Hypervalent iodine catalyzed hofmann rearrangement of carboxamides using oxone as terminal oxidant

Article abstract of DOI:10.1021/jo302375m

Hofmann rearrangement of carboxamides to carbamates using Oxone as an oxidant can be efficiently catalyzed by iodobenzene. This reaction involves hypervalent iodine species generated in situ from catalytic amount of PhI and Oxone in the presence of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in aqueous methanol solutions. Under these conditions, Hofmann rearrangement of various carboxamides affords corresponding carbamates in high yields.

Full text of DOI:10.1021/jo302375m

Note
pubs.acs.org/joc
Hypervalent Iodine Catalyzed Hofmann Rearrangement of
Carboxamides Using Oxone as Terminal Oxidant
Akira Yoshimura,* Kyle R. Middleton, Matthew W. Luedtke, Chenjie Zhu, and Viktor V. Zhdankin*
Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, Minnesota, 55812, United States
S
* Supporting Information
ABSTRACT: Hofmann rearrangement of carboxamides to
carbamates using Oxone as an oxidant can be efficiently
catalyzed by iodobenzene. This reaction involves hypervalent
iodine species generated in situ from catalytic amount of PhI
and Oxone in the presence of 1,1,1,3,3,3-hexafluoroisopropa-
nol (HFIP) in aqueous methanol solutions. Under these
conditions, Hofmann rearrangement of various carboxamides affords corresponding carbamates in high yields.
n recent years, hypervalent iodine reagents have emerged as
environmentally friendly and efficient oxidizing reagents for
In a search for the organoiodine(III)-catalyzed Hofmann
rearrangement, we have investigated the reactions of phenyl-
acetamide 1a using PhI (0.5 equiv) and Oxone (3 equiv) at 40
°C in different solvents (Table 1). The addition of small
amount of water was required to dissolve Oxone in the reaction
mixture. Out of several solvents tested (entries 1−11), we have
found that the presence of a 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP) in the mixture dramatically changes the outcome of this
reaction leading to the formation of the carbamate 2a in high
yield (entry 4). The accelerating effect of fluoroalcohols, such
as HFIP and 2,2,2-trifluoroethanol (TFE), on some reactions of
hypervalent iodine species was previously reported by Kita and
co-workers and several other groups.11 Iodobenzene has the
most pronounced catalytic effect; the use of other iodine
containing precatalysts (2,4,6-Me3C6H2I, 4-MeC6H4I, 4-
CF3C6H4I, 3-HO2CC6H4I, Bu4NI) instead of PhI gave poor
results (entries 12−16). Decreasing amount of PhI from 50 to
20 mol % did not reduce the yields of products (entry 17);
however, smaller amount of PhI (10 mol %) led to a slightly
lower yield (89−93%) (entry 18). Under the same conditions
in the absence of PhI, no reaction occurred (entry 19). In the
absence of HFIP, reasonable yields of products (79−85%)
could be obtained only using 50 mol % or greater amounts of
PhI (entries 1 and 9).
Using the optimized condition with 20 mol % PhI, we have
investigated the conversion of various substituted carboxamides
1 to the respective carbamates 2 (Table 2). In general, all
benzylcarboxamides with either electron-donating or electron-
withdrawing substituents afforded corresponding carbamates 2
in good yields (entries 2−8). As expected, various aliphatic
amides, including primary, second, tertiary, and cyclic
alkylcarboxamides, have also smoothly reacted under the
same conditions giving respective carbamates 2 in good yields
(entries 9−21). Compared to the previous method of Hofmann
rearrangement with the stoichiometric hypervalent iodine
I
various synthetically useful oxidative transformations.1 One of
the most impressive recent achievements in the area of
hypervalent iodine chemistry has been the development of
numerous catalytic reactions utilizing organohypervalent iodine
species in the iodine(I)/iodine(III) catalytic cycle. Most of
these cycles, however, employ m-chloroperoxybenzoic acid (m-
CPBA), which is a potentially explosive and environmentally
unsafe stoichiometric oxidant. Herein, we report a new
procedure for one of the key organic reactions, Hofmann
rearrangement, using catalytic amount of PhI and Oxone
(2KHSO5·KHSO4·K2SO4) as an inexpensive and environ-
mentally safe terminal oxidant.
Hypervalent iodine reagents are particularly important as
oxidants for the Hofmann-type rearrangements, employed in
numerous synthetic works.2−6 The most common reagents for
Hofmann rearrangement include (diacetoxyiodo)benzene,2
[bis(trifluoroacetoxy)iodo]benzene,3 [hydroxy(tosyloxy)]-
iodobenzene,4 N-tosyliminoiodane,5 and their recyclable
analogues.6 Recently, Ochiai and co-workers have first reported
the catalytic version of Hofmann rearrangement using
aryliodides and m-CPBA as terminal oxidant.8 Our group and
Togo’s group reported Hofmann rearrangement using stoi-
chiometric organohypervalent iodine species generated in situ
from PhI and appropriate oxidants.7 However, catalytic
Hofmann rearrangement using Oxone as the terminal oxidant
remains unknown.
