Enhanced nucleophilicity of N-aryl amides with peri-CH and their condensations with formaldehyde

Article abstract of DOI:10.1055/s-2008-1078485

N-Aryl amides with peri-CH are capable to condense with formaldehyde to yield N-hydroxymethylated N-aryl amides. The enhanced nucleophilicity is attributed to the single conjugation of the amide nitrogen with the acyl group but not the aryl group. Infrare

Full text of DOI:10.1055/s-2008-1078485

LETTER
1729
Enhanced Nucleophilicity of N-Aryl Amides with peri-CH and Their
Condensations with Formaldehyde
E
nhancedNucleop
i
hilicity
a
of
N
-
Aryl
n
Amideswith
g
peri-CH Wang,a,b Xiaoxue Cui,a Shasha Liu,a Lili Sun,a Chunbao Li*a
a
Department of Chemistry, College of Science, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27403475; E-mail: lichunbao@tju.edu.cn
b
State Key Laboratory Base of Novel Functional Materials and Preparation Science at Ningbo, Faculty of Materials Science and Chemical
Engineering, Ningbo University, Ningbo 315211, P. R. of China
Received 29 February 2008
When acetamide 1a (Table 1) was treated with an
equimolar amount of K2CO3 and an excess of polyformal-
dehyde in chloroform at room temperature for 1.5 hours,
N-hydroxymethyl-N-(1-naphthyl)acetamide (1b) was
Abstract: N-Aryl amides with peri-CH are capable to condense
with formaldehyde to yield N-hydroxymethylated N-aryl amides.
The enhanced nucleophilicity is attributed to the single conjugation
of the amide nitrogen with the acyl group but not the aryl group. In-
frared measurements provide additional evidence for the enhanced formed in 93% yield.
nucleophilicity of the amides with peri-CH.
A number of solvents (chloroform, ethyl acetate, toluene,
Key words: amides, condensation, nucleophilic addition, alde-
acetone, and THF) and bases (K2CO3, Na2CO3, NaHCO3,
and NaOH) were tested using the hydroxymethylation of
acetamide 1a (Table 1) as the model reaction. It was
found that higher yields could be obtained using chloro-
form as the solvent and K2CO3 as the base. Under this
conditions, a series of substituted N-(1-naphthyl)amides
were hydroxymethylated and the results and the structures
are given in Table 1. These methanol derivatives of N-
aryl-substituted secondary amides, which are not stable in
solutions, but are stable for two weeks when neat, have
not been previous reported in the literature. This type of
compounds are useful intermediates in medicinal chemis-
try and organic synthesis.4 In control experiments, no hy-
droxymethylation occurred for 5a, 9a (Table 1), and N-
[1-(8-methylnaphthyl)]acetamide, because the required
steric interaction between the peri-CH and the amide
group does not exist in these structures. When the steric
hindrance of the acyl group increases, both the reaction
rate and yield decrease notably. No hydroxymethylated
compounds were obtained when the acyl group was piv-
aloyl (4a, Table 1). The differing reaction yield can be ex-
plained by the fact that the bulky group hinders the
approach of the amide toward the formaldehyde even
though the amide is nucleophilic enough. The acyl groups
of amides 2a, 3a, and 4a are bulkier than those of amides
1a, 6a, 7a, 8a, and 10a. Therefore, only the later con-
densed with formaldehyde efficiently (Table 1).
hydes, alcohols
Amides and their reactions are important in both organic
chemistry and biochemistry because many bioactive com-
pounds or their intermediates possess amide groups. One
of the reactions of primary and secondary amides is their
condensation with formaldehyde to form N-hydroxymeth-
yl amides. However, the reaction is limited to primary
amides and N-alkyl amides.1 So far, there has been no
report on the condensation between N-aryl amides and
formaldehyde. We believe this is due to the dual conjuga-
tion of the lone-pair electrons on the nitrogen atom of the
N-aryl amides with both the acyl groups and aryl groups.2
This makes the N-aryl amide nitrogen less nucleophilic. If
a bulky group located close to the amide group on the
aromatic ring can force the acyl group in an out of plane
position with respect to the aromatic ring, only single con-
jugation of the nitrogen lone pair with acyl group is possi-
ble (Figure 1). This is supported by many amide structures
in the Cambridge Structure Database (CSD).3 This type of
amide with peri-CH would be reactive enough to con-
dense with formaldehyde. To test this idea, we carried out
the following experiments.
