Iron(II)-catalyzed amidation of aldehydes with iminoiodinanes at room temperature and under microwave-assisted conditions

Article abstract of DOI:10.1021/jo200284a

A method for the amidation of aldehydes with PhI=NTs/PhI=NNs as the nitrogen source and an inexpensive iron(II) chloride + pyridine as the in situ formed precatalyst under mild conditions at room temperature or microwave assisted conditions is described. The reaction was operationally straightforward and accomplished in moderate to excellent product yields (20-99%) and with complete chemoselectivity with the new C-N bond forming only at the formylic C-H bond in substrates containing other reactive functional groups. By utilizing microwave irradiation, comparable product yields and short reaction times of 1 h could be accomplished. The mechanism is suggested to involve insertion of a putative iron-nitrene/imido group to the formylic C-H bond of the substrate via a H-atom abstraction/radical rebound pathway mediated by the precatalyst [Fe(py)₄Cl₂] generated in situ from reaction of FeCl ₂ with pyridine.

Full text of DOI:10.1021/jo200284a

ARTICLE
pubs.acs.org/joc
Iron(II)-Catalyzed Amidation of Aldehydes with Iminoiodinanes at
Room Temperature and under Microwave-Assisted Conditions
Thi My Uyen Ton, Ciputra Tejo, Stefani Tania, Joyce Wei Wei Chang, and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S Supporting Information
b
ABSTRACT: A method for the amidation of aldehydes with
PhIdNTs/PhIdNNs as the nitrogen source and an inexpen-
sive iron(II) chloride þ pyridine as the in situ formed precatalyst
under mild conditions at room temperature or microwave
assisted conditions is described. The reaction was operationally
straightforward and accomplished in moderate to excellent
product yields (20ꢀ99%) and with complete chemoselectivity
with the new CꢀN bond forming only at the formylic CꢀH
bond in substrates containing other reactive functional groups. By utilizing microwave irradiation, comparable product yields and
short reaction times of 1 h could be accomplished. The mechanism is suggested to involve insertion of a putative iron-nitrene/imido
group to the formylic CꢀH bond of the substrate via a H-atom abstraction/radical rebound pathway mediated by the precatalyst
[Fe(py)4Cl2] generated in situ from reaction of FeCl2 with pyridine.
’ INTRODUCTION
strategies the corresponding acyl sulfonamides were afforded in
good to excellent yields. We subsequently showed that a more
practical copper(I) halide catalyzed version of this reaction could
be realized.13 While less expensive and more ecologically benign
than ruthenium, a drawback of this latter approach was the need
to develop two distinct catalytic Cu(I) systems to achieve a broad
substrate scope that included aromatic compounds. Thus, it
remains a challenge to develop a synthetic method that can effect
such reactions for a wide range of substrates in a manner that
improves or at least maintains the practical and biocompatible
nature of the catalytic system employed. In this regard, we
envisioned that establishing an iron-mediated approach to this
important amide forming reaction could hold promise as the
basis to readdressing this shortcoming.14 Recently, iron com-
plexes and salts have come under renewed scrutiny in the field of
amidation and aziridination of activated CꢀH and CdC bonds
of alkanes and alkenes due to their low cost and less toxic nature
when compared to other transition metals.15,16 However, the
use of iron catalysis to mediate the analogous nitrogen atom or
group insertion reactions at the formylic CꢀH bond of aldehydes
to our knowledge has, thus far, remained unexplored. Herein,
we report the use of the in situ formed complex [FeCl2(py)4]
(py = pyridine) for amidation of a wide variety of aldehydes
with PhIdNSO2Ar at room temperature and under microwave-
assisted conditions (Scheme 1). The acyl sulfonamide products
were afforded in moderate to excellent yields comparable to
those reported for the analogous Ru(II)- and Cu(I)-promoted
reactions.
Establishing methods to amides is an immensely important
pursuit in organic synthesis due to the role of this functional
group as a privileged pharmacophore and building block in a
myriad of biomolecules as well as pharmaceutically interesting
compounds.1 Typically, amide bond synthesis has relied on the
condensation of an amine with a carboxylic acid in the presence
of a coupling reagent.2 Although shown to be highly efficient,
producing H2O as potentially the only byproduct, the utility of
this approach has been lessened by the need for an extra step to
convert the carboxylic acid to a more reactive derivative. This not
only generates additional byproduct but also, in some cases,
synthetic complications in the activated intermediates. For this
reason, the development of alternative synthetic strategies to
this ubiquitously important functional group has received an
immense amount of attention over the years.3ꢀ13 This has
hitherto included Staudinger ligation,4 Beckmann rearrangement
of oximes,5 aminocarbonylation of haloarenes, alkenes, and
alkynes,6 oxidative amidation of alcohols7 and aldehydes,8 hy-
drative amide synthesis with alkynes,9 and amidation of ketones
and thioacids with azides.10
As part of our efforts to develop new methods for amide bond
synthesis, we recently reported one approach that relied on
nitrene insertion at the formyl CꢀH bond of aldehydes with
PhIdNTs as the nitrogen source and [Ru(TTP)(CO)] as the
catalyst.11 At about the same time, Chan and co-workers reported
the same CꢀN bond forming process could be accomplished
with TsNH2 in the presence of [Rh2(esp)2] (esp = R,R,R0,R0-2-
tetramethyl-1,3-benzenedipropionate) as the catalyst and
PhI(OC(O)tBu)2 as the oxidant.12 Thought to proceed via a
highly reactive metal-nitrene/imido species, in both synthetic
Received: February 6, 2011
Published: April 27, 2011
r
2011 American Chemical Society
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Scheme 1. Iron(II)-Catalyzed Amidation of Aldehydes with
PhIdNTs at Room Temperature or under Microwave Irra-
diation (MW)
Table 1. Optimization of Reaction Conditionsa
yield (%)
entry catalyst
FeCl2
ligand
solvent
2a
3a
1
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
DMAP
CH2Cl2
CH2Cl2
CH2Cl2
C6H6
90
78
74
73
40
’ RESULTS AND DISCUSSION
2b FeCl2
3c FeCl2
4c FeCl2
5c FeCl2
6c FeCl2
7c FeCl2
8f FeCl2
9g FeCl2
10 FeCl2
11 FeCl2
12 FeCl2
13 FeCl2
14 FeCl2
In view of the challenges still posed by aromatic aldehydes in
the analogous Cu(I)- and Ru(II)-catalyzed reactions, we began
by examining the amidation of benzaldehyde 1a by a variety of
Fe(II) and Fe(III) salts, and the results are depicted in Table 1.
