Hydroamination and hydroalkoxylation catalyzed by triflic acid. Parallels to reactions initiated with metal triflates

Article abstract of DOI:10.1021/ol061174+

(Chemical Equation Presented) Intermolecular additions of the O-H bonds of phenols and alcohols and the N-H bonds of sulfonamides and benzamide to olefins catalyzed by 1 mol % of triflic acid and studies to define the relationship between these reactions and those catalyzed by metal triflates are reported. Cyclization of an alcohol containing pendant monosubstituted and trisubstituted olefins catalyzed by either triflic acid or metal triflates form products from addition to the more substituted olefin, and additions of tosylamide catalyzed by triflic acid or metal triflates form indistinguishable ratios of the two N-alkyl sulfonamides.

Full text of DOI:10.1021/ol061174+

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4179-4182
Hydroamination and Hydroalkoxylation
Catalyzed by Triflic Acid. Parallels to
Reactions Initiated with Metal Triflates
Devon C. Rosenfeld, Shashank Shekhar, Akihiro Takemiya,
Masaru Utsunomiya, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 6520-8107
john.hartwig@yale.edu
Received May 12, 2006
ABSTRACT
Intermolecular additions of the O−H bonds of phenols and alcohols and the N−H bonds of sulfonamides and benzamide to olefins catalyzed
by 1 mol % of triflic acid and studies to define the relationship between these reactions and those catalyzed by metal triflates are reported.
Cyclization of an alcohol containing pendant monosubstituted and trisubstituted olefins catalyzed by either triflic acid or metal triflates form
products from addition to the more substituted olefin, and additions of tosylamide catalyzed by triflic acid or metal triflates form indistinguishable
ratios of the two N-alkyl sulfonamides.
Mild, metal-catalyzed additions of N-H and O-H bonds
across olefins have been sought for decades, and efforts to
develop such processes have intensified in recent years.
During the past 5 years, we have reported catalysts for
intermolecular additions of amines to vinylarenes and ad-
ditions of amines and phenols to dienes.1 In parallel with
this work on metal-catalyzed reactions, we reported that triflic
acid and sulfuric acid catalyze the intramolecular additions
of the N-H bond of sulfonamides, carbamates, acetamides,
and benzamides across the C-C double bond of alkenes and
vinylarenes.2 Of course, related acid-catalyzed additions of
alcohols to alkenes are classic reactions in organic chemistry.3
Many of the catalysts for intermolecular additions of N-H
and O-H bonds across alkenes that have been reported
recently are either metal triflates or combinations of metal
halides and silver triflate.4-10 These catalysts include copper,
silver, gold, ruthenium, platinum, and palladium complexes.
(2) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471.
(3) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry; John
Wiley and Sons: New York, 2001; p 993.
(4) (a) Coulombel, L.; Favier, I.; Dunach, E. Chem. Commun. 2005, 2286.
(b) Han, X. Q.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747.
(c) Oe, Y.; Ohta, T.; Ito, Y. Synlett 2005, 179. (d) Yang, C. G.; Reich, N.
W.; Shi, Z. J.; He, C. Org. Lett. 2005, 7, 4553.
(5) Karshtedt, D.; Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2005,
127, 12640.
(6) Oe, Y.; Ohta, T.; Ito, Y. Chem. Commun. 2004, 1620.
(7) Qin, H. B.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2006, 128, 4162.
(1) (a) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 6042.
(b) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 1828. (c) Takaya, J.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 5756. (d) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2004, 126, 2702. (e) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608. (f) Utsunomiya, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14286. (g) Pawlas, J.; Nakao,
Y.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 3669. (h)
Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 1166. (i) Lo¨ber,
O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366. (j)
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546. (k)
Kawatsura, M.; Hartwig, J. F. Organometallics 2001, 20, 1960. (l)
Utsunomiya, M.; Kawatsura, M.; Hartwig, J. F. Angew. Chem., Int. Ed.
2003, 42, 5865.
(8) Taylor, J. G.; Whittall, N.; Hii, K. K. M. Chem. Commun. 2005,
5103.
(9) Yang, C. G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966.
10.1021/ol061174+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/18/2006

