Triaryl-Like MONO-, BIS-, and TRISKITPHOS Phosphines: Synthesis, Solution NMR Studies, and a Comparison in Gold-Catalyzed Carbon-Heteroatom Bond Forming 5-exo-dig and 6-endo-dig Cyclizations

Article abstract of DOI:10.1021/acs.organomet.6b00146

A homologous series of triaryl-like KITPHOS-type monophosphines containing one, two, or three bulky 12-phenyl-9,10-dihydro-9,10-ethenoanthracene (KITPHOS) units have been developed, and the influence of increasing steric bulk on their efficacy as ligands in gold(I)-catalyzed carbon-heteroatom bond-forming cyclizations has been investigated. Detailed solution NMR studies on Ph-TRISKITPHOS, its oxide, and the corresponding gold(I) chloride adduct identified a conformational exchange process involving a concerted librational motion of the individual anthracene-derived organic substituents about their P-C bonds. The cessation of this motion at reduced temperatures lowers the molecular symmetry such that the two C₆H₄ rings in each of the KITPHOS units become inequivalent; a lower energy process involving restricted rotation of the biaryl-like phenyl ring has also been identified. Electrophilic gold(I) complexes of these triaryl-like KITPHOS monophosphines catalyze the 5-exo-dig cycloisomerization of propargyl amides to afford the corresponding methylene oxazolines, which were used in a subsequent tandem carbonyl-ene reaction to afford functionalized 2-substituted oxazolines. A comparative survey revealed that catalyst efficiency for cycloisomerization decreases in the order MONOKITPHOS = BISKITPHOS > PPh₃ > TRISKITPHOS. The optimum system also catalyzes the selective 6-endo-dig cyclization of 2-alkynylbenzyl alcohols, 2-alkynylbenzoic acid, and 2-phenylethynyl benzamides; gratifyingly, in several cases the yields obtained are markedly higher and/or reaction times significantly shorter than those previously reported for related gold catalysts. Moreover, these are the first examples of gold(I)-catalyzed 6-endo-dig cycloisomerizations involving 2-phenylethynyl benzamides and, reassuringly, the optimum gold(I)/MONOKITPHOS systems either rivaled or outperformed existing silver or palladium-based catalysts. The steric parameters of this homologous series of phosphines have been quantified and compared with selected triarylphosphines using a combination of Solid-G calculations, to determine the percentage of the metal coordination sphere shielded by the phosphine (the G parameter), and Salerno molecular buried volume calculations (SambVca) to determine the percent buried volume (%V_bur); the corresponding Tolman cone angles have also been determined from correlations.

Full text of DOI:10.1021/acs.organomet.6b00146

Article
pubs.acs.org/Organometallics
Triaryl-Like MONO‑, BIS‑, and TRISKITPHOS Phosphines: Synthesis,
Solution NMR Studies, and a Comparison in Gold-Catalyzed Carbon−
Heteroatom Bond Forming 5-exo-dig and 6-endo-dig Cyclizations
Simon Doherty,* Julian G. Knight,* Daniel O. Perry, Nicholas A. B. Ward, Dror M. Bittner,
William McFarlane, Corinne Wills, and Michael R. Probert
NUCAT, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
S
* Supporting Information
ABSTRACT: A homologous series of triaryl-like KITPHOS-type
monophosphines containing one, two, or three bulky 12-phenyl-9,10-
dihydro-9,10-ethenoanthracene (KITPHOS) units have been developed,
and the influence of increasing steric bulk on their efficacy as ligands in
gold(I)-catalyzed carbon−heteroatom bond-forming cyclizations has
been investigated. Detailed solution NMR studies on Ph-TRISKIT-
PHOS, its oxide, and the corresponding gold(I) chloride adduct
identified a conformational exchange process involving a concerted librational motion of the individual anthracene-derived
organic substituents about their P−C bonds. The cessation of this motion at reduced temperatures lowers the molecular
symmetry such that the two C6H4 rings in each of the KITPHOS units become inequivalent; a lower energy process involving
restricted rotation of the biaryl-like phenyl ring has also been identified. Electrophilic gold(I) complexes of these triaryl-like
KITPHOS monophosphines catalyze the 5-exo-dig cycloisomerization of propargyl amides to afford the corresponding
methylene oxazolines, which were used in a subsequent tandem carbonyl-ene reaction to afford functionalized 2-substituted
oxazolines. A comparative survey revealed that catalyst efficiency for cycloisomerization decreases in the order MONOKITPHOS
= BISKITPHOS > PPh3 > TRISKITPHOS. The optimum system also catalyzes the selective 6-endo-dig cyclization of 2-
alkynylbenzyl alcohols, 2-alkynylbenzoic acid, and 2-phenylethynyl benzamides; gratifyingly, in several cases the yields obtained
are markedly higher and/or reaction times significantly shorter than those previously reported for related gold catalysts.
Moreover, these are the first examples of gold(I)-catalyzed 6-endo-dig cycloisomerizations involving 2-phenylethynyl benzamides
and, reassuringly, the optimum gold(I)/MONOKITPHOS systems either rivaled or outperformed existing silver or palladium-
based catalysts. The steric parameters of this homologous series of phosphines have been quantified and compared with selected
triarylphosphines using a combination of Solid-G calculations, to determine the percentage of the metal coordination sphere
shielded by the phosphine (the G parameter), and Salerno molecular buried volume calculations (SambVca) to determine the
percent buried volume (%Vbur); the corresponding Tolman cone angles have also been determined from correlations.
indole,7 arylpyrazole,8,9 bipyrazole,9 Dalphos,10 and the 2,3-
INTRODUCTION
■
dihydrobenzo[d][1.3]oxophosphole framework.11 Despite the
Arguably, since their introduction bulky electron-rich biaryl
monophosphines have evolved into one of the most powerful
and versatile classes of ligand for transition-metal-catalyzed
resounding success of this class of monophosphine, electron-
deficient bulky triaryl and triaryl-like monophosphines have
also been reported to form highly active catalysts for a host of
carbon−carbon- and carbon−heteroatom-based couplings and
cyclizations.1 The success of these ligands is often attributed to
platinum-group-metal-catalyzed transformations. For example,
ferrocenyl-based triarylphosphine 1,12 ortho dimesitylboryl-
a combination of factors, including (i) their basicity, which
substituted triarylphosphine 2,13 indolyl-based triarylphosphine
3,14 and a hexadimethylammonium-substituted triarylphos-
phine, Bn-Dendriphos15 (Chart 1) all form highly efficient
catalysts for Suzuki−Miyaura cross-coupling that outperform
their triphenylphosphine counterpart and in some cases even
couple extremely challenging substrate combinations such as
electron-rich aryl chlorides and sterically congested systems. In
other examples, the bowl-shaped triarylphosphine 5 accelerates
the rhodium- and copper-catalyzed hydrosilylation of ketones
promotes activation of challenging aryl chlorides,2 (ii) their
steric bulk, which favors formation of the active mono-
phosphine L1Pd0 as well as the product-forming reductive
elimination step,3 (iii) the architecture of the biaryl motif,
which increases catalyst lifetime by stabilizing the low-
coordinate active species through a weak metal−arene
interaction,4 and most recently (iv) the breakthrough develop-
ment of readily activated palladacycle precatalysts that generate
the active monoligated LPd(0) species with remarkable
efficiency under mild conditions.5 As such, the biaryl motif
has been the lead template for the design of alternative systems
based on biaryl-like units, including N-arylpyrroles,6 2-phenyl-
Received: February 22, 2016
© XXXX American Chemical Society
A
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counterparts for the 5-exo-dig cyclization of propargyl amides.24
We have also shown that these phosphines can coordinate to
ruthenium either in a conventional κ(P) manner or as κ(P):η6
eight-electron donors tethered through the proximal phenyl
ring of the biaryl-like fragment to form constrained-geometry
complexes; both types of complexes were shown to form
efficient catalysts for the direct ortho arylation of 2-phenyl-
substituted N-heterocycles.25 As Lewis acid gold(I) complexes
of triphenylphosphine are often the catalysts of choice for
cyclizations initiated by activation of a carbon−carbon multiple
bond toward nucleophilic attack,26 we have pursued this
analogy further and prepared an homologous series of triaryl-
type KITPHOS monophosphines (Ph3−n-Ar-KITPHOS; n =
1−3) and their corresponding gold(I) chloride complexes,
undertaken comprehensive solution NMR studies to investigate
an exchange process that lowers the molecular symmetry from
C3v to C3, explored and quantified their steric properties, and
undertaken a comparative evaluation of their performance as
catalysts for the cycloisomerization of propargyl amides, 2-
alkynylphenyl alcohols, and 2-phenylethynyl benzamides with
the aim of exploring the influence of increasing steric bulk on
catalyst performance. The first substrates were selected as they
are straightforward to prepare and are routinely employed as
benchmarks for comparing and evaluating the performance of
new catalysts and the resulting alkylidene oxazolines are
potentially useful synthons.27 The last two classes of substrate
were chosen because the resulting isochromene and iminoiso-
coumarin motifs are present in a range of important therapeutic
bioactive heterocycles,28 but there is a clear need to identify
more efficient systems, as existing gold(I) catalysts are either
limited by a poor substrate range and/or require long reaction
times or high catalyst loadings due to low activity.29 This study
has demonstrated that catalysts based on triaryl-like MONO-
KITPHOS and BISKITPHOS monophosphines either outper-
form their triphenylphosphine counterpart, in some cases by
quite a large margin, or are markedly more efficient than the
optimum reported system and are thus potential candidates for
reaction development.