This revealed that treating 1a with 10 mol % of FeCl2 (99.5%
purity),17 pyridine (0.4 equiv), and 2 equiv of PhIdNTs as
the nitrogen source in CH2Cl2 at room temperature for 18 h gave
the best result (entry 1). Under these conditions, N-tosylbenzamide
2a was afforded in 90% yield that was found to be comparable
to product yields of 83ꢀ93% obtained for the analogous amida-
tions of 1a with PhIdNTs mediated by Cu(I), Rh(II,II), and
Ru(II).11ꢀ13 Lower product yields of 74ꢀ78% were obtained
when we employed a lower catalyst loading of 5 mol % or 1.5
equiv of PhIdNTs (entries 2 and 3). Likewise, conducting the
reaction with benzene in place of CH2Cl2 as the solvent led to a
comparable product yield of 73% (entry 4). In marked contrast,
the analogous reactions with TsNH2 þ PhI(OAc)2 or chlor-
PhMe
CH3CN
1,4-dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
27
d,e
25
59
88
36
35
8
2-picolinic acid
quinaldic acid
10
36
48
33
32
11
d
2,6-pyridinedicarboxylic acid CH2Cl2
quinoline
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
27h
28
49h
35
28
26
50
24
15 Fe(OTf)2 pyridine
16 FeCl3
pyridine
17 FeCl2
42
15
51
49
55
18 FeBr2
amine-T trihydrate (TsNClNa 3H2O) þ PhIdO as the nitro-
3
19 Fe(OAc)2
20 Fe(OTf)2
21 FeCl3
gen source were also found to give low product yields along with
3a in 8ꢀ35% yield (entries 8 and 9). Similarly, low product yields
along with recovery of 1a and/or the imine adduct were found
when the reaction was performed with 1.5 equiv of PhIdNTs in
other solvent systems or with other pyridyl-based ligands (entries
5ꢀ7 and 11ꢀ14). In our hands, only the analogous reaction of 1a
with PhIdTs mediated by FeCl2 and DMAP afforded 2a in a
comparable yield of 88% (entry 10). An inspection of entries
15ꢀ21 in Table 1 also revealed the reaction to proceed less
effectively with other Fe(II) and Fe(III) salts in the presence or
absence of a ligand. In these reactions, the imine byproduct was
additionally furnished in yields of 8ꢀ55%. More notably, the use
of Fe(OTf)2 was the only instance that was found to be superior
than FeCl2 in mediating the amidation process under ligand free
conditions, furnishing 2a in 50% yield (entry 20). However,
repeating this reaction with pyridine gave a lower product yield of
28% (entry 15). Additionally, the contrasting activities exhibited
by FeCl2 and FeCl3 suggested it was unlikely that these latter
reactions proceeded via a common catalytically active iron
species (entries 1 and 17 vs 16 and 21).
a Unless otherwise stated, all reactions were carried out for 18 h at rt in
the presence of powdered 4 Å MS (400 mg) with [Fe]:py:1a:PhIdNTs
molar ratio = 1:4:10:20. b Reaction conducted with 5 mol % of FeCl2.
c Reaction conducted with 1.5 equiv of PhIdNTs. d No reaction based
on TLC and 1H NMR analysis of the crude mixture. e Near quantitative
f
recovery of 1a. PhIdNTs was replaced by PhI(OAc)2 and TsNH2.
g PhIdNTs was replaced by PhIO and TsNClNa 3H2O. h Recovery of
3
1a in 40ꢀ50% yield.
example of a sterically demanding substrate that was found
to deliver the amidation product in a moderate yield of 46%
(entry 14). On the other hand, reactions of a variety of alkyl
aldehydes examined were found to afford the corresponding acyl
sulfonamide products 2pꢀz in good to excellent yields (entries
15ꢀ25). A similar outcome was found for reactions of aliphatic
aldehydes containing an alkene functional group (entries 26ꢀ29).
More notably, in these reactions where either a competing
aziridination or tertiary CꢀH amidation process was a potential
problem, the corresponding acyl sulfonamides 2e, 2qꢀr, 2uꢀw,
2rꢀε were furnished as the sole product in yields of 48ꢀ99%.
The only substrates examined that failed or found to be less
effective in our hands were 1m and 1x and the carbaldehydes of
furan and thiophene 1ζ and 1η (entries 12, 23, and 31ꢀ32).
Under the standard conditions, reaction of 1x was found to lead to
To define the scope of the present procedure, we next turned
our attentions to the reactions of a variety of aldehydes (Table 2).
In general, these experiments showed that with the FeCl2 and
pyridine combination, reaction of 1a with PhIdNNs gave 2b and
a variety of substituted aromatic aldehydes PhIdNTs afforded
the corresponding acyl sulfonamides 2cꢀo in moderate to
excellent yields (entries 1ꢀ14). This hitherto included substrates
with a pendant Br, Cl, or MeO group at the para positon of the
aromatic, which were previously shown to give the correspond-
ing amide products in moderate yields of 47ꢀ65% in the
analogous Cu(I)-mediated reactions.13 Under our conditions,
the FeCl2-mediated reaction of 1-naphthaldehyde was the only
1
the formation of toluene on the basis of H NMR and ESI-MS
measurements of the crude mixture, whereas 1m and 1ζ resulted
in their recovery and 1η afforded 2η in 20% yield.
Microwave irradiation has been extensively documented in
recent years as a method to accelerate transition metal catalyzed
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ARTICLE
reactions and their potential for scale-up applications.18 With
this in mind, we also investigated the iron mediated transforma-
tion of aldehydes to amides under microwave assisted condi-
tions with 1a, 1o, 1v, 1β, 1ε, and 1η chosen as representative
examples, as shown in Scheme 2. In the presence of 10 mol %
of FeCl2, pyridine (0.4 equiv) and PhIdNTs (2 equiv) in
CH2Cl2 and microwave irradiation for 1 h, these subtrates
provided the corresponding acyl sulfonamide products in
yields of 38ꢀ99%, comparable to those obtained at room
temperature.
on the possible involvement of a radical species in the present
Fe(II)-catalyzed reactions. This would be not inconceivable in
view of the fact that it has been previously reported that
decarbonylation of a phenylacetyl radical has been measured in
the order of kd = 5.2 ꢁ 107 sꢀ1 at 25 °C.19 The premise that the
amidation proceeds via a radical intermediate would be consis-
tent with our findings showing the detection of only the aldehyde
1
based on TLC and H NMR analysis of the crude reaction
mixture of1a þ PhIdNTs exposed to 10 mol % of FeCl2, 40 mol%
of pyridine, and the radical scavenger butylhydroxytoluene (BHT)
under the standard conditions. Indeed, this is further supported by
competitive rate studies under the conditions shown in Figure 1.
