Facile synthesis of N-substituted amides from alcohols and amides

Article abstract of DOI:10.1055/s-0032-1318477

A facile and versatile method for preparing N-substituted amides from alcohols and amides using a Bronsted acid and an alkali metal halide has been developed. Treatment of tertiary alcohols and amides in the presence of an alkali metal halide or methanesulfonic acid in trifluoroacetic acid at elevated temperature afforded the corresponding N-substituted amides in moderate to high yields. Tertiary alcohols with various functional groups such as ether, ester, imide, carbamate, and halogen groups were tolerated under these conditions. This method can be used for the efficient and practical synthesis of various N-substituted formamides without the use of unmanageable cyano compounds. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1318477

PAPER
▌1069
paper
Facile Synthesis of N-Substituted Amides from Alcohols and Amides
N-Substituted Amides from Alcohols and Amides
Iku Okada, Kazuhiro Chiba, Yoshikazu Kitano*
Laboratory of Bio-organic Chemistry, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan
Fax +81(42)3675700; E-mail: kitayo@cc.tuat.ac.jp
Received: 18.01.2013; Accepted after revision: 25.02.2013
modify this reaction in order to develop a versatile method
Abstract: A facile and versatile method for preparing N-substituted
for synthesizing N-substituted amides from alcohols and
amides from alcohols and amides using a Brønsted acid and an al-
amides. Detailed investigation showed that the yield of
the desired compounds could be improved by optimizing
kali metal halide has been developed. Treatment of tertiary alcohols
and amides in the presence of an alkali metal halide or methanesul-
fonic acid in trifluoroacetic acid at elevated temperature afforded the reaction conditions, even if the reaction was carried
the corresponding N-substituted amides in moderate to high yields.
Tertiary alcohols with various functional groups such as ether, ester,
imide, carbamate, and halogen groups were tolerated under these
alcohols and amides have been reported,7 they are limited
conditions. This method can be used for the efficient and practical
synthesis of various N-substituted formamides without the use of
out with alcohols of non-adamantane character. Although
many methods for preparing N-substituted amides from
to the combination of alcohols with amides such as aryl,
benzyl, or propargyl alcohol with benzamide or p-toluene-
sulfonamide. A useful method for converting alkanols
into N-substituted amides with simple amides has not
been reported so far to the best of our knowledge. We de-
scribe herein a facile and versatile method for preparing
N-substituted amides from alcohols and amides in which
nucleophilic substitution is carried out with a Brønsted
acid and an alkali metal halide.
unmanageable cyano compounds.
Key words: amides, alcohols, Brønsted acids, alkali metal halides,
nucleophilic substitution
N-Substituted amides are a very important class of com-
pounds that have been widely utilized as intermediates in
the syntheses of peptide, isonitrile, and other organic com-
pounds.1 In addition, some of these compounds have
served as drugs, lead compounds in drug development,
and insect repellents.2 One of the most common proce-
dures for preparing N-substituted amides is the Ritter re-
action, which is particularly useful for the synthesis of
tertiary alkylamides;3 however, cyano compounds such as
sodium cyanide or trimethylsilyl cyanide are required to
prepare N-substituted formamides using the Ritter reac-
tion,4 and the unmanageability of cyano reagents often
makes this method inconvenient.
The results for the reactions of 2-methyl-2-dodecanol (1a)
with formamide and Brønsted acids are summarized in
Table 1. All reactions included in the table were carried
out at 90 °C in a screw-cap tube, except for entries 7 and
8. The desired N-substituted formamide 1b was obtained
in only 29% yield under the conditions given in entry 1,
which are the optimal conditions for preparing N-adaman-
tylformamides reported by Shokova and co-workers.6 A
dramatic improvement in the yield of the desired for-
mamide 1b was achieved by optimizing the ratio and
amounts of formamide and TFA. It was found that the
mixture composed of formamide and TFA in a ratio of 1:2
afforded the desired product 1b most efficiently (entries
1–6). In addition, formamide 1b was obtained in good to
high yield when more than 30.0 equivalents of TFA were
used (entries 4–6). When the amount of TFA was de-
creased from 30.0 equivalents to 10.0 equivalents, the
amount of byproducts increased and the yield of the de-
sired product decreased considerably. Although the iden-
tities of these byproducts are unclear, many kinds of low
polarity compounds were observed in a TLC analysis. 1H
NMR analysis of the crude product suggested that the cor-
responding 1,2-disubstituted alkenes and TFA esters of
secondary alcohols were generated as byproducts through
carbocation rearrangement. On the other hand, when the
reaction temperature was lowered from 90 °C to 60 °C,
the product yield decreased (entry 7). Furthermore, the N-
substituted amide was not detected at room temperature
(entry 8).
Nevertheless, these N-substituted formamides are well
known as important and versatile intermediates for the
synthesis of isocyanides. In particular, the dehydration of
formamides is a standard method used for preparing iso-
cyanides,1c,5 although this method is not necessarily con-
venient in the case of N-tertiary alkylformamides because
of difficulties involved in obtaining an appropriate for-
mamide precursor. It is therefore desirable to develop a
simple, efficient method for synthesizing N-substituted
formamides without cyano compounds. Shokova and co-
workers have reported the conversion of 1-adamantanol
into the corresponding amides in the presence of for-
mamides and trifluoroacetic acid (TFA).6 This simple
method gives N-adamantylformamides in 92% yield;
however, they also reported that tertiary alcohols of non-
adamantane character such as tert-butyl alcohol were con-
verted into the desired amides in only poor yield (16%).
