Regio- and stereoselective synthesis of cyclic imidates via electrophilic cyclization of 2-(1-alkynyl)benzamides. A correction

Article abstract of DOI:10.1021/jo301958q

The electrophilic cyclization of 2-(1-alkynyl)benzamides affords high yields of cyclic imidates, instead of the previously reported isoindolin-1-ones, where cyclization proceeds on the oxygen of the carbonyl group rather than the nitrogen of the amide fun

Full text of DOI:10.1021/jo301958q

Note
pubs.acs.org/joc
Regio- and Stereoselective Synthesis of Cyclic Imidates via
Electrophilic Cyclization of 2‑(1-Alkynyl)benzamides. A Correction
Saurabh Mehta,†,‡ Tuanli Yao,† and Richard C. Larock*,†
†Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
‡Department of Applied Chemistry, Delhi Technological University, Delhi 110042, India
S
* Supporting Information
ABSTRACT: The electrophilic cyclization of 2-(1-alkynyl)-
benzamides affords high yields of cyclic imidates, instead of the
previously reported isoindolin-1-ones, where cyclization
proceeds on the oxygen of the carbonyl group rather than
the nitrogen of the amide functionality. X-ray crystallography
and spectroscopic techniques have been used to characterize
the products. A correction is hereby provided in order to
rectify the previous misassignment of structure.
he iodocyclization of functionalized alkynes has been a
Tpowerful tool for the synthesis of a wide variety of
heterocyclic and carbocyclic compounds.1 Using this method-
ology, we and others have reported the synthesis of several
important scaffolds, e.g., benzofurans,2 furans,3 benzothio-
phenes,4 indoles,5 carbazoles,6 quinolines,7 isoxazoles,8 pyr-
roles,9 etc.10 As a continuation of our studies, we investigated
the electrophilic cyclization of 2-(1-alkynyl)benzamides and
published a synthesis of what we believed to be isoindolinones
and isoquinolinones (Scheme 1).11 We hereby reassign the
structure of those products as cyclic imidates.
using our previously optimized reaction conditions, and the
structure of the product ii has been established with the help of
single-crystal X-ray and NMR spectroscopic data (Figure 1).12
Scheme 1. Previously Reported Synthesis of Isoindolinones
and Isoquinolinones by the Electrophilic Cyclization of 2-(1-
Alkynyl)benzamides11
Figure 1. X-ray evidence.13
To our surprise, the data indicated that the cyclization had
actually occurred on the oxygen of the carbonyl group rather
than the nitrogen of the amide functionality, leading to the
corresponding cyclic imidates or iminolactones instead of
isoindolin-1-ones. To recheck our earlier results, we synthesized
one of the compounds (26)12 that we reported in our original
publication using our standard experimental procedure, and it
was characterized with the help of single-crystal X-ray
spectroscopic data (Figure 1). It again confirmed the formation
of a cyclic imidate and not an isoindolin-1-one. In addition to
A few years later, in an effort to generate a modest sized
library of isoindolin-1-ones for biological evaluation, we
explored the scope of that earlier methodology and discovered
that we had misassigned their structures. Thus, a new substrate
i, bearing more polar functionality, has been cyclized (eq 1)
the X-ray spectroscopic data, we have also re-examined the 13
C
Received: September 19, 2012
Published: October 30, 2012
© 2012 American Chemical Society
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Note
NMR spectra of the cyclized products. The absence of any
diagnostic signals for the CO bonds in a lactam at δ >160
ppm in the 13C NMR spectra of all of the 5- and 6-membered
ring-containing products further ruled out N-cyclization.14
Furthermore, we examined the hydrolysis of the cyclized
products. The 5-membered cyclic imidate iii was synthesized
from the corresponding alkyne using our standard iodocycliza-
tion procedure. It was then subjected to acid hydrolysis,
yielding the corresponding lactone iv in a moderate yield (eq
2). This result confirms the formation of cyclic imidates upon
Table 1. Iodocyclization of 2-(1-Alkynyl)benzamide 1:
Summary of Optimization Studies
time
(h)
% yield % yield
of 2
entry electrophile
base
solvent
of 3
a
1
2
I2
NaHCO3
CH3CN
CH2Cl2
1
86
54
10
40
b
ICl
0.5
a
0.30 mmol of the 2-(1-alkynyl)benzamide, 3 equiv of I2, and 3 equiv
of NaHCO3 in 3 mL of CH3CN were stirred at room temperature for
b
1 h under Ar. 0.30 mmol of the 2-(1-alkynyl)benzamide and 1.2 equiv
of ICl in 3 mL of CH2Cl2 were stirred at room temperature for 0.5 h
under Ar.
counterparts on the basis of their IR spectra. The 5-membered
ring products generally exhibit a CNR band at 1680−1710
cm−1, while in the 6-membered ring products the correspond-
ing absorption is observed at 1640−1650 cm−1.
cyclization of the 2-(1-alkynyl)benzamides. All of this evidence
supports the formation of cyclic imidates instead of isoindolin-
1-ones.
