Expanding the forefront of strong organic br?nsted acids: Proton-catalyzed hydroamination of unactivated alkenes and activation of au(i) for alkyne hydroamination

Article abstract of DOI:10.1021/acs.orglett.5b00617

The synthesis of a solid, bench-stable, strong organic Br?nsted acid with a computed pK_a of 0.9 is reported. An X-ray crystal structure and DFT calculations are provided which offer insight into the bonding of this acid. The application of this

Full text of DOI:10.1021/acs.orglett.5b00617

Letter
pubs.acs.org/OrgLett
Expanding the Forefront of Strong Organic Brønsted Acids: Proton-
Catalyzed Hydroamination of Unactivated Alkenes and Activation of
Au(I) for Alkyne Hydroamination
Roya Mirabdolbaghi and Travis Dudding*
Department of Chemistry, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario L2S 3A1, Canada
S
* Supporting Information
ABSTRACT: The synthesis of a solid, bench-stable, strong
organic Brønsted acid with a computed pKa of 0.9 is reported.
An X-ray crystal structure and DFT calculations are provided
which offer insight into the bonding of this acid. The
application of this strong organic Brønsted acid as a catalyst
for the intermolecular hydroamination of unactivated alkenes
and as an activator for Au(I)-catalyzed alkyne hydroamination with anilines is described.
he importance of Brønsted acids would be hard to
understate given their importance in countless biological
cultivating a more lucid understanding of H-bonding but also
brings with it the promise of developing a novel H-bonding
catalyst.
Mindful of the above-mentioned limitations and having a
longstanding interest in Brønsted acid catalysis,7 we were
intrigued by the potential of protonating our recently reported
pnictogen based N-centered class of phase-transfer catalysts
(PTCs)8 (e.g., 1·Cl−, Scheme 1) as this action would serve the
T
processes as well as their use in industrial manufacturing and
experimental laboratories worldwide. In this vein, with the
advent of the field of organocatalysis in recent years, the
development and use of metal-free, strong Brønsted acids has
had an influential role, and accordingly, efforts on this front
continue to mount at a rapid pace.1 Most notably, there have
been a number of exceptional applications using nonchiral2 and/
or chiral strong Brønsted acids, such as the pentafluorophenylbis-
(triflyl)methane, polystyrene-bound tetrafluorophenylbis-
(triflyl)methane,3 and N-triflylphosphoramide (NTPA) catalysts
of Yamamoto4 and disulfonimide (BINBAM) catalysts of List,5
to name but a handful.
−
Scheme 1. Synthesis of Dication 1+−H+·2BF4
While these works are impressive, unmet challenges remain
with respect to the advancement of strong Brønsted acids in
catalysis and synthesis; this is particularly evident for catalytic C−
N bond formation. Lacking, in particular, are solid, bench-stable,
strong organic Brønsted acids that, in addition to being
inexpensive or easily prepared, serve the paramount role(s) of
functioning as catalysts, precatalysts, activators, or other
foreseeable useful tasks. Accordingly, the design and synthesis
of new strong organic Brønsted acids offers the promising
potential of achieving reactivity that is unavailable with known
Brønsted acids or, at the very least, provides complementary
patterns of reactivity which are still needed.
From a more fundamental perspective, it is interesting to note
that, despite a general interest in developing new strong organic
Brønsted acids in recent years, H-bonding has been a debated
topic for almost a century that continues to garner appreciable
attention.6 The origin of this controversy can be traced back to
the seminal works of Nobel laureate Linus Pauling and Gilbert
Newton Lewis, who in the early 1900s held opposing views on
the subject, Pauling arguing in favor of the electrostatic “dipole−
dipole” as opposed to Lewis’s view of “partial covalent” character
of H-bonding. Consequently, the advancement of new, strong
organic Brønsted acids not only offers the attractive prospect of
trifold role: (1) a dicationic conjugate acid 1+−H+ would be
generated that foreseeably could be a super acid or at the very
least a strong organic Brønsted acid, (2) dication 1+−H+ would
offer the prospect of gaining insight into H-bonding, and (3)
conceivably, dication 1+−H+ would have synthetic utility.
