Indium-mediated allylation of aldehydes, ketones and sulfonimines with 2-(alkoxy)allyl bromides

Article abstract of DOI:10.1016/j.tetlet.2010.08.064

2-(Alkoxy)propenyl bromides are readily prepared from 1,3-dibromo-2- propanol in a two-step sequence involving hydroxyl protection and sodium hydride-induced dehydrobromination. Indium-mediated allylation of aldehydes, ketones, and sulfonimines with 2-(alkoxy)propenyl bromides furnishes the corresponding homoallylic alcohols and sulfonamines in good yields. The products can be easily transformed into β-hydroxy ketones and esters, as well as substituted dihydropyrans, and protected β-amino acids. Chiral 2-(alkoxy)propenyl halides, derived from (-)-menthol and d-glucal, furnish diastereomerically enriched products.

Full text of DOI:10.1016/j.tetlet.2010.08.064

Tetrahedron Letters 51 (2010) 5609–5612
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium-mediated allylation of aldehydes, ketones and sulfonimines with
2-(alkoxy)allyl bromides
⇑
Heemal Dhanjee, Thomas G. Minehan
Department of Chemistry and Biochemistry, California State University, Northridge, 18111 Nordhoff Street, Northridge, CA 91330, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(Alkoxy)propenyl bromides are readily prepared from 1,3-dibromo-2-propanol in a two-step sequence
involving hydroxyl protection and sodium hydride-induced dehydrobromination. Indium-mediated ally-
lation of aldehydes, ketones, and sulfonimines with 2-(alkoxy)propenyl bromides furnishes the corre-
sponding homoallylic alcohols and sulfonamines in good yields. The products can be easily
transformed into b-hydroxy ketones and esters, as well as substituted dihydropyrans, and protected b-
Received 1 August 2010
Revised 18 August 2010
Accepted 18 August 2010
Available online 24 August 2010
amino acids. Chiral 2-(alkoxy)propenyl halides, derived from (À)-menthol and
D-glucal, furnish diaste-
reomerically enriched products.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
the electrophilic properties8 of this reagent but rather in its potential
toforman allylnucleophileuponexposureto indiummetal.10 Totest
this hypothesis, we decided to prepare MEM derivative 3-bromo-2-
((2-methoxyethoxy)methoxy)propene (3) and investigate its reac-
tivity with aldehydes and ketones in the presence of indium metal.
Exposure of 1,3-dibromo-2-propanol to MEM-Cl9 (1.5 equiv), i-
Pr2NEt (2 equiv), and TBAI (10 mol %) in CH2Cl2 for 36 h gave rise to
The indium-mediated allylation of aldehydes and ketones is a
powerful and stereoselective method for carbon–carbon bond forma-
tion useful in organic synthesis.1 The reaction takes place successfully
in a variety of solvents including water, with allylindium(III) sesqui-
halide intermediates likely for processes occurring in organic sol-
vents2 and allylindium(I) species likely for processes occurring in
aqueous media.1e The allylation reaction has been applied to the syn-
thesis of a variety of complex products and tandem or sequential in-
dium-mediated carbon–carbon bond-forming reactions have been
shown to be especially useful in this regard.3
1,3-dibromo-2-((2-methoxyethoxy)methoxy)propane
2 in 60%
yield. Addition of a DMF solution of 2 to NaH (2.2 equiv) in DMF
at 0 °C, followed by warming to room temperature, furnished bro-
mide 3 in 72% yield. This substance was not purified but used di-
rectly in allylation reactions. It was subsequently found that
trace amounts of water in the DMF solvent employed for the prep-
aration of 3 from 2 gave rise to allylic alcohol 4, which proved dif-
ficult to separate from allylation products 5 (vide infra). The
formation of this byproduct could be completely avoided by stor-
ing the DMF used for the dehydrobromination reaction over acti-
vated 4 Å molecular sieves for several days prior to use. It is
worthy of note that 1,3-dibromo propanol derivatives bearing
non-acetal-type protecting groups (e.g., methyl or menthyl ether)
undergo dehydrobromination with NaH in only very poor yields
(<10%) at room temperature.
The reaction of 3 with representative aldehydes and ketones in
the presence of indium metal is presented in Table 1. The optimal
solvent for the reaction was DMF; reactions performed in THF were
slower, and as previously shown by Saicic,10 mixtures of THF and
water produced b-hydroxyketone 6 (Scheme 2) as the main prod-
uct, presumably formed via hydrolysis of the enol ether functional-
ity of 5 due to the rising acidity5 of the reaction medium as the
reaction progresses. Tetra-n-butylammonium iodide or sodium
iodide (1 equiv) was found to be an important additive necessary
for increasing the reactivity of 3 toward aldehydes and ketones,
A variety of 2-substituted allyl halides have been employed with
great utility in aldehyde and ketone allylation reactions. For
example, it has been shown that 2-(carboxyalkyl)-substituted allyl
halides are useful reagents for the indium-mediated synthesis of
a
-methylene-c
-butyrolactones.4 Furthermore, 2-(trimethylsilyl-
methyl)allyl halides have been employed in the one-pot preparation
of 2,6-disubstituted tetrahydropyrans5 and oxa-bridged seven- and
eight-membered carbocycles6 via indium-mediated allylation of
mono- and dicarbonyl compounds, respectively, in aqueous media.
In this Letter we wish to report our studies on the preparation and
indium-mediated reactions of 2-(alkoxy)allyl halides.
Horning has shown that 3-bromo-2-(tetrahydropyranyloxy)pro-
pene, prepared by sodium hydride-induced elimination of hydrogen
bromide from 1,3-dibromo-2-(tetrahydropyran-2-y1oxy)propane,
is a useful ‘masked’ acetonyl bromide equivalent, reacting with a
variety of carbon nucleophiles to generate products containing
new carbon–carbon bonds (Scheme 1).7 We were interested not in
⇑
Corresponding author. Tel.: +1 818 677 3315; fax: +1 818 677 4068.
E-mail address: thomas.minehan@csun.edu (T.G. Minehan).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.064

5610
H. Dhanjee, T. G. Minehan / Tetrahedron Letters 51 (2010) 5609–5612
Na
CO2Et
Ph
Ph
OTHP
NaH
DMF
OTHP
OTHP
Ph
Ph
(a)
(b)
Br
Br
Br
Br
Br
CO2Et
1
OMEM
OMEM
OH
MEM-Cl
NaH, DMF
X
Br
Br
i-Pr2NEt, CH2Cl2
TBAI, 36h
60%
0°C-rt
72%
2
3 X=Br
4 X=OH
Scheme 1. (a) Horning’s preparation of 1 and its utility as an electrophile. (b) Preparation of MEM derivative 3.
Table 1
1:1 THF/sat. NH4Cl
cat. 6N HCl
O
OH
Scope of indium-mediated allylation of aldehydes and ketones with 3a
R1
R2
R1=Ph,R2=H: 90%
15 min, 25°C
H3C
O
OMEM
OMEM
OH
In(0), DMF
6
+
R1
R2
Br
TBAI, 25°C
MS 4Å
4-6 h
R1
R2
OH
OMEM
O
OH
O3, DMS
5
3
R1
R2
R1
R2
CH2Cl2, CH3OH
MEMO
5
Entry
R1
R2
5
% Yield 5
R1=C5H11, R2=H: 95%
CH3
7
1
2
3
H
H
H
a
b
c
87
91
68
1. NaH, allyl bromide
DMF
O
OMEM
R1
R2
2.
