Optimizing P,N-bidentate ligands for oxidative gold catalysis: Efficient intermolecular trapping of α-oxo gold carbenes by carboxylic acids

Article abstract of DOI:10.1002/anie.201301601

Control confirmed: Optimization of P,N-bidentate ligands (L) reveals the importance of conformation control for intermolecular trapping of reactive α-oxo gold carbene intermediates. As a result, the highly efficient and broadly applicable synthesis of car

Full text of DOI:10.1002/anie.201301601

Angewandte
Chemie
DOI: 10.1002/anie.201301601
Ligand Design
Optimizing P,N-Bidentate Ligands for Oxidative Gold Catalysis:
Efficient Intermolecular Trapping of a-Oxo Gold Carbenes by
Carboxylic Acids**
Kegong Ji, Yulong Zhao, and Liming Zhang*
A few years ago we reported[1] that gold-catalyzed[2] inter-
molecular oxidation of alkynes offered an expedient access to
synthetically versatile a-oxo gold carbene intermediates
(Scheme 1a). This strategy circumvents the use of hazardous
amides efficiently, thus leading to a one-step synthesis of 2,4-
disubstituted oxazoles.[6] Mor-DalPhos (see Scheme 1b),[7]
a bulky P,N-bidentate ligand, was found to be a uniquely
effective ligand, and its role was proposed to enable the
formation of a tricoordinated gold carbene (e.g., A) instead of
the typical dicoordinated one (e.g., A’). The tricoordination
leads to attenuated electrophilicity at the carbene center
(Scheme 1b).
To further develop alkynes as surrogates of hazardous a-
diazo ketones in gold catalysis, especially in the context of
synthetically important intermolecular trapping, we
embarked on expanding the scope of suitable external
nucleophiles beyond carboxamide. Our first target was
carboxylic acids (Scheme 1a), a weaker nucleophile in its
neutral form than carboxamide. Notably, the reaction, if
developed, would offer a novel and rapid access to syntheti-
cally versatile a-carboxymethyl ketones (3; Scheme 1a) from
readily available terminal alkynes and carboxylic acids.
At the outset, we used 1-dodecyne and benzoic acid
(1.2 equiv) as the reacting partners and 8-methylquinoline N-
oxide[4d] as the oxidant, and the results of reaction optimiza-
tion are shown in Table 1. Consistent with our previous
study,[6] cationic gold complexes derived from typical ligands
such as Ph3P, IPr, and BrettPhos (Figure 1a) were largely
ineffective, thus resulting in complex mixtures with little
desired product (entry 1). On the contrary, Mor-DalPhos[7]
again proved to be an effective ligand, and the oxidative gold
catalysis led to the desired a-benzoxymethyl ketone 3a in
a fairly good yield (entry 3). An identical yield was observed
with the ligand L1,[7] which differs from Mor-DalPhos by
having a piperidine ring instead of a morpholine ring
(entry 4). However, the smaller Me-DalPhos[7] was inferior
(entry 2), thus suggesting that the steric size of the pendant
secondary amine might be critical.
Consequently, we modified the piperidine ring of L1 with
different substituents. While the installation of a methyl group
at its 4-position was inconsequential (Table 1, entry 5; see L2
in Figure 1b), the much bigger tert-butyl group was detri-
mental (entry 6). However, to our delight, a 3-methyl group,
as in L4, led to a notable increase of the reaction yield
(entry 7). Moreover, the use of cis-3,5-dimethylpiperidine
(L5) as the pendant amine group resulted in a higher 84%
yield of 3a (entry 8). On the contrary, L6 with a trans-3,5-
dimethylpiperidine ring led to a much less efficient reaction
(entry 9), which could be attributed to deleterious steric
congestion caused by an inevitable axially oriented methyl
group. The piperidine ring in L5 could be replaced with
a morpholine ring (L7) with only a small, yet adverse impact
Scheme 1. a) Trapping a-oxo gold carbenes generated by intermolecu-
lar alkyne oxidation using internal and external nucleophiles. b) Mor-
DalPhos and the previously calculated relative energies (kcalmolÀ1) of
the corresponding gold carbene species. The PBE1PBE/6-311+G**
level of theory was used.[6]
and potentially explosive a-diazo ketone precursors[3] and has
led to the development of various efficient synthetic methods,
by us[1,4] and others,[5] based on intramolecular trapping of a-
oxo gold carbene intermediates. The intermolecular counter-
part, which is likely to be of exceptional synthetic utility,
however, proves to be very challenging because of the highly
electrophilic nature of the carbene center and is often plagued
with overoxidation, reactions with solvents,[4b,g] and intract-
able side reactions. Earlier we reported for the first time that
the reactivity of the gold carbene could be attenuated by using
bidentate phosphine ligands so that it reacted with carbox-
[*] Dr. K. Ji, Dr. Y. Zhao, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry
University of California, Santa Barbara, CA (USA)
E-mail: zhang@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~zhang/index.html
[**] We thank the NIGMS (R01 GM084254) for generous financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301601.