Our current work originated from an unpublished observa-
tion that the addition of cyclohexanol to styrene in the
presence of a combination of a ruthenium precursor and triflic
acid was more likely catalyzed by a phosphonium triflate,
generated from the metal-phosphine complex and acid, than
by a ruthenium complex.11 At a similar time, Spencer
reported that acid can be the true catalyst in Michael additions
of heteroatom nucleophiles to acrylic acid derivatives
conducted with catalytic amounts of metal complexes.12
With these results as a backdrop, we have explored the
addition of various alcohols, carboxylic acids, phenols,
carbamates, and sulfonamides to alkenes and vinylarenes
catalyzed by triflic acid alone.13,14 In addition to exploring
the scope of acid-catalyzed additions, we have compared the
rates, side products, and selectivities of the acid-catalyzed
reactions to those of some of the reactions run with catalytic
amounts of metal triflates. These data show that most
reactions reported with metal triflates as catalyst also occur
with triflic acid as catalyst, that limiting the quantity of acid
is crucial to observing additions in high yields in some cases,
and that the selectivities and side products of the reactions
catalyzed by triflic acid often mirror those observed during
the reactions initiated with metal triflates. These results led
us to develop a substrate that can also help distinguish
between additions of X-H bonds to olefins that occur
intramolecularly and that could be catalyzed by metal
complexes or by acid.
loading of acid is used. However, these conditions do
consume the olefin. We found that some addition product
forms at early times, but that this product undergoes
decomposition in the presence of the large amount of acid.
In contrast, reactions of carboxylic acids, phenols, and
alcohols occurred cleanly in the presence of a smaller, 1 mol
% quantity of triflic acid, as shown in Scheme 1. With this
amount of acid catalyst, addition of anisic acid occurred
within a day at 80 °C, the addition of phenol occurred after
heating at 60 °C for 4 h, and the addition of â-phenethyl
alcohol occurred after 10 h at 70 °C in high isolated yields.
These additions of O-H bonds to olefins catalyzed by
triflic acid were not limited to reactions of the strained
norbornene. Addition of â-phenethyl alcohol to a small
excess of styrene formed the addition product in 41% isolated
yield. When this reaction was conducted for 1 day at 70 °C,
significant decomposition of the product occurs, and the
product from dimerization of styrene increases. Addition of
phenol to cyclohexene formed the addition product in 34%
isolated yield, with the product from hydrovinylation of
cyclohexene comprising less than 5% of the product mixture.
Our studies began with an exploration of the additions of
carboxylic acids, phenols, and alcohols to norbornene. These
reactions are summarized in Scheme 1. Several papers have
Scheme 1
Additions of aliphatic amines to olefins in the presence
of acid do not occur under mild conditions, presumably
because of the leveling effect of the amine. The reactions of
olefins with arylamines can be catalyzed by acid, but
significant amounts of hydroarylation product are formed in
combination with the hydroamination product.14 Further,
control reactions on the addition of aniline to vinylarenes
and dienes did not occur with triflic acid, at least at the
temperatures of the metal-catalyzed processes.1b The sole
production of N-H addition products from reactions cata-
lyzed by L2Pd(OTf)2 or Pd(0) complexes with triflic acid as
cocatalyst1j and the absence of addition product with HOTf
as catalyst alone, as well as the observation of substantial
enantiomeric excess for some additions,1i,j imply that the Pd-
catalyzed hydroaminations of vinylarenes and dienes are truly
metal catalyzed.1b
stated that products from the additions of these reagents to
olefins form in low yield in the presence of 10-15 mol %
of triflic acid,6,8,9 and we found the same result when a large
(12) (a) Wabnitz, T. C.; Yu, J. Q.; Spencer, J. B. Chem.sEur. J. 2004,
10, 484. (b) For a similar study on the additions of arene C-H bonds to
R,â-unsaturated ketones catalyzed by Au(III) and HBF4, see: Dyker, G.;
Muth, E.; Hashmi, A. S. K.; Ding, L. AdV. Synth. Catal. 2003, 345, 1247.
(13) For reactions of anilines with norbornene and vinylarenes catalyzed
by acids with tetraarylborate anions, see ref 14.
(10) Zhang, J. L.; Yang, C. G.; He, C. J. Am. Chem. Soc. 2006, 128,
1798.
(11) Utsunomiya, M.; Hartwig, J. F. Unpublished results.
(14) Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc.
2005, 127, 14542.
4180
Org. Lett., Vol. 8, No. 19, 2006

