Remarkably mild and efficient cetrimonium bromide catalyzed friedel-crafts amidoalkylation of sesamols with N -Boc imines generated in situ in aqueous medium

Article abstract of DOI:10.1055/s-0029-1219802

A remarkably mild and efficient cetrimonium bromide (CTAB) catalyzed Friedel-Crafts amidoalkylation of sesamol or its 2-substituted derivatives with N-Boc imines generated in situ was developed. A wide range of 6-amidoalkyl sesamols were synthesized in high yields. This methodology was also applicable to 2-naphthols.

Full text of DOI:10.1055/s-0029-1219802

LETTER
1415
Remarkably Mild and Efficient Cetrimonium Bromide Catalyzed
Friedel–Crafts Amidoalkylation of Sesamols with N-Boc Imines
Generated In Situ in Aqueous Medium
A
midoalkylation
o
u
f
Sesamols
w
i
ith
N
-Boc-Im
Z
ines hang,a,b Ming-Gui Chen,c Chun-Xia Lian,a Wei-Cheng Yuan,a Xiao-Mei Zhang*a
a
Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax +86(28)85229250; E-mail: xmzhang@cioc.ac.cn
Graduate School of Chinese Academy of Sciences, Beijing 100049, P. R. of China
School of Chemistry and Chemical Engineering, Southwest Petroleum University, Chengdu 610500, P. R. of China
b
c
Received 2 February 2010
generated in situ, through which a wide variety of 6-ami-
doalkyl sesamols were synthesized in high yields.
Abstract: A remarkably mild and efficient cetrimonium bromide
(CTAB) catalyzed Friedel–Crafts amidoalkylation of sesamol or its
2-substituted derivatives with N-Boc imines generated in situ was
developed. A wide range of 6-amidoalkyl sesamols were synthe-
sized in high yields. This methodology was also applicable to 2-
naphthols.
First, we investigated the Friedel–Crafts amidoalkylation
of sesamol 1a with N-Boc imine generated in situ from a-
amido sulfone 2a in water at 30 °C, employing 1.5 equiv-
alents of CsOH as the base (Table 1, entry 1). The reaction
proceeded in two days to afford 64% of the desired prod-
uct 6-amidoalkyl sesamol 3a. Encouraged by this finding,
we next examined the effects of various bases. Among
these bases, Na2CO3 gave a promising yield of 80%. How-
ever, no increase in yield was observed by prolonging the
reaction time to three days (Table 1, entry 10). When the
reaction was performed at higher temperature, many side
products arose and the yield dropped significantly
(Table 1, entry 11).
Key words: sesamol, Friedel–Crafts amidoalkylation, a-amido sul-
fones, CTAB, 6-amidoalkyl sesamols
The Friedel–Crafts aminoalkylation or amidoalkylation of
electron-rich phenols with imines represents an important
transformation for the synthesis of biologically active
compounds and chiral amino alcohol ligands. For exam-
ple, synthesis of 1-aminoalkyl naphthols via Friedel–
Crafts amino- or amidoalkylation of 2-naphthols attracted
much attention due to the importance of the products.1
Recently, Kobayashi and other groups reported several
surfactant-promoted reactions in aqueous medium.7
Therefore, in order to improve the efficiency of this reac-
tion, we introduced surfactants into the reaction mixture.
To our delight, several surfactants accelerated the reaction
dramatically. In the presence of 10 mol% of surfactants
SDS (sodium 1-dodecanesulfonate) and 12-2-12
Sesamol is one of the representative structural motifs of-
ten observed in natural alkaloids and biologically active
compounds.2 As an electron-rich phenol, sesamol and its
derivatives are good nucleophiles that can be employed in
the Friedel–Crafts reaction to construct complex natural
products.3 Jurd has reported the Mannich type Friedel–
Crafts aminoalkylation of sesamol and the application of
the resulting Mannich bases in the synthesis of anti-tumor
agents.4 Recently, Frackenpohl also reported the same re-
action and its application in the synthesis of insecticidal
heterolignans.5 However, to the best of our knowledge, a
systematic study on Friedel–Crafts amidoalkylation of
sesamol with imines has not been reported.
[ethanediyl-1,2-bis(dodecyldimethyl-ammonium
bro-
mide)], the reaction proceeded smoothly to afford more
than 80% yield of the product in five hours (Table 1, en-
tries 12 and 13). Moreover, 10 mol% of CTAB (cetrimo-
nium bromide) provided almost quantitative amounts of
product in five hours (Table 1, entry 14). Further research
indicated that the reaction was actually complete within
only three hours (Table 1, entry 15). However, reducing
the catalyst loading to 5 mol% resulted in an obvious de-
crease of product yield (Table 1, entry 16).
N-Boc imines are of great importance in nucleophilic ad-
dition because they are very reactive electrophiles and the
Boc group can be easily removed from the resulting ad-
ducts, however, N-Boc imines are known to be unstable
and difficult to handle. Gratifyingly, this problem can be
circumvented by generating N-Boc imines in situ from
stable a-amido sulfones.6 Herein, we report a remarkably
mild and efficient Friedel–Crafts amidoalkylation of ses-
amol or its 2-substituted derivatives with N-Boc imines
Having established the optimal reaction conditions, the
generality of this reaction was examined. In the presence
of 10 mol% of CTAB, sesamol or its 2-substituted deriv-
atives underwent Friedel–Crafts amidoalkylation with a
wide variety of a-amido sulfones in water at 30 °C.8,9 The
results are summarized in Table 2.
As can be seen in Table 2, it is clear that the methodology
is quite general. All aryl or alkyl a-amido sulfones tested
underwent the reaction smoothly to provide the corre-
sponding 6-amidoalkyl sesamols in good yields. For aryl
a-amido sulfones, the substituents on the aromatic rings
SYNLETT 2010, No. 9, pp 1415–1417
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x.
x
x.
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Advanced online publication: 25.03.2010
DOI: 10.1055/s-0029-1219802; Art ID: W01910ST
© Georg Thieme Verlag Stuttgart · New York

