Iodine-catalyzed nucleophilic substitution reactions of benzylic alcohols

Article abstract of DOI:10.1055/s-2008-1072652

Molecular iodine efficiently catalyzes the direct nucleophilic substitution of the hydroxy group of benzylic alcohols with carbon and oxygen nucleophiles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072652

LETTER
1045
Iodine-Catalyzed Nucleophilic Substitution Reactions of Benzylic Alcohols
Nucleophilic
S
a
ubstitution
b
Reactions
o
b
f
B
enzylic
A
a
lcohols raja Srihari,* Dinesh C. Bhunia, Pamu Sreedhar, Jhillu S. Yadav
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: srihari@iict.res.in
Received 31 October 2007
tion,10 protection/deprotection,11 and multicomponent re-
actions.12 Our group has been on a long-term project
where iodine is being investigated as catalyst for several
organic reactions.13 In continuation towards these studies,
we have recently demonstrated that iodine could be used
efficiently for nucleophilic substitution reactions of aryl
propargyl alcohols with C- and O-nucleophiles.14 In this
context, we disclose the nucleophilic substitution reac-
tions of substituted benzyl alcohols (1) with O- (2) and C-
(3) nucleophiles in the presence of catalytic amount of io-
dine (see Scheme 1).
Abstract: Molecular iodine efficiently catalyzes the direct nucleo-
philic substitution of the hydroxy group of benzylic alcohols with
carbon and oxygen nucleophiles.
Key words: nucleophilic substitution, benzyl alcohols, carboca-
tion, Lewis acid
The displacement of hydroxy groups in alcohols by nu-
cleophiles is a direct method for C–C bond-formation re-
action. This reaction has gained importance due to readily
available starting materials and also the environmentally
benign byproduct (water) formed during the reaction. The
direct nucleophilic substitution reactions of alcohols are
generally attained by employing stoichiometric amounts
of Lewis acids1 or by using excess of sulfuric acid or phos-
phoric acid.2 Since the hydroxy group is not a good leav-
ing group, very often it has to be derivatized as acetate or
halide for substitution with different nucleophiles.3 Re-
cently, there have been many precedents for the direct nu-
cleophilic substitution reactions of benzyl alcohols,
remarkable are the reactions catalyzed by p-toluene-
sulfonic acid monohydrate, polymer-bound p-toluene-
sulfonic acid,4 metal salts such as Bi, La, Sc, or Hf salts,5
or Fe3a or Au6 catalysis including the more recent InCl3.7
However, these reactions are generally performed at ele-
vated temperatures or require more than catalytic amount
of the catalyst. Therefore, the development of new meth-
ods for direct substitution of hydroxy group is a challeng-
ing goal to organic chemists.
Initially, as a preliminary example, diphenyl carbinol was
treated with propargyl alcohol in the presence of 5 mol%
of iodine at room temperature. Within 20 minutes, the
starting material was completely consumed to produce a
single product that was isolated and characterized as the
propargylated diphenyl carbinol. Encouraged by this re-
sult, we proceeded further, investigating the scope and
generality of this reaction. Thus, various other nucleo-
philes such as allyl alcohol 2b (entry 2), 3-benzyloxypro-
pan-1-ol (2c, entry 3), propargyl alcohol (2a, entries 1 and
4) were treated with benzylic alcohols and found to pro-
duce the corresponding O-nucleophilic substituted prod-
ucts in good yields (see Table 1).
