Soft propargylic deprotonation: Designed ligand enables au-catalyzed isomerization of alkynes to 1,3-Dienes

Article abstract of DOI:10.1021/ja503909c

By functionalizing the privileged biphenyl-2-ylphosphine with a basic amino group at the rarely explored 3′ position, the derived gold(I) complex possesses orthogonally positioned "push" and "pull" forces, which enable for the first time soft propargylic deprotonation and permit the bridging of a difference of >26 pK_a units (in DMSO) between a propargylic hydrogen and a protonated tertiary aniline. The application of this design led to efficient isomerization of alkynes into versatile 1,3-dienes with synthetically useful scope under mild reaction conditions.

Full text of DOI:10.1021/ja503909c

Communication
pubs.acs.org/JACS
Soft Propargylic Deprotonation: Designed Ligand Enables Au-
Catalyzed Isomerization of Alkynes to 1,3-Dienes
Zhixun Wang,‡ Yanzhao Wang,‡ and Liming Zhang*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: By functionalizing the privileged biphenyl-
2-ylphosphine with a basic amino group at the rarely
explored 3′ position, the derived gold(I) complex
possesses orthogonally positioned “push” and “pull” forces,
which enable for the first time soft propargylic
deprotonation and permit the bridging of a difference of
>26 pKa units (in DMSO) between a propargylic
hydrogen and a protonated tertiary aniline. The
application of this design led to efficient isomerization of
alkynes into versatile 1,3-dienes with synthetically useful
scope under mild reaction conditions.
Figure 1. Synergistic acid/base approach toward deprotonation and
1,3-Diene is an important structural motif found in many natural
products1 and can be prepared via isomerization of a C−C triple
bond. Among the known methods,2 only the isomerizations of
ynones to dienone products, facilitated by transition-metal
catalysts,3 such as Ru, Ir, and Pd and organocatalytic phosphine,4
are of significant synthetic utility, as the isomerization of internal
aliphatic and aryl alkynes in the presence of Rh or Pd catalysts
resulted in consistently low diastereoselectivities (dr ≤5).5
Soft enolization of carbonyl compounds6 by using a
combination of a Lewis acid and a mild base is a versatile
strategy in carbonyl chemistry that circumvents the use of strong
bases and hence offers broad functional group compatibility.7 In
this strategy, the acidity of the carbonyl α-hydrogens (pKa in
DMSO ∼16−30) is increased significantly upon the coordina-
tion of the carbonyl oxygen to the Lewis acid,8 owing to the
lowering of its πC−O*; consequently, they can be removed by
mild bases such as Et3N (pKa in DMSO, 9.0). In this mild
deprotonation, the base, a “pushing” force, and the Lewis acid, a
“pull” force, work in concert and typically in a geometrically
orthogonal manner to achieve the outcome (Figure 1A). This
concept, while widely applied in carbonyl chemistry, as far as we
know, has not been extended to alkynes.
The hydrogen α to a C−C triple bond, i.e., propargylic
hydrogens, is weakly acidic with an estimated pKa value in
DMSO >30 for propyne.9 It is typically removed using strong
bases such as n-BuLi, LDA and NaNH2 at ambient or lower
temperatures or using KOH in the presence of excessive heating.
The use of weak bases for its deprotonation, similar to the soft
enolization of carbonyl compounds, would offer an unprece-
dented mild access to the versatile chemistry of propargylic anion
with excellent functional group compatibility. We envisioned
that a similar orthogonal “push−pull” strategy could be
employed. As shown in Figure 1B, instead of an oxophilic
Lewis acid in the case of carbonyl, a carbophilic Lewis acid could
ligand design: (A) soft enolization and (B) orthogonal “push” and “pull”
in propargylic deprotonation. (C) General Au complex framework. (D)
Biphenyl-2-ylphosphine system containing appropriately positioned
acidic and basic sites and with an alkyne substrate bonded. (E) Selected
new ligands prepared for this study.
act as the “pull” force via binding to the C−C triple bond; this
binding would lower the energy of the π⊥*; consequently, the α-
C−H bond parallel to π⊥* becomes more acidic, and a weak
“pushing” base might then be capable of removing it. Herein, we
report a gold-catalyzed isomerization of alkynes into 1,3-dienes,
where a gold complex with a rationally designed ligand enables
for the first time a soft deprotonation of a propargylic C−H bond
(pKa in DMSO >30) with an exceedingly weakly basic tertiary
aniline (pKa in DMSO ∼4).
