Enhancement of reaction efficiency by functionalized alcohols on gold(I)-catalyzed intermodular hydroalkoxylation of unactivated olefins

Article abstract of DOI:10.1021/ol9023166

"Chemical Equation Presented" Intermolecular hydroalkoxylation of unactivated olefins catalyzed by the combination of gold(I) and electron deficient phosphine ligands has been developed. Although pairings of unactivated olefins and common aliphatic alcohols gave unsatisfactory results In gold catalyzed hydroalkoxylations, the use of alcohol substrates bearing coordination functionalities such as halogen or alkoxy groups showed great improvement of reactivity.

Full text of DOI:10.1021/ol9023166

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5510-5513
Enhancement of Reaction Efficiency by
Functionalized Alcohols on
Gold(I)-Catalyzed Intermolecular
Hydroalkoxylation of Unactivated Olefins
Toshifumi Hirai, Akiyuki Hamasaki, Aki Nakamura, and Makoto Tokunaga*
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity,
6-10-1 Hakozaki, Higashi-ku, Fukuoka, Japan 812-8581, and JST (Japan Science and
Technology Agency) CREST, Japan
mtok@chem.kyushu-uniV.jp
Received October 7, 2009
ABSTRACT
Intermolecular hydroalkoxylation of unactivated olefins catalyzed by the combination of gold(I) and electron deficient phosphine ligands has
been developed. Although pairings of unactivated olefins and common aliphatic alcohols gave unsatisfactory results in gold catalyzed
hydroalkoxylations, the use of alcohol substrates bearing coordination functionalities such as halogen or alkoxy groups showed great
improvement of reactivity.
Nucleophilic addition reactions to carbon-carbon multiple
bonds are one of the most important transformations of
unsaturated organic compounds.1 Among them, hydroalkoxy-
lation is a quite straightforward method to access ether
products from unsaturated hydrocarbons. Many methodolo-
gies have been developed by means of metal catalysts (e.g.,
Pd,2 Pt,3 and others4) or acid catalysts (Brønsted acid5 or
Lewis superacid6) to activate C-C multiple bonds. Recently
Au catalysts are drawing great attention because of their
moderate activity for this purpose.7 While the Au-catalyzed
hydroalkoxylation of alkynes8 and allenes9 is relatively well-
developed, the hydroalkoxylation of olefins, regardless of
(6) Lemechko, P.; Grau, F.; Antoniotti, S.; Dun˜ach, E. Tetrahedron Lett.
2007, 48, 5731.
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Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. ReV. 1999, 28, 199. (c)
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Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (c) Hashmi,
A. S. K. Chem. ReV. 2007, 107, 3180.
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Yamamoto, Y. J. Org. Chem. 2006, 71, 4270.
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Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485. (c) Zhang, Z.; Liu, C.;
Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc.
2006, 128, 9066. (d) Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int.
Ed. 2007, 46, 283. (e) Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10,
2079. (f) Horino, Y.; Takata, Y.; Hashimoto, K.; Kuroda, S.; Kimura, M.;
Tamaru, Y. Org. Bioorg. Chem. 2008, 6, 4105. (g) Nishina, N.; Yamamoto,
Y. Tetrahedron Lett. 2008, 49, 4908. (h) Nishina, N.; Yamamoto, Y.
Tetrahedron 2009, 65, 1799.
(3) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 9536.
(4) (a) Oe, Y.; Ohta, T.; Ito, Y. Synlett 2005, 179. (b) Messerle, B. A.;
Vuong, K. Q. Organometallics 2007, 26, 3031. (c) Yu, X.; Seo, S.; Marks,
T. J. J. Am. Chem. Soc. 2007, 129, 7244.
(5) (a) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He,
C. Org. Lett. 2006, 8, 4175. (b) Rosenfeld, D. C.; Shekhar, S.; Takemiya,
A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179.
10.1021/ol9023166 CCC: $xxxx
Published on Web 11/09/2009
 2009 American Chemical Society