Accordingly, we report herein the synthesis, X-ray structure,
hybrid density functional theory (DFT) calculations, and use of
dication 1+−H+ as a strong Brønsted acid catalyst (loadings 0.2
mol %) for intermolecular hydroamination of unactivated
alkenes and as an activator for Au(I)-catalyzed alkyne hydro-
amination with anilines.
At the outset, with the aim of preparing the protonated
derivative of 1+−H+ from reported 1+·Cl−, several factors, such as
the need for 1+−H+ to be a crystalline salt that was easy to handle
and accessible without undue experimental manipulation, were
considered. Attentive to these criteria, initial studies led to the
Received: February 28, 2015
Published: April 8, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00617
Org. Lett. 2015, 17, 1930−1933

Organic Letters
Letter
finding of the bench-stable salt, 1+−H+·2BF4 , which could be
prepared in gram quantities from 1+·Cl− by NaBF4 counterion
exchange, followed by protonation using HBF4 (Scheme 1). An
X-ray structure was then obtained from a single crystal to better
Å) and one of the moderately acidic methyl hydrogens of the
−
N(2)−Me group (ρBCP = 0.009).
Having structural insight, the acidity of 1+−H+·2BF4 was
−
computed to aid our selection of potential reactions for applying
understand the structure and bonding in 1+−H+·2BF4 .
−
1+−H+·2BF4 . To this end, the calculated relative pKa of 1+−H+
−
Notably, the X-ray structure revealed a number of striking
features among which was the presence of a H-bonded water
molecule to the protonated N(1) nitrogen residing at a distance
of 1.83 Å. A restricted optimization calculation at the B3LYP/
LanL2DZ level of theory in which all of the heavy atoms were
frozen and the hydrogens left unconstrained using the X-ray
at the B3LYP/6-31G+(d)//SMD/M06-2x/6-311G++(2df,2p)
level of theory using the IEFPCM solvation model (acetonitrile,
ε = 35.5) was computed to be 0.9 (see the Supporting
Information for details). Meanwhile, the gas-phase proton
affinity (PA) of 1+ [B3LYP/6-31G+(d)//M062x/6-311G+
+(2df,2p)], considering thermal corrections computed at the
B3LYP/6-31G+(d) level of theory, was determined to be 178.8
kcal/mol. At that stage, with insight into the strong Brønsted
−
coordinates of 1+−H+·2BF4 as a starting point to remove any
spatial artifacts resulting from X-ray based assignment of
hydrogen locations provided a very similar structure in all
respects (Figure 1). Apparent from this structure was that the
−
acidity of 1+−H+·2BF4 and mindful of (1) the timely
significance of alkyne/alkene hydroamination as a strategy for
preparing nitrogen-containing molecules9 and (2) current
interest in group 11 gold-catalyzed reactions, we turned to the
use of 1+−H+ as an activator for Au(I)-catalyzed alkyne/alkene
hydroamination.
In this respect, it is noteworthy that the majority of
homogeneous gold-catalyzed processes reported to date have
relied on the use of silver-mediated activation of gold(I)
precatalyst by halogen abstraction. The use of silver activators,
however, is not without shortcomings as silver salts and their
byproducts may negatively impact a reaction by forming various
Au and Ag adducts which are catalytically inactive. Moreover,
silver salts often are light sensitive, relatively expensive,
unavailable commercially, difficult to prepare, and/or have
poor solubility. To address these limitations, the use of a strong
organic Brønsted acids to generate catalytically active Au(I)
species via protonolysis has emerged as a promising compliment
to silver-mediated activation. Accordingly, the use of 1+−H+·
2BF4− as an activator for Au(I)-catalyzed alkyne hydroamination
using gold precatalyst 5 was envisioned. To this end, we were
−
Figure 1. X-ray structure of 1+−H+·2BF4 ·H2O.
