Gold-Catalyzed [4 + 1]-Annulation Reactions between 1,4-Diyn-3-ols and Isoxazoles to Construct a Pyrrole Core

Article abstract of DOI:10.1021/acs.orglett.8b01398

This work reports gold-catalyzed [4 + 1]-annulation reactions between 1,4-diyn-3-ols and isoxazoles or benzisoxazoles to yield pyrrole derivatives. The reaction chemoselectivity is controlled by an initial attack of an isoxazole at a less hindered alkyne to form gold carbenes, further inducing a 1,2-migration of a second alkyne group. A broad substrate scope of 1,4-diyn-3-ols, isoxazoles and even benzisoxazoles highlighted the reaction utility.

Full text of DOI:10.1021/acs.orglett.8b01398

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-Catalyzed [4 + 1]-Annulation Reactions between 1,4-Diyn-3-ols
and Isoxazoles To Construct a Pyrrole Core
Rahul Dadabhau Kardile,† Balaji S. Kale,† Pankaj Sharma, and Rai-Shung Liu*
Frontier Research Center of Matter Science and Technology, Department of Chemistry, National Tsing-Hua University, Hsinchu
30013, Taiwan
S
* Supporting Information
ABSTRACT: This work reports gold-catalyzed [4 + 1]-
annulation reactions between 1,4-diyn-3-ols and isoxazoles or
benzisoxazoles to yield pyrrole derivatives. The reaction
chemoselectivity is controlled by an initial attack of an
isoxazole at a less hindered alkyne to form gold carbenes,
further inducing a 1,2-migration of a second alkyne group. A
broad substrate scope of 1,4-diyn-3-ols, isoxazoles and even
benzisoxazoles highlighted the reaction utility.
etal-catalyzed N,O-functionalizations of unsaturated
hydrocarbons are an important topic in organic
in a cleavage of the triple bond.7 Apart from reactive propiolate
and ynamide derivatives, we are aware of no unactivated
alkynes to participate in these annulations. We report herein
novel gold-catalyzed [4 + 1]-annulations between 1,4-diyn-3-
ols8 and isoxazoles, affording pyrrole products involving an
alkyne cleavage and a 1,2-alkyne migration. This 1,2-alkyne
migration preferably proceeds with an bulky substituted alkyne
as the migration group and a small alkyl- or terminal alkyne as
the N,O-functionalizing site. Such a chemoselectivity is
different from those reported in our previous work.8b Resulting
2,5-disubstituted pyrroles have Z-configured enones preferably,
whereas 2-substituted pyrroles comprise E-configured enones
instead.
M
synthesis.1−3 Catalytic [3 + 2]-cycloadditions of nitrones/
alkenes2 and [4 + 2]-cycloadditions of nitroso/dienes3
represent two prominent reactions with long-standing interest
because of their easy access to useful 1,3- and 1,4-amino
alcohols. In the context of alkynes, isoxazoles emerge as
powerful 1,4-N,O-functionalization reagents using gold cata-
lysts.4,5 Ye4 and Hashmi5 reported gold-catalyzed [3 + 2]-
annulations of ynamides with isoxazoles or benzisoxazoles to
form pyrrole derivatives (eq 1). Such catalytic [3 + 2]-
Table 1 shows the optimization of the reaction of 1,4-diyn-3-
ol 1a with isoxazole 2a (2 equiv) using commonly used
catalysts; the two alkynes of species 1a bear a phenyl and
cyclopropyl to examine the reaction chemoselectivity. An
initial test with IPrAuCl/AgNTf2 (10 mol %) in dichloro-
ethane (DCE, 25 °C, 30 h) afforded Z-configured pyrrole
species 3a (Z/E = 5:1) in 81% (entry 1); we observed no
reactivity for P(OPh)3AuCl/AgNTf2 (entry 2). At 80 °C,
IPrAuCl/AgNTf2 (10 mol %) in DCE enhanced the yield of
compound 3a up to 86% (entry 3). For P(t-Bu)2(o-
bipenyl)AuCl/AgNTf2, the desired 3a was obtained in 66%
yield (Z/E = 10:1) (entry 4). A change of silver salts (AgX, X =
OTf and SbF6) as in entries 5 and 6 maintained the same high
efficiency to yield 3a in 72−83% yields. Other solvents such as
MeNO2 and toluene were less effective to deliver 3a in
moderate yields (40−76%, entries 7 and 8). Other metal
catalysts such as PtCl2/CO and AgOTf were not effective at all
(entries 9 and 10). The molecular structure of compound 3a
was determined by 1H NOE spectra and was further supported
by X-ray diffraction of its relative 3h (Scheme 1, entry 7).