intermolecular or intramolecular fashion, is still a challenging
field triggered by the first report made by He in 200510a and
there are only few subsequent reports.10b,c Here we report
on enhancement of reaction efficiency of intermolecular
hydroalkoxylation of olefins by employing the alcohol
substrates bearing coordination functionalities such as halo-
gen or alkoxy groups. This reaction resulted in desired ether
products in moderate to excellent yields even using unacti-
vated olefins. To the best of our knowledge, it is the first
report on devising alcohol substrates to enhance reaction
efficiency for intermolecular hydroalkoxylation.
The initial screening was done with AuClPPh3/AgOTf
catalyst system which was employed in the first gold-
catalyzed intermolecular hydroalkoxylation of olefins
reported by He.10a As expected from previous reports, a
combination of unactivated olefin (1a) and common
alcohol (2a) produced only trace amount of ether (Table
1, entry 1). The incorporation of chlorine atom on the
Table 2. Optimization of the Reaction Conditionsa
entry olefin (equiv) alcohol (equiv) temp (°C) yieldb, c (%)
1
2
3
4
5
6
1
1
1
2
4
5
1
1
2
1
1
1
85
120
85
85
85
19d
26e
8f
52g
49h
54i
85
a The reactions were carried out on a 1 mmol scale. b GC yield based
on alcohol except entry 3. c The 3-adduct was mainly obtained as 3ab′,
and only a trace amount of 4-adduct was found in each entry. d Contained
1% of 3ab′. e Contained 1% of 3ab′. f Contained a trace amount of 3ab′.
g Contained 9% of 3ab′. h Contained 4% of 3ab′. i Contained 4% of 3ab′.
Table 1. Intermolecular Addition of Various Alcohols to
1-Octenea
conducted with equimolar of 1a and 2b, the yield of the
product was poor (Table 2, entry 1) and a raised
temperature offered only slight improvement (Table 2,
entry 2). The less amount of 1a than 2b depressed reaction
efficiency (Table 2, entry 3). On the other hand, using an
excess amount of 1a to 2b lead increase of the yield (Table
2, entries 4-6).
The efficiency of the reaction was greatly affected by
nature of the phosphine ligand, particularly extent of
electron deficiency. Compared to PPh3, the formation of
the desired ether product was increased along with
lowering the electron density. Although there are few
reports on the ligand effect for gold-catalyzed hy-
droalkoxylation of olefins, similar trends were observed
on the gold-catalyzed hydroalkoxylation of allenes9f and
platinum-catalyzed intramolecular hydroalkoxylation.3 It
is explained by the relationship between electron defi-
ciency and Lewis acidity, and could be recognized as one
evidence for the involvement of the multiple bond
activation by the metal catalyst in the reaction course.
Interestingly, further increase of the yield was observed
by the addition of 1 equivalent of P(C6F5)3 (Table 3, entry
4). The role of the additional phosphine is unclear, but
the fact PPh3 or P(C6F5)3 itself did not show any catalytic
activity for this reaction (data not shown) indicated some
sort of contributions to stabilization of gold complex. The
regioselectivity was indeed different from that of phos-
phine-catalyzed hydroalkoxylation.11
entry
alcohol
CH3CH2OH (2a)
ClCH2CH2OH (2b)
BrCH2CH2OH (2c)
CH3OCH2CH2OH (2d)
CH3OCH2CH2OCH2CH2OH (2e)
product yieldb, c (%)
1
2
3aa
3ab
3ac
3ad
3ae
trace
21e
3
62f
4d
27g
5d
34h
a The reactions were carried out on 1 mmol scale. b GC yield. c The
3-adduct was mainly obtained as 3′, and only a trace amount of 4-adduct
was found in each entries. d The reaction was carried out at 120 °C.
e Contained 1% of 3ab′. f Contained 8% of 3ac′. g Contained 1% of 3ad′.
h Contained 1% of 3ae′.
terminal carbon of alcohol gave the adduct in moderate
yield (Table 1, entry 2). Along with a major C-2 adduct,
small amount of regioisomers were observed due to olefin
isomerization ability of the gold catalyst.10a A similar
result was obtained in the case of bromine atom, but it
was more meaningful (Table 1, entry 3). An alkoxy group
was revealed to have a same effect (Table 1, entries 4
and 5). These results may indicate the reactivity improve-
ment effect was caused by the change of the acidity of
alcohol substrates because of electronegativity of the
incorporated atoms.
The substrate scope was examined with several unactivated
olefins 1a-c and alcohols 2b-e (Table 4). Moderate to good
yields were obtained in most of the combinations. Alcohols
bearing alkoxy group 2d and 2e were not relatively effective
than halogenated alcohols 2b and 2c. In some cases, changing
The optimal material ratio was sought by changing the
reaction conditions (Table 2). When the reaction was
(10) (a) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966. (b)
Kamiya, I.; Tsunoyama, H.; Tsukuda, T.; Sakurai, H. Chem. Lett. 2007,
36, 646. (c) Zhang, X.; Corma, A. Dalton Trans. 2008, 397.
(11) Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc.
2003, 125, 8696.
Org. Lett., Vol. 11, No. 23, 2009
5511

