Amine-catalyzed direct self Diels-Alder reactions of α,β-unsaturated ketones in water: Synthesis of pro-chiral cyclohexanones

Article abstract of DOI:10.1016/S0040-4039(02)01500-9

Amine-catalyzed direct self Diels-Alder reactions of α,β-unsaturated ketones have been developed. (S)-1-(2-Pyrrolidinyl-methyl)pyrrolidine, L-proline and pyrrolidine catalyzed the reaction of α,β-unsaturated ketones to provide cyclohexanone derivatives with good yield (up to 80%) in a single step via in situ-generation of 2-amino-1,3-butadienes and iminium ion-activated enones. Pro-chiral cyclohexanones were selectively prepared with pyrrolidine catalysis in water.

Full text of DOI:10.1016/S0040-4039(02)01500-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6743–6746
Amine-catalyzed direct self Diels–Alder reactions of
a,b-unsaturated ketones in water: synthesis of pro-chiral
cyclohexanones
D. B. Ramachary, Naidu S. Chowdari and Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Department of Molecular Biology, The Scripps Research Institute,
0550 North Torrey Pines Road, La Jolla, CA 92037, USA
1
Received 27 June 2002; revised 18 July 2002; accepted 22 July 2002
Abstract—Amine-catalyzed direct self Diels–Alder reactions of a,b-unsaturated ketones have been developed. (S)-1-(2-Pyrro-
lidinyl-methyl)pyrrolidine, -proline and pyrrolidine catalyzed the reaction of a,b-unsaturated ketones to provide cyclohexanone
L
derivatives with good yield (up to 80%) in a single step via in situ-generation of 2-amino-1,3-butadienes and iminium ion-activated
enones. Pro-chiral cyclohexanones were selectively prepared with pyrrolidine catalysis in water. © 2002 Published by Elsevier
Science Ltd.
The Diels–Alder reaction is one of the most important
transformations in synthetic chemistry for the construc-
tion of six-membered ring systems and many strategies
an attractive single-step route to cyclohexanone
derivatives.
8
1
to catalyze this reaction have been studied. Recently,
Initially, we studied a variety of reaction conditions
involving amine catalysts for the self Diels–Alder reac-
tion of a,b-unsaturated ketone. Since chiral amines
organoamines have been applied as catalysts of Diels–
Alder reactions involving a,b-unsaturated carbonyl
compounds in a LUMO-lowering strategy based on
(S)-1-(2-pyrrolidinylmethyl)pyrrolidine 1 and L-Proline
2
3–6
imine formation (Scheme 1a). Extending our studies of
2 provide enamine intermediates as described above,
we tested these amines along with pyrrolidine 3 as
catalysts for the self Diels–Alder reaction of a,b-unsat-
urated ketone 4 to form cyclohexanone derivatives 5a
3
4
5
organoamine-catalyzed aldol, Michael, Mannich, and
6
related reactions founded on enamine catalysis, we
have reported the first direct asymmetric Diels–Alder
reactions of a,b-unsaturated ketones with nitro olefins.
This strategy involved in situ generation of 2-amino-
9
and 5b. The results are shown in Table 1.
1
,3-butadienes with amine catalysts 1 or 2 providing for
7
the synthesis of cyclohexanones (Scheme 1b).
In this report we demonstrate the utility of amine-cata-
lyzed self Diels–Alder (or double Michael) reactions of
a,b-unsaturated ketones providing for the synthesis of
pro-chiral acyl-substituted cyclohexanones (Scheme 1c).
In this reaction, we envisioned amine activation of the
a,b-unsaturated ketone as a dienophile together with in
situ generation of a 2-amino-1,3-butadiene diene. This
strategy would combine the iminium ion-based route of
2
MacMillan, with our enamine-based activation strat-
7
egy. This type of catalytic Diels–Alder reaction affords
Keywords:
amines;
cyclohexanones;
Diels–Alder
reactions;
organocatalysis; enamines; imines; aqueous media.
*
0
Corresponding author. E-mail: carlos@scripps.edu
Scheme 1.
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01500-9

6
744
D. B. Ramachary et al. / Tetrahedron Letters 43 (2002) 6743–6746
Table 1. Amine-catalyzed self Diels–Alder reaction of a,b-unsaturated ketone 4
c
Entry
1
Enone (mmol)
Catalyst
Solvent
Temperature, reaction time
Conversiona
Yield (%)b
Ratio 5a:5b
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1 (0.3 equiv.)
1 (0.3 equiv.)
