Asymmetric synthesis of α-alkylated N-sulfinyl imidates as new chiral building blocks

Article abstract of DOI:10.1021/jo900046t

(Chemical Equation Presented) α-Alkylation of N-sulfinyl imidates, prepared via condensation of tert-butanesulfinamide with ortho esters, led to α-substituted N-sulfinyl imidates in good-to-excellent diastereomeric ratios (dr up to >99:1) and yields. Depr

Full text of DOI:10.1021/jo900046t

Asymmetric Synthesis of r-Alkylated N-Sulfinyl Imidates as New
Chiral Building Blocks
Filip Colpaert, Sven Mangelinckx,† Guido Verniest,† and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent UniVersity,
Coupure Links 653, B-9000 Ghent, Belgium
norbert.dekimpe@ugent.be
ReceiVed January 9, 2009
R-Alkylation of N-sulfinyl imidates, prepared via condensation of tert-butanesulfinamide with ortho esters,
led to R-substituted N-sulfinyl imidates in good-to-excellent diastereomeric ratios (dr up to >99:1) and
yields. Deprotection of the alkylated N-sulfinyl imidates gave access to the corresponding imidate
hydrochlorides in outstanding yields. These imidate hydrochlorides proved to be excellent intermediates
for an easy transformation to chiral amides in good yields and enantiomeric excess upon simple heating
in chloroform. Hydrolysis of the R-benzylated imidate hydrochlorides afforded the corresponding chiral
esters with >95% ee.
Introduction
our research group prepared chiral aziridines and cyclopropy-
lamines starting from R-chlorinated N-tert-butanesulfinyl imi-
nes.3 Unfortunately, it has been shown in the literature that
attempts to further functionalize N-tert-butanesulfinyl imines via
R-alkylation with alkyl halides were unsuccessful. Indeed, the
electron-withdrawing character of the sulfinyl moiety strongly
attenuates the nucleophilicity of the metalloenamine. In contrast,
a highly diastereoselective R-alkylation of N-tert-butanesulfinyl
amidines has been reported earlier.4 Therefore, it was envisioned
that the significantly more nucleophilic metalloenamines derived
from N-sulfinyl imidates would be sufficiently reactive to enable
R-alkylation. Herein the highly diastereoselective R-alkylation
of chiral N-tert-butanesulfinyl imidates, that is, the precursors
of the aforementioned N-tert-butanesulfinyl amidines,4 used to
prepare R-alkylated N-sulfinyl imidates as new chiral building
blocks, is described. The interest in the synthesis of chiral
R-alkylated N-sulfinyl imidates arises from the fact that N-
sulfinyl imidates can be oxidized to the corresponding N-sulfonyl
imidates, which are known as potentially useful prodrugs for
drugs containing an ester function as well as for drugs containing
Since their introduction three decades ago, sulfinimines have
played an important role in the asymmetric synthesis of a variety
of structurally diverse nitrogen containing compounds.1 N-tert-
butanesulfinamide, as pioneered by Ellman and co-workers, has
drawn great attention in the auxiliary-aided asymmetric synthesis
of a broad range of chiral amines, which are present in numerous
pharmaceutical agents, natural products, and synthetic materials.2
The electron-withdrawing N-sulfinyl auxiliary activates the
imino function for nucleophilic addition, allowing reactions to
proceed at a lower temperature, and exerts a powerful stereo-
directing effect, which results in the addition of enolates and
organometallic reagents to both steric and enolizable sulfin-
imines with high and predictable asymmetric induction. Recently
* To whom correspondence should be addressed. Tel: +32 (0)9 264 59 51.
Fax: +32 (0)9 264 62 43.
† Postdoctoral Fellow of the Research Foundation - Flanders (FWO).
(1) (a) Davis, F. A.; Friedman, A. J.; Kluger, E. W. J. Am. Chem. Soc. 1974,
96, 5000. (b) Davis, F. A. J. Org. Chem. 2006, 71, 8993.
(2) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984. (b) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39. (c) Liu, G.; Cogan, D. A.;
Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278. (d) Lin,
G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem. Res. 2008, 41, 831.
(e) Qin, Y.; Wang, C.; Huang, Z.; Jiang, Y. J. Org. Chem. 2004, 69, 8533. (f)
Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am.
Chem. Soc. 2002, 124, 7880.
(3) (a) Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe, N. Org.
Lett. 2006, 8, 3129. (b) Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe,
N. Org. Lett. 2007, 9, 187. (c) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org.
Chem. 2007, 72, 3211.
(4) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.