Encouraged by the results of their study, we attempted to
We also made numerous attempts to employ other
Brønsted acids such as acetic acid, sulfuric acid, methane-
sulfonic acid (MsOH), and oxalic acid in addition to the
SYNTHESIS 2013, 45, 1069–1075
Advanced online publication: 18.03.2013
DOI: 10.1055/s-0032-1318477; Art ID: SS-2013-F0058-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1070
I. Okada et al.
PAPER
Table 1 Optimization of the Reaction Conditionsa
tion hardly proceeded at all when only MsOH was used
without TFA (entries 14–17).
NHCHO
OH
formamide
Further examination showed that the addition of alkali
metal halides to the reaction mixture improved the yield
of the desired N-substituted formamide. Thus, the same
reaction was examined with 2.0 equivalents of various al-
kali metal halides along with 15.0 equivalents of form-
amide and 30.0 equivalents of TFA (Table 1, entries 18–
22). Among the various alkali metal halides (KCl, LiCl,
KBr, LiBr, LiI), LiBr was the most effective, and 94%
yield of 1b was obtained. On the other hand, addition of
LiBr decreased the yield of the desired formamide at all in
the presence of TFA/MsOH (entries 23 and 24). It is pro-
posed that the role of alkali metal halides in the reaction
system is as a source of halide ions. Halide intermediate
was detected by GLC analysis, by monitoring the reaction
performed under TFA/LiBr conditions (entry 21). The re-
sults indicate that alcohol 1a can be converted into form-
amide 1b via a halide intermediate in the presence of
alkali metal halides, and this halide intermediate may con-
tribute to effective formamide formation. On the basis of
these experiments, the conditions shown in entry 21 were
chosen as the optimum conditions.
Brønsted acid
4
4
90 °C
1a
1b
Entry Formamide TFA
MsOH
(equiv)
Metal halide Yieldb
(equiv)
(equiv)
(equiv)
(%)
1
2.0
10.0
10.0
10.0
30.0
50.0
100.0
100.0
100.0
5.0
–
–
29
51
33
74
81
93
60
n.d.e
71
86
85
91
87
15
10
4
2
5.0
–
–
3
7.0
–
–
4
15.0
25.0
50.0
50.0
50.0
5.0
–
–
5
–
–
6
–
–
7c
8d
9
–
–
–
–
5.0
15.0
9.0
25.0
50.0
10.0
30.0
50.0
100.0
–
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
15.0
15.0
25.0
50.0
5.0
15.0
21.0
25.0
50.0
–
–
–
Subsequently, the scope and limitations of this reaction
were investigated under the optimized conditions. Table 2
displays the results obtained for the formation of the cor-
responding formamides from various tertiary alcohols.
Under the optimized conditions, all linear alcohols exam-
ined gave the corresponding formamides in moderate to
good yields (entries 1–11). Various functional groups
such as halide, ether, ester, imide, and carbamate groups
were tolerated well under these conditions; however,
when fluoride 2a and chloride 3a were used as the starting
materials, two byproducts were observed that resulted
from the nucleophilic substitution of bromide and trifluo-
roacetate anions for the fluoride and chloride moieties.
Improvement of the yields of the reactions described in
entries 1 and 4 was achieved by using MsOH instead of
LiBr. When the TFA/MsOH conditions were used, the de-
sired N-substituted amides were obtained in high yields of
up to 84% (2b) and 86% (3b), whereas 2b and 3b were ob-
tained in 73% and 74% yield, respectively, under simple
TFA conditions. These results indicate that the
TFA/MsOH conditions could become the optimal condi-
tions when formamide formation is inefficient under the
TFA/LiBr conditions. On the other hand, 1-dodecanol and
2-dodecanol, which are primary and secondary alcohols,
afforded the corresponding trifluoroacetates as the main
products under the standard TFA/LiBr conditions (data
not shown).
–
–
–
15.0
25.0
50.0
15.0
15.0
15.0
15.0
15.0
5.0
–
–
–
–
–
–
6
30.0
30.0
30.0
30.0
30.0
7.0
KCl, 2.0
KBr, 2.0
LiCl, 2.0
LiBr, 2.0
LiI, 2.0
LiBr, 2.0
LiBr, 2.0
86
85
88
94
87
69
78
–
–
–
–
3.0
9.0
15.0
21.0
a Reactions were carried out for 8 h.
b Determined by GLC analysis.
c The reaction was carried out at 60 °C.
d The reaction was carried out at room temperature.
e n.d. = not detected.
TFA to decrease the amount of TFA required. Although
combinations of TFA and other Brønsted acids were not The stereoselectivity of the reaction was also examined
efficient for this reaction in many cases, the combination using 1-methyl-1-cyclohexanol derivatives possessing a
of TFA and MsOH gave the desired product in good yield tert-butyl group (9a, 10a), a benzoyloxy group (11a, 12a),
(Table 1, entries 9–13). In particular, the desired product or a benzoyloxymethyl group (13a, 14a) at the 4-position,
1b was obtained in high yield when 15.0, 25.0, and 50.0 as shown in Table 3. The desired formamides 9b and 10b
equivalents each of formamide, TFA, and MsOH were were obtained in good yield under TFA/LiBr and
used (entries 10–13). On the other hand, the desired reac- TFA/MsOH conditions. In addition, the stereoisomeric al-
cohols 9a and 10a gave the same products in approxi-
Synthesis 2013, 45, 1069–1075
© Georg Thieme Verlag Stuttgart · New York

PAPER
N-Substituted Amides from Alcohols and Amides
1071
Table 2 Reaction of Various Linear Alkyl Alcohols 2a–8a to the
tions (entries 9 and 10). This might be attributed to the
greater stability of the benzoyloxymethyl group toward
rearrangement to the carbocation compared to that of the
benzoyloxy group. In contrast, the conversion of alcohol
14a into the corresponding amides was inefficient under
the TFA/LiBr conditions, and the desired products 13b
and 14b were obtained in only 49% yield (entry 11). En-
tries 7–11 show that the stereoisomeric alcohols also gave
the same products in approximately the same ratio, as did
alcohols 9a and 10a. However, the stereoselectivity was
different for 11a and 12a than for 13a and 14a. The ratio
of 11b and 12b was about 2:3 in the case of the cyclohexyl
benzoates (entries 7 and 8), whereas alcohols 13a and 14a
gave the corresponding formamides 13b and 14b in a ratio
of about 3:1 (entries 9–11). These results suggest that the
stereoselectivity is influenced by the functional group at
the 4-position.