On the outset, we decided to use a cationic gold(I) complex,
i.e., LAu+, as the “pull” force as it is in general a potent soft Lewis
acid that binds to C−C triple bonds and can lower the π⊥*. With
combinations of LAu+ and weak bases such as Et3N and PhNMe2
offering no success, we turned to the intramolecular approach
and focused our effort on designing new gold ligands with an
optimally positioned basic site. The gold complex with such a
ligand, as shown in Figure 1C would offer the best chance to
succeed as (a) the “push” and the “pull” forces are orthogonal
and (b) the rigid ligand framework and the intramolecular nature
can minimize the entropy cost during the reaction.
We chose the privileged biphenyl-2-ylphosphine framework
for ligand development. Buchwald et al.10 has developed a variety
of versatile ligands based on this framework for versatile
palladium catalysis;11 but those ligands rarely possess functional
modifications (i.e., beyond alkyl and aryl12 groups) at the bottom
Received: April 23, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
half of the pendant phenyl ring (i.e., the 3′, 4′, and 5′ positions),
perhaps owing to the square planar structures of Pd(II)
complexes. The only exceptions are a 3′-sulfonate derived from
SPhos and a 4′-sulfonate from XPhos for the purpose of
increasing catalyst aqueous solubility.13 On the other hand, these
ligands have found extensive utility in homogeneous gold
catalysis,14 although Au(I) complexes typically assume a
distinctively different linear structure. To this end, there exist
enormous yet largely untapped opportunities15 for the develop-
ment of novel gold catalysis based on new biphenyl-2-
ylphosphine ligands specifically tailored to accommodate the
linear Au(I) complexes. Our simple structural modeling revealed,
as shown in Figure 1D, that with bulky groups on phosphorus
gearing the P−Au−alkyne centroid axis parallel to the pendant
phenyl ring the C−C triple bond would lie roughly at the same
level as the line defined by C3′ and C5′, suggesting that
functionalization of these positions and C4′ would offer unique
and potentially novel reactivities to gold chemistry.15
With the task of soft propargylic deprotonation in hand, we
reasoned that a basic amino group in the form of an aniline
substituted at C3′, C4′, or C5′ would likely present a orthogonal
“push” force and importantly be in close proximity to the
propargylic hydrogens, thereby facilitating the targeted prop-
argylic deprotonation (Figure 1D).
To establish the validity of the above ligand design, we
prepared a range of new biphenyl-2-ylphosphines containing
basic amino groups at the bottom half of the pendant phenyl ring
via two sequential cross-coupling reactions (for details, see SI).
Some selected examples are shown in Figure 1E. Much to our
delight, treating 1-phenyl-1-hexyne (1a) with the gold complex
L1AuCl (5%) derived from the di(adamantan-1-yl)phosphine
containing a 3′-NMe2, i.e., L1, and the chloride scavenger
NaBARF (10%) in PhCF3 at 60 °C for 8 h resulted the formation
of (1E,3E)-hexa-1,3-dienylbenzene (2a), albeit in only 3% yield
(Table 1, entry 1). Just as we suspected, the location of the basic
Indeed, with a more basic piperidine ring in the ligand L3, the
yield 2a was improved to 19% (entry 3). Moreover, by installing
an electron-donating methoxyl group para to the N-heterocycle,
the yield increased to 35% (entry 4). At this stage, we probed the
importance of restricting the rotation of P−C2 bond by the bulky
phosphorus substituents and hence the swinging of the P−Au−
alkyne centroid axis. When both adamantyl groups on the
phosphorus of L4 were replaced with sterically less demanding
cyclohexyl (e.g., L5), the reaction became much less efficient
(entry 5), suggesting that conformational rigidity is crucial for
efficient deprotonation. To further improve this reaction, the
acidity of the gold center was increased by using the ligand L6,
where its phosphorus center was less σ-donating due to the
substitution of an electron-withdrawing para CF3 group. Indeed,
a much improved, respectful 77% yield was achieved with this
ligand after 8 h reaction (84% conversion). Finally, the best
results, 90% yield of 2a with 4% of 1a remained unreacted, were
achieved with the optimal ligand L7, which differs from L6 by
possessing two cis-methyl groups at the 3,5-positions of the
piperidine ring (entry 7). This improvement is attributed to the
more basic nature of the cis-3,5-dimethylpiperidin-1-yl than the
unsubstituted piperidin-1yl. To confirm the identity of this
optimal catalyst, [L7Au]+ BARF−, we first ascertained the
structure of the precatalyst, L7AuCl, by X- ray diffraction studies
(Figure 2A), and then attempted to synthesize it by mixing
Figure 2. Ortep drawings with 50% ellipsoid probability: (A) L7AuCl
and (B) [(L7Au)2]2+ 2BARF− with the counteranions and the solvent
molecule (i.e., DCE) omitted for clarity.