H3C
N
N
Mes
Cl
4
5
H
H
d
e
61
65
Mes
9
Ph
R1=Ph, R2=H: 66%
8
C6H5
Ru
Cl
PCy3
O
7 mol%
78b
toluene, 70°C
OTHP
6
H
f
O
H3C
CH3
6 mol% 9
10 mol% BQ
1. acetone, In(0)
DMF. TBAI
7
8
CH3
CH3
CH3
g
92
89
O
O
CH3
CH3
1
CH3
CH3
h
toluene
THPO
2. KHMDS, allyl bromide
THF, 60°C, 3h
70°C, 1h
10 60%
11 98%
a
Reaction conditions: 3 (2 equiv) aldehyde or ketone (1 equiv), TBAI (1 equiv)
and indium metal (1.5 equiv) combined in DMF (2 M) and stirred at room tem-
perature for 4–6 h.
Scheme 2. Useful transformations of alcohol 5 and THP ether 10.
b
Anti/syn diastereomer ratio = 5:1.
obtained after stirring 10 for 1 h at 70 °C in toluene in the presence
of 6 mol % 9 and 10 mol % benzoquinone (BQ).
leading to decreased reaction times (>24 h?5 h). The optimal con-
ditions for the reaction involved combining the aldehyde or ketone
(1 equiv) with 3 (2 equiv), indium metal (1.5 equiv), and TBAI or NaI
(1 equiv) in DMF (2 M) at room temperature for 4–6 h. Allylation of
glyceraldehyde acetonide (entry 6) led to the expected homoallylic
alcohol as a 5:1 mixture of trans/cis diastereomers.3
Toluenesulfonyl imine 1214 also underwent reaction with 1
(3 equiv) in the presence of indium metal (3 equiv) to produce
homoallylic sulfonamide 13 as a 1:1 mixture of diastereomers in
90% yield (Scheme 3). Treatment of 13 with OsO4/KIO4 under Jin’s
conditions15 cleanly gave rise to sulfonyl-protected b-amino acid
14 in 84% yield.
Enol ethers 5 may be readily transformed into b-hydroxy ke-
tones and esters. Stirring compound 5a in a 1:1 THF/saturated
NH4Cl solution containing a drop of 6 N HCl for 15 min results in
its conversion to ketone 6 in 90% isolated yield; bubbling ozone
through a solution of 5b in 1:1 CH2Cl2/CH3OH at À78 °C for
30 min, followed by exposure to DMS and warming to room tem-
perature, gives rise to MEM ester 7 in 95% yield (Scheme 2). Com-
pound 5a could be easily transformed into the corresponding allyl
ether by treatment with NaH/allyl bromide in DMF; however, at-
tempted ring-closing metathesis with Grubb’s second-generation
catalyst 911 led only to the isomerized acyclic products 8. Repeti-
tion of this reaction in the presence of the isomerization inhibitor
benzoquinone (10 mol %) gave no reaction.12 Since many examples
of enol ether metathesis exist in the literature,13 we surmised that
the methoxyethoxymethyl ether moiety may be inhibiting ring-
closing metathesis by coordination to ruthenium. Thus, we pre-
pared allyl ether 10 from Horning’s THP ether (1) and subjected
it to ring closing metathesis. A 98% yield of dihydropyran 11 was
To explore the extension of this method beyond the use of an
acetone enolate equivalent, we prepared MEM ether 16 from the
known cis,cis-2,6-dibromocyclohexanol (15, Scheme 4).16 Treat-
ment of 16 with NaH in DMF, followed by exposure to benzalde-
hyde and indium metal in DMF overnight, led to the production
of enol ether 17 in 45% yield as a 6:1 mixture of syn/anti diastereo-
mers;17 diene 18,18 formed competitively in both the dehydrobro-
mination and allylation reactions, was also isolated in significant
quantities.
Finally, we envisioned that chiral 3-bromo-2-alkoxypropenyl
halides could be easily prepared by the protocols outlined above
and participate in diastereoselective indium-mediated carbonyl
allylation reactions. Menthyloxymethyl ether 20 was thus synthe-
sized from 1,3-dibromo-2-propanol and symmetrical acetal 1919
(derived from (À)-menthol) under TMSOTf catalysis (Scheme 5).
Dehydrobromination under standard conditions, followed by in-
dium-mediated allylation of benzaldehyde, furnished homoallylic
alcohol 21 in 80% yield. To assess the stereoselectivity of the reac-

H. Dhanjee, T. G. Minehan / Tetrahedron Letters 51 (2010) 5609–5612
5611
ArO2S
SO2Ar
N
+
SO2Ar
Ph
OTHP
HN
HN
THPO
O
In(0), DMF
OsO4, KIO4
2,6-lutidine
Br
TBAI, 25°C
10 h
Ph
H
Ph
HO
1
12 Ar=4-CH3-C6H4
13 90%
14 84%
Scheme 3. Indium-mediated allylation of sulfonimine 12.
Scheme 4. Reactions of the allylindium reagent derived from dibromide 16.
(1.5 equiv) and triphenylphosphine hydrobromide (5 mol %)22 in
CH2Cl2 at room temperature for 16 h to afford O-glycoside 23 in
Br
O
1,3-dibromo-2-propanol
80% yield as a 10:1 mixture of
easily separated by flash chromatography (Scheme 6). Dehydro-
bromination of the -stereoisomer was carried out in DMF with
a/b diastereomers which could be
O
O
O
TMSOTf
50%
a
Br
NaH, and crude enol ether 24 (2 equiv) was reacted with benzalde-
hyde (1 equiv) and indium metal (1.5 equiv) in DMF overnight. The
corresponding homoallylic alcohol 26 was obtained in 90% yield as
3:1 mixture of diastereomers. Repetition of the reaction in THF or
dioxane furnished less than 10% of 26; reaction in 4:1 THF/DMF
provided 26 as a 3:1 mixture of diastereomers in 65% yield after
48 h. Treatment of intermediate allyl bromide 24 with NaI in ace-
tone, isolation of iodide 25, and stirring of crude 25 in THF with in-
dium metal prior to the addition of benzaldehyde gave 26 in 55%
yield, but again as a 3:1 mixture of diastereomers.
20
19
1. NaH, DMF
80% 2. PhCHO, In(0)
DMF, TBAI
R
O
O
1:1 THF/ aq.NH4Cl
Ph
21
1 drop 2N HCl
85%
OH
α =+5° (lit. +55°)
6 R=H,
22 R=
D
R-(-)-MTPA-Cl
py, 1h, rt
90%
O
O
O
CF3
21
Ph OMe
dr=1.4:1
Aqueous acidic hydrolysis of the enol ether function of 26 gave b-
hydroxy ketone 6, whose sign of optical rotation indicated that the
predominant enantiomer possessed the S-configuration.23 The pref-
erential formation of this stereoisomer may be rationalized based on
a transition state assembly in which the pyran ether oxygen and the
C.6 oxygen atom of the carbohydrate simultaneously coordinate the
allylic indium species, as shown in Scheme 6.
In conclusion, we have demonstrated the synthetic utility of the
indium reagents derived from 2-alkoxy-substituted allyl bromides.
Studies directed toward improving the diastereoselectivity of
this process, as well as explorations of the utility of this method
in natural products synthesis, are currently under way and will
be reported in due course.
Scheme 5. Attempted use of the menthyloxymethyl ether as a chiral auxiliary in
indium-mediated allylation.
tion, it was necessary to hydrolyze 21 to b-hydroxyl ketone 6 and
prepare the corresponding Mosher ester20 derivative. Analysis of
the 1H NMR spectrum of ester 22 revealed a disappointing 1.4:1
diastereomer ratio.
Given that tetrahydropyranyl ether
1 undergoes smooth
indium-mediated carbon–carbon bond-forming reactions, we be-
lieved that the use of a carbohydrate auxiliary might give rise to
enhanced diastereoselection in the allylation process. Thus, 3,4,6-
tri-O-methyl-
D
-glucal21 was treated with 1,3-dibromo-2-propanol
Br
MeO
MeO
MeO
MeO
MeO
Br
Br
1. NaH, DMF
HO
Br
MeO
MeO
O
O
O
Br
2. PhCHO
5 mol% PPh3HBr
80%
MeO
O
MeO
O
23 (10:1 α:β)
24
PhCHO
In(0),
TBAI, solvent
MeO
PhCHO
NaI
MeO
MeO
I
MeO
O
26
24
55%, dr=3:1
acetone
In(0),
THF, MS 4Å
OH
O
MeO
O
MeO
O
26
25
OMe
DMF: 90%, dr=3:1
THF: <10%
OMe
O
OH
Dioxane: <10%
1:1 THF/ aq.NH4Cl
1 drop 2N HCl
4:1 THF/DMF: 65%, dr=3:1
6
O
In
O
26
H
O
CH3
(S)-6 αD=-25° (c=0.01, CH2Cl2)
lit. αD=-55°
O
Ph
Scheme 6. Synthesis and indium-mediated allylation reactions of chiral allyl bromide 24.

5612
H. Dhanjee, T. G. Minehan / Tetrahedron Letters 51 (2010) 5609–5612
2. General procedure for the synthesis of homoallylic alcohols
5a–h from 2
References and notes
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Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228.
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3734.
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6. Allatabakhsh, A.; Pham, M.; Minehan, T. G. Heterocycles 2007, 72, 115.
7. (a) Horning, D. E.; Kavadias, G.; Muchowski, J. M. Can. J. Chem. 1970, 48, 975; (b)
Jacobson, R. M.; Ratha, R. A.; McDonald, J. H. J. Org. Chem. 1977, 42, 2545.
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17. The ratio and identity of the syn/anti diastereomers was determined by
hydrolysis of 17 (1:1 THF/saturated NH4Cl, three drops 6 N HCl) to the
corresponding b-hydroxy ketone and comparison of the NMR spectrum with
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A solution of 2 (603 mg, 2 mmol) in DMF (0.6 mL) was added
rapidly to a 0 °C solution of NaH (400 mg, 10 mmol, 60% dispersion
in mineral oil, washed 2Â with dry pentane) in DMF (4 mL) and the
resulting solution was allowed to warm to room temperature and
stir for 30 min. The mixture was diluted with ether (20 mL) and
quenched with saturated NaHCO3 solution (10 mL). The layers
were separated and the organic layer was washed with an addi-
tional portion of saturated NaHCO3 solution (10 mL). The organic
layer was dried over Na2SO4, filtered and concentrated in vacuo
to provide 3 as a light yellow oil.
To a solution of crude 3 in DMF (0.5 mL) was added the
appropriate aldehyde or ketone (1.0 mmol), indium metal
(171 mg, 1.5 mmol), TBAI (369 mg, 1.0 mmol) and 4 Å molecular
sieves (200 mg). The solution was allowed to stir overnight with
protection from light. The reaction mixture was then diluted
with 1:1 ether/ethyl acetate (10 mL) and saturated NaHCO3
solution (10 mL) and the phases were separated. The aqueous
phase was extracted again with ether (10 mL) and the combined
organics were dried over anhydrous sodium sulfate. Filtration
and concentration in vacuo furnished a crude yellow oil. Purifi-
cation by flash chromatography provided homoallylic alcohols
5a–h.
Acknowledgments
We thank the National Institutes of Health (SC2 GM081064-01)
and the Henry Dreyfus Teacher-Scholar Award for their generous
support of our research program.
18. Diene 18 was observed as a minor byproduct (10–20%) in the NaH-induced
dehydrobromination of 16.
19. Shatzmiller, S.; Dolithzky, B.-Z.; Bahar, E. Liebigs Ann. Chem. 1991, 375.
20. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 39, 2543.
21. 3,4,6-Tri-O-methyl-
D-glucal was prepared from commercially available 3,4,6-
Supplementary data
tri-O-acetyl- -glucal by acetate hydrolysis (cat. KCN, MeOH) followed by
D
methylation (NaH, MeI, DMF).
22. Bolitt, V.; Mioskowski, C. J. Org. Chem. 1990, 55, 5812.
23. Schneider, F. Synthesis 1986, 7, 582.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.064.