Iodine(III)-mediated umpolung of bromide salts for the ethoxybromination of enamides

Article abstract of DOI:10.1021/ol400453b

Using (diacetoxyiodo)benzene in conjunction with simple bromide salts in ethanol allows the regioselective ethoxybromination of a wide range of enamides, thus yielding highly versatile α-bromo hemiaminals, which can then be engaged in a broad array of transformations.

Full text of DOI:10.1021/ol400453b

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iodine(III)-Mediated Umpolung of Bromide
Salts for the Ethoxybromination
of Enamides
Sophie Nocquet-Thibault, Pascal Retailleau,† Kevin Cariou, and Robert H. Dodd*
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles,
CNRS, 91198 Gif-sur-Yvette Cedex, France
robert.dodd@icsn.cnrs-gif.fr
Received February 18, 2013
ABSTRACT
Using (diacetoxyiodo)benzene in conjunction with simple bromide salts in ethanol allows the regioselective ethoxybromination of a wide range of
enamides, thus yielding highly versatile R-bromo hemiaminals, which can then be engaged in a broad array of transformations.
In recent years, polyvalent iodine compounds have been at
the center of tremendous activity and research develop-
ments.1 Of special interest are iodine(III) compounds such
as Koser’s reagent2 and (diacetoxyiodo)benzene (PIDA).1,2
One of the particular characteristics of these compounds
is that they behave in a similar fashion to transition-metal
complexes.3 Indeed, around the central iodine atom, ligands
can be exchanged and then transferred through a formal
reductive elimination. In this context, halides can be used
as ligands, in which case an umpolung of the salt4 can
occur to give birth to electrophilic halogen species. Several
combinations of alkali or metal halide salts and hypervalent
iodine(III) derivatives have previously been studied and
reacted with substrates such as carbonyls,5 electron-rich
arenes,6 olefins,7 and even aliphatic CH bonds.8
We have recently explored the reactivity of enamides 1
toward nitrenoids generated from iodine(III) species,
namely iminoiodanes, in the presence of a nucleophile.9a
This set of reaction conditions allowed the oxidative
difunctionalization of the enamide to give the correspond-
ing amino hemiaminal in a completely regio- and stereo-
selective manner (Scheme 1, eq 1).
Extrapolating from this, we reasoned that subjecting the
same type of enamide to a combination of a halide source
and iodobenzene diacetate,10 we could in turn obtain an
R-bromo hemiaminal, which would constitute a highly
versatile synthon for further transformations (Scheme 1,
eq 2).11 Moreover, the low toxicity of iodine(III) derivatives1
and their potential for asymmetric transformations12 led
us to consider that this strategy would provide a valuable
† P.R. ran the X-ray crystallography experiments.
(7) (a) Fabry, D. C.; Stodulski, M.; Hoerner, S.; Gulder, T. Chem.;
Eur. J. 2012, 18, 10834. (b) Pandit, P.; Gayen, K. S.; Khamarui,
S.; Chatterjee, N.; Maiti, D. K. Chem. Commun. 2011, 47, 6933.
(c) Yu, L.; Ren, L.; Yi, R.; Wu, Y.; Chen, T.; Guo, R. Synlett 2011,
579. (d) Sanjaya, S.; Chiba, S. Tetrahedron 2011, 67, 590. (e) Katrun, P.;
Chiampanichayakul, S.; Korworapan, K.; Pohmakotr, M.; Reutrakul,
V.; Jaipetch, T.; Kuhakarn, C. Eur. J. Org. Chem. 2010, 5633. (f) Wu, T.;
Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16355. (g) Fan, R.; Wen,
F.; Qin, L.; Pu, D.; Wang, B. Tetrahedron Lett. 2007, 48, 7444. (h) Liu,
H.; Tan, C.-H. Tetrahedron Lett. 2007, 48, 8220. (i) Emmanuvel, L.;
Shaikh, T. M. A.; Sudala, A. Org. Lett. 2005, 7, 5071. (j) Braddock,
D. C.; Cansell, G.; Hermitage, S. A. Synlett 2004, 461. (k) Hashem,
M. A.; Jung, A.; Ries, M.; Kirschning, A. Synlett 1998, 195.
(8) (a) McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S. Org. Lett.
