Mild and efficient iodine-catalyzed direct substitution of hydroxy group of alcohols with c- and n-nucleophiles

Article abstract of DOI:10.2174/157017811794557787

A mild and efficient iodine-catalyzed direct substitution of hydroxy group of allylic, progargylic and other alcohols with various C- and N-nucleophiles was described in this contribution. C-C and C-N bond formations could be readily achieved by non-metal

Full text of DOI:10.2174/157017811794557787

Letters in Organic Chemistry, 2011, 8, 73-80
73
Mild and Efficient Iodine-Catalyzed Direct Substitution of Hydroxy Group
of Alcohols with C- and N-Nucleophiles
Zhe Liu*, Dong Wang and Yongjun Chen
Centre for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences (ICCAS), Beijing 100080, China
Received July 22, 2010: Revised December 04, 2010: Accepted December 14, 2010
Abstract: A mild and efficient iodine-catalyzed direct substitution of hydroxy group of allylic, progargylic and other
alcohols with various C- and N-nucleophiles was described in this contribution. C-C and C-N bond formations could be
readily achieved by non-metallic and green catalysis for various compounds. This facilitates access to possible
transformations of a broad scope of substrates into bioactive and pharmaceutically important building blocks.
Keywords: Allylation, Bond formation, C-, N-nucleophiles, Green chemistry, Iodine, Isomerization, Propargylation,
Substitution.
High consumption of energy, toxic solvents and metal-catalysts
C-C and C-N bond formation reactions [1] have attracted
tremendous attention and have been widely studied in
synthetic organic chemistry since they provide access to
pretransformation
Nu
R-LG
various
biologically
active
intermediates
and
pathway i)
pharmaceutically important molecules. The set-up of direct
substitution protocols employing general alcohols with C-
and N-nucleophiles is desirable from the point of view of
atom economy [2] and green chemistry [3]. However,
traditional strategies have some limitations in that hydroxy
group in alcohols is generally pretransformed into other
leaving groups which could be easily removed, such as
acetates, carbonates, halides etc. These unnecessary
pretransformations not only bring about high consumption of
energy, toxic organic solvents and precious transition-metal
or rare earth catalysts, but also result in operational
complexity and low efficiency in multistep conversions
(pathway i, Scheme 1). In contrast, direct C-C and C-N bond
formation reactions of alcohols with aromatic or aliphatic
nucleophiles are greener and more economical synthetic
methodologies in which environmentally benign water is the
only byproduct and can be discarded to circumstances
without any pollution. There is no need to input plenty of
preactivators, energy and chemicals, and catalytic C-X bond
formations can be achieved in one step (pathway ii, Scheme
1). In this context, developing new, mild and efficient
strategies for direct substitution of hydroxy groups in
alcohols with aromatic or aliphatic nucleophiles rekindles
chemist’s interests due to the above-mentioned advantages.
pathway ii)
C-, N-Nucleophiles
H2O
R-OH
R-Nu
Green and atom-economical strategy
Scheme 1. Direct substitution of hydroxy groups in alcohols vs.
multistep transformations.
propargylic substitutions of amides [4a-c]. Since the leaving
ability of hydroxy group is not satisfactory under mild
conditions, high reaction temperature is often required.
Although the alkylation of indoles [4d-p], amines and
amides [4q-u] has been studied by Bandini, Ishimura and
other groups, unsatisfactory regioselectivity and narrow
substrate scope are limitations for further practical
applications.
In recent years, iodine has emerged as a versatile Lewis
acid catalyst for various organic transformations such as
Michael addition [5a-c], coupling [5d], cycloaddition [5e],
silylation [5f], protection/deprotection [5g-j] and even multi-
component synthesis [5k-n], in which it can efficiently
activate C=C, C=O, C=N and other functional groups. Iodine
is a cheap and commercially available catalyst with high
tolerance to air and moisture. As an extension of our
previous work [5o], we intend to describe the iodine-
catalyzed direct substitution of alcohols with C- and N-
Nowadays, various transition-metal complexes or metal
Lewis acids, are precious, air/moisture-sensitive and difficult
to handle, they have been widely used to catalyze the allylic,
propargylic substitutions and other alkylations with C- and
N-nucleophiles [4]. In some cases, additives are also
indispensable as copromoters and excessive amine
nucleophiles are often necessary for smooth completion in
nucleophiles to elucidate
propargylation and other alkylation protocols with a versatile
substrate scope under mild reaction conditions.
a more efficient allylation,
Initially, allylation reaction of indoles with E-1,3-
diphenyl-2-propen-1-ol 1a was selected as model reaction to
investigate the iodine-catalyzed direct substitution and the
substrate scope (Fig. 1). Excellent yield of desired product 3-
((E)-1,3-diphenylallyl)-1H-indole 3a was afforded when
indole
*Address correspondence to this author at the Centre for Molecular
Sciences, Institute of Chemistry, Chinese Academy of Sciences (ICCAS),
Beijing 100080, China; Tel: +86-10-62554614; Fax: +86-10-62554449;
E-mail: liuzhe@iccas.ac.cn
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2011, Vol. 8, No. 1
Liu et al.
Table 1. Iodine-Catalyzed Allylation of C-Nucleophiles
C-nucleophile
Product
Entry
Time(h)
Yield%
Ph
Ph
1
7
92
N
H
N
H
2a
3a
Ph
Ph
CH3
2
3
12
10
93
92
N
CH3
H
N
H
2b
3b
Ph
Ph
Br
Br
N
H
2c
N
H
3c
Ph
NO2
Ph
O2N
4
5
6.5
93
N
N
H
H
2d
3d
Ph
Ph
Ph
7
95
N
Ph
H
2e
N
H
3e
Ph
Ph
COOEt
6
10
91
N
COOEt
H
2f
N
H
3f
Ph
Ph
MeO
MeO
7
8
10
80
N
H
2g
N
H
3g
Ph
H3C
6
82
O
H3C
2h
O
Ph
3h

Mild and Efficient Iodine-Catalyzed Direct Substitution
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
75
(Table 1). Contd…..
Yield%
C-nucleophile
Product
Entry
Time(h)
Ph
Ph
OH
OH
9
10
91
79
95
2i
3i
Ph
OH
OH
10
12
Ph
OCH3
H3CO
OCH3
H3CO
OCH3
2j
OCH3
3j
O
O
O
O
11
10
2k
Ph
Ph
3k
OH
stirring with 1a and starting materials were recovered under
such mild condition (Entry 8, 9).
Nu
I2(10mol%)
CH3CN, r. t.
+
Ph
C-nucleophile
Ph
Ph
Ph
To further expand the substrate scope in this direct
substitution methodology, more alcohols with varied
nucleophiles were screened (Fig. 3). Propargylic alcohol 1c,
which is inert or less reactive than allylic counterparts, was
reacted with indoles and amides to achieve good yields and
smooth propargylation (Table 3).
1a
2
3
Fig. (1).
2a was reacted in acetonitrile at room temperature under the
catalysis of 10mol% molecular iodine (Entry 1, Table 1).
Encouraged by this result, various indoles were reacted in
this substitution and corresponding 3-allylated products were
given in excellent yields (Entry 2-7). The direct allylation
was satisfactory for both electron-rich and electron-deficient
indole substrates. Furthermore, this efficient protocol was
expanded to other aromatic compounds 2-methyl furan and
phenols, the expected allylated products were yielded
regioselectively and smoothly under the optimized
conditions (Entry 8-10). The aliphatic nucleophile pentane-
2,4-dione 2k could also be converted into 3k in 95% yield
(Entry 11).
As shown in Fig. (4), Triphenylmethanol 1d was also an
effective alkylating agent which could produce 3-
(triphenylmethyl)-1H-indoles 7a, 7b in several minutes and
excellent yields (Entry 1 and 2, Table 4). However, no
desired N-(triphenylmethyl)carbamate was produced due to
lower nucleophilicity of benzyl carbamate 4d (Entry 3). To
our delight, direct and efficient substitution of electron-
deficient Baylis-Hillman alcohols [4f, 6] 1e, 1f with 2-
methyl-1H-indole 2b and trimethoxybenzene 2l could be
accomplished to give the corresponding alkylation products
in reasonable yields (Entry 4, 5).
Besides of C-nucleophiles, a variety of amides, such as
sulfonamides, carboxamides and carbamates, which are less
nucleophilic, were then investigated in this direct
substitution reaction (Fig. 2, Table 2). It was found that most
amides screened could be efficiently transformed to give N-
o-Allylic and o-propargylic phenols have been reported
in base-promoted cyclization for synthesis of 5-exo
benzofuran or 6-endo benzopyran derivatives [7]. We
hypothesized that this cyclization might be achieved using
our allylated phenols 3i and 3j under basic conditions
(1equiv. of KOBu-t/CH3CN). To our surprise, isomerized
products, i. e. o-alkenyl phenols 8a and 8b (instead of 6-
endo chromene or 5-exo 2,3-dihydrobenzofuran) were
afforded at room temperature which indicate a mild base-
assisted double bond migration [8] occurred to give a more
conjugated and stable aromatic system (Scheme 2).
allylated
compounds
excellent
yields.
p-
Nitrobenzenesulfonamide and benzamide were less reactive
and only moderate yield were afforded (Entry 2, 5). These
reactions were cleanly achieved to give the expected
products without the employment of transition-metal
catalyst, additives or harsh reaction conditions, which
overran the Pd-catalyzed[4r,s] or Bi(OTf)3/KPF6 [4v]
protocols. Nevertheless, since the allylic amination requires
more activation energy at high temperature [4q], both
nicotinamide and p-toluidine remained intact after prolonged
In conclusion, we have described an efficient iodine-
catalyzed direct substitution of hydroxy group of allylic,
progargylic and other alcohols with various C- and N-
nucleophiles under mild conditions [9]. Further studies on

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Letters in Organic Chemistry, 2011, Vol. 8, No. 1
Liu et al.
Table 2. Iodine-Catalyzed Allylation of N-Nucleophiles
N-nucleophile
Product
Entry
Allylic alcohol
Time(h)
Yield%
O
S
NH
O
S
NH2
O
1
1a
12
86
46
O
Ph
Ph
4a
5a
O
O
O2N
S
O2N
S
NH
O
2
3
1a
1a
14
13
NH2
O
4b
Ph
Ph
5b
O
O
H3C
S
H3C
S
NH
O
74
NH2
O
Ph
Ph
4c
5c
Cbz
Cbz
NH
NH2
4d
4
5
1a
1a
14
13
94
43
Ph
Ph
5d
O
O
NH
NH2
4e
Ph
Ph
5e
O
O
NH
6
7
1a
1b
14
91
96
NH2
4f
Ph
Ph
5f
Cbz
NH
4d
9
Ph
CH3
5g
H2N
—
—
8
9
1a
1a
14
20
n.r.
n.r.
O
N
4g
H2N
4h

Mild and Efficient Iodine-Catalyzed Direct Substitution
OH
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
77
Nu
I2(10mol%)
CH3CN, r. t.
+
N-nucleophile
R
Ph
R
Ph
1a: R=Ph
1b: R=CH3
4
5
Fig. (2).
Table 3. Iodine-Catalyzed Propargylation of C- and N-Nucleophiles
Product
Entry
Nucleophile
Time(h)
Yield%
HN
H3C
1
2b
20
33
Ph
Ph
6a
HN
Br
2
3
2c
2f
20
12
81
87
Ph
6b
HN
Ph
EtOOC
Ph
Ph
6c
O
H3C
S
NH
O
4
5
4c
36
84
78
Ph
Ph
6d
Cbz
NH
4d
36
Ph
Ph
6e
OH
Nu
I2(10mol%)
CH3CN, r. t.
+
Nucleophile
Ph
Ph
Ph
Ph
1c
6
Fig. (3).
Table 4. Iodine-Catalyzed Direct Substitution of Alcohols
Nucleophile
Alcohol
Time(h)
Product
Entry
Yield%
Ph
Ph
Ph
Ph
Ph
Ph
2a
0.75
1
98
HO
1d
N
H
7a

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Letters in Organic Chemistry, 2011, Vol. 8, No. 1
Liu et al.
(Table 4). Contd…..
Entry
Nucleophile
Alcohol
Time(h)
Product
Yield%
Ph
Ph
Ph
Br
2c
1d
1d
1
2
3
86
N
H
7b
4d
12
—
n.r.
HN
OH
O
H3C
O
2b
2
4
90
H3CO
1e
H3CO
7c
H3CO
OH
O
OCH3
OCH3
O
5
20
61
H3CO
H3CO
OCH3
Cl
2l
1f
Cl
7d
I2 (10mol%)
CH3CN, r. t.
Alcohol
Nucleophile
Alkylated product
+
7
Fig. (4).
Ph
Ph
Ph
Ph
KOBu-t (1equiv.)
OH
OH
CH3CN, r. t.
3h, 84%
3i
8a
Ph
Ph
OH
OH
KOBu-t (1equiv.)
CH3CN, r. t.
Ph
OCH3
Ph
OCH3
H3CO
H3CO
OCH3
3j
Scheme 2. t-BuOK-assisted isomerization of allylated phenols.
14h, 63%
OCH3
8b

Mild and Efficient Iodine-Catalyzed Direct Substitution
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
79
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ACKNOWLEDGEMENTS
We are grateful for the grants from the National Nature
Science Foundation of China and Chinese Academy of
Sciences for financial support.
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functionalization. A total synthesis of hormothamnione. J. Org.
Chem., 1990, 55, 4349-4356.
a) Yu, Z.; Yan, S.; Zhang, G.; He, W.; Wang, L.; Li, Y.; Zeng, F.
Proazaphosphatrane P(RNCH2CH2)3N (R=Me, i-Pr)-catalyzed
isomerization of allylaromatics, allyl phenyl sulfide, allyl phenyl
sulfone, and bis-allylmethylene double-bond containing
compounds. Adv. Synth. Catal., 2006, 348, 111-117; b) Van
Otterlo, W. A. L.; Ngidi, E. L.; Kuzvidza, S.; Morgans, G. L.;
Moleele, S. S.; De Koning, C. B. Ring-closing metathesis for the
synthesis of 2H- and 4H-chromenes. Tetrahedron, 2005, 61, 9996-
10006; c) Gross, J. L. A concise stereospecific synthesis of
repinotan (BAYꢀ3702). Tetrahedron Lett., 2003, 44, 8563-8565; d)
Dai, S. H.; Lin, C. Y.; Rao, D. V.; Stuber, F. A.; Carleton, P. S.;
Ulrich, H. Selective indirect oxidation of phenol to hydroquinone
and catechol. J. Org. Chem., 1985, 50, 1722-1725; e) Van, T. N.;
Debenedetti, S.; De Kimpe, N. Synthesis of coumarins by ring-
closing metathesis using Grubbs’ catalyst. Tetrahedron Lett., 2003,
44, 4199-4201; f) Urbala, M.; Kuznik, N.; Krompiec, S.; Rzepa, J.
Highly selective isomerization of allyloxyalcohols to cyclic acetals
or 1-propenyloxyalcohols. Synlett, 2004, 7, 1203-1206.
3j: Colorless liquid. 1HNMR (300MHz, CDCl3):ꢁ 3.71(s, 3H)
3.72(s, 3H) 3.81(s, 3H) 5.36(s, 1H) 5.45(d, J=7.0Hz, 1H) 6.21(s,
1H) 6.47(d, J=15.8Hz, 1H) 6.84(dd, J=15.8Hz, 1H) 7.15-7.39 (m,
9H). 13CNMR (75MHz, CDCl3):ꢁ 43.7, 55.9, 61.1, 61.2, 97.3,
115.1, 126.5, 126.6, 127.5, 127.9, 128.6, 128.7, 130.7, 132.3,
136.4, 137.2, 142.6, 150.7, 152.2, 152.8. IR (film): 3410, 3058,
2938, 1603, 1460, 1199, 1127, 910, 732, 697 cm-1. Mass: m/z calcd.
for C24H24O4: 376.1675, found 376.1678.
1
5f: Pale yellow solid, mp. 119-121°C. HNMR (300MHz,CDCl3):ꢁ
1.96(s, 3H) 5.33(s, 1H) 5.73(s, 1H) 5.84(t, J=7.1Hz, 1H) 6.35(dd,
J=15.9Hz, 1H) 6.42(d, J=7.9Hz, 1H) 6.52(d, J=15.9Hz, 1H) 7.18-
7.36(m, 10H). 13CNMR (75MHz,CDCl3):ꢁ 18.8, 54.9, 119.8, 126.6,
127.2, 127.7, 127.9, 128.6, 128.9, 128.9, 131.7, 136.5, 140.1,
141.0, 167.5. IR (KBr): 3304, 3060, 3028, 1654, 1616, 1523, 1210,
967, 746, 696 cm-1. Mass: m/z calcd. for C19H19NO: 277.1467,
found 277.1469.
[8]
7b: Pale white solid, mp. 180-182°C. 1HNMR (300MHz, CDCl3):ꢁ
6.75(s, 1H) 6.83(s, 1H) 7.15-7.24(m, 17H) 7.92(s, 1H). 13CNMR
(75MHz, CDCl3):ꢁ 59.3, 112.4, 112.6, 123.8, 124.8, 125.1, 126.2,
126.5, 127.5, 129.6, 130.7, 135.6, 146.1. IR (KBr): 3436, 3022,
1442, 1108, 905, 731, 699 cm-1. Mass: m/z calcd. for C27H20NBr:
437.0779, found 437.0776.
