Acyclic stereoselection in the reaction of nucleophilic reagents with chiral N-acyliminium ions generated from N-[1-(phenylsulfonyl)alkyl]imidazolidin-2-ones

Article abstract of DOI:10.1021/jo001003x

Optically active N-[1-(phenylsulfonyl)alkyl]imidazolidin-2-ones react at low temperature in the presence of tin tetrachloride to give acyclic N-acyliminium ions. These electrophilic substrates give addition products upon reaction with π-nucleophiles. Allyltrimethylsilane affords the corresponding allylated products in good yields and high diastereoselectivity. The stereochemical outcome of this process can be rationalized by taking into account the preference of the intermediate N-acyliminium ion for an E configuration that favors the attack of the nucleophile from the si-si face. Disappointing results are obtained using silyl ketene acetals; conversely trimethylsilyl enol ether of acetophenone gives the corresponding adducts in high diastereoselectivity. The utilization of trimethylsilyl enol ether of 2-acetylfuran is particularly interesting since the corresponding adducts are obtained with good diastereoselectivity and the furan ring could be amenable of further synthetic transformations.

Full text of DOI:10.1021/jo001003x

J . Org. Chem. 2000, 65, 8277-8282
8277
Acyclic Ster eoselection in th e Rea ction of Nu cleop h ilic Rea gen ts
w ith Ch ir a l N-Acylim in iu m Ion s Gen er a ted fr om
N-[1-(P h en ylsu lfon yl)a lk yl]im id a zolid in -2-on es†
Alessandra Giardina`, Tiziana Mecozzi, and Marino Petrini*
Dipartimento di Scienze Chimiche, Universita` di Camerino, via S. Agostino, 1, I-62032 Camerino,Italy
petrini@camserv.unicam.it
Received J uly 3, 2000
Optically active N-[1-(phenylsulfonyl)alkyl]imidazolidin-2-ones react at low temperature in the
presence of tin tetrachloride to give acyclic N-acyliminium ions. These electrophilic substrates give
addition products upon reaction with π-nucleophiles. Allyltrimethylsilane affords the corresponding
allylated products in good yields and high diastereoselectivity. The stereochemical outcome of this
process can be rationalized by taking into account the preference of the intermediate N-acyliminium
ion for an E configuration that favors the attack of the nucleophile from the si-si face. Disappointing
results are obtained using silyl ketene acetals; conversely trimethylsilyl enol ether of acetophenone
gives the corresponding adducts in high diastereoselectivity. The utilization of trimethylsilyl enol
ether of 2-acetylfuran is particularly interesting since the corresponding adducts are obtained with
good diastereoselectivity and the furan ring could be amenable of further synthetic transformations.
In tr od u ction
R-substituted N-acylamines with excess of nucleophile,
and this represents a viable method to obtain addition
products from enolizable substrates.6 A common item of
the above cited imino derivatives is that they require
rather strong nucleophiles to efficiently afford the cor-
responding addition products.A consistent increase in the
electrophilic aptitude of carbon-nitrogen unsaturated
substrates can be obtained moving to N-acyliminium ions
that are able to react even with weak nucleophiles.7 Such
ions are also referred as R-amidoalkylating cations8 and
are generated according to eq 1. The equilibrium in which
The addition of nucleophilic reagents to carbon-
nitrogen double bonds is a well-recognized method to
obtain interesting target molecules featured by the amino
group.1 Imines are usually poor electrophiles, and this
dictates the use of powerful nucleophilic reagents for the
addition reaction. Such carbanionic reagents in the
presence of enolizable imines very often give deprotona-
tion rather than addition products. These problems can
be partially circumvented using nucleophiles with very
low basicity as organocerium2 or organocopper reagents,3
but their application sometimes gives rather unexpected
results.4 Nitrogen derivatization of imines leads to a
plethora of reactive substrates in which the electrophilic
character may be suitably tuned by the appropriate
choice of the N-substituent.1,5 Reactive N-acylamino
derivatives can also be generated in situ by reaction of
the N-acyliminium ion is involved is usually favored by
acidic catalysts; the subsequent reaction with the nu-
cleophile is an irreversible process and leads to the
addition product. The nature of the acyl group contributes
to the stability of the iminium ion as carbamates show a
greater reactivity over simple amido groups. A suitable
choice of the leaving group X is also essential for the
success of this procedure. R-Oxygenated amides and
carbamates are undoubtlely the most exploited precur-
* To whom correspondence should be addressed. Phone: +39 0737
402253. Fax: +39 0737 637345.
† Dedicated to Professor Goffredo Rosini on the occasion of his 60th
birthday.
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Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8, 1895-1946.
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Volkmann, R. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991; Vol. 1, pp 355-396.
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Press: London, 1994. (b) Matsumoto, T.; Kobayashi, Y.; Takemoto, Y.;
Ito, Y.; Kamijo, T.; Harada, H.; Terashima, S. Tetrahedron Lett. 1990,
31, 4175-4176. (c) Reetz, M. T.; J aeger, R.; Drewlies, R.; Hu¨bel, M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 103-105.
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1079-1082.
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(5) For some recent examples, see: (a) Zwierzak, A.; Napieraj, A.
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Slawin, A.; Takle, A. K. J . Chem. Soc., Perkin Trans. 1 1999, 3343-
3354. (c) Shen, Y.; J iang, G.-F. Synthesis 2000, 99-102. (d) Hayashi,
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D. E.; Fa¨ssler, R.; Carreira, E. M. J . Am. Chem. Soc. 1999, 121, 11245-
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H. Tetrahedron 1985, 41, 4367-4416.
(8) Zaugg, H. A. Synthesis 1984, 85-110 and 181-212.
10.1021/jo001003x CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/08/2000

8278 J . Org. Chem., Vol. 65, No. 24, 2000
Giardina` et al.