1416
H. Zhang et al.
LETTER
Table 1 Screening of Bases and Catalysts in the Friedel–Crafts
Amidoalkylation of Sesamol 1a with a-Amido Sulfone 2aa
Table 2 Friedel–Crafts Amidoalkylation of Sesamol 1 with a-Ami-
do Sulfone 2 Catalyzed by CTABa
R1
OH
O
OH
O
OH
O
O
R1
NHBoc
1a
O
O
OH
R2
Na2CO3
CTAB (10 mol%)
H2O, 30 °C
1a–c
O
O
base (cat.)
H2O, 30 °C
+
+
NHBoc
NHBoc
SO2Ph
NHBoc
3a
3a–s
R2
SO2Ar
2a–q
2a
Entry
1
1 (R1)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1b(Me)
1c (I)
2 (R2)
Time (h) Yield (%)b
Entry
1
Base
Catalyst (mol%) Time (h) Yield (%)b
2a (Ph)
3
3
97
95
90
91
85
95
91
92
96
97
90
88
94
91
85
93
95
83
95
CsOH·H2O
KOH
none
48
48
48
48
48
48
48
48
48
72
48
5
64
76
51
66
73
61
80
73
33
79
70
82
84
97
97
67
2
2b (4-MeC6H4)
2c (3-MeC6H4)
2d (4-MeOC6H4)
2e (2-MeOC6H4)
2f (4-FC6H4)
2g (3-FC6H4)
2h (4-ClC6H4)
2i (4-BrC6H4)
2j (3-BrC6H4)
2k (2-BrC6H4)
2l (3-F3CC6H4)
2m (1-Naph)
2n (2-furyl)
2
none
3
5
3
NaOH
none
4
3
4
LiOH·H2O
Cs2CO3
K2CO3
none
5
5
5
none
6
5
6
none
7
10
5
7
Na2CO3
Na3PO4
NaOAc
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
none
8
8
none
9
5
9
none
10
11
12
13
14
15
16c
17
18
19
10
10
10
5
10
11c
12
13
14
15
16
none
none
SDS (10)
12-2-12 (10)
CTAB (10)
CTAB (10)
CTAB (5)
5
5
5
2o (2- thienyl)
2p (i-Pr)
3
3
5
5
a Unless indicated otherwise, the reaction was conducted with sesa-
mol 1a (0.24 mmol), a-amido sulfone 2a (0.2 mmol) and base (0.3
mmol) in H2O (2.0 mL) with or without catalyst at 30 °C.
b Isolated yield.
2q (c-C6H11)
2a (Ph)
5
30
16
2a (Ph)
c The reaction was performed at 50 °C.
a Unless indicated otherwise, the reaction was conducted with sesa-
mol 1 (0.24 mmol), a-amido sulfone 2 (0.2 mmol) and Na2CO3 (0.3
mmol) in H2O (2.0 mL) with CTAB (10 mol%) at 30 °C. Ar = Ph.
b Isolated yield.
affected the reaction rate to some degree. The reactions of
aryl a-amido sulfones bearing electron-donating groups
on the para-positions completed within only three hours
(Table 2, entries 2 and 4), while reactions of aryl a-amido
sulfones bearing electron-withdrawing groups on the
para-positions proceeded slower (Table 2, entries 6, 8 and
9). Prolonged reaction time was needed for aryl a-amido
sulfones bearing meta- or ortho-substituents on the aro-
matic rings (Table 2, entries 3, 5, 7, and 10–12). In addi-
tion, electron-withdrawing substituents on the meta and
ortho positions of the aromatic rings retarded the rate and
the reaction required to ten hours to complete (Table 2,
entries 7, and 10–12). 1-Naphthyl and heteroaromatic a-
amidosulfones provided the corresponding products in
c Ar = 4-MeC6H4
high yields within five hours (Table 2, entries 13–15). It is
noteworthy that even alkyl a-amidosulfones underwent
the reaction smoothly to afford excellent yields of the
products (Table 2, entries 16 and 17). In addition, 2-meth-
yl sesamol and 2-iodo sesamol reacted with N-Boc imine
generated in situ from a-amido sulfone 2a to give the
products in good yields after an extended reaction time
(Table 2, entries 18 and 19).
Synlett 2010, No. 9, 1415–1417 © Thieme Stuttgart · New York