2012, 14, 4094. (b) Dohi, T.; Takenaga, N.; Goto, A.; Maruyama, A.;
Kita, Y. Org. Lett. 2007, 9, 3129.
(9) (a) Nakanishi, M.; Minard, C.; Cariou, K.; Retailleau, P.; Dodd,
R. H. Org. Lett. 2011, 13, 5792. (b) For a related reaction using Rh
catalysts, see: Gigant, N.; Dequirez, G.; Retailleau, P.; Gillaizeau, I.;
Dauban, P. Chem.;Eur. J. 2012, 18, 90.
(1) (a) Brown, M.; Farid, U.; Wirth, T. Synlett 2013, 424. (b)
Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (c) Wirth,
T. Angew. Chem., Int. Ed. 2005, 44, 3656. (d) Zhdankin, V. V.; Stang,
P. J. Chem. Rev. 2002, 102, 2523. (e) Varvoglis, A. Tetrahedron 1997, 53,
1179. (f) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(2) Koser, G. F. Aldrichimica Acta 2001, 34, 89.
(3) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893.
(4) For another strategy using sulfoxides, see: Klimczyk, S.; Huang,
ꢀ
X.; Fares, C.; Maulide, N. Org. Biomol. Chem. 2012, 10, 4327.
(5) (a) Liu, W. L.; Chen, C.; Zhang, Q.; Zhu, Z.-B. Beilstein J. Org.
Chem. 2012, 8, 344. (b) Lee, J. C.; Park, J. Y.; Yoon, S. Y.; Bae, Y. H.;
Lee, S. J. Tetrahedron Lett. 2004, 45, 191. (c) Akula, R.; Galligan, M.;
Ibrahim, H. Chem. Commun. 2009, 45, 6991. (d) Coats, S. J.; Wasserman,
H. H. Tetrahedron Lett. 1995, 36, 7735.
(6) (a) Tu, D.; Ma, L.; Tong, X.; Deng, X.; Xia, C. Org. Lett. 2012, 14,
4830. (b) Hamamoto, H.; Hattori, S.; Takemaru, K.; Miki, Y. Synlett.
2011, 1563. (c) Hamamoto, H.; Umemoto, H.; Umemoto, M.; Ohta, C.;
Dohshita, M.; Miki, Y. Synlett 2010, 2593. (d) Braddock, D. C.; Cansell,
G.; Hermitage, S. A. Synlett 2004, 461.
r
10.1021/ol400453b
XXXX American Chemical Society

Table 1. Optimization of Reaction Conditions
Scheme 1. Initial Endeavor
temp
t
R, yielda
(%)
entry
X
solvent (°C) (min)
misc
1
2
3
4
5
6
7
8
9
1.8 MeCN
1.4 MeCN
1.4 MeCN
1.4 MeCN
1.4 EtOH
1.4 EtOH
1.1 EtOH
1.2 EtOH
1.2 EtOH
rt
rt
70
10
10
10
10
20
90
25
no MS
MS
Ac, 59
Ac, 72
rt
5 equiv of EtOH Et, 85b
10 equiv of EtOH Et, 95c
rt
alternative to the use of anodic oxidation of bromides,13
toxic bromine,14 or NBS,15which furthermore, have so far
been mostly limited to cyclic enamide derivatives.16
rt
dr 80/20
Et,100d
Et, 91
0
dr 83/17
e
0
Et, 86
0
dr 87/13
Et, 97
Et, 100d
We started byreacting tosyl enamide 1awithanexcessof
iodobenzene diacetate in the presence of a 2-fold amount
of lithium bromide in dry acetonitrile. The lithium salt was
chosen because, as an alkali halide, it is cheap and widely
available and also exhibits a better solubility than other
alkali salts in organic solvents. Under these conditions,
there is no external nucleophile other than the acetate,
which is liberated by reaction of the iodobenzene diacetate
and is regioselectively incorporated in the final product
(Table 1, entry 1). However, this product could only be
isolated in moderate yield (as a mixture of two diastereo-
isomers in a 4:1 ratio) because of the low stability of the
acetoxy hemiaminal moiety.