Chart 1
and ketimines in comparison with the corresponding
triphenylphosphine-based system,16 electron-deficient biaryl
monophosphines form markedly more efficient catalysts than
their electron-rich SPHOS counterpart for the palladium-
catalyzed direct arylation of heterocycles,17 morpholine-
modified triarylphosphine 4 (Mor-DalPhos) outperforms its
electron-rich counterpart in the palladium-catalyzed α-arylation
of acetone with electron-deficient electrophiles,18 triaryl-based
indolylphosphine 3 combines with Pd2(dba)3 to form a highly
efficient catalyst for the borylation of aryl chlorides,19 and bulky
triarylphosphines form highly efficient systems for the selective
telomerization of 1,3-butadiene with methanol.20 The obvious
advantages associated with triaryl monophosphines in compar-
ison with their electron-rich counterparts is greater air stability,
ease of synthesis, and lower cost, which would render them
practical alternatives, provided competitive performance can be
achieved. In this regard, these examples should encourage
further investigations to explore and develop the use of bulky
electron-deficient triaryl-type monophosphines in platinum-
group-metal-catalyzed transformations.
We have also embraced the biaryl design concept and
developed the biaryl-like KITPHOS class of monophosphine
(Chart 1), which bears a close architectural similarity to
Buchwald’s biaryl monophosphines. Specifically, KITPHOS
monophosphines comprise a PR2 group connected to a C−C
double bond, albeit as part of an anthracene-derived bicyclic
framework, and a non-phosphine-containing proximal aryl ring
that can be systematically modified as it is introduced in the
form of a 1-alkynylphosphine oxide.21
RESULTS AND DISCUSSION
■
Phosphine Synthesis and Gold(I) Coordination Chem-
istry. Having recently demonstrated that the diphenylphos-
phino-based KITPHOS monophosphine 8a outperforms its
electron-rich dicyclohexylphosphino counterpart in the gold(I)-
catalyzed cyclization of methylene oxazolines,24 we initiated a
project to establish the influence on performance of increasing
steric bulk within an homologous series of triaryl-like
KITPHOS monophosphines by varying the number of attached
anthracene-derived KITPHOS units. The phosphines required
for this study were prepared in moderate to excellent yield
following the procedure reported in our initial disclosure for the
synthesis of 8a (Scheme 1);24 this involved a Diels−Alder
cycloaddition between anthracene and the corresponding 1-
alkynylphosphine oxide 6a−c, to construct the bicyclic
architecture of the KITPHOS framework, followed by
reduction of the resulting monoxide 7a−c either with
chlorosilane/triethylamine in toluene (7a,b) or chlorosilane/
tributylamine in xylenes (7c). The Diels−Alder reactions were
most conveniently carried out by heating the reactants in sealed
20 mL Wheaton V-20 reaction vials on an Asynt DrySyn
multiposition heating block and using 31P NMR spectroscopy
to monitor the progress of reaction at regular intervals. The
identity and purity of 8a−c have been established by a
Not surprisingly, bulky electron-rich KITPHOS mono-
phosphines are remarkably efficient ligands for a host of
palladium-catalyzed carbon−carbon- and carbon−nitrogen-
based cross-couplings22 as well as gold-catalyzed intramolecular
cyclizations.23 Interested in exploring the extent to which
diphenylphosphino-based KITPHOS monophosphines could
be surrogates for conventional triarylphosphines, we recently
demonstrated that electron-deficient gold(I) complexes of
diphenylphosphino-based KITPHOS monophosphines are
markedly more efficient than their dicyclohexylphosphino
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1-en-1-yl)-9,10-dihydroanthracene units and that the proximal
phenyl rings are directed toward the rim. A closer inspection of
the structure reveals that one of the ortho protons of a C6H4
ring lies directly over and in close proximity (3.1−3.3 Å) to a
C6H4 ring of an adjacent 12-phenyl-9,10-dihydro-9,10-ethe-
noanthracene unit; such a conformer would account for the
Scheme 1
1
high-field-shifted aromatic signal in the low-temperature H
NMR spectrum of 7c. The P−C bond lengths of 1.808(2)−
1.811(2) Å are close to those in triphenylphosphine oxide
(1.798(2)−1.802(2) Å), while the P−O bond length of
1.4745(14) Å is slightly shorter than that of 1.484(1) Å in
the same molecule;31 this shorter P−O bond length may also
be responsible for the slightly larger average O−P−C angle of
114.08(9)° in 7c in comparison with the corresponding angle
of 112.25(6)° in OPPh3.
In order to undertake a comparative evaluation of the efficacy
of triaryl-like KITPHOS monophosphines in gold-catalyzed
cycloisomerizations, the corresponding homologous series of
gold(I) precatalysts LAuCl (9b−d) were prepared by reaction
of [Au(2,2′-thiodiethanol)Cl]32 with the corresponding
KITPHOS monophosphine, according to the procedure
reported for the synthesis of 9a (eq 1);24 in each case the
combination of conventional spectroscopic and analytical
techniques, full details of which are provided in the Supporting
Information. With the aim of exploring the influence on catalyst
efficiency of removing the proximal biaryl-like phenyl ring, 8d
was also prepared for comparative catalyst testing. The
ethynyldiphenylphosphine oxide required for the associated
Diels−Alder cycloaddition step was prepared according to a
previously reported method,30 and the desired phosphine oxide
and corresponding phosphine were both isolated in high yield.