Sch em e 1
sors for N-acyliminium ions. These derivatives are mainly
prepared by electrochemical oxidation of amides,9 partial
reduction of cyclic imides,10 and suitable reactions of
imino derivatives11 and have been successfully used for
the synthesis of biologically active compounds.12 R-Ha-
loamides have found only an occasional utilization as
electrophilic substrates because of their insability.13 Little
attention has also been paid to the R-arylsulfide deriva-
tives that need to be strongly activated before use, the
sulfide moiety being a poor leaving group. These sulfur
derivatives have found some application in the â-lactam
chemistry.7 Cyclic N-acyliminium ions can be readily
formed by reaction of 2-phenylsulfonyl piperidines and
pyrrolidines in the presence of Lewis acids.14 The phe-
nylsulfonyl group is known as a good leaving group, and
furthermore, it has been revealed to be particularly
beneficial in the synthesis of optically active benzene-
sulfonyl lactams that, being solid compounds, are easily
purified by crystallization.15 In connection with our
interest in the utilization of R-amidoalkylphenyl sulfones
as amidoalkylating agents,6b,c we began a study on the
reactivity and stereoselectivity displayed by acyclic N-
acyliminium ion intermediates prepared using optically
active phenylsulfonylimidazolidin-2-ones.
Ta ble 1. Allyla tion of Oxa zolid in on e 4 Usin g Differ en t
Lew is Acid s
entry
Lewis acid
time, h
yield,a
%
1
2
3
4
5
SnCl4
TiCl4
AlCl3
1
4
5
5
24
75
10
28
40
0
EtAlCl2
BF3Et2O
a
Yields of pure, isolated products.
Sch em e 2
Resu lts a n d Discu ssion
Ta ble 2. Syn th esis of P h en ylsu lfon ylim id a zolid in -
2-on es 9
Effect of th e Lew is Acid in Allyla tion Rea ction s.
The Lewis acid exerts a fundamental effect on the general
equilibrium that leads to the formation of the N-acylimin-
ium ion as depicted in eq 1. Both aluminum trichloride
and boron trifluoride etherate have been shown to have
a beneficial effect in reactions of allyltrimethylsilane with
2-phenylsulfonyl pyrrolidines14 and benzenesulfonyl lac-
tams.15 Reaction of oxazolidinone 4 with silane 5 in the
presence of various Lewis acids has revealed that tin
tetrachloride is the most effective activator among the
acids used (Scheme 1, Table 1). These trials have been
entry
aldehyde
8a EtCHO
8b PhCH2CH2CHO
8c (CH3)2CHCH2CHO
8d n-C7H15CHO
sulfone 9 yield,a
%
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9f
84
80
83
78
75
85
88
8e Cl(CH2)5CHO
8f
BnOCH2CH2CH2CH2CHO
8g C5H11CHdCHCH2CH2CHO
9g
a
Yields of pure, isolated products.
made with the aim of using phenylsulfonyl derivatives
of chiral oxazolidinones as substrates for allylation
reaction;16 however, despite various attempts we were
unable to efficiently prepare such substrates.
(9) (a) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D.
J . Org. Chem. 2000, 65, 2484-2493. (b) Lennartz, M.; Sadakane, M.;
Steckhan, E. Tetrahedron 1999, 55, 14407-14420. (c) Wistrand, L.-
G.; Skrinjar, M. Tetrahedron 1991, 47, 573-582. (d) Seebach, D.;
Charczuk, R.; Gerber, C.; Reanaud, P.; Berner, H.; Schneider, H. Helv.
Chim. Acta 1989, 72, 401-425. (e) Shono, T.; Matsumura, Y.; Tsubata,
K. J . Am. Chem. Soc. 1981, 103, 1172-1176.
(10) (a) Schuch, C. M.; Pilli, R. A. Tetrahedron: Asymmetry 2000,
11, 753-764. (b) Yoda, H.; Nakajima, T.; Takabe, K. Synlett 1997, 911-
912. (c) Lee, Y. S.; Kang, D. W.; Lee, S. J .; Park, H. J . Org. Chem.
1995, 60, 7149-7152. (d) Ukaji, Y.; Tsukamoto, K.; Nasada, Y.;
Shimizu, M.; Fujisawa, T. Chem. Lett. 1993, 221-224. (e) Koot,
W.-J .; Van Ginkel, R.; Kranenburg, M.; Hiemstra, H.; Louwrier, S.;
Moolenaar, M. J .; Speckamp, W. N. Tetrahedron Lett. 1991, 32, 401-
404.
(11) (a) Marshall, J . A.; Gill, K.; Seletsky, B. M. Angew. Chem., Int.
Ed. Engl. 2000, 39, 953-956. (b) Yamamoto, Y.; Schmid, M. J . Chem.
Soc., Chem. Commun. 1989, 1310-1312. (c) Hiemstra, H.; Fortgens,
H. P.; Stegenga, S.; Speckamp, W. N. Tetrahedron Lett. 1985, 26,
3151-3154.
(12) (a) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465-
467. (b) Smith, A. B., III; Friestad, G. K.; Barbosa, J .; Bertounesque,
E.; Duan, J . J -W.; Hull, K. G.; Iwashima, M.; Qiu, Y.; Spoors, P. G.;
Salvatore, B. A. J . Am. Chem. Soc. 1999, 121, 10478-10486. (c)
Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1988; Vol. 32, pp 271-339.
(13) (a) Coghlan, P. A.; Easton, C. J . Tetrahedron Lett. 1999, 40,
4745-4748. (b) Mu¨nster, P.; Steglich, W. Synthesis 1987, 223-225.
(c) Williams, R. M.; Sinclair, P. J .; Dongguan, Z.; Chen, D. J . Am. Chem.
Soc. 1988, 110, 1547-1557.
