A mild method for the replacement of a hydroxyl group by halogen: 2. unified procedure and stereochemical studies

Article abstract of DOI:10.1016/j.tet.2020.131441

N,N-Dimethyl- and N,N-diisopropyl-1-halo-2-methyl-l-propenylamines are readily available reagents for the mild deoxyhalogenation of alcohols and hydroxyacids. In this study we showed that the reactivity of the reagents can be tuned by varying the size of the alkyl groups on the reagents: the replacement of methyl by isopropyl groups led to a significant increase of reactivity. We then described a unified procedure for all deoxyhalogenations using the readily available α-chloroenamines as reagents with (bromination, iodination) or without (chlorination) an alkaline bromide or iodide. Finally, we showed that deoxyhalogenation reactions of secondary alcohols were highly stereospecific and generally occurred with inversion of configuration.

Full text of DOI:10.1016/j.tet.2020.131441

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A mild method for the replacement of a hydroxyl group by halogen: 2. unified
procedure and stereochemical studies
Wafa Gati, François Munyemana, Alain Colens, Aladdin Srour, Mathilde Dufour, K.
Harsha Vardhan Reddy, Brigitte Téchy, Gérard Rosse, Ed Schweiger, Qi Qiao, Léon
Ghosez
PII:
S0040-4020(20)30613-X
https://doi.org/10.1016/j.tet.2020.131441
TET 131441
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 May 2020
Revised Date: 12 July 2020
Accepted Date: 23 July 2020
Please cite this article as: Gati W, Munyemana Franç, Colens A, Srour A, Dufour M, Vardhan Reddy KH,
Téchy B, Rosse Gé, Schweiger E, Qiao Q, Ghosez Lé, A mild method for the replacement of a hydroxyl
group by halogen: 2. unified procedure and stereochemical studies, Tetrahedron (2020), doi: https://
doi.org/10.1016/j.tet.2020.131441.
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A mild method for the replacement of a hydroxyl group by halogen: 2.
Unified procedure and stereochemical studies.
Wafa Gati,a† François Munyemana,b† Alain Colens,b Aladdin Srour,a,c Mathilde
Dufour,a K. Harsha Vardhan Reddy,a Brigitte Téchy,b Gérard Rossed Ed Schweiger,d
Qi Qiaod and Léon Ghosez.a,b*
Leave this area blank for abstract info.
aEuropean Institute of Chemistry and Biology (IECB), Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248,
2 rue Robert Escarpit, FR-33607, Pessac, France
bUCLouvain, Place L. Pasteur, 1, B-1348 Louvain-la-Neuve, Belgium
cDepartment of Therapeutic Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt
dDart Neurosciences, 12278 Scripps Summit Dr., San Diego, CA, 92121, USA
†These co-authors contributed equally.

1
Tetrahedron
journal homepage: www.elsevier.com
A mild method for the replacement of a hydroxyl group by halogen: 2. Unified
procedure and stereochemical studies.
Wafa Gati,a† François Munyemana,b† Alain Colens,b Aladdin Srour,a,c Mathilde Dufour,a K. Harsha
Vardhan Reddy,a Brigitte Téchy,a Gérard Rosse,d Ed Schweiger,d Qi Qiaod and Léon Ghosez.a,b*
aEuropean Institute of Chemistry and Biology (IECB), Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, 2 rue Robert Escarpit, FR-33607, Pessac,
France
bUCLouvain, Place L. Pasteur, 1, B-1348 Louvain-la-Neuve, Belgium
cDepartment of Therapeutic Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt
dDart Neurosciences, 12278 Scripps Summit Dr., San Diego, CA, 92121, USA
†These co-authors contributed equally.
ARTICLE INFO
ABSTRACT
Dedicated to Prof. Richard. Taylor for his superb
contribution to organic chemistry as researcher and
editor.
Article history:
Received
Received in revised form
Accepted
Available online
N,N-Dimethyl- and N,N-diisopropyl-1-halo-2-methyl-l-propenylamines are readily available
reagents for the mild deoxyhalogenation of alcohols and hydroxyacids. In this study we showed
that the reactivity of the reagents can be tuned by varying the size of the alkyl groups on the
reagents: the replacement of methyl by isopropyl groups led to a significant increase of reactivity.
We then described a unified procedure for all deoxyhalogenations using the readily available α-
chloroenamines as reagents with (bromination, iodination) or without (chlorination) an alkaline
bromide or iodide. Finally, we showed that deoxyhalogenation reactions of secondary alcohols
were highly stereospecific and generally occurred with inversion of configuration.
2020 Elsevier Ltd. All rights reserved
.
Keywords:
deoxyhalogenation
α-haloenamine
alcohol
alkyl halide
stereochemistry
1. Introduction
an intermediate which converts alcohols into chlorides or
bromides under mild and non-acidic conditions [1,2]. However,
these methods use toxic reagents or produce much waste.
Hydroxyl-containing molecules are plentiful and often cheap
starting materials in organic synthesis. Thus, they have been
extensively used as a convenient source of organic halides.
Several inexpensive and commercially available reagents (eg
HCl, HBr, SOCl2, OPCl3…) have been used for this
transformation which has also been successful on an industrial
scale [1]. However, the strong acidity of these reagents prohibits
their use with acid-sensitive molecules. Accordingly, there has
been much effort to find milder procedures of deoxy-
halogenation of alcohols and other hydroxyl-containing
compounds. Thus, deoxychlorination reactions can be efficiently
performed with oxalyl chloride and a base [1]. Also, the reaction
of a phosphine or a phosphite with chlorine or bromine or the
corresponding carbon tetrahalides (Appel reaction) generates
Several years ago we discovered that tertiary amides such as
1a and 1b could be easily converted into N,N-dimethyl- and N,N-
diisopropyl-1-chloro- and -bromo-2-methyl-l-propenylamines
2a,b and 3a,b in the presence of phosgene (or phosgene dimer or
trimer) or more conveniently with phosphorous oxychloride or
bromide (Scheme 1) [3]. The corresponding iodoenamines 4a, b
could be prepared by halide exchange between 2a,b and an
alkaline iodide [4]. We had indeed demonstrated that α-
haloenamines were in equilibrium with the corresponding
keteniminium halides 5, 6 and 7 and behaved thus as powerful
electrophilic reagents [5]. This equilibrium was responsible for
the ability of α-haloenamines to perform the replacement of a
hydroxyl group by chlorine, bromine and iodine [5-7]. Addition
of hydroxyl-containing compounds such as alcohols, carboxylic
and other hydroxy-acids to the very electrophilic keteniminium
salts led to alkoxy- or acyloxy iminium salts 8, 9 and 10. These
behaved as activated derivatives of the hydroxyl-containing
substrates:
____________
*Corresponding author. Tel. +33 5 4000 2217 ; Fax : +33 5 4000 221E-
mail addresses : l.ghosez@iecb.u-bordeaux.fr
leon.ghosez@uclouvain.be
†These co-authors contributed equally.