O
H
O
N
To expand the scope of the reaction as well as to further
demonstrate the existence of the peri-CH with amide-
group interaction in other aromatic structures, we exam-
ined indole-derived amides, 11a and 12a. When 11a was
treated with ten equivalents of polyformaldehyde, 11b
was obtained in 86% yield. On the other hand, when treat-
ed with one equivalent of polyformaldehyde, 11a yielded
11b and 11c in ca. 1:1.2 molar ratio in 67% yield. Similar
results were obtained when 12a reacted with ten equiva-
lents and one equivalent of polyformaldehyde (Table 1).
We also examined derivatives of N-phenylacetamide
(13a–22a, Table 1), but only 13a and 14a were hy-
droxymethylated (Table 1). The hydroxymethylation of
H
N
H
lone pair outside of the
aromatic ring plane for
N-aryl amide without
lone pair inside of the
aromatic ring plane for
N-aryl amide with peri-
CH: single conjugation
peri-CH: dual conjugation
Figure 1
SYNLETT 2008, No. 11, pp 1729–1733
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078485; Art ID: W03308ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

1730
Q. Wang et al.
LETTER
13a and 14a can be attributed to the larger conformational amides 13a and 14a are strong enough to condense with
free energies of the substituents (peri C–CH and C–CH3),5 formaldehyde, although amide 14a took a longer reaction
which hinder the conjugation of the nitrogen lone pair time.
with the benzene ring. Therefore the nucleophilicity of
Table 1 N-Hydroxymethylation of N-Aryl Amides Using Formaldehyde and K2CO3 at Room Temperature6
O
O
(HCHO)n
Ar
N
Ar
N
H
K2CO3, n-Bu4NBr, r.t.
OH
1b–3b, 6b–8b, 10b–14b
1a–21a
15a, Ar = Ph; 16a, Ar = 2-HOC6H4; 17a, Ar = 2-MeOC6H4; 18a, Ar = 3-O2NC6H4;
19a, Ar = 4-O2NC6H4; 20a, Ar = 4-MeC6H4; 21a, Ar = 4-Me2CHC6H4; 22a, Ar = 2,6-Me2C6H3
Substrate
Product
Time (h)
1.5
Yield (%)a
93
NHAc
HOH2C NAc
1a
1b
O
O
HO
N
HN
2.5
2.5
50b
2a
3a
2b
HOH2C NCOPh
NHCOPh
20
3b
NHCOt-Bu
None
24
24
0
0
4a
5a
NHAc
None
NHAc
HOH2C NAc
1.5
90
NMe2
NHAc
NMe2
6a
7a
6b
HOH2C NAc
3.0
2.0
80
69
N
N
7b
NHAc
HOH2C NAc
N
N
8b
8a
Synlett 2008, No. 11, 1729–1733 © Thieme Stuttgart · New York

LETTER
Enhanced Nucleophilicity of N-Aryl Amides with peri-CH
1731
Table 1 N-Hydroxymethylation of N-Aryl Amides Using Formaldehyde and K2CO3 at Room Temperature6 (continued)
O
O
(HCHO)n
Ar
N
Ar
N
H
K2CO3, n-Bu4NBr, r.t.
OH
1b–3b, 6b–8b, 10b–14b
1a–21a
15a, Ar = Ph; 16a, Ar = 2-HOC6H4; 17a, Ar = 2-MeOC6H4; 18a, Ar = 3-O2NC6H4;
19a, Ar = 4-O2NC6H4; 20a, Ar = 4-MeC6H4; 21a, Ar = 4-Me2CHC6H4; 22a, Ar = 2,6-Me2C6H3
Substrate
Product
Time (h)
24
Yield (%)a
NHAc
N
None
0
9a
NHAc
HOH2C NAc
4.0
87
10a
10b
AcN CH2OH
N
NHAc
CH2OH
11b
5.0
86
N
H
NHAc
11a
N
CH2OH
11c
12b
AcN CH2OH
CO2Et
N
NHAc
CH2OH
3.0
67b,c
CO2Et
N
NHAc
H
12a
CO2Et
N
CH2OH
12c
13b
14b
NHAc
AcN CH2OH
5.0
15
93b
80
13a
14a
Ac
N
CH2OH
NHAc
a Yield from 1H NMR.
b Isolated yield.
c One equivalent polyformaldehyde.