1
Interestingly, the room-temperature H NMR spectra of 7c
and 8c both contain a combination of exchange-broadened
resonances together with sharp well-resolved signals. The
nature of this line broadening was investigated further using a
combination of variable-temperature NMR studies including
2D EXSY and line-shape fitting, details of which are discussed
in the following section. Even though the spectroscopic
properties and analytical data for 7a−d and 8a−d are entirely
consistent with their formulation, the exchange-broadened
resonances in the 1H NMR spectrum of 7c and 8c prompted us
to undertake a single-crystal X-ray study of the former to
compare key structural parameters with those of related triaryl-
type monophosphine oxides; a perspective view of the
molecular structure is shown in Figure 1.
product was purified by slow diffusion of a chloroform solution
layered with methanol. Interestingly, though, the extent of line
broadening is distinctly different from that for either 7c or 8c;
this was confirmed with a variable-temperature 1H NMR study,
which identified two exchange processes in the accessible
temperature range, the results of which are also described in
detail in the following section.
As relatively few gold(I) complexes of KITPHOS mono-
phosphines have been crystallographically characterized,23a,24
single-crystal X-ray analyses of 9a−c were undertaken;
perspective views of the molecular structures are shown in
Figures 2, 3, and 4, respectively. In each case the geometry at
the gold is close to linear and the P−Au−Cl bond angles of
174.78(7)° (9a), 177.88(3)° (9b), and 178.01(4)° (9c) lie well
within the range reported for related complexes.33 The Au−Cl
bond lengths of 2.2814(7) Å (9a), 2.2859(8) Å (9b), and
The molecular structure clearly shows that the phosphorus
atom is buried deep within a bowl-shaped cavity generated by a
near-C3-symmetrical arrangement of the (E)-9-(1-phenylprop-
Figure 1. Molecular structure of 11-[tris(12-phenyl-9,10-dihydro-9,10-
ethenoanthracene)]phosphine oxide (7c). Innocent hydrogen atoms
and the dichloromethane molecules of crystallization have been
omitted for clarity. Ellipsoids are drawn at the 40% probability level.
Figure 2. Molecular structure of 11-(diphenylphosphino)-12-phenyl-
9,10-dihydro-9,10-ethenoanthracene gold(I) chloride (9a). Hydrogen
atoms and the chloroform molecule of crystallization have been
omitted for clarity. Ellipsoids are drawn at the 40% probability level.
C
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remaining proximal phenyl ring involves Cortho and the distance
of 3.195(3) Å is markedly shorter than the corresponding
Au- - -Cipso distance of 3.344(3) Å. In comparison, there are no
significant η1 interactions between the π face of the proximal
phenyl rings and gold in 9a,b; the shortest Au- - -C contacts
within these molecules are 3.328(3) Å (Au- - -Cipso) and
3.317(4) Å (Au- - -Cortho), respectively. As 9d lacks a proximal
phenyl ring and belongs to the triaryl-like class of mono-
phosphine, a single-crystal X-ray structure determination was
also undertaken to provide additional data for use in
quantifying the steric parameters of these phosphines; a
perspective view of the molecular structure is shown in Figure
5. Interestingly, the P−Au−Cl angle of 172.01(3)° shows a
Figure 3. Molecular structure of 11-[bis(12-phenyl-9,10-dihydro-9,10-
ethenoanthracene)]phenylphosphine gold(I) chloride (9b). Hydrogen
atoms and the chloroform molecule of crystallization have been
omitted for clarity. Ellipsoids are drawn at the 40% probability level.
Figure 5. Molecular structure of [11-(diphenylphosphino)-9,10-
dihydro-9,10-ethenoanthracene] gold(I) chloride (9d). Hydrogen
atoms and the chloroform molecule of crystallization has been
omitted for clarity. Ellipsoids are drawn at the 40% probability level.
Figure 4. Molecular structure of 11-[tris(12-phenyl-9,10-dihydro-9,10-
ethenoanthracene)]phenylphosphine gold(I) chloride (9c). Innocent
hydrogen atoms and the chloroform and methanol molecules of
crystallization have been omitted for clarity. Ellipsoids are drawn at the
40% probability level.
much larger deviation from linearity in comparison to 9a−c,
while the rigid framework of the anthracene-derived unit
prevents formation of an Au- - -C6H4 interaction.
Solution-State NMR Studies of 7c−9c. Comparative
NMR studies of these three molecules show that they have very
similar patterns of proton and carbon chemical shifts and
coupling constants (Tables S1 and S2 in the Supporting
Information) that are fully consistent with their proposed
structures. Hindered rotation about the P−C bonds produces a
propeller-like configuration which leads to inequivalence of the
two C6H4 rings in each substituent, and the corresponding
numbering scheme is shown in Figure 6. In all three
compounds exchange behavior leads to spectra with combina-
tions of sharp and broad lines, and the various spectra differ
markedly in appearance from compound to compound at any
given temperature, even though most of the corresponding
2.2921(9) Å (9c) are also similar to those in the six literature-
reported structures of PPh3AuCl,34,35 as are the Au−P bond
lengths that range between 2.222(7) and 2.2308(8) Å.
Interestingly, the 12-phenyl-9,10-dihydro-9,10-ethenoanthra-
cene units of the TRISKITPHOS monophosphine in 9c retain
a near-C3-symmetrical arrangement with the gold center buried
in the cavity formed by the proximal phenyl rings. Figure 4 also
shows that one ortho proton on each 12-phenyl-9,10-dihydro-
9,10-ethenoanthracene unit lies in close proximity to a C6H4
ring (C−H- - -aromatic distances between 2.6 and 3.4 Å) of a
neighboring unit in much the same manner as described for 7c,
which would account for the similarity in their variable
1
-temperature H NMR properties and the presence of the
anomalously high field shifted signal at δ 5.44 (vide infra). In
addition, one of the ortho protons of each C6H5 ring is also
orientated close to a C6H4 ring e.g. C(3)- - -H(40) = 2.765(3)
Å; such an interaction is likely to be the cause of the sharp high-
field signal at δ 6.16. There are also weak η1 interactions
between the gold atom and the ipso carbon atoms of two of the
flanking proximal phenyl rings in 9c; the Au- - -C(17) and
Au- - -C(39) distances of 3.195(3) and 3.219(3) Å, respectively,
are both less than the sum of the van der Waals radii of gold
and carbon and the former is similar to the Au- - -Cispo
interactions reported for gold(I) chloride complexes of
PCy2(o-biphenyl) and PBut2(o-biphenyl).36 In contrast, a
weak interaction between the gold and the π face of the
Figure 6. Compound 7c (E = O), 8c (E = electron lone pair), 9c (E =
Au−Cl). For the phenyl groups the atom numberings are 17 (ipso),
18, 22 (ortho), 19, 21 (meta), and 20 (para). In the second and third
substituents of phosphorus the positions are designated 1′, 2′, ... and
1″, 2″, ..., respectively.
D
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chemical shifts and coupling constants do not differ greatly.
Detailed NMR studies, including 2D-EXSY and line-shape
fitting, were therefore undertaken over the temperature range
165−400 K in CDCl3, CD2Cl2, and o-C6D4(CD3)2 in order to
elucidate the exact nature of the dynamic behavior.
majority of the discussion will concentrate on this species. For
7c and 8c rotation of the phenyl rings was still comparatively
rapid at 165 K, although line broadening of the ortho and meta
resonances at this temperature made apparent the onset of
restricted rotation. It thus appears that the extent of internal
steric congestion is significantly greater in 9c than in 7c or 8c.
For 9c the crystal structure (vide supra) shows that in the
solid state the three organic substituents of phosphorus are very
nearly equivalent, although a propeller twist renders the
molecule chiral and reduces the symmetry from C3v to a
close approximation to C3, as shown in Figure 8. An estimate of
Over the entire temperature range the proton-decoupled 31P
spectrum for each compound remained a single sharp line (ν1/2
< 2 Hz) at δ 18.6, − 24.8, and 5.6 for 7c−9c, respectively,
confirming that the exchange is intramolecular. The proton and
13C spectra can be interpreted on the basis of the structure in
Figure 6, which is essentially static at very low temperatures. A
complete and unequivocal spectroscopic assignment was
achieved using a combination of COSY, NOESY, ROESY,
HSQC, and HMBC 2D spectra together with 1H−{31P}
decoupling and comparisons of 13C spectra obtained at 125 and
175 MHz to identify 31P−13C splittings. All spectra were
consistent with the three individual anthracene-derived organic
substituents of phosphorus remaining fully equivalent through-
out the exchange activity.