Corresponding Formamidesa
OH
NHCHO
formamide
R
R
4
Brønsted acid
90 °C
4
2a–8a
2b–8b
Entry
Substrate
R
Product
Yieldb (%)
1
2a
2a
2a
3a
3a
3a
4a
5a
6a
7a
8a
F
2b
2b
2b
3b
3b
3b
4b
5b
6b
7b
8b
66
73
84
72
74
86
76
86
77
85
55
2c
3d
4
F
F
Cl
5c
6d
7
Cl
Cl
Br
Table 3 Reaction of Various Cyclohexyl Alcohols 9a–14a to the
8
OBz
Corresponding Formamidesa
9
OMe
OH
NHCHO
10
11
phthalimidyl
NHFmoc
R
9a, 11a, 13a
R
9b, 11b, 13b
a Reaction conditions: alcohol 2a–8a (0.5 mmol), formamide (15.0
equiv), TFA (30.0 equiv), LiBr (2.0 equiv), 8 h.
b Isolated yield.
formamide
Brønsted acid
90 °C
OH
NHCHO
c LiBr was not added.
R
R
d TFA (15.0 equiv) and MsOH (15.0 equiv) were used, without LiBr.
10a, 12a, 14a
10b, 12b, 14b
Entry
Substrate
9a
R
Productb
Yieldc (%)
mately the same ratio (entries 1–6); however, the ratio of
9b to 10b changed for the different conditions: it was
about 1:1 under TFA/LiBr conditions (entries 1 and 4) and
3:2 under TFA/MsOH conditions (entries 2 and 5). Fur-
thermore, the ratio of 9b to 10b changed to 2:1 when 30%
camphorsulfonic acid was used instead of MsOH under
TFA conditions (entries 3 and 6). These results suggest
that the stereoselectivity could change for different coun-
teranions.
1d
t-Bu
9b/10b (1:1)
9b/10b (3:2)
9b/10b (2:1)
9b/10b (1:1)
9b/10b (3:2)
9b/10b (2:1)
11b/12b (2:3)
11b/12b (2:3)
13b/14b (3:1)
13b/14b (3:1)
13b/14b (3:1)
82
80
78
77
77
79
17
18
77
76
49
2e
9a
t-Bu
3f
9a
t-Bu
4d
10a
10a
10a
11a
12a
13a
14a
14a
t-Bu
5e
t-Bu
6f
t-Bu
On the other hand, cyclohexyl benzoates 11a and 12a af-
forded the corresponding amides 11b and 12b in trace
yields under TFA/LiBr conditions (data not shown). The
yields of the desired formamides 11b and 12b from alco-
hols 11a and 12a were improved by switching to the
TFA/MsOH conditions, although they were only 17% and
18% (Table 3, entries 7 and 8). In the case of cyclohexyl
benzoates 11a and 12a, disubstituted internal alkene 18
and TFA ester 19 were observed as byproducts. It is pro-
posed that the benzoyloxy group might be rearranged to
carbocation intermediate 16 to afford these rearranged or
eliminated byproducts 18 and 19, as shown in Scheme 1.
Based on this hypothesis, we prepared cyclohexylmethyl
benzoates 13a and 14a, which possess one more methy-
lene than alcohols 11a and 12a. As expected, the desired
formamides 13b and 14b were obtained in good yields
from alcohols 13a and 14a under the TFA/MsOH condi-
7e
OBz
8e
OBz
9e
CH2OBz
CH2OBz
CH2OBz
10e
11d,g
a Reaction conditions: alcohol 9a–14a (0.5 mmol), formamide (15.0
equiv), TFA (30.0 equiv), 8 h.
b Determined by NMR analysis.
c Isolated yield.
d TFA (30.0 equiv) was used, and LiBr (2.0 equiv) was added.
e TFA (15.0 equiv) and MsOH (15.0 equiv) were used.
f TFA (21.0 equiv) and (+)-CSA (9.0 equiv) were used.
g The reaction was carried out for 24 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1069–1075

1072
I. Okada et al.
PAPER
H+
In conclusion, we have developed a facile and versatile
method for converting alcohols into the corresponding N-
substituted amides using amides, Brønsted acids, and al-
kali metal halides. In particular, the combinations of TFA
and LiBr or of TFA and MsOH are effective conditions
for the synthesis of a wide range of N-substituted amides.
The present method can provide a practical approach for
preparing N-substituted or N,N-disubstituted amide com-
pounds.
OH
O
O
– H2O
+
Ph
O
Ph
O
11a, 12a
15
Ph
O
+
O
O
O
Ph
+
NMR spectra were obtained in CDCl3 on a JEOL ECA-600 or JEOL
ECS-400 spectrometer. All 1H NMR data are reported in ppm rela-
tive to tetramethylsilane (TMS). All 13C NMR data are reported in
ppm relative to the central line of the triplet for CDCl3 at 77.0 ppm.