Synlett 2008, No. 11, 1729–1733 © Thieme Stuttgart · New York

1732
Q. Wang et al.
LETTER
Table 2 Carbonyl IR Data for N-Aryl Amidesa
to the single conjugation of the amide nitrogen lone pair
with the acyl group. The N-aryl groups include phenyl,
naphthyl, anthryl, indolyl, and biphenyl. This represents
an example of designing a synthetic reaction based on
peri-CH and amide group interaction. The experiment re-
sults and the infrared data presented herein support the
peri-CH interaction of the N-aryl amides.
Amide
1a
n
C=O (cm–1)
1655
1658
1649
1650
1668
1650
1656
1660
1677
1648
1636
1660
1661
1654
1664
1667
1669
1676
1680
1661
1661
1651
2a
3a
4a
Acknowledgment
5a
We thank NSFC (20572078), TMSTC (05YFGPGX07500) and
NBU Fund (XK200465 and SS2004031) for financial support.
6a
7a
References and Notes
8a
(1) (a) Gupta, R.; Paul, S.; Nanda, P. J. Indian Chem. Soc. 2005,
82, 573. (b) Winstead, M. B.; Heine, H. W. J. Am. Chem.
Soc. 1955, 77, 1913. (c) Zhong, W.; Song, G.; Peng, Y.;
Qian, X. Synth. Commun. 2000, 30, 3801.
(2) (a) Haisa, M.; Kashino, S.; Ueno, T.; Shinozaki, N.;
Matsuzaki, Y. Acta Crystallogr., Sect. B: Struct.
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
21a
22a
Crystallogr. Cryst. Chem. 1980, 36, 2306. (b) Wasserman,
H. J.; Ryan, R. R.; Layne, S. P. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 1985, 41, 783.
(3) (a)Cambridge Structural Database, version 1.8 (May 2007).
(a) Molcanov, K.; Stojkovic, M. R.; Piantanida, I.; Zinic, M.
Acta Crystallogr., Sect. E: Struct. Rep. Online 2006, 62,
o2666. (b) Balasubramamam, V.; Mohamed-Abubakar, S.;
Vittal, J. J.; Valiyaveettil, S. CrystEngComm 2004, 6, 284.
(c) Klika, K. D.; Janovec, L.; Lmrich, J.; Suchar, G.;
Kristian, P.; Sillanpaa, R.; Pihlaja, K. Eur. J. Org. Chem.
2002, 1248.
(4) (a) Royo, M.; Alsina, J.; Giralt, E.; Slomcyznska, U.;
Albericio, F. J. Chem. Soc., Perkin Trans. 1 1995, 1095.
(b) Pianka, M.; Edwards, J. D.; Smith, C. B. F. J. Sci. Food
Agric. 1966, 17, 407. (c) Haworth, R. D.; MacGillivary, R.;
Peacock, D. H. J. Chem. Soc. 1950, 1493.
(5) Eliel, E. L.; Manoharan, M. J. Org. Chem. 1981, 46, 1959.
(6) Typical Experimental Procedure for Hydroxy-
methylation of N-Aryl Amides
A mixture of amides (0.54 mmol, 1 equiv), polyform-
aldehyde (5.40 mmol, 10 equiv), K2CO3 (0.54 mmol, 1
equiv), and PTC (TBAB, 0.02 mmol, 0.05 equiv) in dry
CHCl3 was stirred for the indicated time (Table 1) at r.t.
After completion of the reaction, the unreacted polyform-
aldehyde was removed by filtration and CHCl3 was removed
under vacuum to obtain the crude products. The crude
products were purified by preparative TLC on SiO2 or
analyzed by 1H NMR to determine the yields.
a Measured on KBr disc.
We reasoned that when the amide group interacts with
peri-CH, the lone pair is perpendicular to the p-orbital of
the aromatic ring and is not in a favorable position to con-
jugate with the aromatic ring. Consequently, it is more
likely that it would conjugate better with the acyl group.
This would lead to lower vibrational frequencies of the
hydroxymethylatable amides. Infrared measurements
confirmed that this was indeed the case. Most of the car-
bonyl groups of hydroxymethylatable substrates (1a–3a,
6a–8a, and 10a–14a) have lower frequencies (<1661 cm–1)
than those amides which cannot be hydroxymethylated
(5a, 9a, and 15a–22a, Table 2). Amide 4a has a low fre-
quency (1650 cm–1) but cannot be hydroxymethylated be-
cause the sterochemical effect of the tertiary butyl group
hinders the approach of formaldehyde to the amide.