2 (0.3 equiv.)
2 (0.3 equiv.)
3 (0.3 equiv.)
3 (0.3 equiv.)
3 (0.3 equiv.)-p-TSA
Neat
THF
EtOH
MeOH
THF
rt, 24 h
58
83
70
54
100
90
50
68
52
47
63
70
65
1.6:1
1.0:1
4.5:1
3.5:1
2.0:1
6.0:1
6.0:1
d
2
40°C, 24 h
rt, 5 days
40°C, 24 h
40°C, 8.5 h
40°C, 23 h
40°C, 23 h
d
3
d
4
d
5
e
6
H O
2
f
7
H O
90
2
a
Conversion based on the ratio of 4 and 5, determined by 1H NMR analysis.
Combined isolated yield of 5a and 5b.
b
c
d
e
f
The ratio of diastereoisomers of 5 was determined by 1H NMR.
The reaction was performed using 4 (0.5 mmol) and catalyst (0.15 mmol) in solvent (0.05 mL).
The reaction was performed using 4 (0.5 mmol) and catalyst (0.15 mmol) in H O (0.5 mL).
The reaction was performed using 4 (0.5 mmol), p-TSA (0.075 mmol) and catalyst (0.15 mmol) in H O (0.5 mL).
2
2
We were pleased to find that the reaction of enone 4
with amine 1 in neat conditions at room temperature
for 24 h furnished a 1.6:1 diastereomeric mixture of
Diels–Alder products 5a and 5b in 50% yield (entry 1).
The same reaction in THF at 40°C for 24 h furnished
cyclohexanones 5a and 5b in 68% yield as a 1:1
Examination of the scope of our amine-catalyzed reac-
tions with a variety of a,b-unsaturated ketones is pre-
sented in Table 2. Amines 1, 2 and 3 catalyzed the self
Diels–Alder reaction of a,b-unsaturated ketones 6–12 to
provide cyclohexanone derivatives 13–18 with isolated
10
yields of 47–80%. The diastereoselectivity of these
reactions varied depending on the amine catalyst, the
reactants, as well as the reaction conditions. In four
examples of catalysis using water as the solvent (entries
2, 3, 5 and 6), selectivity towards the exo product was
uniformly increased. The amine-catalyzed self Diels–
Alder reactions of a,b-unsaturated ketones in water
providedthepro-chiralexo-productasthemajorproduct.
While an endo selectivity is typically expected with enone
dienophiles due to secondary orbital interactions, an exo
selectivity is likely the result of more favorable iminium
diastereomeric mixture (entry 2). Next, -proline 2 was
L
tested for the self Diels–Alder reaction of enone 4.
Performing the reaction under proline catalysis (30
mol% of 2) in ethanol at room temperature for 5 days
furnished products 5a and 5b in 52% yield with an
enhanced 4.5:1 diastereomeric ratio (entry 3). The same
reaction in methanol at 40°C for 24 h furnished prod-
ucts 5a and 5b with slightly reduced yield (entry 4).
Since the chiral amines 1 and 2 provided the pro-chiral
cyclohexanone derivative 5a as the major product, we
studied simple pyrrolidine as an achiral amine catalyst
of this reaction. Accordingly, the reaction of enone 4
1
1
ion solvation and hydrophobic interactions in the
transition state as compared to those possible with an
endo-transition state. There appear to be some steric
limitations to this reaction. trans-4-(4-Methoxyphenyl)-
3-methyl-but-3-en-2-one 19 proved to be unreactive with
pyrrolidine under the standard reaction conditions after
48 h. Comparison of this reaction with simple a,b-unsat-
urated ketone 8 (entry 5, Table 2) suggests that 19 is too
sterically demanding for the imine–enamine based Diels–
Alder reaction mechanism proposed here.
(
(
0.5 mmol) with pyrrolidine 3 (0.15 mmol) in THF
0.05 mL) at 40°C for 8.5 h furnished the Diels–Alder
products 5a and 5b in a 2:1 ratio and in 63% yield
entry 5). Next, we performed the reaction in water (0.5
(
mL) at 40°C for 23 h in an attempt to alter the
stereoselectivity of the reaction. We were pleased to find
that under these conditions Diels–Alder products 5a
and 5b could be isolated in 70% yield with improved
exo–endo selectivity (6:1) (entry 6). An attempt to fur-
ther improve this reaction by addition of 15 mol%
p-TSA as a co-catalyst to facilitate equilibration
between imine and enamine intermediates during the
reaction, resulted in slightly reduced yield with conser-
vation of stereoselectivity (entry 7).