The preferential formation of toluene for the amidation of
1x mentioned earlier in entry 23 in Table 2 led us to speculate
Table 2. Iron(II)-Catalyzed Amidation of Aldehydes 1aꢀηa
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Table 2. Continued
a Unless otherwise stated, all reactions were carried out for 18 h at rt in the presence of powdered 4 Å MS with FeCl2 (99.5% purity):17py:1:PhIdNTs
molar ratio = 1:4:10:20. b PhIdNTs was replaced by PhIdNNs. c Trace amount (<1%) of product detected on the basis of 1H NMR analysis of the crude
mixture but not isolated. d Toluene detected on the basis of GC and 1H NMR analysis. e No reaction based on TLC and 1H NMR analysis of the crude
mixture.
co-workers in which a nonpolar transition state and a radical-
type mechanism was proposed.20
Scheme 2. Iron(II)-Catalyzed Amidation of Aldehydes with
PhIdNTs under Microwave Irradiation
In view of recent works showing the true catalytic species in
the reported cross-coupling reactions to be due to trace amounts
of Cu and Pd in the iron salts,21 this possibility was next examined
with 1a and 1k as the test substrates under the conditions
described in Table 3. This initially revealed the amidation of 1a
with PhIdNTs in the presence of 0.05 mol % of Cu2O as the
catalyst gave the corresponding imine 3a as the sole product and
recovery of the aldehyde in 29% and 71% yield, respectively
(entry 3). Repeatingthis process with 1k in place of 1a and 1 mol %
of the metal oxide as well as chloride and triflate salts of Cu(I)
and Cu(II) was found to give a similar outcome (entries 5ꢀ9). In
all of these reactions, the corresponding imine 3k was preferen-
tially afforded in near quantitative yields. The analogous reac-
tions with 1 mol % of either Pd(PPh3)4 or Pd(OAc)2 were also
found to lead to the exclusive formation of the imine adduct in
58ꢀ61% yield and recovery of the substrate in 39ꢀ42% yield
(entries 10 and 11). In marked contrast, the acyl sulfonamide
products 2a and 2k were obtained in respective yields of 92%
and 70% when we carried out the corresponding reactions of
1a and 1k with 10 mol % of FeCl2 of 99.99% purity17 (entries 1
and 4). Likewise, reaction of 1a with 10 mol % of [FeCl2(py)4],
prepared following literature procedure and structurally deter-
mined by X-ray crystallography (see Figure S40 in the Support-
ing Information),22 was found to deliver 2a in 93% yield
(entry 2). The product yields and chemoselectivities obtained
This revealed a log(krel) value of ꢀ0.103 that suggested there
were no significant electronic effects in the amidation process.
With the exception of 1m, the absence of such effects would
also account for our earlier results showing aromatic aldehyde
amidation to proceed well regardless of the presence of an
electron-withdrawing or electon-donating group depicted in
entries 2ꢀ11 in Table 2. Additionally, the near zero reaction
constant is comparable to that found for manganese corrole
catalyzed alkene aziridinations reported by Abu-Omar and
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Figure 1. Linear free-energy correlation of log kX/kH versus σp plot for amidation of para-substituted aldehydes 2a, 2c, 2f, 2k, and 2m.
On the basis of the above results, we tentatively propose the
present iron(II)-catalyzed amidation of aldehydes with PhIdNTs
to proceed by CꢀH bond functionalization as outlined in
Scheme 3.15,23 This could involve the initial formation of the
precatalyst [FeCl2(py)4] from reaction of FeCl2 with pyridine.
Further reaction of this newly formed iron complex with PhId
NSO2Ar then generates the putative highly reactive [Fe]dNSO2Ar
species A.15k,23 In contrast to the analogous CuI-catalyzed aldehyde
amidation reactions,13 subsequent insertion of the nitrene/imido
group from this intermediate to the formylic CꢀH bond of the
substrate via a H-atom abstraction/radical rebound pathway is then
thought to deliver the amide product 2. The obtained product
chemoselectivities are in good agreement with recent DFT calcula-
tions by Bolm and Shaik showing amidation is favored over
aziridination when the nitrogen substituent contains an electron-
withdrawing group and steric effects having little influence in these
reactions.23a The role of pyridine as a ligand in the catalytic system
that tempers the Lewis acidity of FeCl2 through coordination to
the metal center and in situ formation of [FeCl2(py)4] is evident
in a number of experiments examined in this work. First is
the formation of only the acyl sulfonamide product for reactions
of 1 conducted in the presence of the iron(II) salt and pyridine
or [FeCl2(py)4] under the various conditions described in
Tables 1ꢀ3. In contrast, both 2a and 3a were observed on either
removing the nitrogen heterocycle from the reaction conditions or
replacing it with less basic ligands when we examined the amidation
of 1a (entries 11ꢀ14 and 17 in Table 1). We surmise the origin of
the imine byproduct could be due to iron catalyzed hydrolysis of
PhIdNTs to TsNH2 by H2O,24 followed by condensation of this
newly formed aryl sulfonamide with the aldehyde in the presence
of the Lewis acidic metal salt.25
Table 3. Determining the Potential Role of Trace Amounts of
Cu and Pd in the Aldehyde Amidation Processa
entry
substrate
catalyst
FeCl2
product
yield (%)
1b
2c
3d
4b
5
1a, R = H
2a
2a
3a
2k
3k
3k
3k
3k
3k
3k
3k
92
93
29e
70
99
99
99
99
99
61e
58e
1a, R = H
[FeCl2(py)4]
Cu2O
1a, R = H
1k, R = CF3
1k, R = CF3
1k, R = CF3
1k, R = CF3
1k, R = CF3
1k, R = CF3
1k, R = CF3
1k, R = CF3
FeCl2
Cu2O
6
CuCl
7
CuOTf
8
Cu(OTf)2
CuCl2
9
10
11
Pd(PPh3)4
Pd(OAc)2
a Unless otherwise stated, all reactions were carried out for 18 h at rt in the
presence of powdered 4 Å MS with catalyst:py:1:PhIdNTs molar ratio =
0.1:0.4:10:20. b Reaction conducted with 10 mol % of FeCl2 of 99.99%
c
purity17 and 40 mol % of py. Reaction conducted with 10 mol % of
[FeCl2(py)4] and in the absence of py. d Reaction conducted with 0.05 mol
% of Cu2O and 0.2 mol % of py. e Recovery of aldehyde in 39ꢀ71% yield.
in these latter control experiments were also found to be com-
parable to those reported for the same substrates in Tables 1 and
2 using 99.5% pure FeCl2 as the catalyst.17 More importantly, the
contrasting reactivities observed in Table 3 provided evidence
that trace amounts of Cu and Pd impurities present in FeCl2 used
in this work are not the catalytically active species.
