Catalytic Alkyne Arylation Using Traceless Directing Groups

Article abstract of DOI:10.1002/anie.201804955

By using Pd⁰/Mandyphos, we achieved a three-component aminoarylation of alkynes to generate enamines, which are then hydrolyzed to either α-arylphenones or α,α-diarylketones. This Pd-catalyzed method overcomes established known pathways to enable the use of amines as traceless directing groups for C?C bond formation.

Full text of DOI:10.1002/anie.201804955

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Title: Catalytic Alkyne Arylation Using Traceless Directing Groups
Authors: Jung-Woo Park, Bubwoong Kang, and Vy Dong
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Catalytic Alkyne Arylation Using Traceless Directing Groups
Jung-Woo Park,*[a,b] Bubwoong Kang[a] and Vy M. Dong*[a]
Abstract: Using Pd(0)/Mandyphos, we achieve a three-component
aminoarylation of alkynes to generate enamines, which hydrolyze to
either α-arylphenones or α,α-diarylketones. This Pd-catalyzed
method overcomes established pathways to enable the use of amines
as traceless directing groups for C–C bond formation.
alkyne coupling (Figure 1C).13 Overcoming these established
pathways would result in the first alkyne aminoarylation to occur
by three-component coupling. Hydrolysis of the resulting
enamines furnish the α-arylphenone 4 and α,α-diarylketone 5, two
useful building blocks for natural products and pharmaceuticals.14
In nature, regiocontrol results from the selective binding of
substrates in an enzymatic pocket, while synthetic chemists
devise strategies that include tuning of reagents, catalysts, and
directing groups. Hydroamination is an attractive way to
functionalize alkynes, whereby both anti-Markovnikov and
Markovnikov selective variants have been demonstrated.1,2 In
these studies, regioselectivity for the aminopalladation step3
depends on the amine, where bulky amines add to the less
hindered position of a terminal alkyne (Scheme 1A).2a Inspired by
these findings, we hypothesized that amines could be used as
directing groups for C–C bond formation in the related, but less
explored, carboamination of alkynes.4-6 Herein, we report a three-
component carboamination of alkynes that upon hydrolysis
affords access to either α-arylphenone 4 or α,α-diarylketone 5,
depending on choice of the amine (Scheme 1B). This Pd-
catalyzed strategy occurs by a distinct mechanism and offers
complementary scope to emerging hydrative arylation of alkynes
and α-arylation of ketones.7,8 Moreover, we showcase the use of
amines as traceless directing groups for alkyne functionalization.9
Pioneering aminoarylation of alkynes include intramolecular
variants4a-c and annulative examples.4a,d,e To date, only one
intermolecular, two-component aminoarylation has been
demonstrated. In this case, enamines are generated from Michael
acceptors, such as alkyl- or aryl-propynoic esters.6 We imagined
developing a three-component coupling between an amine,
unactivated alkyne, and aryl-electrophile by Pd-catalysis
(Scheme 1B). As part of our design, we proposed that aryl-
electrophile 2 would undergo oxidative addition to Pd(0) to
generate a π-acidic complex, which would bind the alkyne. This
π-complex can undergo addition with an amine to form two
possible regioisomers.
