Microwave-assisted silyloxy-cope rearrangement of syn-aldol products in DMF: Enhancement of rate and diastereoselectivity

Article abstract of DOI:10.1055/s-2006-939729

Microwave-assisted Cope rearrangements of 1,5-dienes embedded in a syn-aldol structure proceed in substantially reduced reaction times and markedly increased diastereoselectivity when conducted in DMF as solvent. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939729

LETTER
1413
Microwave-Assisted Silyloxy-Cope Rearrangement of syn-Aldol Products in
DMF: Enhancement of Rate and Diastereoselectivity
S
ilyloxy-Cope Re
h
arrangemen
r
t
of syn-A
i
ldol
P
s
roducts in
t
D
MF oph Schneider,* Souad Khaliel
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: schneider@chemie.uni-leipzig.de
Received 16 February 2006
TBSO
O
Bn
TBSO
R1
O
Abstract: Microwave-assisted Cope rearrangements of 1,5-dienes
embedded in a syn-aldol structure proceed in substantially reduced
reaction times and markedly increased diastereoselectivity when
conducted in DMF as solvent.
Bn
R1
N
180 °C
N
R2
R4
R3 R4
R2
O
A: toluene, 1–3 h
O
O
O
R3
B: MW, DMF, 15–20 min
Key words: aldol products, Cope rearrangement, diastereoselectiv-
ity, microwave irradiation
2
1
OTBS
R1
R3
COXc
R2
[3.3]Sigmatropic rearrangements belong to the most
fundamental organic transformations and improved vari-
ants continue to broaden the scope of this reaction family.
Their predictable stereospecific reaction path through a
chair-like transition state and a documented complete
chirality transfer offers the possibility to provide products
of high stereochemical purity which are otherwise not
easily accessible.1
R4
3
Scheme 1 Cope rearrangement of aldol products 1 under standard
(A) and microwave (B) conditions.
this process is markedly improved using DMF as solvent.
The selection of DMF as solvent was made on the consid-
eration that only solvents with a sufficiently high dielec-
tric constant are capable of absorbing the electromagnetic
radiation efficiently and converting it into heat.7
In this context we have developed the silyloxy-Cope re-
arrangement of 1,5-dienes 1 embedded in a syn-aldol
structure2 which are directly available using the Evans
asymmetric aldol methodology.3 A rapid, high-yielding,
and stereoselective Cope rearrangement occurs when 1,5-
dienes 1 are heated in toluene at 180 °C (sealed flask) for
1–3 hours depending on the degree of substitution
(Scheme 1). Whereas 1-monosubstituted 1,5-dienes
(R1 = alkyl, R3 and R4 = H) typically rearrange within 1
hour at 180 °C, 1,6-disubstituted 1,5-dienes require ex-
tended heating for 2–3 hours at 180 °C for complete con-
versions. In analogy to the classical Doering experiments4
we have proposed the chairlike transition state 3 to ac-
count for the observed diastereoselectivity of the re-
arrangement giving rise to the Cope products 2 with a Z-
configured silyl enol ether and an E-configured enimide
double bond. The minor diastereomers (not shown here)
originate from the inverted chair-like transition state fur-
nishing products with opposite stereochemistry at every
stereogenic element. The Cope products 2 have proven to
be valuable synthetic intermediates in the synthesis of
enantiomerically pure cyclohexanes, tetrahydropyrans,
piperidines, polyols, and terpenes.5
When 1,5-diene 1a was irradiated in a microwave reactor
at 180 °C in DMF as solvent for just 15 minutes, the Cope
product 2a was formed in 91% yield and 25:1 diastereose-
lectivity (Table 1, entry 1).8 This compares favorably with
our standard thermal reaction conducted in toluene which
requires a reaction time of 1 hour and gives rise to a 10:1
diastereoselectivity. The temperature in the microwave
oven could even be lowered to 140 °C and still 2a was
formed within just 30 minutes in 90% yield. Other 1-
monosubstituted 1,5-dienes 1b–d rearranged under iden-
tical microwave conditions in high yields and excellent di-
astereoselectivities of >25:1 for all examples were tested
(entries 2–4). Whereas 1,5-dienes 1b and 1c displayed
comparable, albeit reduced selectivities in the thermal re-
action in toluene, the selectivity for the silyl-substituted
1,5-diene 1d was markedly increased from 5:1 to >25:1
(entry 4).
The same trend was observed for more highly substituted
1,5-dienes carrying alkyl groups both in the 1- and 6-po-
sition. Thus, 1e–g rearranged in good yields and very high
diastereocontrol (>25:1) within only 20 minutes to furnish
Cope products 2e–g, respectively, with two new chiral
centers (Table 1, entries 5–7). On the contrary, the ther-
mal reactions of 1e–g in toluene at 180 °C required 2–3
hours for complete conversions. In all cases the stereo-
chemical outcome of the rearrangements was consistent
with the chair-like transition state 3 depicted in Scheme 1.
We have now found that the reaction times for the
[3.3]sigmatropic process can be significantly reduced
when the rearrangement is performed under microwave
conditions.6 At the same time the diastereoselectivity of
SYNLETT 2006, No. 9, pp 1413–1415
0
1.
0
6.
2
0
0
6
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-939729; Art ID: G06306ST
© Georg Thieme Verlag Stuttgart · New York