2
Tetrahedron
O
R’Br
Me
R
N
R
1a : R = Me
1b : R = i-Pr
Me
R
N+
R
R
Br
N+
R’OH
R’OH
R
Br-
Br-
Me
C
Me
R
R’
Me
N
R
O
Me
Me
Me
R
Cl
3
6
9
N+
Me
R
R
N
R
R
Cl-
Me
C
R
R
I
Me
N+
N+
I-
Me
R
I-
R
Me
Me
C
R’
Me
N
O
5
2
Me
R
Me
Me
4
7
10
R’OH
R
R
N+
Cl-
R’
R’Cl
Me
2a = TMCE ; 3a =TMBE ; 4a = TMIE
2b = DICE ; 3b = DIBE ; 4b = DIIE
O
R’I
Me
8
Scheme 1. Deoxyhalogenation of alcohols (R’= Alkyl) and carboxylic acids (R’= R”CO)
the carbon atom carrying the oxygen group became quite
sensitive to nucleophilic reagents and allowed nucleophilic attack
by a halide ion to yield the corresponding alkyl or acyl halides
[6,7]. These reactions generally took place at room temperature
or below without the formation of hydrogen halides. As a result
of these mild conditions this new method of deoxyhalogenation
showed a wide substrate scope. Thus, α-haloenamines were
shown to convert a wide variety of oxyacids into highly pure acyl
halides in very good yields [6-8]. Furthermore, the method
allowed the use of these sensitive acyl halides without
purification since the reaction mixture only contained the fairly
inert tertiary amide 1a or 1b as co-product. Thus, TMCE and
TMBE were successfully used to prepare amino acid chlorides or
bromides carrying sensitive protecting groups for peptide
coupling reactions [9, 10]. Remarkably this sequence of reaction
occurred without racemization. Immobilized α-haloenamines
reagents have also been prepared and used in syntheses of
protected amino acid halide monomers and oligomers for the
preparation of polyamides [11]. A wide variety of alcohols were
converted into the corresponding chlorides, bromides or iodides
under these very mild conditions which allowed the presence of
many sensitive functional groups. Interestingly the selectivity of
these reagents could be finely tuned by varying the size of the
alkyl groups on nitrogen. Thus, the simple replacement of two
methyl by two isopropyl groups on nitrogen allowed to
selectively convert primary alcohols in the presence of secondary
alcohols without the use of protecting groups. We should also
emphasize the high atom economy of the method: the co-product
generated in the halogenation reaction is an isobutyramide (1a or
1b) which is the starting material for the synthesis of the α-
haloenamine.
2. Results and discussion
2.1. A unified deoxyhalogenation procedure
Expectedly, the commercially available TMCE 2a has been
preferred by most users of the deoxychlorination reaction. We
had however demonstrated that DICE 2b should be the preferred
reagent when a problem of chemoselectivity arouse [7]. DICE 2b
is not commercially available but can be conveniently prepared in
kg amounts from the corresponding amide 1b, phosphorous
oxychloride and triethylamine [3b]. We recently found that there
could be another reason to prefer DICE 2b to TMCE 2a: the
presence of bulkier groups on nitrogen was indeed found to
considerably increase the reactivity of the reagent as shown by
the competition experiment described in Scheme 2. Even with
only a two-fold excess of reagents 2a and 2b, cyclopentanol
exclusively reacted with the bulkier reagent 2b. Thus, it can be
concluded that DICE was not only more selective but also more
reactive than TMCE.
Scheme 2. Relative reactivities of TMCE and DICE
This increased reactivity probably resulted from the repulsion
between the alkyl groups on nitrogen and carbon which forces
the molecule to adopt a conformation with the nitrogen lone pair
antiperiplanar to the C-Cl bond, favouring thus the formation of a
keteniminium chloride (Scheme 3). As shown earlier [7], the
increased selectivity of DICE resulted from a higher steric
A few years ago, we published the first detailed account
of our studies of this novel deoxyhalogenation procedure. It dealt
with the scope and the chemoselectivity of the reaction [7]. We
now report our studies of (1) an improved procedure for the
deoxybromination and iodination reactions, (2) the
stereochemistry of these halo-deoxygenation reactions.
n→ ꢀ ∗
Scheme 3. Conformation favouring ionization of DICE

3
discrimination in the addition of the alcohol to the keteniminium
carrying bulkier groups (Scheme 1).
We felt that users of these reactions would welcome the
possibility of performing deoxybromination and -iodinations in a
“one-pot” procedure involving the readily available α-
chloroenamine reagents TMCE 2a or DICE 2b and a source of
bromide or iodide ion. We decided to test this “one-pot”
procedure on derivatives of diol 11 derived from Corey’s lactone.
It was expected that the deoxychlorination of this diol could be
somewhat challenging. The reactivity of both hydroxyl group
should indeed be decreased by either the presence of two alkyl
groups β to the primary hydroxyl group or by steric factors
resulting from the presence of a lactone ring cis to the secondary
hydroxyl group. We thus decided to prepare derivatives of 11
carrying a protecting group on one alcohol group (Scheme 6).
Both TMCE and DICE are bench stable reagents, but they are
very sensitive to moisture. However small amounts of hydrolysis
products 1a or 1b in the reagents were shown to be harmless for
the deoxychlorination reaction.
The corresponding deoxybromination reagents TMBE 3a and
DIBE 3b (Scheme 1) could also been prepared in multigram
quantities from N,N-2-trimethyl-propanamide or N,N-
diisopropylisobutyramide and phosphorous oxybromide in the
presence of triethylamine [3b]. Tetramethyliodoenamine TMIE
4a was readily prepared by the reaction of TMCE 2a with a
three- to six-fold excess of a suspension of 4 equivalents dry KI
(or NaI, LiI) in refluxing chloroform (or DCM) to yield around
75% of TMIE after purification by distillation (Scheme 4) [4]. A
halogen exchange was also observed when DICE 2b was reacted
with a suspension of KI in chloroform (Scheme 4). However, the
covalent α-iodoenamine 4b was not observed: it spontaneously
ionized to keteniminium iodide 7b. Clearly the steric interactions
resulting from large substituents on nitrogen (see Scheme 3) and
the presence of a weaker carbon-halogen bond are responsible for
the complete ionization of 4b. Disappointingly a chlorine vs
bromine exchange was not observed when TMCE was reacted
with a suspension of KBr in refluxing chloroform for 12 hours.
Explaining this difference between KI and KBr would be
difficult since both reactions were performed in heterogenous
conditions. However, both 2a and 2b underwent a fast halide
exchange with a 2.5 excess of LiBr or LiI in acetonitrile at room
temperature (1H- and 13C-NMR).
a) TIPSOTf (1.1 equiv), Et3N (1.5 equiv), DMF, 0 °C to r.t., 8 h.; b) TfOH
(1.1 equiv), TIPSH (1.15 equiv) in DCM then Et3N (1.5 equiv), DMF, 0 °C to
r.t., 8 h; c) NaH (1.3 equiv), tBuOH (cat.), THF, 0 °C, 30 min then PMB-Cl
(3 equiv), nBu4N+I- (0.5 equiv), 0 °C to r.t., 36 h; d) TBAF (1.1 equiv) THF, 0
°C, 15 min then r.t. 1 h.; e) NaH, PMB-Cl, DMF, 0°C to r.t., 12 h .
Scheme 6. Synthesis of protected derivatives of diol 11.
The mono-protected derivatives 12, 14 and 15 were prepared
as shown. In a preliminary experiment using a tert-butyldimethyl
silyl protecting group for the primary alcohol of 11, we had
shown that the deoxychlorination gave a complex mixture of
products. This could have resulted from the presence of the cis-
lactone ring or (and) the cleavage of the tert-butyldimethyl silyl
group.