We reasoned that choice of the amine could control
regioselectivity in the nucleopalladation step, whereby bulkier
amines favor addition to the less hindered position. However, a
number of transformations could compete,10 including Buchwald-
Hartwig amination,11 hydroarylation,12 hydroamination,1 and aryl-
Scheme 1. Three-component aminoarylation
To begin our studies, we chose 1-phenyl-1-propyne (1a), 3-
methoxyphenyl triflate (2a), and morpholine (3a) as model
substrates (Table 1). Treatment of 1a, 2a and 3a with Pd and a
variety of bisphosphine ligands gave no desired aminoarylation.15
For example, with a Pd/DPPF catalyst, aryl triflate 2a reacts with
alkyne 1a to form polyenes, with no amine incorporated. We
observed a breakthrough by using a P–N ligand; specifically, the
Fc-PHOX ligand provided aminoarylation in a 23% yield (4aa:5aa
= 3:1), but starting material 2a remained. We examined other
ligands that bear P–N and P–P moieties and found Knochel’s
Mandyphos16 L1 promising. In tuning the aryl-substituents, we
found that L3 gave the best results (85% yield, 4:1 rr). Polyene
mixtures from aryl triflate-alkyne coupling was prevented by use
of high concentration (c > 0.8 M with amine 3a). Weak bases
[a]
[b]
Dr. Jung-Woo Park, Dr. Bubwoong Kang, Prof. Dr. Vy M. Dong
Department of Chemistry
University of California, Irvine
4403 Natural Sciences 1, Irvine, California 92697, United States
E-mail: dongv@uci.edu
Dr. Jung-Woo Park
Center for Catalytic Hydrocarbon Functionalizations
Institute for Basic Science (IBS)
Daejeon 34141, Republic of Korea
E-mail: jwpark84@gmail.com
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201804955
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suppress the amination of aryl triflates, while use of lithium tert-
butoxide (t-BuOLi) base led to Buchwald-Hartwig product, N-
arylmorpholine.17, Thus, the choice of base and ligand were both
critical.
Table 2. Amine effects on regioselectivity[a]
Table 1. Ligand effects on alkyne aminoarylation.[a]
[a] 1 (0.08-0.1 mmol), 2 (1.25 equiv), 3 (1.7 equiv), and MS 4A (25 mg / 0.1
mmol) were applied to the reactions. [b] Determined by 1H NMR using
triphenylmethane as an internal standard.
As shown in Table 3, we used alkynes (1a-1h) and aryl
triflates (2a-2h) to prepare α-arylphenones 4 in 39-77% yields (4-
10:1 rr). Heteroaromatic groups could be incorporated (4f-4g).
Substitution was tolerated on the aryl triflate (2a-2h), including
electron donating and withdrawing groups. Using methyl 3-
phenyl-2-propyn-1-yl ether (1i) gave α-arylphenone 4m, where
the methoxymethyl group was cleaved in situ (48% 4m). Thus,
alkyne 1i can be used as a masked phenylacetylene.
In addition, we accessed
a
natural product, O-
desmethylangolensin (4o), an intestinal bacterial metabolite of
daidzein (soy phytoestrogen),14a,b and precursors of natural
neolignans 4q and 4r.14c the coupling of 1h with aryl triflate 2g and
morpholine (3a) gave ketone 4n after hydrolysis (70% 4n, 10:1 rr).
O-Desmethylangolensin (4o) was obtained by demethylation of
4n using BBr3.21 From alkyne 1e and triflate 2h, we prepared
ketone 4p, a precursor for natural neolignans.
[a] 1 (0.1 mmol), 2 (1.25 equiv), 3 (1.7 equiv), and MS 4A (25 mg / 0.1 mmol)
were applied to the reactions. Yields and regioisomeric ratio (rr) determined by
1H NMR using triphenylmethane as an internal standard. [b] Determined by GC-
FID and GC-MS. DIPEA=N,N’-diisopropylethylamine, MS=molecular sieves,
THF:
tetrahydrofuran,
OTf=trifluoromethanesulfonyl,
DPPF=1,1’-
diphenylphosphinoferrocene.