Our amine-catalyzed Diels–Alder reaction provides for
the scalable preparation of pro-chiral cyclohexanone
derivatives using water as solvent. Cyclohexanone deriva-
tives 13a and 13b were readily prepared on a 1.5 g scale
from enone 6 under very mild conditions (Scheme 2).

D. B. Ramachary et al. / Tetrahedron Letters 43 (2002) 6743–6746
6745
Table 2. Amine-catalyzed self Diels–Alder reactions of a variety of a,b-unsaturated ketones
Entry
1c
R
Catalyst
Solvent
Temperature, reaction time
Product
Yield (%)a
Ratiob a:b
Ph (6)
Ph (6)
2-Furyl (7)
2-Furyl (7)
4-CH OC H (8)
1-Naphthyl (9)
4-NO -C H (10)
CO Me (11)
CO Me (11)
1
3
3
1
3
3
3
2
3
3
THF
THF
THF
THF
THF
THF
THF
40°C, 60 h
40°C, 48 h
40°C, 24 h
40°C, 39 h
40°C, 18 h
40°C, 15 h
40°C, 5 h
rt, 16 h
rt, 38 h
rt, 2 h; 40°C, 2 days
13a, 13b
13a, 13b
14a, 14b
14a, 14b
15a, 15b
16a, 16b
17a, 17b
18a, 18b
18a, 18b
No reaction
75
70
52
47
75
75
80
55
58
–
2.0:1
d
e
e
2
3
4
5
6
7
8
9
1.3:1 (6.0:1)
1.5:1 (2.5:1)
2.0:1
1.0:2 (8.0:1)
1.4:1 (2.5:1)
1.1:1
1:1.3
1:2.3
–
f
c
f
e
e
3
6
4
f
f
2
6
4
f
CH OH
2
3
f
THF
THF
2
1
0f
H (12)
a
b
c
Isolated yield of diastereoisomers.
The ratio was determined by 1H NMR of the extracted reaction mixture.
The reaction was performed using enone (0.5 mmol) and 1 (0.15 mmol) in THF (0.15 mL) at 40°C. After 50% completion, p-TSA (0.075 mmol)
was added to the reaction mixture.
d
The reaction was performed using enone 6 (0.5 mmol) and 3 (0.15 mmol) in THF (0.5 mL) at 40°C. After 24 h, p-TSA (0.075 mmol) was added
to the reaction mixture.
Obtained using enone (0.5 mmol) and 3 (0.15 mmol) in H O (0.5 mL) at 40°C for 15 h.
The reaction was performed using enone (0.5 mmol) and catalyst (0.15 mmol) in solvent (0.05 mL).
e
f
2
12
ee), further studies might yield highly enantio- and
diastereoselective variants of this reaction.
Acknowledgements
This study was supported in part by the NIH
(
CA27489) and The Skaggs Institute for Chemical
Scheme 2.
Biology.
References
Cyclohexanone 13a was then obtained in pure form by
recrystallization from EtOAc–hexane.
1. Reviews: (a) Evans, D. A.; Johnson, J. S. In Comprehen-
sive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Vol.
III, p. 1177; (b) Kagan, H. B.; Riant, O. Chem. Rev.
1992, 92, 1007.
In summary, we have demonstrated for the first time
amine-catalyzed direct self Diels–Alder reactions of a,b-
unsaturated ketones to furnish cyclohexanone deriva-
tives via the in situ formation of dienes and dienophiles
in the form of 2-amino-1,3-butadienes and iminium
activated enones, respectively, from simple a,b-unsatu-
rated ketones. Currently, we have no formal proof that
the mechanism exclusively involves an iminium-acti-
vated a,b-unsaturated ketone as a dienophile since a,b-
unsaturated ketones are themselves reactive in some
Diels–Alder reactions. Precedence for the efficacy of an
iminium ion-based activation mechanism with a,b-
unsaturated ketones is found in the recent studies of
2. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 2458.
3. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am.
Chem. Soc. 2000, 122, 2395; (b) Sakthivel, K.; Notz, W.;
Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123,
5260; (c) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett
2001, 1245.
4. (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.;
Barbas, C. F., III Tetrahedron Lett. 2001, 42, 4441; (b)
Betancort, J. M.; Barbas, C. F., III Org. Lett. 2001, 3,
3737.
2
MacMillan. Therefore, the possibility exists that both
pathways could be operative in our reactions. While the
reactions reported herein are enantioselective with
respect to the minor endo product (entry 3, 5b, 23%
5. (a) Notz, W.; Sakthivel, K.; Bui, T.; Barbas, C. F., III
Tetrahedron Lett. 2001, 42, 199; (b) Cordova, A.; Notz,
W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J.

6
746
D. B. Ramachary et al. / Tetrahedron Letters 43 (2002) 6743–6746
Am. Chem. Soc. 2002, 124, 1842; (c) Cordova, A.; Watan-
abe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am.
Chem. Soc. 2002, 124, 1866.
NMR (399 MHz, CDCl ): l 7.20 (1H, ddd, J=5.2, 1.2
and 0.8 Hz), 6.91 (1H, dd, J=5.2 and 3.6 Hz), 6.81 (1H,
3
ddd, J=3.6, 1.2 and 0.4 Hz), 3.64 (1H, dt, J=11.2 and
6.4 Hz), 3.33 (1H, t, J=11.2 Hz), 2.85–2.70 (2H, m), 1.52
6
. (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
13
1
615; (b) Eder, U.; Sauer, G.; Wiechert, R. Angew.
(3H, s, COCH3); C NMR (100 MHz, CDCl ): l 210.5
3
Chem., Int. Ed. Engl. 1971, 10, 496; (c) Bui, T.; Barbas,
C. F., III Tetrahedron Lett. 2000, 41, 6951.
. Thayumanavan, R.; Dhevalapally, B.; Sakthivel, K.;
(C, CꢀO), 205.4 (C, CꢀO), 144.3 (C, CꢀCH), 127.0 (CH),
125.2 (CH) and 124.2 (CH) [3×aromatic CH], 64.3 (CH),
48.7 (CH ), 42.0 (CH), 33.2 (CH , COCH ); HRMS
7
8
2
3
3
+
Tanaka, F.; Barbas, C. F., III Tetrahedron Lett. 2002, 43,
(MALDI-FTMS): C H O S [MH+] calcd 305.0664,
16
16
2 2
1
3
817.
found 305.0669. 5b: H NMR (399 MHz, CDCl ): l 7.23
3
. For double Michael reactions of a,b-unsaturated ketones,
see: (a) Hallnemo, G.; Ullenius, C. Tetrahedron 1983, 39,
(1H, dd, J=5.2 and 0.8 Hz), 7.18 (1H, dd, J=5.2 and 0.8
Hz), 6.96–6.90 (2H, m), 6.89 (1H, td, J=3.6 and 0.8 Hz),
6.77 (1H, td, J=3.6 and 0.8 Hz), 3.92 (1H, dd, J=11.6
and 6.0 Hz), 3.79 (1H, td, J=10.8 and 4.0 Hz), 3.55 (1H,
t, J=4.8 Hz), 3.23–3.10 (2H, m), 2.76 (2H, dt, J=16.0
1
621; (b) Ueda, T.; Otsuji, Y. Chem. Lett. 1986, 1635; (c)
Mukaiyama, T.; Sagawa, Y.; Kobayashi, S. Chem. Lett.
1
1
986, 1821; (d) Oren, J.; Demuth, M.; Fuchs, B. Synthesis
987, 850; (e) Kanemasa, S.; Kumegawa, M.; Wada, E.;
and 5.6 Hz), 1.95 (3H, s, COCH
FTMS): C16
327.0487.
); HRMS (MALDI-
H O S [MNa+] calcd 327.0484, found
16 2 2
3
+
Nomura, M. Bull. Chem. Soc. Jpn. 1991, 64, 2990; (f)
Takeuchi, N.; Handa, S.; Koyama, K.; Kamata, K.;
Goto, K.; Tobinaga, S. Chem. Pharm. Bull. 1991, 39,
10. The moderate yield originated primarily due to product
losses that result from their low solubility. Reaction
conversion was very good.
11. Breslow, R. Acc. Chem. Res. 1991, 24, 159.
12. Enantiomeric excess was determined by chiral-phase
HPLC analyses. Absolute stereochemistry was not deter-
mined.
1
655; (g) Gossnitzer, E.; Wendelin, W.; Schermanz, K.;
Frieberger, K. Monatsh. Chem. 2001, 132, 1081; (h)
Asato, A. E.; Watanabe, C.; Li, Xiao-Yuan.; Liu, R. S.
H.; Tetrahedron Lett. 1992, 33, 3105.
9
. Relative stereochemistry was assigned by the coupling
1
constant of the a-acyl-hydrogen. Spectral data for 5a: H