pleased to find that 1+−H+·2BF4 (0.2 mol %) under mild
−
N(1)+−H+−O(1) contact exhibits a characteristic quantum
conditions served as a competent activator of gold precatalyst 5
(0.1 mol %) leading to N−C bond forming addition of aniline 3a
to alkyne 2a to afford imine 4a in 22% yield (Table 1, entry 1),
while when the same conditions were applied for 48 h the yield
increased to 60%. Encouraged by this initial finding, we set out to
further explore the scope of this reaction by reacting a range of
substituted alkynes and amines. Notably, the reaction yield
increased to 87% with resonance-donating electron-withdrawing
4-bromo substituent aniline 3b, while the use of 3c having a more
electron-withdrawing and less resonance donating 4-fluoro
substituent led to a decrease in yield (Table 1, entries 2 and
3). Intrigued by this finding, we then subjected 2,5-dichloroani-
line (3d) to the reaction conditions to afford imine 4d in high
yield, 95%, after only 4 h (Table 1, entry 4). Meanwhile, when 3e
having an electron-withdrawing 4-nitro substituent was used, 4e
was obtained in 19% yield (Table 1, entry 5). Moreover, longer
reaction times did not improve the yield, presumably due to
poisoning of the in situ formed Au(I) catalyst. On the other hand,
products 4f and 4g were obtained in low yield from the reactions
of electron-rich 4-alkyl-substituted anilines 3f and 3g (Table 1,
entries 6 and 7). This reduced yield is thought to arise from
greater competitive binding of the Au(I) catalyst by electron-rich
anilines, which in turn diminishes alkyne activation by gold
coordination and ultimately slows the rate of aniline addition.
The subsequent use of 2-ethylaniline (3h), which was anticipated
to afford better yields, as Au(I)−aniline association should be less
favorable due to the presence of an o-alkyl group, afforded
product 4h in moderate yield after 24 h (Table 1, entry 8).
theory of atoms in molecules (QTAIM) bond critical point
(BCP) with density ρ = 0.05 au and Laplacian value ∇2ρbcp
=
0.038 au, thus typifying this interaction as a moderate strength H-
bond (see the Supporting Information). Meanwhile a natural
bond orbital (NBO) analysis of the donor−acceptor nature of
this interaction, uncovered that there was significant charge
transfer from one oxygen lone pair into the antibonding σ*-
orbital of the N+−H bond (ENBO = 40.1 kcal/mol), hence
supporting a noticeable degree of fractional chemical bonding or,
that is, charge-transfer-based “partial covalent” H-bonding
character. The H-bonding/proton-donor ability of N(1) can be
traced not only to the electron deficiency of dication 1+−H+ (see
the Supporting Information for ESP isosurface) but also to the
considerable s-character of this nitrogen as judged from the NBO
computed s1p2.2 hybridization of N(1) and X-ray-determined
C(1)−N(1)−C(4) metric of 122.3°.
−
Conspicuous as well was the displacement of the two BF4
counteranions away from the aromatic cyclopropeninium ring
toward the imidazolium hemisphere of 1+−H+, likely as a result
of the known donor−donor ion pair strain associated with
cyclopropeninium ring systems. One of the BF4− anions resides
toward the lower face of the complex, forming an H-bond with
H(2) of the water molecule (distance = 1.83 Å) and two
hydrogens of the imidazolium unit, based on the presence of
BCPs (ρ = 0.004, 0.009 au) and the computed noncovalent
interaction (NCI) isosurface. The second BF4− anion is located
further from the parent dication, albeit visible is an apparent H-
bond contact with H(3) of the water molecule (distance = 1.90
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Organic Letters
Letter
Table 1. Au(I)-Catalyzed Alkyne Hydroamination Using
Table 2. Au(I)-Catalyzed Alkene Hydroamination Using
Brønsted Acid 1+−H+·2BF4− as an Activator
Brønsted Acid 1+−H+·2BF4− as an Activator
a
b
Yields of isolated products after flash chromatography. Yield
c
increased to 60% after 48 h. Reaction conversion after 48 h was
insignificant (<1%) based on 1H NMR when the Brønsted acid, metal,
or Brønsted acid−metal combination was excluded.
To further investigate the effect of steric interactions on the
reaction, 2,4,6-trimethylaniline (3i) was subjected to the reaction
conditions to generate 4i in a moderate yield (Table 1, entry 9).
Switching to the activated substrate, 4-ethynylanisole (2b),
resulted in a dramatic enhancement in reaction yield (95%)
(Table 1, entry 10). Furthermore, the reaction of the 4-
fluorophenylacetylene and 4-methylphenylacetylene substrates
2c and 2d afforded products in moderate yield, which was
somewhat interesting considering the electronic differences
existing between these substrates (Table 1, entries 11 and 12).