1414
C. Schneider, S. Khaliel
LETTER
Table 1 Cope Rearrangements of Aldol Products 1 under Microwave (DMF, 15–20 min) and Standard (Toluene, 1–3 h) Conditions at 180 °C
Microwave conditions
Standard conditions
Yield (%)b Ratioa Yield (%)b
87
Entry
1,5-Diene
R1
R2
H
R3
H
R4
H
H
H
H
H
H
H
Ratioa
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Me
25:1
91
87
79
85
90
79
81
10:1
>25:1
20:1
Me
Me
H
H
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
82
80
85
87
75
70
Ph
H
SiMe2Ph
Me
H
H
5:1
H
Me
Et
Et
>25:1
>25:1
>25:1
Me
H
1g
Me
Me
a Determined by 1H NMR and 13C NMR of crude product.
b Isolated yield of purified material.
Kinetic experiments indicate that the reaction rate was in- References and Notes
dependent of the solvent used. Thus, 1a was rearranged
(1) Reviews: (a) Nubbemeyer, U. Synthesis 2003, 961; and
references cited therein. (b) Enders, D.; Knopp, M.;
Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847.
(c) Frauenrath, H. Stereoselective Synthesis, In Houben-
Weyl (Methods in Organic Chemistry), Vol. E21d;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995, 3301.
(2) (a) Schneider, C.; Rehfeuter, M. Synlett 1996, 212.
(b) Schneider, C.; Rehfeuter, M. Tetrahedron 1997, 53, 133.
(c) Schneider, C. Synlett 2001, 1079. For related work see:
(d) Black, W. C.; Giroux, A.; Greidanus, G. Tetrahedron
Lett. 1996, 37, 4471. (e) Tomooka, K.; Nagasawa, A.; Wei,
Y.; Nakai, T. Tetrahedron Lett. 1996, 37, 8899.
(3) (a) Evans, D. A.; Bartroli, J.; Shi, T. L. J. Am. Chem. Soc.
1981, 103, 2128. (b) Evans, D. A.; Sjogren, E. B.
Tetrahedron Lett. 1986, 27, 4957.
(4) Doering, W. v. E.; Roth, W. R. Tetrahedron 1962, 18, 67.
(5) For the application of the Cope products in organic synthesis
see: (a) Schneider, C. Synlett 1997, 815. (b) Schneider, C.;
Schuffenhauer, A. Eur. J. Org. Chem. 2000, 73.
with a half-life of t1/2 = 12 min in toluene as well as in
DMF at 180 °C under standard conditions. The half-life
decreased, however, to t1/2 = 3–4 min under microwave
conditions with DMF as solvent at 180 °C. This rate-ac-
celerating effect is believed to originate from a more effi-
cient conversion of electromagnetic radiation into heat
and hence a more rapid heating of the reaction mixture
than under normal conditions.7
The origin of the significant enhancement of diastereo-
selectivity in DMF as solvent, which was also observed
under usual thermal conditions, is not entirely clear at the
moment. We have previously noted that the syn-aldol
structure of 1,5-dienes 1 with an electron-rich allyl silyl
ether fragment and an electron-poor allyl carboximide
fragment is responsible for the high rate and selectivity of
the Cope rearrangement.2c We assume that a highly polar-
ized, yet still concerted, transition state may be involved
in the rearrangement which is expected to benefit from the
dipolar solvent. Theoretical calculations are currently on-
going to shed light on these mechanistic questions.
(c) Schneider, C.; Börner, C. Synlett 1998, 652.
(d) Schneider, C.; Börner, C.; Schuffenhauer, A. Eur. J. Org.
Chem. 1999, 3353. (e) Schneider, C. Eur. J. Org. Chem.
1998, 1661. (f) Schneider, C.; Rehfeuter, M. Tetrahedron
Lett. 1998, 39, 9. (g) Schneider, C.; Rehfeuter, M. Chem.
Eur. J. 1999, 5, 2850. (h) Schneider, C.; Reese, O. Angew.
Chem. Int. Ed. 2000, 39, 2948; Angew. Chem. 2000, 112,
3074. (i) Schneider, C.; Reese, O. Chem. Eur. J. 2002, 8,
2585. (j) Schneider, C.; Tolksdorf, F.; Rehfeuter, M. Synlett
2002, 2098.
In conclusion, we have established a modified protocol
for the execution of the silyloxy-Cope rearrangement of
1,5-dienes embedded in a syn-aldol structure with signifi-
cant effects on the rate and diastereoselectivity. It takes
advantage of the rate enhancement under microwave con-
ditions and uses the highly dipolar solvent DMF to further
enhance the diastereoselectivity of the process.
(6) Davies et al. reported the microwave-assisted Cope
rearrangement of a similar, but ester-derived aldol product in
hexane (190 °C, 70 min) and an ionic liquid (240 °C, 45
min). Our results with the imide-based aldol products 1
compare favorably with these conditions. See: Davies, H. M.
L.; Beckwith, R. E. J. J. Org. Chem. 2004, 69, 9241.
(7) Excellent review: Kappe, C. O. Angew. Chem. Int. Ed. 2004,
43, 6250; Angew. Chem. 2004, 116, 6408.
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie.
We thank Degussa AG for the supply of enantiomerically pure
amino acids and Wacker AG for the generous donation of tert-
butyldimethylsilyl chloride. Souad Khaliel is grateful to the Uni-
versity of Garyounis (Bengazi, Libya) for a doctoral fellowship.
(8) Typical Experimental Procedure.
A microwave reactor ‘microPREP A’ (MLS GmbH,
Germany) with a single magnetron (max. 1200 W, pulsed
irradiation, 2.45 GHz) terminal 320 controller, and easy
CONTROL 06 software was used for the microwave
experiments. A power of max. 500 W was used in all
Synlett 2006, No. 9, 1413–1415 © Thieme Stuttgart · New York