Previously, we have reported that activated iodine(III)
species, hydroxy(phenyl)iodonium ion [PhI(OH)]+, can be
efficiently generated from PhI and Oxone in aqueous
solution.7a,9 This observation has also led us to the develop-
ment of a synthetic procedure for preparation of [bis-
(trifluoroacetoxy)iodo]arenes and [bis(trifluoroacetoxy)iodo]-
perfluoroalkanes.9b Furthermore, we have also found that
Oxone and the catalytic system PhI/Fe(III)-porphyrin can
efficiently oxidize aromatic hydrocarbons.9a,c Several other
groups reported catalytic hypervalent iodine reactions using
Oxone in the iodine(III)/iodine(V) catalytic cycle.10
Received: October 25, 2012
Published: November 26, 2012
© 2012 American Chemical Society
11399
dx.doi.org/10.1021/jo302375m | J. Org. Chem. 2012, 77, 11399−11404

The Journal of Organic Chemistry
Note
valent aminoiodine, which help to accelerate further steps of
the catalytic cycle, such as ligand exchange and 1,2-shift. A
similar reaction mechanism of the catalytic Hofmann rearrange-
ment of carboxamide in presence of m-CPBA was proposed by
Ochiai and co-workers.8
Table 1. Optimization of Catalytic Hofmann Rearrangement
with Oxone
a
In summary, we have developed a new procedure for the
Hofmann rearrangement of various carboxamides using
catalytic hypervalent iodine and Oxone as a terminal oxidant
and HFIP as a co-solvent. This efficient procedure affords
corresponding carbamates in high yields under mild conditions.
The mechanism of this reaction probably involves the electron-
deficient active species formed from hydroxy(phenyl)iodonium
ion or hypervalent aminoiodane and HFIP.
time
(h)
PhI
yields
b
entry
(equiv)
solvents (ratio)
(%)
1
2
3
4
5
6
7
8
9
10
3
3
3
3
3
3
3
3
3
3
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
MeOH−H2O (10:1)
(79)
MeOH−CH2Cl2−H2O (10:10:1)
MeOH−CHCl3−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
MeOH−TFE−H2O (10:10:2)
MeOH−THF−H2O (10:10:1)
MeOH−Et2O−H2O (10:10:1)
MeOH−AcOEt−H2O (10:10:1)
MeOH−hexane−H2O (10:10:1)
(47)
(44)
98 (99)
(82)
c
EXPERIMENTAL SECTION
(13)
(1)
■
All reactions were performed under dry nitrogen atmosphere with
flame-dried glassware. All commercial reagents were ACS reagent
grade and used without further purification. Carboxamides 1 were
from commercial sources (1a, 1b, 1i, 1j, 1t, 1u) or prepared from
corresponding carboxylic acids (Method A) or nitriles (Method B)
according to modified literature procedures described below.
Dichloromethane was distilled from CaH2 immediately prior to use.
Diethyl ether was distilled from Na/benzophenone. NMR spectra
were recorded at 500 MHz (1H NMR) and 125 MHz (13C NMR).
Chemical shifts (δ) are reported in parts per million and referenced
relative to tetramethylsilane. High resolution mass spectra (ESI-
HRMS) were obtained using mass spectrometer with TOF mass
analyzer.
(85)
(28)
MeOH−CH3NO2−H2O
(10:10:1)
11
12
13
14
15
16
17
18
19
3
0.5
MeOH−MeCN−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
MeOH−HFIP−H2O (10:10:1)
(21)
(13)
(87)
(30)
(59)
c
d
3
0.5
e
3
0.5
f
3
0.5
g
3
0.5
h
3
0.5
5
0.2
96 (99)
89 (93)
c
10
3
0.1
none
General Procedure for Synthesis of Carboxamides. Method
A. A solution of substituted carboxylic acid RCO2H (1000 mg) in
excess thionyl chloride (5 mL) was refluxed for 3 h. After reaction, the
resulting solution of RCOCl was cooled on ice, then aqueous NH4OH
(5 mL) was added, and the precipitate was filtered and dried to give
crude carboxamide product. This product was recrystallized from
ethanol to give pure amide 1.
a
All reactions were performed using 3 equiv of Oxone and 1 equiv of
phenylacetamide 1a at 40 °C. Isolated yields (numbers in parentheses
show yields determined from H NMR spectra of reaction mixtures).
No reaction. 2,4,6-Me3C6H2I was used instead of PhI. 4-MeC6H4I
was used instead of PhI. 4-CF3C6H4I was used instead of PhI. 3-
HO2CC6H4I was used instead of PhI. n-Bu4NI was used instead of
b
1
c
d
e
f
g
h
Method B. The substituted nitrile RCN (8.5 mmol) in concentrated
hydrochloric acid (41 mmol) was stirred at 65−70 °C for 2 h. After
reaction, the solution was cooled, and water (4 mL) was added. The
precipitate was filtered and dried to give crude carboxamide product.
This product was recrystallized from ethanol to give pure amide 1.
2-(4-Fluorophenyl)acetamide 1c.12 Reaction of 2-(4-
fluorophenyl)acetic acid according to general procedure method A
afforded 572 mg (58%) of product 1c, isolated as colorless needles
PhI.
species generated in situ, the new method affords carbamates 2
in similar yields.7a
In order to gain additional information about the mechanism
of this catalytic reaction, we have investigated its stereo-
chemistry. It is known from the literature that the rearrange-
ment of amides to amines proceeds with retention of
configuration at the migrating carbon.3a,8 We have found that
the reaction of bicyclic carboxamide 3 with endo configuration
under our condition gave the corresponding carbamate 4 with
retained endo configuration (Scheme 1). This result implied
that the mechanism of the catalytic rearrangement is similar to
that of the classical Hofmann rearrangement induced by
hypervalent iodine species.
