Gold(I)-Catalyzed Hydroxy Group Assisted C(sp2)-H Alkylation of Enaminones with Diazo Compounds to Access 3-Alkyl Chromones

Article abstract of DOI:10.1021/acs.orglett.8b03989

A strategy for expedient synthesis of 3-substituted chromones from easily available o-hydroxyarylenaminones and diazo compounds has been developed. Carefully conducted experimental and computational studies led us to propose an uncommon mechanistic pathway involving the hydroxyl group assisted alkylation of enaminones with in situ generated gold carbenes.

Full text of DOI:10.1021/acs.orglett.8b03989

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold(I)-Catalyzed Hydroxy Group Assisted C(sp2)−H Alkylation of
Enaminones with Diazo Compounds To Access 3‑Alkyl Chromones
Pradip N. Bagle,†,‡ Manoj V. Mane,§,# Shashank P. Sancheti,⊥ Amol B. Gade,†,‡ Samir R. Shaikh,‡,∥
Mu-Hyun Baik,*,§,# and Nitin T. Patil*,⊥
†Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune - 411 008, India
‡Academy of Scientific and Innovative Research, New Delhi - 110 025, India
§Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon - 34141, Republic of Korea
#Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science, Daejeon - 34141, Republic of Korea
∥Center for Materials Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune - 411 008, India
⊥Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhauri, Bhopal - 462 066, India
S
* Supporting Information
ABSTRACT: A strategy for expedient synthesis of 3-substituted chromones from easily available o-hydroxyarylenaminones and
diazo compounds has been developed. Carefully conducted experimental and computational studies led us to propose an
uncommon mechanistic pathway involving the hydroxyl group assisted alkylation of enaminones with in situ generated gold
carbenes.
Scheme 1. Reaction of Enaminones with Diazo
Compounds: Known and Present Work
ransition metal catalyzed carbene transfer reactions that
Temploy diazo reagents are powerful tools in organic
synthesis. Catalysts based on rhodium1 and copper2 have been
particularly effective, but gold has emerged as an interesting
alternative, recently.3 The reactivity observed with gold
catalysts is unique, and selectivities were observed that were
not possible with other metals. Moreover, these reactions are
convenient because they can be conducted without syringe
pumps, which are generally recommended in conventional
carbene transfer chemistry. The very first example of a gold-
catalyzed carbene transfer reaction of ethyl diazoacetate was
reported by Nolan.4 Since then, several remarkable efforts have
been made including N−H/O−H insertions,4,5 C−H
functionalizations,6 cyclopropanations,7 cyclopropenations,8
cycloadditions,9 cross-couplings,10 rearrangements,11 and
others.12
Enaminones have recently been recognized as versatile and
valuable intermediates because of the ambident nucleophilic
and electrophilic characters of the enamine and enone
moieties, respectively, which was utilized by many researchers
for accessing biologically important heterocycles.13 As far as
the reactions of enaminones with diazoketones are concerned,
Kascheres and co-workers were the first to utilize the carbene
transfer strategy for accessing N-substituted pyrroles by
reagents to obtain multiply substituted furans (Scheme 1b).16
Herein, we report the reaction of o-hydroxyarylenaminones
with diazo compounds using a gold catalyst to obtain
functionalized chromones17the structural motif found in
reacting the enaminones with diazoketones (Scheme 1a).14
A
similar strategy was disclosed by Reddy and co-workers to
obtain pyrroles (Scheme 1a).15 In 2012, Park demonstrated
the carbene mediated cycloaddition of enaminones with diazo
Received: December 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03989
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Letter
numerous natural products18 and pharmaceutically important
targets19 (Scheme 1c). The mechanism of the reaction was
established by carefully conducted experimental and computa-
tional studies. We propose that the reaction is triggered by a
hydroxyl assisted C(sp2)−H alkylation of enaminones. To
date, there are only selected examples of a reaction where an
acyclic enamine/enaminone engages a gold carbene, which was
generated in situ from α-diazo compounds in the presence of a
gold catalyst.6h,12a
At the outset, we utilized (E)-3-(dimethylamino)-1-(2-
hydroxyphenyl)-prop-2-en-1-one (1a) and methyl phenyl-
diazoacetate (2a) as model substrates to test our hypothesis.
