Regio- and stereospecific synthesis of (E)-α-iodoenamide moieties from ynamides through iodotrimethylsilane-mediated hydroiodation

Article abstract of DOI:10.1016/j.tetlet.2012.12.101

A facile approach to (E)-α-haloenamide moieties from ynamides using bromo- or iodotrimethylsilane is described. The simple protocol enables a regio- and stereospecific hydrohalogenation of the triple bond in gram-scale and provides a general entry for synthesis of novel enamide analogues.

Full text of DOI:10.1016/j.tetlet.2012.12.101

Tetrahedron Letters 54 (2013) 1309–1311
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regio- and stereospecific synthesis of (E)-
a-iodoenamide moieties
from ynamides through iodotrimethylsilane-mediated hydroiodation
⇑
Akihiro H. Sato, Kazuhiro Ohashi, Tetsuo Iwasawa
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University Otsu, Shiga 520-2194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile approach to (E)-a-haloenamide moieties from ynamides using bromo- or iodotrimethylsilane is
Received 8 December 2012
Revised 24 December 2012
Accepted 26 December 2012
Available online 3 January 2013
described. The simple protocol enables a regio- and stereospecific hydrohalogenation of the triple bond in
gram-scale and provides a general entry for synthesis of novel enamide analogues.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Vinyl halides
Iodotrimethylsilane
Haloenamides
Hydroiodation
Ynamides
Enamides are basic building blocks in organic synthesis.1–3
Structural enamide components are frequently found in natural
products,4,5 and they recently have emerged as a novel type of use-
ful nucleophiles in stereoselective C–C and C–N bond-forming
reactions.6 From the synthetic point of view, haloenamides are ver-
satile variants of enamides. Iodoenamides are especially useful, as
they are readily converted into various functional groups by halo-
gen–metal exchange and are significant for carbon–carbon bond
forming reactions by way of transition-metal catalyzed cross-cou-
pling reactions.7–9 Thus, the weakly bonded iodide and electron-
rich olefin are highly reactive and potentially useful toward the
synthesized nitrogen-containing complex molecules.10,11 Despite
the utility of iodoenamides, their synthetic availability still re-
mains a challenge, because of the inherent difficulty in regio-
and stereoselective hydrohalogenation.12 The stoichiometric addi-
tion of hydrogen iodide (HI) to ynamide is one way to prepare iod-
oenamides; however the hygroscopic and gaseous HI is
inconvenient, and this method often results in poor regio- and ste-
reochemical control, and separation of the resultant isomeric mix-
tures is laborious.13
ure of the keteniminium resonance form, the iodine automatically
unites with the a
-carbon.16 There is still room for improvement in
reaction efficiency, especially in terms of its scale and purity;17 the
prototype system worked using only 0.1 mmol of starting alkynes
and giving the products with E/Z mixtures.
Herein we report a completely regio- and stereospecific synthe-
sis18 of (E)-
a-iodoenamides from ynamides using in situ generated
HI (Scheme 1). The in situ HI was generated from iodotrimethylsi-
lane (TMSI) and H2O,19,20 and quickly added to ynamide in nearly
quantitative yields, exclusively giving single isomer. The method
is compatible with a variety of reaction conditions and is applica-
ble to hydrobromination utilizing TMSBr. Thus, the protocol pro-
vides simple access to (E)-a-haloenamide moieties.
To initiate our search, we focused on TMSI-mediated hydroioda-
tion of 121 (Scheme 1), based on our previous report.19 The mixture
of 1 and TMSI22 was stirred at À78 °C for 15 min, and water was
added, and the reaction was allowed to warm to 0 °C. After usual
workup and purification, the product was isolated without decom-
position and identified as (E)-a-iodoenamide 2 according to an
authentic sample.23–25
The pioneering work for efficient synthesis of iodoenamide
from ynamide via addition of HI was reported by Hsung and co-
workers in 2003:14 the in situ generation of HI from MgI2 and
As summarized in Table 1, the reactivity of 1 conducted via
Scheme 1 was evaluated.26 More than 1.5 equiv of TMSI was
H2O afforded a-iodoenamides with good selectivities of E/Z ratios.
The outcome of stereoselective addition is dictated by the polariza-
tion of the triple bond caused by nitrogen.15 According to the nat-
⇑
Corresponding author. Tel.: +81 77 543 7461; fax: +81 77 543 7483.
E-mail address: iwasawa@rins.ryukoku.ac.jp (T. Iwasawa).
Scheme 1. Synthesis of 2 from 1 via iodotrimethylsilane-mediated hydroiodation.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.101

1310
A. H. Sato et al. / Tetrahedron Letters 54 (2013) 1309–1311
Table 1
needed for completion (entries 1–3), and low temperature was
Evaluation of the reactivity of 1 conducted via Scheme 1a
favorable (entries 3–6). The concentration was increased in entry
7 (1.0 mL CH2Cl2), however, the yield decreased to 80%. Other sol-
vents of toluene, hexane, acetonitrile were successful to give high
yields (entries 8–10). THF and cyclopentyl methyl ether gave only
acceptable yield of 2 (entries 11–12). For entry 13, addition of H2O
to the solvent in advance gave 94% yield. For entries 15 and 16,
(CH3)3SiBr and (CH3)3SiCl were used instead of TMSI; the corre-
Entry
TMSI (equiv)
Temp (°C)
Solvent
Yieldb (%)
1c
2
3
4
5
1.2
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
À78
À78
À78
À20
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Hexane
CH3CN
THF
Cyclopentyl methyl ether
CH2Cl2/H2O (4% v/v)
CH2Cl2
77
98
99
98
85
71
80
98
99
99
65
63
94
95
99
28h
6
25
7d
8
À78
À78
À78
À78
À78
À78
À78
À78
À78
À78
sponding (E)-a-haloenamide was yielded in 99% and 28%, respec-
tively. The respective bond energies of Si–Cl, Si–Br, and Si–I are
113, 96, and 77 kcal/mol:27 the obstinate bond of Si–Cl would be
difficult to activate. It is worth noting that any (Z)- or b-isomer
of 2 was not observed on NMR spectra and TLC analyses from entry
1 through entry 16.
Next, the substrate generality with respect to the ynamides was
investigated, and the results are summarized in Scheme 2. 28 Evans
auxiliary 4a14 was successfully obtained in 99% yield without any
isomers. Application of Hsung’s method gave mixtures of
E:Z = 88:12.29 Iodide 4b immediately decomposed after the isola-
tion: on the other hand, bromide 4c and 4d were stable even in
neat form, presumably due to the stronger bond energy. Similar
stabilities of the vinyl halides were observed in 4e, 4f, 4p, and
4q, although 4j and 4k were both fragile oil. The carbamate,
sulfonamide, and amide groups are accepted for the hydroiodation
9
10
11
12
13
14e
15f
16g
CH2Cl2
CH2Cl2
a
Reaction conditions: 1 (1 mmol), solvent (8 mL), 1 M (CH3)3SiI in CH2Cl2, H2O
(20 mmol).
b
Isolated yields after column chromatography.
23% of 1 was recovered.
1 mL of CH2Cl2 was used.
CH3OH was added instead of H2O.
(CH3)3SiBr was used instead of (CH3)3SiI.
(CH3)3SiCl was used instead of (CH3)3SiI.
Determined by 1H NMR.
c
d
e
f
g
h
Scheme 2. The substrate scope of ynamides under the reaction conditions of 3 (1 equiv), solvent (8 mL/mmol of 3), and 1 M (CH3)3SiX in CH2Cl2 (2 equiv).

A. H. Sato et al. / Tetrahedron Letters 54 (2013) 1309–1311
1311
Press: London; (c) Brandsma, L. Preparative Polar Organometallic Chemistry 2;
(4a–4i), and the transformation also worked well in the presence of
functional groups such as OMe and CN (4j–4m). The reactions at
gram-scale successfully performed in 4f, 4g, 4j, 4k, and 4m. The
synthesis of 4n–4s derived from aliphatic alkynes proceeded very
well, although 4t decomposed in the process of column chroma-
tography: at the present time it is difficult to predict which prod-
Springer: Berlin, 1990; (d) Schlosser, M. In Organometallics in Synthesis
Manual; Schlosser, M., Ed., 2nd ed.; Wiley: Chichester, UK, 2002; pp 1–352.
A
8. (a) Neumann, H.; Seebach, D. Chem. Ber. 1978, 111, 2785; (b) Evans, D. A.;
Crawford, T. C.; Thomas, R. C.; Walker, J. A. J. Org. Chem. 1976, 41, 3947.
9. Galli, C.; Rappoport, Z. Acc. Chem. Res. 2003, 36, 580.
10. (a) Funk, R. L.; Hentley, R. J. Tetrahedron Lett. 2011, 52, 6671; (b) Heffernan, S.;
Carbery, D. R. Tetrahedron Lett. 2012, 53, 5180.
11. (a) Yu, Z.; Jin, Z. J. Am. Chem. Soc 2000, 122, 9840; (b) Liu, X.; Henderson, J. A.;
Sasaki, T.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 16678.
12. (a) Reddy, Ch. K.; Periasamy, M. Tetrahedron Lett. 1919, 1990, 31; (b) Stewart, L.
J.; Gray, D.; Pagni, R. N.; Kabalka, G. W. Tetrahedron Lett. 1987, 28, 4497; (c)
Stone, H.; Schecher, H. Org. Syn. Coll. 1963, 4, 543.
13. (a) Kropp, P. J.; Craword, S. D. J. Org. Chem. 1994, 59, 3102; (b) Hudrlik, P. F.;
Kulkarni, A. K.; Jain, S.; Hudrlik, A. M. Tetrahedron 1983, 39, 877; (c) Griesbaum,
K.; El-Abed, M. Chem. Ber. 2001, 1973, 106.
14. Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.; Frederick, M. O.; Shen,
L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547.
15. (a) Compain, G.; Jouvin, K.; Martin-Mingot, A.; Evano, G.; Marrot, J.;
Thibaudeau, S. Chem. Commun. 2012, 48, 5196; (b) Evano, G.; Coste, A.;
Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840; (c) DeKorver, K. A.; Li, H.; Lohse,
A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064; (d)
Mulder, J. A.; Kurtz, K. C. M.; Hsung, P. R. Synlett 2003, 1379.
ucts of (E)-a-haloenamides are inclined to decompose. Notably,
all the enamides were observed as single isomers even in crude
states, and any E/Z isomeric mixtures were not obtained.
The mechanism for the resulting in perfect stereochemical con-
trol to produce only (E)-adducts is not yet fully known. Deuterioio-
dation of 1 was carried out with D2O, and the deuterium was
thoroughly incorporated for H of 2 as we expected. The result indi-
cates that this reaction does not follow a stepwise path. Possible
chelation30 of the silicon atom with the nitrogen atom and/or the
oxygen atom of the electron-withdrawing group would provide
concerted syn-addition of HI toward the triple bond.14,15,31
In conclusion, commercially available TMSI and TMSBr were
16. Sanapo, G. F.; Daoust, B. Tetrahedron Lett. 2008, 49, 4196.
17. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008.
found to convert ynamides into (E)-a-haloenamides in high yields
18. The regioelectivity of the products in this paper is different from the previous
report (Ref. 19) in which addition of HI to ethynylarenes using TMSI–H2O
system preferentially gave anti-style products. In the above-mentioned
meaning, we used the word ‘specific’ as a sense of ‘ynamide-specific’.
19. Sato, A. H.; Mihara, S.; Iwasawa, T. Tetrahedron Lett. 2012, 53, 3585.
20. Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675.
21. (a) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett.
2004, 6, 1151; (b) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org.
Chem. 2006, 71, 4170.
along with the perfect regio- and stereochemical outcomes. The
method completes the reaction quickly under routine conditions,
and was readily amenable to scale-up. This approach showed
excellent substrate compatibility, and afforded a wide variety of
new (E)-a-haloenamides. The synthetic utility of the products is
clear and we hope this reliable methodology finds widespread
use in organic synthesis. Application and mechanistic elucidation
are ongoing for further development of this reaction and will be re-
ported in due course.
22. Preparation of 1 M TMSI in CH2Cl2, see Supplementary data.
23. We prepared the authentic compound of (E)-a-fashioned 2 according to the
Ref. 14, and confirmed that its 1H NMR and 13C NMR were identical to
compound 2 derived from our method. Elemental analysis also showed good
match as described in Ref. 26.
Acknowledgments
24. Compound 2 derived from our method was converted to the corresponding
olefin using tert-BuLi for lithium–halogen exchange, and the (Z)-olefin was
obtained in 39% yield with typical coupling constants J = 9.1 Hz for cis-form. In
brief, the compound 2 was formed in (E)-fashion.
We are very grateful to Professor Michael P. Schramm at Cali-
fornia State University Long Beach for helpful discussion. We thank
Suzuken Memorial Foundation for the financial support.
25. Similar identification of the stereochemistry in the case of 4a was also ensured;
we prepared the authentic sample of (E)-a-fashioned 4a according to Hsung’s
method in Ref. 14, and its spectroscopic data was the identical to that of 4a
derived from our procedure.
Supplementary data
26. Representative procedure for (E)-a-haloenamide moieties, for 2 (Table 1, entry 3):
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.101.
To a solution of 1 (1 mmol) in anhydrous CH2Cl2 (8 mL) at À78 °C was added
TMSI (1 M in CH2Cl2) dropwise over 5 min. After 15 min stirring, H2O
(20 mmol) was added, and the mixture was allowed to warm to 0 °C over
50 min, and followed by additional stirring for 10 min. The reaction was
quenched at 0 °C with saturated aqueous sodium thiosulfate, stirred for
30 min, and allowed to warm to ambient temperature. To the mixture was
added CH2Cl2, and organic phases were washed with brine, and then dried over
Na2SO4, and concentrated to give a crude product. Purification by silica gel
column chromatography afforded 375 mg of 2 in 99% yield as yellow viscous
materials. 1H NMR (400 MHz, CDCl3) d 7.38–7.28 (m, 10H), 7.17 (s, 1H), 3.74 (s,
3H). 13C NMR (100 MHz, CDCl3) d 153.3, 142.2, 139.1, 135.2, 129.1, 129.02,
129.00, 127.7, 126.9, 124.5, 95.0, 54.0. MS (EI) m/z: 252 ([MÀI]+), 193
([MÀIÀCO2CH3]+). IR (neat): 3063, 2953, 1713 (C@O), 1622 (C@C),
1592 cmÀ1. Anal. Calcd for C16H14INO2: C, 50.68; H, 3.72; N, 3.69. Found: C,
50.66; H, 3.70; N, 3.76.
References and notes
1. (a) Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional
Group Preparations; Wiley-VCH: New York, 1999; (b) Rappoport, Z. The
Chemistry of Enamines. In The Chemistry of Functional Groups; New York:
John Wiley and Sons, 1994.
2. (a) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333; (b) Jiang, L.; Job, G. E.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667.
3. For reviews on enamides, see: (a) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun.
2005, 973; (b) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517; (c)
Hickmott, P. W. Tetrahedron 1975, 1982, 38; (d) Hickmott, P. W. Tetrahedron
1982, 38, 3363; (e) Lenz, G. R. Synthesis 1978, 489.
4. (a) Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.; Sakakibara, T.; Suzuki, Y.;
Thompson, J. F.; Yamauchi, Y.; Kojima, N. J. Antibiot. 1998, 51, 14; (b) Kunze, B.;
Jansen, R.; Sasse, F.; Hofle, G.; Reichenbach, H. J. Antibiot. 1998, 51, 1075; (c) Yet,
L. Chem. Rev. 2003, 103, 4283.
5. For examples on synthesis of enamides, see: (a) Anthoni, U.; Bock, K.; Chevolot,
L.; Larson, C.; Nielsen, P. H.; Christophersen, C. J. Org. Chem. 1987, 52, 5638; (b)
Lin, X.; Weinreb, S. M. Tetrahedron. Lett. 2001, 42, 2631; (c) Pinder, J. L.;
Weinreb, S. M. Tetrahedron. Lett. 2003, 44, 4141; (d) Nakamura, R.; Tanino, K.;
Miyashita, M. Org. Lett. 2003, 5, 3583; (e) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr.
Org. Lett. 2004, 6, 27; (f) Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem.,
Int. Ed. 2005, 44, 3714; (g) Nishikawa, T.; Kajii, S.; Isobe, M. Synlett 2004, 2025;
(h) Sum, C.; Camp, J. E.; Weinreb, S. M. Org. Lett. 2006, 8, 1779; (i) Palimkar, S.
S.; Uenishi, J. Org. Lett. 2010, 12, 4160.
27. (a) Walsh, R. Acc. Chem. Res. 1981, 14, 246; (b) Doncaster, A. M.; Walsh, R. J.
Phys. Chem. 1979, 83, 3037.
28. Full spectroscopic data for all new compounds in Scheme 2 of 1H NMR, 13C
NMR, MS, IR, and Elemental analyses were listed in Supplementary data.
29. We actually attempted the hydroiodation of 4a under the Hsung’s condition
according to Ref. 14.
30. A competitive reaction using a mixture of 3a (1 mmol) and 3g (1 mmol) was
performed under the condition of CH2Cl2 (8 mL), 1 M TMSI (1.5 equiv).
Unexpectedly, the hydroiodation occurred in 3g predominantly: 0.97 mmol
of 4g and 0.03 mmol of 4a were yielded, and 0.03 mmol of 3g and 0.97 mmol of
3a were unreacted. This indicates that the different ability in chelation of
silicon with oxygen between 3a and 3g might regulate the activity of reagent
system.
31. The alternative to the concerted way is synchronous mechanism, see: (a)
Fishcer, J.; Steglich, W. Angew. Chem., Int. Ed. 1979, 18, 167; (b) Bearpark, M.;
Bernardi, F.; Olivucci, M.; Robb, M. A. J. Am. Chem. Soc. 1990, 112, 1732.
6. Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292. and references
therein.
7. (a) Brandsma, L.; Verkruijsse, H. Preparative Polar Organometallic Chemistry 1;
Springer: Berlin, 1987; (b) Wakefield, B. J. Organolithium Methods; Academic