On the basis of the previously reported mechanistic studies
of Hofmann rearrangement using hypervalent iodine reagent-
s,3a,4a,b,8 we propose that the active species 5 [hydroxy-
(phenyl)iodonium ion [PhI(OH)]+ possibly activated by
HFIP] generated from PhI and Oxone in aqueous HFIP
further react with carboxamide 1 to give the hypervalent
amidoiodane 6 via ligand exchange, which then undergoes the
reductive elimination of iodobenzene and the 1,2-shift at the
electron-deficient nitrenium nitrogen atom to give isocyanate 7
(Scheme 2). Subsequently, the addition of methanol to
isocyanate 7 gives the final carbamate 2. The regenerated PhI
continues the catalytic cycle. The presence of HFIP may help to
generate more electron-deficient active species 5 and 6 via
ligand exchange with hydroxy(phenyl)iodonium ion or hyper-
1
(recrystallized from ethanol): mp 157.2−157.6 °C; H NMR (500
MHz, DMSO-d6) δ 7.49 (br s, 1H), 7.34−7.25 (m, 2H), 7.16−7.08
(br s, 1H), 6.90 (br s, 1H), 3.37 (s, 2H).
2-(4-Chlorophenyl)acetamide 1d.13 Reaction of 2-(4-
chlorophenyl)acetonitrile according to general procedure method B
afforded 803 mg (56%) of product 1d, isolated as colorless needles
(recrystallized from ethanol): mp 182.2−182.4 °C (lit.13 mp 180−182
1
°C); H NMR (500 MHz, DMSO-d6) δ 7.49 (br s, 1H), 7.36 (d, J =
8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.91 (br s, 1H), 3.45 (s, 2H).
2-(3-Chlorophenyl)acetamide 1e.13 Reaction of 2-(3-
chlorophenyl)acetonitrile according to general procedure method B
afforded 873 mg (61%) of product 1e, isolated as colorless needles
(recrystallized from ethanol): mp 131.3−131.7 °C (lit.13 mp 126.5−
1
128 °C); H NMR (500 MHz, DMSO-d6) δ 7.53 (br s, 1H), 7.44−
7.18 (m, 4H), 6.95 (br s, 1H), 3.40 (s, 2H).
2-(2-Chlorophenyl)acetamide 1f.13 Reaction of 2-(2-
chlorophenyl)acetonitrile according to general procedure method B
afforded 856 mg (59%) of product 1f, isolated as colorless needles
(recrystallized from ethanol): mp 172.8−173.3 °C (lit.13 mp 168−172
1
°C); H NMR (500 MHz, DMSO-d6) δ 7.46 (br s, 1H), 7.43−7.39
(m, 1H), 7.37−7.33 (m, 1H), 7.29−7.25 (m, 2H), 6.96 (br s, 1H),
3.55 (s, 2H).
2-(4-Bromophenyl)acetamide 1g.14 Reaction of 2-(4-
bromophenyl)acetonitrile according to general procedure method B
afforded 923 mg (50%) of product 1g, isolated as colorless needles
11400
dx.doi.org/10.1021/jo302375m | J. Org. Chem. 2012, 77, 11399−11404

The Journal of Organic Chemistry
Note
a
Table 2. Preparation of Carbamates by Hofmann Rearrangement under Catalytic Conditions
a
All reactions of amides 1 (1 equiv) were performed at 40 °C in the presence of PhI (0.2 equiv) and Oxone (3 equiv) in MeOH−HFIP−H2O.
Isolated yields; the yields shown in parentheses correspond to the literature7a data for the synthesis of carbamates 2 from carboxamides 1 using PhI
b
(1 equiv) and Oxone (2 equiv).
5-Phenylpentanamide 1l.15 Reaction of 5-phenylpentanoic acid
according to general procedure method A afforded 147 mg (15%) of
product 1l, isolated as light brown needles (recrystallized from
ethanol): mp 106.8−107.3 °C (lit.15 mp 102−104 °C); 1H NMR (500
MHz, DMSO-d6) δ 7.44−7.12 (m, 6H), 6.73 (br s, 1H), 2.80−2.50
(m, 2H), 2.50−2.00 (m, 2H), 1.75−1.45 (m, 2H).
Scheme 1. Retention of Configuration in Hofmann
Rearrangement under Catalytic Conditions
6-Phenylhexanamide 1m.16 Reaction of 6-phenylhexanoic acid
(500 mg) according to general procedure method A afforded 228 mg
(46%) of product 1m, isolated as light brown needles (recrystallized
(recrystallized from ethanol): mp 194.1−194.7 °C (lit.14 mp 197−198
°C); 1H NMR (500 MHz, DMSO-d6) δ 7.55−7.44 (br s, 1H), 7.50 (d,
J = 7.3 Hz, 2H), 7.23 (d, J = 7.3 Hz, 2H), 6.92 (br s, 1H), 3.37 (s, 2H).
2-[(4-Trifluoromethyl)phenyl]acetamide 1h.8 Reaction of 2-(4-
trifluoromethyl)acetonitrile according to general procedure method B
afforded 866 mg (50%) of product 1h, isolated as colorless blocks
from ethanol): mp 93.1−93.4 °C (lit.16 mp 94−96 °C); H NMR
1
(500 MHz, DMSO-d6) δ 7.34−7.13 (m, 6H), 6.70 (br s, 1H), 2.56 (t, J
= 7.8 Hz, 2H), 2.04 (t, J = 7.6 Hz, 2H), 1.62−1.46 (m, 4H), 1.27
(quint, J = 7.6 Hz, 2H).