3792 J. Org. Chem. 2009, 74, 3792–3797
10.1021/jo900046t CCC: $40.75 2009 American Chemical Society
Published on Web 04/14/2009

Synthesis of R-Alkylated N-Sulfinyl Imidates
a primary sulfonamide group.5 Furthermore, N-deprotection of
N-sulfinyl imidates leads to the corresponding imidates and their
salts which have been known for nearly a century but for which
only one general direct preparative method exists. This method
of Pinner involves the synthesis of the imidate hydrochloride
salt from the appropriate nitrile and alcohol with anhydrous
hydrogen chloride.6 Several other synthetic methods of specific
imidates have been reported.7 Until now, the Pinner synthesis
was the only method used to prepare chiral R-alkylated
imidates,8 but this synthesis suffers from some limitations, such
as long reaction times and poor yields.6 In our hands, in most
cases the Pinner reaction was accompanied by the formation of
small quantities of the corresponding amides and methyl esters
as side products.9 It should be noted that N-unsubstituted
imidates are useful intermediates for the synthesis of a variety
of compounds, as recently demonstrated in the preparation of
imidazoles and imidazolinones as intermediates in the synthesis
of the angiotensin II antagonist Losartan,10 imidazolines as
precursors of 2,4(5)-connected imidazole crown ethers,11 ben-
zimidazoles as smooth muscle cell proliferation inhibitors,12 and
oxazoles as intermediates in the total synthesis of (-)-Hennox-
azole A13 and as mGluR5 antagonists with applications in the
treatment of drug abuse.14 Furthermore, N-unsubstituted imi-
dates are useful in the preparation of oxazolines as efficient
ligands for the iridium catalyzed enantioselective hydrogenation
of unfunctionalized tetrasubstituted olefins,15 benzoxazoles as
modulators of metabotropic glutamate receptors,16 thiazolines
as starting material for the total synthesis of cystothiazoles A
and C,17 triazoles for the treatment of breathing disorders,18 and
several other interesting heterocycles like quinazolines,19 py-
rimidines,20 and N-acyllactams.21
SCHEME 1. Synthesis of N-Sulfinyl Imidates 3 via
Condensation of (Rs)-tert-Butanesulfinamide 1 with Ortho
Esters 2
TABLE 1. Optimization of the r-Alkylation of N-Sulfinyl Imidate
3c with Benzyl Bromide
conversion of
temp (°C),
time (h)
3c into 4h
yieldb
(%)
entry
base
(%)
dra
1
2
3
4
5
6
7
8
9
1.2 equiv LDAc
1.4 equiv LDAc
1.6 equiv LDAc
1.5 equiv LDAd
1.5 equiv LiHMDSd
1.5 equiv LiHMDSc
0 to rt, 28
0 to rt, 2
0 to rt, 2
-78, 1
-78, 1.5
0 to rt, 1.5
0 to rt, 1.5
63
69f
73:27
71:29
69:31
71:29
71:29
63:37
96:4
57f
36
49f
100
100
100
100
100
42g
c e
,
1.6 equiv KHMDS
63
79
84
1.5 equiv KHMDSd e -78, 1.5
95:5
98:2
,
1.2 equiv KHMDSd e -78, 1.5
,
a Diastereomeric ratio determined via 1H NMR analysis of the crude
reaction mixture. b Yield of (Rs,R)-4h after flash chromatography.
c Deprotonation was performed at 0 °C. d Deprotonation was performed
at -78 °C. e A 0.5 M solution of KHMDS in toluene was used (2:3
THF/0.5 M solution of KHMDS in toluene (v/v)). f Some unidentified
side products were also detected by 1H NMR analysis of the crude
reaction mixture. g (Rs,S)-4h was isolated in 21% yield.
Results and Discussion
After optimization of a literature procedure, the condensation
of (Rs)-tert-butanesulfinamide 1 and ortho esters 2 with a
catalytic amount of p-TsOH without solvent afforded chiral
N-sulfinyl imidates 3a-c in excellent yields (Scheme 1).4,22
The R-alkylation of N-tert-butanesulfinyl imidates 3 with alkyl
halides was optimized by systematically changing the reaction
conditions in the R-alkylation of N-sulfinyl imidate 3c with
benzyl bromide for the synthesis of (Rs,R)-imidate 4h (Table
1). All initial attempts using LDA to deprotonate N-sulfinyl
imidate 3c resulted in incomplete conversion to the R-alkylated
imidate 4h because of the formation of unidentified side products
and moderate diastereoselectivity leading to low yields of 4h
(Table 1, entries 1-4).
(5) (a) Bundgaard, H.; Larsen, J. D. J. Med. Chem. 1988, 31, 2066. (b) Larsen,
J. D.; Bundgaard, H. Int. J. Pharm. 1989, 51, 27.
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Hendrix, J. A.; Horita, K.; Malecha, J. W.; Parkinson, C. J.; Van Sickle, A.
Can. J. Chem. 2001, 79, 1562. (b) Brussee, J.; Loos, W. T.; Kruse, C. G.; Van
der Gen, A. Tetrahedron 1990, 46, 979. (c) Elmore, D. T.; Guthrie, D. J. S.;
Kay, G.; Williams, C. H. J. Chem. Soc., Perkin Trans. 1 1988, 1051.
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Tetrahedron 2004, 60, 5077.
(10) Griffiths, G. J.; Hauck, M. B.; Imwinkelried, R.; Kohr, J.; Roten, C. A.;
Stucky, G. C. J. Org. Chem. 1999, 64, 8084.