1H and 13C NMR data for formamides are reported separately for
each rotational isomer (major, minor) on the basis of 1H NMR anal-
ysis. IR spectra were recorded on a JEOL WINSPEC-50 spectrom-
eter. Electrospray ionization (ESI) was recorded on a JEOL JMS-
T100 mass spectrometer. Chromatographic separations were car-
ried out on a silica gel column (Kanto Chemical 60N, 63–210 μm)
unless otherwise stated. The physical data for compounds 1a–4a,
2b–4b, and 6b–8b were identical to the data we previously report-
ed.1c,8 The intermediates 1-methyl-1,4-cyclohexanediol and 4-(hy-
droxymethyl)cyclohexanone were prepared according to literature
procedures.8,9
16
17
OBz
18
– H+
O
OBz
TFA
F3C
O
19
Scheme 1 Proposed reaction mechanism generating disubstituted in-
ternal alkene 18 and TFA ester 19
Table 4 shows results of the reactions of various amides
with alcohol 1a. The reaction conditions were the same as
those used for synthesizing the N-substituted formamides.
Treatment of the tertiary alcohol with acetamide or benz-
amide afforded the corresponding amides 1c and 1d in
moderate yields (entries 1 and 2). In addition, N,N-disub-
stituted amide 1e was obtained with the N-substituted
formamide, although the yield was not as good (entry 3);
however, improvement in the yield of the desired 1e was
observed when the amounts of starting amide and TFA
were increased (entry 4). These results indicate that not
only formamides but also other kinds of amides can be
prepared using this method.
Preparation of Amides from Alcohols; General Procedure
LiBr (87 mg, 1.0 mmol) and amide (7.5 mmol) were successively
added to a mixture of alcohol (0.5 mmol) and TFA (1.15 mL, 15.0
mmol) in a screw-cap tube. After the reaction mixture was stirred at
90 °C for 8 h, sat. NaHCO3 (30 mL) was added, and the resultant
mixture was extracted with EtOAc (100 mL). The combined ex-
tracts were washed with sat. NaHCO3 and brine, dried (MgSO4),
and concentrated under reduced pressure. The residue was purified
by performing silica gel column chromatography to give the pure
amide.
N-(2-Methyl-2-dodecyl)formamide (1b)
Purified by performing silica gel column chromatography (hexane–
EtOAc, 1:1) to give amide 1b as a colorless oil; yield: 92.5 mg
(81%).
IR (neat): 3282 (br), 3055, 2954, 2924, 2854, 2754, 1686, 1670,
1541, 1468, 1385, 1365, 1265 cm–1.
Table 4 Reaction of Various Amides with Alcohol 1aa
R2
1H NMR (600 MHz, CDCl3): δ (major) = 8.18 (d, J = 12.4 Hz, 1 H),
6.03 (br s, 1 H), 1.49–1.45 (m, 2 H), 1.34–1.20 (m, 22 H), 0.86 (t,
J = 6.9 Hz, 3 H); δ (minor) = 8.01 (s, 1 H), 5.28 (br s, 1 H), 1.67–
1.63 (m, 2 H), 1.34–1.20 (m, 22 H), 0.86 (t, J = 6.9 Hz, 3 H).
OH
N
R1
amide, LiBr
TFA, 90 °C
4
4
O
1a
1c–e
13C NMR (150 MHz, CDCl3): δ (major) = 163.2, 52.9, 43.9, 32.0,
30.0, 29.8, 29.7, 29.7, 29.4, 28.8, 23.9, 22.8, 14.2;
δ (minor) = 160.5, 54.1, 40.8, 32.0, 30.1, 29.8, 29.7, 29.7, 29.4,
27.1, 24.2, 22.8, 14.2.
Entry
Amide
R1
R2
Product Yieldb
(%)
HRMS (ESI): m/z [M + Na]+ calcd for C14H29NNaO: 250.2147;
found: 250.2148.
1
acetamide
benzamide
Me
Ph
H
H
1c
1d
1e
1e
69
40
16
24
2
H
N-(2-Methyl-2-dodecyl)acetamide (1c)
3
N-methylformamide
N-methylformamide
Me
Me
Purified by performing silica gel column chromatography (hexane–
EtOAc, 3:2) to give amide 1c as a white solid; yield: 82.6 mg (69%);
mp 54–55 °C.
4c
H
a Reaction conditions: alcohol 1a (0.5 mmol), amide (15.0 equiv),
TFA (30.0 equiv), LiBr (2.0 equiv), 8 h.
IR (KBr): 3275, 3088, 2962, 2916, 2848, 1641, 1566, 1471, 1371,
1304 cm–1.
1H NMR (600 MHz, CDCl3): δ = 5.16 (br s, 1 H), 1.90 (s, 3 H),
1.67–1.63 (m, 2 H), 1.32–1.20 (m, 22 H), 0.87 (t, J = 6.9 Hz, 3 H).
b Isolated yield.
c TFA (30.0 equiv) and N-methylformamide (60.0 equiv) were used.
13C NMR (150 MHz, CDCl3): δ = 169.4, 53.8, 40.5, 32.0, 30.1,
29.8, 29.8, 29.7, 29.5, 27.0, 24.6, 24.3, 22.8, 14.2.
Synthesis 2013, 45, 1069–1075
© Georg Thieme Verlag Stuttgart · New York

PAPER
N-Substituted Amides from Alcohols and Amides
1073
HRMS (ESI): m/z [M + Na]+ calcd for C15H31NNaO: 264.2303;
found: 264.2302.