Scheme 4. Synthesis of α-iodoenamines 4a,b and keteniminium iodide 7b.
We thus moved to the more stable TIPS protecting group [12]
and studied the deoxychlorination of 12 (Scheme 7). A molar
solution of TMCE 2a in DCM gave the expected chloride 16a
but yields were moderate (Scheme 7, conditions a) and we still
observed some desilylation (20% TIPSOH). The results were
much better with DICE (conditions b) which gave 75% yield of
the desilylated alcohol 17.
Interestingly, we also observed a halogen exchange when TMCE
2a was reacted with a four-fold excess of methyl iodide in
refluxing chloroform (Scheme 5). This could again be readily
explained by the equilibrium between TMCE 2a and the
corresponding keteniminium chloride TMK 5a. Ionization would
be followed by a nucleophilic attack of the chloride ion on the
alkyl iodide to form the corresponding alkyl chloride and TMIE
4a. We also observed that TMBE could be conveniently prepared
in 65% yield after distillation by refluxing a solution of TMCE
2a in dibromomethane for 20 hours.
We then proceeded with the “one-pot” deoxyiodination of 12.
In a first experiment (Scheme 7, conditions c), a suspension of
LiI in a solution of TMCE (1.1 eq.) 2a in dry dichloromethane
was stirred for 10 min. at 0 °C. Adding the alcohol at 0 °C and
Conditions
Yields % purified 16a
16b
17
_______________________________________________________
Scheme 5. Reaction of TMCE with alkyl iodides and dibromomethane.

4
Tetrahedron
a
TMCE, 1 M in DCM
41
-
-
b
c
DICE, 0.5 M in DCM
-
-
75
43 (3:1 mixture of 16a/16b)
46
TMCE + LiI (1.5 eq.), DCM
rt 10 min then 12, 0 °C to r.t.
TMCE + LiI (1.5 eq.), DCM
rt 60 min then 12, 0 °C to r.t
d
-
-
Scheme 7. The first one-pot deoxyiodinations of an alcohol with TMCE and
LiI
stirring the mixture for 3 hours at room temperature yielded a
3:1 mixture of iodo- and chloro-lactone 16a/16b. As
Scheme 10. One-pot procedure for the deoxybromination of isobutanol.
Table 1 One-pot deoxybromination and deoxyiodination of alcohols
anticipated, leaving the TMCE-LiI suspension in DCM for 1
hour at 0 °C before adding the alcohol (conditions d) was
sufficient to suppress the formation of the chlorinated
compound 16a. This rewarding result demonstrated the
feasibility of a deoxyiodination of an alcohol from the in-situ
combination of a chlorinating reagent TMCE and a source of
iodide ion. However, yields were moderate as a result of the
presence of a trialkylsilyl protecting group on the primary
alcohol. TIPSOH was detected in all reactions. The use of a
more stable PMB protecting group on the primary alcohol as
in 14 and a more reactive reagent (DICE) led to a slight
improvement of the yields (66%) of purified 18 (Scheme 8).
Alcohol
Salt
Conditions
Halide % (NMR)
LiBr (2.5)
LiBr (2.5)
CD3CN, rt,
CDCl3, rt,
a
b
100
100
100
KI (2.5)
LiI (2.5)
CD3CN, rt,
CD3CN, rt,
c
d
100
100
100
KI (2.5)
LiI (2.5)
CD3CN, rt,
CDCl3, rt,
e
f
Scheme 8. Deoxychlorination in the presence of a more stable protecting
group.
the case as illustrated in Table
1
(entry a) for the
deoxybromination of 1-naphtalenemethanol, a primary alcohol. A
2.5-fold excess of LiBr was sufficient to quantitatively produce
We also applied this one-pot procedure to the deoxyiodination
of the primary alcohol of 15 (Scheme 9). In spite of presence of
two alkyl groups β to the hydroxyl, the deoxyiodination
procedure worked beautifully under very mild conditions: yields
were high with both LiI (entry a) and KI (entries c and d) in the
presence of TMCE 2a. We did not see any spectacular solvent or
cation effects on the yields of deoxyiodination. Under these mild
conditions, we did not observe any cleavage of the PMB group
[13]. This was however observed when the solution was warmed
at 50 °C (entry b).
1-bromomethyl-naphtalene and amide 1a as shown by 1H and 13
C
NMR. Interestingly, in all reactions of Table 1, TMCE was added
to the solvent already containing both the salt and the alcohol.
Surprisingly, the reaction also worked in chloroform in spite of
the poor solubility of LiBr in this solvent: using the same
conditions, cyclopentanol quantitatively yielded cyclopentyl
bromide (entry b). A quantitative yield of cyclopentyl iodide was
also obtained when TMCE was added to a 2.5-fold excess of LiI
suspended in a solution of cyclopentanol in deuterochloroform.
The procedure could also be applied to the deoxyiodination of
alcohols with TMCE and either LI and KI (Table 1, entry c to f).
The reactions were quite fast (< 30 min).
We have thus demonstrated that a unified procedure for
deoxyhalogenation
reactions
was
now
possible:
deoxychlorination can be conveniently performed with the
readily available TMCE or DICE reagents and the same reagents
can also be used to perform the deoxybromination and
deoxyiodination of alcohols by adding an alkali bromide or
iodide to the mixture. These reactions worked well in solvents
like acetonitrile, dichloromethane or chloroform in spite of the
fact that the mixture was often heterogeneous. This had often an
impact on reaction times. The salts and the glassware had to be
carefully dried. To remain on the safe side, it is recommended to
wait for 15 min before adding the alcohol to the mixture
although, in some cases the reaction was shown to work by
mixing all reactants from the beginning. The presence of small
amounts of N,N-dimethyl- and N,N-diisopropyl isobutyramide 1a
and 1b in TMCE or DICE is not harmful since they are
coproduced in the reaction. Of course, in that case the amount of
TMCE or DICE would have to be adjusted.
Conditions
Yields % (1H-NMR)
______________________________________________________________
LiI (1.5 eq) and 2a (1.1 eq) in DCM, r.t 1.5 h
then 15 at 0 °C, and 4 h. at r.t.
a
82
b
LiI (2 eq) and 2a (1.1 eq) in DCM, r.t 1 h
then 15 at 0 °C,3 h at r.t and 1 h, 50 °C
KI (3 eq) and 2a (1.1 eq) in DCM, r.t. 1.5 h
then 15 at 0 °C and 4 h at r.t.
KI (3 eq) and 2a (1.1 eq) in MeCN, r.t. 1.5 h
then 15 at 0 °C and 4 h at r.t.
mixture (cleavage PMB)
c
87
92
d
______________________________________________________________
Scheme 9. One-pot deoxyiodination of primary alcohol 15.
We then tried to achieve a Cl vs Br exchange by reacting LiBr
with a solution of TMCE in acetonitrile for 30 min. After
addition of isobutanol to the resulting mixture, we rewardingly
obtained a 3:1 mixture of isobutyl bromide and isobutyl chloride
(Scheme 10). We envisioned that it would be possible to favour
the deoxybromination reaction by increasing the concentration of
LiBr which is more soluble in this polar solvent. This was indeed

5
2.2. Stereochemistry of the deoxyhalogenation reactions
The reactions of l-menthol with both TMCE 2a and TMIE
3a were also stereospecific and only few elimination products
were observed (Scheme 13).
The stereochemical course of these deoxyhalogenation
reactions had not been addressed in our earlier reports [6, 7]. A
first hint about the stereochemical course of these
deoxyhalogenation reactions was already provided in Schemes 7
and 8: the substitution of the secondary hydroxyl group of 12 and
14 only gave the diastereoisomer resulting from an inversion of
configuration. We also found that the reaction of trans-4-tert-
butyl cyclohexanol trans-20 with TMCE yielded a 2:1 mixture
of the cis-4-chloro-tert-butyl cyclohexane cis-21 and 4-tert-butyl
cyclohexene 22 (Scheme 11). The reaction with cis-4-tert-butyl
cyclohexanol cis-20 gave a low yield of trans-4-chloro-tert-butyl
cyclohexane trans-21. The major product was 4-tert-butyl
cyclohexene 22.
Scheme 13. Chloro- and iodo-dehydroxylation of l-menthol
This probably resulted from the equatorial position of the
reactive iminium intermediate generated by the addition of l-
menthol to the keteniminium halides derived from TMCE or
TMIE.
Scheme 11. Stereospecific deoxychlorination of cis and trans 4-t-butyl
cyclohexanols
The substitution reactions were thus stereospecific: both cis
and trans alcohols reacted with inversion of configuration in
agreement with a classical Sn2 mechanism. The formation of tert-
butyl cyclohexene resulted from a trans-elimination (E2) from the
reactive cis and trans intermediates (Scheme 12). As expected,
more elimination product was obtained from the cis-alcohol since
in the most stable conformation of its reactive iminium
intermediate, the leaving group is axial. Elimination from the
trans isomer could only occur from a much less stable
conformation carrying two axial bulky groups (Scheme 12).
These observations excluded the formation of the cyclohexene
derivative from the 1-chloro-4-t-butylcyclohexane product since,
in that case, more olefin would have been expected from the
trans alcohol which yields a product with an axial chloride.
Scheme 14 Deoxyhalogenation of 3-ꢁ-cholestanol
α-Haloenamines 2a,b 3a and 4a also smoothly effected the
dehydroxyhalogenation of 3-β-cholestanol 26 at room
temperature to yield 3-α-halo-cholestanes 27a, b, c in high yields
(Scheme 14). All reactions proceeded with inversion of
configuration as with most halogenating agents except for thionyl
chloride [14, 15]. No or very little elimination occurred. This
resulted from the weak basicity of the reagents and the mild
conditions of this procedure. The deoxyiodination could be
performed with the isolated α-iodoenamine TMIE or with the in
situ generated TMIE: in the latter case TMCE and NaI (entry f)
or CsI (entry g) were left for 0.5-1 hour at 0 °C before adding
cholestanol. Here again reaction mixtures were heterogenous
which make meaningless any discussion about reaction times.
Homoallylic alcohols such as cholesterol and pregnenolone
are known to behave differently with halogenating agents as a
result of the intermediate formation of a homoallylic carbocation.
The reaction often gave mixture of substitution, rearrangement
and elimination products and usually the substitution took place
with retention of configuration giving a 3-β-halide [16]. A
notable exception was observed with carbodiiminium iodides
[15b] which reacted with cholesterol to give a 30% yield of 3-α-
iodo-5-cholestene.
Scheme 12. Reactive intermediates for Sn2 and E2 reactions
We found that both pregnenolone 28a and cholesterol 28b
reacted with pure TMIE to give a high yield of the purified β-

6
Tetrahedron
4. Experimental part
iodides 29a, b (Scheme 15). This reaction also proceeded with
complete retention of configuration.
4.1. Materials and Methods
The experimental work was performed at UCLouvain
(Belgium) and more recently at IECB (Univ. Bordeaux, France).
Unless otherwise noted, solvents and reagents were reagent grade
and used without further purification. Chloroform were distilled
over P4O10. Acetonitrile, dichloromethane and THF were dried
with Glass Contour solvent purification system. Reactions were
performed under argon atmosphere in oven-dried round-bottom
flasks with magnetic stirring. Sensitive reagents and solvents
were transferred using plastic or oven-dried glass syringes and
steel needles using standard techniques. At UCLouvain, 1H NMR
spectra were recorded at 60 MHz (Varian T 60), 200 MHz
(Varian Gemini-200 and XL-200), 300 MHz (Brücker Avance
300) and 500 MHz (Brücker AM 500). 13C NMR spectra were
recorded at 50 MHz (Varian Gemini-200, VXR-200). At IECB,
1H-NMR and 13C-NMR were recorded with Bruker Avance II
300 (at 300 MHz and 75 MHz, respectively) in CDCl3, CD2Cl2
and DMSO-d6. Chemical shifts are reported in parts per million
Scheme 15. Deoxyiodination of pregnenolone 28a and cholesterol 28b.
Finally, we studied the influence of the nature of the reagent
(TMCE vs DICE) and of the solvent on the deoxychlorination of
cholesterol 28b (Scheme 15). In all cases, we obtained the 3-β-
chloride 30 as the major product.
1
(ppm) on the δ scale relative to Me4Si (δ = 0 for H NMR) and
CDCl3 (δ = 77.2 for 13C NMR) as an internal reference and the
coupling constants are reported in units of Hertz [Hz].
Multiplicities were abbreviated as follows: s (singlet), br. s
(broad singlet), d (doublet), t (triplet), dd (doublet of doublet), dt
(doublet of triplet), dq (doublet of quadruplet) or m (multiplet).
Infra-red spectra were recorded on
a Perkin-Elmer 681
spectrometer, a Bruker IRFT IFS 55 spectrometer on zinc
selenide plates and a Jasco FT/IR-4600 Spectrometer on a single-
reflection diamond ATR accessory. At UCL, mass spectra were
recorded on Varian Mat 44 and Finnigan Mat-TSQ 70 using
electronic impact at 70 eV, chemical ionization (100 eV, acetone
or mixture of nitrogen oxide and methane) or FAB. At IECB low
resolution mass spectra (MS)/High resolution mass spectra
(HRMS) were recorded with a ThermoElectron LCQ Advantage
and a ThermoElectron Exactive spectrometer, respectively.
Column chromatography was conducted with silica gel 60 Å
(Sigma-Aldrich, 230-400 mesh particle size, 40-63 µm). Flash
chromatography was performed using silica gel 60 or 40-70
(230-400 mesh). Thin layer chromatography (TLC) on Merck
silica gel 60 F254 precoated plates. Visualization was made with
ultraviolet light (λ = 254/365 nm) or using an aqueous potassium
permanganate staining solution. GLC chromatography was
performed using Varian Aerograph 1400 (detector FID, nitrogen)
or Carlo Erba Fractovap (detector FID, nitrogen) on either a
SE30 column or a capillary column type 3700 (length 30
polydimethylsiloxane). RP-HPLC analyses were carried out on a
C18 gravity column (4.6 × 100 mm, 3 μm HPLC grade
acetonitrile and Milli-Q water were used for reverse phase (RP)
HPLC analyses. Melting points were recorded using a Büchi B-
540 apparatus and are uncorrected.
Scheme 16. Deoxychlorination of cholesterol with TMCE and DICE.
We were also able to isolate ꢂ 10% of the 3-ꢃ isomer and
ꢂ5% of diene. Scheme 16 also indicates that the reaction was
successful in a solvent like ethyl acetate and confirmed that
DICE was more reactive than TMCE. The reported yields are
those of purified material.
