Aza Diels-Alder reactions of sulfinimines with the Rawal diene

Article abstract of DOI:10.1016/j.tetasy.2006.04.026

The aza Diels-Alder reaction of optically active sulfinimines with the Rawal diene leads to enantiomerically enriched dihydropyridones with ees up to 90%. The reaction was catalyzed by TMSOTf. The best results were obtained using 10-isobornylsulfinimines.

Full text of DOI:10.1016/j.tetasy.2006.04.026

Tetrahedron: Asymmetry 17 (2006) 1420–1423
Aza Diels–Alder reactions of sulfinimines with the Rawal diene
Robert Kawe˛cki*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, PL-01-224 Warszawa, Poland
Institute of Chemistry, University of Podlasie, ul. 3 Maja 54, PL-08-110 Siedlce, Poland
Received 10 April 2006; accepted 25 April 2006
Available online 24 May 2006
Abstract—The aza Diels–Alder reaction of optically active sulfinimines with the Rawal diene leads to enantiomerically enriched dihydro-
pyridones with ees up to 90%. The reaction was catalyzed by TMSOTf. The best results were obtained using 10-isobornylsulfinimines.
Removal of the sulfinyl auxiliary occurred during workup of the reaction mixture. The reaction most likely proceeds via a stepwise mech-
anism. The addition of lithium 4-N,N0-dimethylamino-1,3-buten-2-olate to sulfinimines, followed by hydrolysis, gave dihydropyridones
in lower yields and with opposite stereochemistry.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of silyloxy dienes. Since the Danishefsky diene was not
reactive, we tried to use 1-dimethylamino-3-t-butyldimeth-
ylsiloxy-1,3-butadiene 2. This diene was developed by
Rawal et al. in 1997.10 It was shown that several classes
of dienophiles including imines, react easily with the Rawal
diene.11 Herein, we report the use of optically active sulfin-
imines in this type of reaction. Diene 2 was prepared from
4-(dimethylamino)-3-buten-2-one according to an original
procedure.10 The reaction of 10-isobornylsulfinimines12
1a–e with diene 2 in CH2Cl2 at ꢀ70 °C gave the expected
dihydropyridones 3 in good yields (Scheme 1 and Table 1).
The aza Diels–Alder reaction is a well established method
for the synthesis of derivatives of tetrahydropyridine.1
The main methodology involves the cycloaddition of imi-
nes with dienes. This type of reaction can usually only be
performed with reactive dienes such as Danishefsky’s diene
or using imines substituted with an electron withdrawing
group. The presence of Lewis acid is often necessary. The
development of an asymmetric version of the hetero-
Diels–Alder reaction is the biggest challenge.2 Several
chiral imines prepared from optically active amines,3 1,2-
amino alcohols,4 a-aminoacids,5 aminosugars6 have been
used in such reactions as dienophiles. However, the
removal of a chiral auxiliary from the nitrogen atom is
often difficult. Such a drawback does not occur in the case
of the sulfinyl group, which can also serve as a powerful
chiral auxiliary.7 Especially useful are N-sulfinyl imines
(sulfinimines), which appeared to be excellent substrates
for the stereoselective synthesis of amines, b-aminoacids,
aziridines, aminoketones, etc.8 To the best of our knowl-
edge only a,b-unsaturated sulfinimines have been used as
dienes in aza Diels–Alder reaction under high pressure.9
The reaction only takes place in the presence of Lewis
acids, preferably TMSOTf. The use of BF3 etherate gave
low yields. Two methods were developed. 10-Isobornyl
and 8-menthylsulfinimines13 1a–f gave product 3 immedi-
ately after quenching the reaction mixture with water
(Method A). In the case of t-butyl and p-tolylsulfinimines,
1g–h open chain products 4 and 5 were obtained and an
additional cyclization step using acid was needed (Method
B). We suspect that products 3a–d are formed via a step-
wise mechanism, that is, (1) Mannich addition to sulfini-
mine, (2) loss of a sulfinyl group and (3) cyclization to a
dihydropyridone. We could not find any spectral evidence
for the presence of an N-sulfinyl tetrahydropyridine deriv-
ative, which would indicate a cycloaddition pathway. Actu-
ally, several pieces of evidence were shown for the stepwise
mechanism in the case of the Danishefsky diene.14 For
dienophiles 1a–f, we only observed cyclized product 3
because 10-isobornylsulfinyl group is a good leaving group.
The driving force for this reaction is the formation of cyclic
2. Results and discussion
Our earlier experience in the reaction of sulfinimines with
silyl nucleophiles prompted us to investigate cycloaddition
*
Tel.: +48 22 3432104; fax: +48 22 632 6681; e-mail: rkaw@icho.edu.pl
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.026