J = 7.5 Hz, 2 H), 5.24 (br s, 1 H), 4.31 (t, J = 6.6 Hz, 2 H), 1.76
(quint, J = 6.6 Hz, 2 H), 1.69–1.65 (m, 2 H), 1.47–1.41 (m, 2 H),
1.38–1.22 (m, 18 H).
13C NMR (150 MHz, CDCl3): δ (major) = 166.6, 163.0, 132.7,
130.5, 129.5, 128.2, 65.1, 52.8, 43.7, 29.8, 29.5, 29.4, 29.4, 29.2,
28.7, 27.0, 23.8; δ (minor) = 166.6, 160.3, 132.7, 130.5, 129.5,
128.2, 65.1, 54.0, 40.6, 29.9, 29.5, 29.4, 29.4, 29.2, 28.6, 26.0, 24.0.
N-(2-Methyl-2-dodecyl)benzamide (1d)
Purified by performing silica gel column chromatography (hexane–
EtOAc, 10:1) to give amide 1d as a white solid; yield: 61.5 mg
(40%); mp 63–64 °C.
IR (KBr): 3286 (br), 3064, 3028, 2956, 2922, 2850, 1633, 1540,
1470, 1329, 1308, 696 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.70 (d, J = 7.3 Hz, 2 H), 7.46 (t,
J = 7.3 Hz, 1 H), 7.41 (t, J = 7.3 Hz, 2 H), 5.82 (br s, 1 H), 1.81–1.77
(m, 2 H), 1.43 (s, 6 H), 1.33–1.22 (m, 16 H), 0.87 (t, J = 6.9 Hz, 3
H).
HRMS (ESI): m/z [M + Na]+ calcd for C21H33NNaO3: 370.2358;
found: 370.2358.
N-(4-tert-Butyl-1-methylcyclohexyl)formamides 9b and 10b
Purified by performing silica gel flash column chromatography
(Yamazen Corporation V003, 40 μm; hexane–EtOAc, 1:0 to 1:1) to
give amides 9b [yield: 39.6 mg (40%)] and 10b [yield: 39.6 mg
(40%)].
13C NMR (150 MHz, CDCl3): δ = 166.9, 136.2, 131.1, 128.6, 126.8,
54.3, 40.7, 32.0, 30.2, 29.8, 29.8, 29.7, 29.5, 27.2, 24.3, 22.8, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C20H33NNaO: 326.2460;
found: 326.2458.
N-(cis-4-tert-Butyl-1-methylcyclohexyl)formamide (9b)
White solid; mp 83–85 °C.
IR (KBr): 3273 (br), 3251 (br), 3051, 2968, 2949, 2868, 2832, 1672,
1655, 1552, 1541, 1446, 1385, 1365 cm–1.
N-Methyl-N-(2-methyl-2-dodecyl)formamide (1e)
Purified by performing silica gel column chromatography (hexane–
EtOAc, 1:1) to give amide 1e as a colorless oil; yield: 29.2 mg
(24%).
1H NMR (600 MHz, CDCl3): δ (major) = 8.12 (d, J = 2.1 Hz, 1 H),
5.02 (br s, 1 H), 2.25–2.20 (m, 2 H), 1.66–1.54 (m, 3 H), 1.47–1.38
(m, 2 H), 1.33 (s, 3 H), 1.27–1.07 (m, 2 H), 0.86–0.83 (m, 9 H);
δ (minor) = 8.24 (d, J = 13.0 Hz, 1 H), 5.56 (br s, 1 H), 1.85–1.79
(m, 2 H), 1.66–1.54 (m, 1 H), 1.47–1.38 (m, 3 H), 1.27–1.07 (m, 4
H), 1.01–0.95 (m, 2 H), 0.86–0.83 (m, 9 H).
13C NMR (150 MHz, CDCl3): δ (major) = 160.7, 53.3, 47.6, 37.2,
32.5, 28.1, 27.6, 22.7; δ (minor) = 163.5, 51.6, 47.5, 39.2, 32.5,
31.8, 27.6, 22.3.
IR (neat): 3481 (br), 2954, 2926, 2854, 1680, 1660, 1466, 1375,
1028 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.29 (s, 1 H), 2.79 (s, 3 H), 1.53–
1.50 (m, 2 H), 1.34–1.19 (m, 20 H), 1.14–1.10 (m, 2 H), 0.86 (t,
J = 6.9 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 161.7, 57.3, 40.2, 31.9, 29.8,
29.6, 29.6, 29.5, 29.3, 27.1, 25.9, 23.7, 22.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C12H23NNaO: 220.1677;
found: 220.1677.
HRMS (ESI): m/z [M + Na]+ calcd for C15H31NNaO: 264.2303;
found: 264.2311.
N-(trans-4-tert-Butyl-1-methylcyclohexyl)formamide (10b)
White solid; mp 102–103 °C.
11-Hydroxy-11-methyldodecyl Benzoate (5a)
Benzoic acid (352 mg, 2.88 mmol) and Et3N (400 μL, 2.87 mmol)
were added successively to a soln of 12-bromo-2-methyl-2-dodeca-
nol (290 mg, 1.04 mmol) in DMF (7 mL). After the reaction mixture
was stirred at 80 °C for 20 h, 1 M HCl (30 mL) was added, and the
resultant mixture was extracted with hexane–EtOAc (2:1, 90 mL).
The combined extracts were washed with 1 M HCl, sat. NaHCO3,
and brine, dried (MgSO4), and concentrated under reduced pressure.
The residue was purified by performing silica gel column chroma-
tography (hexane–EtOAc, 3:1) to give alcohol 5a as a white solid;
yield: 91 mg (27%); mp 43–44 °C.