Spectroscopic Data for Products (Table 1)
N-Hydroxymethyl-N-(naphthalen-1-yl)acetamide (1b)
White syrup, EtOAc–CH2Cl2 (1:8) as eluant, 93% yield. 1H
NMR (500 MHz, CDCl3): d = 7.965–7.891 (m, 3 H), 7.613–
7.549 (m, 2 H), 7.505 (t, J = 7.5 Hz, 1 H), 7.446 (dd, J1 = 7.5
Hz, J2 = 1.5 Hz, 1 H), 5.374 (d, J = 10.0 Hz, 1 H), 4.915 (d,
J = 10.0 Hz, 1 H), 4.320–4.293 (br m, 1 H), 1.803 (s, 3 H).
ESI-MS: m/z (%) = 216.0 (100) [M+ + 1]. Anal. Calcd for
C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.50; H,
6.10; N, 6.55. IR (KBr): 3350.23, 3052.62, 2951.26,
1649.64, 1052.16, 1037.96 cm–1.
N-Hydroxymethyl-N-(naphthalen-1-yl)acrylamide (2b)
White syrup, EtOAc–CH2Cl2 (1:8) as eluant, 50% yield. 1H
NMR (500 MHz, CDCl3): d = 7.941–7.905 (m, 3 H), 7.587–
7.565 (m, 2 H), 7.518–7.487 (m, 1 H), 7.428–7.412 (m, 1 H),
6.444 (dd, J1 = 17.0 Hz, J2 = 2.0 Hz, 1 H), 5.812 (dd,
In summary, we have developed a simple and efficient
procedure for hydroxymethylation of N-aryl amides that
possess a peri-CH and amide-group interaction. The en-
hanced nucleophilicity of the N-aryl amides is attributed
Synlett 2008, No. 11, 1729–1733 © Thieme Stuttgart · New York

LETTER
Enhanced Nucleophilicity of N-Aryl Amides with peri-CH
1733
J1 = 17.0 Hz, J2 = 10.0 Hz, 1 H), 5.478 (dd, J1 = 12.0 Hz,
1005.03 cm–1.
J2 = 2.0 Hz, 1 H), 5.441 (dd, J1 = 10.0 Hz, J2 = 7.0 Hz, 1 H),
5.002 (dd, J1 = 10.0 Hz, J2 = 9.0 Hz, 1 H), 4.329 (t, J = 8.0
Hz, 1 H). ESI-MS: m/z = 228.0 (100) [M+ + 1]. Anal. Calcd
for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.97;
H, 5.79; N, 6.17. IR (KBr): 3398.72, 3055.21, 2928.00,
1653.31, 1049.45, 1029.40 cm–1.
N-Hydroxymethyl-N-(naphthalen-1-yl)benzamide (3b)
White syrup, Et2O–CH2Cl2 (1:15) as eluant, 20% yield.
1H NMR (500 MHz, CDCl3): d = 8.156 (d, J = 8.0 Hz, 1 H),
7.890 (d, J = 8.0 Hz, 1 H), 7.748 (d, J = 13.0 Hz, 1 H), 7.655
(t, J = 7.5 Hz, 1 H), 7.585–7.542 (m, 2 H), 7.299–7.246 (m,
3 H), 7.190 (t, J = 7.5 Hz, 1 H), 7.098–7.045 (m, 3 H), 5.541
(t, J = 9.0 Hz, 1 H), 5.096 (t, J = 9.0 Hz, 1 H), 4.207 (t,
J = 9.0 Hz, 1 H). ESI-MS: m/z (%) = 278.0 [M+ + 1]. Anal.
Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C,
77.97; H, 5.43; N, 5.08. IR (KBr): 3409.95, 3057.77,
2927.19, 1636.20, 1055.98, 1019.09 cm–1.
N-Hydroxymethyl-N-[1-(hydroxymethyl)-2-methyl-1H-
indol-4-yl]acetamide (11b)
Light yellow syrup, PE–EtOAc (1:1) as eluant, 86% yield.
1H NMR (500 MHz, CDCl3): d = 7.395 (d, J = 8.0 Hz, 1 H),
7.158 (t, J = 7.5 Hz, 1 H), 6.931 (d, J = 7.5 Hz, 1 H), 6.258
(s, 1 H), 5.623–5.614 (m, 2 H), 5.061–5.037 (m, 2 H), 3.861
(br t, J = 6.5 Hz, 1 H), 3.322 (br t, J = 5.5 Hz, 1 H), 2.509 (s,
3 H), 1.787 (s, 3 H). ESI-MS: m/z (%) = 248.9 (100) [M+].
Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28.
Found: C, 62.88; H, 6.52; N, 11.27. IR (KBr): 3391.72,
2922.62, 1637.66, 1037.87, 992.20 cm–1.
Ethyl 1-Hydroxymethyl-3-[N-(hydroxymethyl)-
acetamido]-1H-indole-2-carboxylate (12b)
Colorless syrup, Et2O–CH2Cl2 (1:5) as eluant, 65% yield. 1H
NMR (500 MHz, CDCl3): d = 7.662 (d, J = 8.0 Hz, 1 H),
7.568 (d, J = 8.5 Hz, 1 H), 7.468 (t, J = 7.5 Hz, 1 H), 7.269
(t, J = 7.5 Hz, 1 H), 5.838–5.753 (m, 2 H), 5.313–5.279 (m,
1 H), 4.854 (t, J = 9.5 Hz, 1 H), 4.568 (t, J = 8.5 Hz, 1 H),
4.445–4.385 (m, 2 H), 3.822 (t, J = 7.5 Hz, 1 H), 1.885 (s, 3
H), 1.392 (t, J = 7.0 Hz, 3 H). ESI-MS: m/z (%) = 329.0
(100) [M+ + 23]. Anal. Calcd for C15H18N2O5: C, 58.82; H,
5.92; N, 9.1. Found: C, 58.80; H, 5.93; N, 9.15. IR (KBr):
3272.07, 2924.23, 1702.18, 1661.32, 1036.68 cm–1.
Ethyl 3-Acetamido-1-(hydroxymethyl)-1H-indole-2-
carboxylate (12c)
N-[4-(Dimethylamino)naphthalen-1-yl]-N-(hydroxy-
methyl)acetamide (6b)
Colorless syrup, Et2O–CH2Cl2 (1:6) as eluant, 90% yield. 1H
NMR (500 MHz, CDCl3): d = 8.302–8.283 (m, 1 H), 7.911–
7.892 (m, 1 H), 7.583–7.542 (m, 2 H), 7.327 (d, J = 8.0 Hz,
1 H), 7.037 (d, J = 8.0 Hz, 1 H), 5.353–5.325 (m, 1 H),
4.892–4.861 (m, 1 H), 4.048 (br s, 1 H), 2.932 (s, 6 H), 1.811
(s, 3 H). ESI-MS: m/z (%) = 258.9 [M+]. Anal. Calcd for
C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C, 69.73;
H, 7.03; N, 10.83. IR (KBr): 3412.11, 354.34, 2926.98,
1652.68, 1047.83, 970.03 cm–1.
White solid, Et2O–CH2Cl2 (1:5) as eluant, 29% yield. 1H
NMR (500 MHz, CDCl3): d = 8.538 (s, 1 H), 7.958 (d,
J = 7.5 Hz, 1 H), 7.453 (d, J = 8.0 Hz, 1 H), 7.406 (t, J = 6.5
Hz, 1 H), 7.165 (t, J = 6.5 Hz, 1 H), 5.751 (d, J = 8.0 Hz, 2
H), 4.483 (q, J = 7.0 Hz, 2 H), 4.060 (br t, J = 6.0 Hz, 1 H),
2.278 (s, 3 H), 1.487 (t, J = 7.0 Hz, 3 H). ESI-MS: m/z (%) =
277.1 (100) [M+ + 1]. Anal. Calcd for C14H16N2O4: C, 60.86;
H, 5.84; N, 10.14. Found: C, 60.85; H, 5.85; N, 10.13. IR
(KBr): 3266.87, 2924.45, 1691.19, 1660.78, 1053.51,
1018.17 cm–1.
N-(Biphenyl-2-yl)-N-(hydroxymethyl)acetamide (13b)
White solid, EtOAc–PE (1:3) as eluant, 80% yield. 1H NMR
(500 MHz, CDCl3): d = 7.451–7.361 (m, 8 H), 7.305–7.288
(m, 1 H), 5.299–5.271 (m, 1 H), 4.428–4.389 (m, 1 H), 3.753
(br s, 1 H), 1.780 (s, 3 H). ESI-MS: m/z (%) = 263.9 (100)
[M+ + 23]. Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N,
5.81. Found: C, 74.68; H, 6.26; N, 5.83. IR (KBr): 3323.07,
2953.33, 1642.20, 1050.97, 1010.89 cm–1.