LETTER
Silyloxy-Cope Rearrangement of syn-Aldol Products in DMF
1415
experiments and the temperature inside the reaction mixture
1782, 1681 cm–1. 1H NMR (300 MHz, CDCl3): d = 0.13 (s,
6 H, TBS), 0.92 (s, 9 H, TBS), 1.02 (d, J = 7.0 Hz, 3 H, Me),
2.28–2.32 (m, 2 H), 2.79 (dd, J = 13.0, 9.8 Hz, 1 H, benzyl-
H), 2.90 (m, 1 H), 3.34 (dd, J = 13.0, 3.0 Hz, 1 H, benzyl-H),
4.14–4.23 (m, 2 H), 4.31 (dd, J = 10.0, 8.7 Hz, 1 H, 6¢-H),
4.72 (m, 1 H), 6.16 (dd, J = 6.0, 1.0 Hz, 1 H, 7¢-H), 7.21–
7.36 (m, 7 H, 2¢-H, 3¢H, phenyl-H). 13C NMR (75 MHz,
CDCl3): d = –5.30, –5.22, 18.35, 20.94, 25.76, 28.46, 38.06,
40.63, 55.45, 66.18, 115.10, 121.20, 127.40, 129.10, 129.60,
135.60, 138.30, 151.10, 153.50, 165.10. MS (EI, 70eV):
m/z = 429 (1), 414 (10), 372 (20), 185 (100), 91 (45), 73
(99). Anal. Calcd: C, 67.10; H, 8.21; N, 3.26. Found: C,
67.14; H, 8.39; N, 3.13.
was controlled with a ATC-FO 300 fiberoptic sensor
inserted into the reaction vessel and automatically adjusted
to the set temperature. The amount of 300 mg (0.70 mmol)
of 1,5-diene 1a was dissolved in 25 mL dry DMF and placed
in a microwave vessel, which was sealed. The sample was
irradiated for 15 min at 180 °C whereupon the solvent was
evaporated in vacuo. The crude product was analyzed by
NMR to determine the diastereoselectivity (25:1) and
subsequently purified by flash chromatography over silica
gel with Et2O and pentane (1:6) to furnish 275 mg of the
Cope product 2a (91%) as a colorless solid. Mp 60–61 °C;
[a]D20 13.0 (c 1.2, CHCl3). IR (film): n = 3027, 2956, 2858,
Synlett 2006, No. 9, 1413–1415 © Thieme Stuttgart · New York