First, the utilization of Ph3PAuNTf2 (5 mol %) furnished
methyl 2-(4-oxo-4H-chromen-3-yl)-2-phenylacetate (3a) in
14% yield with formation of undesired 4H-chromen-4-one
(4) in 30% yield at 25 °C in dichloromethane (Table 1, entry
and 9). However, the use of AgOTf furnished 3a in 76% yield
(entry 10) with the complete exclusion of undesired 4.
Switching the solvent to DCE, tetrahydrofuran, toluene, and
acetonitrile did not produce any remarkable change to the
reaction outcome.20 The use of AgOTf alone gave the
undesired 4 in 32% yield, and the dimerization of 2a was the
major product (entry 11). The catalytic efficiency of other
catalysts, which are conventionally known for carbene transfer
reactions, was thoroughly investigated.21 For instance, when
Cu(CH3CN)4BF4 was used as a catalyst, 3a was obtained only
in 36% yield (entry 12). On the other hand, the use of
Rh2(OAc)4 did not give 3a; instead, the decomposition of 2a
was noticed (entry 13). Further, lowering of the catalyst
loading to 3 mol % had a detrimental effect on the yield of the
reaction (entry 14). In the absence of XPhosAuCl/AgOTf, no
product was obtained indicating its importance (entry 15).
With an effective catalyst system identified, the substrate
scope was explored (Scheme 2). For instance, substrates
a
Table 1. Optimization Studies
a
Scheme 2. Substrate Scope with o-Hydroxyarylenaminones
b
yield (%)
entry no.
cat M 5 mol %
AgX 5 mol % t (°C)
3a
4
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph3PAuCl
IPrAuCl
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgSbF6
AgBF4
AgOTf
AgOTf
−
25
25
25
25
25
25
60
60
60
60
60
30
30
60
60
14
16
−
30
25
22
29
28
11
15
13
12
−
32
29
−
−
−
JohnPhosAuCl
CyJohnPhosAuCl
BrettPhosAuCl
XPhosAuCl
XPhosAuCl
XPhosAuCl
XPhosAuCl
XPhosAuCl
−
Cu(CH3CN)4BF4
Rh2(OAc)4
XPhosAuCl
−
−
26
43
62
51
45
76
c
−
d
e
36
d
e
−
AgOTf
−
−
f
14
15
59
g
−
a
Reaction conditions: 0.15 mmol of 1a, 0.23 mmol of 2a, catalyst
(entries 1−10, 5 mol % Au(I) catalyst, 5 mol % Ag(I) catalyst; entries
11−13, 5 mol % respective metal catalyst), DCM (1 mL), 36 h
a
Reaction conditions: 0.15 mmol of 1, 0.23 mmol of 2a, 5 mol %
b
(reaction was performed in a sealed tube). Isolated yields (based on
XPhosAuCl, 5 mol % AgOTf, DCM (1 mL), 60 °C, 36−40 h.
c
b
1a). Dimerized product of 2a was observed in 56% (based on 2a).