However, less basic reagents with N-H bonds, such as
amides, carbamates, and sulfonamides, do add to olefins
under acid-catalyzed conditions. Our past intramolecular
additions of sulfonamides, carbamates, acetamides, and
benzamides and the use of metal triflates for additions of
these reagents to alkenes led us to investigate intermolecular
additions of these reagents to alkenes catalyzed by triflic acid
alone. These results are summarized in Scheme 2.
Several reports of the addition of sulfonamides to dienes
catalyzed by metal triflates have appeared recently.7,15 We
found that TsNH2 adds to cyclohexadiene in the presence
of 1 mol % of triflic acid, and that this reaction was nearly
complete after 25 h at 50 °C to form the addition product in
63% isolated yield (eq 5).
Scheme 2
Because the scope of the reactions catalyzed by HOTf and
metal triflates is closely related, we also compared qualita-
tively the rates of the additions in the presence of catalytic
amounts of triflic acid to the rates of additions in the presence
of catalytic amounts of several metal triflates. These compar-
ative studies showed that the rates of reaction catalyzed by
1 mol % of triflic acid were similar to the rates of reactions
catalyzed by metal triflates in equal to or greater amounts.
In particular, reactions of â-phenethyl alcohol with styrene
and norbornene conducted with the combination of 2 mol
% of Cp*Ru(PPh3)Cl2 and 4 mol % of AgOTf as catalyst
required 48 h at 70 °C,6 whereas these two reactions occurred
over 10-16 h at 70 °C when conducted with only 1 mol %
of HOTf. The addition of 4-tert-butyl phenol to cyclohexene
occurred at 85 °C over 15 h in the presence of 2 mol % of
(Ph3P)AuOTf,9 whereas the addition of phenol to cyclohex-
ene occurred at 85 °C over a similar time frame (22 h) with
only 1 mol % of HOTf. Likewise, the addition of p-anisic
acid or phenol to norbornene occurred over 18 h at 80 °C
The addition of p-toluenesulfonamide (TsNH2) to nor-
bornene occurred within hours at room temperature in
dichloroethane solvent to form the exo addition product in
91% yield. Like the reactions of alcohols catalyzed by triflic
acid, the reactions of sulfonamides catalyzed by acid were
not limited to additions to the strained norbornene. The
addition of TsNH2 to cyclohexene and cyclooctene occurred
within a day at 85 °C in 58 and 86% isolated yield. The
addition of benzamide to styrene also occurred at 100 °C in
dioxane solvent over 24 h in 77% yield (eq 3).
8
with 2.5 mol % of Cu(OTf)2 and occurred under the same
conditions providing similar yields with 1 mol % of HOTf.
Further, the reaction of TsNH2 with norbornene catalyzed
by 1 mol % of HOTf occurred at room temperature instead
of the elevated temperatures and higher loadings of metal
triflates.5,10
The reaction between a large number of N-H and O-H
bond donors and olefins catalyzed by metal triflates has been
published, and it is beyond the scope of this work to analyze
each of these processes. However, the side products formed
during some of these reactions and the acid-catalyzed
reactions shed some light on the relationship between these
two processes.
For example, the reactions between phenol and cyclohex-
ene and between TsNH2 and cyclohexene or cyclooctene in
the presence of triflic acid formed a set of side products with
masses equal to twice the mass of the olefin. We presume
these products are regioisomers formed by trapping of the
The reaction between TsNH2 and an excess (4 equiv) of
1-octene occurred to high conversion at 85-90 °C over 16-
24 h in toluene to form an approximately 2:1 ratio of the 2-
and 3-N-octyl tosylamides. The same mixture of isomers in
toluene also formed from reactions conducted in the presence
of catalytic amounts of (Ph3P)AuOTf.10 The formation of
these isomers upon acid-catalyzed chemistry implies that a
carbocation is generated and a 1,2-hydrogen shift competes
with trapping of the carbocation by the sulfonamide.
(15) Brouwer, C.; He, C. Angew. Chem., Int. Ed. 2006, 45, 1744.
Org. Lett., Vol. 8, No. 19, 2006
4181