Having demonstrated the catalytic ability of our Au(I)/1+−
a
b
Yields of isolated products after flash chromatography. Brønsted
acid, 1+−H+·2BF4 , (0.2 mol %), and 5 (0.1 mol %) afforded a
−
c
comparable yield of 86%. No conversion was observed using only 5
−
(0.1 mol %) or when both 1+−H+·2BF4 and 5 were excluded.
−
H+·2BF4 system for alkyne hydroamination, the more
challenging reaction of alkene hydroamination was undertaken.
In this respect, it was of particular interest to see if the unique
reaction conditions provided 7d and 7e in 92% and 93% yield,
respectively (Table 2, entries 4 and 5).
reactivity associated with our Au(I)/1+−H+·2BF4 catalyst
The proposed mechanisms of these alkyne and alkene
hydroamination reactions warrant mention as they likely share
parallels with many previous mechanistic posits while possessing
a number of key differences. The mechanism for alkene
−
would allow for the addition of anilines to unactivated alkenes.
To our delight, the reaction of α-methylstyrene (6a) with aniline
3b and catalytic 1+−H+·2BF4 (0.2 mol %) and 5 (0.1 mol %)
−
hydroamination with catalytic 1+−H+·2BF4 is believed to be
−
afforded Markovnikov addition product 7a in 86% yield.
Nevertheless, a careful analysis of hydroamination background
rates revealed that strong Brønsted acid 1+−H+·2BF4− (0.2 mol
%) in the absence of gold effectively catalyzed alkene
hydroamination with comparable yield (Table 1, entry 1).
Though serendipitous, this result was nonetheless remarkable
given the low loading of Brønsted acid 1+−H+·2BF4− relative to
the larger loadings (e.g., 1−5 mol %) employed for the
intermolecular hydroamination of unactivated alkenes with
anilines reported to date.10 To briefly establish the scope of
this process, a selection of unactivated alkenes were then
intimately tied to the formation of a continuum of highly
−
separated ion pairs composed of weakly associating anionic BF4 ,
cationic 1+, and acidic protonated anilinium moieties which are
strong H+ donors. In this respect, it is notable that Bergman et al.
have previously suggested that decreasing counteranion
association enhances anilinium acidity.11 Importantly, this factor
was critical for facilitating alkene protonation and hydro-
amination with anilines in the authors’ report.
As for alkyne hydroamination, it is thought that the catalytic
cycle for this process initiates with protonolysis of the Au−N
bond of precatalyst 5 by strong Brønsted acid 1+−H+·2BF4− to
generate phthalimide 8 and Lewis acidic gold(I) species 9. At that
−
subjected to the catalytic action of 1+−H+·2BF4 . In this regard,
the reaction of 6a with aniline 3a led to a dramatic decrease in
yield (Table 2, entry 2). On the other hand, 7c was isolated in
moderate 59% yield from the hydroamination of styrene with 3d
(Table 2, entry 3). The reaction of anilines 3d or 3b with
bicyclo[2.2.1]hept-2-ene (6c) as a substrate employing the same
stage, having served its most salient role, 1+−H+·2BF4 shifts
−
from being a strong Brønsted acid to that of a bulky lipophilic
−
cation/(weakly associated) 1+·BF4 ion pair. Functioning in a
−
second role, the diffuse cation 1+ of ion pair 1+·BF4 then
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conceivably acts as an antagonist of Au(I) counterion association
by sequestering BF4 away from the Au(I) metal center, thus
AUTHOR INFORMATION
Corresponding Author
■
−
enhancing the innate reactivity of the electron-deficient gold(I)
catalyst and freeing it for alkyne binding. Regardless, the
hydroamination of an activated Au(I)---alkyne π-complex by
aniline via TS1 subsequently ensues to provide transient addition
*E-mail: tdudding@brocku.ca.
Notes
The authors declare no competing financial interest.
−
product 10. Byproduct phthalimide 8, BF4 , a molecule of water
−
or potentially even 1+·BF4 , then act as a shuttle for proton
ACKNOWLEDGMENTS
■
transfer to provide the Au(I) coordinated enamine 11 after
protodeauration. While it is too early to diagnostically confirm
which of the above scenarios is more favorable, we tentatively
propose that phthalimide 8 mediates proton transfer through
TS2 as depicted in Scheme 2. Subsequently, the catalytic cycle
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) for funding of this
research. We thank Hillary Jenkins of McMaster University for X-
ray analysis.