Two distinct exchange processes were identified: (i)
concerted hindered rotation of each phenyl ring about its
C16−C17 (ipso) axis associated with inequivalence of its two
ortho and of its two meta positions in the proton and 13C
spectra and (ii) concerted librational motion of the individual
organic substituents about their P−C1 bonds associated with
the 3/15, 4/14, 5/13, 6/12, 7/11, and 8/10 equivalences at
higher temperatures. Figure 7 shows a series of proton NMR
Figure 8. Views down the P−Au bond in 9c (C3 axis) showing
interchange of environments of red and blue C6H4 rings as a result of
concerted ca. 44° rotations of each substituent about the P−C1, P−C1′,
and P−C1″ bonds.
the deviation from a true 3-fold axis is provided by the three
dihedral angles Au/P/C1/C16, Au/P/C1′/C16′, and Au/P/C1″/
C
16″, which are 22.65, 22.6, and 20.7°, respectively. Thus,
concerted librations of ca. 44° about the corresponding P−C1
subaxes are sufficient to interconvert the enantiomers and
remove the inequivalences 3/15 etc., as also shown in Figure 8.
It is clear that process ii is that observed in the proton and 13
C
spectra at higher temperatures, and there is no need to
postulate complete freedom of rotation about the P−C1 etc.
bonds.
A striking feature of the proton data for 9c is the large
chemical shift difference between the two ortho (and to a lesser
extent the two meta) protons of the phenyl groups. This can be
attributed to the exposure of one of the ortho protons to the
axial component of the diamagnetic anisotropy (ring current)
of one of the aromatic C6H4 rings in a different substituent. For
example, H18′ would be exposed to ring A as shown in Figure
9, whereas its counterpart in the same ring (H22′) would not
be so influenced. An approximate calculation based on the
tables of Johnson and Bovey37 suggests that H18′ would be
shielded by 1.9 ppm by this effect, although the good
agreement with the observed chemical shift of δ 5.2 ppm
may well be fortuitous. In 7c−9c the large chemical shift
difference between H4 and H14 is also noteworthy, and large
shielding of the last species can be similarly attributed to
exposure to the axial ring current of ring B′: i.e., the other C6H4
ring of a different substituent. The corresponding 13C chemical
shift differences are generally smaller, which is consistent with
their being due to localized magnetic field rather than electronic
effects.
1
Figure 7. Variable-temperature H NMR spectra for gold complex 9c
showing restricted rotation of phenyl groups. Spectra were recorded in
CD2Cl2 at 500 MHz.
spectra of compound 9c in the range 175−230 K which clearly
illustrates the restricted rotation of its phenyl groups.
Corresponding behavior was shown by the ortho and meta
13C resonances, while the para proton and para and ipso 13C
signals remained sharp at all temperatures. Simulations using
the program gNMR gave excellent fits for those ortho and meta
proton resonances which were not overlapped by other signals,
and application of the Eyring equation yielded ΔH⧧ = 37.9 kJ
mol−1 and ΔS⧧ = −4.4 J mol−1 K−1. Only in the case of the gold
complex 9c were the energetics suitable for obtaining
thermodynamic data for both exchange processes in the
accessible temperature range (165−400 K), and therefore the
From band-shape analysis of proton spectra using the
program gNMR, together with intensities of off-diagonal
peaks in 2D EXSY spectra for some slower rates, the exchange
rates for process ii were determined for 7c−9c over a range of
temperatures, and the corresponding Eyring plots are
reproduced in Figure 10. The respective values of ΔH⧧ are
52.1, 66.3, and 75.4 kJ mol−1, and those of ΔS⧧ are −26.5, −
E
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Figure 9. Perspective view of 9c showing exposure of one of the ortho
protons to the axial component of the diamagnetic anisotropy and
views showing the details of this interaction and the radial distance
from the center of ring A.
Figure 11. 500 MHz ROESY NMR spectrum of 9c in CD2Cl2 at 169
K with a mixing time of 200 ms. Off-diagonal NOE peaks are red, and
off-diagonal exchange peaks are blue.
Figure 11. In addition to the negative (red) off-diagonal NOE
signals there are four positive (blue) off-diagonal signals arising
from the slow chemical exchanges H18/H22 (ortho) and H19/
H
21 (meta) when the phenyl group rotates. This exchange also
affects the intensities of NOE signals involving these protons.
The strongest NOE interactions are, as expected, those within
the same substituent between mutually ortho C6H4 protons,
such as H4/H5 and H5/H6, and H18/H19 in the phenyl groups.
These are all associated with interatomic distances of ca. 2.5 Å.
In the solid the three endo bridgehead protons H2 etc. are only
2.7 Å apart and so should have significant mutual NOE
interactions, although their equivalence in solution makes these
unobservable. Nonetheless, the mutual relaxation of these
protons is affected and thus NOE interactions with other
protons are diminished, as is well-known for the protons of
methyl groups.
Figure 10. Eyring plots for the librational motion in 7c−9c based on
the exchange of H4 and H14.
31.5, and −15.6 J mol−1 K−1. The negative entropies of
activation are consistent with a more ordered excited state,
which is to be expected for a concerted process, in which the
Au/P/C1/C16 dihedral angles are close to 0°. The overall
pattern of the free energies of excitation is perhaps not what
would have been expected, and the following points should be
noted.
The mean C−P−C interbond angles in 7c and 9c are 104.5
and 104.9°, respectively, and although the value for 8c is
unfortunately not available, it may be expected to be somewhat
less. On this basis it is difficult to understand the order of the
excitation energies found above, but it should be borne in mind
that the extent of crowding in these species will affect the
energies of both the ground and upper conformational states
for the librational motion. An alternative measure of the
internal congestion is provided by the E/P/C1/C16 etc. dihedral
angles already mentioned. For 7c the mean value is 28.0°, and
for 9c it is 22.0° implying a capacity for less crowding in the
former. Furthermore, the spread of the individual dihedral
angles among the three substituents is much greater in 7c
( 6.4°) than in 9c ( 1.0°), which is again consistent with less
congestion in the former.
Of special importance are the apparent weak NOE
interactions of H14 with H5, H6, and H7. However, the relevant
interatomic distances are 5.46, 7.29, and 6.54 Å, respectively, all
too great for there to be any significant NOE interaction. We
therefore attribute these observed off-diagonal signals to
interaction of H14 with H5′, H6′, and H7′ (in the other portion
of a different substituent), for which the respective distances are
3.96, 3.97, and 3.82 Å, and this serves to confirm the close
similarity of the structures in the solid state and in solution. It is
noteworthy that for the counterpart of H14, i.e. H4, the
corresponding intrasubstituent distances are of course essen-
tially the same, but owing to the propeller twist of the molecule
the intersubstituent distances to H11″, H12″, and H13″ are much
greater: viz., 7.64, 7.50, and 5.81 Å. Thus, no corresponding
NOE interactions are seen, which is again fully consistent with
comparability of the solution- and solid-state structures. It is
also worth noting that in the case of potential H4/H14 etc.
interactions some relevant distances are H4/H14 = 4.50 Å, H4′/
H14 = 3.86 Å, and H4/H14″ = 3.47 Å, any of which could in
principle generate a significant NOE. However, in practice this
will be canceled by slow residual H4/H14 exchange which is still
A proton 500 MHz ROESY spectrum with a mixing time of
200 ms was obtained on 9c in CD2Cl2 at 169 K and is shown in
F
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Organometallics
Article
occurring at 169 K. In view of the high level of internal
congestion in these molecules, there is little opportunity for
significant internal motions; thus, it is indeed to be expected
that the solid- and solution-state structures will be very similar.