LETTER
Amidoalkylation of Sesamols with N-Boc Imines
1417
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Furthermore, when several naphthols were also subjected
to the CTAB-catalyzed Friedel–Crafts amidoalkylation
with imines generated in situ from a-amido sulfone 2a un-
der the optimized reaction conditions, both 2-naphthol
and 6-bromo-2-naphthol underwent the reaction rapidly
to generate the corresponding products 3t and 3u in high
yields (Figure 1). However, the reaction of 1-naphthol
proceeded sluggishly to provide the product 3v in poor
yield.
Ph
NHBoc
OH
Ph
NHBoc
OH
OH NHBoc
Ph
Br
3t 3 h, 91%
3u 5 h, 87%
3v 16 h, 52%
Figure 1 Products of Friedel–Crafts amidoalkylation of naphthols
with N-Boc imine generated in situ from a-amido sulfone 1a
(c) Marianacci, O.; Micheletti, G.; Bernardi, L.; Fini, F.;
Fochi, M.; Pettersen, D.; Sgarzani, V.; Ricci, A. Chem. Eur.
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Y. F.; Wu, L. P.; Zhang, G.; Liu, X.; Zhang, H. L.; Fu, D.;
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In conclusion, we have developed a remarkably mild and
efficient CTAB-catalyzed Friedel–Crafts amidoalkylation
of sesamol or its 2-substituted derivatives with N-Boc im-
ines generated in situ. A wide range of 6-amidoalkyl ses-
amols were synthesized in high yields through this
transformation. This methodology was also appropriate
for 2-naphthols.
(7) (a) Mori, Y.; Kakumoto, K.; Manabe, K.; Kobayashi, S.
Tetrahedron Lett. 2000, 41, 3107. (b) Otto, S.; Engberts,
J. B. F. N.; Kwak, J. C. T. J. Am. Chem. Soc. 1998, 120,
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(8) Friedel–Crafts Amidoalkylation; General Procedure:
N-Boc a-amido sulfone (0.2 mmol, 1.0 equiv), Na2CO3 (0.3
mmol, 1.5 equiv), CTAB (0.02 mmol, 10%) and H2O (2 mL)
were added to a 10-mL glass vial equipped with a small
magnetic stirring bar. Sesamol (0.24 mmol, 1.2 equiv) was
added and, after stirring for the stipulated time at 30 °C, the
mixture was diluted with H2O (3 mL) and extracted with
Et2O (3 × 25 mL). The organic layers were combined, dried
over anhydrous sodium sulfate and concentrated under
reduced pressure. The residue was subjected to silica gel
flash chromatography (EtOAc–Hexanes, 1:10) to give the
pure product.
(9) Tert-butyl (6-Hydroxybenzo[d][1,3]dioxol-5-yl)(phenyl)-
methylcarbamate (3a): Yield: 97%; white solid; mp 168.5–
168.9 °C; 1H NMR (300 MHz, DMSO-d6): d = 9.31 (s, 1 H),
7.61 (d, J = 9.6 Hz, 1 H), 7.29–7.22 (m, 4 H), 7.19–7.14 (m,
1 H), 6.92 (s, 1 H), 6.42 (s, 1 H), 6.11 (d, J = 9.6 Hz, 1 H),
5.88 (s, J = 0.6 Hz, 1 H), 5.84 (s, J = 0.6 Hz, 1 H), 1.39 (s,
9 H); 13C NMR (75 MHz, DMSO-d6): d = 154.99, 148.49,
146.09, 143.67, 139.83, 128.03, 126.63, 126.36, 121.09,
107.39, 100.60, 97.39, 77.99, 51.21, 28.28; HRMS (ESI):
m/z [M + Na]+ calcd for C19H21NNaO5: 366.1317; found:
366.1312
We are grateful for financial support from the National Natural
Science Foundation of China (20772122) and the National Basic
Research Program of China (973 Program) (2010CB833301).
References and Notes
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Synlett 2010, No. 9, 1415–1417 © Thieme Stuttgart · New York

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