REFERENCES
■
Scheme 2. Proposed 1+−H+·2BF4− and Au(I)-Catalyzed Cycle
for Alkyne Hydroamination
(1) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I.
Angew. Chem., Int. Ed. 2011, 50, 6706.
(2) Yamamoto, H. Tetrahedron 2007, 63, 8377.
(3) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Angew. Chem., Int. Ed.
2001, 40, 4077.
(4) (a) Nakashima, D.; Yamamoto, Y. J. Am. Chem. Soc. 2006, 128,
9626. (b) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,
9246. (c) Cheon, C. H.; Yamamoto, H. Org. Lett. 2010, 12, 2476.
(5) García-García, P.; Lay, F.; Rabalakos, C.; List, B. Angew. Chem.
2009, 121, 4427; Angew. Chem., Int. Ed. 2009, 48, 4363.
(6) (a) Arunan, E.; Desitaju, G. R.; Klein, R. A.; Sadlej, J.; Scheiner, S.;
Alkorta, I.; Clary, D. C.; Crabtree, R. H.; Danneberg, J. J.; Hobza, P.;
Kjaergaard, H. G.; Legon, A. C.; Mennucci, B.; Nesbitt, D. J. Pure Appl.
Chem. 2011, 83, 1637. (b) Pimentel, G. C.; McClellan, A. L. The
Hydrogen Bond; Freeman: San Francisco, 1960. (c) Jeffrey, G. A. An
Introduction to Hydrogen Bonding; Oxford University: New York, 1997.
(d) Scheiner, S. Hydrogen Bonding. A Theoretical Perspective; Oxford
University Press: Oxford, 1997.
(7) (a) Creech, G. S.; Zhu, X.-F.; Fonovic, B.; Dudding, T.; Kwon, O.
Tetrahedron 2008, 64, 6935. (b) Gordillo, R.; Dudding, T.; Anderson, C.
D.; Houk, K. N. Org. Lett. 2007, 9, 501. (c) Anderson, C. D.; Dudding,
T.; Gordillo, R.; Houk, K. N. Org. Lett. 2008, 10, 2749. (d) Belding, L.;
Dudding, T. Chem.− Eur. J. 2014, 20, 1032.
(8) Mirabdolbaghi, R.; Dudding, T.; Stamatatos, T. Org. Lett. 2014, 16,
2790.
(9) (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (b) Brunet, J.
̈
J.; Neibecker, D. In Catalytic Heterofunctionalization; Togni, A.,
Grutzmacher, H., Eds.; Wiley-VCH: New York, 2001; pp 91−141.
̈
(c) Beller, M.; Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad, J.;
completes with dissociation of the Au(I) catalyst and enamine
tautomerization to afford imine 12. Ongoing mechanistic studies
are underway to gain insight in to these hydroamination
reactions, and the findings of this work, which are anticipated
to provide valuable understanding for improving these processes,
will be reported in due course.
To summarize, we have reported the synthesis of a solid,
bench-stable, strong organic Brønsted acid which can be
prepared in gram quantities. X-ray structural data and DFT
calculations offering insight into the bonding of this strong
organic Brønsted are also provided. The use of this Brønsted acid
as catalyst for the hydroamination of unactivated alkenes and as
an activator for Au(I)-catalyzed alkyne hydroamination with
anilines is described.
Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002, 1579. (d) Hong,
S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (e) Muller, T. E.; Hultzsch,
̈
K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. rev. 2008, 108, 3795.
(f) Mizushima, E.; Hayashi, T.; M. Tanaka, M. Org. Lett. 2003, 5, 3349.
́
(10) (a) Marcsekova, K.; Doye, S. Synthesis 2007, 1, 145. (b) Lapis, A.
A. M.; Neto, B. A. D.; Scholten, J. D.; Nachtigall, F. M.; Eberlin, M. N.;
Dupont, J. Tetrahedron Lett. 2006, 47, 6775. For amines other than
aniline, see: Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya,
M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179.
(11) Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005,
127, 14542.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure, spectroscopic data for all new
compounds, crystallographic data (CIF), and computational
details for 1+−H+·2BF4 . This material is available free of charge
−
via the Internet at http://pubs.acs.org.
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DOI: 10.1021/acs.orglett.5b00617
Org. Lett. 2015, 17, 1930−1933