(4R,5S)-1,5-Dim eth yl-4-p h en ylim id a zolid in -2-on e
a s a Ch ir a l Au xilia r y. Several years ago, Pearson and
co-workers17 prepared some R-amidoalkyltolyl sulfones
using an ephedrine-derived imidazolidin-2-one 7.18 These
sulfones are formed as single diastereomers and have
been used to produce optically active organolithium
derivatives suitable for reaction with electrophiles. Com-
pounds 9 have been prepared by reaction of imidazolidin-
2-one 7 with an aldehyde and sodium benzenesulfinate
following the procedure of Pearson (Scheme 2, Table 2).
Reaction of imidazolidinones 9 with allyltrimethylsilane
5 in the presence of tin tetrachloride at -78 °C gives the
corresponding allylated products 10 in good yields and
with high diastereomeric ratios (Scheme 3, Table 3). The
(16) (a) Gage, J . R.; Evans, D. A. Org. Syntheses 1989, 68, 77-82.
(b) Lewis, N.; McKillop, A.; Taylor, R. J . K.; Watson, R. J . Synth.
Commun. 1995, 25, 561-568.
(17) Pearson, W. H.; Lindbeck, A. C.; Kampf, J . W. J . Am. Chem.
Soc. 1993, 115, 2622-2636.
(18) (a) Review: Roos, G. H. P. Recent Res. Dev. Synth. Org. Chem.
1998, 1, 151-170. (b) Clark, W. M.; Bender, C. J . Org. Chem. 1998,
63, 6732-6734. (c) Bongini, A. Cardillo, G. Gentilucci, L. Tomasini, C.
J . Org. Chem. 1997, 62, 9148-9153. (d) Drewes, S. E.; Malissar, D. G.
S.; Roos, G. H. P. Chem. Ber. 1993, 126, 2663-2673. (e) Roder, H.;
Helmchen, G.; Peters, E.-M.; Peters, K.; Von Schnering, H.-G. Angew.
Chem., Int. Ed. Engl. 1984, 23, 898-899.
(14) Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V. Tetrahedron
1991, 47, 1311-1328.
(15) (a) Ostendorf, M.; Romagnoli, R.; Cabeza Pereiro, I.; Roos, E.
C.; Moolenaar, M. J .; Speckamp, W. N.; Hiemstra, H. Tetrahedron:
Asymmetry 1997, 8, 1773-1789. (b) Ostendorf, M.; Van der Neut, S.;
Rutjes, F. P. T. J .; Hiemstra, H. Eur. J . Org. Chem. 2000, 105-113.

Reaction of Nucleophilic Reagents with N-Acyliminium Ions
J . Org. Chem., Vol. 65, No. 24, 2000 8279
Sch em e 3
Sch em e 4
Ta ble 3. Syn th esis of Allylim id a zolid in -2-on es 3
Ta ble 4. Syn th esis of Ester s 15 by Rea ction of Silyl
Keten e Aceta ls 14 w ith Su lfon es 9
entry
sulfone 9
allyl derivative 10
dra
yield,b %
silyl ketene
acetal 14
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9f
10a
10b
10c
10d
10e
10f
10g
95:5
95:5
94:6
95:5
93:7
95:5
97:3
74
70
75
68
70
80
72
sulfone
ester
15
yield,b
%
entry
9
R1
R2
dra
1
2
3
4
9a
9b
9c
9d
Et
Et
Et
Ph
t-BuMe2
Me
Me
15b
15c
15d
60:40
70:30
65:35
30
57
44
9g
Me
Diastereomeric ratio was evaluated by 1H NMR analysis.
Yields of pure, isolated products.
a
Diastereomeric ratio was evaluated by 1H NMR analysis.
Yields of pure, isolated products.
a
b
b
stereochemistry of the newly formed stereocenter in
compound 10 has been inferred taking into account the
relative stability between the intermediate N-acylimin-
ium ions 11 (eq 2). Molecular mechanics calculations17
Sch em e 5
Ta ble 5. Syn th esis of Keton es 17-19 by Rea ction of Silyl
En ol Eth er s 16 w ith Su lfon es 9
silyl enol
ether 16
ketones
17-19
entry
sulfone 9
dra
yield,c %
have shown for reactive ion 11-(Z) derived from 9a an
energy level of 1.6 kcal/mol higher than 11-(E). This
difference is mainly due to 1,3-allylic strain between the
alkyl chain and the carbonyl oxygen in 11-(Z). The attack
of allyltrimethylsilane from the less hindered upper side
of 11-(E) (si-si face) leads to the preferential formation
of the allylated product 10. This assumption has been
confirmed by X-ray crystallographic analysis carried out
for compound 10c. The allylic moiety in compounds 10
is amenable to further synthetic transformations to give
a carbonyl or a carboxylic group by oxidative procedures;
however, the addition of ester derivatives to N-acylimin-
ium ions would represent a direct route to the synthesis
of â-aminoester analogues.19 Silyl ketene acetals add to
chiral cyclic N-acyliminium ions with modest diastereo-
selectivity,20 and similar results have been observed for
the reaction of imidazolidinones 9 with silyl ketene
acetals 12 (Scheme 4, Table 4).The stereoselectivity and
the chemical yields obtained by this procedure are
invariably low, and the use of sterically hindered tert-
butyldimethylsilyl acetal 12a prevents any addition of
the nucleophile to the iminium ion. Silyl enol ethers
obtained from ketones have been exploited as reagents
for addition reactions with N-acyliminium ions in a
number of examples with better success.12b,21 Particularly
1
2
3
4
5
6
7
8
9
9b
9c
9d
9e
9f
9c
9a
9b
9c
9d
16a
16a
16a
16a
16a
16b
16c
16c
16c
16c
17b
17c
17d
17e
17f
18
19a
19b
19c
19d
95:5
>99:1b
95:5
99
97
75
87
98
58
78
91
85
70
98:2b
>99:1b
70:30
90:10
>99:1b
98:2b
10
98:2b
a
Diastereomeric ratio was evaluated by 1H NMR analysis.