The use of LiHMDS (lithium bis(trimethylsilyl)amide) as a
base gave full conversion at -78 °C in 1.5 h and resulted in a
better yield of (Rs,R)-4h (42%, entry 5). It was also possible to
isolate the other diastereomer (Rs,S)-4h (21%) because of the
moderate diastereoselectivity of the reaction (dr 71:29). Repeat-
ing the reaction at room temperature led, not surprisingly, to
an even lower stereoselectivity (Table 1, entry 6). The best
results were obtained when KHMDS was used as a base leading
to enhanced diastereoselectivities and yields at lower temper-
ature or upon the use of less equivalents of KHMDS (Table 1,
entry 7-9). Finally, treating N-sulfinyl imidate 3c with 1.2 equiv
of KHMDS for 45 min at -78 °C followed by a reaction with
1.3 equiv of benzyl bromide at -78 °C for 1.5 h afforded N-tert-
butanesulfinyl imidate 4h with excellent diastereoselectivity (dr
(11) Zimmerman, S. C.; Cramer, K. D.; Galan, A. A. J. Org. Chem. 1989,
54, 1256.
(12) Elokdah, H. M.; Sie-Yearl, C.; Sulkowski, T. S. PCT Int. Appl. 039390,
1996; Chem. Abstr. 2006, 126, 131460.
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Theberge, A. B.; Carroll, K. A.; Kurihara, T.; Wessler, J. D. J. Org. Chem.
2008, 73, 142.
(14) Iso, Y.; Kozikowski, A. P. Synthesis 2006, 243.
(15) Schrems, M. G.; Neumann, E.; Pfaltz, A. Heterocycles 2008, 76, 771.
(16) Bessis, A.-S.; Bolea, C.; Bonnet, B.; Epping-Jordan, M.; Poirier, N.;
Poli, S.-M.; Rocher, J. P.; Thollon, Y. PCT Int. Appl. 123703, 2005; Chem.
Abstr. 2005, 144, 88317.
(17) Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem. 2001, 66, 8463.
(18) Konetzki, I.; Bouyssou, T.; Hoenke, C.; Schnapp, A. Ger. Offen DE
102005007654, 2006; Chem. Abstr. 2006, 145, 249212.
(19) Connolly, D. J.; Lacey, P. M.; McCarthy, M.; Saunders, C. P.; Carroll,
A.-M.; Goddard, R.; Guiry, P. J. J. Org. Chem. 2004, 69, 6572.
(20) Cabaj, J.; Doskocz, J.; Soloducho, J.; Chyla, A. Heterocycles 2006, 68,
137.
(21) Wirth, W.; Wangermann, K.; Botta, A. Ger. Offen DE 4401927, 1995;
Chem. Abstr. 1995, 123, 135889.
(22) Owens, T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem. 2003, 68, 3.
J. Org. Chem. Vol. 74, No. 10, 2009 3793

Colpaert et al.
TABLE 2. Asymmetric r-Alkylation of N-Sulfinyl Imidates 3 with Alkyl Halides
entry
R1
R2X
temp (°C)
product 4
(Rs,R)-4a
(Rs,R)- and (Rs,S)-4b
(Rs,R)-4c
(Rs,R)-4d
(Rs,R)-4e
(Rs,S)- and (Rs,R)-4b
(Rs,R)-4f
(Rs,R)-4g
(Rs,R)-4h
(Rs,S)-4g
drc
yieldd (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Et
Et
Et
Et
Pr
BnBr
EtI
allyl Br
PrI
BnBr
MeI
allyl Br
PrI
BnBr
EtI
allyl Br
MeI
-78
-78 to rt
-78
-78 to rt
-78
-78
-78
-78 to rt
-78
98:2
70:30
98:2
76:24
96:4
78:22
>99:1
>99:1
98:2
77
e
75
49f
90
g
88
78
84
79
85
34h
9
10
11
12
Pr
Pr
Pr
-78 to rt
-78
-78
>99:1
>99:1
79:21
(Rs,R)-4i
(Rs,S)-4d
b
a 2:3 THF/0.5 M solution of KHMDS in toluene (v/v). Determined by H NMR analysis with Pirkle’s alcohol. c Diastereomeric ratio determined via
1H NMR analysis of the crude reaction mixture. d Yield of a single diastereomer 4 after flash chromatography. e The diastereomers 4b could not be
separated via flash chromatography resulting in 4b (32%, dr 78:22 and 48%, dr 57:43). f The major diastereomer (Rs,R)-4d was isolated in 49% yield,
and additionally, a mixture of diastereomers 4d (dr 36:64) was isolated in 28% yield. g The diastereomers 4b could not be separated via flash
chromatography, resulting in 4b (80%, dr 76:24). h The major diastereomer (Rs,S)-4d was isolated in 34% yield, and additionally, a mixture of
diastereomers 4d (dr 73:27) was isolated in 46% yield.
1
TABLE 3. N-Deprotection of r-Alkylated N-Sulfinyl Imidates 4 to
98:2), giving access to (Rs,R)-imidate 4h in 84% yield after
the Corresponding Imidate Hydrochlorides 5
chromatography.