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Table 1: Optimization of the reaction conditions.[a]
limiting reagent, L5 was a significantly better ligand than L7
for the gold catalysis (compare entries 12 and 13). Moreover,
the reaction yield in the former case is nearly quantitative,
which is impressive considering the difficulties previously
encountered in trapping these reactive gold carbene species
and really showcased the opportunities in method develop-
ment based on ligand design/development. Other solvents
such as DCE (entry 14) and toluene (entry 15) were suitable
for this reaction, albeit not nearly as good as PhCl. Although
the oxidant, 8-methylquinoline N-oxide, had to be introduced
to the reaction slowly by a syringe pump to avoid over
oxidation, the reaction proceeded smoothly at ambient
temperature.
With the optimized reaction conditions given in Table 1,
entry 13, the scope of the transformation was first examined
with various carboxylic acids. As shown in Table 2 (entries 1–
6), various substituted benzoic acids reacted smoothly,
affording the desired products in mostly excellent yields.
Even a Bpin group was tolerated, and the relatively low yield
was due to the coelution of the boronated product 3 f with 8-
methylquinoline (entry 5). The reaction also worked well with
other conjugated acids such as thiophene-2-carboxylic acid
(entry 7), trans-cinnamic acid (entry 8), trans-3-(2-furyl)-
acrylic acid (entry 9), and trans, trans-hexa-2,4-dienoic acid
(entry 10), thus delivering the corresponding products in
greater than 90% yields. Acetic acids with the a-carbon atom
functionalized by a 1-methylindol-3-yl (entry 11), trimethyl-
silyl (entry 12), chloro (entry 13), and phenoxy group
(entry 14), were all suitable substrates, and functionalized a-
carboxymethyl ketones were again isolated in good to
excellent yields. The reaction with N-Boc-protected proline,
however, only resulted in a serviceable yield of the corre-
sponding product (entry 15). Other carboxylic acids such as
cyclopropanecarboxylic acid (entry 16) and adamantane-1-
carboxyclic acid (entry 17) also proceeded well. While these
reactions were run on a 0.2 mmol scale, a 3 mmol scale was
readily implemented with the reaction in entry 2 even with
only 2 mol% of the catalyst and 3c was isolated in 82% yield.
The reaction also proceeded smoothly with various
terminal alkynes. As shown in Table 3, phenylacetylene
(entry 1) and 1-ethynylcyclohexene (entry 4) were excellent
substrates, and so are the acetylenes substituted by cyclic
(entries 2 and 3) or remotely functionalized linear alkyl
groups (entries 5–7). The reaction yields were good to
Entry 1a/2a Catalyst
Yield [%][b]
1
2
1:1.2
1:1.2
[LAuCl](5 mol%)/NaBArF (10 mol%)
<7[c]
11
4
[(Me-DalPhos)AuCl](5 mol%)/
NaBArF (10 mol%)
4
3
1:1.2
[(Mor-DalPhos)AuCl](5 mol%)/
68
NaBArF (10 mol%)
4
4
5
6
7
8
9
10
11
12
13
14
15
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1.3:1
1.3:1
1.3:1
1.3:1
[L1AuCl](5 mol%)/NaBArF (10 mol%)
68
68
18
75
84
30
79
63
86
98[d]
95
88
4
[L2AuCl](5 mol%)/NaBArF (10 mol%)
4
[L3AuCl](5 mol%)/NaBArF (10 mol%)
4
[L4AuCl](5 mol%)/NaBArF (10 mol%)
4
[L5AuCl](5 mol%)/NaBArF (10 mol%)
4
[L6AuCl](5 mol%)/NaBArF (10 mol%)
4
[L7AuCl](5 mol%)/NaBArF (10 mol%)
4
[L8AuCl](5 mol%)/NaBArF (10 mol%)
4
[L7AuCl](5 mol%)/NaBArF (10 mol%)
4
[L5AuCl](5 mol%)/NaBArF (10 mol%)
4
[L5AuCl](5 mol%)/NaBArF (10 mol%)[e]
4
[L5AuCl](5 mol%)/NaBArF (10 mol%)[f]
4
[a] The reaction was run with everything except the oxidant in a vial
capped with a septum, and the oxidant was introduced into the reaction
mixture over a 12 h period using a syringe pump. Initially, [1a]=0.1m.
