Iodoarene-catalyzed cyclizations of unsaturated amides

Article abstract of DOI:10.1021/acs.orglett.5b00333

The cyclization of N-alkenylamides catalyzed by iodoarenes under oxidative conditions is presented. Five-, six-, and seven-membered rings with a range of substitutions can be prepared by this route. Preliminary data from the use of chiral iodoarenes as pr

Full text of DOI:10.1021/acs.orglett.5b00333

Letter
pubs.acs.org/OrgLett
Iodoarene-Catalyzed Cyclizations of Unsaturated Amides
Ali Alhalib,‡ Somaia Kamouka,‡ and Wesley J. Moran*
Department of Chemistry, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, U.K.
S
* Supporting Information
ABSTRACT: The cyclization of N-alkenylamides catalyzed by
iodoarenes under oxidative conditions is presented. Five-, six-, and
seven-membered rings with a range of substitutions can be prepared by
this route. Preliminary data from the use of chiral iodoarenes as
precatalysts show that enantiocontrol is feasible.
esearch in hypervalent iodine chemistry has gained
considerable momentum in recent years.1 In particular,
hypervalent iodine-mediated cyclization of N-allylamides
(Scheme 1).12 Their report was limited to five-membered
R
the emergence of catalytic and enantioselective processes with
iodine(III) species is starting to make these competitive with
metal catalysis.2 Recent examples include the catalytic
enantioselective spirolactonization of phenols,3 dioxygenation
of styrenes,4 and intramolecular C−H/C−H cross-coupling.5
This ability to effect “metal-like” synthetic transformations
without the toxicity, supply, or cost issues of transition-metal
salts is attractive.
Scheme 1. Cyclization of N-Alkenylamides by Iodine(III)
Species
We have previously developed catalytic methods using in situ
generated hypervalent iodine species and have reported the
oxidative cyclization of δ-alkynyl β-keto esters6 and the
enantioselective oxidative cyclization of δ-keto acids.7 We
wished to extend this catalytic concept to the formation of
useful heterocycles such as oxazolines and dihydrooxazines.
Oxazolines are common structural motifs found in natural
products with notable biological activities, e.g., the leupyrrins,
active against fungi and eukaryotic cells,8 and the bistratamides,
which possess anticancer properties (Figure 1).9 Dihydroox-
azines are useful synthetic intermediates in organic synthesis,10
and derivatives possessing fungicidal activity have also been
reported.11
In this paper, we disclose our results on the catalytic
cyclization of unsaturated amides to give oxazolines,
dihydrooxazines, and larger ring analogues. At the beginning
of our study, Moon and Harned published the stoichiometric
ring formation and the use of terminal alkenes, and the
products described were all racemic. Herein, we reveal catalytic
conditions for the cyclization and expand the scope of the
process to include other ring sizes and more substituted
alkenes. In addition, we have achieved enantiocontrol in this
cyclization using chiral iodoarenes.
There are few examples in the literature of iodoarene-
catalyzed reactions involving alkenes.4,13 One issue with these
processes is the potential for undesired oxidation of the olefin
in preference to the iodoarene especially as common oxidants
for the conversion of iodoarenes into the active iodine(III)
species include peracids.
We began our investigation with N-allylbenzamide 1a and
used reaction conditions similar to those used by us in previous
reports, namely iodobenzene as the precatalyst with an oxidant,
m-CPBA, an acid, TFA, and a solvent, acetonitrile, at room
Received: February 2, 2015
Published: March 5, 2015
Figure 1. Examples of natural products containing oxazolines.
© 2015 American Chemical Society
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Letter
temperature (Table 1, entry 1). Unfortunately, these conditions
led to no conversion of the starting material; not even
Scheme 2. Scope of Cyclization of Monosubstituted Alkenes
Table 1. Investigation of Reaction Conditions
a
entry
ArI
oxidant
yield (%)
1
2
3
4
5
6
7
8
9
iodobenzene
iodobenzene
2-iodoanisole
3-iodoanisole
4-iodoanisole
5-iodo-m-xylene
2-iodoanisole
2-iodoanisole
m-CPBA
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
m-CPBA
Oxone
0
6
62
9
10
13
0
0
Selectfluor
0
a
Yields of isolated compounds. Selectfluor: 1-chloromethyl-4-fluoro-
1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
epoxidation of the alkene occurred. However, changing the
oxidant to Selectfluor led to a small amount of the desired
product 2a being formed (entry 2). Importantly, a basic workup
of the reaction mixture was required in order to isolate the
product. Changing the iodoarene catalyst led to surprising
variations in yield: 2-iodoanisole led to a 62% yield (entry 3),
whereas 3-iodoanisole, 4-iodoanisole and 5-iodo-m-xylene
provided low yields of isoxazoline (entries 4−6). We have
demonstrated previously that the presence of a 2-methoxy
substituent stabilizes aryliodine(III) species.14 Guilbault and
Legault demonstrated that the steric hindrance caused by the
introduction of a methyl group ortho to the iodine atom in
iodoarene precatalysts led to drastic rate enhancements in the
α-tosyloxylation of ketones.15 Using 2-iodoanisole as catalyst,
the oxidant was varied; however, the use of m-CPBA and
Oxone both led to no conversion (entries 7 and 8). Finally,
running the reaction without the 2-iodoanisole, but with the
Selectfluor, led to complete recovery of the starting amide,
showing that the iodoarene is necessary for this process to
proceed (entry 9).
reaction conditions (Scheme 3). Methyl derivative 2p was
formed in 81% yield, whereas the phenyl derivative 2q was not
Scheme 3. Scope of Cyclization of Disubstituted Alkenes
With the optimized cyclization reaction conditions in hand,
we next studied the scope of this process (Scheme 2). A variety
of arylamides were successfully cyclized including electron-rich
and electron-poor examples to provide the corresponding
oxazolidinones 2a−e in good yields. Subjecting acetamide 1f to
the reaction conditions led to a mixture of products, and 2f
could not be isolated in pure form. Furan oxazoline 2g was
isolated in 79% yield, and 2h was isolated as a ∼1:1 mixture of
diastereomers in 74% combined yield. The cyclization of
amides 1i−m was investigated next, and we were pleased to
find that the six-membered rings 2i−m formed in good yields.
However, 2 equiv of Selectfluor was generally required for
complete conversion to occur in these cases. In addition, the
seven-membered ring 2n was successfully formed in 30% yield.
However, the eight-membered ring 2o was not formed. In
theory, 2n or 2o could cyclize to the corresponding pyrrolidine
or piperidine, but neither of these was observed.
isolated. In the latter case, complete conversion of the starting
material was observed, but several unidentified products were
formed which could not be separated. Cis-1,2-disubstituted
alkene 1r cyclized to the bicycle 2r in 56% yield as one
diastereomer. No sign of the other diastereomer was detectable
by NMR analysis of the crude reaction mixture. Attempts to
cyclize a trisubstituted alkene were unsuccessful as undesired
background alkene addition processes occurred.
The mechanism of this cyclization is proposed to involve
oxidation of the iodoarene to the iodine(III) species which
activates the alkene to intramolecular attack by the amide
oxygen to generate intermediate 3 (Scheme 4). Nucleophilic
addition of TFA, or its conjugate base, breaks the alkyl carbon−
iodine bond in 3, which regenerates the iodoarene catalyst and
releases the cyclized product 4. This compound 4 cannot be
isolated as it is unstable, but it is believed to be the
With a desire to increase the scope of the cyclization further,
1,1-disubstituted alkenes 1p and 1q were subjected to the
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Scheme 4. Postulated Cyclization Reaction Mechanism
Table 2. Preliminary Chiral Precatalyst Screening
2i
5
a
a
yield
(%)
yield
b
b
entry cat.
solvent
MeCN
er
(%)
er
1
2
3
4
5
6
6
6
6
6
6
6
86
75
10
11
0
82:18
67:33
79:21
63:37
0
0
c
MeCN
MeCN
MeCN
MeOH
d
e
0
0
10
28
63:37
76:24
1:1 MeCN/
MeOH
37
71:29
76:24
7
6
1:2 MeCN/
MeOH
51
34
81:19
trifluoroacetate. Nonetheless, treatment of this with 2 M NaOH
solution provides the stable alcohol 2.
8
9
7
7
MeCN
<5
0
n.d.
0
1:2 MeCN/
MeOH
99
75:25
With an effective cyclization process in hand, we turned our
attention to the use of chiral iodoarene precatalysts 6−10 in
order to develop an enantioselective version of this process.16
When bisdimethylamide precatalyst 6 was used, a very good
yield of 2i was obtained with moderate enantioselectivity of
82:18 er (Table 2, entry 1). Interestingly, the amount of
precatalyst could be lowered to 10 mol % without a drop in
yield, compared to the use of 2-iodoanisole. To determine the
effect of temperature on the cyclization, the reaction was
repeated at +50 and at −10 °C; however, selectivity was lower
in the former case and about the same in the latter (entries 2
and 3). Conducting the reaction with bistrifluoromethanesulfo-
namide instead of TFA led to lower yield and lower selectivity
(entry 4). Using methanol as solvent instead of acetonitrile led
to formation of methyl ether 5 in place of alcohol 2i, but in low
yield and with 63:37 er (entry 5). Using a 1:1 or 2:1
acetonitrile/methanol mixture as solvent led to formation of
separable mixtures of 2i and 5 (entries 6 and 7). The
enantiomeric ratio of ether 5 was up to 81:19, equaling the
highest obtained for 2i. We then screened a few other related
precatalysts 7−10 but did not see superior selectivity. With
diisopropylamide precatalyst 7, the conversion in MeCN was
very low; however, changing to a 1:2 mixture of MeCN and
MeOH led to complete conversion to ether 6 with 75:25 er
(entry 9). Mesityl amide 8 and ethers 9 and 10 led to moderate
yields and enantioselectivites (entries 10−12). However, with
the tert-butyl ester precatalyst 10 the major enantiomers of
products formed were opposite to the other precatalysts (entry
12).
10
11
12
8
9
MeCN
MeCN
53
23
49
75:25
72:28
35:65
0
0
10 1:2 MeCN/
19
34:66
MeOH
a
b
Yields of isolated compounds. Determined by chiral HPLC analysis.
Reaction performed at 50 °C. Reaction performed at −10 °C.
Bistrifluoromethanesulfonamide used instead of TFA.
c
d
e
Scheme 5. Enantioselective Formation of Isoxazoline 2a
Further work on related cyclizations, and efforts to improve
observed enantioselectivities, is underway and will be reported
in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data and copies of H and 13C NMR spectra
1
for novel compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Cyclization of amide 1a to generate isoxazoline 2a was also
performed using chiral precatalyst 7, and the product was
generated in 84.5:15.5 er (Scheme 5).
In conclusion, the cyclization of unsaturated amides using
catalytic quantities of iodoarenes has been developed. 2-
Iodoanisole has proven to be a superior precatalyst compared
to other iodoarenes tested in this process. In addition, chiral
iodoarenes have been utilized to impart enantioselectivity, and
levels of control up to 81:19 er have been achieved so far.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: w.j.moran@hud.ac.uk.
Author Contributions
‡A.A. and S.K. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful to the State of Libya for graduate studentships
(A.A. and S.K.).
■
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