Reaction was completed within 12 h.
d
Controlled addition of 2a (0.23 mmol) in dry DCM (0.5 mL) was
e
performed via syringe pump over 1 h. Decomposition of 2a was
observed within 6−8 h. 3 mol % XPhosAuCl and 3 mol % AgOTf
were used. Starting materials 1a and 2a recovered quantitatively.
f
bearing alkyl and aryl substituents such as −Me and −Ph gave
access to 3-alkyl chromones 3b and 3c in 76% and 73% yields,
respectively. Various halo substituents on the phenyl ring did
not affect the yield of the reaction (3d−3f), enabling the
possibility for introduction of versatile functional groups via
metal catalyzed cross-coupling reactions. The X-ray crystallog-
raphy data for 3d (5i, vide infra) have been obtained which
unequivocally confirmed the structure.20 It was found that
substrates with electron-withdrawing substituents (acyl, −CN,
−NO2) at the para-position of the −OH group gave lower
yields (3h−3j); whereas, substrates bearing an electron-
donating substituent (−OMe) at the para-position of −OH
group afforded a higher yield (3g, 80%). However, the o-
hydroxyarylenaminones possessing alkyl (−Me), electron
donating (−OMe) and halo (−F, −Br, −I) substituents at
the para-position of the keto group gave 3k−3o in 64−73%
g
1). Next, a variety of gold catalysts were examined (entries 2−
6). Gratifyingly, XPhosAuNTf2 was found to be the best
catalyst giving 3a in 43% yield along with undesired 4 in 11%
yield (entry 6). The yield of desired product 3a was enhanced
remarkably when the reaction was carried out at 60 °C, giving
3a in 62% yield (entry 7). Next, various silver salts were
screened in combination with XPhosAuCl. The use of AgSbF6
and AgBF4 did not improve the yield of the reaction (entries 8
B
DOI: 10.1021/acs.orglett.8b03989
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Organic Letters
Letter
yields. Even the disubstituted o-hydroxyarylenaminones gave
the corresponding 3-alkyl chromones in good yields (3p, 89%;
3q, 67%). The reaction of the o-hydroxyarylenaminones
equipped with an alkyne substituent gave 3-alkyl chromone
3r without formation of any side product via cyclopropena-
tion.7 A fused analogue of chromone (3s) was also obtained in
83% yield, when respective o-hydroxyarylenaminones were
subjected to the standard reaction conditions. The benzofuran
appended substrate produced 3t in 71% yield. Notably, a
potential side product as a result of C3-functionalization of
benzofuran was not observed.11a
Scheme 4. Mechanistic Studies
Next, the scope and limitation of diazo compounds (2) were
examined (Scheme 3). As expected, reactions of diazo ester
reacted with 2a (eq 1). These experiments suggest that the C-
alkylation of enaminones is assisted by the hydroxyl group on
the aryl moiety. It is also possible that 4 is generated first and
undergoes alkylation with 2a in the presence of the gold
catalyst. However, substrate 4 failed to provide 3a under the
established reaction conditions (eq 2, left side) which renders
this possibility unlikely. Alternatively, the reaction might
involve the o-alkylation in 1a via gold-catalyzed carbene
transfer to produce intermediate 10 which may spontaneously
undergo a 1,3 alkyl shift22 followed by loss of N,N-
dimethylamine to form 3a. To test for this mechanistic
pathway, substrate 10 was prepared by NaH mediated reaction
of 1a with methyl 2-bromo-2-phenylacetate in THF.20
However, failure of 10 to produce 3a under the optimized
reaction conditions clearly ruled out this possibility (eq 2, right
side).
a
Scheme 3. Substrate Scope with Diazo Compounds
To conceptualize these observations into a complete
catalytic cycle, quantum chemical calculations based on density
functional theory (DFT) were carried out (Figure 1). The
reaction leading to the formation of the key intermediate 11 is
explained in the Supporting Information (see Figure S1). As
shown in Figure 1, 11 can readily engage in a nucleophilic
attack at the gold carbene23 moiety to afford 12, in a step that
is very viable with an associated barrier of only 3.8 kcal/mol.
