2-Iodoethanols from aldehydes, diiodomethane and isopropylmagnesium chloride

Article abstract of DOI:10.1016/j.tetlet.2005.02.093

Diiodomethane and iodoform react with i-PrMgCl by halogen-metal exchange. The resulting magnesium reagents tolerate several functional groups, but aldehydes are converted selectively into iodoethanols in good to high yields. These mild reagents preserve r

Full text of DOI:10.1016/j.tetlet.2005.02.093

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2551–2554
2-Iodoethanols from aldehydes, diiodomethane and
isopropylmagnesium chloride
Hannes A. Braun, Reinhard Meusinger and Boris Schmidt*
Darmstadt Technical University, Clemens Scho¨pf-Institute for Organic Chemistry and Biochemistry, Petersenstr. 22,
D-64287 Darmstadt, Germany
Received 18 January 2005; revised 15 February 2005; accepted 16 February 2005
Abstract—Diiodomethane and iodoform react with i-PrMgCl by halogen–metal exchange. The resulting magnesium reagents toler-
ate several functional groups, but aldehydes are converted selectively into iodoethanols in good to high yields. These mild reagents
preserve racemization prone centres. The substrate controlled diastereoselectivity provides straightforward access to important
intermediates of peptidomimetics.
Ó 2005 Elsevier Ltd. All rights reserved.
Amino acid derived epoxides and 2-haloethanols are
extremely versatile intermediates for the synthesis of
protease inhibitors.1–3 Several synthetic strategies are
known, but they are either lengthy, require diazo-
methane or harsh conditions. Most organic chemists
have rather mixed feelings using diazomethane for the
synthesis of the intermediate a-chloroketones. The less
hazardous siladiazomethane is significantly more expen-
sive and therefore limited to small scale reactions. How-
ever, it can be replaced by dimethylsulfoxonium
methylide.4 Nevertheless, a reliable, straightforward
and inexpensive approach is still very desirable. Some
of these requirements are fulfilled by lithium organyls,5
their strong basicity impedes the conversion of di- and
oligopeptides, yet they provide access to a-chloro-
ketones from N,N-dibenzylated amino acid esters.15
The umpolung of ClCH2I or CH2I2 and subsequent
addition to aldehydes provides access to epoxides,6 but
requires methyllithium at À78 °C. The deprotonation
of CH2Cl2 by n-BuLi and addition to ketones furnished
tertiary b-dichloroalcohols.7 A more recent approach to
the respective iodo species utilized diiodomethane or
iodoform and air-sensitive and expensive SmI2, which
can be replaced by metallic samarium and iodoform.8,9
Here we report the efficient synthesis of 2-iodoethanols
and 2,2-diiodoethanols from safe and convenient pre-
cursors. Seeking a safer replacement of methyllithium,
we decided to investigate i-PrMgCl, which has a remark-
able potential for iodine–magnesium exchanges. The
late G. Ko¨brich already reported the halogen–metal
exchange of bromoform and dibromomethane with
n-BuLi. On the contrary, the analogous chloro com-
pounds react by deprotonation.10 The former reactivity
continues in diiodomethane and iodoform, and may be
improved by magnesium alkyls. We expected these mag-
nesium reagents to favour late transition states, to toler-
ate a wide range of functional groups, to display reduced
basicity, and thus allow stereoselective conversion of
polyfunctional peptides.11 The rate of the halogen–metal
exchange depends on the electron density to a great ex-
tent that the stepwise activation of geminal diiodides is
feasible. The detailed kinetics and energetics were re-
ported by Hoffmann and the potential of this reaction
was revealed in a number of publications already.12–14
The activation of iodoform or diiodomethane by
i-PrMgCl proceeded rapidly in tetrahydrofuran at
À78 °C (Scheme 1).
The addition of i-PrMgCl to aldehydes was considerably
slower at this temperature. Addition of an aldehyde
after complete iodo-magnesium exchange (15 min)
resulted in similar yields and selectivities as obtained
for the simultaneous addition (Table 1). Both C1
nucleophiles, which are derived from long-lived ate
complexes,12 reacted with aldehydes (1a–d) at À78 °C
Keywords: Halogen–metal exchange; Iodomethane; Protease
inhibitors.
*
Corresponding author. Tel.: +49 6151 163075; fax: +49 6151
163278; e-mail addresses: boris.schmidt@imail.de; schmibo@oc.
chemie.tu-darmstadt.de
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.093

2552
H. A. Braun et al. / Tetrahedron Letters 46 (2005) 2551–2554
methodology,8 but complement the diiodomethane
iPrMgCl, CH2I2, THF
O
OH
derived lithium reagents, which provide epoxides.6
I
I
-78˚C, 15 min
0˚C, 1-2 h
R
R
2a-d
1a-d
The turnover of 1e was remarkably slow, it reacted just
marginally under these conditions. Consequently, the
formylacetophenone 1d underwent iodomethylation at
the aldehyde only. The benzoic anhydride 1f underwent
rapid conversion into a multitude of unidentified prod-
ucts. The conversion of the acid chloride 1g did not take
place, but reactivity could have been enhanced by either
chelation assistance or the reported trans-metallation
into a copper reagent.15 The differences between the
two nucleophilic reagents (Scheme 1) became apparent
in the reaction with cinnamic aldehyde, which was con-
verted into the cyclopropyl-methanol 2b by diiodome-
thane and into the anticipated diiodinated allyl alcohol
3b by CHI3. Two pathways lead to the cyclopropane
2b: (a) an initial Michael addition is followed by cycliza-
tion and iodomethylation,16 or (b) an iodomethylation
of the aldehyde is followed by a Simmons–Smith-like
cyclopropanation, which is reported to occur with high
syn-stereoselectivity, but modest yields for CH2I2/
i-PrMgCl and allyl alcohols.17 Therefore, we have moni-
tored the reaction at different ratios of aldehyde and
CH2I2/i-PrMgCl to establish the mode of action. The
allyl alcohol 4 (Scheme 2) was identified as the dominant
intermediate, which was converted into 2b by a second
equivalent of CH2I2/i-PrMgCl. The exclusive anti con-
figuration of the cyclopropane was determined by
NMR spectroscopy and revealed the dormant carbenoid
reactivity. The relative configuration of the alcohol was
tentatively assigned in analogy to the results of Bolm
and Pupowicz.17
O
R
OH
iPrMgCl, CHI3, THF
-78˚C, 15 min
0˚C, 1-2 h
R
I
1a,b
3a,b
Scheme 1.
Table 1. Reactions of aldehydes, ketones and carboxylic acid deriva-
tives according to Scheme 1 with 2.0 equiv of CH2I2 or CHI3 and
i-PrMgCl
Reagent
Aldehyde
Product
Yielda
[%]
OH
O
O
I
CH2I2/i-PrMgCl
96
Ph
Ph
2a
1a
OH
CH2I2/i-PrMgCl
CH2I2/i-PrMgCl
91b
73
I
Ph
Ph
Ph
1b
2b
OH
Ph
O
I
1c
2c
O
OH
I
CH2I2/i-PrMgCl
69
O
O
1d
2d
The reaction of the Evans imide 5 with CH2I2/i-PrMgCl
(Scheme 3) resulted in the unexpected, selective iodome-
thylation of the urethane to furnish the iodoacetate 6,
initially in low yield. However, when the reaction mix-
ture was kept at À25 °C for three days we obtained 6
as a single product. There is precedence for this reactiv-
ity of Evans imides.18 Vinylmagnesium chloride reacted
in a similar fashion to result in vinylation of the ure-
thane. A tetrahedral intermediate, similar to Weinreb-
amides, was suggested for this monoalkylation.
O
O
CH2I2/i-PrMgCl
CHI3/i-PrMgCl
Conversion < 10c
Ph
Ph
1e
OH
I
91
Ph
I
I
1a
3a
3b
OH
O
O
CHI3/i-PrMgCl
CH2I2/i-PrMgCl
82d
I
Ph
Ph
1b
O
Sluggish reaction
No reaction
O
CH2I2 / iPrMgCl (1.1 equiv)
THF, 2h, -78˚C
OH
Ph
Ph
O
Ph
I
1f
Ph
Ph
O
68% conversion
4
1b
CH2I2/iPrMgCl
Cl
Scheme 2.
1g
a Isolated yields.
b Diastereomeric mixture: syn/anti 96:4, assigned by NMR.17
CH2I2 / iPrMgCl
(4 equiv),
THF, -78˚C / 15 h,
-25˚C / 3d
c Determined by HPLC.
O
O
O
d Contains 4% of 2,2-diiodo-1-(2-iodo-3-phenylcyclopropyl)ethanol
(mixture of diastereomers, d.r. > 3:1) and 3% of 2,2-diiodo-1-(2-
phenylcyclopropyl)ethanol.
O
H
N
N
I
O
82%
O
Ph
Ph
to the b-iodo-(2a–d) and b-diiodo compounds (3a and
b). The formation of epoxides was not observed even
at 0 °C for 2 h. These results are similar to the samarium
5
6
Scheme 3.

H. A. Braun et al. / Tetrahedron Letters 46 (2005) 2551–2554
2553
ology20 which provides access to the diastereomer when
the nitrogen is dibenzylated. The substrate controlled
diastereoselectivity provides straightforward access to
important intermediates of peptidomimetics. The chiral
induction by additional ligands is subject to ongoing
investigations.
R
R
CH2I2 / iPrMgCl
(5 equiv), THF
Z
Val Leu
N
Z
Val Leu
N
I
H
H
-78 ˚C, 15 min
0˚C, 1-2 h
O
OH
7a: R = iBu
7b: R = Bn
7c: R = sBu
7d: R = iPr
8a: R = iBu (82%)
8b: R = Bn (77%)
8c: R = sBu (86%)
8d: R = iPr (87%)
Acknowledgements
CHI3 / iPrMgCl
(5 equiv), THF
I
This work was supported by the Deutsche Forschungs-
gemeinschaft (SPP1085 SCHM1012-3) and the EU
contract LSHM-CT-2003-503330 (APOPIS).
Z
Val Leu
N
Z
Val Leu
N
I
-78 ˚C, 15 min
0˚C, 2 h
H
H
O
OH
7d
9 (77%)
Scheme 4.
Supplementary data
After these initial experiments we addressed the
iodomethylation of peptide aldehydes, which are impor-
tant intermediates for the synthesis of protease inhibi-
tors. The deprotonation of the acidic amides required
5-fold excess of the reagent. This was not a nuisance, be-
cause the deprotonation froze the configuration of the
P1–P3 positions of the tripeptide mimetics 7a–d. The
aldehydes were used as 3:1 mixtures of diastereomers,
as obtained from the oxidation of alcohols by IBX in
DMSO, followed by aqueous work up. The iodomethyl-
ation and diiodomethylation provided the compounds
8a–d and 9 (Scheme 4), apparently without epimeriza-
tion of the P1 position as judged by HPLC. The diaste-
reoselectivity of the reaction was always better than 2:1
as judged by HPLC.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.02.093.
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