Analogously, a variety of new chiral R-alkylated N-sulfinyl
imidates 4 were prepared in good-to-excellent diastereomeric
ratios (dr 70:30 to >99:1) and yields (75-90%) using the
optimized reaction conditions (Table 2). When the reaction was
performed using iodoethane or 1-iodopropane as the electrophile,
entry
R1
R2
product 5
yielda (%)
no reaction occurred at -78 °C, and therefore, the reaction was
performed at higher temperatures (-78 °C to rt) to achieve full
conversion (entries 2, 4, 8, and 10). It is noteworthy that the
R-alkylation of N-sulfinyl imidates 3 with benzyl bromide and
allyl bromide resulted in high diastereoselectivity (dr 96:4 to
>99:1; entries 1, 3, 5, 7, 9, and 11), while in all the other cases
where the N-tert-butanesulfinyl imidate 4 contained an R-methyl
group a lower diastereoselectivity was observed (dr 70:30 to
79:21; entries 2, 4, 6, and 12), which resulted in a difficult
separation by flash chromatography. The enantiomeric excess
of N-tert-butanesulfinyl imidates 4 was determined by compar-
1
2
3
4
5
6
7
8
9
Me
Me
Me
Et
Et
Et
Pr
Pr
Pr
Pr
Bn
allyl
Pr
Bn
allyl
Pr
Bn
Et
allyl
Me
R-5a
R-5c
R-5d
R-5e
R-5f
R-5g
R-5h
S-5g
R-5i
S-5d
80
92
96
88
94
87
77b
90
85
87
10
a Yield after precipitation from Et2O. b Reaction conditions: 5 equiv
of HCl, dioxane, 0 °C, 5 min.
1
ing H NMR data obtained from the addition of R-Pirkle’s
alcohol as a chiral shift reagent23 to racemic mixtures of N-tert-
butanesulfinyl imidates 4, prepared with rac-tert-butanesulfi-
namide 1 as starting material, and from the addition of R-Pirkle’s
alcohol to the chiral prepared N-(tert-butanesulfinyl)imidates 4
(see Supporting Information). These experiments allowed to
conclude an enantiomeric excess of >98% for imidates 4. The
Z-stereochemistry of the N-tert-butanesulfinyl imidates 4, that
is, with the sulfinyl group and the methoxy function at the same
side of the carbon-nitrogen double bond, was ascertained by
This afforded the imidate hydrochlorides 5 in high yield
(80-96%) after precipitation from diethyl ether (Table 3, entries
1-6 and 8-10). Imidate hydrochloride R-5h was prepared by
treatment of N-tert-butanesulfinyl imidate (Rs,R)-4h with 5 equiv
of HCl in dioxane for 5 min at 0 °C (Table 3, entry 7). The use
of more equivalents of HCl, higher temperature, and/or longer
reaction time led to the formation of the corresponding amide.
Imidate hydrochloride R-5c is a known compound in the
literature, prepared by the Pinner method starting from the corr-
esponding chiral nitrile, which is synthesized from the corre-
sponding chiral ester, prepared using the Evans R-alkylation
method.8a Comparing the optical rotations of the newly prepared
imidate R-5c ([R]D + 35.9 (c 1.0, CHCl3) vs + 35.8 in lit.8a)
afforded a first proof on the stereochemical outcome of the
alkylation reaction. All efforts to determine the enantiomeric
excess of imidate hydrochlorides 5 by chiral HPLC failed
because of partial conversion to esters 6 on column.
1
executing several aromatic solvent-induced shift (ASIS) H
NMR experiments on imidates 3a and 4a.24
In the next step, the chiral N-tert-butanesulfinyl imidates 4
were N-deprotected by simple treatment with a saturated solution
of anhydrous HCl (20 equiv of HCl) in dioxane for 1 h at rt.
(23) Pirkle, W. H.; Sikkenga, D. L.; Pavlin, M. S. J. Org. Chem. 1977, 42,
384.
(24) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Schamp, N. Synthesis 1982,
43.
3794 J. Org. Chem. Vol. 74, No. 10, 2009

Synthesis of R-Alkylated N-Sulfinyl Imidates
SCHEME 2. Synthesis of Chiral Esters 6 from Imidate
Hydrochlorides 5
corresponding free imidate, but chromatography led only to a
35% conversion of the free imidate to amide S-8g (entry 2).
Therefore, the free imidate of salt S-5g was stirred with silica
gel in diethyl ether for 20 h at room temperature, affording full
conversion to amide S-8g which was isolated in 85% yield (entry
3). However, performing the latter method with imidate
hydrochloride R-5c and R-5e gave an incomplete conversion
to amides R-8c and R-8e of 86 and 87%, respectively (entries
4 and 5). Furthermore, when treating the free imidate of R-5c
with several acids like p-TsOH and HCl, no reaction occurred.
Heating of imidate hydrochloride R-5c at reflux temperature in
chloroform for 16 h finally afforded chiral amide R-8c in 72%
after recrystallization from diethyl ether (entry 6). Repeating
the latter method on imidate hydrochlorides R-5a, R-5e, R-5f,
R-5i, and S-5d gave access to optically pure amides R-8a, R-8e,
R-8f, R-8i, and S-8d in a 74-99% yield after recrystallization
from diethyl ether (entries 7-11).
Amide R-8c and the S-enantiomer of amide 8a are known
compounds in the literature,8a,28 both prepared by the Evans
methodology. Comparison of the optical rotations ([R]D R-8a
- 48.1 (c 0.5, EtOH) vs S-8a + 53.1 in lit.,28 [R]D R-8c - 15.7
(c 1.1, CHCl3) vs - 22.9 in lit.8a) further confirmed the assigned
stereochemistry of the obtained compounds. The overall trans-
formation of imidates 3 to chiral amides 8 is clearly competitive
with the methodology to prepare chiral amides via aminolysis
of Evans’s chiral oxazolidinones in terms of yields and
simplicity.8a,28,29
The enantiomeric excess of amides 8 was determined by
comparing 1H NMR data obtained from the addition of
R-Pirkle’s alcohol to racemic mixtures of amides 8, prepared
with rac-tert-butanesulfinamide 1 as starting material, and from
the addition of R-Pirkle’s alcohol to the enantiomerically pure
prepared amides 8. These experiments, in addition to chiral
HPLC or chiral GC analysis, allowed to conclude >95% ee for
amides 8 (see Supporting Information).
In analogy with a model proposed in a report on the
asymmetric synthesis of 1,3-amino alcohols from N-sulfinyl
imines,30 the stereoselectivity of the alkylation reaction to
imidates 4 can be explained with a model in which the reaction
proceeds via transition state A instead of B (Figure 1).
Upon deprotonation of N-sulfinyl imidate 3, the E-enolate
will be preferentially formed with the R1 group and the NSOtBu
group at opposite sides of the C-C double bond.25 The
stereoselectivity can be explained by the fact that the steric
repulsion between the tert-butyl group and the approaching alkyl
halides (R2-X) in transition state B is a determining factor to
drive the reaction via transition state A.
The R-benzylated imidate hydrochlorides R-5a and R-5e were
treated with water to achieve the formation of chiral esters 6
(Scheme 2). Stirring imidate hydrochloride R-5a in water for
24 h at room temperature gave access to ester R-6a in 73%
yield after flash chromatography. However, treating imidate
hydrochloride 5e with water for 24 h at room temperature
afforded only 44% conversion to ester R-6e. Therefore, imidate
hydrochloride R-5e was heated in water for 24 h at reflux
temperature, giving full conversion to ester R-6e which was
isolated in 74% yield (Scheme 2). All attempts to convert the
other R-alkylated imidate hydrochlorides 5 to the corresponding
esters failed, leading to incomplete conversions, amide forma-
tion, or complex reaction mixtures. Stirring imidate hydrochlo-
ride R-5g in water for 20 h at room temperature gave access to
a mixture of the corresponding ester (36%) and amide (64%).
Surprisingly, upon heating imidate hydrochloride R-5g in water
for 24 h at reflux temperature, no formation of the corresponding
ester was observed, but instead the formation of the correspond-
ing amide was observed in the 1H NMR spectrum of the crude
reaction mixture. An analogous treatment of imidate hydro-
chloride R-5d afforded a complex mixture without ester
formation.
Furthermore, N-sulfinyl imidates 3a and 4d could be easily
oxidized with m-CPBA to the corresponding N-sulfonyl imidates
7 in excellent yields (Scheme 3). According to a literature
procedure,25 N-sulfonyl imidate 7d was treated with a catalytic
amount of DBU in DMF/H2O (95:5) at room temperature to
achieve the formation of the corresponding ester 6d. Unfortu-
nately, only a very low yield of the corresponding N-unsubsti-
tuted imidate was formed.
Ester R-6a is a known compound in the literature, prepared
by the Evans methodology,26 thus allowed a comparison of the
optical rotations ([R]D - 35.3 (c 0.5, CHCl3) vs - 33.7 in lit.26),
and confirmed the assigned stereochemistry of ester R-6a. Also,
ester R-6e is a known compound in the literature, but no optical
rotation was reported.27 The enantiomeric excess of esters 6
was determined by chiral HPLC (see Supporting Information).
In the final part, chiral amides 8 were prepared starting from
imidate hydrochlorides 5 (Table 4). In a first attempt, imidate
hydrochloride R-5a was treated with saturated NaHCO3(aq) for
30 min at room temperature, forming the corresponding free
imidate, followed by flash chromatography on silica gel leading
to amide R-8a in 87% yield (entry 1). Via an analogous
treatment, imidate hydrochloride S-5g was converted to the
Conclusions
It was demonstrated that chiral R-substituted N-sulfinyl
imidates are formed as new chiral building blocks in high yields
with good-to-excellent diastereomeric ratios via R-alkylation of
N-sulfinyl imidates. N-Deprotection of the alkylated N-sulfinyl
SCHEME 3. Synthesis of N-Sulfonyl Imidates 7 and Attempted DBU-Catalyzed Hydrolysis to the Corresponding Esters 6
J. Org. Chem. Vol. 74, No. 10, 2009 3795

Colpaert et al.