Table 1. Ligand Optimization and Conditions Study of Gold-
Catalyzed Isomerization of Alkynes to Dienes
a
L7AuCl and NaBARF in DCE. Instead, its dimeric complex,
[(L7Au)2]2+ 2BARF−, was isolated, and its structure was again
revealed by X-ray diffraction studies (Figure 2B). This dimer
complex was also capable of catalyzing the reaction albeit less
potent than the in situ generated catalyst (comparing entry 8 and
entry 7), which is consistent with that the dimeric complex needs
to dissociate into the catalytically active monomer.16
b
b
entry
L
yield (conv.)
entry
L
yield (conv.)
1
2
3
4
5
L1
L2
L3
L4
L5
3% (9%)
0% (6%)
6
7
8
L6
77% (84%)
90% (96%)
54% (55%)
L7
c
19% (23%)
35% (40%)
4% (8%)
d
9
L7
L7
∼1% (<4%)
−
−
The conventional counteranions such as NTf2 , OTf−, SbF6 ,
e
f
10
92%
−
−
BF4 , and PF6 , being more coordinating than BARF−, were
surprisingly detrimental to the reaction, and only a trace of 2a
was detected (entry 9, for more studies of the counteranions, see
SI). Finally, the catalyst loading of L7AuCl could be lowered
down to 2 mol % without affecting the reaction efficiency, and the
diene 2a was isolated in 92% yield after 12 h reaction (entry 10).
Notably, the reaction was highly diastereoselective, and the other
double bond isomers were formed in scant amounts.
a
Reactions were performed in α,α,α-trifluorotoluene at 60 °C for 8 h
b
in vials. NMR yield using diethyl phthalate as the internal reference.
c
Dimeric complex, [(L7Au)2]2+ 2BARF− (2.5 mol %), was used as the
d
catalyst. L7AuCl (6 mol %)/AgX (5 mol %) (X = NTf2, SbF6, BF4,
OTf, and PF6) was used as the catalyst. 2 mol % of L7AuCl used;
reaction time: 12 h. Isolated yield, dr = 49:1.
e
f
site of the ligand turned out to be crucial as no 2a was detected
when the Me2N group was moved to the C4′ position as in the
ligand L2 (entry 2). Our subsequent ligand optimization was
focused on increasing the basicity of the aniline nitrogen and the
acidity of the gold center. As such, the resulting gold complex
should be more capable of promoting deprotonation of the
propargylic hydrogen and hence increasing the reaction yield.
With the optimized conditions in Table 1, entry 10 in hand, the
scope of this isomerization of alkynes into 1,3-diene was first
examined with a range of internal arylalkynes. As shown in Table
2, entries 1−6, 1-phenyl-1-hexynes with substituents of varying
nature on the benzene ring underwent the gold catalysis
smoothly, affording the desired conjugated 1,3-dienes in mostly
excellent yields except in the case of entry 1. Notably, both C−C
B
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Communication
a
synthetic potential of this gold catalysis, we subjected the ethyl
ynenoate 1k to the optimized reaction conditions. Gratifyingly,
the anticipated trienoate 2k was isolated in 73% yield (entry 10).
An even better yield was obtained with the alkenyl ester substrate
(entry 11). The methyl ketone analogue 1m, however, resulted in
a much lower yet serviceable yield (entry 12). Extension of this
catalysis to nonconjugated internal alkynes such as 6-dodecyne
was complicated by poor regioselectivity; however, with terminal
alkynes 1n and 1o that possess tertiary propargylic carbon
centers, the isomerizations were highly efficient, affording 1,3-
dienes 2n and 2o in 80% and 84% yield, respectively. On the
other hand, with linear terminal alkyne 1p, no diene product was
observed. Instead, the allene 2p′ was formed in 30% yield along
with 7% of remaining 1p, 11% yield of the hydration product
methyl ketone, and 52% yield of the alkyne migration product 4
(eq 2). Attempts to improve the allene formation were
unsuccessful due to the reversible nature of the isomerization.