Given previous works demonstrating iron-catalyzed hydro-
lysis of the iminoiodinane to the aryl sulfonamide by H2O to
occur via iron-nitrene/imido species of the type A and/or B,24
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Scheme 3. Tentative Reaction Pathway for CꢀN Bond
Formation
Figure 2. Possible amidation intermediates 4 and 5.
conditions (see Figure 35 in the Supporting Information).
Monitoring the progress of the reaction by 13C NMR spectros-
copy revealed the presence of two major signals in aliquots taken
from the reaction mixture. These were, namely, that of the
labeled benzaldehyde substrate 13C-1a decreasing in intensity
and that of labeled amide product 13C-2a increasing in intensity.
the competitive formation of the imine byproduct also implies
the involvement of such intermediates in our reactions. Indeed,
this speculation was supported by 1H NMR measurements of an
equimolar CD2Cl2 sample of [FeCl2(py)4] and PhIdNTs (see
Figure S37 in the Supporting Information). The resultant dark
brown homogeneous solution was found to be diamagnetic with
well-resolved 1H NMR signals at normal fields that showed the
methyl and ortho and meta aromatic CꢀH resonances of the tosyl
group shifted downfield by 0.10ꢀ0.35 ppm relative to the
respective signals in PhIdNTs and TsNH2. Subsequent addition
of 1a to this CD2Cl2 sample then led to the detection of 2a by 1H
NMR and TLC analysis.
’ CONCLUSION
In summary, an efficient and practical iron-catalyzed synthetic
route to acyl sulfonamides based on nitrene/imido insertion
into the formylic CꢀH bond of aldehydes has been reported.
These results show that the reaction tolerates a structurally
diverse set of starting aldehydes and compliment earlier works
mediated by Ru(II) and Cu(I) catalysts. While the product yields
and chemoselectivities obtained are also comparable, the present
method was shown to benefit from a low-cost and extremely
simple catalytic system generated in situ from iron(II) chloride
and pyridine and withstand microwave irradiation to achieve
short reaction times. Similarly as for the analogous copper-
catalyzed amidation reactions, our studies suggest the reaction
to proceed by rate-determining insertion of an iron-nitrenoid
species into the aldehydric CꢀH bond. However, it differs in that
the CꢀN bond-forming process is more likely to follow a radical
rather than a concerted mechanistic pathway.
Although further NMR analysis and mass spectrometry was
not able to elucidate the exact structure of A, measurement of the
deuterium kinetic isotope effect with 1a and benzaldehyde-d6
as the test substrates revealed a kH/kD value of 4.4 based on
LCꢀMS analysis. This suggested that CꢀH bond cleavage
resulting in the formation of the proposed radical species B is
most probably the rate-determining step. This value is also
comparable to kH/kD values reported for the analogous CuI-
catalyzed benzaldehyde amidation reaction,13 nitrene/imido
insertion into the dibenzyl ether in the presence of CuCl as
catalyst,26 and [Ru(TMP)(NNs)2] (H2TMP = 5,10,15,20-tetra-
mesitylporphyrin)-mediated amidation of ethyl benzene.27
While the above results are consistent with a H-atom abstrac-
tion/radical rebound pathway depicted in Scheme 3, other
possible pathways were considered but discounted on the basis
of the following control experiments. In addition to acting as a
ligand to form the tetrapyridyliron(II) complex, we considered
the possibility that pyridine could react with PhIdNTs and
formation of the nitrene transfer agent N-tosyliminopyridine 4
shown in Figure 2.28 With this in mind, the reaction of 1a with an
authentic sample of 4 in the presence of the iron catalyst under
the standard conditions was first examined. Analysis of the
resultant crude reaction mixture by TLC and 1H NMR analysis
showing only the presence of the aldehyde substrate led us to
conclude the involvement of such a nitrene transfer agent to be
less likely. Similarly, the competitive formation of the imine
byproduct 3a under certain conditions mentioned in Table 1 or
its subsequent oxidation derivative 5 shown in Figure 2 led us
to consider pathways in which these intermediates could be
involved.29 However, our findings showing only the recovery of
the starting material for the respective reactions of 3a and 5
exposed to 10 mol % of FeCl2 and 40 mol % of pyridine under the
standard conditions led us to also rule out the possibility of amide
bond formation occurring via such intermediates. The direct
conversion of the aldehyde to the amide functional group was
further supported by our findings for the reaction of 1a labeled
with 13C at the aldehyde position in CD2Cl2 under the standard
’ EXPERIMENTAL SECTION
General Remarks. All reactions were performed under a nitrogen
atmosphere at ambient temperature unless otherwise stated.
PhIdNTs,30 PhIdO,31 and [Ru(TTP)CO]32 (H2TTP = meso-tetrakis-
(p-tolyl)porphyrin) were prepared according to known literature pro-
cedures. Unless specified, all reagents and starting materials were
purchased from commercial sources and used as received; FeCl2 used
in this work was of either 99.5% or 99.99% purity.17 Solvent were
purified prior to use following literature procedures; CH2Cl2 and MeCN
were purified prior to use by distilling over CaH2; pyridine was distilled
over KOH and benzaldehyde was distilled under reduced pressure.
Analytical thin layer chromatography (TLC) was performed using
precoated silica gel plate. Visualization was achieved by UVꢀvis light
(254 nm) followed by treatment with ninhydrin stain and heating.
Flash chromatography was performed using silica gel using a gradient
solvent system (EtOAc/n-hexane as eluant). Unless otherwise stated,
1H and 13C NMR spectra were measured on a 300 MHz spectrometer.
Unless otherwise stated, chemical shifts (ppm) were recorded in CDCl3
solution with tetramethylsilane (TMS) as the internal reference
standard. Multiplicities are given as s (singlet), bs (broad singlet),
d (doublet), dt (doublet of triplet), t (triplet), bt (broad triplet), tt (triple
of triplets), q (quartet), dd (doublet of doublets), quin (apparent
quintet) or m (multiplet). The number of protons (n) for a given
resonance is indicated by nH, and coupling constants are reported as a
J value in Hz. Low resolution mass spectra were determined on a mass
spectrometer and reported as a ratio of mass to charge (m/z). High
resolution mass spectra (HRMS) were obtained using a LCꢀHRMS
mass spectrometer. Kinetic isotope measurements were conducted on
a benchtop atmospheric pressure LCꢀMS mass spectrometer with 0.1%
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formic acid in 95:5 H2O:/MeCN as the mobile phase. Reactions
conducted under microwave conditions were carried out with a CEM
Discover Labmate microwave synthesizer with an internal IR sensor
located at the bottom of the cavity, irradiation at 2450 MHz and
temperature, power and pressure settings at 25 °C, 200 W and 17 bar,
respectively.
2H), 7.39ꢀ7.26 (m, 4H), 2.44 (s, 3H); 13C NMR (125 MHz) δ 163.5,
145.4, 140.0, 135.1, 129.6, 129.4, 129.3, 129.1, 128.5, 21.6; MS (ESI)
m/z 310 [M þ H]þ.
4-Fluoro-N-tosylbenzamide (2j)35. White solid; 1H NMR δ
9.70 (bs, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.87 (dd, J = 8.4, 5.1, 2H), 7.33 (d,
J = 8.1 Hz, 2H), 7.07 (t, J = 8.4 Hz, 2H), 2.43 (s, 3H); 13C NMR δ 163.6,
145.4, 135.3, 130.8, 130.6, 129.7, 128.6, 127.3, 116.2, 115.9, 21.7. MS
(ESI) m/z 294 [M þ H]þ.
General Procedure for FeCl2 þ Pyridine Catalyzed Amida-
tion of Aldehydes with PhIdNTs or PhIdNNs. To a suspension
of FeCl2 (0.05 mol) and powdered 4 Å MS (400 mg) in CH2Cl2 (2 mL)
was added pyridine (0.2 mmol). After 5 min of stirring, PhIdNTs or
PhIdNNs (1 mmol) was added followed by addition of the aldehyde
(0.5 mmol). The reaction was stirred at room temperature for 18 h (or
1 h under microwave conditions), after which the crude mixture was
filtered through Celite, washed with EtOAc, evaporated to dryness, and
purified by silica gel flash column chromatography (n-hexanes/EtOAc as
eluant) to give the acyl sulfonamide product.
4-Trifluoromethyl-N-tosylbenzamide (2k)6c. White solid; 1H
NMR δ 9.78 (bs, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.1 Hz, 2H),
7.65 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H); 13C NMR
δ 163.5, 145.7, 135.1, 134.6, 134.4, 129.8, 128.7, 128.5, 125.9, 125.8,
125.1, 21.7; MS (ESI) m/z 344 [M þ H]þ.
4-Acetoxy-N-tosylbenzamide (2l). White solid; mp 138ꢀ
1
139 °C; H NMR δ 9.39 (bs, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.83 (d,
J = 8.7 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 2.43 (s,
3H), 2.32 (s, 3H); 13C NMR δ 163.4, 154.6, 145.3, 129.7, 129.5, 128.7,
122.2, 21.7, 21.1; IR (neat, cmꢀ1) 3018, 2399, 1759, 1705, 1602, 1425,
1165, 1066; MS (ESI) m/z 318 [M þ H]þ; HRMS (ESI) calcd for
C16H16NO5S 334.0749, found 334.0762.
N-Tosylbenzamide (2a)6c. White solid; 1H NMR δ 9.83 (bs, 1H),
8.03 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 7.5 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H),
7.36 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 2.39 (s, 3H); 13C NMR
δ 164.6, 145.2, 135.5, 133.5, 131.1, 129.7, 128.9, 128.6, 128.0, 21.7; MS
(ESI) m/z 276 [M þ H]þ.
6c
1
N-(4-Nitrophenylsulfonyl)benzamide (2b)33. White solid;
1H NMR (CD3COCD3, 400 MHz) δ 8.45 (d, J = 8.8 Hz, 2H), 8.37
(d, J = 8.8 Hz, 2H), 7.95 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.48
(t, J = 8.0 Hz, 2H); 13C NMR δ 165.8, 150.7, 145.6, 133.2, 132.1, 129.8,
128.6, 128.4, 124.1; MS (ESI) m/z 307 [M þ H]þ.
2-Methyl-N-tosylbenzamide (2n) . White solid; H NMR δ
9.17 (bs, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.5, 1H), 7.34 (d, J =
8.1 Hz, 2H), 7.29ꢀ7.35 (m, 1H), 7.17 (d, J = 7.5, 1H), 7.13ꢀ7.18 (m,
1H), 2.44 (s, 3H), 2.33 (s, 3H); 13C NMR δ 166.5, 145.2, 138.0, 135.6,
132.1, 131.8, 131.6, 129.6, 128.5, 127.5, 125.9, 21.7, 20.1; MS (ESI) m/z
290 [M þ H]þ.
4-Methoxy-N-tosylbenzamide (2c)6c. White solid; 1H NMR δ
9.21 (bs, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.31 (d,
J = 8.1 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 2.42 (s, 3H); 13C
NMR δ 163.8, 145.1, 135.7, 130.0, 129.6, 128.6, 126.5, 123.3, 114.1,
55.5, 21.7; MS (ESI) m/z 306 [M þ H]þ.
6c
1
N-Tosyl-1-napthamide (2o) . Yellow solid; H NMR δ 8.81
(bs, 1H), 8.17 (m, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.1 Hz, 1H),
7.82 (m, 1H), 7.65 (dd, J = 7.2, 0.9 Hz, 1H), 7.47ꢀ7.52 (m, 2H),
7.33ꢀ7.42 (m, 3H), 2.45 (s, 3H); 13C NMR δ 165.9, 145.3, 135.5, 133.7,
132.9, 130.0, 129.9, 129.7, 128.6, 128.5, 127.9, 126.8, 126.6, 124.9, 124.4,
21.7; MS (ESI) m/z 326 [M þ H]þ.
4-tert-Butyl-N-tosylbenzamide (2d)34. White solid; 1H NMR δ
9.69 (bs, 1H), 8.05 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.40 (d,
J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 2.41 (s, 3H), 1.27 (s, 9H); 13C
NMR δ 164.4, 157.3, 145.1, 135.7, 129.6, 128.6, 128.2, 127.9, 125.8,
35.1, 31.0, 21.7; MS (ESI) m/z 332 [M þ H]þ.
N-Tosylpropionamide (2p)36. White solid; 1H NMR δ 8.85 (bs,
1H), 7.94 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 2.43 (s, 3H), 2.29
(q, J = 7.5 Hz, 2H), 1.06 (t, J = 7.5 Hz, 3H); 13C NMR δ 171.8, 145.2,
135.6, 129.7, 128.3, 29.5, 21.7, 8.2; MS (ESI) m/z 228 [M þ H]þ.
3-Methyl-N-tosylbutanamide (2q)37. White solid; 1H NMR δ
8.99 (bs, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 2.41
(s, 3H), 2.10 (d, J = 6.3 Hz, 2H), 2.00ꢀ2.06 (m, 1H), 0.86 (d, J = 6.6 Hz,
6H); 13C NMR δ 171.1, 145.2, 135.7, 129.7, 128.4, 45.3, 25.7, 22.3, 21.8;
MS (ESI) m/z 256 [M þ H]þ.
4-Isopropyl-N-tosylbenzamide (2e). White solid; mp 155ꢀ
157 °C; 1H NMR δ 9.36 (bs, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.79 (d, J =
8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 2.89 (quin,
J = 6.9 Hz, 1H), 2.40 (s, 3H), 1.19 (d, J = 6.9 Hz, 6H); 13C NMR δ 164.7,
155.0, 145.1, 135.7, 129.6, 128.7, 128.6, 128.3, 126.9, 34.2, 23.6, 21.7; IR
(neat, cmꢀ1) 3273, 3020, 2964, 1697, 1608, 1427, 1215, 1166, 1070; MS
(ESI) m/z 318 [M þ H]þ; HRMS (ESI) calcd for C17H20NO3S
318.1164, found 318.1164.
N-Tosylisobutyramide (2r)37. Pale yellow solid; 1H NMR (400
MHz) δ 8.86 (bs, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H),
2.39ꢀ2.46 (m, 4H), 1.09 (d, J = 7.2 Hz, 6H); 13C NMR (100 MHz) δ
175.0, 145.4, 135.7, 129.9, 128.6, 35.9, 22.0, 18.8; MS (ESI) m/z 344
[M þ H]þ.
6c
1
4-Methyl-N-tosylbenzamide (2f) . White solid; H NMR δ
9.56 (bs, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.32 (d,
J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 2.41 (s, 3H), 2.34 (s, 3H); 13C
NMR δ 164.5, 145.1, 144.4, 135.6, 129.6, 129.5, 128.6, 128.3, 128.0,
21.7, 21.6; MS (ESI) m/z 290 [M þ H]þ.
N-Tosylpivalamide (2s)38. Pale yellow solid; 1H NMR δ 8.68 (bs,
1H), 7.95 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 2.43 (s, 3H), 1.14
(s, 9H); 13C NMR δ 176.0, 145.0, 135.6, 129.6, 128.4, 40.0, 26.7, 21.6;
MS (ESI) m/z 256 [M þ H]þ.
4-Phenyl-N-tosylbenzamide (2g). White solid; mp 200ꢀ
1
202 °C; H NMR δ 9.07 (bs, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.87 (d,
N-Tosylheptanamide (2t)11. Pale yellow solid; 1H NMR δ 9.19
(bs, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H),
2.23 (t, J = 7.5 Hz, 2H), 1.56 (t, J = 6.9 Hz, 2H), 1.20ꢀ1.26 (m, 6H), 0.82
(t, J = 6.9 Hz, 3H); 13C NMR δ 171.5, 145.1, 135.6, 129.6, 128.3, 36.3,
31.3, 28.5, 24.3, 22.4, 21.7, 13.9; MS (ESI) m/z 284 [M þ H]þ.
N-Tosylcyclopropanecarboxamide (2u)11. White solid; 1H
NMR δ 8.88 (bs, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz,
2H), 2.44 (s, 3H), 1.56ꢀ1.51 (m, 1H), 1.02 (m, 2H), 0.87ꢀ0.83 (m,
2H); 13C NMR δ 172.3, 145.1, 135.6, 129.6, 128.3, 21.7, 14.7, 9.7; MS
(ESI) m/z 240 [M þ H]þ.
J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H),
7.46ꢀ7.35 (m, 5H), 2.44 (s, 3H); 13C NMR δ 164.5, 145.5, 144.6, 139.4,
137.1, 130.7, 129.4, 129.0, 128.8, 128.4, 128.3, 127.1, 127.0, 20.6; IR
(neat, cmꢀ1) 3286, 3018, 1697, 1606, 1425, 1334, 1215, 1165; MS (ESI)
m/z 352 [M þ H]þ; HRMS (ESI) calcd for C20H18NO3S 352.1007,
found 352.0991.
13
1
4-Bromo-N-tosylbenzamide (2h) . White solid; H NMR δ
9.53 (bs, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.54 (d,
J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H); 13C NMR δ 163.4,
145.0, 134.9, 131.8, 129.6, 129.3, 129.1, 128.2, 21.3; MS (ESI) m/z 354
[M þ H]þ.
N-Tosylcyclopentanecarboxamide (2v)11. White solid; 1H
NMR δ 8.67 (bs, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1 Hz,
2H), 2.62 (m, 1H), 2.43 (s, 3H), 1.51ꢀ1.82 (m, 8H); 13C NMR δ 173.9,
4-Chloro-N-tosylbenzamide (2i)13. Pale yellow solid; 1H NMR
(500 MHz) δ 9.63 (bs, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz,
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ARTICLE
145.0, 135.7, 129.6, 128.3, 45.5, 29.6, 25.9, 21.7; MS (ESI) m/z 268
[M þ H]þ.
added pyridine (0.2 mmol). After 5 min of stirring, PhIdNTs (1 mmol)
and BHT (0.75 mmol) followed by 1a (0.5 mmol) were added. The
reaction was stirred at room temperature for 18 h, after which the crude
mixture was filtered through Celite, washed with EtOAc, and evaporated to
dryness. The reaction mixture was then analyzed by 1HNMRspectroscopy.
Procedure for Competitive Rates Studies. To a suspension of
FeCl2 (0.05 mol) and powdered 4 Å MS (400 mg) in CH2Cl2 (2 mL)
was added pyridine (0.2 mmol). After 5 min of stirring, PhIdNTs
(0.5 mmol) was added followed bya solutionof benzaldehyde (0.6 mmol)
and p-substituted benzaldehyde (0.6 mmol). After 2 h, the solution was
assayed via GC analysis.
N-Tosylcyclohexanecarboxamide (2w)37. White solid; 1H
NMR δ 8.12 (bs, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.4 Hz,
2H), 2.44 (s, 3H), 2.13 (tt, J = 11.6, 3.5 Hz, 1H), 1.76 (t, J = 13.8 Hz,
4H), 1.63 (bd, J = 9.9 Hz, 2H), 1.12ꢀ1.40 (m, 6H); 13C NMR δ 173.7,
145.0, 135.6, 129.6, 128.3, 45.1, 28.7, 25.4, 25.2, 21.7; MS (ESI) m/z 282
[M þ H]þ.
3-Phenyl-N-tosykpropanamide (2y)11. White solid; 1H NMR
δ 8.96 (bs, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H),
7.18ꢀ7.25 (m, 3H), 7.04 (d, J = 7.5 Hz, 2H), 2.86 (t, J = 7.7, 2H), 2.54
(t, J = 7.7, 2H), 2.44 (s, 3H); 13C NMR δ 170.2, 145.2, 139.6, 135.5,
129.6, 128.6, 128.4, 128.3, 126.5, 38.0, 30.3, 21.7; MS (ESI) m/z 304
[M þ H]þ.