carbocation intermediate with the excess of olefin. This
reaction of the carbocation apparently competes with trapping
of the carbocation by the phenol or the sulfonamide. Most
important for assessing the relationship between acid- and
metal-catalyzed reactions, these same side products were
formed during the reaction of cyclohexene and cyclooctene
with TsNH2 conducted with catalytic amounts of (Ph3P)-
AuOTf.
Scheme 4
Considering the potential that the metal complexes serve
as precatalysts for the formation of a protic acid catalyst,
we sought to develop protocols to distinguish between these
two types of additions. One protocol involves measuring the
ratios of products formed between an N-H and O-H bond
donor and two different olefins. The second protocol allows
analysis of intramolecular reactions and involves the addition
of an O-H bond across two different olefins that are distinct
in their steric properties and ability to stabilize a carbocation.
Results from the first protocol are shown in Scheme 3.
than complexes of more substituted olefins. Of course, the
acid-catalyzed addition would occur faster to the 2,2-
disubstituted olefin than to the monosubstituted olefin
because it would form a more stable carbocation intermedi-
ate. Indeed, cyclization of this substrate in the presence of 1
or 10 mol % of triflic acid for 12 h in toluene at 80 °C formed
only the product from cyclization at the more substituted
olefin. This product was isolated in 61% yield from a reaction
conducted with 1 mol % of HOTf. The reactions initiated
with 2.5 mol % of Cu(OTf)2; with 10 mol % of AgOTf;
with 2 mol % of [Cp*RuCl2]2, 4 mol % of PPh3 and 2.5 mol
% of AgOTf; with 5 mol % of (Ph3P)AuCl and 5 mol % of
AgOTf; and with 10 mol % of FeCl3 under conditions
published for the reactions of alcohols with olefins also
formed the product from cyclization at the more substituted
olefin.
Scheme 3
Thus, we have shown that triflic acid in weakly basic
solvents catalyzes the additions of a broad range of O-H
and N-H bond donors to unactivated alkenes. The rates and
product ratios from reactions catalyzed by acid and metal
triflates were similar, and cyclization of a diene resulted in
the same product from reaction at the more substituted of
the olefins when metal triflate or triflic acid alone was used
as catalyst. Therefore, one must consider carefully whether
the additions of weakly basic substrates with N-H and O-H
bonds to olefins catalyzed by metal triflates are true metal-
catalyzed processes or if the metal simply generates a protic
acid.
The reaction of TsNH2 with 4 equiv each of cyclohexene
and cyclooctene was conducted. The reaction in the presence
of 1 mol % of triflic acid led to a 1:4 ratio of the product
from addition of cyclohexene and cyclooctene. The ratio of
products fluctuated during the course of the reaction, but by
no more than 15% of the average value. The measured ratios
for the addition products appeared to reflect the kinetic ratio
because addition of 3 equiv of cyclooctene and 1 mol % of
triflic acid to N-cyclohexyl-p-toluenesulfonamide did not
produce any detectable N-cyclooctyl-p-toluenesulfonamide
after 12 h at 90 °C and 4 h at 120 °C. The ratio of these two
products formed from the same reaction catalyzed by (Ph3P)-
AuOTf (Scheme 3) is clearly similar to the ratio formed from
the acid-catalyzed process.16
Acknowledgment. We thank the NIH (GM-55382) for
support of this work. M.U. thanks Mitsubishi Chemicals for
support.
Supporting Information Available: Reaction procedures,
substrate synthesis, and characterization of reaction products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL061174+
The second protocol involves cyclization of an alcohol
containing a monosubstituted and a 2,2-disubstituted olefin,
with this reaction being shown in Scheme 4. We assume
that metal-catalyzed O-H or N-H additions by a combina-
tion of olefin coordination and insertion or by a combination
of olefin coordination and nucleophilic attack would be faster
to the less substituted olefin than to the more substituted
olefin; complexes of less substituted olefins are more stable
(16) One could also envision using the ratio of endo and exo isomers
formed from addition of O-H and N-H bond donors to norbornene
catalyzed by acid and by a metal complex to distinguish the two pathways.
Although a mixture of endo and exo isomers was stated to be observed
from the addition catalyzed by 10 mol % of triflic acid after 18 h at 80-85
°C,7,9 we have observed greater than 95% of the exo isomer after 95%
conversion of the olefin (4 h, 90 °C) during reactions conducted with 1, 2,
or 5 mol % of triflic acid, with 5 mol % of (Ph3P)AuCl/AgOTf in toluene,
or 2.5 mol % of Cu(OTf)2 in dioxane for 2-4 h. At longer reaction times
(ca. 22 h), we began to observe an increase in the amount of endo isomer.
4182
Org. Lett., Vol. 8, No. 19, 2006