R. Kawe˛cki / Tetrahedron: Asymmetry 17 (2006) 1420–1423
1421
R
S
NMe2
TMSOTf / CH2Cl2
+
H
N
N
O
-70 oC
OTBS
Ar
O
Ar
(2S)
(SS)
2
1
3
1a R = iborOTMS, Ar = Ph
3a Ar = Ph
1b R = iborOTMS, Ar = 3'-ClC6H4
1c R = iborOTMS, Ar = 3'-O2NC6H4
1d R = iborOTMS, Ar = 2-Furyl
1e R = iborOH, Ar = 3'-ClC6H4
1f R = mentOTMS, Ar = 3'-ClC6H4
1g R = p-Tol, Ar = Ph
3b Ar = 3'-ClC6H4
3c Ar = 3'-O2NC6H4
3d Ar = 2-Furyl
1h R = t-Bu, Ar = Ph
Me Me
OH
Me Me
OTMS
Me
Me
OTMS
mentOTMS
Me
iborOTMS
iborOH
Scheme 1.
Table 1. Synthesis of dihydropyridinones
Entry
Substrate
R
Ar
Methoda
Product
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
iborOTMS
iborOTMS
iborOTMS
iborOTMS
iborOH
mentOTMS
p-Tol
t-Bu
Ph
A
A
A
A
A
A
B
3a
3b
3c
3d
3b
3b
3a
3a
82
82
80
61
75
98
51
40
60
68
90
69
14
12
(89)b
49
30-ClC6H4
30-O2NC6H4
2-Furyl
30-ClC6H4
30-ClC6H4
Ph
1g
1h
Ph
B
a Method A: quench with water. Method B: quench with water, then aqueous acidic hydrolysis. Details in Section 4.
b de of 4 (see Scheme 2). Epimerization was not observed at either C-2 or the sulfur atom.
sulfinate (sultin)12 in the presence of the acid. This is also
R
S
2
R
S
NMe2
the case for 8-menthyl derivative 1f. Complete splitting of
the sulfinyl group was even observed when the reaction
mixture was quenched with satd aq NaHCO3. Removal
of the t-butyl and p-tolylsulfinyl groups proved more diffi-
cult. In this case, we observed the formation of enaminones
of type 4.15 They can be cyclized to dihydropyridone 3 in
the presence of acid, which is strong enough to cleave the
sulfinyl group (Scheme 2).
TMSOTf / CH2Cl2
H
N
O
H+ / H2O
N
O
3a
-70 oC
Ph
Ph
O
(SS)
1g R = p-Tol
1h R = t-Bu
4a R = p-Tol (de = 89 %)
4b R = t-Bu
Scheme 2.
For the p-tolyl derivative we used acetic acid while for t-
butyl we used 4 M HCl. However, the overall yield was lower
than using sulfinimines 1a–f. The diastereoselectivity of the
addition to 10-isobornylsulfinimines 1a–d (R = ibor-
OTMS) was good (60–90% ee). The steric effect of the
TMS group seems to be important as the sulfinimine 1e
(R = iborOH) gave a low ee value. Surprisingly, the addi-
tion to 8-menthylsulfinimine 1f was not stereoselective
(12% ee). The use of a t-butylsulfinyl group also resulted
in low ee of the product.
The stereochemistry of the addition of silyl nucleophiles to
the C@N bond in sulfinimines has been well described
by the Davis–Cram model.16 The preferred conformation
of the sulfinimine is that it has a synperiplanar arrangement
around the S–N bond.9,17 Nucleophile likely attacks this
molecule from the si side (Fig. 1).