IR (KBr): 3275 (br), 3047, 2968, 2956, 2939, 2864, 1668, 1651,
1545, 1466, 1390 cm–1.
1H NMR (600 MHz, CDCl3): δ (major) = 8.30 (d, J = 12.4 Hz, 1 H),
5.62 (br s, 1 H), 1.84–1.79 (m, 2 H), 1.74–1.47 (m, 5 H), 1.32 (s, 3
H), 1.23–1.12 (m, 2 H), 0.88–0.84 (m, 9 H); δ (minor) = 8.03 (d,
J = 2.1 Hz, 1 H), 5.17 (br s, 1 H), 2.06–2.01 (m, 2 H), 1.74–1.47 (m,
3 H), 1.39 (s, 3 H), 1.23–1.12 (m, 2 H), 1.06–0.99 (m, 2 H), 0.88–
0.84 (m, 9 H).
13C NMR (150 MHz, CDCl3): δ (major) = 162.6, 52.8, 47.6, 40.0,
32.4, 27.6, 24.6, 23.5; δ (minor) = 160.4, 54.1, 47.7, 37.7, 32.4,
27.7, 23.4, 22.2.
IR (KBr): 3510 (br), 3398 (br), 3091, 3064, 3034, 2966, 2929, 2854,
1720, 1468, 1452, 1275, 1116, 712 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.03 (dd, J = 7.8, 1.4 Hz, 2 H),
7.54 (t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 4.31 (t, J = 7.0
Hz, 2 H), 1.76 (quint, J = 7.0 Hz, 2 H), 1.47–1.25 (m, 16 H), 1.20
(s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 166.8, 132.9, 130.7, 129.6, 128.4,
71.1, 65.3, 44.1, 30.3, 29.7, 29.6, 29.4, 29.4, 29.4, 28.9, 26.2, 24.5.
HRMS (ESI): m/z [M + Na]+ calcd for C12H23NNaO: 220.1677;
found: 220.1675.
4-Hydroxy-4-methylcyclohexyl Benzoates 11a and 12a
Pyridine (1.5 mL, 19 mmol) was added to a soln of 1-methyl-1,4-
cyclohexanediol (cis/trans mixture, 1.37 g, 10.6 mmol) in CH2Cl2
(20 mL). The reaction mixture was cooled to ice bath temperature,
and BzCl (1.5 mL, 13 mmol) was added dropwise to the solution.
After the reaction mixture was stirred at 0 °C for 2 h, brine (30 mL)
was added, and the resultant mixture was extracted with EtOAc
(100 mL). The combined extracts were washed with 1 M HCl, sat.
NaHCO3, and brine, dried (MgSO4), and concentrated under re-
duced pressure. The residue was purified by performing silica gel
column chromatography (hexane–EtOAc, 3:1 to 2:1) to give alco-
hols 11a [yield: 345 mg (14%)] and 12a [yield: 233 mg (10%)].
HRMS (ESI): m/z [M + Na]+ calcd for C20H32NaO3: 343.2249;
found: 343.2251.
11-(Formylamino)-11-methyldodecyl Benzoate (5b)
Purified by performing silica gel column chromatography (hexane–
EtOAc, 1:1) to give amide 5b as a white solid; yield: 149.2 mg
(86%); mp 66–67 °C.
IR (KBr): 3209 (br), 3086, 2976, 2926, 2852, 1716, 1689, 1481,
1282, 1126, 717 cm–1.
cis-4-Hydroxy-4-methylcyclohexyl Benzoate (11a)
White solid; mp 83–87 °C.
1H NMR (600 MHz, CDCl3): δ (major) = 8.20 (d, J = 12.4 Hz, 1 H),
8.05–8.02 (m, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2
H), 5.88 (br s, 1 H), 4.31 (t, J = 6.6 Hz, 2 H), 1.76 (quint, J = 6.6 Hz,
2 H), 1.51–1.47 (m, 2 H), 1.47–1.41 (m, 2 H), 1.38–1.22 (m, 18 H);
δ (minor) = 8.05–8.02 (m, 3 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.43 (t,
IR (KBr): 3435 (br), 3410 (br), 3093, 3064, 2966, 2953, 2941, 2922,
2870, 2850, 1714, 1686, 1377, 1323, 1288, 1271, 1115, 1028, 989,
710 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1069–1075

1074
I. Okada et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 7.5 Hz, 2 H), 7.54 (t,
J = 7.5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 2 H), 5.02–4.95 (m, 1 H), 1.98–
1.84 (m, 4 H), 1.82–1.74 (m, 2 H), 1.62–1.53 (m, 2 H), 1.28 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 166.2, 132.9, 130.8, 129.6, 128.4,
72.6, 68.7, 36.7, 29.8, 27.4.
HRMS (ESI): m/z [M + Na]+ calcd for C14H18NaO3: 257.1154;
found: 257.1169.
in THF (60 mL) at 0 °C under an argon atmosphere. After the reac-
tion mixture was stirred at temperatures from 0 °C to r.t. for 16 h,
sat. NH4Cl (50 mL) was added, and the resultant mixture was ex-
tracted with EtOAc (100 mL). The combined extracts were washed
with brine, dried (MgSO4), and concentrated under reduced pres-
sure to give 4-(hydroxymethyl)-1-methylcyclohexanol [cis/trans
mixture, yield: 1.54 g (95%)]. The obtained crude alcohol was used
in the next step without further purification. Pyridine (3.0 mL, 37.0
mmol), BzCl (3.0 mL, 26.0 mmol), and DMAP (140 mg) were suc-
cessively added to a soln of the above alcohol (cis/trans mixture,
1.66 g, 11.5 mmol) in CH2Cl2 (30 mL). After the reaction mixture
was stirred at r.t. for 1 d, brine (30 mL) was added, and the resultant
mixture was extracted with EtOAc (150 mL). The combined ex-
tracts were washed with 1 M HCl, sat. NaHCO3, and brine, dried
(MgSO4), and concentrated under reduced pressure. The residue
was purified by performing silica gel column chromatography (hex-
ane–EtOAc, 3:1 to 2:1) to give alcohols 13a [yield: 575 mg (20%)]
and 14a [yield: 217 mg (8%)].
trans-4-Hydroxy-4-methylcyclohexyl Benzoate (12a)
White solid; mp 67–68 °C.