Table 2. Reaction Scope
We propose a mechanism in Scheme 1 using 1a as the
substrate: in line with our initial design, the coordination of 1a to
Scheme 1. Proposed Reaction Mechanism
a
Reaction conditions: L7AuCl (2 mol %) and NaBARF (10 mol %) in
b
c
α,α,α-trifluorotoluene, 60 °C. Isolated yield. Minor isomer has a
newly formed (Z)-π bond. L7AuCl (5 mol %). DCM as solvent and
reaction temperature was 40 °C.
d
e
double bonds in the major products are in (E)-configurations,
while the C−C double bonds distal to the benzene ring in the
minor products possess (Z)-geometry; it appears that the
selectivity for the most stable all (E)-products increases as the
aromatic substituents move away from the alkyne. A thiophen-3-
yl terminated alkyne (i.e., 1h) also underwent the gold-catalzyed
isomerization without incident (entry 7).
The gold catalysis can also tolerate ethereal moieties in close
proximity to the C−C triple bond. For example, the phenyl
alkyne 1i containing a γ-benzyloxy group reacted efficiently to
afford the allylic benzyl ether 2i in 88% yield (entry 8). Of more
significance is the formation of the synthetically versatile dienyl
benzyl ether 2j upon subjecting (4-(benzyloxy)but-1-yn-1-
yl)benzene (i.e., 1j) to the reaction conditions (entry 9). The
relatively low isolation yield was due to its labile nature. When N-
phenylmaleimide, a dienophile, was added to the initial reaction
mixture, it did not impede the gold catalysis and, moreover,
reacted with in situ generated 2j smoothly to deliver the Diels−
Alder adduct 3 in a respectful 62% yield (eq 1). Some polyene
natural products1 feature multiple conjugated C−C double
bonds with further conjugated carbonyl groups. To illustrate the
L7Au+, as shown in the structure A, would enable propargylic
deprotonation even with such a weak base (pKa in DMSO ∼4).
The resulting allenylgold intermediate B could undergo ipso-
protodeauration to deliver the gold allene complex C. It is
notable that the aniline nitrogen acts as a proton shuttle in these
two steps, and there must be some conformational flexibility
along the C2−P bond in order to enable the proton relocation. If
the allene substituents could stabilize a developing carbocation, it
is conceivable that an equilibrium between C and a gold-
substituted allylic cation (i.e., D) would be established. The latter
structure would again position a C−H bond α to the allyl cation
moiety near the aniline nitrogen. A consequential intramolecular
deprotonation would then afford the dienylgold complex E,
C
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Journal of the American Chemical Society
Communication
which could undergo internal ipso-protodeauration to afford the
diene product 2a and regenerate the catalyst. In these latter
tranformations, the aniline again serves as a proton shuttle. The
observed high E-selectivity can be rationalized by that the
intermediate D adopts the most stable conformation (as shown),
and its transformation to the diene product is very facile. Hence,
the net result of this gold catalysis would be two sequential
aniline-assisted proton shuttling. It is important to point out that
the previously reported isomerizations using transition-metal
catalysts likely precede via a characteristically different
mechanism, where a metal hydride serves as the intermediate
and sequential migratory insertion and β-hydride elimination is
the recurring theme.
ACKNOWLEDGMENTS
We are grateful for the generous financial support by NIH (R01
GM084254) and NSF (CHE-1301343).
■
REFERENCES
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The proposed mechanism indicates that allene can be formed
upon the first proton migration and metal decomplexation. This
is consistent with the observed formation of 2p′ (see eq 2).
However, in the other cases, allene intermediates were mostly
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and its allene isomer 7 to the optimal reaction conditions (eq 3).
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In summary, by functionalizing the privileged biphenyl-2-
ylphosphine with a basic amino group at the rarely explored 3′
position, the derived gold(I) complex possesses orthogonally
positioned “push” and “pull” forces, which enables for the first
time soft propargylic deprotonation and permits the bridging of a
difference of >26 pKa units (in DMSO) between a propargylic
hydrogen and a protonated tertiary aniline. The application of
this design led to efficient isomerization of alkynes into versatile
1,3-dienes with synthetically useful scope under mild reaction
conditions. The work constitutes a dramatic deviation from the
classic soft deprotonation of carbonyl compounds and reveals
new opportunities to access organometallic species such as B and
E via deprotonative process under exceptionally mild conditions.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, compound characterization, and spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
zhang@chem.ucsb.edu
Author Contributions
‡Z.W. and Y.W. contributed equally.
Notes
The authors declare no competing financial interest.
D
dx.doi.org/10.1021/ja503909c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX