A convenient protocol for the α-iodination of α,β- unsaturated carbonyl compounds with I2 in an aqueous medium

Article abstract of DOI:10.1055/s-2005-868495

A variety of cyclic and acyclic α,β-unsaturated carbonyl compounds undergo α-iodination exclusively, in high yields, with I ₂, in aqueous THF catalyzed by DMAP and quinuclidine.

Full text of DOI:10.1055/s-2005-868495

LETTER
1263
A Convenient Protocol for the a-Iodination of a,b-Unsaturated Carbonyl
Compounds with I in an Aqueous Medium
2
P
M
rotocol
f
or the
a
-Iodi
a
nation of
a
,
r
b
-
Unsatu
i
rated C
e
arbonyl
C
ompou
E
nds
w
ith I 2 . Krafft,* John W. Cran
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850)6447409; E-mail: mek@chem.fsu.edu
Received 20 October 2004
During our synthetic program, we required an expedient
method for the synthesis of a range of a-iodo, a,b-unsat-
urated carbonyl compounds. We envisaged that, owing to
its greater nucleophilicity, DMAP might be a superior
Abstract: A variety of cyclic and acyclic a,b-unsaturated carbonyl
compounds undergo a-iodination exclusively, in high yields, with I2
in aqueous THF catalyzed by DMAP and quinuclidine.
Key words: a,b-unsaturated carbonyl compounds, a-iodination,
aqueous medium, regioselective
7
catalyst to pyridine. In addition, we speculated that an
aqueous reaction medium would stabilize the zwitterionic
intermediate 1, both by solvation and through the Brøn-
sted acid character of water, extending its lifetime and
thus its reactivity towards electrophiles.
a-Iodinated, a,b-unsaturated carbonyl compounds are
useful intermediates in organic synthesis, especially in
1
From our preliminary study with cyclohex-2-enone as the
test substrate, we were pleased to find that both assertions
were correct (Table 1). Employing 0.2 equiv of DMAP
and excess iodine in organic solvents, little or no reaction
transition metal-mediated reactions. However, their
preparation is somewhat limited. The a-iodination of a,b-
unsaturated carbonyl compounds has previously been
2
achieved with iodine-PDC and iodine-bis(tetra-n-butyl-
3
was observed (entries 1 and 2). However, when a H O–
ammonium) peroxydisulfate systems. Indirectly, the
2
THF (1:1) solvent system was used, a yield of 20% of 2a
Negishi group has iodinated a,b-unsaturated enones via a-
4
was obtained (entry 3). With the addition of K CO to re-
silyl enones. However, the most commonly employed
2
3
move the in situ generated HI, full conversion to 2a was
observed after two hours (entry 4). The reaction was com-
pletely regioselective and proceeded without the forma-
tion of any hydroiodination products. In contrast, after 5.5
hours under identical conditions with pyridine as the cat-
alyst, only 33% conversion was observed (entry 5). With
water as the solvent, the reaction appeared to be sluggish
approach, developed by the Johnson group, employs
pyridine as a catalyst and co-solvent. It is proposed that
the reaction follows a Baylis–Hillman type pathway
5
(
Scheme 1).
O
O
I
I
(
entry 6), and the addition of a surfactant resulted in a
messy reaction, giving rise to a mixture of products along
N
N
with recovered starting material (entry 7). Without K CO3
2
1
and employing a stoichiometric amount of DMAP, the re-
action was also slow and had not gone to completion after
24 hours (entry 8). In the absence of DMAP (entry 9) no
‘background’ iodination was observed. Methanolic condi-
tions failed to give clean conversion to the desired prod-
O
H
I
O
I
N
ucts and a 1:1 MeCN–H O mixture was found to be a
2
relatively efficient medium, but still inferior to a H O–
2
THF mixture (entries 10 and 11, respectively). Although
Scheme 1 Proposed Baylis–Hillman type pathway
1
:1 H O–acetone and H O–t-BuOH mixtures (entries 12
2 2
and 13, respectively) were found to be as efficient as the
Optimization by the McNelis group subsequently re- H O–THF mixture with our test substrate, the conversion
2
vealed that only sub-stoichiometric amounts of pyridine rates were generally inferior over a wider range of sub-
6
are required, although in many cases long reaction times strates.
or high catalyst loading are necessary for high rates of
The reactivity of several typical Baylis–Hillman catalysts
was examined (Table 2). None were found to be as
conversion. It was also found that only cyclic a,b-unsatur-
ated enones easily iodinate, while linear molecules require
refluxing over extended periods of time for satisfactory
conversion rates.
8
efficient as DMAP, although the non-toxic nature of
imidazole might make it the catalyst of choice in pharma-
ceutical applications (entry 1). Given the reactivity of
imidazole, it was surprising that benzimidazole was un-
reactive (entry 2). Likewise, DABCO failed, as did tri-
ethylamine (entries 3 and 6, respectively). Surprisingly,
SYNLETT 2005, No. 8, pp 1263–1266
1
7.
0
5.
2
0
0
5
Advanced online publication: 25.04.2005
DOI: 10.1055/s-2005-868495; Art ID: S10304ST
©
Georg Thieme Verlag Stuttgart · New York

1
264
M. E. Krafft, J. W. Cran
LETTER
Table 1 a-Iodination of Cyclohex-2-enone under Various Conditions
O
O
I2 (2 equiv), DMAP
I
2a
Entry
DMAP (equiv)
Solvent
CH Cl
Base
Time (h)
Yield of 2a (%)
1
2
3
4
5
6
7
8
9
0.2
–
–
–
20
5
Trace
0
2
2
0.2
THF
0.2
H O–THF (1:1)
20
2
20
2
0.2
H O–THF (1:1)
K CO
99
2
2
3
3
3
3
0.2 (Pyridine)
H O–THF (1:1)
K CO
5.5
2
33
2
2
0.2
0.2
0.2
0
H O
K CO
20
2
2
H O (Triton-X)
K CO
5
Mixture
86
2
2
H O–THF (1:1)
–
24
2
2
H O–THF (1:1)
K CO
0
2
2
3
3
3
3
3
10
11
12
13
0.2
0.2
0.2
0.2
H O–MeOH (1:1)
K CO
2
57
2
2
H O–MeCN (1:1)
K CO
2
86
2
2
H O–Me CO (1:1)
K CO
2
98
2
2
2
H O–t-BuOH (1:1)
K CO
2
99
2
2
quinuclidine, N,N,N¢,N¢-tetramethyl-1,3-propanediamine erned by a combination of nucleophilicity verses steric
and DBU (entries 4, 7 and 8, respectively), reported to hindrance, with DMAP having the most favorable combi-
be very efficient catalysts for the Baylis–Hillman reac- nation of high nucleophilicity and low steric hindrance.
9
–11
tion,
were also ineffective. Although no clear trend
Optimization studies showed that reducing the amount of
DMAP leads to a lower reaction rate (Table 3). In con-
trast, with a full equivalent of DMAP, iodination is com-
plete in only 15 minutes (entry 1). However, useful
conversions are still obtainable, even with very low cata-
lyst loading (entries 5 and 6).
emerged, it is likely that the catalyst suitability is gov-
Table 2 a-Iodination of Cyclohex-2-enone Using Commonly Em-
ployed Baylis–Hillman Catalysts
O
O
I2 (2 equiv), cat. (0.2 equiv),
I
Table 3 Effect of Catalyst Loading on a-Iodination of Cyclohex-2-
enone
K2CO3 (1.2 equiv),
THF/H2O (1:1)
2a
O
O
Entry
Catalyst
Time (h)
Yield of 2a (%)
I
I2 (1.5 equiv), DMAP (see table)
K2CO3 (1.2 equiv), THF/H2O (1:1)
1
2
3
4
5
6
7
8
Imidazole
Benzimidazole
DABCO
5.5
3
79
Trace
0
2
a
Entry
DMAP (equiv) Time (h)
Yield of 2a (%)
3
1
2
3
4
5
6
1
0.25
99
99
89
79
76
58
Quinuclidine
Piperidine
Triethylamine
TMPDA
5.5
5.5
3
36
70
0
0.2
2
2
2
2
2
0.1
0.05
0.025
0.01
5.5
3
25
0
DBU
Synlett 2005, No. 8, 1263–1266 © Thieme Stuttgart · New York

LETTER
Protocol for the a-Iodination of a,b-Unsaturated Carbonyl Compounds with I2
1265
Additional equivalents of iodine do not accelerate the re- Table 4 DMAP-Catalyzed a-Iodination of a,b-Unsaturated
Carbonyl Compounds under Optimized Conditionsa
action, but if less than 1.5 equiv is employed the reaction
fails to go to completion. This was also found to be true
Entry Substrate
1
Time
Product
Yield
(%)
with the amount of K CO where 1.2 equiv appeared op-
2
3
(
h)
timum. Presumably, the equilibrium (Equation 1) caused
by a slow reaction between iodine and water accounts for
2
2a
I
99
O
1
2
the need for an excess of these reagents.
O
I2 + H2O
HOI + HI + K CO3
KOI + KI + CO2 + H2O
2
2
1
2b
2c
I
99
50
O
Equation 1
O
3
24
I
The scope of the method was investigated and the exam-
ples are illustrated in Table 4. Overall, a wide range of
substrates was found to readily iodinate with no b-iodina-
tion or hydro-iodination products observed. As expected,
relative reaction rates and overall yields were dependant
on the ability of the substrate to act as a Michael acceptor.
O
O
4
5
6
48
6
2d
2e
2f
I
16
O
O
Cyclic-enones unsubstituted at the b-position (entries 1
and 2) were rapidly converted to the iodide, although the
iodination of cyclohepten-2-enone (entry 3) was sluggish
and after 24 hours had undergone just 50% conversion.
The presence of a b-substituent on a cyclic enone was
found to be particularly deleterious to the reaction (entry
68b
I
I
O
O
O
92b
2.5
4
). Linear enones (entries 5–11), which are generally poor
Ph
O
substrates for iodination using available methods, were
converted in high yields and in a relatively short period of
time, with the exception of sterically hindered mesityl ox-
ide (entry 10). Notably, no polymerization of the products
was observed. For alkenes unsubstituted at the b-position
Ph
7
8
2.5
2g
2h
I
I
99
O
O
O
O
4
0
75
85
2
2
(
entries 5 and 6), quinuclidine was found to be a superior
catalyst, owing to its greater nucleophilicity in the ab-
sence of steric inhibition. In addition to a,b-unsaturated
aldehydes and ketones, uracil (entry 12), the C-5 substitut-
ed analogs of which are important intermediates for the
9
4
0
2i
2j
I
I
70
90
O
O
O
O
1
3
synthesis of chemotherapeutic agents and biological
Et
Et
1
4
probes, was found to quickly iodinate in nearly quantita- 10
tive yield.
45
44
5
27
32
97
Unfortunately, more hindered systems gave less satisfac-
tory results (entries 4, 10 and 11). Although increasing the
amount of DMAP to 1 equiv had the effect of accelerating
the reaction rate, overall yields were still low, and if left
for long periods of time (>48 h) apparent in situ decompo-
sition of the products was observed.
1
1
1
2
Ph
2k
2l
Ph
I
O
O
O
I
HN
O
Our protocol was less efficient when extended to the iodi-
nation of a,b-unsaturated esters and nitriles (Table 5).
When DMAP was employed as the catalyst, almost no io-
dination was observed even after extended periods of
time, while quinuclidine was found to catalyze the iodina-
tion of methyl acrylate in a modest 45% yield (entry 1)
and the more sterically hindered ethyl crotonate in a 25%
yield (entry 2). The iodination of acrylonitrile gave only a
trace amount of the desired product (entry 3). Unfortu-
nately, further efforts at optimization such as longer reac-
tion times, higher catalyst loading and performing the
reactions in the dark, were not successful.
NH
HN
O
O
NH
a
DMAP (0.2 equiv), I (2 equiv), K CO (1.2 equiv), H O–THF (1:1).
2
2
3
2
b
0
.2 Equiv quinuclidine.
In conclusion, we have developed a method for the a-io-
dination of carbonyl compounds with iodine, employing
mild aqueous conditions. The method appears to be of
more general applicability than current literature proce-
dures, except for highly sterically hindered substrates. In
the absence of steric hindrance, substitution of DMAP for
quinuclidine allows for the protocol to be extended to the
Synlett 2005, No. 8, 1263–1266 © Thieme Stuttgart · New York

1
266
M. E. Krafft, J. W. Cran
LETTER
a-iodination of a,b-unsaturated esters, albeit in modest
(3) Whang, J. P.; Yang, S. G.; Kim, Y. H. Chem. Commun.
997, 1355.
4) Alimardanov, A.; Negishi, E. Tetrahedron Lett. 1999, 40,
839.
1
yields.
(
Table 5 a-Iodination of a,b-Unsaturated Esters and Nitriles
3
X
I
X
I2 (1.5 equiv), K2CO3 (1.2 equiv)
Quinuclidine (0.2 equiv) , H2O/THF
(5) Johnson, C. J.; Adam, J. P.; Braun, M. P.; Senanayake, C. B.
W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett.
R
R
2m–o
1
992, 33, 917.
6) Djuardi, E.; Bovonsombat, P.; McNelis, E. Synth. Commun.
997, 24, 2497.
7) Spivey, A. C.; Arseniyadis, S. Angew. Chem. Int. Ed. 2004,
3, 5436.
(
(
(
Entry
X
R
Time (h) Product Yield (%)
1
1
2
3
CO Me
H
24
24
24
2m
2n
2o
45
2
4
8) For review of Baylis–Hillman chemistry, see: Basavaiah, D.;
CO Et
Me
H
25
2
Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
CN
Trace
(9) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem.
003, 68, 692.
10) Lee, K. Y.; GowriSankar, S.; Kim, J. N. Tetrahedron Lett.
004, 45, 5485.
11) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311.
2
(
(
2
Typical Procedure for a-Iodination Reaction
(12) Burger, J. D.; Liebhafsky, H. A. Anal. Chem. 1973, 45, 600.
(13) Bergstrom, D.; Lin, X.; Wang, G.; Rotstein, D.; Beal, P.;
Norrix, P.; Ruth, J. Synlett 1992, 179.
To a stirred solution of cyclohex-2-enone (0.1 mL, 1.0 mmol) in 1:1
THF–H O (5 mL) was added K CO (166 mg, 1.2 mmol), I (381
2
2
3
2
mg, 1.5 mmol) and DMAP (24 mg, 0.2 mmol) successively. Upon
completion, the reaction mixture was diluted with EtOAc (10 mL)
and washed with sat. Na S O (20 mL) and 0.1 M HCl (20 mL) suc-
(14) Goodwin, J. T.; Glick, G. D. Tetrahedron Lett. 1993, 34,
5549.
(15) Compound 2l was extracted with acetonitrile.
2
2
3
1
5
cessively. The mixture was subsequently extracted with EtOAc
(16) Selected data:
1
and dried over MgSO , before concentration and purification by
Compound 2f: H NMR (300 MHz, CDCl ): d = 6.83 (d,
4
3
flash column chromatography afforded 220 mg of the a-iodoenone
J = 2.1 Hz, 1 H, CHH=C), 6.86 (d, J = 2.1, 1 H, CHH=C),
1
6
2
a (99% yield). All novel compounds were fully characterized; all
7.46 (t, J = 6.8 Hz, 2 H, Ar), 7.59 (t, J = 7.5 Hz, 1 H, Ar),
1
13
other compounds were identified from their H NMR spectra. Com-
pounds 2a, 2b, 2k: ref. ; compounds 2c, 2i: ref. ; compound 2d:
ref. ; compound 2e: ref. ; compound 2g: ref. ; compound 2h: ref. ;
7.81 (d, J = 7.2 Hz, 2 H, Ar). C NMR (75 MHz CDCl ):
3
5
2
d = 107.9, 128.5 (2 C), 129.9 (2 C), 133.1, 133.8, 191.7.
4
17
18
6
1
Compound 2j: H NMR (300 MHz, CDCl ): d = 2.00 (s, 3 H,
3
compound 2l: ref.3
13
CH ), 2.04 (s, 3 H, CH ), 2.50 (s, 3 H, CH ). C NMR (75
3
3
3
MHz, CDCl ): d = 22.1, 28.9, 30.9, 95.9, 145.7, 199.4.
3
1
Compound 2m: H NMR (300 MHz, CDCl ): d = 3.92 (s, 3
3
Acknowledgment
13
H, OCH ), 6.67 (s, 1 H, CHH=C), 7.55 (CHH=C). C NMR
3
(
75 MHz CDCl ): d = 53.7, 95.8, 139.9, 163.0.
3
1
This work was supported by the MDS Research Foundation and the
National Science Foundation. JWC acknowledges the MDS Re-
search Foundation for a postdoctoral fellowship.
Compound 2n: H NMR (300 MHz, CDCl ): d = 1.16 (t,
J = 7.2 Hz, 3 H, CH CH ), 1.81 (d, J = 6.6 Hz, 3 H,
CH CHC), 4.11 (q, J = 7.2 Hz, 2 H, CH CH ), 7.15 (q,
J = 6.6 Hz, 1 H, CH CHC). C NMR (75 MHz CDCl ): d =
3
2
3
3
2
3
1
3
3
3
1
4.2, 22.9, 62.5, 96.9, 148.3, 162.8.
References
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1) For review of a-iodo carbonyl compounds in synthesis, see:
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2) Bovonsombat, P.; Angara, G. J.; McNelis, E. Tetrahedron
Lett. 1994, 35, 6787.
(
(
Synlett 2005, No. 8, 1263–1266 © Thieme Stuttgart · New York