When naphth-2-ol (3a, entries 6, 9, and 12), p-cresol (3d,
entry 11), and resorcinol (3c, entries 8 and 15) were treat-
ed, the products obtained were only the C-nucleophilic
products rather the O-nucleophilic products, also in the re-
sulting products substitution was present only on electron-
rich carbon site resulting in a single regioisomer as evi-
denced from spectral data.15 For example, the regioisomer
formed from the reaction of 1a with 3a was assumed to be
product 5a, inline with literature precedent having a melt-
During the last decade molecular iodine has been well ex-
plored as a versatile catalyst for several organic transfor-
mations such as synthesis of bis(indolyl)methanes,8
thioketalization of carbonyl compounds,9 Michael addi-
R3
Nu
OH
O
I2, MeCN
R2
R2
R2
NuH or R3OH
R1
or
+
R1
R1
r.t., 15–30 min
90-96%
1
2
3
4
5
R1 = H, OH, OMe
2 = Ph, Me
R
NuH = naphth-2-ol, indole, resorcinol, anisole, p-cresol
3 = allyl, propargyl, 3-benzyloxypropyl
R
Scheme 1
SYNLETT 2008, No. 7, pp 1045–1049
x
x.
x
x.
2
0
0
8
Advanced online publication: 28.03.2008
DOI: 10.1055/s-2008-1072652; Art ID: D35607ST
© Georg Thieme Verlag Stuttgart · New York

1046
P. Srihari et al.
LETTER
Plausible mechanism
HO
+
O
+
O
H
I
H
I
I
OH
+
R
R
R
R
– I–
– HOI
O
+
HI
+
HOI
R
– H+
Scheme 2
O
OH
I2, MeCN
Me
Me
+
HO
r.t., 25 min
88%
MeO
MeO
96% ee
(+)
Scheme 3
ing point of 110 °C in agreement with the known prod- present protocol to give the corresponding products in
uct.16a Similarly, anisole (3e, entry 14) responded well to good yields.
give the C-nucleophilic product.16b The data clearly re-
When a reaction of chiral 1-(4-methoxyphenyl)ethanol17
veals that the diaryl carbinols react faster than aryl alkyl
with allyl alcohol was studied, racemic product was ob-
carbinols (see Table 1). This may be attributed towards
tained (see Scheme 3). This example clearly reveals that
the formation of a more stable carbocation intermediate,
SN1 type of mechanism is involved in this reaction. Dur-
which would facilitate the reaction towards the product. A
plausible mechanism is shown in Scheme 2.
ing the course of these studies, we needed product 5a for
one of our academic programs in larger amounts (≥ 2 g).
The resulting HI may facilitate the generation of a car- For this, a two-gram reaction was run and we noticed that
bocation from the activated aryl alcohols. And since the within one hour complete consumption of the starting ma-
carbocation is involved in the process, the reaction may terial occurred and resulted in 94% of the required prod-
proceed through SN1 mechanism. Benzyl alcohol, a-phen- uct. Thus this protocol was also found to be amenable for
yl ethyl alcohol, and a-phenyl ethyl alcohols with elec- large-scale synthesis.
tron-withdrawing groups (entries 5 and 16) did not
respond to this protocol, but a-phenyl ethyl alcohols bear-
ing electron-releasing groups responded well under the
Table 1 Iodine-Catalyzed Nucleophilic Substitution Reactions of Aryl Alcohols
Entry Aryl carbinol
Nucleophile
Producta
Time (min) Yield (%)b
1
1a
2a
4a
15
95
OH
OH
O
2
3
1a
1a
2b
4b
4c
20
20
92
92
OH
O
O
2c
HO
O
O
Synlett 2008, No. 7, 1045–1049 © Thieme Stuttgart · New York

LETTER
Nucleophilic Substitution Reactions of Benzylic Alcohols
1047
Table 1 Iodine-Catalyzed Nucleophilic Substitution Reactions of Aryl Alcohols (continued)
Entry Aryl carbinol
Nucleophile
Producta
Time (min) Yield (%)b
4
1b
2a
4d
15
92
OH
Me
O
OH
Me
MeO
MeO
5
1c
2b
3a
4e
5a
no reaction
OH
OH
Me
NO2
O
Me
NO2
6
7
1a
1a
20
15
96
90
OH
HO
3b
5b
5c
NH
N
H
8
1a
3c
25
93
OH
OH
OH
OH
9
1d
1d
3a
3b
5d
5e
20
15
95
96
OH
OH
Me
OH
HO
Me
HO
10
NH
N
H
Me
HO
11
12
1d
1b
3d
3a
5f
30
15
90
95
OH
Me
Me
OH
Me
HO
5g
OH
Me
MeO
Synlett 2008, No. 7, 1045–1049 © Thieme Stuttgart · New York

1048
P. Srihari et al.
LETTER
Table 1 Iodine-Catalyzed Nucleophilic Substitution Reactions of Aryl Alcohols (continued)
Entry Aryl carbinol
Nucleophile
Producta
Time (min) Yield (%)b
13
1b
3b
5h
10
92
NH
Me
MeO
14
1b
3e
3c
3b
5i
20
90
OMe
OMe
Me
MeO
15
16
1e
5j
30
90
OH
OH
OH
Me
OH
Me
OH
1f
5k
no reaction
OH
Me
NH
Me
F
F
a Products were characterized by MS, IR, 1H NMR, and 13C NMR spectroscopy.
b Isolated yields after column chromatography.
37, 4227. (c) Khalaf, A. A.; Roberts, R. M. J. Org. Chem.
1969, 34, 3571. (d) Khalaf, A. A.; Roberts, R. M. J. Org.
Chem. 1971, 36, 1040. (e) Sundberg, R. J.; Laurino, J. P. J.
Org. Chem. 1984, 49, 249. (f) Davis, B. R.; Johnson, S. J.;
Woodgate, P. D. Aust. J. Chem. 1987, 40, 1283.
In conclusion, an efficient benzylic substitution reaction
with different nucleophiles has been demonstrated using
elemental iodine. Reactions at ambient temperature with
shorter reaction times and operationally simple proce-
dures involving readily available inexpensive iodine
make this procedure a very attractive and valid contribu-
tion to the existing procedures. Application of the present
protocol for other nucleophilic substitution reactions are
currently in progress and will be published in due course.
(3) For reactions of benzyl acetates, benzyl halides, benzyl
ethers, and benzyl carbonates for nucleophilic substitution
reactions, see: (a) Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.;
Beller, M. Angew. Chem. Int. Ed. 2005, 44, 3913.
(b) Shiina, I.; Suzuki, M. Tetrahedron Lett. 2002, 43, 6391.
(c) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M.
Angew. Chem. Int. Ed. 2005, 44, 238.
(4) Sanz, R.; Martinez, A.; Miguel, D.; Alvarez-Gutierrez, J. M.;
Rodriguez, F. Adv. Synth. Catal. 2006, 348, 1841.
(5) (a) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv.
Synth. Catal. 2006, 348, 1033. (b) Noji, M.; Ohno, T.; Fuji,
K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68,
9340. (c) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007,
72, 5161.
(6) Liu, J.; Muth, E.; Flore, U.; Henkel, G.; Merz, K.;
Sauvageau, E.; Schwake, E.; Dyker, G. Adv. Synth. Catal.
2006, 348, 456.
Acknowledgment
D.C.B. thanks CSIR, New Delhi for financial assistance.
References and Notes
(1) (a) Coote, S. J.; Davies, S. G.; Middlemiss, D.; Naylor, A.
Tetrahedron Lett. 1989, 30, 3581. (b) The benzylic alcohol
bearing strong electron-donating group reacts without any
catalyst. See: Takahashi, H.; Kashiwa, N.; Kobayashi, H.;
Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2002, 43,
5751.
(7) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem. Int. Ed.
2006, 45, 793.
(8) Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 44,
1959.
(2) (a) Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1973, 38,
1388. (b) Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1972,
Synlett 2008, No. 7, 1045–1049 © Thieme Stuttgart · New York

LETTER
Nucleophilic Substitution Reactions of Benzylic Alcohols
1049
(9) (a) Samajdar, S.; Basu, M. K.; Becker, F. F.; Banik, B. K.
Tetrahedron Lett. 2001, 42, 4425. (b) Nabajyoti, D.; Sarma,
J. C. Chem. Lett. 2001, 794.
mixture was washed with sat. aq Na2S2O3 solution and
extracted with EtOAc. The organic layer was separated and
washed with brine, dried over anhyd Na2SO4, and the solvent
was evaporated under vacuum. The resulting crude product
was purified by silica gel column chromatography (EtOAc–
hexane as the eluents).
Spectroscopic Data of Representative Examples
Compound 4c: yellow liquid. IR (neat): 3061, 3029, 2924,
2859, 1952, 1601, 1493, 1452, 1094, 1028, 739, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.91 (p, J = 6.1 Hz, 2 H),
3.53 (t, J = 6.1 Hz, 2 H), 3.58 (t, J = 6.2 Hz, 2 H), 4.44 (s, 2
H), 5.26 (s, 1 H), 7.13–7.30 (m, 15 H). 13C NMR (100 MHz,
CDCl3): d = 142.0, 138.1, 127.8, 127.1, 127.0, 126.8, 126.7,
126.5, 83.2, 72.5, 66.9, 65.5, 29.8. MS (EI): m/z = 355 [M+
+ Na]. HRMS: m/z calcd for C23H24O2Na: 355.1673; found:
355.1683.
(10) (a) Chu, C.; Gao, S.; Sastry, M. N. V.; Yao, C. Tetrahedron
Lett. 2005, 46, 4971. (b) Gao, S.; Tzeng, T.; Sastry, M. N.
V.; Chu, C.; Liu, J.; Lin, C.; Yao, C. Tetrahedron Lett. 2006,
47, 1889. (c) Lin, C.; Hsu, J.; Sastry, M. N. V.; Fang, H.; Tu,
Z.; Liu, J.; Yao, C. Tetrahedron 2005, 61, 11751.
(11) (a) Kumar, H. M. S.; Reddy, B. V. S.; Reddy, E. J.; Yadav,
J. S. Chem. Lett. 1999, 857. (b) Nabajyoti, D.; Jadab, C. S.
Synth. Commun. 2000, 30, 4435. (c) Nabajyoti, D.; Jadab,
C. S. J. Org. Chem. 2001, 66, 1947.
(12) (a) Bhosale, R. S.; Bhosale, S. V.; Bhosale, S. V.; Wang, T.;
Zubaidha, P. K. Tetrahedron Lett. 2004, 45, 9111.
(b) Phukan, P. J. Org. Chem. 2004, 69, 4005. (c) Lin, C.;
Fang, H.; Tu, Z.; Liu, J.; Yao, C. J. Org. Chem. 2006, 71,
6588.
(13) For our earlier contributions, see: (a) Yadav, J. S.;
Subba Reddy, B. V.; Subba Reddy, U. V.; Krishna, A. D.
Tetrahedron Lett. 2007, 48, 5243. (b) Yadav, J. S.; Reddy,
B. V. S.; Narayana Kumar, G. G. K. S.; Swamy, T.
Tetrahedron Lett. 2007, 48, 2205. (c) Yadav, J. S.;
Balanarsaiah, E.; Raghavendra, S.; Satyanarayana, M.
Tetrahedron Lett. 2006, 47, 4921. (d) Yadav, J. S.;
Satyanarayana, M.; Raghavendra, S.; Balanarsaiah, E.
Tetrahedron Lett. 2005, 46, 8745. (e) Yadav, J. S.; Reddy,
B. V. S.; Srinivas, M.; Sathaiah, K. Tetrahedron Lett. 2005,
46, 3489. (f) Yadav, J. S.; Reddy, B. V. S.; Rao, K. V.; Raj,
K. S.; Rao, P. P.; Prasad, A. R.; Gunasekar, D. Tetrahedron
Lett. 2004, 45, 6505. (g) Yadav, J. S.; Reddy, B. V. S.;
Reddy, P. M. K.; Gupta, M. K. Tetrahedron Lett. 2005, 46,
8493. (h) Yadav, J. S.; Reddy, B. V. S.; Shubashree, S.;
Sadashiv, K. Tetrahedron Lett. 2004, 45, 2951. (i)Yadav, J.
S.; Reddy, B. V. S.; Venkateshwar Rao, C.; Chand, P. K.;
Prasad, A. R. Synlett 2001, 1638. (j) Yadav, J. S.; Reddy, B.
V. S.; Reddy, M. S. Synlett 2003, 1722. (k) Yadav, J. S.;
Reddy, B. V. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron
Lett. 2002, 43, 9703. (l) Yadav, J. S.; Reddy, B. V. S.; Rao,
C. V.; Rao, K. V. J. Chem. Soc., Perkin Trans. 1 2002, 1401.
(14) Srihari, P.; Bhunia, D. C.; Sreedhar, P.; Mandal, S. S.;
Reddy, J. S. S.; Yadav, J. S. Tetrahedron Lett. 2007, 46,
8120.
Compound 5a: solid; mp 110–112 °C.16a IR (KBr): 3491,
3057, 2924, 1616, 1593, 1490, 1387, 1200, 1135, 812, 740,
701 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.97 (d, 1 H,
J = 8.7 Hz), 7.76 (dd, 1 H, J = 7.8 Hz), 7.72 (d, 1 H, J = 8.7
Hz), 7.20–7.42 (m, 12 H), 7.06 (d, 1 H, J = 8.7 Hz), 6.41 (s,
1 H), 5.27–5.40 (br s, 1 H). 13C NMR (75 MHz, CDCl3): d =
152.9, 141.8, 133.5, 129.8, 129.7, 129.3, 129.2, 128.9,
127.3, 126.9, 123.3, 123.0, 120.3, 119.9, 48.6. MS (EI):
m/z = 310 [M+]. Anal. Calcd (%) for C23H18O: C, 89.03; H,
5.80. Found: C, 89.4; H, 5.64.
Compound 5e: white solid; mp 86–88 °C. IR (KBr): 3444,
2964, 3024, 2964, 2855, 2372, 1876, 1599, 1509, 1444,
1331, 1254, 1090, 823, 743 cm–1. 1H NMR (200 MHz,
CDCl3 + DMSO): d = 1.62 (d, J = 7.0 Hz, 3 H), 4.20 (q,
J = 7.0 Hz, 1 H), 6.62 (d, J = 8.6 Hz, 2 H), 7.02 (d, J = 8.6
Hz, 2 H), 6.83 (dt, J = 1.1, 8.9 Hz, 2 H), 6.93–7.06 (m, 2 H),
7.21–7.30 (m, 1 H), 8.57 (br s, 1 H, NH), 10.13 (s, 1 H, OH).
13C NMR (100 MHz, CDCl3): d = 153.9, 136.4, 135.5, 126.7,
125.4, 119.7, 119.3, 117.9, 116.9, 113.8, 113.7, 110.0, 34.6,
21.4. MS (EI): m/z = 238 [M+ + H]. HRMS: m/z calcd for
C16H16NO: 238.1231; found: 238.1239.
(16) Only a single product was obtained in all these cases. For
regioselectivity purpose, the analytical data of the products
5a and 5i were compared with the data obtained from the
earlier literature and was found to be in accordance, see:
(a) Mustafa, A.; Mansour, A. K. J. Org. Chem. 1960, 25,
2223. (b) Clennan, E. L.; Pan, G.-I. Org. Lett. 2003, 5, 4979.
(17) Optically active p-methoxy a-phenyl ethanol was obtained
from the corresponding ketone following the standard
reduction procedure using CBS catalyst; ee was calculated
using chiral HPLC.
(15) General Experimental Procedure
To a solution of the benzylic alcohol (1 mmol) and
nucleophile (1.2 mmol) in MeCN (3 mL) was added I2 (5
mol%) and the mixture was stirred at 0 °C to r.t. After
completion of the reaction (monitored by TLC), the reaction
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