Steric Properties of Triaryl-Like KITPHOS Mono-
phosphines: Comparison with Triarylphosphines. The
steric properties of bulky triaryl and triaryl-like phosphines have
been suggested to be integral to their efficacy as ligands in a
host of platinum-group-metal-catalyzed transformations1 and
gold-catalyzed inter- and intramolecular additions to carbon−
carbon multiple bonds.38 As the steric bulk of the triaryl-like
KITPHOS class of monophosphine can be modified in a
systematic manner and interested in identifying applications of
this class of phosphine in catalysis, we have attempted to
quantify their steric properties using the percent buried volume
(%Vbur) model and Solid-G calculations in order to compare
with their more common triarylphosphine counterparts. The
percent buried volume model was introduced by Nolan and
Cavello39 to overcome the limitations of the Tolman model,40
which can be either inadequate or ineffective for calculating the
steric parameters of N-heterocyclic carbenes and phosphines
with structurally elaborate architecture; it was designed to
better define the steric pressure brought about by these ligands.
In this model, the percent buried volume is defined as the
percent of the total volume of a sphere occupied by a ligand
and is calculated using the SambVca. software.41 As there is an
excellent correlation between the steric properties quantified by
the Tolman cone angle and the percent buried volume values
calculated from crystal structure data on gold(I) complexes of
the type [PR3AuCl], the percent buried volumes for 9a−d have
been determined to compare with the corresponding values for
selected gold(I) complexes of conventional triarylphosphines,
full details of which are presented in Table 1. The %Vbur value
based coordination complexes. The anomalously large %Vbur
value for 9c may be reconciled by appreciating that the gold
atom sits deep within a bowl-shaped cavity formed by a near-
C3-symmetric arrangement of bicyclic anthracene-derived
KITPHOS fragments with the proximal aryl rings projecting
toward the rim. A qualitative estimate of the steric contribution
provided by the proximal phenyl ring in KITPHOS mono-
phosphines can obtained by comparing the %Vbur value of 32.3
for 9a with that of 28.9 for 9d, which corresponds to a 3.4%
increase in the buried volume; the latter value is similar to that
of 29.9 calculated for PPh3AuCl. In comparison, we have
previously commented that the corresponding difference
between PCy2Ph and Cy-JohnPhos in [LAuCl] provides a
measure of the steric influence of the proximal phenyl ring in
dicyclohexyl-based arylphosphines; in this case the %Vbur values
of 32.7 and 46.7, respectively, correspond to an increase in the
buried volume by 14%. Similarly, a measure of the steric
influence on the introduction of a single o-phenyl ring into
triphenylphosphine can be obtained from the %Vbur values of
29.9 and 42.6 for PPh3AuCl and [PPh2(o-biphenyl)AuCl],
respectively; this increase in buried volume of 12.7% aligns with
the increase of 14% from PCy2Ph to [JohnPhosAuCl].
Interestingly, the increase in %Vbur of 3.4 that results from
introducing a proximal o-phenyl ring into 8d is much smaller
than the corresponding increase for PCy2Ph and PPh3, which
supports our earlier observation that KITPHOS mono-
phosphines appear to be sterically malleable and capable of
adjusting their bulk according to the immediate surroundings:
i.e., the space available around the metal center. Thus, there
appear to be subtle differences in the factors that influence the
steric bulk of KITPHOS monophosphines in comparison with
their biaryl counterparts which may well be manifested in their
performance as ligands for catalysis.
The steric parameters for selected triaryl-like KITPHOS
monophosphines and triarylphosphines relevant to this study
have also been determined using Solid-G calculations, details of
which are given in Table 2. This approach provides a measure
Table 1. %Vbur Values and Cone Angles Calculated for
KITPHOS Monophosphines and Selected Triarylphosphines
in [LAuCl]
a
entry
complex
%Vbur
cone angle θ/deg
Table 2. Comparison of G Parameters and Associated Cone
b
1
Ph-MONOKITPHOSAuCl
Ph-BISKITPHOSAuCl
Ph-TRISKITPHOSAuCl
MONOKITPHOSAuCl
PPh2(o-biphenyl)AuCl
PMes3AuCl42
32.3
47.4
64.5
28.9
42.6
45.0
43.6
29.9
39.4
37.3
38.9
58.7
156
Angles for KITPHOS Monophosphines and Selected
b
a
2
229
Triarylphosphines
b
3
310
a
b
b
entry
phosphine
G param
cone angle θ/deg
4
140
b
5
206
1
Ph-MONOKITPHOS (8a)
Ph-BISKITPHOS (8b)
Ph-TRISKITPHOS (8c)
H-MONOKITPHOS (8d)
H-BISKITPHOS
38.0
47.6
58.4
30.0
31.8
33.6
27.8
59.3
43.6
48.5
152.2
174.5
199.4
132.8
137.2
141.7
127.0
201.4
165.2
176.5
6
212
211
145
194
184
188
2
7
P(2,4,6-(OMe)3C6H2)3AuCl43
PPh3AuCl35
3
8
4
9
P(o-tol)3AuCl44
5
10
11
12
P(C6F5)3AuCl45
6
H-TRISKITPHOS
PPh3
PPh(9-anthracenyl)2AuCl46
7
47
t
P(SiMe2 Bu)3
8
PMes3
bowl-shaped Phos16
a
b
9
%Vbur for Au−P bond length at 2.28 Å. Calculated by linear
10
PPh2(o-biphenyl)
regression.
a
b
Calculated using Solid-G.48 Equivalent cone angle calculated from
the nonlinear relationship Ω = 100[1 − cos(θ/2)], where G = 100(Ω/
of 32.3 determined for 9a is close to that of 29.9 for PPh3AuCl,
while BISKITPHOS is significantly larger and the %Vbur of 47.4
is closer to that of 45.0 for trimesitylphosphine and 43.6 for
2,4,6-((MeO)3C6H2)3P (entries 6 and 7); other common
triarylphosphines including PPh(anthracenyl)2, P(o-tolyl)3, and
P(C6F5)3 have intermediate %Vbur values (entries 9−11). In
comparison, the %Vbur value of 64.5 for TRISKITPHOS in 9c is
among the largest to be documented and is larger than that of
4π).
of the steric congestion in terms of the percentage of the metal
coordination sphere shielded by the ligand; quantitatively, the
G parameter provides a measure of the probability of an
incoming reagent not accessing the meal center.48 The G
parameters for the homologous series of phenyl-substituted
KITPHOS monophosphines increases steadily with increasing
t
58.7 for P(SiMe2 Bu)3, (entry 12), which does not form metal-
G
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number of anthracene-derived KITPHOS units, from 38.0 to
58.4 (entries 1−3), while the corresponding values for their
unsubstituted counterparts are all significantly smaller and
increase gradually from 30.0 to 33.6 (entries 4−6). The
difference in the calculated G parameters of 8.0 between 8a
(38.0) and 8d (30.0) is much smaller than the corresponding
difference of 20.7 for PPh3 and PPh2(o-biphenyl) (entries 7 and
10, respectively), which further supports the disparate effect on
steric properties of introducing a proximal phenyl ring onto an
aryl-like KITPHOS monophosphine in comparison with its aryl
counterpart, as noted above for the trend in %Vbur. Although
further studies and data will be required to lend validity to this
interpretation, the introduction of a single proximal phenyl ring
into triphenylphosphine appears to have a more marked and
profound influence on steric congestion than for KITPHOS
monophosphines.
