Facile synthesis of α-iodo carbonyl compounds and α-iodo dimethyl ketals using molecular iodine and trimethylorthoformate

Article abstract of DOI:10.1016/j.tetlet.2008.03.151

A novel and direct method for the synthesis of α-iodo ketones and α-iodo dimethyl ketals from acetophenones using iodine and trimethylorthoformate under neutral conditions is described herein.

Full text of DOI:10.1016/j.tetlet.2008.03.151

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3810–3813
Facile synthesis of a-iodo carbonyl compounds and a-iodo dimethyl
ketals using molecular iodine and trimethylorthoformate
J. S. Yadav *, G. Kondaji, M. Shiva Ram Reddy, P. Srihari
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 December 2007; revised 26 March 2008; accepted 28 March 2008
Available online 8 April 2008
Abstract
A novel and direct method for the synthesis of a-iodo ketones and a-iodo dimethyl ketals from acetophenones using iodine and
trimethylorthoformate under neutral conditions is described herein.
Ó 2008 Elsevier Ltd. All rights reserved.
O
O
The synthesis of a-halogenated ketones particularly
a-iodo ketones and their applications as reaction inter-
mediates have attracted considerable attention in various
organic transformations.1 Several methods are available
for the synthesis of a-iodo ketones which are either
obtained directly by treating ketones with different combi-
nations of reagents such as iodine–cerium(IV) ammonium
nitrate—in alcohol or acetic acid,2 iodine–mercury(II)
chloride,3 iodine–selenium dioxide,4 NIS–p-toluenesulfonic
acid,5 [hydroxy(tosyloxy)iodo]benzene (Koser’s reagent,
HTIB) with MgI2,6 Selectfluor F-TEDA-BF4–I2,7
I2–bis( tetra-n-butylammonium)peroxydisulfate,8 I2/urea–
MeO OMe
I
I
I2, TMOF
or
R
R
R
DCM, r.t, 5-6 h
68-82%
R = OH, Me, F, OTBS, OAc, OBn
Scheme 1.
64-78%
In continuation of our studies towards the total synthe-
sis of biologically active natural products,15 we were inter-
ested in the total synthesis of colombiasin A. Towards the
synthesis, we wanted to homologate compound 1 to com-
pound 2 (Scheme 2). By applying the known protocol15a
for this conversion in the presence of trimethyl orthofor-
mate with iodine under the specified conditions, we
obtained a mixture of a-iodinated dimethyl ketal 3 and
a-iodinated ketone 4 rather than the expected homologated
compound 2.16b We believe this reaction to be substrate
specific as the reaction worked well with substrate 5 under
the reported conditions.16a
H 2O2,9
I2–1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate),10 polymer supported
pyridinium dichloroiodate,11 molecular iodine in DME at
90 °C12 or indirectly by treating enol silyl ethers or enol
acetates with iodinating agents such as iodine cop-
per(II)nitrate or iodine–silver acetate.13 However, all these
reactions employ either harsh acidic conditions, toxic metal
salts or elevated temperatures, and thus a simple procedure
for a-iodination is welcome to overcome the disadvantages
of existing procedures. Herein, we report a novel and
direct method for the synthesis of a-iodo ketones or a-iodo
dimethyl ketals using iodine14 and trimethylorthoformate
under mild conditions (Scheme 1).
This result prompted us to further investigate this reac-
tion. Thus, acetophenone was examined at room tempera-
ture using iodine and trimethylorthoformate. To our
delight, a mixture of a-iodinated acetophenone and
keto protected a-iodinated compound was the only
products observed. These results led us to optimize this
transformation for the preparation of a-iodo acetophenon-
es and a-iodo ketals.
*
Corresponding author. Tel.: +91 4027193030; fax: +91 4027160387.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.151

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3810–3813
3811
OMe O
OMe
Me
CO2Me
Me
OMe O
OMe
OMe
Me
5
I2, TMOF
r.t.
2
MeO OMe
OMe
OMe O
I
OMe
Me
Me
I
+
1
OMe
OMe
3
4
Scheme 2.
Accordingly, several substituted acetophenones were
treated with iodine and trimethylorthoformate and the
results are shown in Table 1. The advantage of this reaction
is that the present protocol tolerated common protecting
groups such as tert-butyldimethylsilyl, benzyl and acetate.
The product selectivity for simple acetophenones with
respect to the protected or unprotected a-iodo compounds
could be modified by a slight variation in the workup pro-
cedures. Upon completion of the reaction, if the reaction
mixture was quenched with aqueous saturated Na2S2O3
Table 1
Preparation of a-iodo acetophenones and a-iodo ketals
Sl. no.
1
Ketone a
a-Iodo ketonea
b
Time (h)
5
Yieldb (%)
72
a-Iodo ketala
c
Time (h)
5
Yieldb (%)
73
O
O
MeO OMe
I
I
O
O
MeO OMe
I
I
2
3
5
5
76
64
5
5
78
68
HO
HO
HO
O
O
MeO OMe
I
I
H3C
H3C
H3C
O
O
MeO OMe
I
I
4
5
4
5
76
74
4
5
79
74
F
F
F
O
O
MeO OMe
I
I
TBSO
BnO
TBSO
TBSO
O
O
O
MeO OMe
I
I
6
7
5
5
78
74
5
5
82
77
BnO
BnO
O
MeO OMe
I
I
AcO
AcO
O
AcO
O
I
8
9
6
5
73
75
—
O
O
I
—
—
O
O
I
10
5
73
(continued on next page)

3812
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3810–3813
Table 1 (continued)
Sl. no.
Ketone a
a-Iodo ketonea
b
Time (h)
5
Yieldb (%)
70
a-Iodo ketala
c
Time (h)
Yieldb (%)
O
OMe
I
11
—
O
OMe
O
OMe
I
OMe
Me
12
6
75
6
70
O
Me
O
MeO
a
The products were characterized by IR, 1H NMR and mass spectroscopy.
Isolated yields after column chromatography.
b
O
Acknowledgement
MeO OMe
I
I2, TMOF
rt, 4 h, 60%
G.K. and M.S.R. thank the CSIR, New Delhi, for finan-
cial assistance.
6
I
7
Scheme 3.
References and notes
solution and extracted with dichloromethane, the a-iodin-
ated dimethoxy ketal was the main product. However,
when the reaction mixture was stirred with water before
washing with aq saturated Na2S2O3 solution, the a-iodin-
ated ketone was the major product.17 It is noteworthy to
mention that ring directed iodination or a,a-diiodination
was never observed during this process. When cyclohexa-
none and its derivatives were reacted, compounds 8a, 9a
and 10a gave only the corresponding a-iodo keto products
8b, 9b and 10b, no a-iodo dimethyl ketals were observed.
When 1,3-cyclohexadiones 11a and substituted 1,3-cyclo-
hexadiones 12a were subjected to the present conditions,
the corresponding iodo substituted compounds 11b, 12b
and the aromatized product 12c18 were obtained. All the
products were characterized and analyzed by studying their
spectral properties.19 However, when 2-heptanone 6 was
subjected to the present protocol, a,a0-diiodo dimethoxy
ketal 7 was obtained as the only product (Scheme 3).
Mechanistically, we believe that initially an enol ether is
formed followed by the iodination to give the a-iodo di-
methoxy ketal (Scheme 4), which on hydrolysis with water
in the presence of HI affords the a-iodo ketone.
1. Selected examples: (a) Kims, S.; Lim, C. J. Angew. Chem., Int. Ed.
2004, 43, 5378–5380; (b) Kondo, J.; Shinokubo, H.; Oshima, K.
Angew. Chem., Int. Ed 2003, 42, 825–827; (c) Shimizu, M.; Kobayashi,
F.; Hayakawa, R. Tetrahedron 2001, 57, 9591–9595.
2. Horiuchi, C. A.; Kiji, S. Bull. Chem. Soc. Jpn. 1997, 70, 421–426.
3. Barluenga, J.; Martiznez-Gallo, J. M.; Najera, C.; Yus, M. Synthesis
1986, 678–680.
4. Bekaert, A.; Barberan, O.; Gervais, M.; Brion, J.-D. Tetrahedron Lett.
2000, 41, 2903–2905.
5. Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S. J. Org.
Chem. 1993, 58, 3194–3195.
6. Lee, J. C.; Park, J. Y.; Yoon, S. Y.; Bae, Y. H.; Lee, S. J. Tetrahedron
Lett. 2004, 45, 191–193.
7. Stavber, S.; Jereb, M.; Zupan, M. Chem. Commun. 2002, 488–489.
8. Whang, J. P.; Yang, S. G.; Kim, Y. H. Chem. Commun. 1997, 1355–
1356.
9. (a) Pavlinac, J.; Zupan, M.; Staver, S. Org. Biomol. Chem. 2007, 5,
699–707; (b) Jereb, M.; Ikra, J.; Zupan, M.; Stavber, S. Lett. Org.
Chem. 2005, 2, 465–468.
10. Jereb, M.; Stavber, S.; Zupan, M. Synthesis 2003, 853–858.
11. Sket, B.; Zupet, P.; Zupan, M.; Dolenc, D. Bull. Chem. Soc. Jpn.
1989, 62, 3406–3408.
12. Rao, M. L. N.; Jadhav, D. N. Tetrahedron Lett. 2006, 47, 6883–6886.
13. (a) Cort, A. D. J. Org. Chem. 1991, 56, 6708–6709; (b) Rubottom, G.
M.; Mott, R. C. J. Org. Chem. 1979, 44, 1731–1733.
14. For our few earlier contributions with iodine see: (a) Yadav, J. S.;
Satyanarayana, M.; Raghavendra, S.; Balanarsaiah, E. Tetrahedron
Lett. 2005, 46, 8745–8748; (b) Yadav, J. S.; Balanarsaiah, E.;
Raghavendra, S.; Satyanarayana, M. Tetrahedron Lett. 2006, 47,
4921–4924; (c) Yadav, J. S.; Reddy, B. V. S.; Narayana Kumar, G. G.
K. S.; Swamy, T. Tetrahedron Lett. 2007, 48, 2205–2208; (d) Srihari,
P.; Sridhar, P.; Bhunia, D. C.; Reddy, J. S. S.; Mandal, S. S.; Yadav,
J. S. Tetrahedron Lett. 2007, 48, 8120–8124.
In conclusion, an efficient simple protocol for the con-
version of acetophenones to a-iodoacetophenones and
a-iododimethoxy ketals has been described. This strategy
may find applications in the total synthesis of several bio-
active natural products involving either the a-iodo keto
product or the a-iodo dimethyl ketal substrate.
O
OMe
O
MeO OMe
I
I
TMOF, I2
-HI
HI, H2O
Scheme 4.

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 3810–3813
3813
15. For our recent publications on natural products see: (a) Yadav, J. S.;
Basak, A. K.; Srihari, P. Tetrahedron Lett. 2007, 48, 2841–2843; (b)
Yadav, J. S.; Chetia, L. Org. Lett. 2007, 9, 4587–4589; (c) Yadav, J.
S.; Pratap, T. V.; Rajender, V. J. Org. Chem. 2007, 72, 5882–5885.
16. (a) Srikrishna, A.; Lakshmi, B. V. Tetrahedron Lett. 2005, 46, 7029–
7031; Even substrate 5 gave iodinated products at room temperature,
which on prolonged heating yielded the homologated product.
However, compound 2 was obtained at a later stage following the
procedure reported in (b) Maruyama, K.; Kozuka, T. Bull. Chem.
Soc. Jpn. 1978, 51, 3586–3589.
17. We assume that the acid HI generated by the addition of water is
responsible for the cleavage of dimethoxy ketal to ketone.
18. Similar aromatic compounds were prepared using TFAA and sulfuric
acid from dimedones, see: Nelson, P. H.; Nelson, J. T. Synthesis 1992,
1287–1291.
19. General experimental procedure: a-Iodo dimethyl ketals: A mixture of
keto compound (1.0 mmol) and iodine (2.0 mmol) in trimethylortho-
formate (5 mL) was stirred at room temperature for the appropriate
amount of time. After completion of the reaction as indicated by
TLC, the reaction mixture was diluted with dichloromethane (10 mL)
and the organic layer was washed with saturated aq Na2S2O3
(2 ꢀ 10 mL) and brine (1 ꢀ 10 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography using ethyl acetate/
hexane (1:9) as eluent to afford the pure a-iodo dimethoxy ketal. a-
Iodo ketones: A mixture of keto compound (1.0 mmol) and iodine
(2.0 mmol) in trimethylorthoformate (5 mL) was stirred at room
temperature for the appropriate amount of time. After completion of
the reaction as indicated by TLC, the reaction mixture was diluted
with water (10 mL) and stirred for an additional 15 min. Then the
reaction mixture was extracted with dichloromethane (10 mL),
washed with saturated aq Na2S2O3 (2 ꢀ 10 mL) and brine
(1 ꢀ 10 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by silica gel
column chromatography using ethyl acetate/hexane (1:9) as eluent to
afford the pure a-iodo ketone. Spectroscopic analysis for 3: 1H NMR
(CDCl3, 300 MHz): d 7.05 (d, J = 1.3 Hz, 1H), 6.70 (d, J = 1.3 Hz,
1H), 3.98 (s, 2H), 3.82 (s, 3H), 3.75 (s, 3H), 3.25 (s, 6H), 2.31 (s, 3H).
13C NMR (CDCl3, 75 MHz): d 154.82, 149.92, 132.67, 117.41, 113.7,
101.47, 60.74, 55.68, 49.48, 16.97, 7.81. ESIMS: m/z 389 (M++Na).
HRMS calcd for C13H19O4NaI, 389.0225; found 389.0220. Com-
pound 4: 1+H NMR (CDCl3, 300 MHz): d 6.92 (d, J = 1.3 Hz, 1H),
6.85 (d, J = 1.3 Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 2.30
(s, 3H). 13C NMR (CDCl3, 75 MHz): d 195.82, 155.73, 151.65, 133.51,
130.28, 122.47, 111.93, 62.52, 55.85, 16.44, 7.86. ESIMS: m/z 342.9
(M++Na). HRMS calcd for C11H13O3NaI, 342.9807; found 342.9820.