with 1d and several alcohols gave excellent yields (Table
5). Nucleophilic additions to norbornenes tend to produce
Table 3. Effect of Phosphine Ligandsa
Table 5. Hydroalkoxylation Reactions of Norbornenea
entry
gold catalyst
AuClPPh3
AuClP(4-CF3C6H4)3
AuClP(C6F5)3
yieldb, c (%)
entry
alcohol
product
yieldb (%)
1
2
3
4
54d
56e
79f
92g
1
2
3
4
ClCH2CH2OH (2b)
3db
3dd
3df
92
93
97
92
CH3OCH2CH2OH (2d)
ClCH2CH2CH2OH (2f)
CH3OCH2CH2CH2OH (2g)
AuClP(C6F5)3 + P(C6F5)3
3dg
a The reactions were carried out on a 1 mmol scale. b GC yield. c The
3-adduct was mainly obtained, and only a trace amount of 4-adduct was
found in each entry. d Contained 4% of 3ab′. e Contained 3% of 3ab′.
f Contained 12% of 3ab′. g Contained 8% of 3ab′.
a The reactions were carried out on a 1 mmol scale. b Isolated yield.
exo adduct, this trend was also observed in the case of
the gold-catalyzed hydroalkoxylation. Stereochemistry of
the products was determined by comparison of H NMR
1
the added phosphine to electron deficient one greatly
improved the yields (Table 4, entries 2,7, and 8).
chemical shift of C-1 proton between the alcohol adducts
and reported or synthesized norborneol derivatives (see
Supporting Information for detailed stereochemistry de-
termination).
A large scale reaction was attempted with 10 mmol of
alcohol (2b) and 50 mmol of olefin (1a) (ten times larger
than other entries) under the same condition. As shown in
eq 1, 76% of major and 13% of minor adducts were found
on GC analysis, and 87% of the products were isolated as a
mixture of isomers. Though the product ratio was slightly
changed, it was revealed this catalyst system was practical
even for large scale reaction.
Table 4. Hydroalkoxylation Reactions under the Optimized
a
Condition Using PPh3 or P(C6F5)3
The detailed reaction mechanism is still unclear, but some
experimental results lead to several presumptions. The
reaction conducted under the condition of Table 1 with
1-octene (1a) and 2,2,2-trifluoroethanol, having less coor-
dinating fluorine atoms than chlorine or bromine atom,
proceeded in slightly lower yield than Cl or Br case (ca. 8%
for F3 vs 20% for Cl, 54% for Br). This result may indicate
coordinating functionalities were actually playing different
a The reactions were carried out on a 1 mmol scale. b GC yield. c The
reaction was carried out at 120 °C. d Contained 21% of 3ac′. e Contained
17% of 3ac′. f Contained 2% of 3ad′. g Contained 6% of 3ad′. h Contained
1% of 3ae′. i Contained trace amount of 3ae′.
(12) (a) Gimeno, M. C.; Laguna, A. Chem. ReV. 1997, 97, 511. (b)
Carvajal, M. A.; Novoa, J. J.; Alvarez, S. J. Am. Chem. Soc. 2004, 126,
1465.
Norbornene (1d) has a reactive double bond due to its
rigid bicyclostructure. As expected, all reactions conducted
5512
Org. Lett., Vol. 11, No. 23, 2009

role from induction of chelate effect. Indeed it is generally
believed Au(I) takes a linear two-coordination mode,12 so
the intermediate is hard to be stabilized by chelation with
2-functionalized ethanols. However it does not mean to
negate a formation of four coordinated Au(I) intermediate
since Au(I) is able to take three- or four-coordination modes
under several situation.12,13 The other possibility may be
explained by acidity of the hydroxyl group. The function-
alized alcohols used in this study have acidities as pKa around
14-1514 because of electron-withdrawing nature of substit-
uents. On the other hand both of ethanol and phenol, having
more weaker (pKa ) 16) or stronger (pKa ) 10) acidity,
gave only trace amount of the ether products. The moderate
acidity might be necessary to proceed the reaction efficiently.
Equilibrium experiments were also performed. When a 1:1
mixture of 1-octene (1a) and 2-chloroethanol (2b) was treated
with AuClPPh3 and AgOTf, ca. 50% of the ether products
and ca. 50% of octenes (presumably formed by iso-
merization10a (Table S1) and/or addition-elimination pro-
cess) were found by GC analysis at the reaction period of 6
days, and this ratio did not practically change up to 8 days
(Table S2). A reversal pathway was also investigated with
3ab under the same condition and a similar product ratio
was obtained at the time of 7 days (Table S3). On the other
hand, similar procedures using the combination of 1a and
methanol, or 2-methoxyoctane did not form any alcohol
adducts or eliminated products. This result indicated there
were no appropriate mechanisms for gold-catalyzed hy-
droalkoxylation using methanol.
In conclusion, a gold-catalyzed intermolecular hydroalkoxy-
lation of unactivated olefins has been developed. A significant
improvement of reaction efficiency was observed by employ-
ing alcohol substrates bearing coordination functionalities.
In addition, the catalyst system with electron deficient
phosphines were also found to effectively catalyze the
objective reaction. The studies on detailed mechanism of the
reaction are underway.
Acknowledgment. This work was supported by a Grant-
in-Aid for Global-COE program, “Science for Future Mo-
lecular Systems”, Scientific Research (A) (No. 20245014),
and on Priority Areas (No. 20037052, Chemistry of Concerto
Catalysis) from the Ministry of Education, Culture, Science,
Sports and Technology of Japan.
Supporting Information Available: Experimental pro-
cedures and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9023166
(13) Ito, H.; Saito, T.; Miyahara, T.; Zhong, C.; Sawamura, M.
Organometallics 2009, 28, 4829.
(14) Richard, J. P.; Heo, C. K.; Toteva, M. M. J. Phys. Org. Chem.
2008, 21, 531.
Org. Lett., Vol. 11, No. 23, 2009
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