One-pot synthesis of α-iodo-substituted α,β-unsaturated aldehydes from propargylic alcohols

Article abstract of DOI:10.1021/jo070230x

(Chemical Equation Presented) An efficient one-pot method for the preparation of α-iodosubstituted α,β-unsaturated aldehydes (α-iodoenals) from propargylic alcohol is developed. The reaction proceeds via an iodoallene intermediate, which is generated in s

Full text of DOI:10.1021/jo070230x

On the other hand, allenes have recently attracted great
attention from organic chemists due to their diverse reactivities.3
Various synthetic methodologies have been developed based
on allene chemistry. For example, Ma and co-workers have
reported the stereoselective iodohydroxylation of 1,2-allenyl
sulfides that generates 2,3-iodohydroxylation products.4 How-
ever, as far as our knowledge is concerned, there have been
only a few reports on the reactions of haloallenes.5 In the course
of their investigation of allene iodination, Coulomb and co-
workers have reported that 1-(3-iodopropa-1,2-dienyl)benzene
is converted into 2-iodo-3-phenylacrylaldehyde by treatment
with I2-MgI2 and H2O.2e During our recent study, we have
found that iodoallenes can be efficiently converted into R-io-
doenals under an atmosphere of O2 at room temperature
(Scheme 1).6
One-Pot Synthesis of r-Iodo-Substituted
r,â-Unsaturated Aldehydes from Propargylic
Alcohols
Shufeng Chen and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS),
Green Chemistry Center (GCC), and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry, Peking UniVersity, Beijing
100871, China
wangjb@pku.edu.cn
ReceiVed February 3, 2007
Since iodoallenes can be easily prepared from propargylic
alcohols, we have conceived that this reaction may be useful in
the synthesis of R-iodo-substituted R,â-unsaturated aldehydes.
Herein we report a one-pot reaction to prepare R-iodoenals from
the propargylic alcohols through in situ generation of iodoallenes
by the reaction of propargylic alcohols with aqueous HI,
followed by the oxidation of the iodoallenes with molecular
oxygen (Scheme 2).
An efficient one-pot method for the preparation of R-iodo-
substituted R,â-unsaturated aldehydes (R-iodoenals) from
propargylic alcohol is developed. The reaction proceeds via
an iodoallene intermediate, which is generated in situ by the
reaction of propargylic alcohol with aqueous HI. The
iodoallene intermediate is further transformed to an R-io-
doenal derivative in good overall yield by oxidation with
molecular O2.
Propargylic alcohols could be easily prepared by reaction of
aldehydes with a Grignard reagent or lithium acetylide.7 Having
prepared a series of propargylic alcohols, 1a-k, we employed
1a (Ar ) Ph) as the substrate to test the one-pot reaction.
Treatment of compound 1a with aqueous HI in toluene resulted
(3) For recent reviews, see: (a) Modern Allene Chemistry; Krause, N.,
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b) Ma,
S. Acc. Chem. Res. 2003, 36, 701-712. (c) Wei, L. -L.; Xiong, H.; Hsung,
R. P. Acc. Chem. Res. 2003, 36, 773-782. (d) Brandsma, L.; Nedolya, N.
A. Synthesis 2004, 735-745. (e) Ma, S. Chem. ReV. 2005, 105, 2829-
2871.
(4) (a) Ma, S.; Hao, X.; Huang, X. Org. Lett. 2003, 5, 1217-1219. (b)
Ma, S.; Hao, X.; Meng, X.; Huang, X. J. Org. Chem. 2004, 69, 5720-
5724.
(5) (a) Ruitenberg, K.; Kleijn, H.; Elsevier, C. J.; Meijer, J.; Vermeer,
P. Tetrahedron Lett. 1981, 22, 1451-1452. (b) Elsevier, C. J.; Mooiweer,
H. H.; Kleijn, H.; Vermeer, P. Tetrahedron Lett. 1984, 25, 5571-5572. (c)
Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1985, 50, 3042-3045. (d)
Caporusso, A. M.; Polizzi, C.; Lardicci, L. J. Org. Chem. 1987, 52, 3920-
3923. (e) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 8214-
8219. (f) Caporusso, A. M.; Filippi, S.; Barontini, F.; Salvadori, P.