Procedure for the Amidation of 1a or 1k with PhIdNTs
Mediated by a Variety of Copper and Palladium Catalysts.
To a suspension of the copper or palladium catalyst stated in Table 3
(5 μmol) and powdered 4 Å MS (400 mg) in CH2Cl2 (2 mL) was added
pyridine (0.02 mmol). After 5 min of stirring, PhIdNTs (1 mmol)
followed by 1a (0.1 mmol) or 1k (0.5 mmol) was added, and the
resultant reaction mixture was stirred at room temperature for 18 h.
On completion, the reaction mixture was filtered through Celite, washed
with EtOAc, and evaporated to dryness. The crude mixture was then
analyzed by 1H NMR spectroscopy.
Methyl 4-(4-methylphenylsulfonamido)-4-oxobutanoate
(2z)39. White solid; 1H NMR δ 9.00 (bs, 1H), 7.93 (d, J = 8.4 Hz, 2H),
7.34 (d, J = 8.1 Hz, 2H), 3.65 (s, 3H), 2.58ꢀ2.60 (m, 4H), 2.44 (s, 3H);
13C NMR (100 MHz) δ 173.0, 169.7, 145.1, 135.6, 129.6, 128.3, 52.1,
31.0, 28.2, 21.7; MS (ESI) m/z 286 [M þ H]þ.
3-Methyl-N-tosylbut-2-enamide (2r)40. Pale yellow solid; 1H
NMR δ 8.87 (bs, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 1H),
5.62 (s, 1H), 2.43 (s, 3H), 2.10 (s, 3H), 1.84 (s, 3H); 13C NMR δ 163.4,
160.2, 144.7, 135.9, 129.6, 128.3, 115.5, 27.6, 21.6, 20.5; MS (ESI) m/z
254 [M þ H]þ.
(4-(Trifluoromethyl)phenyl)-N-tosylmethanimine (3k)44.
1H NMR δ 9.09 (s, 1H), 8.06 (d, J = 7.8 Hz, 2H), 7.91 (d, J = 8.5 Hz,
2H), 7.76 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H); 2.45 (s, 3H); 13C
NMR δ 168.5, 145.1, 137.5, 131.4, 130.3, 129.9, 128.2, 126.1, 21.7; MS
(ESI) m/z 328 [M þ H]þ.
(E)-N-Tosylhex-2-enamide (2β)41. Yellow oil; 1H NMR δ 9.29
(bs, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 6.98 (dt, J =
15.4, 7.0 Hz, 1H), 5.85 (d, J = 15.4 Hz, 1H), 2.41 (s, 3H), 2.14 (q, J = 7.0
Hz, 2H), 1.37ꢀ1.44 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR δ
163.5, 151.0, 145.1, 135.7, 129.6 128.4, 121.4, 34.3, 21.7, 21.1, 13.6; MS
(ESI) m/z 268 [M þ H]þ.
Procedure for the Synthesis of [FeCl2(py)4]22. Pure iron
powder (0.09 mol) was slowly and carefully added to 15 mL of 5 M
HCl [CAUTION: a large volume of H2(g) is evolved on addition to
HCl and care should be exercised] over a period of 45 min. When all
of the H2(g) was evolved, MeOH (20 mL, sodium-dried) was added,
and under a dry nitrogen atmopshere, the solution was filtered into
a flask containing 100 mL of pyridine (purified by distillation in a dry
N2 atmosphere prior to use). Intensely yellow crystals of tetrakis-
(pyridyl)iron(II) chloride separated out immediately from the solution
and were allowed to stand overnight under a dry N2 atmosphere. The
crystals were then filtered off, recrystallized from distilled pyridine, and
dried in a vacuum desiccator. IR (neat, cmꢀ1) 3420, 3312, 3198, 1605,
1487, 1223, 1042, 756, 694.
42
1
N-Tosylcinnamamide (2γ) . White solid; H NMR δ 8.00 (d,
J = 8.4 Hz, 2H), 7.69 (d, J = 15.6 Hz, 2H), 7.46 (m, 3H), 7.33ꢀ7.38 (m,
5H), 6.44 (d, J = 15.8, 1H), 2.43 (s, 3H); 13C NMR δ 163.2, 146.0, 145.2,
135.7, 133.7, 131.0, 129.7, 129.0, 128.5, 128.4, 117.3, 21.7; MS (ESI)
m/z 302 [M þ H]þ.
2-Phenyl-N-tosylpent-2-enamide (2δ). White solid, mp
1
118ꢀ120 °C H NMR δ 7.93 (d, J = 8.3 Hz, 2H), 7.46ꢀ7.38 (m,
3H), 7.33 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 1.56 Hz, 2H), 7.03 Hz (t, J = 7.7
Hz, 1H), 2.43 (s, 3H), 1.96 (quin, J = 7.6 Hz, 2H), 0.93 (t, J = 7.5 Hz,
3H); 13C NMR δ 163.7, 147.9, 145.0, 135.6, 133.5, 133.3, 129.6, 129.5,
129.4, 128.9, 128.6, 23.0, 21.7, 13.0; IR (neat, cmꢀ1) 3365, 3284, 3022,
2970, 2933, 1701, 1627, 1597, 1492, 1406, 1342, 1215, 1176, 1145; MS
(ESI) m/z 330 [M þ H]þ; HRMS (ESI) calcd for C18H20NO3S
330.1164, found 330.1164.
Procedure for Amidation Reaction of 1a with [FeCl2(py)4].
To a suspension of tetrakis(pyridyl)iron(II) chloride (0.05 mmol),
PhIdNTs (1 mmol), and powdered 4 Å MS (400 mg) in 2 mL of
CH2Cl2 was added 1a (0.5 mmol). The reaction was stirred at room
temperature for 18 h, after which the mixture was filtered through Celite,
washed with EtOAc, evaporated to dryness, and purified by silica gel
flash column chromatography to furnish 2a as the sole product.
Procedure for Reaction of [Fe(py)4Cl2] þ PhIdNTs. To a
yellow suspension of [Fe(py)4Cl2] (25 μmol) in CD2Cl2 (1 mL) was
added PhIdNTs (0.1 mmol). The mixture was stirred at room tem-
perature and under N2. After 10 min, a homogeneous brown solution
was obtained and assayed via 1H NMR spectroscopy (See Figure S37 in
the Supporting Information).
N-Tosylcyclohex-1-enecarboamide (2ε). White solid, mp
1
164ꢀ166 °C; H NMR δ 8.76 (bs, 1H), 7.98 (d, J = 8.4 Hz, 2H),
7.33 (d, J = 8.1 Hz, 2H), 6.77 (s, 1H), 2.43 (s, 3H), 2.16 (m, 4H), 1.57
(m, 4H);13C NMR δ 165.2, 144.9, 139.1, 135.8, 131.8, 129.5, 128.5,
25.8, 23.6, 21.72, 21.69, 21.1; IR (neat, cmꢀ1) 3275, 3018, 1693, 1417,
1215, 1161; MS (ESI) m/z 280 [M þ H]þ; HRMS (ESI) calcd for
C14H18NO3S 280.1007, found 280.1015.
N-Tosylthiophene-2-carboxamide (2η)6c. White solid; 1H
NMR δ 8.04 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 3.5 Hz, 1H), 7.59 (d,
J = 4.7 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.07 (t, J = 4.39 Hz, 1H), 2.43
(s, 3H); 13C NMR δ 158.7, 145.3, 135.9, 135.4, 133.7, 131.1, 129.6,
128.6, 128.2, 21.7; MS (ESI) m/z 282 [M þ H]þ.
Procedure for Kinetic Isotope Study. To a suspension of
FeCl2 (25 μmol) and powdered 4 Å MS (400 mg) in CH2Cl2 (2 mL)
was added pyridine (0.1 mmol). After 5 min of stirring, PhIdNTs
(0.25 mmol) was added followed by a solution of benzaldehyde
(0.3 mmol) and d6-benzaldehyde (0.3 mmol). After 2 h, the solution
was assayed via LCꢀMS analysis.
43
1
Phenyl-N-tosylmethanimine (3a) . H NMR (400 MHz) δ
9.03 (s, 1H) 7.94ꢀ7.88 (m, 4H), 7.62 (t, J = 7.4 Hz, 1H) 7.49 (d, J = 7.7
Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H); 13C NMR (100 MHz) δ
170.1, 144.6, 135.2, 135.0, 132.4, 131.3, 129.8, 129.2, 128.1, 21.7; MS
(ESI) m/z 260 [M þ H]þ.
Procedure for the Synthesis of 3a43. To a solution of benzalde-
hyde 1a (10 mmol) and p-toluenesulfonamide (10 mmol) in 50 mL of
CH2Cl2 was added trifluoroacetic anhydride (11 mmol). The reaction was
refluxed for 12 h after which the reaction mixture was poured into cold
water, extracted with CH2Cl2, dried with MgSO4, evaporated to dryness,
and recrystallized to give the title compound as a white solid in 81% yield.
Procedure for Amidation of 1a with PhIdNTs in the
presence of FeCl2 þ Pyridine and BHT. To a suspension of FeCl2
(0.05 mol) and powdered 4 Å MS (400 mg) in CH2Cl2 (2 mL) was
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Procedure for the Synthesis of 428a. To a suspension of
[Ru(TTP)CO] (0.2 mmol, 0.1 equiv) and PhIdNTs (3 mmol, 1.5
equiv) in 2 mL of CH2Cl2 in the presence of powdered 4 Å molecular
sieves (400 mg) was added pyridine (2 mmol, 1 equiv). The reaction was
stirred at 30 °C until completion based on TLC analysis, after which the
reaction mixture was cooled to room temperature, filtered, evaporated
to dryness, and purified by silica gel flash column chromatography
Scholarship award (to J.W.W.C.) as well as helpful comments
and suggestions made by the Editor and referees are also grate-
fully acknowledged.
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1
(CH2Cl2/acetone as eluant) to afford the product in 63% yield. H
NMR δ 8.45 (d, J = 5.7 Hz, 2H), 7.96 (t, J = 7.8, 1H), 7.54ꢀ7.61 (m,
4H), 7.15 (d, J = 8.2 Hz, 2H), 2.34 (s, 3H); 13C NMR δ 145.2, 141.7,
138.9, 138.6, 129.3, 127.1, 126.9, 21.4; MS (ESI) m/z 249 [M þ H]þ.
Procedure for the Synthesis of 529. To a suspension of
powdered KOH (7 mmol) and m-chloroperoxybenzoic acid (2.2 mmol)
in 1 mL of CH2Cl2 was added a solution of 3 (2 mmol) in 3 mL of
CH2Cl2. After 5 min, the suspension was filtered, evaporated to dryness,
and dried under vacuum to afford the product as a white solid in 90%
yield. 1H NMR δ 7.93 (d, J = 8.4 Hz, 2H), 7.37ꢀ7.46 (m, 7H), 5.44 (s,
1H), 2.49 (s, 3H); 13C NMR δ 162.3, 146.4, 131.5, 131.4, 130.6, 130.1,
129.4, 128.7, 128.3, 76.3, 21.9; MS (ESI) m/z 276 [M þ H]þ.
Procedure for FeCl2-Catalyzed Reaction of 1a with 4. To a
suspension of FeCl2 (0.05 mmol), 4 (1 mmol), and powdered 4 Å MS
(400 mg) in 2 mL of CH2Cl2 was added 1a (0.5 mmol). The reaction
was stirred at room temperature for 18 h, after which the mixture was
filtered through Celite, washed with EtOAc, and evaporated to dryness.
The reaction mixture was then analyzed by 1H NMR spectroscopy.
Procedure for FeCl2 þ Pyridine Catalyzed Reaction of 3a
or 5. A suspension of FeCl2 (0.05 mmol), pyridine (0.2 mmol), and
powdered 4 Å MS (400 mg) were stirred for 5 min in 2 mL of CH2Cl2.
On completion, PhIdNTs or PhI(OAc)2 (1 mmol) and 3a or 5
(0.5 mmol) were added. The reaction was stirred at room temperature
for a further 18 h, after which the mixture was filtered through Celite,
washed with EtOAc, and evaporated to dryness. The reaction mixture
was then analyzed by 1H NMR spectroscopy.
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’ ASSOCIATED CONTENT
S
Supporting Information.
Technical specifications for
b
FeCl2 of 99.5% and 99.99% purity, 1H and 13C NMR spectra for
all starting materials and products, and CIF file of [FeCl2(py)4].
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: waihong@ntu.edu.sg.
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’ ACKNOWLEDGMENT
This work is supported by a College of Science Start-Up Grant
and University Research Committee Grant (RG55/06) from
Nanyang Technological University (NTU). A Nanyang Presi-
dent’s Graduate Scholarship (to T.M.U.T.) and Undergraduate
Research Experience on Campus stipend (to S.T.) from NTU,
the Singapore Millennium Foundation (SMF) for a SMF PhD
4902
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The Journal of Organic Chemistry
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