1
7c: Brown liquid. HNMR (300MHz, CDCl3):ꢁ 2.23(s, 3H) 2.39-
2.57(m, 4H) 3.73(s, 3H) 5.30(s, 1H) 6.76(d, J=7.8Hz, 2H) 6.92(t,
J=7.5Hz, 1H) 7.00-7.22(m, 5H) 7.29(s, 1H) 8.01(s, 1H). 13CNMR
(75MHz, CDCl3):ꢁ 12.1, 26.4, 34.9, 37.2, 55.2, 110.5, 111.4, 113.6,
119.0, 119.2, 120.6, 127.9, 129.3, 132.5, 134.0, 135.4, 148.9,
157.9, 159.8, 208.9. IR (film): 3392, 3011, 2922, 1694, 1246, 1036,
752 cm-1. Mass: m/z calcd. for C22H21NO2: 331.1572, found
331.1568.
[9]
Representative experimental procedure:
Methacrylamide 4f (48 mg, 0.56 mmol) and E-1,3-diphenyl-2-
propen-1-ol 1a (119 mg, 0.57 mmol) were added into a flask at
room temperature. Acetonitrile (15 ml) was then poured and the
resulting mixture was vigorously stirred. Molecular iodine (14.4
mg, 0.057 mmol) was added and the mixture was stirred for 14
hours, monitored by TLC. After the completion of reactions,
saturated solution of Na2S2O3 (2ꢀ5 ml) was poured, followed by
the addition of water and ether (3ꢀ5 ml) to extract the crude
product. Organic solvents were combined, dried by anhydrous
Na2SO4 and evaporated under vacuum. The residue was purified by
flash chromatography to afford clean product 5f as a pale yellow
solid (144 mg, yield= 91%).
7d: Yellow oil. 1HNMR (300MHz, CDCl3):ꢁ 2.35-2.66(m, 4H)
3.63(s, 6H) 3.77(s, 3H) 5.58(s, 1H) 6.12(s, 2H) 7.01-7.25(m, 5H).
13CNMR (75MHz, CDCl3):ꢁ 24.1, 32.5, 33.5, 52.9, 53.3, 89.1,
108.9, 125.3, 127.2, 128.6, 138.9, 144.7, 156.5, 157.7, 157.8,
206.2. IR (film): 3004, 2936, 1700, 1461, 1114, 818, 752 cm-1.
Mass: m/z calcd. for C21H21ClO4: 372.1128, found 372.1131.
8a: Colorless oil. 1HNMR (300MHz, CDCl3):ꢁ 3.17(d, J=7.3Hz,
2H) 5.29(s, 1H) 6.77(t, 1H) 6.98-7.75(m, 16H). 13CNMR (75MHz,
CDCl3):ꢁ 36.5, 117.3, 117.7, 123.5, 124.7, 126.2, 126.8, 127.9,
128.3, 128.6, 128.7, 129.2, 129.9, 132.9, 133.8, 139.3, 139.8,
150.5. IR (film): 3506, 3058, 3028, 2922, 1594, 1195, 815, 754,
698 cm-1. Mass: m/z calcd. for C25H20O: 336.1514, found 336.1522.
8b: Colorless liquid. 1HNMR (300MHz, CDCl3):ꢁ 3.40(t, J=9.6Hz,
2H) 3.55(s, 3H) 3.81(s, 3H) 3.89(s, 3H) 4.99(s, 1H) 6.42(s, 1H)
6.58(t, J=9.6Hz, 1H) 7.18-7.32(m, 10H). 13CNMR (75MHz,
CDCl3):ꢁ 36.4, 55.9, 60.7, 61.0, 94.9, 111.4, 126.2, 127.6, 128.4,
128.5, 128.6, 132.6, 133.0, 136.3, 139.9, 140.5, 149.1, 151.7,
154.1. IR (film): 3439, 3058, 2936, 1607, 1491, 1458, 1232, 1125,
1031, 757, 698 cm-1. Mass: m/z calcd. for C24H24O4: 376.1675,
found 376.1678.
Spectrum data for unknown compounds:
3h: Yellow oil. 1HNMR (300MHz, CDCl3):ꢁ 2.34(s, 3H) 4.93(d,
J=7.3Hz, 1H) 5.98(d, J=2.0Hz, 1H) 6.05(d, J=2.0Hz, 1H) 6.48(d,
J=15.9Hz, 1H) 6.65(dd, J=15.9Hz, 1H) 7.28-7.46(m, 10H).
13CNMR (75MHz, CDCl3):ꢁ 13.7, 48.5, 106.1, 107.6, 126.5, 126.9,
127.5, 128.4, 128.5, 128.6, 130.2, 131.5, 137.2, 141.5, 151.5,
154.3. IR (film): 3059, 3027, 1599, 1218, 965, 745, 697 cm-1.
Mass: m/z calcd. for C20H18O: 274.1400, found 274.1355.