A gold(i)-catalysed chemoselective three-component reaction between phenols, α-diazocarbonyl compounds and allenamides

Article abstract of DOI:10.1039/c9cc09470a

Gold(i) catalysts are considered to be efficient in promoting sp² C-H bond insertion at the para position of unprotected phenols because of the exceptionally chemical reactivity of gold-stabilized carbophilic carbocations. Herein, we present a

Full text of DOI:10.1039/c9cc09470a

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A gold(I)-catalysed chemoselective three-component reaction of
phenols, α-diazocarbonyl compounds and allenamides
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Sifan Yu, Jinzhou Chen, Gengxin Liu, Jinping Lei, Wenhao Hu* and Huang Qiu*
Gold(I) catalysts are considered to be efficient in promoting sp2 C-H Zhou8e and Fu’s groups.9 Very recently, highly selective C(sp2)−H
bond insertion at para position of unprotected phenols because of bond functionalization of unprotected phenols with α-aryl-α-
the exceptionally chemical reactivity of gold-stabilized carbophilic diazoesters at specific position have been extensively
carbocations. Herein, we present
a
gold(I)-catalysed three- explored,10 and gold catalysts are efficient in promoting
component reaction of phenols, diazo carbonyl compounds and C(sp2)−H bond insertion at para position of unprotected phenols
allenamides, affording the corresponding three-component because of the exceptional chemical reactivity of gold-stabilized
reaction products with excellent geometric selectivity (E:Z > 20:1) carbophilic carbocations.11 Herein, we present
a
gold(I)-
in moderate to high yields (up to 90%) under mild condition. catalyzed O-H selectivity of unprotected phenols and α-
Additionally, gram-scale transformation and diverse diazocarbonyl compounds in the presence of an electrophile
transformations of the resulting product show the high synthetic (Scheme 1b).
a
utility of present three-component protocol.
Our research group and others have previously reported a
series of novel multicomponent reactions (MCRs) via trapping
of reactive intermediates with diverse electrophiles. These
novel MCRs have not only provided efficient synthetic methods
for the construction of highly polyfunctional organic molecules,
but also shed light on the mechanism of their corresponding
parent X−H (X = C(sp2), N, O, S) insertion reactions.12-14 The rapid
development and wide application of these reactive
intermediates, especially protic oxonium ylides and zwitterionic
intermediates in novel MCRs, have prompted us to consider the
chemoselectivity of unprotected phenols with α-aryl-α-
diazoesters when electrophiles are added. And following
explorations on this topic have resulted in the discovery of a
gold(I)-catalysed chemoselective three-component reaction of
phenols, α-aryl-α-diazoesters and an allenamide.15-17
We initiated our studies with the investigation of the Rh-,
Pd-, Cu-, B-, Au-catalyzed three-component reactions of 4-
bromo-phenol 1a and methyl α-phenyl α-diazoacetate 2a with
various electrophiles including imines, aldehydes, isatins,
chalcones, α, β-unsaturated γ-keto esters and allenamides.
Fortunately, reaction of 4-bromophenol 1a and methyl α-
phenyl α-diazoacetate 2a with allenamide 3a in the presence of
5.0 mol% commercially available JohnPhosAu(MeCN)SbF6 at 25
Due to the importance of phenol motifs in natural products
and drug scaffolds,1 transformations of commercially available
and easily obtained simple phenols into their structurally
complex derivatives have attracted considerable attention of
organic synthetic chemists as well as medicinal chemists.2-3
Particularly, phenol derivatives that contain a quaternary
carbon at oxygen position have shown unique biological
activities and receptor binding characteristics to diverse human
cancers as well as neurologic diseases (Scheme 1a).4-6 Thus,
developing highly efficient synthetic methods toward these
compounds is highly in demand. Transition metal-catalyzed
carbene migratory insertion reaction of α-diazocarbonyl
compounds into phenolic O-H bonds is among the most
versatile, efficient and rapid transformations for synthesis of α-
aryloxy carbonyl compounds.7 An array of typical transition
metals (e.g., Rh, Pd, Cu, Fe, Ru) have been proved to be highly
selective to the O-H bond insertion,8 and pioneer works on the
asymmetric vision of O-H bond insertion have been achieved by
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. E-
mail: huwh9@mail.sysu.edu.cn; qiuhuang@mail.sysu.edu.cn
℃
in 1,2-dichloroethane (DCE) afforded three-component
coupling product 4a in 36% yield during the course of our
explorations of those MCRs (Table 1, entry 1). Other (C6F5)3B,
Cu(I), Cu(II), Pd(II) and Rh(II) catalysts failed to give 4a (Table 1,
entries 2-8). We further explored the ancillary ligands and
† Electronic Supplementary Information (ESI) available: Copies of NMR spectra for
all products related to this article; and X-ray single crystal structure analysis data for
4i. CCDC 1887654. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/x0xx00000x
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Table 1 Optimization of the reactiona
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DOI: 10.1039/C9CC09470A
Yieldb/% of
Entrya
Catalyst/mol%
Solv.
T./oC
4a/12/13a/14a/15/16
1
2
L1Au(MeCN)SbF6(5.0)
(C6F5)3B(10.0)c
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
PhMe
CHCl3
THFh
DCM
DCM
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0h
36/ <5/ 17/ 7/ 14/ 15
<5/ <5/ <5/ 70/ 12/ <5
<5/ <5/ <5/ <5/ <5/ <5
<5/ <5/ 15/ <5/ 40/ <5
<5/ <5/ 73/ <5/ 9/ <5
<5/ <5/ 34/ <5/ 25/ <5
<5/ <5/ 48/ <5/ 20/ <5
<5/ <5/ 35/ <5/ 25/ <5
<5/ 23/ 21/ 16/ 15/ <5
<5/ 35/ 30/ 18/ 9/ 18
33/ <5/ 16/ <5/ 15/ 13
30/ <5/ 15/ <5/ 16/ 11
<5/ 61/ <5/ <5/ 10/ 15
<5/ 54/ <5/ <5/ 15/ 10
<5/ 54/ <5/ <5/ 15/ 10
<5/ 30/ <5/ 10/ 29/ 22
69(67)g/ <5/ 13/ <5/ 10/ 15
18/ <5/ 14/ <5/ 9/ 16
50/ <5/ 19/ 8/ 5/ <5
3
CuI(5.0)d
4
Cu(MeCN)4PF6(5.0)c
Cu(MeCN)4BF4(5.0)c
CuOTf(5.0)c
5
Scheme 1 Phenol derivatives and transformations with various
catalysts.
6
7
[PdCl(allyl)]2(5.0)e
Rh2(OAc)4(2.0)e
8
9
PPh3AuNTf2(5.0)f
PPh3AuSbF6(5.0)f
L1AuNTf2(5.0)f
counter anions of the gold catalysts for the three-component
reaction (Table 1, entries 10-16). Disappointingly, no enhanced
yield of 4a was obtained. Interestingly, we observed that gold
catalysts with different ancillary ligands and counter anions
heavily influenced the selectivity of selected reaction, which is
in agreement with current reports.10c We then explored
different solvents for the three-component reaction (Table 1,
entries 17-20). Dichloromethane (DCM) was proved to be the
best solvent so far, giving 4a in 69% yield; chloroform (CHCl3)
and toluene were capable for this transformation, albeit in
lower yield of the product 4a; whereas tetrahydrofuran (THF)
10
11
12
13
14
15
16
17
18
19
20
21
22
L1AuSbF6(5.0)f
L2AuNTf2(5.0)f
L2AuSbF6(5.0)f
IPrAuNTf2(5.0)f
IPrAuSbF6(5.0)f
L1Au(MeCN)SbF6 (5.0)
L1Au(MeCN)SbF6 (5.0)
L1Au(MeCN)SbF6(5.0)
L1Au (MeCN)SbF6(5.0)
L1Au(MeCN)SbF6(5.0)
L1Au(MeCN)SbF6(5.0)
<5/ <5/ <5/ <5/ 40/ <5
50/ <5/ 23/ <5/ 5/ 15
42/ <5/ 27/ 7/ 6/ 13
40
aStandard conditions: 1a/2a/3a = 0.40/0.48/0.48 mmol, 2a and 3a in
2.0 mL solvent were introduced by syringe pump to a solution of 1a,
catalyst in 4.0 mL solvent at 25oC under N2 atmosphere for 1.0 h, and
the resulting mixture was stirred for another 2.0 h. L1 = JohnPhos, L2
was incompatible with this reaction. Disappointingly,
a
decrease or increase in temperature failed to improve the yield
of this transformation (Table 1, entries 21&22).
=
(2,4-ditBu2C6H3O)3P. bDetermined by 1H NMR spectroscopy
With the optimized reaction conditions in hand, we then
sought to examine the substrate scope of the present
transformation, which was summarized in Table 2. To our
delight, simple phenol 1b was well tolerated in current reaction
system and gave 4b in 66% yield (the para C-H insertion product
14 was also obtained in 12% isolated yield). A range of
structurally diverse phenols that contain alkyl-, alkoxy-, aryl-,
hydroxyl, ester groups as well as halides at para and / or meta
position were proven to be compatible with this reaction,
affording the corresponding three-component products in
moderate to good yields. Particularly, we were also pleased to
find that hydroquinone can be tolerated, furnishing the mono-
substituted product 4f, albeit in 35% yield; Additionally, the
structure of 4i was confirmed by X-ray crystal diffraction
analysis (CDCC 1887654). Gratifyingly, estrone was also worked
well and successfully afforded 4r in 62% yield. When sterically
hindered ortho-bromophenol was employed, corresponding
three-component product 4s was obtained in synthetically
interesting yield (39%). Various α-aryl-α-diazoesters were then
analyses using 1, 3, 5-trimethoxybenzene as an internal standard.
cThe resulting mixture was stirred for another 5.0 h. Most of 3a are
unconverted. dThe resulting mixture was stirred for another 5.0 h. All
components are unconverted. eThe resulting mixture was stirred for
another 1.0 h. Most of 1a and 3a are unconverted. f0.02 mmol LnAuCl
was added in dry DCE (1.0 mL), and then AgX (X = SbF6, NTf2) (1.0
equiv) was added. After the mixture was stirred under N2
atmosphere at 25 oC for 20 min, the precipitation of AgCl was
removed by filtration through needle filter. The filtrate was directly
g
used without further purification. Isolated yield. hReaction time is
6.0 h.
To demonstrate the synthetic utility of present protocol
(Scheme 2), we have performed a gram-scale three-component
reaction of 4-phenylphenol 1g, methyl
α-phenyl-α-diazoester
2a, and allenamide 3a in the presence of reduced catalyst
loading (4.0 mol % JohnPhosAu(MeCN)SbF6) at 25 ℃ in DCM
for2.0 h, affording 4g in satisfactory yield (1.11 g, 84% yield).
When treated with H2 in the presence of Pd/C, 4g could easily
be reduced to the corresponding product
enabled an efficient access to alcohol product
respectively. Furthermore, treatment of 4g with LiOH solution
and subsequent 6.0 N HCl solution afforded that contains a
formyl and carboxyl group in 80% yield. Treatment of 4g with
6N HCl afforded enamine hydrolysis product in 88% yield,
5
in 78% yield; LiBH4
6
in 85% yield,
screened, furnishing their respective products 4t
– 4y with
excellent geometric selectivity (E: Z > 20:1) in satisfying yields
(64 – 75% yield). α- Aryl-α-diazo ketones reacted with 1a and 3a
smoothly to afford the corresponding 4z, 4A in satisfying yields.
Notably, N-tosyl- derived allenes 3b and 3c were also suitable
substrates, furnishing 4B and 4C in 36% and 43% yields,
respectively.
7
8
while in the presence of methanol, 4g underwent a subsequent
enamine hydrolysis / acetalisation process and afforded acetal
2 | Chem. Commun., 20xx, 00, 1-3 | 2
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Table 2 Substrate scopea
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DOI: 10.1039/C9CC09470A
Scheme 3 Control experiments and proposed mechanism.
cyclopropane 12 ring-opening transformations with phenol 1b
by a stepwise process. With these control experiments in hand,
we proposed a plausible mechanism for this three-component
reaction, which was shown in Scheme 3b. The reaction
proceeded through Au(I)-associated protic oxonium ylide
11 in 69% yield. Moreover, product 8 could be readily converted
into corresponding amine
9 in 65% yield though reductive
intermediate II, which was generated from gold carbene
phenols . Dissociation of the gold catalyst from II afforded enol
intermediate III. Subsequently, III reacted with electrophilic
gold-associated iminium salt IV 17
affording key intermediate
which further underwent protodeauration to give observed
three-component product
I and
amination. Remarkably, ozonolysis of 4g and subsequent
reductive work-up successfully furnished 10 in 90% yield.
To gain more mechanistic insights of present three-
component reactions, further control experiments were
performed (Scheme 3a). Firstly, treatment of either O-H
1
,
V,
4
.
insertion product or C-H insertion product of with allenamide
3
In order to further understand the chemoselectivity and
validate the proposed mechanism of this three-component
reaction, we performed DFT calculations for the O-H and C-H
reactions, which was shown in Fig. 1. These results indicated
that the three-component reaction dominantly proceeded with
the O-H insertion pathway, because the free energy barrier for
the O-H insertion (6.06 kcal/mol) was significantly much lower
than the C-H insertion (22.14 kcal/mol). And the C-H insertion
in three-component reaction was unfavored because of the
high energy barrier. While for the two-component reactions,
both the O-H and C-H insertions were possible, and the O-H
insertion is only slightly more favored than the C-H insertion.
These calculation results agreed well with the controlled
experimental observations, in which the yields of the Pro-
under optimized reaction conditions failed to afford detectable
three component reaction product 4b. The cyclopropane 12
was also a possible intermediate, which might undergo a ring-
opening process with phenol to furnish the observed product.
To clarify this issue, we successfully prepared both trans- and
cis-cyclopropane 12 by treating allenamide
phenyldiazoacetate 2a in the presence of 5.0 mol
JohnPhosAu(MeCN)SbF6. However, upon addition of phenol 1b
3 with methyl
%
,
three-component product 4b was not observed under standard
reaction conditions by LC-MS or 1HNMR. These control
reactions excluded the possibility that the multicomponent
reaction products were formed from the addition of the O-H
insertion product 13 or C-H insertion product 14 to
3 or the
O
:
Pro-C (O-H:C-H product) increased from 51%:34% in two-
component to about 66%:0% in three-component reactions.
In summary, we have disclosed gold-catalyzed
chemoselective three-component reaction of phenols,
a
α
-
diazocarbonyl compounds and allenamides under mild reaction
conditions. The present transformation can be very easily scaled
up and shows high functional group tolerance. Furthermore, in
the presence of easily obtained simple reagents, corresponding
three-component product can be readily transformed into
diverse products that contain versatile functional groups (e.g.
hydroxyl, formyl, carboxyl, acetal) in satisfying yields. Work
Scheme 2 Gram-scale reaction and synthetic applications of 4g
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transition state, pro-O: product of the O-H process, pro-C: product of
C-H process. The transition state structures are shown in Fig. S4.
Phenol derivatives and transformations with various catalysts.
9
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We acknowledge the financial support from Guangdong
Innovative and Entrepreneurial Research Team Program (No.
2016ZT06Y337). National Natural Science Foundation of China
(21801255 & 21901262), and Natural Science Foundation of
Guangdong Province (2018A030310141).
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Conflicts of interest
There are no conflicts to declare.
Liu, S. –F. Yu, W. –H. Hu, H. Qiu, Chem. Commun., 2019, 55
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DOI: 10.1039/C9CC09470A
N2
Au
Ar2
N
High O-H selectivity & excellent E selectivity
Ar2O
H
O
+
+
N
Ar1
COR
Exceptionally mild reaction conditions
Broad substrate scope & high yield
ROC
Ar1
R = OMe, Me
N2
Ar1 COR
Ar2
Ar1
R
N
O
Au(I)
[Au]
Ar2
N
Diverse
transformations
N2
OH
O
ROC
Ar1
[Au]
Ar1 COR
R =
OMe, Me
Gold(I)
catalytic
cycle
Ar1
R
Gold (I)
catalytic
cycle
O
Ar2
1
Au(I)
OH
N
[Au]
Ar2OH
N
Single catalyst
Double roles
Ar2
[Au]
[Au]
Ar1
O
- [Au]
+ [Au] Ar1
MeO2C
OH
N
O
H
Ar2
R
IIb
IIa