TABLE 4. Synthesis of Chiral Amides 8 from Imidate Hydrochlorides 5
entry
1
R1
R2
reaction conditions
product 8
R-8a
yieldb (%)
87
Me
Bn
(1) sat. NaHCO3(aq), 30 min, rt
(2) SiO2 (chromatography)
(1) sat. NaHCO3(aq), 30 min, rt
(2) SiO2 (chromatography)
(1) sat. NaHCO3(aq), 30 min, rt
(2) SiO2, Et2O, rt, 20 h
(1) sat. NaHCO3(aq), 30 min, rt
(2) SiO2, Et2O, rt, 20 h
(1) sat. NaHCO3(aq), 30 min, rt
(2) SiO2, Et2O, rt, 20 h
CHCl3, ∆, 16 h
2
3
4
5
Pr
Et
S-8g
S-8g
R-8c
R-8e
c
Pr
Et
85
d
Me
Et
allyl
Bn
e
6
7
8
9
10
11
Me
Me
Et
Et
Pr
allyl
Bn
Bn
allyl
allyl
Me
R-8c
R-8a
R-8e
R-8f
R-8i
S-8d
72
75
99
74
92
79
CHCl3, ∆, 16 h
CHCl3, ∆, 16 h
CHCl3, ∆, 16 h
CHCl3, ∆, 16 h
Pr
CHCl3, ∆, 16 h
a Determined by 1H NMR with Pirkle’s alcohol (R-8a, R-8c, and R-8e) by chiral HPLC (R-8a and R-8e) and by chiral GC (R-8c). b Yield after
chromatography or recrystallization from Et2O. c 35% conversion to S-8g. d 86% conversion to R-8c. e 87% conversion to R-8e.
1H NMR (300 MHz, CDCl3): δ 1.21 (3H, d × d, J ) 7.6, 7.6 Hz),
1.22 (9H, s), 2.68 (1H, d × q, J ) 14.6, 7.6 Hz), 2.71 (1H, d × q,
J ) 14.6, 7.6 Hz), 3.77 (3H, s). 13C NMR (75 MHz, CDCl3): δ
10.8, 21.9, 26.3, 54.2, 55.7, 178.0. MS (ES, pos. mode) m/z (%):
192 (M + H+, 100). HRMS: calcd for C8H17NO2S, 192.1053 [M
+ H]+; found, 192.1048 [M + H]+.
Synthesis of r-Alkylated N-tert-Butanesulfinyl Imidates 4. The
synthesis of (Rs,R)-methyl N-tert-butanesulfinyl-2-methyl-3-phe-
nylpropanimidate 4a is representative. To a 0.5 M solution of
KHMDS (1.2 equiv, 10.06 mL, 5.03 mmol) in toluene was added
THF (7 mL) (2:3 THF/0.5 M solution KHMDS in toluene (v/v)),
and the solution was cooled to -78 °C. Rs-Methyl N-tert-
butanesulfinyl propanimidate 3a (1 equiv, 0.80 g, 4.19 mmol) in
THF (8 mL) was slowly added, and the resulting solution was stirred
for 45 min at -78 °C. Benzyl bromide (1.3 equiv, 0.65 mL, 5.45
mmol) was then added, and the reaction mixture was stirred at -78
FIGURE 1. Proposed stereochemical model for the R-alkylation of
°C for 1.5 h. To the reaction mixture was added 2 N AcOH/THF
N-sulfinyl imidates 3.
(10 mL), which was cooled to the same temperature as the reaction
vessel before the addition. A saturated aqueous solution of NaHCO3
(10 mL) was then added to the mixture upon stirring. The aqueous
imidates gave access to enantiopure imidate hydrochlorides in
excellent yields, as useful intermediates for an easy transforma-
tion to chiral amides upon simple heating in chloroform.
phase was extracted with EtOAc (3 × 15 mL). The combined
organic phases were dried (MgSO4), filtered, and evaporated in
Hydrolysis of the R-benzylated imidate hydrochlorides afforded
the corresponding chiral esters with >95% ee. By comparing
the optical rotations of the synthesized imidates, esters, and
amides with literature data from known compounds, evidence
was obtained about the stereochemical outcome of the alkylation
reaction.
vacuo. The crude product was purified by flash chromatography to
yield 0.91 g (3.23 mmol) of pure (Rs,R)-methyl N-tert-butanesulfi-
nyl-2-methyl-3-phenylpropanimidate 4a. Rf ) 0.16 (7:3 petroleum
ether/Et2O). Yield: 77%. [R]D - 118.0 (c 2.6, CHCl3). Ee >98%.
IR (cm-1): νmax 1075, 1603, 2946. 1H NMR (300 MHz, CDCl3): δ
1.10 (3H, d, J ) 6.6 Hz), 1.18 (9H, s), 2.64 (1H, d × d, J ) 13.2,
9.1 Hz), 3.07 (1H, d × d, J ) 13.2, 5.8 Hz), 3.57-3.66 (1H, m),
3.72 (3H, s), 7.14-7.33 (5H, m). 13C NMR (75 MHz, CDCl3): δ
16.3, 21.7, 38.8, 39.8, 53.8, 55.5, 126.1, 128.1, 128.9, 138.7, 178.2.
