platinum(II): (e) Jennings, P. W.; Hartman, J.
W.; Hiscox, W. C. Inorg. Chim. Acta 1994, 222, 317. (f) Kataoka, Y.;
Matsumoto, O.; Tani, K. Organometallics 1996, 15, 5246. (g) Hartman, J.
W.; Sperry, L. Tetrahedron Lett. 2004, 45, 3787. By palladium(II): (h)
Imi, K.; Imai, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 3127.
(5) For regioselective hydration controlled by participation of keto or
ether neighboring groups, see ref 4e,h.
(6) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845.
(7) For a PtII-catalyzed hydration of 3- and 4-pentyn-1-ol, see: Lucey,
D. W.; Atwood, J. D. Organometallics 2002, 21, 2481.
(10) All reactions documented in Tables 1-3 (aprotic solvents) yielded
mixtures of cycloisomerization products (endo-enol and E/Z-mixtures of
exo-enol ethers). These were derivatized after completion of the reaction
to spiroketals (Tables 1-3) or acetals (Tables 2 and 3) to facilitate GC and
NMR analyses.
(11) Triflic acid, AgOTf, ClAuPPh3, and PdCl2(PhCN)2 were all
incompetent catalysts for the cycloisomerization of 1b.
(8) For a nice application in total synthesis, see: Trost, B. M.; Horne,
D. B.; Woltering, M. J. Angew. Chem., Int. Ed. 2003, 42, 5987.
(9) No experimental details regarding isolation, purification, and deter-
mination of selectivity were provided in the Utimoto paper.6 We added
camphorsulphonic acid and MgSO4 at the end of the reaction to ensure
complete conversion to the spiroketals (>95%) for GC analysis.
4908
Org. Lett., Vol. 8, No. 21, 2006

Table 3. Metal-Catalyzed Hydroalkoxylation of 4-Alkynolsa,b
Table 4. Tandem Cycloisomerization/Acetal Formationa
product
(ratio)e
yield
(%)e
entry
R
catalystc
derivd
1
2
3
4
5
6
7
8
9
OTHP (8b) [Cl2Pt(CH2CH2)]2
OTHP (8b) [Cl2Pt(CH2CH2)]2
OTBS (8c) [Cl2Pt(CH2CH2)]2
A
A
A
B
B
B
B
B
A
B
A
A
B
B
3:2 (1:11)
3:2 (1:9)
70
60
58
93
85
90
88
87
>95
90
3:2 (1:3.7)
9d:6d (1:2.3)
9e:6e (1:2.3)
9f:6f (1:2.5)
9g:6g (1:1.7)
9e:6e (2.6:1)
3:2 (2:1)
9e:6e (1:1.3)
3:2 (3.7:1)
3:2 (6.6:1)
9e:6e (6:1)
9f:6f (4:1)
OAc (8d)
Et (8e)
[Cl2Pt(CH2CH2)]2
[Cl2Pt(CH2CH2)]2
OMOM (8f) [Cl2Pt(CH2CH2)]2
OMe (8g)
Et (8e)
[Cl2Pt(CH2CH2)]2
PdCl2
OH (1a)
PdCl2(PhCN)2
PdCl2(PhCN)2
MeAuPPh3/AgPF6
10 Et (8e)
11 OH (1a)
12 OTBS (8c) MeAuPPh3/AgPF6
13 Et (8e) MeAuPPh3/AgPF6
14 OMOM (8f) MeAuPPh3/AgPF6
92
73
90
94
a Reaction conditions: alkynol (1.0 equiv), MeOH (5.0 equiv),
[Cl2Pt(CH2CH2)]2 (1.0 mol %), THF:HC(OMe)3 (10:1, 0.2 M), 23 °C,
10-30 min. b Ratio (NMR) of 6-exo vs 7-endo products (entries 1-7), and
5-exo vs 6-endo products (entries 10-13). c Determined by NMR. d Isolated
yield. e Reaction in THF only. f The 6-endo products included 5-18% of
the corresponding dihydropyrans. g Reaction run with 5% MeAuPPh3/AgPF6
(1:1) in Et2O:HC(OMe)3 (10:1) for 40.5 h.
a Reactions at 23 °C in Et2O (entries 2-7, 9, 10), dioxane (entry 1),
iPr2O (entries 11-14), or refluxing aq MeCN (entry 8). b Reaction time
was 30 min (entries 1-8, 11), 13 h (entries 12-14), or 3 h (entries 9, 10).
c Catalyst loading: 1% (entries 1-7, 11), 5% (entries 8, 12-14), and 3%
(entries 9, 10). d Derivatization method A: CSA, aq MeCN; then MgSO4.