Our proposed mechanism for this electrophilic cyclization is
shown in Scheme 3. There are several reports in the literature
that indicate the ambident nature of the amide group as a
nucleophile and also the fact that different products can be
obtained from amides under different reaction conditions using
various reagents.19 It appears that under our reaction
conditions, the oxygen atom is more nucleophilic than the
nitrogen atom presumably due to the delocalization of the lone-
pair of electrons and/or due to the steric hindrance on the
nitrogen atom of the amide group. Moreover, the O-selective
cyclization in the iodocyclization reactions in olefinic amide
substrates has been explained on the basis of the HSAB theory;
that is, an oxygen atom, being more electronegative than the
nitrogen atom, preferentially attacks the iodine−olefin π-
complex that has been characterized as a hard electrophile.20
Thus, the nucleophilic attack by the oxygen atom of the amide
group on the carbon−carbon triple bond activated by
coordination to I+ is followed by deprotonation to afford the
corresponding cyclic imidates.
Recently, Chen et al. have reported their results for the I2-
mediated cyclization of nitrone−alkynes, and they too seem to
have mischaracterized the products as isoindolin-1-ones instead
of cyclic imidates.15 In light of the evidence given above, we are
hereby correcting all of the schemes and tables reported
previously by us for the electrophilic cyclization of 2-(1-
alkynyl)benzamides to indicate that cyclic imidates are actually
formed.
Scheme 2 shows the two-step approach we have used to
prepare the cyclic imidates, which involves (1) the preparation
of 2-(1-alkynyl)benzamides by a Sonogashira reaction16 and
(2) electrophilic cyclization. The synthesis of previously
prepared starting amides can be found in our original
publication,11 while the synthesis of two new amides is
reported in the Supporting Information.17
The 2-(1-alkynyl)benzamide 1 was chosen as the substrate
for optimization of this electrophilic cyclization process, and the
best conditions are shown in Table 1.11
Using these optimized conditions, a wide variety of 2-(1-
alkynyl)arenecarboxamides with substitution on the amide
nitrogen atom, the aromatic ring, and the remote end of the
alkyne moiety have been examined in this cyclization process.
The cyclized products have been characterized by spectral and
analytical data, and the results (with corrected structures of the
products) are presented in Table 2.18 The relative stereo-
chemistry (Z/E) of the other cyclic imidates is assigned by
analogy to the compounds ii and 26. Furthermore, as described
in the original paper, the 5-membered-ring-containing cyclic
imidates have been distinguished from their 6-membered
Based upon our studies, we believe that in general various
factors determine the regiochemical outcome of the reaction,
including the stability of the presumed intermediate carboca-
tion, the relative rates of the competing reactions, the nature of
the electrophile, and the relative stabilities of the possible
products. As far as the electrophile is concerned, better
regioselectivity has been observed when I2 was used as
compared to the more reactive electrophile ICl that generally
affords larger amounts of the six-membered cyclic imidate
(compare entries 1 and 2, 6 and 7, and 8 and 9 in Table 2). In
most cases, the 5-membered cyclic imidate has been isolated as
Scheme 2. Two-Step Approach to Cyclic Imidates
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a
Table 2. Electrophilic Cyclization of 2-(1-Alkynyl)arenecarboxamides
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Table 2. continued
a
All reactions were run under the following conditions, unless otherwise specified: 0.3 mmol of alkynamide, 3 equiv of electrophile and 3.0 equiv of
b
NaHCO3 in 3 mL of CH3CN at room temperature for 1 h. 0.3 mmol of alkynamide and 1.2 equiv of electrophile in 3 mL of CH2Cl2 at room
temperature for 0.5 h.
Scheme 3. Proposed Mechanism for the Iodocyclization of 2-(1-Alkynyl)arenecarboxamides
the major product, although there are a few exceptions to this.
For example, using a cyclohexenyl group at the distal end of the
alkyne, the 6-membered cyclic imidate was isolated as the major
(entries 14 and 15) or the only product (entries 23 and 24), no
matter whether ICl or I2 is used. In general, the formation of a
5-membered ring seems to be faster than the corresponding 6-
membered ring, except for the reactions of substrates with a
cyclohexenyl group at the distal end of the alkyne, where other
factors, e.g. the thermodynamic stability of the products seems
to take precedent over kinetic factors.
Even the TMS group containing alkyne substrate 25
underwent smooth iodocyclization with I2 (entry 13). The 5-
membered cyclic imidate 26 was obtained in 77% yield, along
with a small amount of a diiodo derivative corresponding to the
6-membered cyclic imidate 27. Obviously, the silyl group in the
6-membered cyclic imidate has undergone iododesilylation
either prior to or soon after cyclization. Similarly, cyclic imidate
32 bearing two electron-donating methoxy substituents on the
aromatic ring and a silyl moiety has been obtained in a good
yield (entry 16).
The reaction of the alkene-containing amide 46 with I2
affords a mixture of cyclic imidates 47 and 48 in which the six-
membered ring product 48 predominates, presumably due to
ring strain (entry 25).
In a few cases (entries 10, 11, and 17), recognizable products
could not be isolated, presumably due to the poor stability of
the initial cyclic intermediates and/or the final products. In the
case of a primary amide (entry 10), the desired cyclic imidate
could not be isolated presumably because of the absence of any
group helping to stabilize the positive charge on the N atom
(Figure 2a). The reaction also fails to yield the desired product
in the case of a tertiary amide (entry 11). The possible reason
in this case might be that under the reaction conditions the
ethyl group on the nitrogen atom is not as good a leaving group
as a proton (Figure 2b). Also, the reaction fails in the case of a
terminal alkyne (entry 17), presumably due to the absence of
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Note
reported various synthetic routes to cyclic imidates/iminolac-
tones containing 5- and 6-membered rings.21 Since there is
generally a remarkable similarity in the reactivity and
bioactivities of the oxygen species and their nitrogen counter-
parts, one would anticipate that these cyclic imidates might
have potential bioactivities similar to those of their structurally
similar isocoumarin and isoindolin-1-one counterparts. In fact,
the biological potential of this heterocyclic scaffold has been
investigated in a few cases and important biological activities
have been observed. For example, gossylic iminolactone (GIL,
I) derived from the natural product gossypol (II) has been
found to exhibit anti-HIV activity (Figure 3).22 Furthermore,
Figure 2. Possible unstable intermediates involved in the failed
reactions.
any group to stabilize the positive charge on the alkyne (Figure
2c).
The cyclic imidates produced by iodocyclization can be
further elaborated using various palladium-catalyzed processes.
For example, the Sonogashira reaction of cyclic imidate 2 yields
the coupling product 49 in very good yield (eq 3). In fact, in a
continuation of our research group’s efforts to synthesize new
heterocycles with novel biological activities, we have synthe-
sized a midsized library of these cyclic imidates, the results of
which will be published elsewhere.
Figure 3. Biologically active cyclic imidates and related compounds.
It is important to mention that in our original paper, our
iodocyclization chemistry was applied to the synthesis of the
biologically interesting isoindolinone alkaloid cepharanone B
(Scheme 4). In fact, the cyclic imidate 53 was prepared in an
80% yield, and subsequent desilylation and Suzuki coupling
with 2-bromophenylboronic acid afforded the corresponding
imidate 54 in a good yield. Our subsequent attempts to
synthesize cepharanone B failed for obvious reasons.
Hegde et al. reported several cyclic imidate derivatives III of 5-
amino-2,6-bis(polyfluoroalkyl)pyridine-3-carboxylates having
interesting herbicidal activities.23 This has generated further
interest in the synthesis and study of this relatively unexplored
scaffold.
In conclusion, under the mild electrophilic cyclization
conditions reported here, 2-(1-alkynyl)arenecarboxamides
undergo O-cyclization leading to cyclic imidates, with
reasonable regio- and stereoselectivity. The resulting iodine-
containing products can be elaborated to more complex
As far as the synthesis and applications of these cyclic
imidates are concerned, there have been some studies on this
heterocyclic scaffold. Over the years, several groups have
Scheme 4. Failed Attempt To Synthesize Cepharanone B
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Note
135.0, 135.6, 146.1, 148.7, 153.4; IR (neat, cm−1) 1645; HRMS calcd
for C21H14INO 423.0120, found 423.0129.
products using known organopalladium chemistry. Finally, the
methodology can be further extended to the regioselective
synthesis of 5-membered ring lactones by hydrolysis of the
cyclic imidates.
Hydrolysis of the Cyclic Imidate iii. A 150 mg (0.39 mmol)
portion of the cyclic imidate iii was mixed with 2.4 mL of 6 N HCl,
and the reaction mixture was heated at 100 °C for 15 min and at 60 °C
for 15 h. The reaction mixture was then extracted with EtOAc, dried
(MgSO4), and purified by column chromatography using EtOAc−
hexane as the eluent.
(E)-3-(1-Iodobutylidene)isobenzofuran-1(3H)-one (iv). Purifi-
cation by flash chromatography (hexane/EtOAc) afforded the lactone
iv as yellow oil in 69% yield: 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J
= 7.6 Hz, 3H), 1.62−1.72 (m, 2H), 2.99 (t, J = 7.6 Hz, 2H), 7.60 (t, J
= 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 8.77
(d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.2, 22.8, 41.9,
88.1, 124.3, 125.8, 126.5, 130.4, 134.3, 138.4, 144.4, 165.8; HRMS
calcd for C12H11IO2 313.98038, found 313.98122.
EXPERIMENTAL SECTION
■
General Procedure for Preparation of the Amides. To a
solution of the corresponding organic iodide (1.0 mmol) and the
terminal alkyne (1.2 mmol, 1.2 equiv) in Et3N (4 mL) were added
PdCl2(PPh3)2 (1.4 mg, 2 mol %) and CuI (2.0 mg, 1 mol %). The
resulting mixture was then heated under an N2 atm at 55 °C. The
reaction was monitored by TLC to establish completion. When the
reaction was complete, the mixture was allowed to cool to room
temperature, and the ammonium salt was removed by filtration. The
solvent was removed under reduced pressure and the residue was
purified by column chromatography on silica gel to afford the
corresponding 2-(1-alkynyl)benzamide.
ASSOCIATED CONTENT
■
S
N-Methyl-4,5-dimethoxy-2-(phenylethynyl)benzamide (i).
Purification by flash chromatography (hexane/EtOAc) afforded the
product in 87% yield: 1H NMR (400 MHz, CDCl3) δ 3.07 (d, J = 4.8
Hz, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 7.01 (s, 1H), 7.39−7.41 (m, 3H),
7.51−7.53 (m, 2H), 7.65 (br s, 1H), 7.67 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 27.0, 56.2, 56.3, 88.1, 94.5, 112.1, 112.7, 115.1, 122.4,
128.8, 129.05, 129.13, 131.5, 149.6, 150.5, 166.6; HRMS calcd for
C18H17NO3 295.12084, found 295.12139.
General Procedure for Electrophilic Cyclization of the 2-(1-
Alkynyl)arenecarboxamides by I2. The 2-(1-alkynyl)-
arenecarboxamide (0.30 mmol), I2 (3.0 equiv), NaHCO3 (3.0
equiv), and CH3CN (3 mL) were placed in a 4 dram vial and flushed
with N2. The reaction mixture was stirred at room temperature for 1 h
unless otherwise indicated. The reaction mixture was then diluted with
ether (50 mL), washed with satd aq Na2S2O3 (25 mL), dried
(MgSO4), and filtered. The solvent was evaporated under reduced
pressure, and the product was isolated by chromatography on a silica
gel column.
N-[(E)-3-(Iodo(phenyl)methylene)-5,6-dimethoxyisobenzo-
furan-1(3H)-ylidene]methanamine (ii). Purification by flash
chromatography (hexane/EtOAc) afforded the product in 79% yield:
1H NMR (400 MHz, CDCl3) δ 3.15 (s, 3H), 3.97 (s, 3H), 4.03 (s,
3H), 7.25−7.29 (m, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.63 (d, J = 7.6 Hz,
2H), 8.29 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 35.1, 56.46, 56.53,
71.6, 103.9, 106.9, 125.3, 128.0, 128.2, 129.5, 130.4, 140.7, 147.3,
151.8, 154.8 (one signal missing due to overlap); HRMS calcd for
C18H16INO3 421.01749, found 421.01870.
* Supporting Information
General experimental methods, reaction procedures, corrected
names and characterization data, copies of H and 13C NMR
1
spectra for previously unreported compounds, and X-ray
crystallographic data for compounds ii and 26. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: larock@iastate.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Institute of General
Medical Sciences (GM070620 and GM079593) and the
National Institutes of Health Kansas University Center of
Excellence for Chemical Methodologies and Library Develop-
ment (P50 GM069663) for support of this research. We also
acknowledge Johnson Matthey, Inc., and Kawaken Fine
Chemicals Co., Ltd. for donations of palladium catalysts and
thank Dr. Arkady Ellern and the Molecular Structure
Laboratory of Iowa State University for providing X-ray
crystallographic data for products ii and 26.
N-[(E)-3-(1-Iodobutylidene)isobenzofuran-1(3H)-ylidene]-
aniline (iii). Purification by flash chromatography (hexane/EtOAc)
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7.22−7.36 (m, 7H), 7.59−7.73 (m, 4H), 8.05 (d, J = 7.5 Hz, 1H), 8.86
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NOTE ADDED IN PROOF
■
During the review of our paper, Opatz et al. reported a similar
O-cyclization in the iodocyclization of 2-(1-alkynyl)-
benzamides. See: Schlemmer, C.; Andernach, L.; Schollmeyer,
D.; Straub, B. F.; Opatz, T. J. Org. Chem. 2012, 77, 10118−
10124.
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dx.doi.org/10.1021/jo301958q | J. Org. Chem. 2012, 77, 10938−10944