Octanamide 1n.17 Reaction of octanoic acid according to general
procedure method A afforded 267 mg (27%) of product 1n, isolated as
light brown needles (recrystallized from ethanol): mp 103.7−103.9 °C
1
(recrystallized from ethanol): mp 149.9−150.5 °C; H NMR (500
MHz, DMSO-d6) δ 7.66 (d, J = 8.0 Hz, 2H), 7.59 (brs, 1H), 7.49 (d, J
= 8.0 Hz, 2H), 6.98 (br s, 1H).
11401
dx.doi.org/10.1021/jo302375m | J. Org. Chem. 2012, 77, 11399−11404

The Journal of Organic Chemistry
Note
were added Oxone (460 mg, 0.75 mmol) and PhI (10 mg, 0.05
mmol). The reaction was stirred at 40 °C for 5−9 h (reaction
completion was controlled by TLC). After completion, the reaction
mixture was filtered, the inorganic solids on the filter were washed with
CH2Cl2, then 5% aqueous Na2S2O3 (5 mL) was added to the filtrate,
and the resulting solution was extracted with dichloromethane. The
organic phase was dried over anhydrous Na2SO4 and concentrated.
Purification by preparative TLC (hexane−ethyl acetate = 2:1 or 3:1)
afforded analytically pure carbamates 2.
Scheme 2. Proposed Reaction Mechanism
Methyl N-Benzylcarbamate 2a.7a Reaction of 2-phenylacetamide
1a (34 mg, 0.25 mmol) according to general procedure afforded 40 mg
(96%) of product 2a, isolated as colorless needles (recrystallized from
dichloromethane−hexane): mp 62.2−62.9 °C (lit.12 mp 63−65 °C);
1H NMR (500 MHz, CDCl3) δ 7.37 (t, J = 7.8 Hz, 2H), 7.31−7.25
(m, 3H), 4.98 (br s, 1H), 4.37 (d, J = 5.5 Hz, 2H), 3.70 (s, 3H).
Methyl N-(4-Methylbenzyl)carbamate 2b.7a Reaction of 2-(p-
tolyl)acetamide 1b (37 mg, 0.075 mmol) according to general
procedure afforded 43 mg (96%) of product 2b, isolated as colorless
needles (recrystallized from dichloromethane−hexane): mp 71.5−72.2
°C (lit.7a mp 68−70 °C); 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J =
7.5 Hz, 2H), 7.14 (d, J = 7.5 Hz, 2H), 4.92 (br s, 1H), 4.33 (d, J = 5.5
Hz, 2H), 3.7 (s, 3H), 2.34 (s, 3H).
Methyl N-(4-Fluorobenzyl)carbamate 2c.23 Reaction of 2-(4-
fluorophenyl)acetamide 1c (38 mg, 0.25 mmol) according to general
procedure afforded 39 mg (86%) of product 2c, isolated as colorless
needles (recrystallized from dichloromethane−hexane): mp 70.7−71.2
(lit.17 mp 109−110 °C); 1H NMR (500 MHz, DMSO-d6) δ 7.23 (br s,
1H), 6.67 (br s, 1H), 2.02 (t, J = 7.3 Hz, 2H), 1.56−1.40 (m, 2H),
1.34−1.16 (m, 8H), 0.86 (t, J = 6.5 Hz, 3H).
1
°C; H NMR (500 MHz, CDCl3) δ 7.30−7.21 (m, 2H), 7.25−6.98
(m, 2H), 5.09 (br s, 1H), 4.32 (d, J = 5.5 Hz, 2H), 3.69 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 162.4 (d, JCF = 245.9 Hz), 157.3, 134.6,
7-Chloroheptanamide 1o.18 Reaction of 7-chloroheptanenitrile
according to general procedure method B afforded 123 mg (11%) of
product 1o, isolated as colorless needles (recrystallized from ethanol):
mp 81.9−82.6 °C (lit.18 mp 82−83 °C); 1H NMR (500 MHz, DMSO-
d6) δ 7.21 (br s, 1H), 6.67 (br s, 1H), 3.62 (t, J = 7.5 Hz, 2H), 2.03 (t,
J = 7.5 Hz, 2H), 1.76−1.65 (m, 2H), 1.53−1.43 (m, 2H), 1.42−1.32
(m, 2H), 1.30−1.21 (m, 2H).
3
2
129.4 (d, JCF = 245.9 Hz), 115.7 (d, JCF = 21.6 Hz), 52.5, 44.6.
Methyl N-(4-Chlorobenzyl)carbamate 2d.24 Reaction of 2-(4-
chlorophenyl)acetamide 1d (42 mg, 0.25 mmol) according to general
procedure afforded 46 mg (93%) of product 2d, isolated as colorless
needles (recrystallized from dichloromethane−hexane): mp 80.9−81.6
°C; 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.0 Hz, 2H), 7.22 (d, J
= 8.0 Hz, 2H), 5.09 (br s, 1H), 4.33 (d, J = 5.5 Hz, 2H), 3.7 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 157.1, 137.2, 133.2, 128.8, 128.8, 52.3,
44.4.
7-Bromoheptanamide 1p.19 Reaction of 7-bromoheptanenitrile
according to general procedure method B afforded 526 mg (48%) of
product 1p, isolated as colorless needles (recrystallized from ethanol):
mp 83.2−83.6 °C (lit.19 mp 84 °C); 1H NMR (500 MHz, DMSO-d6)
δ 7.21 (br s, 1H), 6.67 (br s, 1H), 3.52 (t, J = 7.8 Hz, 2H), 2.03 (t, J =
7.5 Hz, 2H), 1.84−1.74 (m, 2H), 1.54−1.43 (m, 2H), 1.42−1.33 (m,
2H), 1.31−1.20 (m, 2H).