Method B: PPTS, MeOH, HC(OMe)3. e Determined by GC (entries 1-3,
9, 11, 12) or by NMR (entries 4-8, 10, 13, 14).
in a THF:HC(OMe)3 (10:1) solvent mixture (Table 4, entries
1-7). This reaction is very fast and no dihydropyran products
could be detected. Entries 1-4 demonstrate that various
alcohol protecting groups, including the labile THP-ether,
were stable to the reaction conditions. Furthermore, second-
ary alcohols were excellent substrates for this reaction and
provided products resulting from excellent 6-exo selectivity
and anomeric stabilization (entries 6 and 7). Entry 8 dem-
onstrates the possibility of obtaining bicycloketals when
cyclized intermediates can be trapped intramolecularly. Not
surprisingly, 3-decynol provided 2-hexyl-2-methoxytetrahy-
drofuran via a 5-endo pathway (entry 9).
Finally, reaction of 4-alkynols was nonselective to mildly
5-exo-selective (Table 4, entries 10-12), whereas the cor-
responding cyclizations in anhydrous diethyl ether displayed
modest to good 6-endo selectivity (Table 3, entries 1-7).
Changing to a MeAuPPh3/AgPF6 catalyst system did improve
somewhat the 5-exo-selectivity for this tandem cyclization/
methoxylation of 4-alkynols (compare entries 12 and 13).
Nevertheless, the highest 5-exo selectivities are achieved
according to the conditions in Table 3, entries 11-14.
A mechanistic hypothesis consistent with the available data
is depicted in Figure 2. Initial coordination of the alkynol to
PtII (A f B) activates it for intramolecular attack by the
alcohol to yield endo-C or exo-C adducts.
oxymethyl)oxy substituents did not improve selectivity
(1.7-2.5:1, entries 4, 6, and 7) versus the alkyl control
(2.3:1, entry 5). It is of interest to note that PdII-catalyzed
cycloisomerization of 4-undecynol (8e) was only marginally
5-exo selective with PdCl2 (entry 8) and nonselective with
PdCl2(PhCN)2 (entry 10), contrasting with reported results.6,12
After an extensive screen, we found that a MeAuPPh3/
AgPF6 combination functions as an effective catalyst for the
cycloisomerization of 4-alkynols with 5-exo selectivities
ranging from 4:1 to 6-6.6:1 (Table 3, entries 12-14).13 This
catalyst combination also provided better 5-exo selectivity
than PdII for the cycloisomerization of 4-nonyne-1,9-diol
(compare entries 9 and 11).6,9
Having identified conditions for efficient 6-exo, 5-exo, and
6-endo selective cycloisomerizations of internal alkynols, we
became interested in the possibility to effect a tandem
cycloisomerization/acetal formation to obtain acetals di-
rectly.10,14 To this end, various methylacetals were generated
with good 6-exo selectivity upon reaction of 5-alkynols with
5 equiv of MeOH in the presence of 1% [Cl2Pt(CH2dCH2)]2
(12) With the same substrate and reaction conditions that we used in
this study, Utimoto6 reports 95% 6-endo selectivity with PdCl2(PhCN)2,
and 95% 5-exo selectivity with PdCl2.
(13) To the best of our knowledge, this catalyst combination has not
been reported. The optimal solvent is Pr2O, yielding a 10-20% increase
Deprotonation followed by reprotonation at carbon would
then deliver the transient platinated oxocarbenium species
i
in selectivity versus Et2O. Upon mixing MeAuPPh3 and AgPF6, a black
precipitate forms that can be filtered. The remaining solution retains full
catalytic activity with similar selectivity. Other AgI salts gave lower yields
and selectivities and MeAuPPh3 or AgPF6 alone were catalytically
incompetent. Cationic gold(I) complexes generated from halide abstraction
of ClAuPPh3 with various AgI salts gave lower yields and selectivities.
(14) 1H NMR analysis of the cycloisomerization of 5-dodecyn-1-ol (1e)
in THF-d8 at low conversion revealed the presence of detectable levels of
2-heptyl-2-dodec-5-ynyloxy tetrahydropyran, indicating that acetals could
be formed directly under the reaction conditions.