Next, we focused on achieving regiocontrol via the amine
(Table 2). We studied cyclic amines and found morpholine (3a)
optimal for high yields and selectivity for the α-arylphenone 4a
(4a:5a = 4:1, 68% 4a, entry 1).18 We examined acyclic secondary
amines and discovered that the steric bulk of the amine could
switch the regioselectivity to favor α,α-diarylacetone 5a. For
example, the use of N-methyl-α-methylbenzylamine (3b) resulted
in preference for 5a over 4a (2.1:1 rr). To improve regioselectivity,
we designed and prepared N-methyl-α-isopropylbenzylamine
(3e).19 Increasing the size of the α-substituent from a methyl group
to an isopropyl group resulted in an increase of 2.1:1 to greater
than 20:1 rr.20
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10.1002/anie.201804955
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Table 3. Preparation of α-arylphenone 4 using morpholine (3a)[a]
analogue of BRL-15572, an antidepressant from GlaxoSmithKline
(eq 1).23
Table 4. Preparation of α,α-diarylketone 5 using amine 3ea
[a] 1 (0.08-0.1 mmol), 2 (1.25 equiv), 3 (1.7 equiv), and MS 4A (25 mg / 0.1
mmol) were applied to the reactions. See SI for detailed reaction conditions.
Regioisomeric ratio (rr) determined by 1H NMR using an internal standard.
Isolated yields of major isomer 5a-l. [b] 0.25 mmol 1a was used.
[a] 1 (0.08-0.1 mmol), 2 (1.25 equiv), 3 (1.7 equiv), and MS 4A (25 mg / 0.1
mmol) were applied to the reactions. See SI for detailed reaction conditions.
Yields and regioisomeric ratio (rr) determined by 1H NMR using
triphenylmethane as an internal standard. 1H NMR yield of the major isomer 4
are in parenthesis. [b] 0.25 mmol 1a was used. [c] 0.5 mmol 1a was used. [d]
Methyl 3-phenyl-2-propyn-1-yl ether (1i) was used. [e] Reaction condition: BBr3
(10 equiv), DCM, rt, 12 h. MeDO: methylenedioxy, TIPS: triisopropylsilyl.
On the basis of our observations and literature,3,4c we propose
the mechanism shown in Scheme 2. The Pd(0)-complex activates
the aryl triflate 2 to form arylpalladium(II)-intermediate 6.
Nucleopalladation with amine
vinylpalladium(II)-intermediate
3
7.
then occurs to afford
Regioselectivity for
nucleopalladation depends on the sterics of the amine 3a versus
3e. Amines bearing small substituents (e.g., 3a) favor attack of
the carbon adjacent to aryl group, while amines bearing large
substituents (e.g., 3e) favor the carbon distal. Reductive
elimination of vinylpalladium 7 generates enamine 8 and
regenerates Pd(0).
With amine 3e, we apply analogous conditions to make α,α-
diarylacetones
5 (Table 4). Three-component coupling of
arylalkynes (1a, 1b, 1j–1p) with substituted aryl triflates (2a–2f)
yielded α,α-diarylacetones 5 in 48–79% isolated yields for the
major isomer. From ketone 5a, which was prepared by three-
component aminoarylation with amine 3e, we prepared a MeO-
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10.1002/anie.201804955
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fusion of a new ring via two new bonds. For reviews on intramolecular
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Scheme 2. Proposed mechanism
Future studies involve (1) designing chiral amines for
stereoselective applications23 and (2) elucidating the mechanism
to guide other alkyne functionalizations.
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Acknowledgements
Funding by the National Science Foundation (CHE-1465263), the
National Institutes of Health (1R35GM127071), and the Institute
for Basic Science (IBS-R10-Y1). B.K. thanks the Uehara
Memorial Foundation for a postdoctoral fellowship.
Keywords: alkynes • aminoarylation • multi-component coupling
• palladium • regiocontrol
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Entry for the Table of Contents
COMMUNICATION
By developing a Pd(0)/Mandyphos
catalyst, we have achieved a three-
component aminoarylation of alkynes
to generate enamines, which upon
hydrolysis yield either α-arylphenones
or α,α-diarylketones. This Pd-
Dr. Jung-Woo Park,* Dr. Bubwoong
Kang, Prof. Dr. Vy M. Dong*
Page No. – Page No.
Title
catalyzed method overcomes well-
established pathways to enable the
use of amines as traceless directing
groups for C–C bond formation.
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