Diastereomeric ratio was evaluated by HPLC analysis. c Yields
b
of pure, isolated products.
effective has been the trimethylsilyl enol ether of ac-
etophenone 16a , which is a largely planar molecule that
is able to discriminate the less sterically demanding face
of imidazolidinones 9 (Scheme 5, Table 5). This reflects
on the high stereoselectivity observed for the efficient
synthesis of ketones 17. The importance of the phenyl
group for the stereochemical outcome of this process is
particularly evident by testing the behavior of the tri-
methylsilyl enol ether derived from acetone 16b (Table
(21) (a) Ollero, L.; Mentink, G.; Rutjes, F. P. T. J .; Speckamp, W.
N.; Hiemstra, H. Org. Lett. 1999, 1, 1331-1334. (b) Seebach, D.;
Renaud, P.; Helv. Chim. Acta 1986, 69, 1704-1710. (c) Dhimane, H.;
Vannucci-Bacque´, C.; Hamon, L.; Lhommet, G. Eur. J . Org. Chem.
1998, 195, 5-1963. (d) Mooiweer, H. H.; Ettema, K. W. A.; Hiemstra,
H.; Speckamp, W. N. Tetrahedron 1990, 46, 2991-2998. (e) Brown,
D. S.; Earle, M. J .; Fairhurst, R. A.; Heaney, H.; Papageorgiou, G.;
Wilkins, R. F.; Eyley, S. C. Synlett 1990, 619-621. (f) Ginzel, K.-D.;
Brungs, P.; Steckhan, E. Tetrahedron 1989, 45, 1691-1701.
(19) Enantioselective Synthesis of â-Amino Acids; J uaristi, E., Ed.;
Wiley-VCH: New York, 1997.
(20) (a) Asada, S.; Kato, M.; Asai, K.; Ineyama, T.; Nishi, S.; Izawa,
K.; Shono, T. Chem. Commun. 1989, 486-488. (b) Kim, C. U.; Luh, B.;
Partyka, R. A. Tetrahedron Lett. 1987, 28, 507-510.

8280 J . Org. Chem., Vol. 65, No. 24, 2000
Giardina` et al.
Sch em e 6a
diastereoselectivity. Poor results are obtained using silyl
ketene acetals, while the trimethylsilyl enol ether of
acetophenone reacts efficiently to give the corresponding
ketones 17. The phenyl group of acetophenone can be
replaced by the furan ring mantaining the same efficacy
in terms of chemical yield and diastereoselectivity.
Unfortunately, deprotection of the imidazolidinone ring
is not a trivial task since it is resistant to cleavage even
under harsh conditions.17 The utilization of this procedure
for the synthesis of nitrogenous derivatives exploiting
more practical chiral auxiliaries is currently under study
in our laboratories.
Exp er im en ta l Section
1H NMR studies were performed at 300 MHz in CDCl3 as
solvent.13C NMR studies were performed at 75 MHz in CDCl3
as solvent. Dichloromethane was dried by refluxing it over
calcium hydride and then distilled. All chemicals used are
commercial. 6-Chlorohexanal,25 5-(benzyloxy)pentanal,26 silyl
ketene acetals 14,27 and silyl enol ethers 1628,29 were prepared
following literature methods.
Gen er a l P r oced u r e for th e P r ep a r a tion of P h en ylsu l-
fon yl Der iva tives 4 a n d 5. These compounds were prepared
using the procedure described by Pearson.17 Some imidazoli-
din-2-ones 9 were further purified by crystallization using
hexanes-ethyl acetate.
a
Key: (a) OsO4 (cat.), N-methylmorpholine N-oxide (NMO)
t-BuOH-THF-H2O, rt, 90%; (b) NaIO4, MeOH-H2O, rt, 81%; (c)
PhMgBr, THF, -78 °C, 77%; (d) Pr4NRuO4 (cat.), NMO, CH3CN,
rt, 88%.
5, entry 6) that upon reaction with imidazolidinone 9c
fails to give the same excellent results in the synthesis
of ketone 18. The trimethylsilyl enol ether of 2-acetyl-
furan 16c was tested in the reaction with imidazolidi-
nones 9 (Scheme 5). As shown in Table 5, the diastereo-
selectivities obtained with enol ether 16c are comparable
with those observed using the phenyl analogue 16a . The
furan ring does not give any appreciable competitive side
reaction with the intermediate N-acyliminium ion, and
the corresponding ketones 19 are isolated in good yields.
Since the furan nucleus can be easily cleaved under
various conditions,22 ketones 19 may become useful
intermediates for the preparation of interesting building
blocks in synthesis. Other simple enol ethers as ethyl
vinyl ether and isopropenyl acetate have been used for
this reaction but they gave only disappointing results
with imidazolidinones 9 under the same conditions and
using different Lewis acids.
Although it seems reasonable that the stereochemistry
of the additional stereocenter in compounds 17-19
matches with that observed for the allylated products 10,
a chemical correlation between a representative com-
pound 10c and ketone 17c was pursued (Scheme 6).
Thus, allyl derivative 10c was converted into aldehyde
20 by a two-step double-bond cleavage (OsO4, N-meth-
ylmorpholine N-oxide (NMO); NaIO4).23 Reaction of al-
dehyde 20 with phenylmagnesium bromide in THF at
-78 °C gave a diastereomeric mixture of alcohols 21 (85:
15), which were oxidized using TPAP-NMO.24 The
resulting ketone was found to be identical to compound
17c obtained by direct reaction of sulfone 9c with silyl
enol ether 16a .