IR (KBr): 3307 (br), 3238 (br), 3086, 3062, 3030, 2962, 2953, 2943,
2929, 2879, 2856, 1716, 1450, 1344, 1278, 1113, 917, 712 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.03 (d, J = 7.5 Hz, 2 H), 7.55 (t,
J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 5.23–5.19 (m, 1 H), 2.06–
1.99 (m, 2 H), 1.85–1.76 (m, 4 H), 1.62–1.55 (m, 2 H), 1.32 (s, 3 H),
1.16 (br s, 1 H).
13C NMR (150 MHz, CDCl3): δ = 166.0, 132.9, 131.0, 129.6, 128.4,
70.7, 69.4, 34.9, 30.3, 26.8.
HRMS (ESI): m/z [M + Na]+ calcd for C14H18NaO3: 257.1154;
cis-(4-Hydroxy-4-methylcyclohexyl)methyl Benzoate (13a)
White solid; mp 92–93 °C.
found: 257.1156.
IR (KBr): 3352 (br), 3286 (br), 3062, 3034, 2964, 2931, 2914, 2860,
1712, 1450, 1280, 1117, 715 cm–1.
4-(Formylamino)-4-methylcyclohexyl Benzoates 11b and 12b
Purified by performing silica gel column chromatography (Fuji Si-
lysia Chemical NH DM-1020, 100–200 mesh; hexane–EtOAc, 1:1)
to give amides 11b [yield: 8.9 mg (7%)] and 12b [yield: 13.4 mg
(10%)].
1H NMR (600 MHz, CDCl3): δ = 8.04 (d, J = 7.7 Hz, 2 H), 7.55 (t,
J = 7.7 Hz, 1 H), 7.44 (t, J = 7.7 Hz, 2 H), 4.19 (d, J = 6.2 Hz, 2 H),
1.88–1.82 (m, 3 H), 1.76–1.71 (m, 2 H), 1.50 (dt, J = 12.7, 3.4 Hz,
2 H), 1.29–1.22 (m, 5 H).
13C NMR (150 MHz, CDCl3): δ = 166.7, 133.0, 130.5, 129.6, 128.5,
70.8, 69.0, 39.1, 36.3, 26.9, 26.3.
cis-4-(Formylamino)-4-methylcyclohexyl Benzoate (11b)
Colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20NaO3: 271.1310;
found: 271.1322.
IR (neat): 3290 (br), 3061, 2943, 2868, 2758, 1712, 1682, 1535,
1450, 1275, 1115, 1026, 714 cm–1.
1H NMR (600 MHz, CDCl3): δ (major) = 8.17 (d, J = 2.1 Hz, 1 H),
8.05–8.00 (m, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.41 (m, 2 H), 5.14
(s, 1 H), 5.07–4.97 (m, 1 H), 2.32–2.27 (m, 2 H), 1.99–1.91 (m, 2
H), 1.75–1.65 (m, 2 H), 1.59–1.53 (m, 2 H), 1.46 (s, 3 H);
δ (minor) = 8.33 (d, J = 12.4 Hz, 1 H), 8.05–8.00 (m, 2 H), 7.57–
7.53 (m, 1 H), 7.46–7.41 (m, 2 H), 5.65 (br d, J = 12.4 Hz, 1 H),
5.07–4.97 (m, 1 H), 1.99–1.91 (m, 4 H), 1.84–1.79 (m, 2 H), 1.75–
1.65 (m, 2 H), 1.41 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ (major) = 166.1, 161.0, 133.0,
130.7, 129.6, 128.4, 72.2, 52.8, 34.3, 27.2, 26.4; δ (minor) = 166.0,
163.5, 133.1, 130.5, 129.6, 128.5, 71.3, 51.5, 35.9, 29.5, 26.8.
HRMS (ESI): m/z [M + Na]+ calcd for C15H19NNaO3: 284.1263;
found: 284.1263.
trans-(4-Hydroxy-4-methylcyclohexyl)methyl Benzoate (14a)
White solid; mp 71–72 °C.
IR (KBr): 3334 (br), 3282 (br), 3088, 3066, 3032, 2960, 2943, 2887,
2862, 1714, 1450, 1276, 1120, 711 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.04 (dd, J = 7.6, 1.4 Hz, 2 H),
7.55 (tt, J = 7.6, 1.4 Hz, 1 H), 7.43 (t, J = 7.6 Hz, 2 H), 4.18 (d,
J = 6.4 Hz, 2 H), 1.78–1.65 (m, 5 H), 1.56–1.38 (m, 4 H), 1.24 (s, 3
H), 1.10 (br s, 1 H).
13C NMR (150 MHz, CDCl3): δ = 166.7, 132.9, 130.6, 129.7, 128.4,
69.8, 69.2, 38.1, 36.7, 31.6, 25.1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20NaO3: 271.1310;
found: 271.1310.