[b] Measured by 1H NMR analysis using diethyl phthalate as the internal
standard. [c] L=Ph3P, IPr, or BrettPhos. The 1H NMR spectra of the
crude reaction mixture were mostly messy. [d] Yield of isolated product
was 96%. [e] DCE was used as the solvent. [f] Toluene was used as the
solvent.
À
excellent. Even with heteroatoms placed close to the C C
triple bond and hence to the in situ formed electrophilic gold
carbene center, this intramolecular reaction still led to a good
(entry 8) or serviceable yield (entry 9).
The ligand optimization by modification of the pendant
piperidine/morpholine ring deserves further examination. In
our previous carboxamide trapping chemistry,[6] the smaller
Me-DalPhos was found to be equally effective as a bidentate
ligand such as Mor-DalPhos. On the contrary, in this
chemistry, the steric size of the pendant amino group is
crucial for the reaction outcome (see Table 1). We attribute
the difference to the decreased nucleophilicity of the carbonyl
oxygen group in the carboxylic acid[8] as compared to that in
the carboxamide. It is reasonable to suspect that steric
shielding around the gold carbene center would facilitate, to
Figure 1. a) known ligands. b) Newly developed P,N-bidentate ligands.
Ad=adamantyl.
on the reaction outcome (entry 10). Interestingly, replacing
the methyl groups in L7 with bigger phenyl groups (L8)
resulted in a yield even lower than that obtained with by Mor-
DalPhos (entry 11). This result, along with that of L3, suggest
that there is an optimal steric bulk for the pendant six-
membered ring in this reaction. When benzoic acid was the
2
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Table 2: Reaction scope with different carboxylic acids.[a,b]
Table 3: Reaction scope with various alkynes.[a,b]
Entry
1
Product
Yield [%]
94
Entry
1
Product
Yield [%]
3b
3c
3d
3e
3s
3t
93
92
95
94
2
3
4
2
3
4
96
91
92
3u
3v
5
6
3w
3x
90
90
5
3 f
66 (85[c])
6
7
8
3g
3h
3i
68
90
94
7
8
3y
3z
92
76 (85[c])
9
3aa
59
9
3j
97
93
[a] Initially [2]=0.1m. The oxidant was introduced to the reaction vial
using a syringe pump. [b] Yields of isolated products are shown. [c] Yield
determined by NMR spectroscopy. Phth=phthaloyl, Ts=4-toluenesul-
fonyl.
10
3k
11
3l
90
12
13
14
3m
3n
3o
92
80
78
a certain extent, slower reactions with small nucleophiles by
minimizing side reactions with sterically demanding nucleo-
philes. With regard to the ligands L1 and Mor-DalPhos, the
enhanced efficiency with L5 could be attributed a priori to the
bulkier piperidine ring. However, two cis methyl groups could
at the same time impose conformation rigidity to the N-
heterocycle. Scheme 2a outlines two chair conformers of the
gold carbene intermediate with L1 as its ligand. It is note-
worthy that the X-ray diffraction studies of Mor-DalPhos
palladium complexes by Stradiotto and co-workers[7a] reveal
that the morpholine ring can adopt the chair conformation as
shown in B’ and twist boat conformations. The conformer B’,
though understandably less stable and hence less populated,
does not provide sufficient steric protection to the carbene
center. Consequently, the reaction could be improved if the
conformers including B’ and other less shielding ones could be
minimized. We surmise that the two cis methyl groups in L5
might play the role of locking the piperidine into a conforma-
tion identical to that in B. As such, the carbene center is
constantly shielded and hence would react preferably with
smaller nucleophiles, such as carboxylic acids, rather than
15
16
17
3p
3q
3r
54
91
80
[a] Initially [2]=0.1m; the oxidant was introduced to the reaction vial
over a 12 h period using a syringe pump. [b] Yields of isolated products
are shown. [c] Yield determined by NMR spectroscopy. Boc=tert-
butoxycarbonyl, Pin=pinacolato.
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dration of the ketones 3ac and 3ad, which in turn were
obtained in excellent yields by the oxidative gold catalysis.