3. Conclusion
In summary we have shown that it was possible to perform
deoxybromination and -iodination reactions by in situ conversion
of the readily available TMCE and DICE into the corresponding
bromo- or iodoenamines using a bromide or an iodide salt. Our
studies also revealed that increasing the size of the nitrogen
substituents in the haloenamine reagent dramatically increased
the reactivity of the reagent. We had shown before [7] that it also
increased the selectivity of the α-haloenamine. Thus, DICE,
DIBE and DIIE are all more reactive AND more selective that
the corresponding TMCE, TMBE and TMIE. Not surprisingly
the present study showed that the reaction with secondary
alcohols took place with clean inversion of configuration.
Homoallylic alcohols such as cholesterol or pregnenolone reacted
with retention of configuration as expected. Although it had been
thoroughly studied for more than hundred years, the
deoxyhalogenation reaction still draws the attention of synthetic
chemists in particular in process chemistry [17]. We believe that
this mild, sustainable, chemo- and diastereoselective deoxy-
halogenation method will be welcome by synthetic chemists
interested in the selective transformation of sensitive substrates.
We will soon describe other applications as well as an extension
of this method to the replacement of hydroxyl groups by fluorine.
4.2. Synthesis of α-haloenamines
TMCE 2a, DICE 2b and TMBE 3a were prepared from
amides 1a and 1b following the previously described procedures
[3b]. TMBE 3a could also be prepared from TMCE by halogen
exchange (5.2.1.). Both TMBE 3a and TMIE 4a were also
obtained in the following reactions:
1-Bromo-N,N,2-trimethyl-1-propen-1-amine 3a
(TMBE).
Method a
A solution of 8.03 g TMCE 2a in 30 ml dry dibromomethane
CH2Br2 was refluxed for 20 hours in a flask protected from light
(aluminum foil). Distillation gave 6.95 g (65%) of 3a, Eb.: 58-62

7
°C/30 Torr. 1H NMR (200 MHz, CDCl3): δ 2.25 (s, 6H), 1.78 (s,
6H); 13C NMR (20 MHz, CDCl3): δ 140.04, 125.71, 43.46, 21.36.
complete formation of H2 gas. The reaction mixture was stirred
for an additional hour at room temperature. Then it was
cannulated at 0 °C under inert atmosphere into a flask containing
50 g of diol 11 (290.4 mmol), 60.8 mL of Et3N (1.5 equiv, 435.6
mmol) and 300 mL of anhydrous DMF. The reaction mixture
was stirred overnight at room temperature. After addition of
water (7-10 volumes), the crude mixture was extracted with ethyl
acetate. The extract was washed with brine and dried over
MgSO4. Evaporation of the solvent quantitatively yielded 12 as
an oil which was more than did not need further purification
(purity > 95%). It was directly used in the next step.
Method b
This is the method used for the “one-pot” deoxybromination
of alcohols. 1-Chloro-N,N,2-trimethyl-1-propen-1-amine (132.3
μl, 1 mmol) 2a was added to a solution of dry LiBr (217.12 mg,
2.5 mmol) in CD3CN (1 ml). The mixture was stirred for 30 min
to exclusively yield the title compound 3a and N,N,2-
trimethylpropionamide 1a. 1HNMR (300 MHz, CD3CN)
confirmed the disappearance of 2a, showing only the two
characteristic singlets for 3a at 2.28 ppm and 1.73 ppm for
(N(CH3)2) and (C(CH3)2) respectively and the signals for 1a. 13C
NMR (75.48 MHz, CD3CN) showed signals at 137.85 (CBr),
125.45 (C(CH3)2), 42.65 (N(CH3)2), 20.46 (CH3)2.
4.3.2. Synthesis of hydroxy-lactone 14
3.16 g (1.3 equiv., 79.1 mmol) of sodium hydride and 60 mL
of DMF were introduced in a flame dried 500 mL flask. A
solution of compound 11 in 20 mL of DMF was added dropwise
to the mixture at 0 °C (ice-bath). After 1 hour, p-methoxybenzyl
chloride (24.7 mL, 3 equiv., 237.4 mmol) was added to the
reaction mixture and the allowed to run for 12 hours at the same
temperature. The reaction was quenched by slow addition of
water and the resulting mixture was extracted with ethyl acetate
(3x). The organic phase was washed with brine and dried over
MgSO4. After evaporation of the volatile material, the crude
residue was purified by chromatography over silica gel
(petroleum ether: ethyl acetate 95:5 to 80:20) to yield 20% of
pure compound 14 as yellow oil; TLC (petroleum ether : ethyl
acetate, 4:1) Rf = 0.4; 1H NMR (300 MHz, CDCl3): δ = 2.08-
2.17 (m, 1H), 2.40 (d, J = 15.3 Hz, 1H), 2.58 (dd, J = 18.4, 3.3
Hz, 1H), 2.90 (dd, J = 18.4, 11.0 Hz, 1H), 3.05-3.06 (m, 1H),
3.27-3.36 (m, 1H), 3.83 (s, 3H), 4.31-4.33 (m, 1H), 4.31 (d, J =
11.4 Hz, 1H), 4.54 (d, J = 11.4 Hz, 1H), 5.11 (t, J = 6.6 Hz, 1H),
6.9 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H) ppm.; 13C NMR
(75 MHz, CDCl3): δ = 35.5, 37.3, 40.3, 55.3, 56.9, 70.9, 82.1,
84.3, 113.9, 129.3, 129.5, 159.4, 176.5, 177.4 ppm.
1-Iodo-N,N,2-trimethyl-1-propen-1-amine 4a
(TMIE).
Method a
Anhydrous KI (60 g, 0.36 mole) was suspended into a solution
of TMCE 2a in 40 ml anhydrous chloroform. The reaction flask
was protected from moisture by an oil trap and from light by an
aluminum foil. The suspension was refluxed for 5 h then filtered
under a stream of argon. The precipitate was washed with 2 x 20
ml of dichloromethane. Evaporation of the solvents from the
combined organic phases at atmospheric pressure followed by
vacuum distillation yielded 23.1 g (75%) 4a, Eb.: 61-63 °C/9
Torr. 1H NMR (200 MHz, CDCl3): δ 2.05 (s, 6H), 1.88, 6H); 13
NMR (20 MHz, CDCl3): δ 132.84, 129.06, 45.52, 23.30.
C
Method b
A solution of 4 g (0.03 mole) TMCE 2a and 7g (0.05 mole)
methyl iodide in 15 ml dry chloroform was refluxed for 5 days in
a flask protected from light (aluminum foil). Distillation gave 3.8
g (56%) 4a. Replacing methyl by ethyl iodide gave 62% yield of
4a after 70 hours reflux.
4.3.3. Synthesis of hydroxy-lactone 15
4.3.3.1. PMB protection of alcohol 12.
4.3. Syntheses of hydroxy-lactones 12, 14, 15.
3.16 g (1.3 equiv., 79.1 mmol) of sodium hydride, 60 mL of
THF and 0.2 mL of tBuOH were introduced in a flame dried 500
mL flask. A solution of compound 2 in 20 mL of THF was added
dropwise to the mixture at 0 °C (ice-bath). After 1 hour, the
reaction mixture was treated first with p-methoxybenzyl chloride
(24.7 mL, 3 equiv., 237.4 mmol) then by tetrabutylammonium
iodide (11.2 g, 0.5 equiv., 39.5 mmol, addition in one portion).
After 15 min at 0 °C the mixture was stirred for 14 hours at room
temperature. The reaction was quenched by slow addition of
water and the resulting mixture was extracted with ethyl acetate
(3x). The organic phase was washed with brine and dried over
MgSO4. After evaporation of the volatile material, the crude
residue was purified by chromatography over silica gel.
(petroleum ether: ethyl acetate 95:5 to 80:20) to yield 17.2 g
(63%) of pure compound 13. as pale yellow oil; TLC (petroleum
ether : ethyl acetate, 4:1 ) Rf = 0.38; 1H NMR (300 MHz,
CDCl3): δ = 1.06-1.10 (m, 21H), 2.17-2.30 (m, 3H), 2.51-2.61
(m, 1H), 2.76-2.83 (m, 2H), 3.68 (ddd, J = 5.3, 10.1, 15.3 Hz,
2H), 3.82 (s, 3H), 3.97 (dd, J = 4.7, 9.7 Hz, 1H), 4.36 (d, J =
11.4 Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H), 4.96-5.01 (m, 1H), 6.87-
6.93 (m, 2H), 7.23-7.34 (m, 2H) ppm.; 13C NMR (75 MHz,
CDCl3): δ = 11.9, 18.0, 35.7, 37.4, 39.4, 54.7, 55.3, 63.2, 70.8,
81.0, 84.4, 113.8, 129.3, 130.2, 159.2, 177.3 ppm.
4.3.1. Synthesis of hydroxy-lactone 12
Method a
Et3N (18.2 mL, 1.5 equiv.) was added to diol 11 (15g, 87.1
mmol) in DMF (150 mL). TIPSOTf (25.7 mL, 1.1 equiv) was
slowly syringed in the solution at 0 °C. The mixture was stirred
at room temperature for 36 hours. Then water (7-10 volumes)
was added and the crude mixture was extracted with ethyl
acetate. The extract was washed with brine and dried over
MgSO4. Evaporation of the solvent left an oily residue which was
purified by flash chromatography over silica gel (petroleum ether
and ethyl acetate 4:1 to 3:2). Yield: 24.3 g (85%) of pure
hydroxy-lactone 12. White solid; TLC (petroleum ether : ethyl
acetate, 3:2) Rf = 0.43; 1H NMR (300 MHz, CDCl3): δ = 1.07-
1.13 (m, 21H), 2.00-2.07 (m, 3H), 2.46-2.57 (m, 2H), 2.61-2.70
(m, 1H), 2.82 (dd, J = 9.8, 17.8 Hz, 1H), 3.73 (dd, J = 6.8, 9.9
Hz, 1H), 3.86 (dd, J = 5.1, 9.9 Hz, 1H), 4.11-4.23 (m, 2H), 4.95
(td, J = 3.0, 7.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ =
11.8, 18.0, 35.3, 39.5, 40.9, 55.5, 64.6, 75.7, 83.8, 177.2 ppm.;
ESI-MS calculated for C17H33O4Si ([M+H]+) : 329.2, found
329.2.
Method b
4.3.3.2. Cleavage of TIPS group
A solution of TIPSOTf was prepared by dropwise addition of
TIPSH (1.15 equiv, 333.9 mmol, 68.4 mL) to a solution of TfOH
(28.3 mL, 1.1 equiv, 319.4 mmol) in 100 mL of dry DCM at 0 °C
under argon atmosphere. The ice bath was maintained until
Tetrabutylammonium fluoride (42.1 mL, 42.1 mmol, 1M in
THF) was added dropwise to a solution of a 17.2 g (38.3 mmol)
of 12 in 70 mL THF at 0 °C. After 15 min at 0 °C, the ice bath
was removed, and the reaction was allowed to warm up to room

8
Tetrahedron
4.4.3. Deoxychlorination of 14: Synthesis of
temperature. After full consumption of starting material (TLC
chloro-lactone 18
analysis) the reaction was immediately (caution: longer reaction
time will decrease the yield) quenched by addition of a saturated
solution of ammonium chloride (50 mL). The organic phase was
extracted with ethyl acetate (3 times), washed with water then
brine and finally dried over magnesium sulfate to give a crude
residue after evaporation of volatiles under vacuum. The crude
material was purified by chromatography over silica gel (ethyl
acetate and petroleum ether 4:1 to 5:0) to yield 9.9 grams of 15
(88% yield) ; light yellow oil ; TLC (ethyl acetate 100%) Rf =
DICE 2b (1.1 equiv.) was added dropwise under argon
atmosphere to a solution of lactone 14 in 5 mL of dry DCM. The
resulting mixture was left for 10-15 minutes at room temperature.
After completion of the reaction (TLC control), the solvent was
evaporated under reduced pressure and the desired product was
purified by column chromatography using petroleum ether and
1
ethyl acetate (4:1) as eluant to isolate pure product 18. H NMR
(300 MHz, CDCl3): δ = 2.23-2.36 (m, 2H), 2.50 (d, J = 16.2 Hz,
1H), 2.68-2.84 (m, 3H), 3.56 (dd, J = 9.3, 6.2 Hz, 1H), 3.68 (dd,
J = 9.2, 6.2 Hz, 1H), 3.81 (s, 3H), 4.46-4.47 (m, 2H), 4.58-4.61
(m, 1H), 5.08-5.14 (m, 1H), 6.9 (d, J = 8.7 Hz, 2H), 7.25 (d, J =
8.6 Hz, 2H) ppm.; 13C NMR (75 MHz, CDCl3): δ = 33.5, 40.0,
43.8, 51.0, 55.3, 63.0, 69.5, 73.1, 83.5, 113.8, 129.2, 130.0,
159.3, 176.5 ppm.
1
0.34; H NMR (300 MHz, CDCl3): δ = 2.03-2.08 (m, 3H), 2.40
(d, J = 15.6 Hz, 1H), 2.60-2.73 (m, 2H), 3.37 (d, J = 6.3 Hz,
2H), 3.67 (s, 3H), 3.80 (dd, J = 3.9, 8.8 Hz, 1H), 4.23 (d, J = 11.3
Hz, 1H), 4.36 (d, J = 11.3 Hz, 1H), 4.82-4.87 (m, 1H), 6.76 (d, J
= 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H) ppm.;13C NMR (75 MHz,
CDCl3): δ = 35.8, 37.0, 39.6, 54.5, 55.1, 62.6, 70.5, 81.5, 84.7,
113.7, 129.1, 130.2, 159.1, 177.8 ppm; ESI-MS calculated for
C16H24O5N ([M+NH4]+) : 310.1654, found 310.1650.
4.4.4. Deoxyiodination of 15: synthesis of iodo-
lactone 19
4.4. Deoxyhalogenations of hydroxy-lactones 12, 14 and 15.
TMCE 2a (1.1 equiv) was added dropwise under argon
atmosphere to a suspension of LiI or KI (see scheme 9 for
stoichiometry details) in dry DCM. The resulting mixture was
left for 1-1.5 hours at room temperature. Lactone 15 was then
added at 0 °C and the reaction was allowed to reach room
temperature. After 4 hours, the NMR yields were determined by
integration of the characteristic protons of iodo-lactone 19. After
evaporation of the volatile material, the crude residue of one
sample was purified by chromatography over silica gel
(petroleum ether: ethyl acetate 95:5 to 80:20) to isolate pure
4.4.1. Deoxychlorination of 12: synthesis of
chlorhydrine 17
DICE 2b (4.83 mL, 1.1 equiv, 23.4 mmol) was added
dropwise at 0 °C under argon atmosphere to a solution of
hydroxy-lactone 12. (7 g, 21.3 mmol) in 25 mL of dry DCM. The
resulting mixture was left for 30 minutes at room temperature.