Tetrahedron Lett. 2000, 41, 1227-1230. (g) Trost, B. M.; Stiles, D. T.
Org. Lett. 2005, 7, 2117-2120. (h) Shen, L.; Hsung, R. P.; Zhang, Y.;
Antoline, J. E.; Zhang, X. Org. Lett. 2005, 7, 3081-3084. (h) Sromek, A.
W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500-
10501. (i) Caporusso, A. M.; Zampieri, A.; Aronica, L. A.; Banti, D. J.
Org. Chem. 2006, 71, 1902-1910. (j) Xu, L.; Huang, X.; Zhong, F. Org.
Lett. 2006, 8, 5061-5064.
R-Iodoenals and their derivatives have been used widely in
organic synthesis as a class of important building blocks.1 There
have been some investigations on the development of synthetic
methodologies of these R-iodo-substituted R,â-unsaturated car-
bonyl compounds.2 The majority of the synthetic routes to this
family of compounds involve key steps based on the halogen
exchange of vinyl bromides with iodide ion2b or R-iodination
of R,â-unsaturated carbonyl compounds.2g Considering the
limited methods available for their preparation, further develop-
ment of synthetically useful methodologies for R-iodoenals is
highly desirable.
(1) (a) Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Org.
Lett. 2003, 5, 2497-2500. (b) Bowman, W. R.; Bridge, C. F.; Brookes, P.;
Cloonan, M. O.; Leach, D. C. J. Chem. Soc., Perkin Trans. 1 2002, 58-
68. (c) Berteina, S.; De Mesmaeker, A.; Wendeborn. S. Synlett 1999, 1121-
1123. (d) Bowman, W. R.; Bridge, C. F.; Cloonan, M. O.; Leach, D. C.
Synlett 2001, 765-768. (e) Gagnier, S. V.; Larock, R. C. J. Org. Chem.
2000, 65, 1525-1529. (f) Negishi, E. J. Organomet. Chem. 1999, 576, 179-
194.
(2) (a) Smith, A. B., III; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J.
Org. Chem. 1982, 47, 1855-1869. (b) Suzuki, H.; Aihara, M.; Yamamoto,
H.; Takamoto, Y.; Ogawa, T. Synthesis 1988, 236-238. (c) Barluenga, J.;
Rodriguez, M. A.; Campos, P. J. J. Am. Chem. Soc. 1988, 110, 5567-
5568. (d) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B.
W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917-
918. (e) Coulomb, F.; Roumestant, M. L.; Gore, J. Bull. Soc. Chim. Fr.
1973, 3352-3359. (f) Antonioletti, R.; D’Auria, M.; Piancatelli, G.; Scettri,
A. Tetrahedron Lett. 1981, 22, 1041-1042. (g) Krafft, M. E.; Cran, J. W.
Synlett 2005, 1263-1266.
(6) For the oxidation of allenes, see: (a) Sakaguchi, S.; Watase, S.;
Katayama, Y.; Sakata, Y.; Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1994,
59, 5681-5686. (b) Ba¨ckvall, J. -E.; Jonasson, C. Tetrahedron Lett. 1997,
38, 291-294. (c) Jonasson, C.; Ba¨ckvall, J. -E. Tetrahedron Lett. 1998,
39, 3601-3604. (d) Jonasson, C.; Karstens, W. F. J.; Hiemstra, H.; Ba¨ckvall,
J. -E. Tetrahedron Lett. 2000, 41, 1619-1622. (e) Crandall, J. K.; Rambo,
E. Tetrahedron. 2002, 58, 7027-7036. (f) Piera. J.; Na¨rhi, K.; Ba¨ckvall, J.
-E. Angew. Chem., Int. Ed. 2006, 45, 6914-6917. (g) Lotesta, S. D.; Hou,
Y.; Williams, L. J. Org. Lett. 2007, 9, 869-872. (h) Shangguan, N.; Kiren,
S.; Williams, L. J. Org. Lett. 2007, 9, 1093-1096.
(7) (a) Nielsen, T. E.; Le Quement, S.; Tanner, D. Synthesis 2004, 1381-
1390. (b) Midland, M. M. J. Org. Chem. 1975, 40, 2250-2252.
10.1021/jo070230x CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/25/2007
J. Org. Chem. 2007, 72, 4993-4996
4993

TABLE 2. One-Pot Synthesis of r-Iodo-Substituted
r,â-Unsaturated Aldehydes 2a-k from Propargylic Alcohols 1a-k
SCHEME 1. Oxidation of Iodoallene
2a-k,
reaction
time (h)
yielda
(%)
entry
1a-k, Ar
1a, C6H5
1b, p-CH3C6H4
1c, o-CH3C6H4
1d, p-CH3OC6H4
1e, p-FC6H4
1f, p-C1C6H4
1g, o-BrC6H4
1h, p-PhC6H4
1i, trans-PhCH=CH-
1j,
1
2
3
4
5
6
7
8
9
4
4
4
2
4
2
4
14
3
1
2a, 68
2b, 66
2c, 70
2d, 61
2e, 71
2f, 53
2g, 58
2h, 54
2i, 50
2j, 40
SCHEME 2. One-Pot Synthesis of r-Iodoenals from
Propargylic Alcohols
10
11
1k,
1.5
2k, 48b
TABLE 1. Effect of Solvent on the One-Pot Synthesis of 2a
a Yields after column chromatographic purification with silica gel. b This
compound was isolated as a mixture of E and Z isomers.
reaction
time (h)
yielda
(%)
entry
solvent
PhCH3
1
2
3
4
5
6
4
6
7
7
4
4
68
<20
25
SCHEME 3. Reaction of 1l
THF
CH3OH
pentane
ClCH2CH2Cl
neat
28
30
b
a Yields after column chromatographic purification with silica gel. b 2a
was not formed. Instead, a small amount of 3a could be identified in the
course of the reaction.
ring could be tolerated, and the reaction gave moderate to good
overall yields of the products 3a-k. It was found that substrates
with a phenyl ring bearing an electron-donating group generally
gave slightly higher yields (Table 2, entries 2-4), while
substrates with an electron-withdrawing substituent on the
phenyl ring, such as halogen, gave moderately high yields
(entries 5-9). Moreover, it was noted that this approach was
also applicable to the substrates bearing heteroaromatic ring
substituents (entries 10 and 11). The stereoselectivities were
in the formation of iodoallene intermediate 3a.8,9 Without
separation of 3a, oxygen was then introduced carefully into the
organic phase of the reaction mixture at 50 °C for 4 h.
R-Iodoenal 2a was obtained in 68% isolated yield. The
configuration of the CdC bond in 2a was determined by the
NOE study.10 A trace amount of trans-cinnamaldehyde, which
was derived from Meyer-Schuster rearrangement,11 could be
1
1
detected from the crude products by a H NMR study.
examined by H NMR of the crude product. It was found that
To optimize the reaction conditions, we next carefully
examined the effect of the solvents on this one-pot reaction.
The results are summarized in Table 1. Toluene was found to
be the most suitable solvent for this transformation (Table 1,
entry 1), whereas a low yield of 2a was obtained when using a
polar solvent such as THF and methanol (entries 2 and 3). Other
solvents, such as pentane and ClCH2CH2Cl, could not improve
the yield of the reaction (entries 4 and 5). Interestingly, no
R-iodoenal 2a product was observed when the reaction was
carried out without solvent, although iodoallene 3a intermediate
was also formed under this condition (entry 6).
all the reactions only gave products with Z configuration, except
the reaction with 1k, in which a mixture of Z and E isomers
was obtained (entry 11).
When a substrate with a strong electron-withdrawing sub-
stituent, such as 1l, was employed in this reaction, no expected
R-iodoenal 2l could be obtained. Instead, the diiodo product 4
was isolated in 60% yield under identical reaction conditions
(Scheme 3). This may be attributed to the destabilization effect
of the p-nitrophenyl group for the generation of propargylic
cation, which is assumed an intermediate in the formation of
iodoallene. The addition of I2, which can be generated from
iodide through oxidation by O2, to the triple bond affords the
diiodo product 4.
The scope of the reaction under optimized conditions is
summarized in Table 2. Various substitutions on the aromatic
Besides, it has been noted that this method is also applicable
to the alkyl-substituted tertiary propargylic alcohols, albeit with
slightly low yields (Scheme 4). For propargylic alcohol 7, the
reaction gave an E and Z mixture of R-iodoenals with low
selectivity. For secondary alcohol, it was observed that the
reaction under identical conditions gave a diiodide product.
Because bromoallene could also be generated when propar-
gylic alcohol was treated with aqueous HBr,8 naturally it was
conceivable that this method might be extended to the prepara-
tion of R-bromo-substituted R,â-unsaturated aldehydes. When
propargylic alcohol 1a was subjected to aq HBr, followed by
treatment with molecular oxygen at 50 °C, the expected
R-bromo-substituted R,â-unsaturated aldehyde 9 was indeed
(8) For the preparation of haloallenes, see: (a) Montury, M.; Gore, J.
Synth. Commun. 1980, 10, 873-879. (b) Elsevier, C. J.; Meijer, J.; Tadema,
G.; Stehouwer, P. M.; Bos, H. J. T.; Vermeer, P.; Runge, W. J. Org. Chem.
1982, 47, 2194-2196. (c) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1984,
49, 1649-1650. (d) Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W.
J. Org. Chem. 1985, 50, 364-367. (e) Jayanth, T. T.; Jeganmohan, M.;
Cheng, M. J.; Chu, S. Y.; Cheng, C. H. J. Am. Chem. Soc. 2006, 128,
2232-2233.
(9) The reaction of 1a with (TMS)Cl-NaI in CH3CN between 0 °C and
room temperature resulted in a complex mixture; no allene products could
be identified.
(10) For the details of the NOE experiment, see the Supporting
Information.
(11) For a review on Meyer-Schuster rearrangement, see: Swaminathan,
S.; Narayanan, K. V. Chem. ReV. 1971, 71, 429-438.
4994 J. Org. Chem., Vol. 72, No. 13, 2007

SCHEME 4. Reaction of Alkyl-Substituted Propargylic
Alcohol
SCHEME 7. Proposed Mechanism
SCHEME 8. One-Pot Reaction from Aldehydes
SCHEME 5. Synthesis of r-Bromoenal
product could be identified in this reaction. These experiments
obviously do not support the proposed reaction mechanism.
An alternative mechanism involving radical intermediates is
then proposed (Scheme 7). Thus, allenyl radical 12 is generated
upon heating 3a in toluene. In the presence of molecular oxygen,
iodoperoxide 13 is generated, which is then converted to carbon
radical 14 through homolytic cleavage of the O-O bond. Carbon
radical 14 is finally trapped by an iodine atom or molecular
iodine to afford R-iodoenal 2a. To prove this radical reaction
mechanism, we introduced TEMPO to the system to trap the
radical intermediate. The reaction became very sluggish in the
presence of TEMPO and resulted in a complex mixture.
Addition of Bu3SnH to the reaction also gave a complex mixture
with the formation of a trace amount of cinnamaldehyde.
Although these observations seem to favor a radical mechanism,
further experiments will be needed to firmly establish the
reaction mechanism.13
Finally, a one-pot transformation of three-step reactions from
aldehydes to R-iodoenals directly was explored. Thus, aldehydes
15-17 were treated with ethynylmagnesium bromide in anhy-
drous toluene at 0 °C. After completion of the addition, the
mixture was quenched with aqueous HI, followed by careful
introduction of O2 into the organic phase at 50 °C for several
hours. After workup, the R-iodoenals 2a, 2b, and 2e were
isolated in 45%, 59%, and 60% overall yields, respectively
(Scheme 8). It was again noted that a small amount of Meyer-
Schuster rearrangement products was detected in all cases.
In conclusion, we have described an efficient one-pot
procedure for the preparation of R-iodo-substituted R, â-unsat-
urated aldehydes from easily available propargylic alcohols by
reaction with aqueous HI and molecular O2. This one-pot
transformation provides a convenient, inexpensive, and efficient
method for the preparation of various R-iodoenals.
SCHEME 6. Mechanistic Studies
isolated (Scheme 5). However, the yield of 9 was only 23%.
The diminished yield could be attributed to the low reactivity
of bromoallene intermediate 10.
A possible reaction mechanism to account for the formation
of R-iodoenal is shown in Scheme 6. In the presence of O2, HI
may be oxidized to give hypoiodous acid, HOI.12 HOI adds to
the iodoallene intermediate 3a, which was generated in situ by
the reaction of propargylic alcohol with aqueous HI, to give
the diiodide intermediate 11. Subsequent elimination of HI
affords R-iodoenal 2a. To substantiate this mechanism, we
prepared the hypothesized diiodide intermediate 11 according
to a literature procedure by the reaction of 3a with H5IO6/
NaHSO3 in CH3CN-H2O.12b Diiodide 11 was found to be a
stable compound. When it was heated in toluene at 70 °C for a
long time in the presence of O2 or I2, no reaction occurred and
the starting materials were recovered. To examine whether HOI
was generated in our reaction, styrene was subjected to the
reaction conditions (aq HI, O2, 50 °C in PhCH3) since HOI is
known to add to an alkene readily.12b-e However, no iodohydrin
Experimental Section
General Procedure for the One-Pot Synthesis of r-Iodoenals.
To a solution of propargyl alcohol (100 mg) in toluene was added
aqueous HI (2 mL) at room temperature. After 5 min, O2 gas was
(12) (a) Walker, N.; Tevault, D. E.; Smardzewski, R. R. J. Chem. Phys.
1978, 69, 564-568. (b) Masuda, H.; Takase, K.; Nishio, M.; Hasegawa,
A.; Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1994, 59, 5550-5555. (c)
Asensio, G.; Andreu, C.; Boix-Bernardini, C.; Mello, R.; Gonza´lez-Nun˜ez,
M. E. Org. Lett. 1999, 1, 2125-2128. (d) LeBlond, C. R.; Rossen, K.;
Gortsema, F. P.; Zavialov, I. A.; Cianciosi, S. J.; Andrews, A. T.; Sun, Y.
Tetrahedron Lett. 2001, 42, 8603-8606. (e) De Corso, A. R.; Panunzi, B.;
Tingoli, M. Tetrahedron Lett. 2001, 42, 7245-7247.
(13) One of the reviewers has suggested other pathways that do not
involve the departure of the iodide. These pathways provide a rationale for
the observed Z selectivity of the products. See the Supporting Information.
We thank the reviewer for the suggestions on the reaction mechanism.
J. Org. Chem, Vol. 72, No. 13, 2007 4995

introduced carefully into the organic phase, and the mixture was
stirred for several hours at 50 °C. The progress of the reaction was
monitored by TLC. After completion of the reaction, the resulting
solution was extracted with toluene three times, and the combined
organic phase was washed with concentrated Na2S2O3 and NaHCO3
and then dried over Na2SO4. After removal of the solvent under
vacuum, the crude product was purified by column chroma-
tography.
with concentrated Na2S2O3 and NaHCO3 and then dried over
anhydrous Na2SO4. After removal of the solvent under vacuum,
the crude product was purified by column chromatography.
Data for (Z)-2-iodo-3-phenylacrylaldehyde (2a):2b yield 68%;
IR (neat) 1686, 1591 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.49-
7.54 (m, 3H), 8.00-8.04 (m, 2H), 8.11 (s, 1H), 8.80 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 105.8, 128.6, 130.4, 131.6, 134.0, 155.8,
189.0; EI-MS (m/z, relative intensity) 258 (M+, 100), 131 (31).
Typical Procedure for the Three-Step One-Pot Synthesis of
2a, 2b, and 2e from Aldehydes. Under a nitrogen atmosphere,
ethynylmagnesium bromide (1 mmol) was added via syringe to a
solution of aldehyde (0.5 mmol) in dry toluene (6 mL) at 0 °C.
After the resulting solution was stirred for 10 min, aqueous HI (5
mL) was introduced at the same temperature. Then O2 was
introduced carefully to the organic phase, and the mixture was
stirred for several hours at 50 °C. The progress of the reaction was
monitored by TLC. The resulting solution was extracted with
toluene three times, and the combined organic phase was washed
Acknowledgment. This project is generously supported by
the Natural Science Foundation of China (Grant Nos. 20572002
and 20521202) and the Ministry of Education of China.
Supporting Information Available: Characterization data and
1H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO070230X
4996 J. Org. Chem., Vol. 72, No. 13, 2007