To push the reaction forward, a proton transfer from the
hydroxyl group to the carbene moiety is required. This is
accomplished in a stepwise fashion, where the gold complex
migrates first to bind to the carbonyl oxygen of the ester
functionality, forming intermediate 13. Now the carbon site is
available for proton transfer, while the freshly formed
phenoxide moiety will engage the metal fragment to give the
stable intermediate 14, traversing the 13-TS with a barrier of
14.5 kcal/mol. Then, the proton migration from the C(sp3)−H
to the oxygen of the O−AuLn fragment generates 15, which is
5.1 kcal/mol higher in energy than 14. The transition state 14-
TS connecting these two intermediates gives rise to a barrier of
9.9 kcal/mol. In order to initiate the final cyclization reaction,
another proton transfer to the amine functionality takes place
to form 16, which is finally ready to undergo intramolecular
cyclization to give the final product 3a via spontaneous loss of
N,N-dimethylamine with regeneration of the gold catalyst
(LnAu+). The overall free energy barrier for this ring formation
step is computed to be 30.2 kcal/mol. This mechanism
incorporated the experimental observations; most notably, it
clarifies the importance of the hydroxyl group during the
C(sp2)−H alkylation of enaminones.
a
Reaction conditions: 0.15 mmol of 1a, 0.23 mmol of 2, 5 mol %
XPhosAuCl, 5 mol % AgOTf, DCM (1 mL), 60 °C, 36−40 h.
b
c
Reaction completed within 8 h. The starting material 1a was
recovered quantitatively.
comprising ethyl, tert-butyl, and benzyl groups instead of the
methyl group maintained the same reaction profile giving 5a−
5c in good yields (61%−75%). A diazo compound bearing an
alkyl substituent such as −Me on the aromatic group reacted
smoothly to give 5d in 82% yield. Moreover, halide
substituents had no significant effect on the outcome of the
reaction giving 5e−5i in yields ranging from 51% to 62%. The
reaction of the diazo ester bearing a bulkier naphth-1-yl group
probably succumbed to its steric effects giving a lower yield of
the desired 3-alkyl chromone 5j (40%). In addition to α-diazo
esters, other diazo compounds including diazo-oxindole,
dimethyl-2-diazomalonate, and α-diazo ketone were also
examined. Among them, diazo-oxindole provided 5k in 74%
yield; whereas, α-diazo ketones (cf. 5l), alkyl diazo ester (cf.
5m), and dimethyl-2-diazomalonate (cf. 5n) failed to react.
Surprisingly, 3-substituted aryldiazoacetates were found to be
inert under the present reaction conditions (cf. 5o and 5p).
To better understand the mechanism, a few control
experiments were conducted (Scheme 4). When the reaction
of phenylenaminone (6) with 2a was performed under the
standard reaction conditions, the expected product 7 was not
obtained at all (eq 1). Similarly, the anticipated product 9 was
not obtained when the benzyl protected substrate 8 was
To demonstrate the synthetic potential of the reaction, the
intramolecular Heck reaction24 of 5i under Pd(OAc)2/
JohnPhos catalysis was conducted (Scheme 5). Pleasingly,
the biologically important rigid flavone 17 was obtained in 66%
yield.25
C
DOI: 10.1021/acs.orglett.8b03989
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Figure 1. Free energy profile for the formation of 3a.
Scheme 5. Product Modification
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the IISER Bhopal is gratefully
acknowledged. P.N.B. and A.B.G. thank CSIR for the award of
the Senior Research Fellowship. S.P.S. thanks IISER Bhopal for
Research Fellowship. This research was supported in part by
the Institute for Basic Science (IBS-R010-A1) in the Republic
of Korea.
In summary, gold-catalyzed reactions of o-hydroxyaryl-
enaminones with diazo compounds have been explored. The
combined experimental and computational mechanistic studies
led us to propose a mechanistic pathway involving the hydroxyl
group assisted C(sp2)−H alkylation of enaminones with diazo
compounds. The idea of directing group assisted carbene
transfer reactions in gold catalysis should be applicable to a
vast number of substrates leading to a number of new
reactivities.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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Corresponding Authors
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E
DOI: 10.1021/acs.orglett.8b03989
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