Methyl N-(3-Chlorobenzyl)carbamate 2e.25 Reaction of 2-(3-
chlorophenyl)acetamide 1e (42 mg, 0.25 mmol) according to general
procedure afforded 43 mg (86%) of product 2e, isolated as a colorless
1
2-Methylhexanamide 1q.20 Reaction of 2-methylhexanoic acid
according to general procedure method A afforded 75 mg (8%) of
product 1q, isolated as light brown needles (recrystallized from
oil: H NMR (500 MHz, CDCl3) δ 7.30−7.22 (m, 3H), 7.16 (d, J =
6.0 Hz, 1H), 5.12 (br s, 1H), 4.34 (d, J = 5.5 Hz, 2H), 3.70 (s, 3H).
Methyl N-(2-Chlorobenzyl)carbamate 2f.24 Reaction of 2-(2-
chlorophenyl)acetamide 1f (42 mg, 0.25 mmol) according to general
procedure afforded 44 mg (88%) of product 2f, isolated as colorless
ethanol): mp 62.2−62.8 °C (lit.20 mp 68.5−69 °C); H NMR (500
1
MHz, DMSO-d6) δ 7.19 (br s, 1H), 6.64 (br s, 1H), 2.23−2.13 (m,
1H), 1.54−1.40 (m, 1H), 1.32−1.13 (m, 5H), 0.96 (t, J = 6.5 Hz, 3H),
0.85 (t, J = 7.0 Hz, 3H).
1
oil: H NMR (500 MHz, CDCl3) δ 7.42−7.33 (m, 2H), 7.26−7.20
(m, 2H), 5.24 (br s, 1H), 4.44 (d, J = 6.5 Hz, 2H), 3.68 (s, 3H).
Methyl N-(4-Bromobenzyl)carbamate 2g.26 Reaction of 2-(4-
bromophenyl)acetamide 1g (54 mg, 0.25 mmol) according to general
procedure afforded 52 mg (85%) of product 2g, isolated as colorless
needles (recrystallized from dichloromethane−hexane): mp 93.7−94.4
°C; 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 8.3 Hz, 2H), 7.16 (d, J
= 8.3 Hz, 2H), 5.09 (br s, 1H), 4.31 (d, J = 6.0 Hz, 2H), 3.69 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 157.1, 137.7, 131.7, 129.2, 121.3, 52.3,
44.5.
2,2-Dimethylhexanamide 1r.21 Reaction of 2,2-dimethylhexanoic
acid (500 mg) according to general procedure method A afforded 83
mg (17%) of product 1r, isolated as colorless needles (recrystallized
from ethanol): mp 92.5−92.9 °C (lit.21 mp 93−93.5 °C); H NMR
1
(500 MHz, DMSO-d6) δ 6.97 (br s, 1H), 6.69 (br s, 1H), 1.42−1.37
(m, 2H), 1.28−1.19 (m, 2H), 1.18−1.09 (m, 2H), 1.03 (s, 6H), 0.86
(t, J = 7.3 Hz, 3H).
Cyclopentanecarboxamide 1s.22 Reaction of cyclopentanecarbox-
ylic acid according to general procedure method A afforded 107 mg
(11%) of product 1s, isolated as light brown needles (recrystallized
from ethanol): mp 171.3−172.2 °C (lit.22 mp 174−175 °C); 1H NMR
(500 MHz, DMSO-d6) δ 7.29 (br s, 1H), 6.66 (br s, 1H), 1.82−1.68
(m, 2H), 1.66−1.54 (m, 4H), 1.54−1.43 (m, 2H).
Methyl N-(4-Trifluoromethylbenzyl)carbamate 2h. Reaction of 2-
[(4-trifluoromethyl)phenyl]acetamide 1h (51 mg, 0.25 mmol)
according to general procedure afforded 45 mg (78%) of product
2h, isolated as colorless needles (recrystallized from dichloro-
1
methane−hexane): mp 88.5−89.2 °C; H NMR (500 MHz, CDCl3)
Bicyclo[2.2.1]heptane-2-carboxamide 3.8 Reaction of norbornane-
2-carboxylic acid (endo major isomer) according to general procedure
method A afforded 94 mg (10%) of product 3, isolated as white solid
δ 7.58 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 5.22 (br s, 1H),
4.42 (d, J = 6.0 Hz, 2H), 3.70 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
157.4, 143.0, 130.0 (d, 2JCF = 32.6 Hz), 127.8, 125.8 (d, 3JCF = 3.9 Hz),
124.3 (q, JCF = 272.1 Hz), 52.6, 44.8; HRMS (ESI): calcd for
C10H10F3NO2Na ([M + Na]+): 256.0561, found: 256.0552.
1
(endo:exo = 88:12); H NMR (500 MHz, DMSO-d6) δ 7.12 (br s,
1H), 6.71 (br s, 1H), 2.60−2.40 (m, 2H), 2.20−2.08 (m, 1H), 1.56−
Methyl N-(1-Phenylpropyl)carbamate 2i.5 Reaction of 2-phenyl-
butanamide 1i (41 mg, 0.25 mmol) according to general procedure
1.51 (m, 1H), 1.50−1.22 (m, 6H), 1.19−1.10 (m, 1H).