3-[1-(P h en ylsu lfon yl)p r op yl]oxa zolid in -2-on e (4): yield
90%; mp 130 °C; IR (cm-1, KBr) 1760, 1320, 1145; 1H NMR δ
ppm 1.02 (t, 3H, J ) 7.4 Hz), 1.85-2.11 (m, 1H), 2.24-2.46
(m, 1H), 3.59 (q, 1H, J ) 9.0 Hz), 3.97-4.09 (m, 1H), 4.25-
4.45 (m, 2H), 4.89 (dd, 1H, J ) 11.7, 3.5 Hz), 7.55-7.75 (m,
3H), 7.88-7.98 (m, 2H). Anal. Calcd for C12H15NO4S (269.31):
C, 53.52; H, 5.61; N, 5.20. Found: C, 53.59; H, 5.57; N, 5.15.
(4R,5S,1′S)-1,5-Dim eth yl-3-[1-(p h en ylsu lfon yl)p r op yl]-
4-p h en ylim id a zolid in -2-on e (9a ): yield 84%; mp 119 °C;
[R]20D ) -88.1 (c 1.9, CHCl3); IR (cm-1, KBr) 1690, 1380, 1140;
1H NMR δ ppm 0.63 (t, 3H, J ) 7.3 Hz), 0.72 (d, 3H, J ) 6.6
Hz), 1.35-1.53 (m, 1H), 1.83-2.03 (m, 1H), 2.48 (s, 3H), 3.67
(dq, 1H, J ) 8.6, 6.6 Hz), 5.09 (d, 1H, J ) 8.7 Hz), 5.22 (dd,
1H, J ) 9.9, 4.2 Hz), 7.20-7.38 (m, 5H), 7.52-7.68 (m, 3H),
7.95-8.01 (m, 2H). Anal. Calcd for C20H24N2O3S (372.48): C,
64.49; H, 6.49; N, 7.52. Found: C, 64.56; H, 6.42; N, 7.57.
(4R,5S,1′S)-1,5-Dim eth yl-3-[1-(p h en ylsu lfon yl)-3-m eth -
ylbu tyl]-4-p h en ylim id a zolid in -2-on e (9c): yield 83%; mp
116 °C; [R]20 ) -113.4 (c 1.8, CHCl3); IR (cm-1, KBr) 1690,
D
1
1374, 1136; H NMR δ ppm 0.22 (d, 3H, J ) 6.6 Hz), 0.73 (d,
3H, J ) 6.6 Hz), 0.76 (d, 3H, J ) 6.6 Hz), 1.12-1.30 (m, 1H),
1.42-1.55 (m, 2H), 2.47 (s, 3H), 3.63 (dq, 1H, J ) 8.5, 6.6 Hz),
5.11 (d, 1H, J ) 8.5 Hz), 5.34 (dd, 1H, J ) 10.1, 4.1 Hz), 7.20-
7.35 (m, 5H), 7.55-7.80 (m, 3H), 7.95-8.00 (m, 2H); 13C NMR
δ ppm 15.1, 21.4, 22.9, 23.1, 24.8, 29.3, 33.6, 57.3, 59.2, 73.3,
126.6, 128.8, 128.9129.3, 129.4, 134.3, 138.0, 138.3, 161.8.
Anal. Calcd for C22H28N2O3S (400.53): C, 65.97; H, 7.05; N,
6.99. Found: C, 66.05; H, 7.00; N, 7.04.
Gen er a l P r oced u r e for th e P r ep a r a tion of Allyloxa zo-
lid in -2-on e 6 a n d Allylim id a zolid in -2-on es 10. Sulfone 4
or 9 (1 mmol) was dissolved in CH2Cl2 (10 mL), and the
solution was cooled at -78 °C. SnCl4(1.25 mmol) was then
added dropwise over 10 min, and the temperature was kept
at -78 °C for 30 min. Allyltrimethylsilane (1.25 mmol)
dissolved in CH2Cl2 (5 mL) was then added dropwise, and after
In summary, the N-acyliminium ions obtained from
optically active imidazolidin-2-ones 9 are able to react
with nucleophilic reagents affording the corresponding
addition products. The most effective Lewis acid for the
formation of the iminium ion is tin tetrachloride for all
the unsaturated reagents tested. Reaction with allyltri-
methylsilane is a very efficient process giving the corre-
sponding allylated products in good yields and high
(25) Wasserman, H. H.; Gambale, R. J .; Pulwer, M. J . Tetrahedron
1981, 37, 4059-4067.
(26) Ohtsuka, Y.; Oishi, T. Chem. Pharm. Bull. 1991, 39, 1359-
1364.
(22) Sargent, M. V.; Dean, F. M. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 4, pp 599-656.
(27) Mikami, K.; Matsumoto, S.; Ishida, A.; Takamuku, S.; Suenobu,
T.; Fukuzumi, S. J . Am. Chem. Soc. 1995, 117, 11134-11141.
(28) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues,
J . Tetrahedron 1987, 43, 2075-2088.
(29) Saitoh, T.; Oyama, T.; Sakurai, K.; Niimura, Y.; Hinata, M.;
Horiguchi, Y.; Toda, J .; Sano, T. Chem. Pharm. Bull. 1996, 44, 956-
966.
(23) Nicolaou, K. C.; Hepworth, D.; King, N. P.; Finlay, R. W.;
Scarpelli, R.; Pereira, M. M. A.; Bollbuck, B.; Bigot, A.; Werschkun,
B.; Wissinger, N. Chem. Eur. J . 2000, 6, 2783-2800.
(24) Griffith, W. P.; Ley, S. W. Aldichim. Acta 1990, 23, 13-19.

Reaction of Nucleophilic Reagents with N-Acyliminium Ions
J . Org. Chem., Vol. 65, No. 24, 2000 8281
1 h at -78 °C the temperature was slowly warmed to room
temperature. The reaction mixture was then diluted with CH2-
Cl2 (15 mL) and washed with brine (5 mL), and the organic
phase was dried over MgSO4. After removal of the solvent at
reduced pressure, the allylation product 6 or 10 obtained was
purified by column chromatography (hexanes-ethyl acetate
(7:3)).