MS (ES, pos. mode) m/z (%): 282 (M + H+, 100). HRMS: calcd
for C15H23NO2S, 282.1522 [M + H]+; found, 282.1504 [M + H]+.
Synthesis of Imidate Hydrochlorides 5. The synthesis of
imidate hydrochloride 5a is representative. To a solution of (Rs,R)-
methyl N-tert-butanesulfinyl-2-methyl-3-phenylpropanimidate 4a
(0.40 g, 1.42 mmol) in dioxane (10 mL) was added dropwise freshly
prepared saturated dioxane/HCl (15 mL, ∼20 equiv HCl). The
mixture was allowed to stir for 1 h. Then the reaction mixture was
concentrated in vacuo. Precipitation in diethyl ether afforded 0.24 g
(1.14 mmol) of pure R-methyl 2-methyl-3-phenylpropanimidate
hydrochloride 5a. Yield: 80%. [R]D - 21.2 (c 1.3, CHCl3). Mp
Experimental Section
Synthesis of N-tert-Butanesulfinyl Imidates 3. The synthesis
of Rs-methyl N-tert-butanesulfinyl propanimidate 3a is representa-
tive. To a round-bottomed flask charged with Rs-tert-butanesulfi-
namide 1 (3.00 g, 24.79 mmol) were added trimethyl orthopropi-
onate 2 (3 equiv, 9.98 g, 74.37 mmol) and p-toluenesulfonic acid
monohydrate (0.005 equiv, 0.02 g, 0.12 mmol). The reaction
mixture was stirred for 3 h at 100 °C, and the volatile materials
were removed in vacuo. The crude oil was purified by vacuum
distillation (57 °C, 0.1 mmHg) to yield 4.40 g (23.04 mmol) of
pure Rs-methyl N-tert-butanesulfinyl propanimidate 3a. Yield: 93%.
[R]D - 120.3 (c 2.9, CHCl3). IR (cm-1): νmax 1073, 1607, 2948.
3796 J. Org. Chem. Vol. 74, No. 10, 2009

Synthesis of R-Alkylated N-Sulfinyl Imidates
119.3-119.5 °C. IR (cm-1): νmax 1644, 2870. 1H NMR (300 MHz,
CDCl3): δ 1.29 (3H, d, J ) 6.9 Hz), 2.84 (1H, d × d, J ) 13.5, 8.0
Hz), 3.06 (1H, d × d, J ) 13.5, 7.4 Hz), 3.43-3.55 (1H, m), 4.22
column: MeOH (50%)/20 mM NH4HCO3 + 0.1% diethylamine in
water (v/v) (50%), 0.5 mL min-1, 25 °C, tR (S-8a) ) 13.44 min, tR
1
(R-8a) ) 18.64 min (see Supporting Information). H NMR (300
(3H, s), 7.22-7.33 (5H, m), 11.55 (1H, br s), 12.52 (1H, br s). 13
C
MHz, CDCl3): δ 1.19 (3H, d, J ) 6.9 Hz), 2.47-2.59 (1H, m),
2.64-2.71 (1H, m), 2.92-3.02 (1H, m), 5.36 (1H, br s), 5.69 (1H,
br s), 7.12-7.31 (5H, m). All spectroscopic data were in good
agreement with reported data.28,31
NMR (75 MHz, CDCl3): δ 16.7, 39.7, 40.3, 60.8, 127.2, 128.9,
129.1, 136.9, 182.8. MS (ES, pos. mode) m/z (%): 178 (M + H+
- HCl, 100). Anal. Calcd for C11H16ClNO: C, 61.82; H, 7.55; N,
6.55. Found: C, 62.08; H, 7.72; N, 6.70.
Synthesis of S-2-Ethylpentanamide 8g. To S-methyl 2-ethyl-
pentanimidate hydrochloride 5g (0.13 g, 0.72 mmol) was added a
saturated aqueous solution of NaHCO3 (10 mL). The reaction
mixture was stirred for 30 min at room temperature and subse-
quently extracted with diethyl ether (3 × 15 mL). The combined
organic phases were dried (MgSO4), filtered, and evaporated in
vacuo. The resulting free imidate was dissolved in diethyl ether (5
mL), and silica gel (1.00 g) was added. The reaction mixture was
stirred for 20 h at room temperature, subsequently filtered, and
evaporated in vacuo. Recrystallization from diethyl ether afforded
0.09 g of pure S-2-ethylpentanamide 8g. Yield: 85%. [R]D - 1.4
(c 1.0, CHCl3). Mp 121.6-121.9 °C. IR (cm-1): νmax 1653, 3370.
1H NMR (300 MHz, CDCl3): δ 0.89-0.96 (6H, m), 1.22-1.66
(6H, m), 2.01-2.10 (1H, m), 5.54 (1H, br s), 5.95 (1H, br s). 13C
NMR (75 MHz, CDCl3): δ 12.1, 14.2, 20.9, 26.1, 35.0, 48.8, 178.4.
MS (ES, pos. mode) m/z (%): 130 (M + H+, 100). Anal. Calcd for
C7H15NO: C, 65.07; H, 11.70; N, 10.84. Found: C, 64.93; H, 11.60;
N, 10.80.
Synthesis of R-Methyl 2-Methyl-3-phenylpropanoate 6a.
R-Methyl 2-methyl-3-phenylpropanimidate hydrochloride 5a (0.18
g, 0.84 mmol) was dissolved in H2O (10 mL). The reaction mixture
was stirred for 24 h at room temperature, subsequently poured in
a saturated aqueous solution of NaHCO3 (15 mL), and extracted
with diethyl ether (3 × 15 mL). The combined organic phases were
dried (MgSO4), filtered, and evaporated in vacuo. The crude product
was purified by flash chromatography to yield 0.11 g of pure
R-methyl 2-methyl-3-phenylpropanoate 6a. Rf ) 0.60 (6:4 petro-
leum ether/Et2O). Yield: 73%. [R]D - 35.3 (c 0.5, CHCl3) vs -
33.7 in lit.26 Ee ) 99.4%, HPLC Daicel Chiralcel OJ-RH column:
MeOH (75%)/20 mM NH4HCO3 + 0.1% diethylamine in water
(v/v) (25%), 0.5 mL min-1, 20 °C, tR (R-6a) ) 26.53 min, tR (S-
6a) ) 29.00 min (see Supporting Information). 1H NMR (300 MHz,
CDCl3): δ 1.14 (3H, d, J ) 6.6 Hz), 2.62-2.79 (2H, m), 2.97-3.05
(1H, m), 3.62 (3H, s), 7.10-7.36 (5H, m). All spectroscopic data
were in good agreement with reported data.26,27
Synthesis of N-tert-Butanesulfonyl Imidates 7. The synthesis
of methyl N-tert-butanesulfonyl propanimidate 7a is representative.
Rs-Methyl N-tert-butanesulfinyl propanimidate 3a (0.15 g, 0.79
mmol) was dissolved in CH2Cl2 (4 mL). m-CPBA (1.5 equiv, 0.20 g,
1.18 mmol) was then added in one portion. The reaction mixture
was stirred for 5 min at room temperature, subsequently poured in
a saturated aqueous solution of NaHCO3 (10 mL), and extracted
with dichloromethane (3 × 10 mL). The combined organic phases
were washed with 2 M NaOH (3 × 10 mL), and the mixture was
subsequently dried (MgSO4), filtered, and evaporated in vacuo to
yield 0.11 g of pure methyl N-tert-butanesulfonyl propanimidate
7a. Yield: 86%. IR (cm-1): νmax 1122, 1290, 1613, 2925. 1H NMR
(300 MHz, CDCl3): δ 1.23 (3H, t, J ) 7.2 Hz), 1.47 (9H, s), 2.89
(2H, q, J ) 7.2 Hz), 3.78 (3H, s). 13C NMR (75 MHz, CDCl3): δ
10.1, 24.1, 27.6, 55.1, 58.7, 178.2. MS (ES, pos. mode) m/z (%):
208 (M + H+, 100).
Synthesis of R-2-Methyl-3-phenylpropanamide 8a. The syn-
thesis of amide 8a is representative for the synthesis of amides 8c,
8d, 8e, 8f, and 8i. R-Methyl 2-methyl-3-phenylpropanimidate
hydrochloride 5a (0.14 g, 0.66 mmol) was dissolved in chloroform
(10 mL). The reaction mixture was stirred for 16 h at reflux
temperature and subsequently evaporated in vacuo. Recrystallization
from diethyl ether afforded 0.08 g of pure R-2-methyl-3-phenyl-
propanamide 8a. Yield: 75% (yield is 87% according to an
alternative procedure; see Supporting Information). [R]D - 48.1 (c
0.5, EtOH) vs + 53.1 in lit. for S-8a.28 Mp 113.3-113.6 °C vs
113-114 °C in lit.28 Ee ) 99.8%. HPLC Daicel Chiralcel OD-RH
Acknowledgment. The authors are indebted to the Research
Foundation - Flanders (FWO - Flanders) and Ghent University
(BOF) for financial support. Janssen Pharmaceutica (Johnson
& Johnson) and Prof. Dr. K. Abbaspour Tehrani (VUB) are
thanked for the assistance in the generation of some analytical
data.
Supporting Information Available: General experimental
conditions and spectroscopic data for N-sulfinyl imidates 3,
R-alkylated N-sulfinyl imidates 4, imidate hydrochlorides 5,
chiral esters 6, N-sulfonyl imidates 7, and chiral amides 8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO900046T
(25) Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc. 2008,
130, 1804.
(26) Delinck, D. L.; Margolin, A. L. Tetrahedron Lett. 1990, 47, 6797.
(27) Colombo, M.; De Amici, M.; De Micheli, C.; Pitre´, D.; Carrea, G.;
Riva, S. Tetrahedron: Asymmetry 1991, 2, 1021.
(28) Davies, S. G.; Dixon, D. J. Synlett 1998, 963.
(29) For a review on the use of chiral oxazolidinones, see: Ager, D. J.;
Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3.
(30) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003, 125,
11276.
(31) Kenyon, J.; Phillips, H.; Pittman, V. P. J. Chem. Soc. 1935, 1072.
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