Cross-coupling of meyer-schuster intermediates under dual gold-photoredox catalysis

Article abstract of DOI:10.1021/acs.orglett.5b03531

Under dual gold/photoredox catalytic conditions, intermediates from the Meyer-Schuster rearrangement underwent an efficient cross-coupling with arene diazonium salts, leading to α-arylated enones. Diazonium salts assisted the dissociation of the propargyl

Full text of DOI:10.1021/acs.orglett.5b03531

Letter
pubs.acs.org/OrgLett
Cross-Coupling of Meyer−Schuster Intermediates under Dual Gold−
Photoredox Catalysis
Jiwon Um, Hokeun Yun, and Seunghoon Shin*
Department of Chemistry and Center for New Directions in Organic Synthesis (CNOS), Research Institute for Natural Sciences,
Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea
S
* Supporting Information
ABSTRACT: Under dual gold/photoredox catalytic conditions, intermediates from the Meyer−Schuster rearrangement
underwent an efficient cross-coupling with arene diazonium salts, leading to α-arylated enones. Diazonium salts assisted the
dissociation of the propargyl hydroxyl group by forming alkoxydiazenes in the Meyer−Schuster rearrangement, and the coupling
was proposed to proceed through an allenyl methyl ether.
he Meyer−Schuster rearrangement converts readily
Tavailable propargyl alcohols into α,β-unsaturated carbonyl
compounds in an atom-economical fashion, and thus, consid-
erable attention has been paid to the related catalytic methods.1 A
tandem reaction incorporating cross-coupling of the C(sp2)−M
intermediate in this transformation would broaden its utility,
providing an efficient route to diverse α-arylated enones that
serve as precursors for many pharmaceutically interesting
heterocycles as well as substrates for asymmetric organo-
catalysis.2
Although related tandem [3,3]-rearrangement/cross-coupling
of propargyl esters has been documented in gold and indium
catalysis employing propargyl esters,3 cross-coupling of the
Meyer−Schuster intermediates obtained from propargyl alco-
hols has been achieved only through a Cu system (Scheme 1A).4
Recently, Glorius6a,b and Toste6c,d introduced a combination of
visible-light photoredox with gold catalysis, leading to C(sp3)−
C(sp2) coupling, employing aryl diazonium salts.5,6 These
seminal reports spurred renewed interest in gold-catalyzed
cross-coupling because the Au(I)−Au(III) redox cycle can be
accessed without using strong stoichiometric oxidants. Thus far,
however, C(sp2)−C(sp2) cross-coupling under these dual
catalytic systems has been limited to stable vinyl gold
intermediates that can be isolated and characterized (Scheme
1B).6c,e,7 For a successful cross-coupling of unstable C(sp2)−Au
intermediates, both oxidative addition and reductive elimination
must be faster than the competing proto-demetalation. Such in
situ cross-coupling of C(sp2)−metal species has intrinsic
advantages over the current cross-coupling technology via C−
H functionalization in that no directing group (and its
installation/detachment steps) is required to obtain regioselec-
tive coupling, and more diverse cyclic or acyclic C(sp2)−M
intermediates could be utilized in the cross-coupling by virtue of
the complexity-generating power of gold catalysis. This aspect
underscores the importance of cross-coupling of transient
C(sp2)−M intermediates in electrophilic metal catalysis.
Toward cross-coupling of unstable C(sp2)−Au species, the
Meyer−Schuster rearrangement was selected because gold
complexes are one of the most selective catalysts for this
transformation over competing side pathways, such as
dehydration or Rupe rearrangements. Through our previous
study on a Au-catalyzed tandem Meyer−Schuster rearrange-
ment/ring expansion,8 we determined that a π-bound allenol, I,
plays a key role in the stereodetermining step by racemization of
the allene axis and inducing ring expansion. We posited that the
corresponding σ-bound enone−Au complex II would couple
with a photo-redox-generated aryl radical, leading to α-arylated
enones. Under these photocatalytic conditions, this method-
ology would raise an interesting issue of Z/E selectivity.9
Scheme 1. Cross-Coupling of C(sp2)−M Intermediates
With a tertiary propargyl alcohol 1a and diazonium 2a as test
substrates, we examined various conditions for the tandem
Meyer−Schuster/cross-coupling (Table 1). Initially, finding
Received: December 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03531
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Organic Letters
Letter
Table 1. Optimized Conditions for the Tandem Meyer−
Scheme 2. Substrate Scope for Au/Photoredox α-Arylative
Meyer−Schuster Rearrangement
a
a
Schuster Rearrangement/Arylative Cross-Coupling
b
b
entry
deviation from standard conditions
none
3aa (%)
4aa (%)
1
2
92
32
42
71
63
69
47
45
41
70
41
43
40
56
87
60
34
0
6
38
45
19
31
10
10
8
cd
,
[(Ph3P)Au]OTf (2.5%)
c
3
Ph3PAuI
c
4
Ph3PAuBr
c
5
Ph3PAuF
6
additive (NaHCO3, 1 equiv)
e
7
(NH4)2Fe(SO4)2·6H2O (10%)
e
8
Fe(OTf)2 (10%)
e
9
Fe(acac)3 (10%)
5
f
10
11
12
13
14
15
16
17
18
19
20
21
22
riboflavin (20%)
14
34
32
36
16
8
f
Ir[dF(CF3)ppy]2(dtbpy)PF6 (2.5%)
f
Ir(dFppy)2(phen)PF6 (2.5%)
f
Ir(ppy)2(dtbbpy)PF6 (2.5%)
f
fac-Ir(ppy)3 (2.5%)
ArN2BF4 (3 equiv)
ArN2BF4 (2 equiv)
ArN2BF4 (1 equiv)
13
11
0
g
Ph2IOTf
no Au catalyst
no photocatalyst
no light
0
0
trace
trace
32
0
0
no photocatalyst, 50 °C
61
a
1a (0.1 mmol), 2a (0.4 mmol) in the presence of Ph3PAuCl (2.5 mol
b
%), and Ru(bpy)3(PF6)2 (2.5 mol %) in degassed MeOH. Isolated
yields. Instead of Ph3PAuCl. Generated in situ from Ph3PAuCl and
c
d
AgOTf (2.5 mol % each) in CH2Cl2, followed by filtration and
e
evaporation of solvents. Instead of Ru(bpy)3(PF6)2 with no light.
f
g
Instead of Ru(bpy)3(PF6)2. Instead of 2a.
optimal conditions was deemed challenging because protonated
enone II, due to its strong acidity, may rapidly undergo proto-
demetalation. After substantial trials, we found that 1a undergoes
an efficient cross-coupling with p-nitrophenyldiazonium 2a,
affording 3aa in 92% isolated yield (entry 1). Suppression of
proto-demetalation to 4aa was not effective using a cationic
Au(I) catalyst (entry 2). Other Au(I)−halides, unfortunately,
proved to be less efficient than Au(PPh3)Cl (entries 3−5). Use of
base additive adversely affected the desired Meyer−Schuster
rearrangement/cross-coupling (entry 6). Other Au(I)−SET
catalysts (entries 7−9) and photocatalysts (entries 10−14) in
place of Ru(bpy)32+ proved to be less efficient, giving a significant
amount of 4aa. Notably, riboflavin (20 mol %) in place of
Ru(bpy)32+ gave 70% of 3aa. Use of smaller amount of 2a led to
lower yield, and diphenyliodonium salt6b was completely inactive
(entries 15−18). The reaction did not proceed at all in the
absence of gold catalyst, photocatalyst, or in the dark (entries
19−21), and the thermally generated aryl radical6e gave only a
modest yield of 3aa (entry 22). It is important to note that, while
10 mol % of gold catalyst was required in previous dual Au/
photoredox systems,6 Au loading could be reduced significantly
(2.5 mol % of Ph3PAuCl).
a
1a (0.1 mmol), 2a (4 equiv) in the presence of Ph3PAuCl (2.5 mol
%), and Ru(bpy)3(PF6)2 (2.5 mol %) in degassed MeOH (0.1 M).
Isolated yields after chromatography. E/Z ratio.
b
alcohols were widely accommodated in this reaction, as
demonstrated in the formation of 3ba−3la. In the case of
substrates with different R2 and R3 groups, a mixture of double
bond isomers of modest E/Z ratio was obtained (3ia−3la, vide
infra in eqs 1−3). Substrates bearing secondary propargyl
alcohols were also viable substrates (3ma−3og), although the
yields were somewhat lower than that of tertiary propargyl
alcohols.
With these optimized conditions, the scope of the α-arylative
Meyer−Schuster rearrangement was examined (Scheme 2). In
terms of the arene diazonium salts, electron-deficient arenes
generally gave yields of the coupled products (3aa−3ae) higher
than that of electron-rich ones (2f). Various tertiary propargyl
B
DOI: 10.1021/acs.orglett.5b03531
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Considering the possible photocatalyzed E/Z isomerization
under the current conditions,9 the E/Z ratio in the formation of
3ia−3la likely results from the differential excitation of E- and Z-
isomers to the photostationary equilibrium (energy ratchet)9b
and not from the Meyer−Schuster mechanism. Thus, it was of
interest whether the E to Z isomerization occurs during the
formation of α-arylated enones. As in eq 1, changing the
photocatalyst from Ru(bpy)32+ (2.5 mol %) to riboflavin (20 mol
%) in the formation of 3ia indeed led to an increased E
preference (Z/E = 32:68, cf. 3ia (Z/E = 48:52) in Scheme 2). In
addition, when the isolated 3ia (with Z/E = 36:64) was subject to
blue LED irradiation (∼460 nm), E to Z isomerization occurred
to give a Z-enriched mixture (Z/E = 72:28). Among the other
products tested, only enyne 3ja displayed photoresponsive
behavior, giving Z/E isomerization (eq 3).
Scheme 4. Proposed Mechanism
To further probe the mechanism of this tandem Meyer−
Schuster/cross-coupling, the following control experiments were
conducted (Scheme 3). Mixing propargyl alcohol 1a with
Scheme 3. Reaction of Propargyl Alcohols with Diazonium
Salts
Scheme 5. Synthesis of Pyrazoles and Pyrazolines
diazonium salt 2e in methanol led to a Nicholas reaction,
affording propargyl methyl ether 5a in 18 h at rt (eq 4).
Surprisingly, this substitution could be effected even with a
catalytic amount of diazonium salt 2e (20 mol %) over an
extended time period. We interpreted that the substitution is
mediated by (propargyloxy)diazene I for the activation and
dissociation of the hydroxyl group. Thus, formed propargyl
methyl ether 5a turned out to be a viable Meyer−Schuster
substrate, as well, to form 3ae (eq 5).
both Ru(II) and Au(I) catalysts at rt. We propose that the keys
for the successful cross-coupling with the labile C(sp2)−Au
include the formation of the allenyl ethers, and in this protocol,
arene diazonium salts play triple roles as oxidants, coupling
partners, and catalytic activators for the dissociation of propargyl
alcohols. The latter aspect will have interesting implications in
the transformations of propargyl alcohols, which is currently
sought after in this laboratory.
Based on the above results and our previous work,6e,8 we
propose the mechanism of the tandem Meyer−Schuster
arylation as follows (Scheme 4): Photoredox oxidative addition
of aryl diazonium into neutral (L)AuCl would form cationic
Au(III) complex II,6c−e which, in turn, activates propargyl
alcohol 1 (or I) to form III. Here, the R group can also be a
diazenyl group (NNAr, eq 4) or Me group (eq 5). The
hydrogen-bond-guided addition of methanol and elimination of
ROH from IV8 would give a π-complex of the allenyl ether
V.10Finally, reductive elimination from the subsequent σ-
complex VI would afford the coupled product 3. The higher
yields of tertiary propargyl alcohol substrates, compared to those
of the secondary alcohols, suggest a rate-limiting dissociation of
the OR group, which is facilitated by forming labile alkoxydiazene
III. Also notable in this mechanism is the formation of the allenyl
methyl ether complex V rather than an allenol,8 which suppresses
undesired proto-deauration. Finally, the α-aryl enones could be
readily transformed into pharmaceutically interesting pyrazoles
and pyrazolines according to Scheme 5.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03531.
Full characterization data of all new products and
experimental procedures (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sshin@hanyang.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
In summary, we have reported herein a dual gold/photo-
catalyzed tandem Meyer−Schuster/cross-coupling of propargyl
alcohols into α-arylated enones under low catalyst loading of
The authors thank the National Research Foundation of Korea
(NRF- 2012M3A7B4049653 and NRF-2014-011165) for
generous financial support. We thank KBSI for HR-MS analysis.
C
DOI: 10.1021/acs.orglett.5b03531
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Letter
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DOI: 10.1021/acs.orglett.5b03531
Org. Lett. XXXX, XXX, XXX−XXX