Gold-Catalyzed Stereoselective Domino Cyclization/Alkynylation of N-Propargylcarboxamides with Benziodoxole Reagents for the Synthesis of Alkynyloxazolines

Article abstract of DOI:10.1002/adsc.201900264

A concise and highly stereoselective synthesis of alkynyloxazolines via a gold-catalyzed domino cyclization-alkynylation cascade of N-propargylcarboxamides with benziodoxole reagents is reported. This new protocol, which represents an attractive alternati

Full text of DOI:10.1002/adsc.201900264

Title: Gold-Catalyzed Stereoselective Domino Cyclization/Alkynylation
of N-Propargylcarboxamides with Benziodoxole Reagents for the
Synthesis of Alkynyloxazolines
Authors: Ximei Zhao, Tian Bing, Yangyang Yang, Xiaojia Si, Florian
Mulks, Matthias Rudolph, Frank Rominger, and A. Stephen K.
Hashmi
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900264
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10.1002/adsc.201900264
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Gold-Catalyzed Stereoselective Domino Cyclization/Alkyny-
lation of N-Propargylcarboxamides with Benziodoxole Reagents
for the Synthesis of Alkynyloxazolines
Ximei Zhao,a Bing Tian,a Yangyang Yang,a Xiaojia Si,a Florian F. Mulks,a,b Matthias
Rudolph,a Frank Rominger,a A. Stephen K. Hashmi a,c*
a
Organisch-Chemisches Institut, Heidelberg University, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Zernike Institute for Advanced Materials, Rijksuniversiteit Groningen, Nijenborgh 4, 9747 AG Groningen, The
b
Netherlands
c
Affiliation a Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah, Saudi
Arabia
[Phone: (+49)-(0)6221-54-8413; Fax:(+49)-(0)6221-54-4205; E-mail: r; Homepage: http://www.hashmi.de]
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A concise and highly stereoselective synthesis of stereoselectivity. A comparison of the computed energies of
alkynyloxazolines via a gold-catalyzed domino cyclization- the isomers of the product suggests kinetic control as the
alkynylation cascade of N-propargylcarboxamides with cause of the observed selectivity.
benziodoxole reagents is reported. This new protocol, which
represents an attractive alternative to two step sequences
based on Sonagashira couplings, offers a broad substrate
scope, excellent functional group tolerance, and perfect
Keywords: benziodoxole; gold catalysis; oxazolines;
oxidative alkynylation; propargylamides
isolation and purification of the sensitive[5h]
Introduction
halogenated
oxazoline
intermediates,
which
inevitably consumes additional time, labour, and
resources. In addition, this method cannot provide
access to products bearing reactive halogen
substituents like bromides or iodides for further
subsequent functionalization, as these also will react
under the palladium-catalyzed conditions of the
Oxazolines are important heterocycles ubiquitous in
bioactive natural products and pharmaceuticals.[1] In
addition, they also function as useful synthetic
intermediates,[2] protecting groups,[3] as well as
valuable ligands[4] in synthetic and catalytic
chemistry. Therefore, effective ways to synthesize
and functionalize oxazolines are highly desirable.
Traditional methods for accessing these heterocycles
start from carboxylic acids, esters, nitriles,
hydroxyamides, aldehydes and olefins.[1c] Another
versatile and effective way is the transition metal-
catalyzed cyclization of N-propargylcarboxamides,[5]
with Brønsted acids,[6] or under strong basic
Sonogashira
coupling.
Hence,
a
cyclization/alkynylation process that can be carried
out in a domino procedure would be advantageous to
the existing strategies.
Alkynyl-substituted hypervalent iodine compounds
are powerful reagents for the formation of new C-
alkynyl bonds by electrophilic alkynylation
reactions.[11] In 2009, Waser and co-workers reported
the first direct C-H alkynylation of pyrroles and
indoles by using [(triisopropylsilyl)ethynyl]benzio-
doxolone (TIPS-EBX (4a)) in combination with
AuCl as catalyst.[12] Since then, the use of TIPS-EBX
for a direct ethynyl transfer reactions has been
extensively exploited.[11a,b] For instance, a Pd-
catalyzed cyclization-alkynylation cascade of olefins
with TIPS-EBX reported by Waser et al. lead to
oxyalkynylation products of alkenes.[13] Patil’s group
has addressed a gold-catalyzed aminoalkynylation of
alkynes by using TIPS-EBX to access alkynylated
conditions.[7] Among
these
N,O-heterocycles,
alkynyl-substituted oxazolines represent a highly
interesting class of functionalized building blocks for
synthetic chemistry, a fruitful follow-up chemistry is
enabled by the subsequent functionalization of the
alkynyl groups.[8] Traditionally, these compounds are
synthesized by Sonogashira cross coupling
reactions.[9] But this transformation is based on the
availability of the corresponding halogenated
oxazolines, which are usually accessed through the
cyclization-halogenation reaction of propargylamides
(Scheme 1a).[10] This two-step strategy requires
quinalizinones.[14]
In
2013,
a
modified
1
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10.1002/adsc.201900264
Advanced Synthesis & Catalysis
ethynylbenziodoxole reagent (TIPS-EBX* (4b)) was
developed by Waser et al., this reagent was
exceptionally efficient for domino cyclization-
alkynylation process of allenyl ketones to access C3-
alkynylated furans.[15] In addition, it also acted
effectivly in the gold-catalyzed C(sp)–C(sp) cross-
coupling reaction of terminal alkynes with alkynyl-
substituted hypervalent iodine reagents for the
synthesis of unsymmetrical 1,3-diynes.[16] Inspired by
this, we envisaged a domino process (Scheme 1b) on
the basis of our previous studies on the gold-
catalyzed cyclization of propargylamides (Scheme
2)[5g] and one-pot strategies based on this
reactivity.[17]
catalysts with ligands like IPrAuCl or PPh3AuCl did
not afford 3b (entry 2 and 3). Changing the solvent to
THF gave a positive result, affording 3b in 23% yield
(entry 4). Other screened solvents, DCM, CH3CN,
i
and PrOH, generated 3b in much lower yields (entry
5-7). By decreasing the reaction temperature to 0 °C,
the yield increased to 36% (entry 9), while at 50 °C
and -20 °C the coupling was less efficient (entry 8
and 10). Adding 0.5 equiv. of AcOH again improved
the reaction, yielding 48% of 3b (entry 11). The yield
could be further increased to 67% by raising the
amount of AuCl to 15 mol% (entry 12). Among the
screened amounts of AcOH, 0.2, 0.8, and 1.0 equiv.
were less efficient, affording 3b in lower yields (entry
13-15). Changing the additive to Zn(OTf)2, Yb(OTf)3,
Sc(OTf)2, NaOAc, or Na2CO3, and 2-picolinic acid
significantly decreased the yield (entry 16-21).
Another EBX derivative (4a) did also afford 3b, but
in much lower yield (entry 22). Control experiments
without catalyst showed no reaction (entry 23).
Table 1. Optimization of the reaction conditions.a)
En
try
Yield
(%)b)
T
Catalyst
Solvent
Additive
[oC]
Scheme 1. Previous synthesis of alkynyl-substituted
1
2
AuCl
IPrAuCl
PPh3AuCl
AuCl
Et2O
Et2O
Et2O
THF
RT
RT
RT
RT
RT
RT
RT
50
0
-
9
ND
ND
23
alkylidenoxazolines
and
gold-catalyzed
domino
-
cyclization/alkynylation process
3
-
4
-
5
AuCl
DCM
CH3CN
iPrOH
THF
-
8
6
AuCl
-
8
7
AuCl
-
trace
10
8
AuCl
-
9
AuCl
THF
-
36
10
11
12
13
14
15
16
AuCl
THF
-20
0
-
4
Scheme 2. Gold-catalyzed cyclization of propargylamides
AuCl
THF
AcOH (0.5 eq.)
AcOH (0.5 eq.)
AcOH (0.2 eq.)
AcOH (0.8 eq.)
AcOH (1.0 eq.)
Zn(OTf)2 (0.15
eq.)
48
67(64)c)
AuCl
AuCl
THF
THF
0
0
46
Results and Discussion
AuCl
THF
0
61
AuCl
THF
0
54
First we used propargylamide 1a as the test substrate
with EBX* derivative 4b in the presence of AuCl (10
mol%) in Et2O. To our disappointment, only trace
amounts of the desired product could be detected by
1H NMR, together with a large amount of oxazole 7a.
This is in line with our previous work, which showed
that in the presence of AuIII, the oxazolines 3 readily
aromatize to oxazoles 7.[5c] This seems to be initiated
by the oxidation of AuI to AuIII in the presence of 4b.
To prevent this isomerisation, compounds 1 with
tertiary propargylic substituents were used for the
subsequent conversions.
Thus N-propargylamide 1b and TIPS-EBX* 4b
were used as the model substrates to optimize the
reaction conditions (Table 1). Preliminary results
showed the desired transformation, 9% of the product
3b were detected (10 mol% AuCl, Et2O, RT; entry 1),
but this would be stoichiometric in gold. Other gold
AuCl
THF
0
10
17
18
AuCl
AuCl
THF
THF
0
0
Yb(OTf)3 (0.15
eq.)
48
26
Sc(OTf)2 (0.15
eq.)
19
20
21
AuCl
AuCl
AuCl
THF
THF
THF
0
0
0
NaOAc (1.0 eq.)
Na2CO3 (1.0 eq.)
2-Picolinic acid
(1.0 eq.)
trace
trace
20
22
23
AuCl
None
THF
THF
0
0
AcOH (0.5 eq.)
AcOH (0.5 eq.)
20d)
NDe)
a)
Reaction conditions: entries 1-11, 1b (0.1 mmol), 4b
(0.12 mmol), catalyst (10 mol%), and additive in 2 mL of
solvent; entries 12-21, 1b (0.1 mmol), 4b (0.12 mmol),
b)
catalyst (15 mol%), and additive in 2 mL of solvent.
Measured by 1H NMR with dibromomethane as the
2
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10.1002/adsc.201900264
Advanced Synthesis & Catalysis
c)
d)
internal standard. Yield of isolated product. Reaction
conditions: 1b (0.1 mmol), 4a (0.12 mmol), catalyst (15
mol%), and additive reacted in 2 mL of solvent. e) Reaction
conditions: 1b (0.1 mmol), 4b (0.12 mmol), and additive
reacted in 2 mL of solvent.
Table
propargylcarboxamides
2.
Scope
with
regard
to
the
N-
Under the optimized conditions (1.2 equiv of
ethynylbenziodoxole 4b, 15 mol% AuCl, 0.5 equiv of
AcOH, THF, 0 °C), the scope with respect to the N-
propargylcarboxamides 1 was then investigated
(Table 2). A wide range of substituents at the phenyl
group were compatible, giving the desired products in
good to moderate yields (3b-q). With regard to
methyl-substituted amides, substituents at m- and p-
positions of the phenyl group gave the corresponding
products in much higher yields (3d, 3e) than o-aryl-
substituted amide (3c), probably due to the steric
hindrance. Amides bearing methoxyl groups at the
aromatic rings, no matter at o-, m, or p-positions
produced products 3f-h in moderate yields, while a
two-fold methoxy-substituted amide afforded 3i in
32% yield. Importantly, substrates with electron-
withdrawing groups including fluoride (3j), chloride
(3k, 3l), bromide (3m), iodide (3n), trifluoromethyl
(3o), ester (3p), and nitro functionalities (3q) all
turned out to be tolerated and afforded corresponding
products in 45-59% yields, which opens the door for
downstream manipulation at such positions. Besides
phenyl amides, a naphthyl amide also gave product
3r in fair yield (31%). When the phenyl group was
changed to heterocycles including pyridine (3s), furan
(3t) and thiophene (3u), the yields remained good to
moderate (31-62%). In addition to aromatic amides,
an aliphatic amide also afforded product 3v in 45%
yield. The phenyl amide bearing a cyclohexyl group
instead of dimethyl group gave product 3w in
moderate yield (50%). Finally, an internal phenyl
amide was investigated to give 3x in 26% yield.
Table 3. Scope with regard to the ethynylbenziodoxoles
Next, the utility of various EBX* analogues for the
gold-catalyzed domino cyclization-alkynylation
reaction was investigated with 1b as the reaction
t
partner (Table 3). As shown in Table 3, BuMe2Si-
t
EBX* (4c), BuPh2Si-EBX* (4d), and Ph-EBX* (4e)
all worked with the reaction, affording products 3y,
3z, and 3aa in 34%, 36%, and 37% yields,
respectively.
In order to gain insight into the reaction
mechanism, we performed the experiment with
compound 3ab under the standard conditions
(Scheme 3). After stirring at 0 °C for 5 h, still no
conversion was observed. This result proves that the
Scheme 3. Reaction of 3ab under standard conditions
gold-catalyzed
domino
cyclization/alkynylation
reaction does not proceed via 3ab as intermediate,
followed by the direct sp2-C-H alkynylation. We also
performed a deuterium labeling experiment with
deuterated alkyne 1b-d (H:D = 4:96) under the
standard conditions (Scheme 4). Based on the
corresponding 1H NMR spectroscopic data, this
reaction afforded product 3b-d with a ratio of H:D of
4:96 at the vinylic position.
3
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10.1002/adsc.201900264
Advanced Synthesis & Catalysis
In order to analyze the relative thermodynamic
stability of the two diastereomeric products (E)-3b
and (Z)-3b, we conducted a computational study. A
DFT-D3 analysis (B3LYP-D3(BJ)/6-31G*, CPCM =
8.93)[21]
shows
that
the
(E)-isomer
is
thermodynamically favoured by a small margin of
G = −1.2 kJ/mol (Zero-point corrected energy
difference: E0 = −2.6 kJ/mol, enthalpy difference:
H = −2.8 kJ/mol). As Figure 1 shows, due to the
slim alkynyl subunit the tertiary carbon with the gem-
dimethyl substitution and the C-C triple bond do not
show a strong steric repulsion (Figure 1, left), and
thus the energy of the (E)-isomer is not increased by
such an steric interaction. Taking into account the
error margin of the calculations, both structures
essentially have almost the same energies, and the
experimentally observed selectivity cannot result
from thermodynamic control but has to be based on
kinetic control.
Scheme 4. Deuterium labeling experiments
From the above experiments and the conclusions
from previous reports,[5g,18] a plausible mechanism[19]
for
the
gold-catalyzed
domino
cyclization/alkynylation reaction is described in
Scheme 5. Initially, the carbonyl oxygen atom
stereoselectively attacks alkyne, which is
-
coordinated to gold, from the backside in an 5-exo-
dig fashion to form vinyl-gold intermediate B. After
that, the oxidative addition of intermediate B (which
due to the negatively charged chloride ligand on gold
is a locally negatively charged ate-complex of gold(I),
and thus easier to oxidize) and compound 4b affords
intermediate C,[20] which then undergoes ligand
exchange and reductive elimination to give the active
gold(I) catalyst and the final product 3b, which is
obtained in 100% trans-configuration, which is based
on the trans-selective formation of the vinylgold
intermediate. In addition, the increased yield of
product 3b upon the addition of 0.5 equiv of acetic
acid (Table 1, entry 11) is probably due to the
protonation of the alkoxid in complex C which assists
the formation of 8, thus accelerating the catalytic
cycle and the formation of the desired product.
Figure 1. Minimalized structures of the two diastereomeric
products (E)-3b (left) and (Z)-3b (right).
Finally, we succeeded in growing single crystals of
the desilylated derivative 3q’. An single crystal X-ray
crystal structure analysis of 3q’[22] fully confirmed the
(E)-geometry of the product and thus is in full accord
with the mechanistic proposal (Figure 2).
Figure 2. Solid state molecular structure of 3q’.
Scheme 5. Plausible mechanism for the gold-catalyzed
domino cyclization-alkynylation reaction
4
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10.1002/adsc.201900264
Advanced Synthesis & Catalysis
Research Infrastructures activity of the Structuring the European
Research Area program (contract number 730897) and support
by the state of Baden-Württemberg through bwHPC
Conclusion
In conclusion, we have developed a novel, concise,
efficient, and highly stereoselective synthesis of
alkynyloxazolines by the gold-catalyzed domino
cyclization/alkynylation of propargylamides with
benziodoxole reagents. Simple and mild conditions,
broad substrate scope, excellent functional group
tolerance, and 100% diastereoselectivity make this
new strategy attractive and practical for synthetic
chemistry in order to access interesting building
blocks.
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μmol) of 4b, 3.49 mg (15.0 μmol) of AuCl, and 2.86 μL
(50.0 μmol) of AcOH gave 23.5 mg (64.0 μmol) of 3b
(yield = 64%).
Colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.97 (d, 2H,
J = 7.5 Hz), 7.53-7.50 (m, 1H), 7.45-7.42 (m, 2H), 5.48 (s,
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5
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10.1002/adsc.201900264
Advanced Synthesis & Catalysis
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10.1002/adsc.201900264
Advanced Synthesis & Catalysis
FULL PAPER
Gold-Catalyzed
Stereoselective
Domino
Cyclization/Alkynylation
of
N-Propargylcar-
boxamides with Benziodoxole Reagents for the
Synthesis of Alkynyloxazolines
Adv. Synth. Catal. Year, Volume, Page – Page
Ximei Zhao, Bing Tian, Yangyang Yang, Xiaojia
Si, Florian F. Mulks, Matthias Rudolph, A. Stephen
K. Hashmi*
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