Org. Lett., Vol. 8, No. 21, 2006
4909

that gave a 96% yield of 2-heptyl-2-methoxy-tetrahydro-2H-
pyran from alkynol 1e (Table 4, entry 5). Moreover, the
PtII-catalyzed tandem cycloisomerization/hydromethoxylation
of 4-pentyn-1-ol (10) in CD3OD afforded uniquely [D5]-2-
MeO-2-Me-tetrahydrofuran (11) after 3 min at room tem-
perature (Scheme 2). Stirring the reaction mixture for an
Scheme 2. Deuterium Labeling Experiment
Figure 2. A mechanistic hypothesis.
additional 19 h gave 13 with additional deuterium incorpora-
tion at the methyl carbon (12% D) and at the C3-methylene
carbon (28% D). These results rule out the intermediacy of
enol ether [D1]-F for the fast formation of 11, as this would
lead to H/D scrambling via oxocarbenium 12 as observed
for the slower formation of 13 from 11.
In conclusion, we have developed efficient protocols for
the PtII- and AuI-catalyzed oxy-functionalization of unacti-
vated internal alkynes. Zeise’s dimer ([Cl2Pt(CH2dCH2)]2)
was identified as an efficient and selective catalyst for the
intramolecular hydroalkoxylation of 5-alkynols and 3-alkynols.
For the 5-exo selective cycloisomerization of 4-alkynols, we
identified a new catalyst combination obtained by premixing
MeAuPPh3 and AgPF6. The studies reported herein also have
led to an efficient tandem hydroalkoxylation/acetal formation
and include experiments that provided initial mechanistic
insight into this process. Additional mechanistic studies and
applications of this methodology to natural product synthesis
will be reported in the future.
exo-D and endo-D. In the absence of MeOH, we propose
this proton transfer to be the rate-limiting and selectivity-
determining step (i.e. exo-C and endo-C can establish a
preequilibrium via B), favoring the formation of the 6-endo-
isomer (endo-D, n ) 1) to the extent of 2.3:1 (Table 3, entry
5). Deplatination leads to the cycloisomerization products
exo-F and endo-F. Certain alkoxy-functionality can further
enhance 6-endo-selectivity (up to 9:1; Table 3, entry 2),
perhaps via stabilization of charge build-up in the transition
state leading to endo-D (see D′).15,16 In the presence of
MeOH, proton transfer is fast and cyclization to C becomes
rate limiting: 5-exo addition is favored slightly over 6-endo
addition and independent of alkoxy functionality (Table 4,
entries 10-12). Now, methoxylation precedes deplatination
to yield methylacetals exo-E and endo-E, completing the
catalytic cycle.17
Additional evidence indicates that enol ethers (F) are not
intermediates en route to acetals E.18 First, 6-heptyl-3,4-
dihydro-2H-pyran (endo-F, n ) 1, R ) heptyl) was recovered
unchanged when subjected to the same reaction conditions
Acknowledgment. Financial support was provided by the
Robert A. Welch Foundation and Merck Research Labora-
tories.
(15) At this moment, we speculate that OTHP is better at stabilizing
developing positive charge. For the proton transfer leading to exo-D (n )
1), stabilization of charge build-up through a seven-membered interaction
would be less efficient.
(16) In agreement with this analysis, the 6-endo selectivity observed for
the PtII-catalyzed cyclization of 8b in Et2O (9:1, Table 3, entry 2) eroded
to 2.7:1 when performed in THF, i.e., the level of that observed for
cyclization of 8e (2.3:1, Table 3, entry 5).
Supporting Information Available: Experimental pro-
cedures, characterization data, GC chromatograms, and
copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) A bifurcation between acetal formation (f E) and direct deplati-
nation (f F) is supported by the following observation: reaction of 1e
with 1% [Cl2Pt(CH2dCH2)]2 in THF with the more hindered 2-propanol
(5 equiv) yielded a 1:1 mixture of 6-heptyl-3,4-dihydro-2H-pyran and
2-heptyl-2-isopropoxytetrahydro-2H-pyran, whereas no dihydropyran prod-
uct was observed with methanol as the trapping nucleophile under otherwise
identical conditions.
OL0619819
(18) Others have suggested that addition of the second alcohol could
occur on metal-bound intermediates, see refs 2b, 2f, and 4g. For the cationic
gold(I)-catalyzed double hydromethoxylation of alkynes, ab initio calcula-
tions located an aurated species similar to platinated oxocarbenium
intermediate D, see ref 4a.
4910
Org. Lett., Vol. 8, No. 21, 2006