3-(1-Eth ylbu t-3-en yl)oxa zolid in -2-on e (6): yield 78%; oil;
IR (cm-1, neat) 1692; 1H NMR δ ppm 0.88 (t, 3H, J ) 7.4 Hz),
1.32, 1.70 (m, 2H), 2.10-2.40 (m, 2H), 3.35 (m, 2H), 3.70-
3.85 (m, 1H), 4.21-4.33 (m, 2H), 4.97-5.12 (m, 2H), 5.61-
5.85 (m, 1H). Anal. Calcd for C9H15NO2 (169.22): C, 63.88; H,
8.93; N, 8.28. Found: C, 63.96; H, 8.88; N, 8.25.
15.2, 7.4 Hz), 3.71 (dq, 1H, J ) 8.7, 6.6 Hz), 3.81-3.98 (m,
1H), 4.60 (d, 1H, J ) 8.7 Hz), 6.45-6.52 (m, 1H), 7.12-7.16
(m, 1H), 7.20-7.35 (m, 5H), 7.55-7.60 (m, 1H). Anal. Calcd
for C20H24N2O3 (340.42): C, 70.57; H, 7.11; N, 8.23. Found:
C, 70.65; H, 7.04; N, 8.28.
(4R,5S,1′R)-1,5-Dim eth yl-3-[1-(2-m eth ylp r op yl)-3-oxo-
3-fu r ylp r op yl]-4-p h en ylim id a zolid in -2-on e (19c): yield
85%; mp 132 °C; [R]20 ) -2.2 (c 5.2, CHCl3); IR (cm-1, KBr)
D
1
1690; H NMR δ ppm 0.66 (d, 3H, J ) 6.4 Hz), 0.74 (d, 3H,
J ) 6.6 Hz), 0.88 (d, 3H, J ) 6.4 Hz), 1.05-1.26 m, 1H), 1.38-
1.62 (m, 2H), 2.70 (s, 3H), 3.05 (dd, 1H, J ) 15.1, 7.4 Hz), 3.31
(dd, 1H, J ) 15.1, 6.8 Hz), 3.71 (dq, 1H, J ) 8.7, 6.6 Hz), 4.05-
4.24 (m, 1H), 4.60 (d, 1H, J ) 8.7 Hz), 6.50-6.52 (m, 1H),
(4R,5S,1′R)-1,5-Dim eth yl-3-(1-eth ylbu t-3-en yl)-4-p h en -
7.12-7.15 (m, 1H), 7.18-7.33 (m, 5H), 7.56-7.58 (m, 1H); 13
C
ylim id a zolid in -2-on e (10a ): yield 74%; mp 61 °C; [R]20
)
NMR δ ppm 15.0, 22.6, 23.2, 25.4, 29.4, 42.9, 50.0, 57.2, 62.6,
112.7, 118.1, 128.6, 128.8, 138.1, 146.9, 150.0, 153.1, 162.3,
187.8. Anal. Calcd for C22H28N2O3 (368.47): C, 71.71; H, 7.66;
N, 7.60. Found: C, 71.80; H, 7.70; N, 7.65.
D
+38.6 (c 3.4, CHCl3); IR (cm-1, KBr) 1692; 1H NMR δ ppm
0.72 (d, 3H, J ) 6.6 Hz), 0.73 (t, 3H, J ) 7.3 Hz), 0.98-1.35
m, 2H), 2.18-2.48 (m, 2H), 2.68 (s, 3H), 3.62 (dq, 1H, J ) 8.7,
6.6 Hz), 3.68-3.85 (m, 1H), 4.44 (d, 1H, J ) 8.7 Hz), 4.98-
5.11 (m, 2H), 5.63-5.84 (m, 1H), 7.28-7.21 (m, 5H). Anal.
Calcd for C17H24N2O (272.39): C, 74.96; H, 8.88; N, 10.28.
Found: C, 75.06; H, 8.81; N, 10.29.
(3R)-3-[(4R,5S)-3,4-Dim eth yl-2-oxo-5-p h en ylim id a zoli-
d in -1-yl]-5-m eth ylh exa n a l (20). Allyl derivative 10c (0.45
g, 1.5 mmol) was dissolved in a mixture of THF (6 mL), tert-
butyl alcohol (6 mL), and water (1.2 mL), and then N-
methylmorpholine N-oxide (0,195 g, 1.65 mmol) and OsO4
(0.004 g, 0.015 mmol) were added at 0 °C. The mixture was
stirred for 10 min at 0 °C and then for 6 h at room temperature
before being quenched with saturated aqueous Na2SO3 (4 mL).
The solution was stirred at room temperature for 1 h and then
was diluted with water (10 mL) and extracted with CHCl3
(3 × 20 mL). The organic phase was dried over MgSO4, and
after evaporation of the solvent the crude mixture of diols was
purified by column chromatography (hexanes-ethyl acetate
(6:4)) giving 0.45 g (90%) of a white solid. These diols (0.40 g,
1.2 mmol) were dissolved in a mixture of methanol (6 mL) and
water (3 mL), and then, under vigorous stirring, NaIO4 (1.54
g, 7.2 mmol) was added at 0 °C. Stirring was continued for 30
min at room temperature, and then water (10 mL) was added.