General Procedure for Catalytic Hofmann Rearrangement
of Carboxamides. To a solution of amide 1 (0.25 mmol) in a solvent
mixture of MeOH (0.75 mL), HFIP (0.75 mL), and H2O (0.075 mL)
1
afforded 46 mg (96%) of product 2i, isolated as a light brown oil: H
NMR (500 MHz, CDCl3) δ 7.35 (t, J = 7.5 Hz, 2H), 7.32−7.28 (m,
11402
dx.doi.org/10.1021/jo302375m | J. Org. Chem. 2012, 77, 11399−11404

The Journal of Organic Chemistry
Note
3H), 5.11 (br s, 1H), 4.68−4.54 (m, 1H), 3.66 (s, 3H), 1.92−1.72 (m,
2H), 0.92 (t, J = 7.5 Hz, 3H).
afforded 36 mg (92%) of product 2t, isolated as colorless needles
(recrystallized from dichloromethane−hexane): mp 74.6−75.2 °C
Methyl N-Pentylcarbamate 2j.5 Reaction of hexanamide 1j (29
mg, 0.25 mmol) according to general procedure afforded 33 mg (92%)
of product 2j, isolated as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 4.62 (br s, 1H), 3.66 (s, 3H), 3.22−3.06 (m, 2H), 1.49 (quint, J = 7.0
Hz, 2H), 1.38−1.24 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H).
(lit.7a mp 73.5−74.5 °C); H NMR (500 MHz, CDCl3) δ 4.53 (br s,
1
1H), 3.65 (s, 3H), 3.48 (br s, 1H), 1.98−1.86 (m, 2H), 1.75−1.65 (m,
2H), 1.64−1.56 (m, 1H), 1.4−1.28 (m, 2H), 1.22−1.06 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 156.2, 51.8, 49.8, 33.5, 25.5, 24.8.
Methyl N-(1-Adamantanyl)carbamate 2u.7a Reaction of 1-
adamantanecarboxamide 1u (45 mg, 0.25 mmol) according to general
procedure afforded 51 mg (98%) of product 2u, isolated as colorless
needles (recrystallized from dichloromethane−hexane): mp 118.4−
118.9 °C (lit.7a mp 118−120 °C); 1H NMR (500 MHz, CDCl3) δ 4.51
(br s, 1H), 3.61 (s, 3H), 2.08 (s, 3H), 1.93 (s, 6H), 1.67 (s, 6H).
endo-Methyl N-Bicyclo[2.2.1]-2-heptyl-carbamate 4.33 Reaction
of bicyo[2.2.1]heptane-2-carboxamide (endo:exo = 88:12) 3 (35 mg,
0.25 mmol) according to general procedure afforded 34 mg (81%;
endo:exo = 88:12) of product 4, isolated as white solid: 1H NMR (500
MHz, CDCl3): δ 4.71 (br s, 1H), 3.92 (br s, 1H), 3.66 (s, 3H), 2.46−
2.31 (m, 1H), 2.20 (s, 1H), 2.14−1.98 (m, 1H), 1.66−1.06 (m, 6H),
0.69 (d, J = 13 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 156.8, 52.3,
51.9, 40.4, 38.1, 37.9, 37.0, 29.9, 21.4.
Methyl N-(2-Phenylethyl)carbamate 2k.27 Reaction of 3-phenyl-
propanamide 1k (37 mg, 0.25 mmol) according to general procedure
afforded 41 mg (91%) of product 2k as a colorless oil: 1H NMR (500
MHz, CDCl3) δ 7.31 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.19
(t, J = 7.5 Hz, 2H), 4.74 (br s, 1H), 3.65 (s, 3H), 3.52−3.34 (m, 2H),
2.81 (t, J = 6.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 157.0, 138.8,
128.9, 128.6, 126.5, 52.0, 42.2, 36.2.
Methyl N-(4-Phenylbutyl)carbamate 2l.8 Reaction of 5-phenyl-
pentanamide 1l (44 mg, 0.25 mmol) according to general procedure
1
afforded 44 mg (85%) of product 2l as a colorless oil: H NMR (500
MHz, CDCl3) δ 7.27 (t, J = 7.5 Hz, 2H), 7.22−7.14 (m, 3H), 4.68 (br
s, 1H), 3.65 (s, 3H), 3.24−3.10 (m, 2H), 2.62 (t, J = 7.3 Hz, 2H). 1.64
(quint, J = 7.3 Hz, 2H), 1.52 (quint, J = 7.3 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 157.1, 142.1, 128.4, 128.3, 125.8, 52.0, 40.9, 35.5,
29.6, 28.5.
ASSOCIATED CONTENT
■
Methyl N-(5-Phenylpentyl)carbamate 2m.28 Reaction of 6-
phenylhexanamide 1m (46 mg, 0.25 mmol) according to general
procedure afforded 46 mg (84%) of product 2m as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 7.27 (t, J = 7.5 Hz, 2H), 7.20−7.14 (m,
3H), 4.69 (br s, 1H), 3.65 (s, 3H), 3.20−3.06 (m, 2H), 2.61 (t, J = 7.5
Hz, 2H). 1.68−1.59 (m, 2H), 1.56−1.47 (m, 2H), 1.35 (quint, J = 7.5
Hz, 2H).
S
* Supporting Information
Copies of NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Methyl N-Heptylcarbamate 2n.29 Reaction of octylamide 1n (36
mg, 0.25 mmol) according to general procedure afforded 37 mg (86%)
of product 2n, isolated as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 4.70 (br s, 1H), 3.66 (s, 3H), 3.24−3.08 (m, 2H), 1.55−1.44 (m,
2H), 1.38−1.21 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H).
Corresponding Author
*E-mail: ayoshimu@d.umn.edu; vzhdanki@d.umn.edu.
Notes
The authors declare no competing financial interest.
Methyl N-(6-Chloro)hexylcarbamate 2o.30 Reaction of 7-chlor-
ohexanamide 1o (41 mg, 0.25 mmol) according to general procedure
ACKNOWLEDGMENTS
■
1
afforded 41 mg (85%) of product 2o, isolated as a colorless oil: H
This work was supported by a research grant from the National
Science Foundation (CHE-1009038).
NMR (500 MHz, CDCl3) δ 4.64 (br s, 1H), 3.66 (s, 3H), 3.53 (t, J =
6.5 Hz, 2H), 3.18 (q, J = 6.5 Hz, 2H), 1.78 (quint, J = 7.5 Hz, 2H),
1.56−1.42 (m, 2H), 1.39−1.30 (m, 2H).
REFERENCES
Methyl N-(6-Bromo)hexylcarbamate 2p.31 Reaction of 7-bromo-
hexanamide 1p (52 mg, 0.25 mmol) according to general procedure
■
(1) For a book and selected reviews on hypervalent iodine chemistry,
see: (a) Hypervalent Iodine Chemistry; Wirth, T., Ed.; Springer-Verlag:
Berlin, 2003. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108,
5299−5358. (c) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073−2085.
(d) Ochiai, M.; Miyamoto, K. Eur. J. Org. Chem. 2008, 4229−4239.
(e) Uyanik, M.; Ishihara, K. Chem. Commun. 2009, 2086−2099.
(f) Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185−1197.
(2) (a) Moriarty, R. M.; Chany, C. J., II; Vaid, R. K.; Prakash, O.;
Tuladhar, S. M. J. Org. Chem. 1993, 58, 2478−2482. (b) Okamoto, N.;
Miwa, Y.; Minami, H.; Takeda, K.; Yanada, R. Angew. Chem., Int. Ed.
2009, 48, 9693−9696.
1
afforded 47 mg (78%) of product 2p, isolated as a colorless oil: H
NMR (500 MHz, CDCl3) δ 4.70 (br s, 1H), 3.66 (s, 3H), 3.41 (t, J = 7
Hz, 2H), 3.18 (q, J = 6.3 Hz, 2H), 1.86 (quint, J = 7 Hz, 2H), 1.57−
1.41 (m, 4H), 1.39−1.31 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
157.3, 52.2, 41.1, 34.0, 32.9, 30.1, 28.0, 26.1.
Methyl N-(2-Methyl)pentylcarbamate 2q. Reaction of 2-methyl-
hexanamide 1q (32 mg, 0.25 mmol) according to general procedure
1
afforded 29 mg (73%) of product 2q, isolated as a colorless oil: H
NMR (500 MHz, CDCl3) δ 4.47 (br s, 1H), 3.65 (s, 3H), 1.46−1.24
(m, 7H), 1.13 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 6.3 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 156.5, 51.8, 47.1, 36.9, 28.1, 22.6, 21.3, 14.0;
HRMS (ESI): calcd for C8H17NO2Na ([M + Na]+) 182.1157, found:
182.1158.
(3) (a) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.;
Blodgett, J. K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272−4276.
(b) Boutin, R. H.; Loudon, G. M. J. Org. Chem. 1984, 49, 4277−4284.
(4) (a) Lazbin, I. M.; Koser, G. F. J. Org. Chem. 1986, 51, 2669−
2671. (b) Moriarty, R. M.; Enache, L. A.; Zhao, L.; Gilardi, R.;
Mattson, M. V.; Prakash, O. J. Med. Chem. 1998, 41, 468−477.
(5) Yoshimura, A.; Luedtke, M. W.; Zhdankin., V. V. J. Org. Chem.
2012, 77, 2087−2091.
(6) (a) Tohma, H.; Maruyama, A.; Maeda, A.; Maegawa, T.; Dohi,
T.; Shiro, M.; Morita, T.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43,
3595−3598. (b) Yusubov, M. S.; Funk, T. V.; Chi, K.-W.; Cha, E.-H.;
Kim, G. H.; Kirschning, A.; Zhdankin, V. V. J. Org. Chem. 2008, 73,
295−297.
Methyl N-(2,2-Dimethyl)butylcarbamate 2r. Reaction of 2,2-
dimethylpentanamide 1r (36 mg, 0.25 mmol) according to general
procedure afforded 30 mg (70%) of product 2r, isolated as a colorless
1
oil: H NMR (500 MHz, CDCl3) δ 4.54 (br s, 1H), 3.61 (s, 3H),
1.64−1.56 (m, 2H), 1.35−1.20 (m, 4H), 1.27 (s, 6H), 0.90 (t, J = 7.3
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 155.3, 52.7, 51.4, 40.6, 27.0,
26.3, 23.1, 14.1; HRMS (ESI): calcd for C9H19NO2Na ([M + Na]+)
196.1313, found: 196.1314.
Methyl N-Cyclopentylcarbamate 2s.32 Reaction of cyclopentane-
carboxamide 1s (30 mg, 0.25 mmol) according to general procedure
afforded 30 mg (83%) of product 2s, isolated as colorless oil: 1H NMR
(500 MHz, CDCl3) δ 4.63 (br s, 1H), 3.97 (br s, 1H), 3.65 (s, 3H),
2.02−1.88 (m, 2H), 1.71−1.53 (m, 4H), 1.44−1.32 (m, 2H).