annulations with ynamides were expanded smoothly to other
N−O heterocycles, including 1,2,4-oxadiazoles,6a 1,4,2-dioxa-
zoles,6b and 4,5-dihydro-1,2,4-oxadiazoles.6c We recently
reported [4 + 1]-annulation reactions between isoxazoles and
propiolate derivatives in a distinct [4 + 1]-annulation, resulting
Received: May 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01398
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituted pyrrole products 3n−t. We tested the reactions on
substrates 1b bearing one phenyl and one n-butyl at the
alkynes, affording pyrrole derivatives 3b and 3b′ in two
structural isomers (3b/3b′ = 5:1), with the pyrrolyl aldehyde
preferably adjacent to the n-butyl group, which is indicative of
Table 1. [4 + 1]-Annulations of Isoxazole with 1,4-Diyn-3-ol
1
a 1,2-shift of phenylalkyne. The H NMR chemical shifts of
their pyrrolyl aldehydes are distinguishable (δ 10.0 3b and δ
9.6 3b′). This chemoselectivity is also valid for compounds
3c,d, which has a formyl group nearby the cyclopropyl group.
Similarly, 1,4-diyn-3-ols 1e−i bearing various p-phenyl
substituents, X = F, Cl, Br, Me, and OMe gave compounds
3e−i of the same type (Z/E > 6.1:1, entries 4−8). The
molecular structure of pyrrole derivative 3h was characterized
by X-ray diffraction, further manifesting a 1,2-shift of the
arylalkyne moiety. We prepared symmetric alkyne derivatives
1j−m, delivering pyrrole products 3j−m in high yields (87−
94%, entries 9−12). We also prepared additional 1,4-diyn-3-ols
1n−q bearing a terminal alkyne and one internal alkyne (R =
Ph, n-Bu, 3-thienyl, and 2-methylvinyl); their resulting
products 3n−q were produced, again, from a 1,2-shift of an
internal alkyne. This migration was confirmed by X-ray
diffraction of compound 3n bearing an E-configured enone.
In the case of substrates 1r−t bearing 2-, 3-, or 4-substituted
phenyl groups, their resulting pyrroles 3r−t were produced in
70−73% yields (entries 17−19).
b
time
(h)
temp yield (%) of
entry
1
catalyst
solvent
DCE
(°C)
3a (Z/E)
1a
IPrAuCl/
AgNTf2
(PhO)3PAuCl/
AgNTf2
IPrAuCl/
AgNTf2
LAuCl/AgNTf2
IPrAuCl/AgOTf
IPrAuCl/AgSbF6
IPrAuCl/
AgNTf2
IPrAuCl/
AgNTf2
PtCl2/CO
AgOTf
30
20
6
25
81 (5:1)
2
3
DCE
DCE
25
80
78
86 (5:1)
4
5
6
7
20
4
20
24
DCE
DCE
DCE
MeNO2
80
80
80
80
66 (10:1)
83 (10:1)
72 (4:1)
40 (2:1)
15
10
40
8
24
toluene
80
76 (4:1)
18
9
10
24
24
DCE
DCE
80
80
90
90
a
b
1a = 0.17 M, 2a = 0.34 M. Product yields are obtained after
purification from a silica column. IPr = 1,3-bis(diisopropylphenyl)
imidazol-2-ylidene, L = P(t-Bu)2(o-biphenyl).
We examined the scope of isoxazoles to assess the reaction
generality (Scheme 2). With a model 1,4-diyn-3-ol 1a, 5-
Scheme 1. Reactions on Various 1,4-Diyn-3-ols
Scheme 2. Reactions on Various Substituted Isoxazoles
a
b
1a = 0.17 M, 2 = 0.34 M. Product yields are obtained after
purification from a silica column. IPr = 1,3-bis(diisopropylphenyl)-
imidazol-2-ylidene.
substituted isoxazoles 2b−d afforded desired 4b−d in 86−98%
yields their enones exit in Z-configurations exclusively (entries
1−3). For 3-substituted isoxazoles, their resulting pyrroles 4e−
4f comprised Z-configured enones as well; the yields were 97−
95% (entries 4−5). 3,5-Disubstituted isoxazoles 2g−i were also
suitable to these [4 + 1]-annulations to yield the expected
compounds 4g−i in 58−71% yields, reflecting the steric effects
of the two substituents on the product yields (entries 6−8).
Apart from isoxazoles 2, we were delighted to observe the
applicability of benzisoxazoles to these annulations; the
availability of distinct pyrrole derivatives 6 certainly increases
the scope of synthetic utility. As shown in eq 4, gold-catalyzed
annulations of 1,4-diyn-3-ol 1a with benzisoxazole 5a and its 6-
substituted analogues 5b,c delivered products 6a−c in
excellent yields (94−98%, eq 4). The molecular structure of
compound 6a was characterized by X-ray diffraction. We also
a
b
1a = 0.17 M, Product yields are obtained after purification from a
silica column. IPr = 1,3-bis(diisopropylphenyl)imidazol-2-ylidene.