In conclusion, we have developed a highly efficient and
broadly applicable synthesis of carboxymethyl ketones from
Scheme 2. a) Two chair conformers of the tricoordinated gold carbene
with L1 as the bidentate ligand. b) ORTEP drawing of [L5AuCl] with the
solvent molecules omitted.[11] The thermal ellipsoids are shown at 50%
probability. c) L9 in two different chair conformers. d) The structure of
L10.
bigger ones, including the oxidant. An X-ray diffraction study
of [L5AuCl][11] confirmed the preferred shielding chair
conformation for the cis-3,5-dimethylpiperidine ring (Sche-
me 2b). In the case of L8, the phenyl groups are likely too
bulky to hinder the carbene formation or the productive
approach by a carboxylic acid.
To offer more insight into the importance of conformation
control, we prepared the ligand L9 (Scheme 2c), wherein an
ortho-methyl group on the benzene ring is installed to
essentially prohibit the piperidine ring from adopting the
chair conformation shown as L9ax and likely minimizes the
contribution of other nonchair conformers. Indeed, the gold
catalyst afforded 3a in 83% yield [Eq. (1)], which is much
better than that obtained with L1 (where the ortho-Me is
absent) and virtually identical to that obtained by L5 (see
Table 1, entry 8). When L10, with an ortho-methyl group and
a pendant cis-3,5-dimethylpiperidine was used for the gold
catalysis, the reaction efficiency remained the same [Eq. (1)],
readily available carboxylic acids and terminal alkynes under
exceptionally mild reaction conditions. In this oxidative gold
catalysis, the highly electrophilic a-oxo gold carbene inter-
mediate is most likely generated, and its challenging inter-
molecular trapping by weakly nucleophilic carboxylic acids is
achieved upon extensive optimization of the P,N-bidentate
ligands coordinated to the gold center. While the steric bulk
of the pendant amino group in these ligands is beneficial to
a certain extent, controlling the conformation of the sterically
suitable piperidine ring to provide better shielding to the
carbene center appeared to be important to achieve the high
efficiency. Importantly, the reaction products can be rapidly
converted into synthetically versatile cyclic structures. Fur-
ther studies employing other types of nucleophiles including
so-far unyielding enol ethers are currently underway.
thus suggesting that the role of the piperidine methyl groups Experimental Section
General procedure for gold-catalyzed synthesis of a-carboxymethyl
in L5 is to fix the desired chair conformation of the N-
heterocycle instead of providing additional steric bulk.
This one-step, generally applicable, and efficient synthesis
of functionalized carboxylmethyl ketones permits rapid
access to various useful cyclic structures. For example, the 2-
ketones: The carboxylic acid (0.2 mmol), alkyne (0.26 mmol),
[L5AuCl] (0.01 mmol), and NaBArF (0.02 mmol) were added
4
sequentially to a 3 dram vial containing 2 mL of chlorobenzene.
The resulting mixture was stirred at room temperature. To this vial
a solution of N-oxide (47.7 mg, 0.3 mmol) in 4 mL of chlorobenzene
was then added using a syringe pump over a 12 h period. Upon
completion, the reaction mixture was concentrated under vacuum.
The residue was purified by chromatography on silica gel (eluent:
hexanes/ethyl acetate) to afford the desired product 3.
Received: February 25, 2013
Revised: March 4, 2013
Published online: && &&, &&&&
alkenyloxazole 4 was isolated in 80% yield by the combina-
tion of the gold catalysis and a subsequent BF3·Et2O-
promoted condensation[9] in a one-pot process [Eq. (2)].
Moreover, the phenone intermediate 3ab, isolated in 93%
yield, has been previously converted into the g-lactone 5 in
72% yield [Eq. (3)].[10] Another approach to cyclized prod-
ucts is shown in Equation (4), where DBU effectively
promoted sequential intramolecular aldol reaction and dehy-
Keywords: carbenes · conformation analysis · gold · oxidation ·
.
P,N ligand
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Communications
Ligand Design
K. Ji, Y. Zhao, L. Zhang*
&&&& — &&&&
Optimizing P,N-Bidentate Ligands for
Oxidative Gold Catalysis: Efficient
Intermolecular Trapping of a-Oxo Gold
Carbenes by Carboxylic Acids
Control confirmed: Optimization of P,N-
bidentate ligands (L) reveals the impor-
tance of conformation control for inter-
molecular trapping of reactive a-oxo gold
carbene intermediates. As a result, the
highly efficient and broadly applicable
synthesis of carboxymethyl ketones from
readily available carboxylic acids and
terminal alkynes proceeds under mild
reaction conditions.
6
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