[4-(Formylamino)-4-methylcyclohexyl]methyl Benzoates 13b
and 14b
Purified by performing silica gel column chromatography (Fuji Si-
lysia Chemical NH DM-1020, 100–200 mesh; hexane–EtOAc, 1:1)
to give amides 13b [yield: 78.5 mg (57%)] and 14b [yield: 26.1 mg
(19%)].
trans-4-(Formylamino)-4-methylcyclohexyl Benzoate (12b)
Colorless oil.
IR (neat): 3296 (br), 3059, 2947, 2860, 2756, 1716, 1682, 1533,
1450, 1275, 1115, 714 cm–1.
1H NMR (600 MHz, CDCl3): δ (major) = 8.13 (d, J = 1.4 Hz, 1 H),
8.03–8.00 (m, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.42 (m, 2 H), 5.37
(br s, 1 H), 5.19–5.15 (m, 1 H), 2.07–2.01 (m, 2 H), 1.92–1.80 (m,
6 H), 1.48 (s, 3 H); δ (minor) = 8.30 (d, J = 12.4 Hz, 1 H), 8.03–8.00
(m, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.42 (m, 2 H), 6.16 (br s, 1 H),
5.19–5.15 (m, 1 H), 1.92–1.80 (m, 6 H), 1.75–1.71 (m, 2 H), 1.42
(s, 3 H).
cis-[4-(Formylamino)-4-methylcyclohexyl]methyl Benzoate
(13b)
White solid; mp 139–140 °C.
IR (KBr): 3311, 3049, 2964, 2947, 2933, 2912, 2850, 2762, 1714,
1682, 1658, 1539, 1286, 1122, 717 cm–1.
1H NMR (600 MHz, CDCl3): δ (major) = 8.13 (s, 1 H), 8.02 (d,
J = 7.8 Hz, 2 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H),
5.14 (br s, 1 H), 4.16 (d, J = 6.2 Hz, 2 H), 2.29–2.24 (m, 2 H), 1.84–
1.69 (m, 3 H), 1.42 (s, 3 H), 1.37–1.20 (m, 4 H); δ (minor) = 8.25
(s, 1 H), 8.02 (d, J = 7.8 Hz, 2 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.43 (t,
J = 7.8 Hz, 2 H), 5.76 (br s, 1 H), 4.16 (d, J = 6.2 Hz, 2 H), 1.84–
1.69 (m, 5 H), 1.50 (dt, J = 13.7, 3.4 Hz, 2 H), 1.37–1.20 (m, 5 H).
13C NMR (150 MHz, CDCl3): δ (major) = 166.0, 161.0, 133.1,
130.8, 129.6, 128.5, 70.1, 53.3, 32.5, 26.5, 26.4; δ (minor) = 165.9,
163.4, 133.0, 130.7, 129.6, 128.5, 69.8, 51.8, 34.4, 29.9, 26.2.
HRMS (ESI): m/z [M + Na]+ calcd for C15H19NNaO3: 284.1263;
found: 284.1270.
(4-Hydroxy-4-methylcyclohexyl)methyl Benzoates 13a and 14a
MeLi (1.14 M in Et2O; 29.5 mL, 33.6 mmol) was added dropwise
to a soln of 4-(hydroxymethyl)cyclohexanone (1.43 g, 11.2 mmol)
13C NMR (150 MHz, CDCl3): δ (major) = 166.7, 160.8, 133.1,
130.4, 129.6, 128.5, 69.4, 53.4, 36.6, 35.9, 28.0, 25.0;
Synthesis 2013, 45, 1069–1075
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PAPER
N-Substituted Amides from Alcohols and Amides
1075
δ (minor) = 166.6, 163.5, 133.1, 130.3, 129.6, 128.5, 69.2, 51.8,
37.8, 36.5, 31.9, 24.5.
References
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HRMS (ESI): m/z [M + Na]+ calcd for C16H21NNaO3: 298.1419;
found: 298.1420.
trans-[4-(Formylamino)-4-methylcyclohexyl]methyl Benzoate
(14b)
Colorless oil.
IR (neat): 3292 (br), 3059, 2931, 2862, 2756, 1716, 1689, 1535,
1450, 1275, 1115, 714 cm–1.
1H NMR (600 MHz, CDCl3): δ (major) = 8.05 (d, J = 2.1 Hz, 1 H),
8.02 (d, J = 7.6 Hz, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.42 (m, 2 H),
5.26 (s, 1 H), 4.21–4.18 (m, 2 H), 2.01–1.97 (m, 2 H), 1.91–1.67 (m,
5 H), 1.43 (s, 3 H), 1.39–1.29 (m, 2 H); δ (minor) = 8.32 (d, J = 12.4
Hz, 1 H), 8.02 (d, J = 7.6 Hz, 2 H), 7.57–7.53 (m, 1 H), 7.46–7.42
(m, 2 H), 5.86 (br s, 1 H), 4.21–4.18 (m, 2 H), 1.91–1.67 (m, 5 H),
1.63–1.57 (m, 2 H), 1.39–1.29 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ (major) = 166.7, 160.5, 133.0,
130.4, 129.6, 128.5, 68.9, 54.0, 36.3, 35.9, 25.4, 22.9;
δ (minor) = 166.6, 162.7, 133.1, 130.3, 129.6, 128.5, 68.7, 52.7,
38.4, 36.2, 25.5, 25.3.
HRMS (ESI): m/z [M + Na]+ calcd for C16H21NNaO3: 298.1419;
found: 298.1409.
Acknowledgment
This work was partially supported by a Grant-in-Aid for the Acce-
lerating Utilization of University IP Program from the Japan Sci-
ence and Technology Agency.
(7) (a) Das, B.; Reddy, P. R.; Sudhakar, C.; Lingaiah, M.
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8424.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1069–1075