ꢀ20
20 h dr 88/12
a Isolated yields after chromatography on silica gel unless otherwise
mentioned. b Conversion determined by 1H NMR, along with 15%
of R = Ac. c Conversion determined by 1H NMR, along with 5% of
R = Ac. d Conversion determined by 1H NMR. e 10 mol % of PIDA and
20 mol % of LiBr were added after 60 min.
group, ethanol was added as an external nucleophile but
competitive addition of the acetate was still observed
(entries 3 and 4). Finally, complete chemoselectivity in
favor of ethoxy products was obtained by using ethanol
as the solvent (entry 5). Lowering the temperature to 0 °C
increased the diastereoselectivity, and the optimal amount
of reagents was found to be 1.2 equiv of PIDA and
2.4 equiv of lithium bromide, which efficiently provided
97% of the desired product 3a with a 87:13 diastereomeric
ratio (entries 6ꢀ8). Diminishing the temperature further
to ꢀ20 °C only increased the reaction time without any
real improvement of the diastereoselectivity (entry 9).
The relative configuration of the major diastereoi-
somer was attributed from the X-ray data obtained
for ethoxy-3a (Figure 1) which was further confirmed
from the X-ray data obtained for compound 3p (see
Table 2).
Adding molecular sieves to the reaction mixture allowed
shorter reaction times while improving the yield to some
extent (entry 2), but the stability of the adduct remained
an issue. Assuming this problem was due to the acetoxy
(10) For metal-free reactions involving enamides and (diacyloxyiodo)-
benzenes, see: (a) Zhao, F.; Liu, X.; Qi, R.; Zhang-Negrerie, D.; Huang, J.;
Du, Y.; Zhao, K. J. Org. Chem. 2011, 76, 10338. (b) Yu, W.; Du, Y.; Zhao,
K. Org. Lett. 2009, 11, 2417. (c) Huang, X.; Shao, N.; Huryk, R.; Palani, A.;
Aslanian, R.; Seidel-Dugan, C. Org. Lett. 2009, 11, 867. (d) Shao, N.;
Huang, X.; Palani, A.; Aslanian, R.; Buevich, A.; Piwinski, J.; Huryk, R.;
Seidel-Dugan, C. Synthesis 2009, 2855. (e) Huang, X.; Shao, N.; Palani, A.;
Aslanian, R.; Buevich, A. Org. Lett. 2007, 9, 2597. (f) Huang, X.; Shao, N.;
Palani, A.; Aslanian, R. Tetrahedron Lett. 2007, 48, 1967.
(11) An illustration of this versatility, for cyclic R-iodo-hemiaminals,
can be found in: (a) Norton Matos, M. R. P.; Afonso, C. A.; Batey, R. A.
Tetrahedron 2001, 61, 1221. (b) Norton Matos, M. R. P.; Afonso,
C. A. M.; McGarvey, T.; Lee, P.; Batey, R. A. Tetrahedron Lett. 1999,
40, 9189.
(12) (a) Farid, U.; Wirth, T. In Asymmetric Synthesis II; Christmann,
€
M., Brase, S., Eds.; Wiley-VCH: Weinheim, 2012; pp 197ꢀ203. (b) Liang,
H.; Ciufolini, M. A. Angew. Chem., Int. Ed. 2011, 50, 11849. (c) Uyanik,
M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1376.
(13) (a) Shono, T.; Matsumura, Y.; Onomura, O.; Ogaki, M.;
Kanazawa, T. J. Org. Chem. 1987, 52, 536. (b) Shono, T.; Matsumura,
Y.; Ogaki, M.; Onomura, O. Chem. Lett. 1987, 1447.
(14) (a) Kelleher, S.; Quesne, P.-Y.; Evans, P. Beilstein J. Org. Chem.
200910.3762/bjoc.5.69. (b) Sugiura, M.; Asai, K.; Hamada, Y.; Hatano, K.;
Kurono, Y.; Suezawa, H.; Hirota, M. Chem. Pharm. Bull. 1997, 45, 928. (c)
Shono, T.; Matsumura, Y.; Onomura, O.; Yanada, Y. Tetrahedron Lett.
1987, 28, 4073.
(15) (a) Le Corre, L.; Kizirian, J.-C.; Levraud, C.; Boucher, J.-L.;
Bonnet, V.; Dhimane, H. Org. Biomol. Chem. 2008, 6, 3388. (b) Levraud,
C.; Calvet-Vitale, S.; Bertho, G.; Dhimane, H. Eur. J. Org. Chem. 2008,
1901.
Figure 1. ORTEP drawings for OEt-3a and 3p.