Methyl N-Cyclohexylcarbamate 2t.7a Reaction of cyclohexanecar-
boxamide 1t (32 mg, 0.25 mmol) according to general procedure
(7) (a) Zagulyaeva, A. A.; Banek, C. T.; Yusubov, M. S.; Zhdankin, V.
V. Org. Lett. 2010, 12, 4644−4647. (b) Moriyama, K.; Ishida, K.;
Togo, H. Org. Lett. 2012, 14, 946−949.
(8) Miyamoto, K.; Sakai, Y.; Goda, S.; Ochiai, M. Chem. Commun.
2012, 48, 982−984.
11403
dx.doi.org/10.1021/jo302375m | J. Org. Chem. 2012, 77, 11399−11404

The Journal of Organic Chemistry
Note
(9) (a) Yusubov, M. S.; Zagulyaeva, A. A.; Zhdankin, V. V. Chem.
Eur. J. 2009, 15, 11091−11094. (b) Zagulyaeva, A. A.; Yusubov, M. S.;
Zhdankin, V. V. J. Org. Chem. 2010, 75, 2119−2122. (c) Yoshimura,
A.; Neu, H. M.; Nemykin, V. N.; Zhdankin, V. V. Adv. Synth. Catal.
2010, 352, 1455−1460. (d) Yusubov, M. S.; Nemykin, V. N.;
Zhdankin, V. V. Tetrahedron 2010, 66, 5745−5752.
(10) (a) Thottumkara, A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett.
2005, 7, 2933−2936. (b) Uyanik, M.; Akakura, M.; Ishihara, K. J. Am.
Chem. Soc. 2009, 131, 251−262. (c) Thottumkara, A. P.; Vinod, T. K.
Org. Lett. 2010, 12, 5640−5643.
(11) (a) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684−
3691. (b) Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007,
129, 2772−2773. (c) Dohi, T.; Yamaoka, N.; Kita, Y. Tetrahedron
2010, 66, 5775−5785.
(12) Hamdouchi, C.; Sanchez-Martinez, C.; Gruber, J.; del Prado,
M.; Lopez, J.; Rubio, A.; Heinz, B. A. J. Med. Chem. 2003, 46, 4333−
4341.
(13) Andrews, P. A.; Brinkworth, R. I.; Partridge, A. C.; Reiss, J. A.
Aust. J. Chem. 1988, 41, 1717−1725.
(14) Tanaka, K.; Yoshifuji, S.; Nitta, Y. Chem. Pharm. Bull. 1988, 36,
3125−3129.
(15) Reid, E. B.; Ruby, W. R. J. Am. Chem. Soc. 1951, 73, 1054−1061.
(16) Wenkert, E.; Barnett, B. F. J. Am. Chem. Soc. 1960, 82, 4671−
4675.
(17) Nathan, A.; Alexandra, J. P.; Jonathan, M. J. W. Org. Lett. 2007,
9, 3599−3601.
(18) Nesmeyanov, A. N.; Zakharkin, L. I. Izv. Akad. Nauk SSSR, Ser.
Khim. 1955, 224−232.
(19) Durand, P.; Richard, P.; Renaut, P. J. Org. Chem. 1998, 63,
9723−9727.
(20) Goerner, L. G.; Holzschuh, A. A. J. Org. Chem. 1958, 23, 1346−
1349.
(21) Mcelvain, S. M.; Aldridge, C. L. J. Am. Chem. Soc. 1953, 75,
3987−3993.
(22) Bonne, D.; Dekhane, M.; Zhu, J. J. Am. Chem. Soc. 2005, 127,
6926−6927.
(23) This compound is commercially available from Aurora
Screening Library; Cat. Number: K03.099.335.
(24) Leathen, M. L.; Peterson, E. A. Tetrahedron Lett. 2010, 51,
2888−2891.
(25) Song, H. B.; Choi, M. H.; Koo, I. S.; Oh, H. K.; Lee, I. Bull.
Korean Chem. Soc. 2003, 24, 91−94.
(26) Clarke, C. T.; Elliott, J. D.; Jones, J. H. J. Chem. Soc., Perkin
Trans. 1 1978, 1088−1090.
(27) Ito, Y.; Ushitora, H. Tetrahedron 2006, 62, 226−235.
(28) Dicks, P. F.; Glover, S. A.; Goosen, A.; McCleland, C. W.
Tetrahedron 1987, 43, 923−934.
(29) Hiegel, G. A.; Hogenauer, T. J. Synth. Commun. 2005, 35,
2091−2098.
(30) Badamshina, E. R.; Grigorieva, V. A.; Komratova, V. V.; Ol’khov,
Y. A.; Lodygina, V. P.; Gorbushina, G. A.; Baturin, S. M. Intern. J.
Polym. Mater. 1993, 19, 117−125.
(31) Daniel, B.; Jean-Claude, B.; Gabriele, F.; Martin, K.; Franz, K.;
Markm P.; Marcel, V. Eur. Pat. Appl. 2002, EP 1245558 A1 20021002.
(32) Guin, J.; Muck-Lichtenfeld, C.; Grimme, S.; Studer, A. J. Am.
Chem. Soc. 2007, 129, 4498−4503.
(33) Kirmse, W.; Siegfried, R. J. Am. Chem. Soc. 1983, 105, 950−956.
11404
dx.doi.org/10.1021/jo302375m | J. Org. Chem. 2012, 77, 11399−11404