After full consumption (checked by TLC) of starting material, the
solvent was evaporated and the crude residue was dissolved in 20
mL of anhydrous THF and cooled to 0 °C. Tetrabutylammonium
fluoride (21.3 mL, 21.3 mmol, 1M in THF) was then added
dropwise at 0 °C, then the ice bath was removed and the reaction
was allowed to warm up to room temperature. After full
consumption of starting material (TLC analysis) the reaction was
immediately (caution: longer reaction time will decrease the
yield) quenched by addition of a saturated solution of ammonium
chloride (50 mL). The organic phase was extracted with ethyl
acetate (3 times), washed with water then brine and finally dried
1
compound 19; H NMR (300 MHz, CDCl3): δ = 2.16-2.25 (m,
3H), 2.55 (dd, J = 17.4, 2.1 Hz, 1H), 2.66-2.74 (m, 1H), 2.82 (dd,
J = 17.4, 10.2 Hz, 1H), 3.58 (d, J = 6.2 Hz, 2H), 3.81 (s, 3H),
3.90 (dd, J = 10.2, 5.1 Hz, 1H), 4.35 (d, J = 11.4 Hz, 1H), 4.54
(d, J = 11.4 Hz, 1H), 4.97 (td, J = 6.5, 2.8 Hz, 1H), 6.9 (d, J = 8.7
Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H) ppm.; 13C NMR (75 MHz,
CDCl3): δ = 35.5, 37.1, 39.3, 54.0, 55.3, 63.1, 70.8, 81.2, 83.9,
113.9, 129.3, 130.0, 159.3, 177.2 ppm.
4.5. Deoxyhalogenations of cyclopentanol and 1
naphtalenemethanol (Table 1)
over magnesium sulfate to give
a crude residue after
concentration in vacuo. The crude material was purified by
chromatography on silica gel (ethyl acetate and petroleum ether
1:1 to 1:0) to yield 3 grams of chlorhydrine 17. Light yellow oil
(3g, 75 % yield over 2 steps); TLC (petroleum ether: ethyl
TMCE (1 mmol) was syringed in a solution of 1 mmol of 1-
naphthalenemethanol or cyclopentanol and dry LiBr, LiI or KI
(2.5 mmol) in deuterated acetonitrile or chloroform under argon
atmosphere. The suspension was stirred at room temperature for
15-30 min. 13C NMR of the crude mixtures revealed the
formation of the titled compounds through detection of the
characteristic signals at δ 32.04 ppm, δ 4.17 ppm corresponding
to naphthyl CH2-Br, CH2-I respectively and at δ 53.59 ppm, δ
29.81 ppm for cyclopentyl CH-Br, CH-I respectively.
1
acetate, 1:1) Rf = 0.19. H NMR (300 MHz, CDCl3): δ = 2.21-
2.30 (m, 1H), 2.42 (dt, J = 4.7, 15.6 Hz, 1H), 2.54 (d, J = 16.2
Hz, 1H), 2.74-2.95 (m, 3H), 3.86 (dd, J = 5.7, 10.9 Hz, 1H), 3.94
(dd, J = 8.9, 10.9 Hz, 1H), 4.68 (td, J = 1.5, 5.6 Hz, 1H), 5.18 (td,
J = 4.4, 7.1 Hz, 1H) ppm.;13C NMR (75 MHz, CDCl3): δ = 33.6,
39.4, 43.9, 52.9, 62.2, 62.9, 83.7, 176.6 ppm; ESI-MS calculated
for C8H10O3 ([M-H]-) : 189.0318, found 189.0321.
4.6. Deoxyhalogenations of cis- and trans-t-butyl-cyclohexanol
and l-menthol
4.4.2. Deoxyiodination of 12: Synthesis of iodo-
lactone 16b
4.6.1. Deoxychlorination of cis-t-butyl-
cyclohexanol
TMCE 2a (1.1 equiv) was added dropwise under argon
atmosphere to a suspension of LiI (1.5 equiv.) in dry DCM. The
resulting mixture was left for 1 hours at room temperature.
Lactone 12 was then added at 0 °C and the reaction was allowed
to reach room temperature. After reaction completion (TLC
check), the solvent was evaporated and the desired compound
16b was purified by chromatography over silica gel (petroleum
TMCE 2a (0.094.5 g, 0.7 mmol) was syringed into a solution
of 0.1 g (0.64 mmol) cis-t-butyl-cyclohexanol in CDCl3 under a
stream of argon. The solution was left at room temperature for 3
hrs. The crude mixture was analyzed by GC and 1H NMR
(comparison with authentic samples). It showed the expected
amide 1a and a 3:1 mixture of 4-t-butylcyclohexene and trans-t-
butyl chloride.
1
ether: ethyl acetate 95:5 to 80:20); H NMR (300 MHz, CDCl3):
δ = 1.08 (s, 21H), 2.19-2.23 (m, 1H), 2.34 (dt, J = 15.4, 4.9 Hz,
1H), 2.55 (d, J = 16.1 Hz, 1H), 2.69-2.90 (m, 3H), 3.84 (dd, J =
10.0, 6.5 Hz, 1H), 3.97 (dd, J = 10.0, 6.9 Hz, 1H), 4.60 (m, 1H),
5.15 (td, J = 7.1, 4.5 Hz, 1H) ppm.; 13C NMR (75 MHz, CDCl3):
δ = 11.9, 18.0, 33.8, 39.7, 43.9, 53.5, 62.7, 63.4, 83.7, 176.8 ppm.
4.6.2. Deoxychlorination of trans-t-butyl-
cyclohexanol
TMCE 2a (0.236 g, 1.77 mmol) was syringed into a solution
of 0.251 g (1.64 mmol) trans-t-butyl-cyclohexanol in CDCl3

9
under a stream of argon. The solution was left at room
temperature for 12 h. The crude mixture was analyzed by GC and
1H NMR (comparison with authentic samples). It showed the
expected amide 1a and a 1:2.15 mixture of 4-t-butylcyclohexene
and cis-t-butyl chloride.
1.08-2.03 (m, 31H), 4.97-4.99 (m, 1H) ppm.; 13C RMN (75
MHz, CDCl3): δ = 12.1, 13.4, 18.6, 20.8, 22.5, 22.7, 23.7, 24.1,
27.7, 27.9, 28.1, 31.7, 32.6, 34.3, 35.2, 35.7, 36.1, 36.4, 38.1,
38.6, 39.4, 39.9, 41.9, 42.5, 53.7, 56.2, 56.4 ppm.