1422
R. Kawe˛cki / Tetrahedron: Asymmetry 17 (2006) 1420–1423
an atmosphere of argon. The Rawal diene was synthesized
R
O
from 4-(dimethylamino)-3-buten-2-one.10 Sulfinimines
1a–e,12,18 1g19 and 1h20 were obtained as described in original
procedures.
:
N
C
Ar
:Nu
4.1.1. (1R,2R,4R,SS)-N-[(1E)-3-Chlorophenylmethylene]-2-
(2-trimethylsilyloxy-4-methylcyclohexyl)propane-2-sulfina-
mide, 1f. This compound was obtained according to the
procedure described earlier.18 To a solution of sulfinamide
(651 mg, 2.2 mmol) and 3-chlorobenzaldehyde (369 mg,
2.6 mmol) in THF (10 mL) was added tetraethoxytitanium
(1.10 g, 4.8 mmol) and the mixture stirred at rt for 16 h. A
saturated solution of KCl (1.5 mL) was added and the sus-
pension filtered through Celite. The precipitate was washed
with ethyl acetate. The filtrate was dried (MgSO4) and
evaporated. Chromatography on silica gel (AcOEt–hexane
1:1) gave a colourless oil (0.82 g, 90%). Spectral data for 1f:
Figure 1.
This results in the formation of a product with a like con-
figuration. In the case of (SS)-sulfinimines 1, the dihydro-
pyridone also has an (S)-configuration at C-2. Opposite
effect is observed when the nucleophilic reagent contains
metal as counterion. The addition is controlled by a che-
lated transition state. This is usually the case when organ-
olithium or Grignard reagents are used. To check this
hypothesis, an enolate was generated from 4-(dimethyl-
amino)-3-buten-2-one using LDA or NaHMDS as a base.
The reaction with sulfinimine 1g gave two diastereoiso-
meric sulfinamides 4a and 5a. The conversion of the sub-
strate as well as the diastereoisomeric excess was low.
However, the direction of diastereoselectivity of this pro-
cess was opposite to that observed when the Rawal diene
was used. The major diastereoisomer had an unlike config-
uration (Scheme 3).
[a]D21 = +92.9 (c 1.03, acetone). IR (neat) 1074; 1600 cmꢀ1
.
1H NMR (CDCl3): d 0.16 (s, 9H), 0.86–1.21 (m, 3H), 0.92
(d, J = 6.3 Hz, 3H), 1.00 (s, 3H), 1.25 (s, 3H), 1.31–1.54 (m,
1H), 1.61–1.75 (m, 1H), 1.82–2.10 (m, 3H), 3.76 (ddd,
J = 4.2, 10.2, 10.2 Hz, 1H), 7.34–7.49 (m, 2H), 7.69 (dt,
J = 7.0, 1.6 Hz, 1H), 7.87 (t, J = 1.6 Hz, 1H), 8.49 (s,
1H). 13C NMR (CDCl3): d 1.1; 16.6; 17.5; 22.0; 26.2;
31.3; 34.4; 45.4; 49.1; 65.2; 73.1; 127.8; 128.6; 130.0;
131.9; 134.9; 135.9; 161.1. Anal. Calcd for C20H32ClNO2S-
Si: C, 58.01; H, 7.79; N, 3.38. Found: C, 58.08; H, 7.81; N,
3.23.
O
S
O
S
NMe2
NMe2
O
O
1. Base
H
H
4.2. General method for the aza Diels–Alder reactions of
sulfinimines. Method A
Tol
N
Tol
N
+
Me
NMe2
2. 1g
Ph
O
Ph
To a solution of sulfinimine 1 (0.26 mmol) and Rawal diene
2 (117 mg, 0.52 mmol) in dry dichloromethane (3 mL),
TMSOTf (145 mg, 0.65 mmol) was added dropwise at
ꢀ70 °C. The resulting mixture was stirred for 3.5 h at
ꢀ70 °C. Water (2 mL) was then added and the mixture
warmed to rt. The mixture was alkalized with satd aq
NaHCO3 and extracted with CH2Cl2. The organic phase
was dried over MgSO4, filtered and evaporated. The solid
residue was purified by chromatography on silica gel
(AcOEt–hexane 25:10). Yields and enantiomeric enrich-
ment are shown in Table 1. Ee was determined by HPLC
(Nucleodex b-PM, MeOH–0.1% TEAA in H2O pH = 4.0
45:55).
4a
5a
Base: NaHMDS
LDA
1
1
:
:
1.8
2.4
Scheme 3.
3. Conclusion
We have demonstrated that optically active sulfinimines
may act as formal dienophiles. The use of highly reactive
dienes as well as Lewis acid is necessary. The reaction of
the Rawal diene with 10-isobornylsulfinimines in the pres-
ence of TMSOTf leads to enantiomerically enriched, N-
unsubstituted dihydropyridones in good yields. Removal
of the sulfinyl group occurs during aqueous workup. The
stereoselectivity of the reaction is modest; the method is
limited to 2-aryl substituted derivatives.
The configuration at C-2 of dihydropyridone 3a was estab-
lished by comparison of the specific rotation sign of the
known derivative.21 Spectral data of dihydropyridones
were identical to that published elsewhere.
4.3. General method for the aza Diels–Alder reactions of
sulfinimines. Method B
4. Experimental
4.1. General
The conditions of diene addition were the same as above.
The crude product was dissolved in MeOH (4 mL) and
concentrated aq HCl (2 mL) was added. The mixture was
kept at rt for 5 h. MeOH was removed by evaporation
and the residue neutralized with satd aq NaHCO3 solution.
The mixture was extracted with CH2Cl2 and dried over
MgSO4. The product was purified by chromatography on
silica gel (AcOEt–hexane 25:10).
NMR spectra were recorded at 200 and 500 MHz (1H). All
spectra were referenced to a residual solvent peak (chloro-
form 7.26 and 77.0 ppm for 1H and 13C, respectively).
Dichloromethane was distilled from CaH2. All experi-
ments, except for acidic hydrolysis, were conducted under