(16) For acyclic enamines, see: (a) Alix, A.; Lalli, C.; Retailleau, P.;
ꢂ
With this set of optimized conditions in hand, we went
on to probe the scope of the reaction. First, varying the
ꢁ
ꢁ
Masson, G. J. Am. Chem. Soc. 2012, 134, 10389. (b) Jokic, M.; Skaric, V.
Tetrahedron Lett. 1994, 35, 2937.
B
Org. Lett., Vol. XX, No. XX, XXXX

sulfonamide protecting group had only a small influence
on the course of the reaction (Table 2, 1aꢀd) though the
tosyl group was the most satisfying in terms of yield and
diastereoselectivity. The slight variations in the diastereo-
isomeric ratio are consistent with steric effects, while
the more electron-withdrawing nosyl group only caused a
moderatelossinefficiency. Moreover, comparison between
the 1H NMR spectra of the various R-bromo hemiaminals
obtained and 3a showed that the major diastereoisomer
was the same in all cases. Replacement of the phenyl by a
p-methoxyphenyl, a benzyl, an allyl, or a methyl group
(1eꢀh) ledto incrementalimprovementsofthedr, probably
due to subtle variations of the steric hindrance. It is
noteworthy that this reaction proved to be highly chemo-
selective, as neither the electron-rich anisyl6 (1e) nor the
allyl7 (1g) moieties were affected in this transformation. On
the other hand, switching from a sulfonamide to an amide
or a carbamate proved highly detrimental. Indeed, when
submitted to the reaction conditions, N-Ac compounds
only gave a complex mixture (1i,j). This phenomenon was
slightly lesspronounced forN-Boc substrates, in which case
the formation of the desired product could be observed
before it decomposed (1k,l). When differently function-
alized substrates such as (E)-2-aminoacrylates were sub-
jected to the same reaction conditions (1mꢀp), the dr
were consistently above the 90/10 threshold (as observed
for the crude material, the adducts were often isolated as a
single diastereoisomer) and the yields remained excellent,
with the major isomer corresponding to that obtained for
(E)-2-aminostyrenes (as evidenced by the X-ray analysis
of 3p, Figure 1). In contrast, the Z isomers gave the desired
product in lower yields and with almost no diastereoselec-
tivity (1q,r). Finally, it should be noted that, despite the
oxidative nature of the reaction conditions, free alcohols
are tolerated and give the corresponding adducts with
moderate yields but excellent diastereoselectivities (1s,t).
The strong discrepancy observed between the reactivity
of the E and Z isomers raised a few questions concerning
the mechanism of this transformation. First, at this stage,
the exact nature of the electrophile remains conjectural.
In the presence of bromide ions a series of equilibria
could take place between iodobenzene diacetate and
iodobenzene dibromide 5 through the mixed species 4
(Scheme 2).5ꢀ8,18 For both in situ generated iodine(III)
reagents a reductive elimination can take place, producing
acetyl hypobromite or bromine. Formally, all four species
can be considered as Brþ sources for the reaction.
Table 2. Substrate Scope for the Ethoxybromination17
s.m.
R
PG
Ts
R0
t (min)
dra
yieldb (%)
1a
1b
1c
1d
1e
1f
Ph
Ph (E)
25
30
40
25
60
20
50
20
50
40
30
45
120
150
90
40
60
45
30
90
87/13
83/17
76/24
92/8
97
Ph
Ph
Ph
PhSO2 Ph (E)
88
Ms
Ns
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
89
81c
71d
88c
89
PMP Ts
Bn Ts
Allyl Ts
77/23
83/17
90/10
92/8
1g
1h
1i
Me
Ph
Bn
Ph
Bn
PhSO2 Ph (E)
89
Ac
Ph (E)
N.D.
N.D.
79/21
71/29
92/8
c.m.
c.m.
49e
N.D.
79e
73e
55e
74
1j
Ac
Ph (E)
1k
1l
Boc
Boc
Ph (E)
Ph (E)
1m PMP Ts
CO2Me (E)
CO2Me (E)
CO2Me (E)
CO2Me (E)
CO2Me (Z)
CO2Me (Z)
CH2OH (E)
CH2OH (E)
1n
1o
1p
1q
1r
1s
1t
Bn
Bn
Ts
92/8
Ns
92/8
Allyl Ts
Bn Ts
Allyl Ts
Bn Ts
Allyl Ts
91/9
52/48
55/45
92/8
52
65
60e,f
46f
92/8
a Calculated by 1H NMR analysis of the crude material. N.D. = not
determined. b Isolated yields after chromatography on silica gel. c.m. =
complex mixture. c Reaction run with 1.4 equiv of PIDA and 2.8 equiv
of LiBr. d 10 mol % of PIDA and 20 mol % of LiBr were added
after 30 min. e Isolated as a single diastereoisomer. f Reaction run with
1.2 equiv of PIDA and 4.5 equiv of LiBr on a 1 mmol scale.
Scheme 2. Generation of the Electrophilic Species
Depending on the various stereoelectronic effects at
play, one form might be favored over the other, thus
influencing the final diastereoselective ratio as the addition
of the external nucleophile (ethanol) would proceed
through an SN2 and/or SN1 type mechanism. Indeed,
(Z)-enamide would give rise to cis-6 in which unfavorable
1,2 steric interaction would displace the equilibrium to-
ward the iminium and therefore cause a drastic lowering
of the diastereoselectivity (as was observed for substrates
1q,r). Lastly, it should be pointed out that the X-ray data
for the major stereoisomer (both for R0 = Ph, 3a and for
R0 = CO2Me, 3p) are consistent with an SN2-type opening
of bromonium trans-6a by ethanol.
We then assume that the reaction between the enamide 1
and the electrophilic bromonium species (whatever its
exact nature) would stereospecifically lead to bridged
bromonium 6, which would be in equilibrium with imi-
nium 7 (Scheme 3).
(17) dr were calculated using 1H NMR analysis of the crude material.
The slightly higher values reported in the Supporting Information
correspond to isolated products.
(18) For the isolation and characterization of such compounds, see:
(a) Braddock, D. C.; Cansell, G.; Hermitage, S. A.; White, A. J. P. Chem.
Commun. 2006, 1442. (b) Amey, R. L.; Martin, J. C. J. Org. Chem. 1979,
44, 1779.
As already stated, these R-bromo hemiaminals are
highly versatile synthons, and so we went on to probe their
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Mechanistic Proposal
Scheme 4. Exploiting the Versatility of the Adductsa
behavior in several transformations. First, using a Lewis
acid such as boron trifluoride etherate allows the regenera-
tion of iminium 7 (and putatively bromonium 6) and the
subsequent addition of soft nucleophiles such as triethylsi-
lane and allyltrimethylsilane (Scheme 4). Both reduction
and allylation proceed smoothly to give R-bromo amines
(8 and 9) inmoderate togood yields (unoptimized) and asa
single diastereomer for 9a and 9b. Diallylic compound 9b
could be elaborated further by Grubbs’ second-generation
catalyst-triggered ring-closing metathesis, which yielded
the corresponding tetrahydropyridine 10 quantitatively.
The bromo moiety could also be exploited. Simple treat-
ment of the free alcohols 3s and 3t with sodium hydroxide
cleanly afforded R-amino epoxides 11a and 11b. N-Allyl
substrate 8b could be cyclized under either palladium-
catalyzed19 or radical-initiatedconditions togive two types
of substituted pyrrolidines 12 and 13, respectively.
In summary, using a combination of PIDA and lithium
bromide in ethanol enabled the regioselective alkoxybro-
mination of variously substituted enamide derivatives with
excellent yield and selectivity. The resulting R-bromo
hemiaminals could then be elaborated further using various
strategies ranging from radical to transition-metal-catalyzed
transformations. Efforts toward the development of an
a The relative configuration of compounds 9a, 9b, 10, 11a, and 11b,
isolated as single diastereoisomers, could not be ascertained.
asymmetric variant of this transformation and its use for
the synthesis of biologically relevant targets are currently
underway in our laboratory.
Acknowledgment. We thank the Institut de Chimie des
Substances Naturelles for financial support and a fellow-
ꢁ
ship (S.N.-T.) We also thank Dr. Geraldine Masson (ICSN)
for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and characterization of compounds. This materi-
al is available free of charge via the Internet at http://
pubs.acs.org.
(19) Zhou, W.; An, G.; Zhang, G.; Han, J.; Pan, Y. Org. Biomol.
Chem. 2011, 9, 5833. In this paper, the authors report the formation of
the sole endo isomer with 86% yield from the same starting compound.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX