Metal-free amidation of ether sp3 C-H bonds with sulfonamides using PhI(OAc)2

Article abstract of DOI:10.1039/c4ra09665g

A selective protocol for the metal-free α-C-H amidation of ethers using sulfonamides and hypervalent iodine oxidants has been developed. The absence of precious metals and the conditions employed make the method environmentally attractive. A number of cyclic and acyclic, linear and branched ethers have been successfully amidated, and a broad sulfonamide scope has been demonstrated. Two unusual reactions, namely the amidation of an unactivated tert-butyl group and a tandem C-C coupling reaction, are also described. This journal is

Full text of DOI:10.1039/c4ra09665g

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Metal-free amidation of ether sp3 C–H bonds with
sulfonamides using PhI(OAc)2†
Cite this: RSC Adv., 2014, 4, 47951
a
b
a
b
*
*
Jesus Campos,‡ Sarah K. Goforth,‡ Robert H. Crabtree and T. Brent Gunnoe
´
A selective protocol for the metal-free a-C–H amidation of ethers using sulfonamides and hypervalent
iodine oxidants has been developed. The absence of precious metals and the conditions employed make
the method environmentally attractive. A number of cyclic and acyclic, linear and branched ethers have
been successfully amidated, and a broad sulfonamide scope has been demonstrated. Two unusual
reactions, namely the amidation of an unactivated tert-butyl group and a tandem C–C coupling reaction,
are also described.
Received 2nd September 2014
Accepted 17th September 2014
DOI: 10.1039/c4ra09665g
www.rsc.org/advances
sulfonamides for in situ generation of iminoiodinanes (PhI ¼
Introduction
NSO2R), thus expanding the scope of the prior strategies based
on preformed iminoiodinanes (Scheme 1).7–10
Direct amidation of sp3 C–H bonds remains an important
and challenging task with applications ranging from produc-
tion of valuable organic targets to enhancing the utility of
readily available but inert aliphatic substrates. The classical
strategy for these atom-economical transformations involves
transition metal catalysts that are able to mediate nitrene
insertion into C–H bonds.1–11 The many pharmaceutical appli-
cations for oxidative coupling of C–H and N–H bonds require
rigorous removal of trace amounts of these catalysts, which are
oen based on toxic and expensive precious metals. Elimi-
nating the need for the metal catalysts is thus desirable from a
standpoint of simplication and economy.12–14
While a majority of the metal-free processes for C–H ami-
dation and amination have been applied to oxidative coupling
of N–H bonds to sp and sp2 C–H bonds of unsaturated
alkynes,38 arenes,23,35,37,39,40 alkenes,25–27,41 and azoles,20,31,32,42,43
several examples of sp3 C–H amidation of benzylic16–19,22–24,41 and
allylic18,21,30 bonds have also been reported. In addition, Muniz
˜
and coworkers described the amidation of an a-methyl group of
a ketone.25 Metal-free amidation is rare for sp3 C–H bonds
unactivated by adjacent double bonds. The I2-catalyzed oxida-
tive coupling of purines with tetrahydrofuran (THF) oxidized by
PhI(OAc)2 is known,29 and a similar system utilizing PhI(OAc)2
as oxidant but involving stoichiometric I2 has been reported for
intramolecular amidation of alkyl sulfonamides.36 Most prom-
inently, Ochiai and coworkers discovered a highly active
hypervalent bromine reagent, p-(CF3)(Ph)BrNTf (Tf ¼ CF3SO2),
for a-C–H amidation of alkyl ethers (eqn (1))34 and also, in a
striking example, for regioselective amidation of unfunctional-
ized alkanes.33
A variety of amine and oxidant combinations have been used
for metal-free amination, amidation and imidation of C–H
bonds. The oxidants in these systems include peroxides (tert-
butyl hydroperoxide,15–18 di-tert-butyl peroxide,19 H2O2 20, ben-
zoquinones,21 chloramine-T,22 and hypervalent halogen
species.23–35 Additional organic catalysts (e.g., I2
and n-
15,24,29
Bu4NI)17,18 and stoichiometric additives (e.g., I2,16,22,35–37 N-iodo-
n
succinimide,16,20 Bu4NI,16 KI,16,28 TsOH19 and AcOH15,20) are
oen involved and perform various functions. Hypervalent
iodine species, particularly iodosobenzene derivatives such as
PhI(OAc)2, are prevalent in both metal-catalyzed and metal-free
processes for C–H amidation.1–10,23–32,35 Owing to their high
oxidation potential, these species are documented to activate
(1)
aDepartment of Chemistry, Yale University, 225 Prospect Street, New Haven,
Connecticut 06520, USA. E-mail: robert.crabtree@yale.edu
bDepartment of Chemistry, University of Virginia, Charlottesville, Virginia 22904-
4319, USA. E-mail: tbg7h@virginia.edu
† Electronic supplementary information (ESI) available: Experimental procedures,
1H and 13C NMR data for all new compounds, additional optimization data, and
crystallographic details for compounds 2a, 2d,
10.1039/c4ra09665g
8 and 12. See DOI:
Scheme 1 In situ formation of an iminoiodinane from a hypervalent
iodine oxidant.
‡ These authors contributed equally to this work.
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The present work began with an initial nding that reaction reactions and near-quantitative conversion of the sulfonamide to
of 2,2,2-trichloroethoxysulfonamide in neat THF in the pres- the functionalized compound 2a. The rst step in our screening
ence of PhI(OAc)2 selectively produces the a-C–H amidation was to test different oxidants. Whereas the hypervalent iodine
product (eqn (2)). The simple sulfonamide/PhI(OAc)2 system oxidants PhI(OAc)2 and PhI(OPiv)2 (OPiv ¼ pivalate) worked equally
offers some advantages over the specialized p-(CF3)(Ph)BrNTf well and led to almost quantitative formation of 2a (entry 6), the
reagent reported for amidation of alkyl ethers with sulfon- uorinated PhI(TFA)2 (TFA ¼ triuoroacetate) yielded poor results
amides.34 The air- and moisture-stable and commercially (entry 7). We focused on PhI(OAc)2 due to its lower price and higher
available PhI(OAc)2 is more convenient than p-(CF3)(Ph)BrNTf, stability compared to its pivalate analogue. Although chloramine-T
which must be handled under inert atmosphere and whose two- has been shown to be an excellent nitrene source for the a-CH
step synthesis involves BrF3 and liberates HF.41,44 Additionally, amidation of ethers using a copper catalyst,45 product formation
extending the reaction scope to new sulfonamides while using was barely detected under our metal-free conditions (entry 8).
preformed reagents is limited by the necessity to synthesize a Acetoxylation of activated C–H bonds has been previously identied
different reagent for each case. In this work, we sought to as an undesired side reaction in the amidation of C–H bonds using
explore the potentially broader amide substrate scope offered PhI(OR)2/sulfonamide systems.24,46 With the aim of avoiding this
for direct a-C–H amidation of alkyl ethers using the simple deleterious pathway and, at the same time, looking for cheaper and
sulfonamide/PhI(OAc)2 system.
greener alternatives,47,48 we tested a series of iodine-containing
salts49,50 (entries 9–12), although with unsuccessful results. In
addition, the same product selectivity was achieved using this
method in several common organic solvents but with diminished
reaction rates (entries 13–16).
(2)
In terms of the sulfonamide scope, we obtained excellent
yields with both aromatic and aliphatic sulfonamides (Table 2).
This constitutes an important benet compared to the previous
metal-free amidation of ethers reported by Ochiai, which,
despite its excellent activity, was limited to the highly reactive p-
(CF3)(Ph)BrNTf reagent.34 In our system, a-CH amidation of
THF takes place with excellent yields for substituted and
unsubstituted aromatic sulfonamides (entries 1–5), although no
conversion was detected in the case of the –OMe and –NH2
Results and discussion
We rst optimized the experimental conditions for the a-CH ami-
dation of THF using PhI(OAc)2/2,2,2-trichloroethoxysulfonamide
(1a) (Table 1). Although amidation takes place even at room
temperature (entry 1), mild heating (60 ꢀC, entry 4) leads to faster
Table 1 Conditions screening for the amidation of THFa
Entry
Oxidant
Solvent
T (ꢀC)
t (h)
Yieldb (%)
1
2
3
4
5
6
7
8
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OPiv)2
PhI(TFA)2
Chloramine-Tf
NH4IO3
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
25
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
10
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
53
77
89
91
94
93
23
3g
<1
<1
<1
<1
71
83
42
56
c
d
e
9
10
11
12
13
14
15
16
KIO3
KIO4
nBu4NIO4
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
DCE/THF (1 : 1)
MeCN/THF (1 : 1)
Toluene/THF (1 : 1)
Cyclohexane/THF (1 : 1)
a
Conditions: 1a (0.2 mmol, 46 mg), oxidant (0.4 mmol, 2 equiv.), THF or mixed solvent (2 mL), reactions carried out under N2 atmosphere. b Yields
determined by 1H NMR spectroscopy using trimethoxybenzene as internal standard. c 1 Equiv. of PhI(OAc)2. d 1.5 Equiv. of PhI(OAc)2. e 3 Equiv. of
PhI(OAc)2. f Chloramine-T was used instead of the pair 1a/PhI(OAc)2. The -NTs adduct was detected in this case.
g
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Table 2 Sulfonamide scope on the a-CH amidation of THFa
ꢀ
Under our optimized conditions (60 C, 2 h, 1.5–2 equiv.
PhI(OAc)2), a series of aliphatic and aromatic, cyclic and
acyclic ethers were tested as substrates for amidation with
1a/PhI(OAc)2; however, the results were unsatisfactory in
terms of yields (from 5 to 10%) and selectivity, except for the
cyclic tetrahydropyran (THP, 50% yield). Both the less polar
character of acyclic ethers compared to THF and their
slightly higher a-C–H bond dissociation energies55 might
contribute to the decreased activity. Further optimization of
reaction conditions for diethyl ether (Table S1 in the ESI†)
resulted in a maximum yield of 35% for the desired amidated
product, but its formation was accompanied by a number of
other unidentied species (60% overall sulfonamide conver-
sion). Interestingly, we observed improved activity and consid-
erably enhanced selectivity under microwave irradiation (MW,
120 ꢀC, 10 min) in the neat ethers (Table 3, entries 4, 5; and
Table S2†). We carried out the same reactions in pressurized
microwave vials but heated in a conventional oil bath (Table 3,
yields in parentheses).56–58 The results were almost identical,
suggesting a thermal origin for the improved yields and selec-
tivity under microwave irradiation. For the sake of comparison,
we undertook the a-CH amidation of THF under MW conditions
and obtained yields comparable to those observed under mild
thermal heating.
The addition of iodine in catalytic or stoichiometric
amounts in conjunction with hypervalent iodine oxidants
has been widely and successfully employed in other C–H
amidation reactions.24,29,35–37 We observed an interesting
effect with the addition of variable amounts of iodine. In the
presence of catalytic amounts (2 mol% I2 relative to sulfon-
amide) the yields for linear acyclic ethers increased consid-
erably. For instance, the yield for di-n-butyl ether increased
from 12 to 54% (entries 9 and 10), whereas that of di-n-propyl
ether increased from 27 to 68% (entries 6 and 7). However,
amidation of cyclic ethers (THF and THP) was not affected by
the presence of trace amounts of iodine, which even had a
deleterious effect in the case of tert-butyl ethers. In all cases,
higher amounts of iodine (0.5 equiv.) greatly suppressed
product formation. In contrast, 0.5 equiv. of I2 was previously
found to be the optimal loading for benzylic amidations by
Fan and coworkers who obtained lower yields at both 1 equiv.
of I2 and 0.05 to 0.2 equiv. of I2.24 These results highlight the
importance of testing a wide range of I2 concentrations in
optimizing this type of reaction.
Entry
Substrate
–R
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
1b
1c
1d
1e
1f
1g
1h
1i
–C6H5
89
90
92
95
71
<1
<1
92
89
96
–C6H4(p-Me)
–C6H4(p-Cl)
–C6H4(p-Br)
–C6H4(p-COOH)
–C6H4(p-OMe)
–C6H4(p-NH2)
–(CH2)Ph
1j
1k
–CH3
–CF3
a
Conditions: 1b–k (0.2 mmol), oxidant (0.3 mmol, 1.5 equiv.), neat THF
(2 mL), 60 ꢀC, 2 h, reactions carried out under N2 atmosphere. b Yields
were determined by 1H NMR spectroscopy using trimethoxybenzene as
internal standard.
derivatives (entries 6 and 7). Aliphatic sulfonamides also gave
excellent conversions and high selectivity for the a-CH position
(entries 8–10). The broad sulfonamide scope exhibited by our
method is especially signicant considering the useful biolog-
ical and pharmacological properties of molecules based on the
N-(methoxoalkyl)sulfonamide framework.51–54
The new functionalized THF compounds 2a–k were charac-
terized by H and 13C{1H} NMR spectroscopy as well as high-
1
resolution mass spectrometry (see ESI†). A characteristic 1H
NMR resonance in the range from 5.20 to 5.42 ppm is assigned
to the O–CH–NH proton and is common to all compounds 2a–k;
the corresponding 13C{1H} signal appears at ca. 85 ppm. The
molecular structures of two of these species (2a and 2d) were
further conrmed by X-ray diffraction studies (Fig. 1). Their C–N
bond distances are identical within the experimental error, with
˚
˚
values of 1.472(8) A and 1.470(4) A for 2a and 2d, respectively,
which are consistent with single bond character. Different
rotameric orientations of the THF ring are present in each
structure, likely due to packing forces.
While linear cyclic and acyclic ethers gave the expected a-
amidated products, both aromatic and branched aliphatic
ethers exhibited a different reactivity. The branched di-iso-
propyl ether could not be amidated under our experimental
conditions; instead we observed the formation of isopropyl
acetate (7) as the major product, due to direct acetoxylation,
determined by 1H NMR aer addition of an authentic sample
of 7. In contrast, acetoxylation was barely detected with the
other ether substrates. Surprisingly, reaction of tert-butyl
methyl ether and tert-butyl ethyl ether gave completely
different outcomes. The former yielded compound 8 where
the O-methyl fragment is doubly functionalized and the tert-
butoxy groups released. The molecular structure of 8 is
Fig. 1 ORTEPs of compounds 2a and 2d. 50% Thermal ellipsoids are
shown. Most hydrogen atoms have been omitted for clarity.
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Table 3 a-CH amidation of ethersa
Entry
Substrate
Product
Additive (equiv.)
Yieldb (%)
Selectivityc
1
—
62 (56)
59
3
60 (51)
70
0.82 (0.79)
0.76
0.20
0.83 (0.78)
0.89
2
3
4
5
I2 (0.02)
I2 (0.5)
—
I2 (0.02)
6
7
8
—
I2 (0.02)
I2 (0.5)
27 (27)
68
<1
0.49 (0.44)
0.84
0.10
9
10
—
I2 (0.02)
12 (12)
54
0.21 (0.24)
0.86
11
12
—
I2 (0.02)
14
26
—
—
13
14
15
—
I2 (0.02)
I2 (0.5)
79 (85)
60
15
0.98 (0.94)
0.83
0.30
16
17
—
I2 (0.02)
14 (13)
3
0.61 (0.54)
0.10
18
—
—
10, 1.5d, 11, 1.9d
10, 5.6d, 11, 3.5d
—
—
19
a
Conditions: 1a (0.5 mmol), PhIO(Ac)2 (0.55 mmol, 1.1 equiv.), neat ether (2 mL), microwave radiation (MW): 120 ꢀC, 10 min. Reactions carried out
under N2 atmosphere. Yields were determined by 1H NMR spectroscopy using trimethoxybenzene as internal standard. Values between
b
parentheses correspond to yields obtained under identical conditions as for MW experiments but heating in conventional oil bath.
c
d
Selectivities were calculated for sulfonamide as the limiting reagent. These yields are calculated based on the ether (instead of the
sulfonamide) as the limiting reagent, since the reaction also proceeds in the absence of 1a.
consistent with the reduced number of resonances appearing ethers cannot be amidated using the present method; instead
1
in its H and 13C{1H} NMR spectra and was conrmed by X- they experience C–O cleavage and further oxidation to yield
ray diffraction (Fig. 2). On the other hand, tert-butyl ethyl benzaldehyde and benzoic acid. The same transformation
ether was converted into compound 9 aer a-CH amidation has previously been reported under related conditions and
of the ethyl group and unexpected b-CH amidation of the tert- mainly investigated as a protocol for the synthesis of alde-
butyl fragment. This species was unambiguously character- hydes from benzylic ethers.61–63 Although these reactions
1
ized by H and 13C{1H} NMR spectroscopy, as well as HRMS were accelerated by the addition of the sulfonamide and
(FT-ICR). It constitutes a rare example of amidation of especially by the presence of the hypervalent iodine oxidant,
unactivated primary C–H bonds. A somewhat related reaction they proceed even in the absence of these additives (see ESI
has been recently reported by Che and coworkers, where the for more details, Table S3†).
C–H bond of a tert-butyl fragment was also aminated,
Purication of the functionalized ethers reported in this
although in low yield as a result of competition with the more work proved difficult. In most cases extensive decomposition
reactive benzylic C–H bond.59 Finally, and in contrast to the occurred during attempted column chromatography on both
related copper-catalyzed process,60 we observed that benzylic silica gel and alumina. In some cases degradation of the
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Scheme 3 Amidation of THF with methyl tosylamide.
acetoxylation product (compound 14 in Scheme 3) as evidenced
by1 H and 13C{1H} NMR spectroscopy in comparison with
literature data.70 This reaction is presumably base-mediated as
the yields were dependent on the amount of amine present, and
the same product could be formed using inorganic base K2CO3
in place of the amine.
To investigate the feasibility of the classic mechanism for
in situ nitrene formation (Scheme 1), which requires a primary
sulfonamide,6,10,11 we tested the reactivity of methyl tosylamide
with THF. Interestingly, we found that amidated product is
formed in 14% yield along with 17% of the acetoxylation
product (Scheme 3). Compound 13 displays 1H and 13C{1H}
NMR spectra similar to a previously reported and related
product derived from cyclohexyl tosylamide.71 This result
suggests that in situ nitrene formation is not the only available
pathway in the present system, and there is at least one other
mechanism implicated that would account for the amidation
using secondary sulfonamides.
Fig. 2 ORTEPs of compounds 8 and 12. 50% Thermal ellipsoids are
shown. Most hydrogen atoms have been omitted for clarity.
amidated compounds was observed aer mild work-up or even
upon standing in air for several days. The intrinsic reactivity of
these species gave rise to an interesting derivative (12,
Scheme 2), which is formed from Friedel–Cras alkylation of
electron-rich trimethoxybenzene (employed as an internal
standard for1 H NMR spectroscopy analysis). The Friedel–
Cras coupling of sulfonamides with aromatic compounds
typically employs N-sulfonyl aldimines,64–67 but the direct use
of N,O-acetals has been less explored. In an elegant study, Du
Bois and co-workers developed a related rhodium-catalyzed
one-pot amidation/nucleophilic addition process using ethers,
sulfonamides and nucleophiles such as allylsilanes, silyl enol
ethers, and ketene acetals.68 Another interesting related
process for the synthesis of 3-oxyindoles via tandem amida-
tion/acetoxylation/Friedel–Cras reaction has been recently
described.69 The molecular structure of 12 was elucidated by X-
ray diffraction studies of suitable crystals grown by slow
diffusion of pentane into a dichloromethane solution of the
compound (Fig. 2). The length of the new C–C bond, 1.512(3)
The amidation of THF by sulfonamide 1a was completely
shut down by addition of the radical trap TEMPO, suggesting a
mechanism involving radicals. Two distinct radical-based
mechanisms for PhI(OAc)2-based systems have been proposed
in the literature for oxidative C–N functionalization of sp3
benzylic C–H bonds. In an account by Cho and Chang involving
imidation of benzylic C–H bonds using PhI(OAc)2 alone, a
carbon-centered radical R1(cCH)R2 at the benzylic position was
proposed from a single-electron transfer (SET) reaction between
the benzylic substrate R1(CH2)R2 (R1 ¼ Ar) and PhI(OAc)2
(Scheme 4, pathway A).23 A second SET to form a carbocation
R1(+CH)R2; followed by attack by a sulfonimide nitrogen and
removal of a proton would then produce the nal amidation
product. Accounts describing amidation and amination of sp3
carbons using PhI(OAc)2/I2 systems are in general agreement in
proposing mechanisms involving formation of a nitrogen-
centered R3R4Nc radical resulting from reaction of the
oxidant/I2 combination with substrate either thermally or by
photoactivation.24,29,36,37 Subsequent hydrogen atom transfer
(HAT) produces a carbon-centered radical R1(cCH)R2, which
abstracts iodine from R3R4NI to propagate the production of the
R3R4Nc radical. Substitution of the R1(CH)R2 I species with
either R3R4NH or AcOH can lead to formation of amination/
amidation product or the undesired acetoxylation byproduct.
In our system, a substantial KIE of kH/D ¼ 9.3 is observed for
the reaction of 1a in a 1 : 1 mixture of THF and THF-d8 with 2
equiv. of PhI(OAc)2. Under identical conditions aer addition of
2 mol% I2, the kH/D is decreased to 2.2. The large difference in
KIE between these two cases implies a change in mechanism
which may involve a shi from pathway A operative with
PhI(OAc)2 alone to pathway B upon addition of I2 (Scheme 4).
Future studies will focus on further elucidating the reaction
˚
˚
A, and that of the adjacent C–N bond, 1.490(3) A, are both
indicative of single bonds.
Attempts to perform amination reactions of primary and
secondary alkyl amines with THF using PhI(OAc)2 led to
Scheme 2 Formation of compound 12 by C–C coupling between 6
and trimethoxybenzene.
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mechanism(s) implicated and understanding the dependence
of the role of I2 on the identity of the ether substrate.
Conclusions
In summary, we have developed a metal-free protocol for the
selective amidation of sp3 C–H bonds in ethers using inexpen-
sive and commercially available reagents. The resulting func-
tionalized ethers are valuable nitrogen-containing compounds
with potential biological and pharmacological properties. The
reactions proceed without the need of precious-metal catalysts,
with minimal use of organic solvents and under mild condi-
tions. Higher reaction temperatures, achieved most conve-
niently by microwave irradiation, allow for reaction times in the
scale of several minutes, thus reducing energetic costs and
making the process environmentally attractive. Preliminary
studies suggest several radical mechanistic pathways in
competition.
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