N-Hydroxymethyl-N-(quinolin-5-yl)acetamide (7b)
White solid, CH2Cl2–Et2O (1:2) as eluant, 80% yield. 1H
NMR (500 MHz, CDCl3): d = 8.980 (dd, J1 = 4.5 Hz,
J2 = 1.5 Hz, 1 H), 8.362 (d, J = 8.5 Hz, 1 H), 8.164 (d, J = 8.5
Hz, 1 H), 7.758–7.726 (m, 2 H), 7.523–7.492 (m, 2 H),
5.187–5.152 (m, 1 H), 5.129–5.094 (m, 1 H), 4.383 (br t,
J = 7.0 Hz, 1 H), 1.178 (s, 3 H). ESI-MS: m/z (%) = 216.9
(100) [M+]. Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59;
N, 12.96. Found: C, 66.64; H, 5.60; N, 12.95. IR (KBr):
3266.71, 3192.02, 2926.37, 1660.64, 1051.17, 1000.55 cm–1.
N-Hydroxymethyl-N-(isoquinolin-5-yl)acetamide (8b)
White syrup, EtOH–CH2Cl2 (1:15) as eluant, 69% yield.
1H NMR (500 MHz, CDCl3): d = 9.331 (s, 1 H), 8.631 (d,
J = 6.0 Hz, 1 H), 8.049 (dd, J1 = 7.5 Hz, J2 = 1.5 Hz, 1 H),
7.797 (d, J = 6.0 Hz, 1 H), 7.695–7.652 (m, 2 H), 5.300 (d,
J = 10.5 Hz, 1 H), 4.989 (d, J = 10.5 Hz, 1 H), 1.791 (s, 3 H).
ESI-MS: m/z (%) = 216.9 (100) [M+]. Anal. Calcd for
C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C, 66.66;
H, 5.60; N, 12.95. IR (KBr): 3247.57, 2922.58, 1667.28,
1054.27, 1032.91 cm–1.
N-(Anthracen-9-yl)-N-(hydroxymethyl)acetamide (10b)
Yellow solid, PE–EtOAc (1:1) as eluant, 87% yield.
1H NMR (500 MHz, CDCl3): d = 8.537 (s, 1 H), 8.135 (d,
J = 8.5 Hz, 2 H), 8.077 (d, J = 8.5 Hz, 2 H), 7.612 (d, J = 7.0
Hz, 2 H), 7.545 (t, J = 7.0 Hz, 2 H), 5.270 (d, J = 8.0 Hz, 2
H), 4.344 (br t, J = 7.5 Hz, 1 H), 1.674 (s, 3 H). ESI-MS:
m/z (%) = 266.0 (100) [M+ + 1]. Anal. Calcd for C17H15NO2:
C, 76.96; H, 5.70; N, 5.28. Found: C, 76.97; H, 5.71; N, 5.30.
IR (KBr): 3331.89, 3056.89, 2951.33, 1645.44, 1051.71,
N-Hydroxymethyl-N-(2-isopropylphenyl)acetamide
(14b)
Colorless syrup, Et2O–CH2Cl2 (1:5) as eluant, 50% yield. 1H
NMR (500 MHz, CDCl3): d = 7.404 (dd, J1 = 8.0 Hz,
J2 = 1.5 Hz, 1 H), 7.372 (dt, J1 = 7.0 Hz, J2 = 1.0 Hz, 1 H),
7.231 (dt, J1 = 8.0 Hz, J2 = 2.0 Hz, 1 H), 7.162 (dd, J1 = 7.5
Hz, J2 = 1.0 Hz, 1 H), 5.234 (dd, J1 = 10.0 Hz, J2 = 7.0 Hz, 1
H), 4.744 (t, J = 10.0 Hz, 1 H), 4.002 (t, J = 8.0 Hz, 1 H),
3.124 (m, 1 H), 1.818 (s, 3 H), 1.231 (d, J = 6.5 Hz, 3 H),
1.203 (d, J = 7.0 Hz, 3 H). ESI-MS: m/z (%) = 208.0 (100)
[M+ + 1]. Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N,
6.76. Found: C, 69.52; H, 8.28; N, 6.75. IR (KBr): 3326.96,
2963.94, 1652.29, 1048.75, 1027.57 cm–1.
Synlett 2008, No. 11, 1729–1733 © Thieme Stuttgart · New York