The resulting solution was extracted with CHCl3 (3 × 20 mL),
and the organic phase was dried over MgSO4. After the
evaporation of the solvent at reduced pressure, the crude
product was purified by column chromatography (hexanes-
ethyl acetate (8:2)) affording 0.30 g (81%) of pure aldehyde
(4R,5S,1′R)-1,5-Dim eth yl-3-[1-(2-eth ylpr opyl)bu t-3-en yl]-
4-p h en ylim id a zolid in -2-on e (10c): yield 75%; mp 117 °C;
[R]20 ) +48.8 (c 2.7, CHCl3); IR (cm-1, KBr) 1690; 1H NMR δ
D
ppm 0.48 (d, 3H, J ) 6.7 Hz), 0.76 (d, 3H, J ) 6.6 Hz), 0.77-
0.83 (m, 1H), 0.84 (d, 3H, J ) 6.5 Hz), 0.96-1.12 (m, 1H),
1.35-1.61 (m, 1H), 2.26-2.37 (m, 2H), 2.70 (s, 3H), 3.67 (dq,
1H, J ) 8.7, 6.6 Hz), 3.95-4.10 (m, 1H), 4.43 (d, 1H, J ) 8.7
Hz), 5.00-5.14 (m, 2H), 5.64-5.85 (m, 1H), 7.29-7.38 (m, 5H);
13C NMR δ ppm 15.2, 22.6, 23.1, 25.1, 29.8, 38.4, 43.0, 51.7,
57.6, 60.2, 117.0, 128.6, 128.6, 128.9, 136.7, 139.1, 162.9. Anal.
Calcd for C19H28N2O (300.44): C, 75.96; H, 9.39; N, 9.32.
Found: C, 76.05; H, 9.44; N, 9.30.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ester s 15
a n d Keton es 17-19. Sulfone 9 (1 mmol) was dissolved in CH2-
Cl2 (10 mL), and the solution was cooled at -78 °C. SnCl4 (1.25
mmol) was then added dropwise over 10 min, and the tem-
perature was kept at -78 °C for 30 min. Enol derivative 16
(1.5 mmol) dissolved in CH2Cl2 (5 mL) was then added
dropwise, and after 1,h at -78 °C, the temperature was
warmed to -40 °C. After 30 min at -40 °C, the mixture was
quenched with brine (5 mL) and diluted with CH2Cl2 (15 mL).
The organic phase was separated and dried over MgSO4. After
evaporation of the solvent at reduced pressure, the crude
carbonyl derivative was purified by column chromatography
(hexanes-ethyl acetate (8:2)).
20: mp 122 °C; [R]20 ) +48.7 (c 3.8, CHCl3); IR (cm-1, KBr)
D
1
1715; H NMR δ ppm 0.61 (d, 3H, J ) 6.5 Hz), 0.76 (d, 3H,
J ) 6.5 Hz), 0.88 (d, 3H, J ) 6.4 Hz), 0.95-1.04 (m, 1H), 1.21-
1.34 (m, 1H), 1.38-1.62 (m, 1H), 2.70 (s, 3H), 2.72-2.80 (m,
2H), 3.61-3.64 (m, 1H), 4.15-4.31 (m, 1H), 4.15-4.31 (m. 1H),
4.47 (d, 1H, J ) 8.6 Hz), 7.15-7.40 (m, 5H), 9.65 (t, 1H, J )
2.5 Hz); 13C NMR δ ppm 15.0, 22.7, 22.9, 25.2, 29.4, 43.0, 47.8,
48.1, 57.2, 61.7, 128.8, 128.9, 129.1, 138.1, 162.3, 201.6. Anal.
Calcd for C18H26N2O2 (302.41): C, 71.49; H, 8.67; N, 9.26.
Found: C, 71.55; H, 8.64; N, 9.31.
(4R,5S,1′R)-1,5-Dim eth yl-3-[1-(2-m eth ylp r op yl)-3-oxo-
3-p h en ylp r op yl]-4-p h en ylim id a zolid in -2-on e (17c): yield
97%; mp 94 °C; [R]20 ) +12.6 (c 3.4, CHCl3); IR (cm-1, KBr)
D
1
1692; H NMR δ ppm 0.70 (d, 3H, J ) 6.4 Hz), 0.74 (d, 3H,
J ) 6.6 Hz), 0.89 (d, 3H, J ) 6.4 Hz), 1.05-1.24 (m, 1H), 1.45-
1.68 (m, 2H), 2.71 (s, 3H), 3.20 (dd, 1H, J ) 16.2, 6.1 Hz), 3.50
(dd, 1H, J ) 16.2, 7.5 Hz), 3.71 (dq, 1H, J ) 8.8, 6.6 Hz), 4.01-
4.18 (m, 1H), 4.50 (d, 1H, J ) 8.8 Hz), 7.18-7.31 (m, 5H), 735-
7.55 (m, 3H), 7.82-7.97 (m, 2H); 13C NMR δ ppm 14.6, 22.0,
22.9, 25.0, 28.9, 42.4, 42.7, 49.5, 56.7, 62.9, 128.1, 128.2, 128.3,
128.4, 128.6, 133.0, 136.1, 137.6, 161.0, 198.5. Anal. Calcd for
(4R,5S)-1-[(1R)-1-(2-Hyd r oxy-2-p h en yleth yl)-3-m eth yl-
bu tyl]-3,4-d im eth yl-5-p h en ylim id a zolid in -2-on e (21). Al-
dehyde 20 (0.28 g, 0.92 mmol) was dissolved in dry THF (10
mL) and then cooled at -78 °C. Phenylmagnesium bromide
(2.3 M in ether, 0.44 mL, 1.0 mmol) was then added dropwise,
and stirring was continued at the same temperature for 1 h.
The mixture was quenched by addition of saturated aqueous
NH4Cl (5 mL), and the temperature was allowed to warm to
room temperature. The resulting mixture was extracted with
CHCl3 (3 × 20 mL), and the organic phase was dried over
MgSO4. After the evaporation of the solvent at reduced
pressure, the crude product was purified by column chroma-
tography (hexanes-ethyl acetate (7:3)) giving 0.27 g (77%) of
alcohol 21 as a 85:5 mixture of diastereomers: IR (cm-1, KBr)
C
24H30N2O2 (378.51): C, 76.16; H, 7.99; N, 7.40. Found: C,
76.10; H, 8.01; N, 7.34.