R. Kawe˛cki / Tetrahedron: Asymmetry 17 (2006) 1420–1423
1423
20
4.3.1. 2,3-Dihydro-2-phenyl-4(1H)-pyridinone, 3a. ½aꢁD
¼
þ195:3 (c 2.51, EtOH). Spectral data are identical to those
reported.21
References
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20
to those reported.22
4.3.3. 2,3-Dihydro-2-(3-nitrophenyl)-4(1H)-pyridinone, 3c.
Mp = 172–178 °C. IR (KBr) 3313; 1610; 1588; 1554;
1533 cmꢀ1. H NMR (CDCl3): d 2.66 (1/2ABX, J = 16.0,
1
5.3 Hz, 1H); 2.74 (1/2ABX, J = 16.0, 13.3 Hz, 1H), 4.91
(dd, J = 13.3, 5.3 Hz, 1H); 5.12 (br, 1H); 5.19 (d,
J = 7.6 Hz, 1H); 7.31 (dd, J = 7.6, 6.8 Hz, 1H); 7.60 (t,
8.0, 1H); 7.73 (d, J = 8.0 Hz, 1H); 8.21 (ddd, J = 8.0, 2.0,
1.0 Hz, 1H); 8.30 (d, J = 2.0 Hz, 1H). 13C NMR (CDCl3):
d 44.4; 57.8; 101.0; 121.5; 123.5; 130.2; 132.6; 142.2; 148.7;
150.6; 191.0. HRMS (EI) calcd for C11H10O3N2 218.0691
(M+). Found 218.0684.
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4.3.4. 2,3-Dihydro-2-(2-furyl)-4-(1H)-pyridinone, 3d. ½aꢁD
¼
þ430:1 (c 0.565, CHCl3). Enantiomeric excess of this deriv-
ative was established by 1H NMR using t-butyl-
phenylphosphinothioic acid23 as the chiral solvating agent.
Spectral data are identical to those reported.22
˜
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A solution of enaminone 2 (70 mg, 0.62 mmol) in THF
(1 mL) was slowly added to a solution of NaHMDS (1 mL,
0.6 M, toluene) in THF (1 mL) at ꢀ50 °C. The reaction mix-
ture was stirred for 1 h at ꢀ 65 °C and a solution of sulfini-
mine 1g (150 mg, 0.62 mmol) in THF (1 mL) was added. The
reaction mixture was kept at ꢀ65 °C for 1 h and quenched
with satd aq NH4Cl solution. The diastereoisomer ratio
was established from 1H NMR spectra. Enaminones 4 and
5 were hydrolyzed in aq AcOH/MeOH for 16 h at rt. The
solution was alkalized with NaHCO3 and extracted with
CH2Cl2 to give dihydropyridone 3a. Purification as above.
15. The structure of 4a was established using only NMR data
(because of purification problems).
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3397.
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Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou,
P.; Carroll, P. J. Org. Chem. 1997, 62, 2555–2563.
20. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J.
A. J. Org. Chem. 1999, 64, 1278–1284.
The structure of 4a was established using NMR data only
(because of purification problems). 1H NMR (CDCl3,
200 MHz): d 2.27 (s, 3H); 2.70 (br, 3H); 2.92 (m, 2H);
2.94 (br, 3H); 4.74 (ddd, J = 6.1 Hz, 1H); 4.88 (d,
J = 12.6 Hz, 1H); 5.93 (d, J = 6.1 Hz, 1H); 7.03–7.19 (m,
7H); 7.37–7.46 (m, 3H). 13C NMR (CDCl3, 50 MHz): d
21.1; 36.8 br; 44.6 br; 47.9 br; 53.6; 96.1 br, 125.8; 126.7;
126.8; 127.9; 128.9; 140.5, 141.3; 142.0; 152.8; 194.7.
21. Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem.
Soc. 1994, 116, 4719–4728.
Acknowledgements
22. Kawecki, R. Synthesis 2001, 828–830.
This work was mainly supported by the Institute of Organic
Chemistry Polish Academy of Sciences in Warsaw Grants
for statute activity.
´
23. Omelanczuk, J.; Mikołajczyk, M. Tetrahedron: Asymmetry
1996, 7, 2687–2694.