Table 3. Comparison of the 5-exo-dig Cycloisomerization of
Propargylamides 10a−e Catalyzed by Gold Complexes of
a
KITPHOS Monophosphines 8a−d and PPh3
Gold-Catalyzed C−O and C−N Bond-Forming Cyclo-
isomerizations. Having previously demonstrated that gold(I)
complexes of electron-rich KITPHOS monophosphines form
highly efficient catalysts for the cycloisomerization of propargyl
amides24 and reasoning that their electron-deficient sterically
tunable triaryl-like counterparts 8a−d would both enhance
Lewis acidity and enable substrate accessibly to be modulated
in a systematic manner, we chose this transformation to
conduct an initial comparison and evaluation of the perform-
ance of 9a−d against PPh3AuCl; full details are given in Table
3.
In a typical reaction, catalyst was generated in situ
immediately prior to addition of substrate by treating a
dichloromethane solution of the corresponding gold(I)
chloride precatalyst with silver triflate for 30 min. Under
these conditions catalysts formed from 9a,b both gave excellent
conversions for each of the substrates tested (10a−e) and both
consistently outperformed their triphenylphosphine counter-
part, in some cases by quite a margin. For comparison, the
catalyst generated from 9c gave poor conversions under the
same conditions and in the same time, which may be due to
restricted access of the substrate to the gold center, which is
effectively surrounded by or embedded deep in the triaryl-like
cavity. As the proximal aryl ring of biaryl monophosphines has
been proposed to stabilize catalytic intermediates with respect
to deactivation through formation of a weak arene−gold
interaction,49 comparative catalyst testing was extended to 9d
in order to investigate the influence on efficiency of removing
the proximal biaryl-like aryl ring from 9a. The data in Table 3
reveal that the conversions obtained with 9d are consistently
lower than those obtained with its biaryl-like counterpart and
more closely correlate with those obtained with triphenylphos-
phine: further evidence that a proximal phenyl ring can exert a
positive effect on catalyst performance. In this regard,
Hammond and Xu have recently highlighted the importance
of ortho substitution and electron density matching within the
ligand.38a The former was suggested to prevent deactivation of
the catalyst by forming weakly stabilizing Au- - -C interactions,
while the latter facilitates regeneration of the cationic gold
catalyst by favoring turnover-limiting protodeauration of the
a
Reaction conditions: 2 mol % of 9a−d or PPh3AuCl, 2 mol % of
AgOTf, 0.5 mmol of propargyl amide, CH2Cl2, room temperature.
b
c
Isolated yields. Average of three runs. Data obtained from the
literature.24
that AgOTf is not an active cycloisomerization catalyst for
propargyl amides, they do not exclude a more subtle role for
adventitious silver such as interception of gold(I) intermediates,
as recently reported by Gagne
́
and co-workers,52a or even false
negative results due to formation of a less active chloride-
bridged digold complex.52b,c
The cycloisomerization-derived methylene oxazolines 11a−e
were considered ideal candidates for use as the olefinic partners
in the carbonyl-ene reaction; the resulting products would be
synthetically versatile β-hydroxy-, β-ester-substituted oxazolines
12a−d (Table 4). With the aim of developing a single-pot
tandem reaction sequence based on cycloisomerization of
propargyl amides 10a−e followed by a Lewis acid catalyzed
asymmetric carbonyl-ene reaction with the resulting methylene
intermediate gold σ complex.50 Since a slight excess of silver
b
triflate is typically used to ensure quantitative activation of the
precatalyst and Lewis acid silver salts have been reported to
activate alkynes toward cycloisomerization,51 a series of parallel
catalytic control experiments were conducted under the same
conditions with 2 mol % of AgOTf in the absence of
precatalyst. Although these experiments conclusively show
H
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Article
only 30 min at room temperature. However, disappointingly,
under the same conditions the corresponding reaction between
11a−d and ethyl trifluoropyruvate gave the desired product in
near-quantitative yield but as a racemic mixture. As copper(II)
complexes of bis(oxazolines) are among the most efficient
catalysts for the carbonyl-ene reaction, an optimized literature
protocol was also applied to the reaction between 11a−d and
methylene cyclopentane.54 Again, while quantitative yields were
also obtained in short reaction times, in each case the product
was isolated as a racemic mixture. Interestingly, quantitative
yields were also obtained in control reactions conducted in the
absence of catalyst, which strongly suggests that the racemic
product results from a competing uncatalyzed process. Even
though we have not been able to develop an asymmetric
version of the methylene oxazoline-based carbonyl-ene
reaction, the rapid uncatalyzed nature of this transformation
enabled a tandem single-pot protocol for the synthesis of highly
functionalized 2-substituted oxazolines to be developed with
each step proceeding in excellent conversion to afford 12a−d in
high yields.
Table 4. Carbonyl-Ene Reaction between Oxazolines 11a−d
a
and Ethyl Trifluoropyruvate
entry
R
compound
yield (%)
1
2
3
4
t-Bu
12a
12b
12c
12d
94
95
91
94
C6H11
C6H5
2-thienyl
a
Conditions: 5 mol % of [PdCl2{(S)-BINAP}]/5 mol % of AgSBF6,
CH2Cl2, 30 min, room temperature.
oxazoline enophile, the reaction of a purified sample of 11a−e
toward ethyl trifluoropyruvate was examined using previously
optimized conditions and catalysts for the corresponding
reaction between methylene cyclopentane and ethyl trifluor-
opyruvate as a lead.53 Following a previously optimized
protocol, 5 mol % of (S)-PdCl2(BINAP)/AgSbF6 catalyzed
the carbonyl-ene reaction between methylene cyclopentane and
ethyl trifluoropyruvate with remarkable efficiency and gave the
expected α-hydroxy ester in excellent yield and 98% ee after
Encouraged by the efficiency of 8a,b as ligands for the gold-
catalyzed cycloisomerization of propargyl amides, comparative
catalyst testing was extended to include the regioselective C−O
bond-forming cycloisomerization of 2-alkynylbenzyl alcohols to
generate isochromenes with the aim of investigating whether
a
Table 5. Gold-Catalyzed Cycloisomerization of 2-Alkynylbenzyl Alcohols
a
Reaction conditions unless specified otherwise: 0.5−2.0 mol % of 9a/0.5−2.0 mol % of AgOTf or 0.5−2.0 mol % of AgOTf, 0.4 mmol of 2-
b
alkynylbenzyl alcohol, CH2Cl2, room temperature. Conversions determined by 1H NMR spectroscopy using 1,3-dinitrobenzene as internal
standard. Average of three runs. 2.5−5.0 mol % of precatalyst, data obtained from the literature.55
c
I
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Article
steric bulk influences endo-/exo-dig selectivity. These hetero-
cycles are important targets, as they are found in a host of
bioactive compounds with a range of therapeutic properties,
including activity against various human cancer cell lines as well
as antioxidant and antifungal properties.28 While a gold(I)
complex of trimesitylphosphine catalyzes the selective 6-endo-
dig cycloisomerization of 2-alkynylbenzyl alcohols to afford the
corresponding isochromenes, a high catalyst loading (5.0 mol
%) and/or long reaction time was required to achieve
acceptable yields across only a limited range of substrates.55
Similarly, iridium(III) hydride complexes also catalyze the
selective 6-endo-dig cyclization of these substrates but a catalyst
loading of 4 mol % and reaction temperatures between 60 and
85 °C were required to obtain high conversions.56 Our
preliminary evaluation focused on the selective 6-endo-dig
cyclization of 2-hex-1-ynylbenzyl alcohol 13a to afford
isochromene 14a using 0.5 mol % of gold precatalyst activated
with AgOTf in dichloromethane at room temperature (Table
5). Under these conditions, 9a gave the desired isochromene in
98% yield, whereas the sterically more congested 9b,c gave
markedly lower conversions of 64% and 19%, respectively
(entries 1−3). Parallel catalyst testing with 9d, which lacks a
proximal phenyl ring, gave the 6-endo-dig product in 37% yield
under the same conditions (entry 4), which is comparable to
the yield of 27% obtained with PPh3AuCl/AgOTf (entry 5).
Encouraged by the high conversions obtained with 9a after
short reaction times and under mild conditions, catalyst testing
was extended to include the cyclization of a series of 2-
alkynylbenzyl alcohols, 2-(2-(phenylethynyl)phenyl)ethan-1-ol,
and 2-(phenylethynyl)benzoic acid, the details of which are
summarized in Table 5 and eq 2. Excellent conversions and
this change in selectivity but note that a mixture of regioisomers
has previously been obtained from the gold-catalyzed cyclo-
isomerization of 2-nitro-1-(2-(arylethynyl)phenyl)ethan-1-ols,
generated in situ via a copper-catalyzed asymmetric Henry
reaction between o-alkynylbenzaldehyde and nitromethane; in
general, electron-donating groups on the alkynyl fragment
favored the 6-endo-dig pathway while those with electron-
withdrawing groups favored 5-exo-dig cyclization.57 There have
been several reports of the synthesis of 1H-isochromenes on
the basis of the domino addition/cycloisomerization of an
alkynylbenzaldehyde in the presence of a protic nucleophile
and a carbophilic silver,51b,c,e,58a gold,58b or indium58c Lewis
acid catalyst; however, in each case the loading was markedly
higher than the 0.5 mol % required for the 9a/AgOTf-catalyzed
cyclizations described here. A series of parallel control
experiments in the presence of 2 mol % of AgOTf gave low
conversion under the same conditions, even after extended
reaction times, which provides convincing evidence for catalysis
by a gold(I) species (entries 6, 8, 11, 13, and 15).
The competitive performance of 9a prompted us to explore
its efficacy as a catalyst for the cyclization of 2-(2-
(phenylethynyl)phenyl)ethan-1-ol (16), a substrate that has
previously been reported to be unreactive toward cyclization by
iridium−hydride- and gold−phosphine-based systems (eq
2).55,56 Reassuringly, 2 mol % of 9a/AgOTf catalyzed this
transformation with remarkable efficacy and reached 100%
conversion to afford a 89:11 mixture of 1-benzylideneisochro-
mane (17) and 4-phenyl-1,2-dihydrobenzo[d]oxepine (18)
after 16 h at room temperature; the two isomers were
distinguished and identified and their structures confirmed by
the use of an INADEQUATE spectrum. During the preparation
of this paper, Naoe et al. reported the first example of this
cyclization and obtained an 87:13 mixture of products in favor
of the 6-exo-dig regioisomer by using 5 mol % IPrAuCl/AgOTf
at 50 °C.59 While the observed selectivity is entirely in keeping
with previous examples of gold-catalyzed cyclizations involving
alkynes,60 there have been reports of 7-endo-dig cyclization
involving terminal and arylated alkynes.61 For example, gold(I)
complexes of electron- deficient hollow-shaped triethynylphos-
phines are the ligands of choice for 6-exo- and 7-endo-dig
cyclizations involving tethered alkynes; the efficiency of these
systems in comparison with that of conventional phosphines
was proposed to be associated with the cavity of the ligand,
which forces the nucleophile in close proximity to the gold-
activated alkyne.61h,i
While the cyclization of 2-alkynylbenzoic acids provides
access to five- and six-membered lactones and can be catalyzed
by strong acids and palladium, gold, or silver compounds, the
products are often obtained as a mixture of regioisomers.62 For
example, AuCl-catalyzed lactonization of 19 occurs with a
marked preference for 5-exo-dig cyclization to afford a 91:9
mixture of the exo and endo regioisomers 20 and 21,
respectively,62b and the corresponding palladium-catalyzed
transformation also occurs with moderate 5-exo-dig selectivity
to afford a 56:23 mixture of regioisomers (Table 6 entries 1 and
2).62d Interestingly, in a comparative study 0.5 mol % of 9a/
AgOTf catalyzed the cyclization of 19 with remarkable
efficiency but gave a complete switch in selectivity to afford
the 6-endo-dig regioisomer as the exclusive product, in near-
quantitative yield after only 15 min at room temperature (Table
6, entry 3). Such a dramatic change in selectivity and
improvement in efficiency is intriguing, and further studies
are clearly required to explore and develop an understanding of
complete 6-endo-dig regioselectivity were obtained for the
cycloisomerization of 13b,c with 0.5 mol % of 9a/AgOTf,
which gave the corresponding isochromenes as the sole product
after only 1 h at room temperature (entries 7 and 10).
The conversion of 98% obtained for 13b is quite remarkable
in comparison to the 31% yield reported for the same
transformation using 2.5 mol % [(Mes3PAu)2Cl][BF4] and a
reaction time of 24 h (entry 9).55 The cyclization of 13d was
markedly more challenging and required 2 mol % 9a/AgOTf
and a reaction time of 16 h to reach complete conversion to the
6-endo-dig regioisomer (entry 12). Gratifyingly, regardless of
the extended reaction times, 9a either competed with or
outperformed previously reported systems for this trans-
formation, including [(Mes3PAu)2Cl][BF4], which required a
catalyst loading of 5 mol % to reach 75% conversion after 24 h
(entry 14), and [IrH(2-acetylphenyl) (acetone)(PPh3)2]SbF6,
which gave isochromene 13d in 70% yield after 2 h at 85 °C in
the presence of 3 mol % of catalyst. In contrast, the
corresponding p-tolyl-substituted 2-alkynylbenzyl alcohol 13e
only required 0.5 mol % of 9a/AgOTf and a reaction time of 1
h to reach 100% conversion; even though the 6-endo-dig
regioisomer was the major product, the formation of the 5-exo-
dig regioisomer was rather unexpected considering the minor
structural/electronic difference between 13d and 13e (entry
15). At this stage we cannot offer a conclusive explanation for
J
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a copper-mediated coupling−cyclization sequence between a 2-
iodobenzamide and a terminal alkyne occurred via the 6-endo-
dig pathway to provide a complementary pathway to
isoquinolin-1(2H)-ones; however, further studies will be
required to assess the relative merits of this system against
our KITPHOS-based gold catalysts.64 As 9a/AgOTf forms an
efficient and selective catalyst for the 6-endo-dig cyclization of 2-
(phenylethynyl)benzamides, it will be interesting to apply this
combination to the cycloisomerization of 2-(1-alkynyl)-
phenylacetamides, as this reaction has recently been catalyzed
by PPh3AuCl/AgSbF6 with complete 7-endo-dig selectivity;
however, 10 mol % catalyst and a reaction temperature of 120
°C was required to achieve practical yields.61d,e,g On the basis
that silver salts have been reported to catalyze this cyclization, a
series of control experiments were conducted under identical
conditions with 5 mol % AgOTf. Even though slightly higher
yields were obtained with AgOTf than with 9a/AgOTf for each
substrate tested, we are confident that the yields obtained with
9a reflect the activity of an electrophilic gold cation, as there is a
reassuringly close correlation between the performance of
catalyst generated in situ and its isolated cation [AuL]OTf.24
Table 6. Comparison of the Cycloisomerization of 2-
Alkynylbenzoic Acid Catalyzed by 9a, AuCl, and
PdCl(MeCN)2
a
amt of catalyst
(mol %)
conversion
b
catalyst
time
2 h
(%)
20:21
1
2
3
AuCl/AgNTf2
PdCl2(MeCN)2
9a/AgOTf
5.0
10.0
0.5
82
89
1:0.1
1:0.4
0:1
24 h
15 min
100
a
Reaction conditions: 0.5 mol % of 9a/0.5 mol % of AgOTf, 0.4 mmol
b
of 2-alkynylbenzoic acid, CH2Cl2, room temperature. Conversions
determined by 1H NMR spectroscopy using 1,3-dinitrobenzene as
internal standard. Average of three runs.
the factors that control the regioselectivity of this trans-
formation.
Finally, the high yields obtained for the cyclization of 2-
alkynylbenzoic acids, the switch in regioselectivity, and the
close similarity between the bioactivity of isocoumarins and
their nitrogen-based 1H-isochromene-1-imine counterparts
prompted us to apply the same system to the intramolecular
cycloisomerization of 2-(phenylethynyl)benzamides 22a−c
(Table 7). Under the same conditions, 2 mol % of 9a/
AgOTf catalyzed the 6-endo-dig O-cyclization of 22a−c to give
good yields of the corresponding 1H-isochromen-1-imine in
reasonably short reaction times and with no evidence for
competing 5-exo-dig or N-6-endo-dig cyclization. As far as we
are aware, there have been no reports of the gold(I)-catalyzed
cycloisomerization of 2-(phenylethynyl)benzamides for a direct
comparison; however, 9a/AgOTf competes with AgOTf in
dichloroethane and outperforms AgSbF6 in toluene, which
requires a higher reaction temperature, longer reaction time,
and 25 mol % of catalyst to achieve acceptable yields of the 6-
endo-dig cyclization product.63a,b In a more recent development,
CONCLUSIONS
■
Gold(I) complexes of electron-deficient triaryl-like MONO-
KITPHOS and BISKITPHOS monophosphines containing one
and two 12-phenyl-9,10-dihydro-9,10-ethenoanthracene units,
respectively, are markedly more efficient catalysts than their
triphenylphosphine counterpart for a range of carbon−
heteroatom bond-forming cyclizations, whereas the corre-
sponding TRISKITPHOS-based catalyst gave low conversions.
Moreover, we present the first examples of gold(I)-catalyzed 6-
endo-dig cycloisomerizations involving 2-(phenylethynyl) ben-
zamides and, gratifyingly, gold(I)/MONOKITPHOS either
rivals or outperforms all existing silver and palladium-based
systems. Interestingly, TRISKITPHOS monophosphine bears a
close architectural similarity to the bowl-shaped class of
phosphine in that the bulkiness occurs at the periphery with
Table 7. Comparison of the Gold-Catalyzed 6-endo-Dig Cycloisomerization of 2-(Phenylethynyl)benzamides 22a−c against
a
AgOTf
a
Reaction conditions: 2.0 mol % of 9a/2.0 mol % of AgOTf or 2.0 mol % of AgOTf, 0.4 mmol of 2-(phenylethynyl)benzamide, CHCl3, 60 °C.
Yields determined by H NMR spectroscopy using dinitrobenzene as internal standard. Average of three runs.
b
1
K
DOI: 10.1021/acs.organomet.6b00146
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Organometallics
Article
were characterized by NMR spectroscopy and mass spectrometry and
unknown products by NMR spectroscopy, mass spectrometry, high-
resolution mass spectrometry (HRMS), and elemental analysis.
the proximal aryl-like phenyl rings oriented toward the rim of
the bowl. In this regard, even though TRISKITPHOS is not an
effective ligand for gold-catalyzed cycloisomerizations, the
unique catalytic environment presented by the array of
anthracene-derived biaryl-like units and the steric bulk of this
phosphine could stabilize active low-coordinate species while
allowing substrate access. The high level of internal steric
congestion in Ph-TRISKITPHOS, its oxide, and the corre-
sponding gold(I) chloride is responsible for hindered rotation
about the P−C bond, which lowers the molecular symmetry
such that the two C6H4 rings in each of the 12-phenyl-9,10-
dihydro-9,10-etheno-anthracene units become inequivalent; a
lower energy process involving restricted rotation of the biaryl-
like phenyl ring has also been identified in a detailed and
thorough solution NMR study. Although this investigation has
been restricted to a relatively narrow range of cyclizations, the
high yields obtained across a diverse and challenging range of
substrates at low catalyst loadings and under mild conditions is
extremely encouraging, which suggests that this system may be
an ideal candidate for use in reaction development.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00146.
Full details of experimental procedures, characterization
1
data for all new compounds, variable-temperature H
NMR spectra and selected COSY, EXSY, NOESY,
ROESY, HSQC, and HMBC 2D spectra for compounds
7c−9c, and details of catalyst testing (PDF)
X-ray crystallographic data for compounds 7c and 9a−d
(crystallographic data can also be obtained free of charge
from the Cambridge Crystallographic Data Centre
(CCDC 1454006, 1454008, 1454009, 1454010, and
1455028) via www.ccdc.cam.ac.uk/data_request/cif)
(CIF)
EXPERIMENTAL SECTION
■
AUTHOR INFORMATION
General Procedure for the Gold-Catalyzed Cycloisomeriza-
tion of Propargylamides. A flame-dried Schlenk flask charged with
precatalyst LAuCl (0.01 mmol), AgOTf (0.0026 g, 0.01 mmol) and
dichloromethane (2 mL) was stirred for 30 min, after which propargyl
amide (0.5 mmol) was added and the reaction mixture was stirred at
room temperature for the allocated time. The reaction mixture was
diluted with diethyl ether, 1,3-dinitrobenzene (0.084 g, 0.5 mmol) was
added as an internal standard, and the resulting mixture was passed
through a short silica plug, flushing with ethyl acetate. The solvent was
removed under reduced pressure and the residue analyzed by 1H
NMR spectroscopy to determine the conversion before the product
was purified by column chromatography, with hexane/ethyl acetate as
eluent; all known products were characterized by NMR spectroscopy
and mass spectrometry.
■
Corresponding Authors
*E-mail for S.D.: simon.doherty@ncl.ac.uk.
*E-mail for J.G.K.: julian.knight@ncl.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge Newcastle University for funding
(N.A.B.W. and D.O.P.) and Johnson Matthey for generous
loans of palladium salts. We acknowledge the use of the EPSRC
UK National Service for Computational Chemistry Software
(NSCCS) at Imperial College London in carrying out this
work. Many thanks to Elwood, Jake, and Ella for their loyal and
unwavering support. This paper is dedicated to the memory of
Professor Malcolm H. Chisholm (FRS).
General Procedure for the Carbonyl-Ene Reaction between
Methylene Oxazoline and Ethyl Trifluoropyruvate. A flame-
dried Schlenk flask was charged with PdCl2(BINAP) (0.020 g, 25
μmol), AgSbF6 (0.0137 g, 50 μmol), and dichloromethane (2 mL) and
the mixture stirred for 0.5 h to generate the active catalyst (or
Cu(OTf)2 (0.018 g, 50 μmol) and BOX (2,2′-isopropylene bis[(4S)-4-
tert-butyl-2-oxazoline]) (0.015 g, 50 μmol) were used to generate the
catalyst). After this time methylene oxazoline (0.5 mmol) and ethyl
trifluoropyruvate (0.75 mmol) were added, and the reaction mixture
was stirred at room temperature for the specified time. Decane (0.097
mL, 0.5 mmol) was added as an internal standard, and the reaction
mixture was passed through a short silica plug with ethyl acetate. The
solvent was removed under reduced pressure and the residue analyzed
by gas chromatography to determine the conversion and enantiose-
lectivity. Known products were characterized by NMR spectroscopy
and mass spectrometry.
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L
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DOI: 10.1021/acs.organomet.6b00146
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