(4R,5S,1′R)-1,5-Dim et h yl-3-(1-h ep t yl-3-oxo-3-p h en yl-
p r op yl)-4-p h en ylim id a zolid in -2-on e (17d ): yield 75%; oil;
[R]20D ) +14.6 (c 2.8, CHCl3); IR (cm-1, neat) 1690; 1H NMR δ
ppm 0.74 (d, 3H, J ) 6.6 Hz), 0.85 (t, 3H, J ) 6.3 Hz), 1.08-
1.45 (m, 10H), 1.53-1.75 (m, 2H), 2.71 (s, 3H), 3.20 (dd, 1H,
J ) 16.2, 6.1 Hz), 3.62 (dd,1H, 16.2, 7.5 Hz), 3.68 (dq, 1H, J )
8.7, 6.6 Hz), 3.82-4.04 (m, 1H), 4.58 (d, 1H, J ) 8.7 Hz), 7.15-
7.32 (m, 5H), 7.36-7.55 (m, 3H), 7.85-7.98 (m, 2H). Anal.
Calcd for C27H36N2O2 (420.59): C, 77.10; H, 8.63; N, 6.66.
Found: C, 77.18; H, 8.68; N, 6.70.
1
3400; H NMR (major diastereomer) δ ppm 0.44 (d, 3H, J )
6.6 Hz), 0.78 (d, 3H, J ) 6.4 Hz), 0.82 (d, 3H, J ) 6.6 Hz),
0.88-0.98 (m, 1H), 1.06-1.18 (m, 1H), 1.24-1.48 (m, 1H),
1.68-1.85 (m, 1H), 1.92-1.05 (m, 1H), 2.75 (s, 3H), 3.58-3.80
(m, 2H), 4.18-4.39 (m, 1H), 4.45 (d, 1H, J ) 8.8 Hz), 4.50-
4.62 (m, 1H), 7.19-7.45 (m, 10H). Anal. Calcd for C24H32N2O2
(380.53): C, 75.75; H, 8.48; N, 7.36. Found: C, 75.71; H, 8.53;
N, 7.40.
(4R,5S,1′R)-1,5-Dim eth yl-3-(1-eth yl-3-oxo-3-fu r ylpr opyl)-
4-p h en ylim id a zolid in -2-on e (19a ): yield 78%; oil; [R]20
)
D
+15.7 (c 1.2, CHCl3); IR (cm-1, neat) 1690; 1H NMR δ ppm
0.72 (d, 3H, J ) 6.6 Hz), 0.86 (t, 3H, J ) 7.3 Hz), 1.25-1.40
(m, 1H), 1.55-1.78 (m, 1H), 2.68 (s, 3H), 3.06 (dd, 1H, J )
Oxid a tion of Alcoh ol 21. Alcohol 21 (0.25 g, 0.66 mmol)
was dissolved in dry acetonitrile (3 mL), and then N-methyl-

8282 J . Org. Chem., Vol. 65, No. 24, 2000
Giardina` et al.
morpholine N-oxide (0.12 g, 1.0 mmol), powdered 4 Å molecular
sieves (0.30 g), and tetra-n-propylamonium perruthenate (0.01
g, 0.03 mmol) were added at room temperature. After being
stirred for 1 h, the solvent was evaporated at reduced pressure
and the black residue was suspended in CH2Cl2 (20 mL) and
then filtered over a short pad of Florisil. The clear solution
was evaporated at reduced pressure, and the residue was
purified by column chromatography (hexanes-ethyl acetate
(8:2)) affording 0.22 g (88%) of ketone 17c.
used, with 187 parameters varied. In refinements were used
weights according to the scheme w ) 1/[σ2(Fo2) + (0.0794P)2
2
+ 0.0282P] where P)(Fo + 2Fc2)/3.
The hydrogen atoms were located by geometrical calculation
and refined using a “riding” model. The final agreement indices
were R1 ) 0.0457 and wR2) 0.1079. Goodness of fit on F2
)
1.15. Largest difference peak and hole was 0.136 and -0.222
e Å-3
.
Cr yst a l St r u ct u r e of Allyl Der iva t ive 10c. Cr yst a l
Da t a : C19H28N2O, M ) 300.4, monoclinic, space group P21,
a ) 8.830(2) Å, b ) 6.685(5) Å, c ) 15.246(3) Å, â ) 96.97 (3)°,
U ) 893.3(7) Å3, Z ) 2, Dc ) 1.12 Mg m-3, F(000) ) 328, λ )
0.710 69 Å, T ) 293 K, (Mo KR) µ ) 0.069 mm-1, crystal
dimensions 0.70 × 0.30 × 0.20 mm. A total of 1829 reflections
were collected (1716 unique, Rint )0.0191).
Ack n ow led gm en t. The authors are greatly in-
debted to Prof. E. Foresti (University of Bologna) for the
X-ray crystallographic analysis of compound 10c. Fi-
nancial support from the University of Camerino (Na-
tional Project “Stereoselezione in Sintesi Organica.
Metodologie e Applicazioni”) is gratefully acknowledged.
Da ta Collection a n d P r ocessin g. Intensity data were
collected on an Enraf-Nonius CAD-4 diffractometer using
graphite monochromated Mo KR radiation, ω/2θ scan mode,
range 2.32° < θ < 24.98°. The unit cell parameters were
determinated by least-squares refinement on diffractometer
angles for 25 automatically centered reflections 3.78° < θ <
7.21°.
Su p p or tin g In for m a tion Ava ila ble: Spectral and physi-
cal data for compounds not included in the Experimental
Section. X-ray molecular structure and crystal data of com-
pound 10c. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O001003X
Str u ctu r e An a lysis a n d Refin em en t. The structure was
solved by direct method and refined by full-matrix least-
squares on F2, using the SHELX program packages.30 In the
final refinement cycles 1407 reflections having I > 2σ(I) were
(30) (a) Sheldrick, G. M. SHELXS86, Acta Crystallogr., 1990 Sect.
A 46, 467. (b) Sheldrick, G. M. SHELXL93, Program for Crystal
Structure Refinement, University of Gottingen, Germany, 1993.