We assessed the scope of the reactions using various 1,4-
diyn-3-ols and IPrAuCl/AgOTf in hot DCE (80 °C); our focus
was the selectivity of a 1,2-alkyne migration. Z-Configured
enones were produced from 2,5-disubstituted pyrroles 3b−m,
whereas E-configured enones were obtained exclusively from 2-
B
DOI: 10.1021/acs.orglett.8b01398
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Plausible Mechanism
prepared 1,4-diyn-3-ol 1u bearing a tertiary alcohol, and its
corresponding product 3u bears a ketone group at the C(2)-
pyrrole position (eq 5). To clarify the E−Z selectivity, Z-
configured pyrrolyl N-enone 4d was treated with p-TSA (10
mol %) in hot toluene (110 °C, 2 h), allowing an efficient
isomerization to its E-isomer exclusively (eq 6). The N-enone
moiety of species 4d is readily removed with 10 mol % of DBU
catalyst in hot toluene,9 yielding unsubstituted pyrrole
compound 7 in 87% yield (5 h, 110 °C).
The regioselectivity of the isoxazole attack in these [4 + 1]-
annulations is different from what we expected. For N-
hydroxyanilines as nucleophiles, the regioselectivity preferably
occurs at the arylalkyne moiety rather than at the alkylalkyne.8b
To clarify the steric effect, we examined the reactions on 1,4-
diyn-3-ol 1v bearing an isopropyl group of a different size.
Under the standard conditions, the resulting products 3v and
3v′ have two isomers in significant proportions (3v/3v′ =
3.6:1) (eq 7). However, in the case with tert-butylalkyne
undergoes a protodeauration to form Au-π-3-yn-1-imine E and
ultimately yields the observed product 3a. In the case of
terminal alkynes 1n−t, we note that only E-isomeric products
3n−t are produced exclusively; this observation is not
surprising because their Z-configured enone moieties are very
planar to allow an efficient conjugation with the pyrrole
nitrogen, rendering the Z−E isomerization very rapid.
We also note that cyclopropyl shows the best chemo-
selectivity among various alkyl-substituted alkynes (see
Scheme 3). A cyclopropyl group is well-known to stabilize
the neighboring carbocation through electronic effect. In this
system, we envisage that the two cyclopropyl sigma C−C
bonds will overlap the carbocation center of gold-π-alkyne
moiety in a bisected conformation A, rendering the
nucleophilic attack feasible.10
In summary, this work reports novel gold-catalyzed [4 + 1]-
annulations11 between 1,4-diynols and isoxazoles to yield
trisubstituted pyrrole derivatives12 efficiently; the reactions
proceed very chemoselectively for nonsymmetric 1,4-diynols.
The utility of these annulations is manifested by a broad range
of 1,4-diyn-3-ols and isoxazoles or even benzisoxazoles. Our
mechanistic analysis suggests that an isoxazole preferably
attacks at a less bulky alkyne as the initial step to yield gold
carbenes, whereas the remaining bulky alkyne undergoes a 1,2-
alkyne migration to form α-formyl propargylgold intermedi-
ates, before proceeding to the products.
ASSOCIATED CONTENT
■
S
* Supporting Information
derivative 1w, a distinct product 3w′ was formed as the sole
product with the pyrrolyl aldehyde neighboring the phenyl
group, reflecting the bulky effect of the alkyl substituent (eq 8).
Scheme 3 shows a plausible mechanism to rationalize the
reaction chemoselectivity, which is greatly affected by the steric
sizes of the alkynes (eq 8). We envisage that LAu+ coordinates
the two alkynes in π-bonding modes involving A and A′. An N-
attack of isoxazole at π-arylalkyne A′ is usually faster than at
the alkyl-substituted alkyne A because the former stabilizes a
carbocation at the C(α)-carbon more efficiently. However, this
chemoselectivity is varied, as an isozaxole is very bulky,
rendering species B′ difficult to form. A less hindered
environment such as species B is accessible to form α-hydroxy
iminogold carbenes C via an isoxazole cleavage. A 1,2-alkyne
shift of species C delivers propargylgold species D that
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01398.
Experimental details and spectral data of all compounds
(PDF)
Accession Codes
CCDC 1833352−1833353 and 1833496 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.8b01398
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) For gold-catalyzed [4 + 1]-annulations, see the following
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rsliu@mx.nthu.edu.tw.
ORCID
Rai-Shung Liu: 0000-0002-2011-8124
Author Contributions
†R.D.K. and B.S.K. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Education (MOE 106N506CE1)
and the Ministry of Science and Technology (MOST 107-
3017-F-007-002), Taiwan, for financial support of this work.
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DOI: 10.1021/acs.orglett.8b01398
Org. Lett. XXXX, XXX, XXX−XXX