4.7.4. Deoxyiodination of pregnenolone 28a:
synthesis of product 29a
4.6.3. Deoxychlorination of l-Menthol
TMIE (0.5 g, 2.2 mmol.) 2a was syringed into a solution of 0.64 g
(2 mmol) in dichloromethane at room temperature. After 12 h, the
solvent was removed in vacuo and then solid residue was treated
with anhydrous acetone and filtered. Recrystallisation in acetone
gave 29a as a colorless solid, m.p. 128-129 °C. The structure was
assigned by comparison with literature data, eg: 1H NMR (200
MHz, CDCl3) δ = 0.62 (s, 3H), 1.04 (s, 3H), 2.12 (s, 3H), 4.04
(txt, 3JH3ax-Hax=11.95, 3JH3ax-Heq=4.76, 1H), 5.34 (m, 1H).
TMCE 2a (1.00 g, 7.5 mmol) was syringed into a solution of
l-menthol (1.063 g, 6.8 mmol.) in CDCl3 at 0 °C under a stream
of argon. The solution was left at room temperature for 5 h. The
1
crude mixture was analyzed by GC and H NMR (comparison
with authentic samples). It showed the expected amide 1a and
neomenthyl chloride 24 (1H NMR: 87%).
4.6.4. Deoxyiodination of l-Menthol
TMIE 4a (1.00 g, 4.4 mmoles) was syringed into a solution of
l-menthol (0.63 g, 4.0 mmol.) in CDCl3 at 0 °C under a stream of
argon. The solution was left at room temperature for 5 h. The
4.7.5. Deoxyiodination of cholesterol 28b:
synthesis of product 29b
1
TMIE (0.6 g, 2.67 mmol.) 2a was syringed into a solution
of 0.94 g (2.4 mmol) in dichloromethane at room temperature.
After 12 h, the solvent was removed in vacuo and the solid
residue was recrystallized in acetone to give 29b as a colourless
solid, m.p. 106 °C, identical to an authentic sample [19, 20].
crude mixture was analyzed by GC and H NMR (comparison
with authentic samples). It showed the expected amide 1a and
neomenthyl iodide 25.
4.7. Deoxyhalogenations of sterols
4.7.1. Deoxychlorination of 3-ꢁ-cholestanol 26:
synthesis of product 27a
4.7.6. Deoxychlorination of cholesterol 28b:
synthesis of product 30[21].
TMCE 2a (1.1 equiv.) was added dropwise under argon
atmosphere to a solution of cholestanol 26 in 5 mL of dry DCM.
The resulting mixture was left for 12 hours at room temperature.
After completion of the reaction (TLC control), the solvent was
evaporated under reduced pressure and the desired product was
purified by column chromatography using petroleum ether as
DICE 2b (1.1 equiv.) was added dropwise under argon
atmosphere to a solution of cholesterol 28b in 5 mL of dry DCM.
The resulting mixture was left for 15 minutes at room
temperature. After completion of the reaction (TLC control), the
solvent was evaporated under reduced pressure and the desired
product was purified by column chromatography using petroleum
1
1
eluant. 90% yield. H NMR (300 MHz, CDCl3) δ = 0.69 (s, 3H),
ether as eluant. 74% yield. H NMR (300 MHz, CDCl3) δ = 0.68
0.82 (s, 3H), 0.89 (d, J = 1.3 Hz, 3H), 0.91 (d, J = 1.3 Hz, 3H),
0.94 (d, J = 6.5 Hz, 3H), 1.03 -2.03 (m, 31H), 4.53-4.55 (m, 1H)
ppm.; 13C NMR (75 MHz, CDCl3) δ = 11.9, 12.1, 18.1, 20.8,
22.6, 22.9, 23.9, 24.2, 28.0, 28.1, 28.3, 30.2, 35.5, 35.8, 36.1,
36.2, 36.6, 39.2, 39.5, 40.0, 42.6, 53.9, 56.3, 56.5, 60.7 ppm.
(s, 3H), 0.87 (d, J = 1.26 Hz, 3H), 0.90 (d, J = 1,32 Hz, 3H), 0.92
(d, J = 6.5 Hz, 3H), 1.05 (s, 3H), 1.04-2.70 (m, 28H), 3.73-3.75
(m, 1H), 5.38-5.39 (m, 1H) ppm.; 13C RMN (75 MHz, CDCl3): δ
= 11.6, 18.5, 19.1, 20.7, 22.3, 22.7, 23.5, 24.1, 27.9, 28.1, 31.5,
33.2, 35.7, 36.0, 36.3, 38.9, 39.3, 39.6, 42.1, 43.2, 49.8, 55.9,
56.4, 60.1, 122.3, 140.6 ppm.
4.7.2. Deoxybromination of 3-ꢁ-cholestanol 26:
synthesis of product 27b[18].
Acknowledgments
DICE 2b (1.1 equiv) was added dropwise under argon
atmosphere to a suspension of LiBr (2.5 equiv.) in 5 mL of dry
DCM. The resulting mixture was left for 1 hour at room
temperature. 3-ꢁ-cholestanol 26 was then added at 0 °C and the
reaction run for further 4 hours. After completion of the reaction
(TLC control), the solvent was evaporated under reduced
pressure and the desired product was purified by column
We warmly thank the following organisations for their generous
support to our work: The General Agency for Cooperation and
Development
(AGCD,
Belgium),
UCLouvain,
Dart
Neurosciences LLC (USA), the Institute for Scientific Research
in Industry and Agriculture (IRSIA, Belgium), the National
Fondation for Scientific Research (FNRS. Belgium), the Rwanda
Government, the Institut Français d’Egypte au Caire (IFE) and
the Science and Technology Development Fund (STDF, Egypt),
the Institut Servier, the European Institute of Chemistry and
Biology (IECB, France) and CNRS (France). This work has
benefited from the facilities and expertises of the Biophysical and
Structural Chemistry plateform (BPCS) at IECB, CNRS
1
chromatography using petroleum ether as eluant. 96% yield. H
NMR (300 MHz, CDCl3) δ = 0.68 (s, 3H), 0.82 (s, 3H), 0.87 (d, J
= 1.3 Hz, 3H), 0.90 (d, J = 1.3 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H),
1.02-2.03 (m, 31H), 4.74-4.77 (m, 1H) ppm.; 13C RMN (75 MHz,
CDCl3): δ = 11.9, 12.2, 18.5, 20.6, 22.4, 22.7, 23.7, 24.0, 27.8,
28.0, 28.1, 30.9, 31.7, 32.8, 35.3, 35.7, 36.1, 37.2, 39.4, 39.8,
40.0, 42.5, 53.7, 55.9, 56.1, 56.3 ppm.
UMS3033,
Inserm
US001,Bordeaux
University http://www.iecb.ubordeaux.fr/index.php/fr/plateforme
stechnologiques
4.7.3. Deoxyiodination of 3-ꢁ-cholestanol 26:
synthesis of product 27c
DICE 2b (1.1 equiv) was added dropwise under argon
atmosphere to a suspension of NaI or CsI (2.5 equiv.) in 5 mL of
dry DCM. The resulting mixture was left for 1 hours at room
temperature. 3-ꢁ-cholestanol 26 was then added at 0 °C and the
reaction run for further 4 hours. After completion of the reaction
(TLC control), the solvent was evaporated under reduced
pressure and the desired product was purified by column
chromatography using petroleum ether as eluant. 72% yield. 1H
NMR (300 MHz, CDCl3) δ = 0.68 (s, 3H), 0.82 (s, 3H), 0.89 (d, J
= 1.3 Hz, 3H), 0.91 (d, J = 1.3 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H),
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: