The high stereoselectivity of the tandem sequence Diels-Alder reaction/Ireland-Claisen rearrangement starting from substituted O-(E)-buta-1,3-dienyl ketene acetals and cyclic dienophiles

Article abstract of DOI:10.1055/s-2007-983773

A new tandem reaction leads to bicyclic cyclohexene derivatives with complete control of the relative configuration of the four chiral centers formed. The high diastereoselectivity is the consequence of an endo-selective Diels-Alder reaction followed by an Ireland-Claisen rearrangement that proceeds via a boat-like transition state. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983773

PAPER
2379
The High Stereoselectivity of the Tandem Sequence Diels–Alder Reaction/
Ireland–Claisen Rearrangement Starting from Substituted O-(E)-Buta-
1,3-dienyl Ketene Acetals and Cyclic Dienophiles
High
S
tereoselecti
ivityof
c
the
T
andem
o
Sequence
D
l
iels–A
a
lder
R
eacti
s
on/Ireland–Clais
S
en Rearrangem
o
ent ldermann,a Jörg Velker,b Antonia Neels,c Helen Stoeckli-Evans,c Reinhard Neier*d
a
b
c
d
Novartis Institutes for BioMedical Research Basel, Global Discovery Chemistry, Lichtstraße 35, 4056 Basel, Switzerland
Actelion Pharmaceuticals Ltd., Innovation Centre, 4123 Allschwil, Switzerland
Institut de Microtechnique, Université de Neuchâtel, rue Emile-Argand 11, case postale 158, 2009 Neuchâtel, Switzerland
Institut de Chimie, Université de Neuchâtel, rue Emile-Argand 11, case postale 158, 2009 Neuchâtel, Switzerland
Fax +41(32)7182511; E-mail: reinhard.neier@unine.ch
Received 9 January 2007
Dedicated to Professor Paul A. Wender in honor of his 60th birthday
ylphosphoramide (15–25% in THF/2-MeTHF) can be
replaced by sodium hexamethyldisilazanide/1,3-dimeth-
yl-3,4,5,6-tetrahydropyrimidin-2(1H)-one, (10–15% in
THF/2-MeTHF), which maintained the high yield and the
Abstract: A new tandem reaction leads to bicyclic cyclohexene de-
rivatives with complete control of the relative configuration of the
four chiral centers formed. The high diastereoselectivity is the con-
sequence of an endo-selective Diels–Alder reaction followed by an
Ireland–Claisen rearrangement that proceeds via a boat-like transi- excellent diastereoselectivity.3d The workup is best
tion state.
achieved by addition of iodomethane at the reaction tem-
perature in order to quench the base before addition of the
hexane–water mixture.
Key words: cycloaddition, Diels–Alder reaction, rearrangement,
stereoselectivity, tandem reaction
O
OTBS
R
O
One-pot reactions combining several transformations rep-
resent effective strategies to increase the efficiency of or-
ganic synthesis.1 Our group has demonstrated the
effectiveness of the tandem sequence combining Diels–
Alder cycloaddition reactions with [3,3]-sigmatropic rear-
rangements.2–4 In this communication we wish to report
R
O
O
a, b
c
1a–f
2a–f
an improved stereoselective access to substituted O-buta- Scheme 1 Reagents and conditions: (a) t-BuOK, THF, –78 °C; (b)
RCH2COCl; (c) LiHMDS or NaHMDS, TBDMSCl, THF, 2-MeTHF,
HMPA or DMPU, < –110 °C; MeI, –110 °C; hexane–H2O, –110 °C
to r.t.
1,3-dienyl-O-(trialkylsilyl)-substituted ketene acetals of
type 2 and a study of their reactivity and diastereoselectiv-
ity in the tandem sequence Diels–Alder reaction/Ireland–
Claisen rearrangement.
Table 1 Synthesis of O-(E)-Buta-1,3-dienyl-Substituted (Z)-Ketene
We have recently shown that buta-1,3-dienyl carboxylates
1 are suitable precursors of the desired ketene acetals 2.3d,e
The subsequent synthesis of the ketene acetals 2 proved to
be experimentally challenging. To avoid fragmentation5
lowering the reaction temperature below –110 °C proved
to be imperative.5b We had to use polar co-solvents such
as carcinogenic hexamethylphosphoramide to maintain
the reactivity of the lithium enolate against the trapping
agent. Applying in situ quench (ISQ) methodology6 using
tert-butyldimethylsilyl chloride allowed ketene acetals 2
to be obtained in excellent and reproducible yields
(Scheme 1, Table 1).
Acetals
R
(E)-Buta-1,3-
dienyl ester
Yield
(%)
Ketene
acetal
Yield
(%)
H
1a
1b
1c
1d
1e
1f
70
78
53
58
40
81
2a
2b
2c
2d
2e
2f
81
Me
61
t-Bu
65
OMe
OTBDMS
NPhth
75a
67
43a
The substituted ketene acetals 2b–f were selectively ob-
tained as their Z-diastereomers. The structure and relative
configuration of product 2f, isolated by crystallization
from pentane, was confirmed by X-ray analysis.7 The tox-
ic mixture lithium hexamethyldisilazanide/hexameth-
a LHMDS in combination with HMPA was used.
The ketene acetals 2a–f underwent the desired tandem re-
action sequence Diels–Alder reaction/Ireland–Claisen re-
arrangement under mild reaction conditions and in good
yields (Scheme 2, Table 2). The reaction of N-phenylma-
leimide, as an archetypical cyclic dienophile, with a slight
excess of ketene acetal was complete after three hours at
SYNTHESIS 2007, No. 15, pp 2379–2387
x
x.
x
x
.
2
0
0
7
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-983773; Art ID: C00607SS
© Georg Thieme Verlag Stuttgart · New York

2380
N. Soldermann et al.
PAPER
60 °C. The rearrangement reaction following the Diels– rearrangement. To determine the relative configuration of
Alder reaction was rapid; in the 1H NMR spectra no sig- the exocyclic chiral center, the X-ray structure of the free
nals were detected that could have been attributed to the acid 5 (Figure 1) was determined. A boat-like transition
intermediate Diels–Alder product. The silyl esters, the state of the Ireland–Claisen rearrangement is compatible
products of the tandem process, were deprotected by treat- with the observed relative configuration. The relative con-
ment with 40 mol% hydrogen hexafluorosilicate8 and the figuration of the product 3c was identical to the relative
resulting carboxylic acids were directly converted into the configuration of 5 as confirmed by its X-ray structure. The
methyl ester by treatment with diazo(trimethylsilyl)meth- relative configuration of the products 3b,d,f was tenta-
ane. Purification by chromatography yielded the products tively attributed based on the 1H NMR coupling pattern.
3a–f in 43–83% overall yield over the four synthetic
steps; thus, the average yield of each individual reaction
step is 80–95%.
In acyclic [3,3]-sigmatropic shifts the chairlike transition
state is preferred.9 The rearrangements of cyclohexenyl
ester enolates are less selective and can involve both boat-
like as well as chairlike transition states.10,11 To obtain an
O
OTBS
insight into the high stereoselectivity of our tandem pro-
cess, we determined the X-ray structure of the Diels–
Alder product 4 (Figure 1).
R
O
R
O
O
c
a, b
1a–f
2a–f
O
N
d, e
O
O
O
N
O
O
R
3a–f
Scheme 2 Reagents and conditions: (a) t-BuOK, THF, –78 °C;
(b) RCH2COCl; (c) LiHMDS, TBDMSCl, THF, 2-MeTHF, HMPA,
< –110 °C; MeI, –110 °C; hexane–H2O, –110 °C to r.t.; (d) THF, 60
°C, 3 h; (e) H2SiF6, DME; (f) TMSCHN2, THF, MeOH.
Figure 1 The X-ray structures of the Diels–Alder product 4 and of
the product of the sequence Diels–Alder reaction/Ireland–Claisen
rearrangement 5.5,7
Table 2 Synthesis of the Tandem products 3a–f
The annulated N-phenylmaleimide ring imposes a boat
conformation on the cyclohexene ring. Prior to the rear-
rangement the ketene acetal substituent located in an
equatorial position has to switch to an axial or pseudo-
axial position. A chairlike transition state imposes strong
steric interactions of the Z-enolate with the opposite flag-
pole position. The boatlike transition state avoids these
destabilizing contacts as shown in Figure 2.
Ketene acetal
R
Tandem product Yield (%)
2a
H
3a
3b
3c
3d
3ea
3f
70
77
70
66
40
65
2b
Me
2c
t-Bu
OMe
OTBDMS
NPhth
2d
In conclusion, we report an improved and more environ-
mentally friendly synthesis of the (Z)-ketene acetals 2a–f.
These substituted butadiene derivatives undergo a highly
controlled tandem process Diels–Alder reaction/Ireland–
2e
2f
a R = OH.
TBS
a)
b)
The NMR spectra showed the signals for one single dia-
stereomer. The relative configuration of the chiral centers
in the cyclohexene ring was confirmed by the observation
of two trans-diaxial coupling constants for Hax of the
methylene group in 3a–f. All the substituents attached to
the cyclohexene ring of the products 3 are cis. The relative
configuration of the products is compatible with an endo-
selective Diels–Alder reaction followed by a suprafacial
Hax
Hax
O
O
O
H
H
H
R
R
H
TBSO
Figure 2 The two diastereomeric transition states for the Ireland–
Claisen rearrangement for the sequence leading from 2 to 3; (a) the
chairlike transition state; (b) the boatlike transition state; for clarity
the five-membered ring of N-phenylmaleimide has not been drawn.
Synthesis 2007, No. 15, 2379–2387 © Thieme Stuttgart · New York

PAPER
High Stereoselectivity of the Tandem Sequence Diels–Alder Reaction/Ireland–Claisen Rearrangement
2381
13C NMR (100 MHz, CDCl3): d = 167.8 [C(1)], 138.7 [C(1.1)],
Claisen rearrangement with the cyclic dienophile N-phe-
nylmaleimide. Three carbon–carbon bonds are formed in
131.7 [C(1.3)], 117.2 [C(1.4)], 116.0 [C(1.2)], 20.6 [C(2)].
this one-pot reaction. The relative configuration of the MS (EI, 70 eV): m/z (%) = 112 (51) [M]+, 70 (34), 69 (23), 43 (100).
four centers of chirality can be unequivocally deduced
from the reaction mechanism. The high preference for the
boatlike transition state of the Ireland–Claisen rearrange-
ment is especially important for the overall diastereose-
(E)-Buta-1,3-dienyl Propanoate (1b)
Using crotonaldehyde (4.14 g, 60 mmol) and propanoyl chloride
(6.8 g, 73 mmol) according to the general procedure, purification by
distillation gave pure 1b as a clear liquid; yield: 4.98 g (66%); bp 50
lectivity of our reaction sequence.
°C/18.7 mbar; Rf (hexane–Et2O, 2:1) = 0.58.
IR: 3090 (w), 2986 (w), 2945 (w), 2886 (vw), 1762 (s), 1658 (m),
1464 (w), 1421 (m), 1360 (m), 1270 (w), 1232 (m), 1153 (s), 1114
(m), 1086 (m), 997 (m), 974 (w), 925 (w), 904 (w), 877 (w), 806
(w), 790 cm–1 (w).
All moisture-sensitive reactions were carried out under argon or N2
using oven-dried glassware. All reagents were of commercial qual-
ity if not specifically mentioned. Solvents were freshly distilled pri-
or to use. Flash chromatography (FC): SDS silica gel A C.C.
Chromagel (35–70 mm); under positive pressure, 0.5–0.9 bar. TLC:
precoated silica gel thin-layer sheets 60 F 254 from Merck, detec-
tion by UV or/and basic KMnO4 soln. GC: Perkin Elmer SIGMA
3B Dual FID chromatograph with Macherey-Nagel SE 54-DF-0.25
(0.25 mm, 0.32 mm × 25 m) and Perkin Elmer LCI-100 integrator or
Agilent 6890 Series with HP-5 crosslinked 5% PhMe siloxane (0.25
mm, 0.32 mm × 30 m) and ChemStation. HPLC: Knauer HPLC pro-
grammer 50 with Knauer HPLC pump 64 pumps, Applied Biosys-
tems 757 absorbance detector (254 nm), Shimadzu C-R18
Chromatopak integrator, and Knauer Li Chrosorb 17RP18 column
(7 mm, 4 × 250 mm). Melting points: Büchi B 510; uncorrected.
Refractive index (nD): Carl Zeiss. IR Spectra: Perkin Elmer FT-IR
1720 X. NMR Spectra: Bruker Avance-400 (400 and 100 MHz) or
Varian Gemini XL-2000 (200 and 50 MHz), at r.t., if not specified;
TMs as internal reference. MS: ESI: Finnigan LCQ; EI: Nermag RC
3
1H NMR (400 MHz, CDCl3): d = 7.40 [dq, J(1.1,1.2) = 12.4 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.7 Hz, 1 H, H-C(1.1)],
6.26 [dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.2) = 11.0 Hz,
3J(1.3,1.4a) = 10.3 Hz, J(1.3,1.1) = 0.6 Hz, 1 H, H-C(1.3)], 6.01
4
[ddt, 3J(1.2,1.1) = 12.4 Hz, 3J(1.2,1.3) = 11 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.7 Hz,
1
H, H-C(1.2)]); 5.18 [ddt,
2J(1.4b,1.4a) = 1.6 Hz, 3J(1.4b,1.3) = 16.9 Hz, 4J(1.4b,1.2) ≈
5J(1.4b,1.1) = 0.8 Hz,
1
H, Hb-C(1.4)], 5.05 [ddt,
3J(1.4a,1.3) = 10.3 Hz, 2J(1.4a,1.4b) = 1.6 Hz, 4J(1.4a,1.2) ≈
5J(1.4b,1.1) = 0.7 Hz, 1 H, Ha-C(1.4)], 2.40 [q, 3J(2,3) = 7.5 Hz, 2
H, H-C(2)], 1.16 [d, 3J(3,2) = 7.5 Hz, 3 H, H-C(3)].
13C NMR (100 MHz, CDCl3): d = 171.2 [C(1)], 138.7 [C(1.1)],
131.7 [C(1.3)], 116.9 [C(1.4)], 115.8 [C(1.2)], 27.2 [C(2)], 8.7
[C(3)].
MS (EI, 70 eV): m/z (%) = 126 (34) [M]+, 97 (2), 86 (21) 84 (35),
70 (16), 69 (11), 57 (100), 51 (11) 49 (29).
+
30-10 (70 eV); DCI: NH4 ; HR-MS: Bruker FTMS 4.7T Bio-
APEXII. Elemental analyses were performed by the Chemistry de-
partment of the Ecole d’ingénieurs et d’architectes, Fribourg (CH)
and by the Ciba-Geigy SA at 1723 Marly (CH).
HRMS: m/z [M]+ calcd for C7H10O2: 126.06764; found: 126.06753.
Buta-1,3-dienyl 3,3-Dimethylbutanoate (1c)
Using crotonaldehyde (1.37 g, 20 mmol) and 3,3-dimethylbutanoyl
chloride (2.68 g, 20 mmol) according to the general procedure, pu-
rification by flash chromatography (hexane–EtOAc, 95:5) gave
pure 1c as a clear liquid; yield: 2.9 g (86%); Rf (hexane–Et2O,
2:1) = 0.77.
(E)-Buta-1,3-dienyl Esters 1; General Procedure
Crotonaldehyde (distilled) (60 mmol) was added dropwise over 10
min to a mechanical stirred soln of t-BuOK (70 mmol) in THF (40
mL) at –78 °C under N2; after 10 min the yellow enolate was
formed. A soln of the desired electrophile (acid chloride, anhydride,
or activated ester) (70 mmol) in THF (10 mL) was added over 10
min. The mixture became orange-red at the beginning and orange at
the end of the addition. The mixture was stirred at –78 °C for 15 min
and then the cooling bath was removed and the reaction quenched
with H2O and extracted with Et2O (3 × 50 mL). The extracts were
washed with Na2CO3 soln (3 × 10 mL), NH4Cl soln (3 × 10 mL),
and NaCl soln (3 × 10 mL) and dried (Na2SO4).
IR: 2960 (m), 2909 (m), 2871 (m), 1752 (s), 1707 (m), 1659 (m),
1477 (m), 1467, 1419 (m), 1397 (m), 1368 (m), 1352 (m), 1322 (m),
1222 (s), 1127 (vs), 1032 (m), 996 (m), 963 (m), 926 (m), 898 (m),
425 cm–1 (m).
3
1H NMR (400 MHz, CDCl3): d = 7.40 [dd, J(1.1,1.2) = 12.4 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
6.27 [dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.4a) = 10.3 Hz,
3J(1.3,1.2) = 10.8 Hz, J(1.3,1.1) = 0.5 Hz, 1 H, H-C(1.3)], 6.03
4
[ddt, 3J(1.2,1.1) = 12.3 Hz, 3J(1.2,1.3) = 11.1 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.7 Hz, 1 H, H-C(1.2)], 5.19 [ddt, 2J(1.4b,1.4a) = 1.6
(E)-Buta-1,3-dienyl Acetate (1a)
Using crotonaldehyde (4.14 g, 60 mmol) and AcCl (5.5 g, 70 mmol)
according to the general procedure, purification by distillation gave
pure 1a as a clear liquid; yield: 3.7 g (55%); bp 32–34 °C/18.7 mbar;
Rf (hexane–Et2O, 2:1) = 0.5.
3
4
5
Hz, J(1.4b,1.3) = 16.9 Hz, J(1.4b,1.2) ≈ J(1.4b,1.1) = 0.7 Hz, 1
H, H-C(1.4b)], 5.06 [ddt, 2J(1.4a,1.4b) = 1.6 Hz, 3J(1.4a,1.3) = 10.3
Hz, 4J(1.4a,1.2) ≈ 5J(1.4a,1.1) = 0.7 Hz, 1 H, H-C(1.4a)], 2.27 [s, 2
H, H-C(2)], 1.04 [s, 9 H, (CH3)3C].
IR: 3090 (w), 3041 (w), 2979 (w), 1762 (s), 1660 (s), 1420 (m),
1373 (s), 1305 (w), 1289 (w), 1218 (s), 1176 (s), 1109 (s), 1047 (m),
998 (s), 958 (w), 926 (s), 893 (s), 836 (w), 653 cm–1 (w).
13C NMR (100 MHz, CDCl3): d = 169.0 [C(1)], 138.5 [C(1.1)],
131.8 [C(1.3)], 117.0 [C(1.4)], 115.8 [C(1.2)], 47.5 [C(2)], 30.9
[C(3)], 29.5 ([CH3)3C(3)].
MS (CI): m/z = 169.12 [M + H]+.
HRMS: m/z [M + H]+ calcd for C10H17O2: 169.1223; found:
3
1H NMR (400 MHz, CDCl3): d = 7.39 [dd, J(1.1,1.2) = 12.4 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
6.26 [dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.2) = 11.0 Hz,
3J(1.3,1.4a) = 10.3 Hz, J(1.3,1.1) = 0.5 Hz, 1 H, H-C(1.3)], 6.03
4
169.1224.
[ddt, 3J(1.2,1.1) = 12.4 Hz, 3J(1.2,1.3) = 11.0 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.7 Hz, 1 H, H-C(1.2)], 5.21 [ddt, 2J(1.4b,1.4a) = 1.6
3
4
5
Buta-1,3-dienyl Methoxyacetate (1d)
Hz, J(1.4b,1.3) = 16.9 Hz, J(1.4b,1.2) ≈ J(1.4b,1.1) = 0.7 Hz, 1
H, Hb-C(1.4)], 5.08 [ddt, 2J(1.4a,1.4b) = 1.6 Hz, 3J(1.4a,1.3) = 10.2
Hz, 4J(1.4a,1.2) ≈ 5J(1.4a,1.1) = 0.6 Hz, 1 H, Ha-C(1.4)], 2.14 [s, 3
H, H-C(2)].
Using crotonaldehyde (10 mL, 0.12 mol) and methoxyacetyl chlo-
ride (13.6 mL, 0.15 mol) according to the general procedure, the
crude product was filtered through Celite and purification by distil-
Synthesis 2007, No. 15, 2379–2387 © Thieme Stuttgart · New York

2382
N. Soldermann et al.
PAPER
lation gave pure 1d as a clear liquid; yield: 9.95 g (58%); bp 41 °C/
0.05 mbar; Rf (hexane–Et2O, 2:1) = 0.43.
1419 (w), 1392 (m), 1368 (m), 1344 (w), 1305 (m), 1256 (s), 1187
(s), 1154 (vs), 1096 (m), 1006 (m), 995 (m), 940 (w), 924 (m), 905
(m), 841 (vs), 817 (m), 781 (s), 743 (w), 708 (w), 683 (w), 665 (w),
582 (vw), 498 (vw), 484 cm–1 (vw).
IR: 3090 (w), 2934 (w), 2832 (w), 1775 (s), 1659 (m), 1452 (w),
1420 (m), 1376 (w), 1291 (w), 1243 (m), 1190 (s), 1167 (s), 1132
(s), 998 (m), 929 (m), 905 (m), 835 (w), 727 (w), 660 (w), 569
cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 7.42 [dd, 3J(1.1,1.2) = 12.3 Hz, 1
H, H-C(1.1)], 6.26 [dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.4a) = 10.3
3
3
Hz, J(1.3,1.2) = 11.1 Hz, 1 H, H-C(1.3)], 6.04 [dd, J(1.2,1.1) ≈
11.9 Hz, 3J(1.2,1.3) = 11.2 Hz, 1 H, H-C(1.2)], 5.20 [ddt,
2J(1.4b,1.4a) = 1.5 Hz, 3J(1.4b,1.3) = 16.9 Hz, 4J(1.4b,1.2) ≈
5J(1.4b,1.1) = 0.7 Hz, 1 H, H-C(1.4b)], 5.08 [ddt, 2J(1.4a,1.4b) = 1.5
Hz, 3J(1.4a,1.3) = 10.25 Hz, 4J(1.4a,1.2) ≈ 5J(1.4a,1.1) = 0.8 Hz, 1
H, H-C(1.4a)], 4.31 [s, 2 H, H-C(2)], 0.92 [s, 9 H, SiC(CH3)3], 0.1
[s, 6 H, Si(CH3)2].
3
1H NMR (400 MHz, CDCl3): d = 7.42 [dd, J(1.1,1.2) = 12.3 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
6.25 [dddd, 3J(1.3,1.4b) = 16.90 Hz, 3J(1.3,1.4a) = 10.3 Hz,
3J(1.3,1.2) = 11.0 Hz, J(1.3,1.1) = 0.5 Hz, 1 H, H-C(1.3)], 6.06
4
[ddt, 3J(1.2,1.1) = 12.3 Hz, 3J(1.2,1.3) = 11.0 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.7 Hz, 1 H, H-C(1.2)], 5.21 [ddt, J(1.4b,1.4a) = 1.6
2
Hz, 3J(1.4b,1.3) = 16.9 Hz, 4J(1.4b,1.2) ≈ 5J(1.4b,1.1) = 0.7 Hz, 1 H,
Hb-C(1.4)], 5.09 [ddt, 2J(1.4a,1.4b) = 1.6 Hz, 3J(1.4a,1.3) = 10.2 Hz,
4J(1.4a,1.2) ≈ 5J(1.4a,1.1) = 0.7 Hz, 1 H, Ha-C(1.4)], 4.10 [s, 2 H, H-
C(2)], 3.45 [s, 3 H, H-C(2¢)].
13C NMR (100 MHz, CDCl3): d = 168.5 [C(1)], 138.0 [C(1.1)],
131.3 [C(1.3)], 117.3 [C(1.4)], 116.4 [C(1.2)], 61.2 [C(2)], 25.5
[SiC(CH3)3], –5.6 [Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 167.2 [C(1)], 137.8 [C(1.1)],
131.2 [C(1.3)], 117.8 [C(1.4)], 116.8 [C(1.2)], 69.3 [C(2)], 59.4
[C(2¢)].
MS (EI, 70 eV): m/z (%) = 142 (10) [M]+, 114 (24), 84 (6), 68 (10),
53 (7), 45 (100), 39 (22).
MS (ESI): m/z = 264.3 [M – H + Na]+.
Buta-1,3-dienyl (1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)ace-
tate (1f)
Using crotonaldehyde (5 mL, 60 mmol) and (1,3-dioxo-2,3-dihy-
dro-1H-isoindol-2-yl)acetyl chloride (13.4 g, 60 mmol) diluted in
THF (60 mL) according to the general procedure; extraction with
EtOAc gave a crude product that was crystallized (hexane) and fi-
nally recrystallized (pentane) to give pure 1f as a yellow powder;
yield: 11.62 g (81%); mp 142–143 °C; Rf (hexane–Et2O, 2:1) =
0.20.
Anal. Calcd for C7H10O3 (142.15): C, 59.15; H, 7.09. Found: C,
59.04; H, 7.09.
Buta-1,3-dienyl (tert-Butyldimethylsiloxy)acetate (1e)
Activated Precursor 4-Nitrophenyl (tert-Butyldimethyl-
siloxy)acetate
IR: 3071 (vw), 2975 (vw), 2936 (vw), 1782 (m), 1765 (s), 1723 (s),
1719 (s), 1658 (w), 1615 (vw), 1471 (w), 1418 (s), 1396 (m), 1366
(m), 1343 (vw), 1318 (w), 1192 (s), 1169 (s), 1112 (m), 1092 (w),
1073 (w), 1020 (vw), 998 (w), 955 (m), 932 (m), 915 (w), 747 (m),
715 (m), 631 (w), 530 cm–1 (w).
To a soln of (tert-butyldimethylsiloxy)acetic acid (1.295 g, 6.8
mmol) in CH2Cl2 (34 mL) were added DCC (1.54 g, 7.48 mmol), 4-
nitrophenol (950 mg, 6.83 mmol), and DMAP (74 mg, 0.6 mmol).
After 48 h at r.t., the mixture was filtered and poured into H2O (30
mL). The organic phase was washed with H2O (3 × 30 mL) and
dried (Na2SO4). After evaporation, the crude product was purified
by flash chromatography (hexane–EtOAc, 95:5) to give a yellow oil
that crystallized; yield: 923 mg (43%); mp 44–46 °C; Rf (hexane–
EtOAc, 9:1) = 0.44.
1H NMR (400 MHz, CDCl3): d = 7.89–7.87 [m, 2 H, HPhth-C(2.3)],
7.75–7.73 [m, 2 H, HPhth-C(2.4)], 7.35 [dd*, 3J(1.1,1.2) = 12.2 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
6.24 [dddd, 3J(1.3,1.4b) = 16.8 Hz, 3J(1.3,1.2) = 11.0 Hz,
3J(1.3,1.4a) = 10.2 Hz, J(1.3,1.1) = 0.5 Hz, 1 H, H-C(1.3)], 6.08
4
IR: 3117 (w), 3087 (w), 3024 (w), 2954 (s), 2930 (vs), 2895 (m),
2857 (s), 2741 (vw), 2119 (w), 1793 (s), 1737 (m), 1700 (m), 1617
(m), 1594 (s), 1527 (vs), 1491 (s), 1472 (m), 1463 (m), 1444 (m),
1388 (m), 1349 (vs), 1325 (m), 1305 (m), 1253 (s), 1210 (vs), 1162
(s), 1020 (vs), 1048 (m), 1014 (m), 1005 (m), 957 (w), 919 (m), 867
(s), 840 (vs), 786 (s), 762 (s), 712 (m), 675 (m), 636 (m), 570 (w),
494 (m), 438 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 8.27 and 7.31 [2 d, system
AA¢BB¢, 2J(A,B) = 9.2 Hz, 2 H each, Harom], 4.52 [s, 2 H, H2-C(2)],
0.94 [s, 9 H, SiC(CH3)3], 0.15 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 169.42 [C(1)], 154.99 [C(1.4)],
145.33 [C(1.1)], 125.20 and 122.14 [C(1.3) and C(1.3¢) or C(1.2)
and C(1.2¢)], 61.65 [C(2)], 25.62 [SiC(CH3)3], 18.30 [SiC(CH3)3],
–4.48 [Si(CH3)2].
[ddt, 3J(1.2,1.1) = 12.2 Hz, 3J(1.2,1.3) = 11.1 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.6 Hz, 1 H, H-C(1.2)], 5.23 [ddt, J(1.4b,1.4a) = 1.6
2
Hz, 3J(1.4b,1.3) = 16.8 Hz, 4J(1.4b,1.2) ≈ 5J(1.4b,1.1) = 0.7 Hz, 1 H,
Hb-C(1.4)], 5.11 [ddt, 2J(1.4a,1.4b) = 1.6 Hz, 3J(1.4a,1.3) = 10.2 Hz,
4J(1.4a,1.2) ≈ 5J(1.4a,1.1) = 0.6 Hz, 1 H, Ha-C(1.4)], 4.52 [s, 2 H, H-
C(2)].
13C NMR (100 MHz, CDCl3): d = 167.2 [CPhth(2.1)], 164.4 [C(1)],
138.1 [C(1.1)], 134.3 [CPhth(2.4)], 131.8 [CPhth(2.2)], 131.0 [C(1.3)],
123.7 [CPhth(2.3)], 118.2 [C(1.4)], 117.3 [C(1.2)], 38.5 [C(2)].
MS (EI, 70 eV): m/z (%) = 257 (0.2) [M]+, 188 (17), 161 (13), 160
(100), 133 (5), 104 (4), 77 (5), 76 (3).
Anal. Calcd for C14H11NO4 (257.24): C, 65.37; H, 4.31; N, 5.45.
Found: C, 65.17; H, 4.63; N, 5.15.
MS (ESI): m/z = 334.11 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C14H21NNaO5Si: 334.1081; found:
O-[(E)-Buta-1,3-dienyl)-O-(trialkylsilyl)ketene Acetals 2;
General Procedure
334.1089.
Procedure A: 1 M LHMDS in THF (20 mL, 20 mmol) was added to
2-MeTHF (15 mL) in a 200-mL flask equipped with a mechanical
stirrer. The soln was cooled to –60 °C, then HMPA (6.5 mL, dis-
tilled over Na) was rapidly added followed by the trapping agent
TBDMSCl or TIPSCl (15 mmol) dissolved in THF (10 mL) was
added. The yellow soln was cooled to –110 °C (EtOH, N2). At this
temperature the desired (E)-buta-1,3-dienyl ester (15 mmol) dis-
solved in THF/2-MeTHF (2:1, 15 mL) was added over 10 min. The
temperature must remain below –110 °C in order to avoid decom-
position of the ketene acetal enolate. The mixture was then stirred
at ca. –115 °C for 1.5 h. The reaction was quenched at this temper-
Buta-1,3-dienyl (tert-Butyldimethylsiloxy)acetate (1e)
Using crotonaldehyde (205 mg, 3 mmol) and 4-nitrophenyl (tert-
butyldimethylsiloxy)acetate12 (900 mg, 3 mmol) according to the
general procedure, the crude product was purified by flash chroma-
tography (hexane–EtOAc, 98:2), giving pure 1e as a yellow oil;
yield: 435 mg (60%); Rf (hexane–EtOAc, 2:1) = 0.85.
IR: 3090 (w), 3072 (w), 3040 (w), 2955 (s), 2931 (s), 2897 (m),
2858 (s), 2741 (vw), 1782 (s), 1757 (m), 1731 (m), 1660 (m), 1605
(w), 1593 (w), 1518 (w), 1496 (w), 1473 (m), 1464 (m), 1443 (m),
Synthesis 2007, No. 15, 2379–2387 © Thieme Stuttgart · New York

PAPER
High Stereoselectivity of the Tandem Sequence Diels–Alder Reaction/Ireland–Claisen Rearrangement
2383
ature with NH4Cl soln (30 mL) or 2 M NaH2PO4 (30 mL) and
poured into pentane (150 mL). The aqueous phase was extracted
with pentane (3 × 150 mL), the extracts were washed with NH4Cl
soln (3 × 30 mL) and NaCl soln (3 × 30 mL), and dried (Na2SO4).
The crude yellow oil was purified by distillation.
C(3)], 0.95 [s, 9 H, SiC(CH3)3], 0.17 (s, 6 H, Si-CH3). * Only two
signals of the quartet are resolved.
13C NMR (100 MHz, CDCl3): d = 154.0 [C(1)], 145.1 [C(1.1)],
132.2 [C(1.3)], 114.2 [C(1.4)], 113.4 [C(1.2)], 78.0 [C(2)], 25.6
[SiC(CH3)3], 18.0 [SiC(CH3)3], 9.6 [C(3)], –4.4 (SiCH3).
Procedure B: As described in procedure A with 1 M NaHMDS in-
stead of 1 M LHMDS and DMPU (6 mL) instead of HMPA.
MS (EI, 70 eV): m/z (%) = 240 (1.4) [M]+, 183 (11), 115 (17), 75
(19), 74 (29), 73 (100) 59 (32), 45 (25).
Anal. Calcd for C13H24O2Si (240.42): C, 64.95; H, 10.06. Found: C,
64.92; H, 10.09.
[1-(Buta-1,3-dienyloxy)vinyloxy]tert-butyldimethylsilane (2a)
Using 1 M LHMDS in THF (50 mL, 50 mmol), HMPA (14 mL)],
TBDMSCl (7.5 g, 50 mmol), and 1a (4.34 g, 38.7 mmol) according
to procedure B, purification by distillation gave pure 2a as a clear
colorless liquid; yield: 6.97 g (80%); bp 47 °C/0.08 mbar; Rf (hex-
ane–Et2O, 2:1) = 0.65.
[1-(Buta-1,3-dienyloxy)-3,3-dimethylbut-1-enyloxy]tert-butyl-
dimethylsilane (2c)
Using 1 M NaHMDS in THF (10 mL, 10 mmol), DMPU (3 mL),
TBDMSCl (1.5 g, 10 mmol), and 1c (1.26 g, 7.5 mmol) according
to procedure B, with purification by distillation gave pure 2c as a
clear colorless liquid; yield: 1.39 g (65%); bp 64 °C/0.05 mbar; Rf
(hexane–Et2O, 2:1) = 0.84.
IR: 3091 (vw), 3049 (vw), 2959 (m), 2932 (m), 2888 (w), 2861 (m),
1662 (s), 1657 (s), 1605 (vw), 1536 (vw), 1473 (w), 1465 (w), 1419
(w), 1392 (w), 1364 (w), 1316 (m), 1291 (m), 1256 (s), 1177 (m),
1153 (s), 1025 (s), 1005 (m), 994 (m), 957 (vw), 922 (m), 894 (w),
843 (s), 827 (s), 813 (m), 788 (s), 762 cm–1 (w).
IR: 3090 (vw), 3046 (vw), 2957 (vs), 2931 (s), 2861 (m), 2901 (m),
2861 (m), 1679 (vs), 1655 (s), 1605 (vw), 1472 (m), 1463 (m), 1418
(w), 1393 (m), 1352 (s), 1311 (vw), 1288 (vw), 1256 (s), 1225 (s),
1159 (vs), 1041 (m), 1009 (s), 992 (m), 947 (m), 917 (w), 890 (w),
841 (s), 825 (s), 813 (m), 785 (m), 714 (w), 672 (w), 621 (w), 559
(vw), 493 cm–1 (vw).
1H NMR (400 MHz, CDCl3): d = 6.59 [dd*, 3J(1.1,1.2) = 12.1 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
6.25 [dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.2) = 11.0 Hz,
3J(1.3,1.4a) = 10.3 Hz, J(1.3,1.1) = 0.6 Hz, 1 H, H-C(1.3)], 5.91
4
[ddt, 3J(1.2,1.1) = 12.1 Hz, 3J(1.2,1.3) = 11.0 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.7 Hz, 1 H, H-C(1.2)], 5.13 [ddt, 2J(1.4b,1.4a) = 1.7
3
1H NMR (400 MHz, CDCl3): d = 6.44 [dd, J(1.1,1.2) = 12.1 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
6.25 [ddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.4a) = 10.4 Hz,
3J(1.3,1.2) = 11.0 Hz, 1 H, H-C(1.3)], 5.81 [ddt, 3J(1.2,1.1) ≈ 11.8
Hz, 3J(1.2,1.3) = 11.1 Hz, 4J(1.2,1.4a) ≈ 4J(1.2,1.4b) ≈ 0.6 Hz, 1 H,
H-C(1.2)], 5.09 [ddt, 2J(1.4b,1.4a) = 1.7 Hz, 3J(1.4b,1.3) = 16.9 Hz,
3
4
5
Hz, J(1.4b,1.3) = 16.9 Hz, J(1.4b,1.2) ≈ J(1.4b,1.1) = 0.7 Hz, 1
H, Hb-C(1.4)], 4.98 [ddt, 2J(1.4a,1.4b) = 1.7 Hz, 3J(1.4a,1.3) = 10.3
Hz, 4J(1.4a,1.2) ≈ 5J(1.4a,1.1) = 0.7 Hz, 1 H, Ha-C(1.4)], 3.41, 3.39
[2 d, 3J = 2.7 Hz, 2 H, H2-C(2)], 0.95 [s, 9 H, SiC(CH3)3], 0.20 (s, 6
H, Si-CH3). * Only two signals of the quartet are resolved.
5
4J(1.4b,1.2) ≈ J(1.4b,1.1) ≈ 0.7 Hz, 1 H, H-C(1.4b)], 4.94 [ddt*,
13C NMR (100 MHz, CDCl3): d = 159.0 [C(1)], 143.5 [C(1.1)],
132.0 [C(1.3)], 115.1 [C(1.4)], 114.5 [C(1.2)], 66.0 [C(2)], 25.5
[SiC(CH3)3], 18.1 [SiC(CH3)3], –4.8 (SiCH3).
MS (EI, 70 eV): m/z (%) = 227 (1.9) [M + 1]+, 211 (1.4, [M – 15]+),
169 (14), 127 (19), 117 (14), 115 (18), 99 (10), 75 (28), 74 (39), 73
(100), 59 (30), 45 (13).
2J(1.4a,1.4b) = 1.7 Hz, 3J(1.4a,1.3) = 10.3 Hz, 1 H, H-C(1.4a)],
3.67 [s, 1 H, H-C(2)], 1.09 [s, 9 H, (CH3)3C], 0.96 [s, 9 H,
(SiC(CH3)3], 0.19 [s, 6 H, (CH3)2Si].
13C NMR (100 MHz, CDCl3): d = 153.2 [C(1)], 145.2 [C(1.1)],
132.2 [C(1.3)], 114.3 [C(1.4)], 113.3 [C(1.2)], 92.8.0 [C(2)], 30.8
[C(4)], 29.6 [C(3)], 25.9 [C(CH3)3], 18.1 [SiC(CH3)3], –4.0
[Si(CH3)2].
HRMS: m/z [M + H]+ calcd for C12H22O2Si: 227.1462; found:
227.1451.
MS (EI, 70 eV): m/z (%) = 283 (3.4) [M]+, 189 (24), 173 (75), 169
(17), 157 (13), 143 (11), 127 (19), 117 (40), 115 (31), 99 (21), 84
(10), 83 (30), 75 (44), 74 (12), 73 (100), 57 (35), 55 (16), 47 (16),
45 (31), 44 (13), 43 (54), 42 (21), 41 (97).
[1-(Buta-1,3-dienyloxy)prop-1-enyloxy]tert-butyldimethyl-
silane (2b)
Using 1 M LHMDS in THF (40 mL, 40 mmol), HMPA (11 mL),
TBDMSCl (6.0 g, 40 mmol), and 1b (3.84 g, 30 mmol) according
to procedure A with purification by distillation gave pure 2b; yield:
5.96 g (83%). Alternatively, using 1 M NaHMDS in THF (20 mL,
20 mmol), DMPU (6 mL), TBDMSCl (3.0 g, 20 mmol), and 1b
(1.89 g, 15 mmol) according to procedure B with purification by
distillation gave pure 2b as a clear colorless liquid; yield: 3.02 g
(84%); bp 53 °C/0.06 mbar; Rf (hexane–Et2O, 2:1) = 0.7.
MS (DCI): m/z (%) = 283 (100) [M + H]+.
[1-(Buta-1,3-dienyloxy)-2-methoxyvinyloxy]tert-butyldimethyl-
silane (2d)
Using 1 M LHMDS in THF (20 mL, 20 mmol), HMPA (6.5 mL),
TBDMSCl (3.0 g, 20 mmol), and 1d (2.14 g, 15 mmol) according
to procedure A, with purification by distillation gave pure 2d as a
colorless oil; yield: 2.87 g (75%); bp 63 °C/0.06 mbar; Rf (hexane–
Et2O, 2:1) = 0.63.
IR: 3091 (w), 3048 (vw), 2959 (m), 2931 (s), 2887 (w), 2861 (m),
1692 (s), 1657 (s), 1605 (vw), 1473 (w), 1464 (w), 1418 (w), 1389
(m), 1363 (w), 1338 (s), 1290 (w), 1256 (s), 1195 (s), 1174 (s), 1153
(s), 1095 (m), 1055 (s), 993 (m), 919 (m), 906 (m), 842 (s), 824 (m),
810 (s), 787 cm–1 (s).
IR: 3089 (vw), 2952 (m), 2932 (s), 2898 (m), 2860 (m), 2832 (m),
1719 (m), 1656 (s), 1604 (vw), 1473 (m), 1464 (m), 1446 (w), 1446
(w), 1418 (w), 1392 (w), 1363 (m), 1340 (s), 1290 (vw), 1254 (s),
1202 (s), 1171 (s), 1138 (s), 1001 (s), 940 (w), 915 (w), 889 (w), 842
(s), 826 (s), 813 (m) 788 cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 6.49 [dd*, 3J(1.1,1.2) = 12.1 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
1H NMR (400 MHz, CDCl3): d = 6.50 [dq, J(1.1,1.2) = 12.2 Hz,
3
6.23 [dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.2) = 11.0 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
3J(1.3,1.4a) = 10.3 Hz, J(1.3,1.1) = 0.6 Hz, 1 H, H-C(1.3)], 5.83
4
6.20 [dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.2) = 11.0 Hz,
[ddt, 3J(1.2,1.1) = 12.1 Hz, 3J(1.2,1.3) = 11 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.7 Hz, 1 H, H-C(1.2)], 5.09 [ddt, 2J(1.4b,1.4a) = 1.7
Hz, 3J(1.4b,1.3) = 16.9 Hz, 4J(1.4b,1.2) ≈ 5J(1.4b,1.1) = 07 Hz, 1 H,
3J(1.3,1.4a) = 10.3 Hz, J(1.3,1.1) = 0.6 Hz, 1 H, H-C(1.3)], 5.81
4
[ddt, 3J(1.2,1.1) = 12.2 Hz, 3J(1.2,1.3) = 11.0 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.8 Hz, 1 H, H-C(1.2)], 5.48 [s, 1 H, H-C(2)], 5.06
2
3
Hb-C(1.4)], 4.93 [ddt, J(1.4a,1.4b) = 1.7 Hz, J(1.4a,1.3) = 10.3
2
3
4
4
5
[ddt, J(1.4b,1.4a) = 1.8 Hz, J(1.4b,1.3) = 16.9 Hz, J(1.4b,1.2) ≈
5J(1.4b,1.1) = 0.8 Hz, 1 H, Hb-C(1.4)], 4.91 [ddt, 2J(1.4a,1.4b) = 1.7
Hz, J(1.4a,1.2) ≈ J(1.4b,1.1) = 0.6 Hz, 1 H, Ha-C(1.4)], 3.81 (q,
3J(2,3) = 6.6 Hz, 1 H, H-C(2)], 1.52 [d, J(3,2) = 6.6 Hz, 3 H, H-
3
Synthesis 2007, No. 15, 2379–2387 © Thieme Stuttgart · New York

2384
N. Soldermann et al.
PAPER
Hz, 3J(1.4a,1.3) = 10.3 Hz, 4J(1.4a,1.2) ≈ 5J(1.4a,1.1) = 0.7 Hz, 1 H,
Ha-C(1.4)], 3.49 [s, 3 H, (H-C(3)], 0.94 [s, 9 H, SiC(CH3)3], 0.18 (s,
6 H, SiCH3).
13C NMR (100 MHz, CDCl3): d = 146.8 [C(1.1)], 145.9 [C(1)],
132.2 [C(1.3)], 117.7 [C(2)], 113.9 [C(1.4)], 112.4 [C(1.2)], 60.0
[C(3)], 25.5 [SiC(CH3)3], 18.2 [SiC(CH3)3], –4.8 (SiCH3).
Hz, 3J(1.4b,1.3) = 16.9 Hz, 4J(1.4b,1.2) ≈ 5J(1.4b,1.1) = 0.7 Hz, 1 H,
Hb-C(1.4)], 5.05 [ddt, 2J(1.4a,1.4b) = 1.6 Hz, 3J(1.4a,1.3) = 10.3 Hz,
4J(1.4a,1.2) ≈ 5J(1.4a,1.1) = 0.7 Hz, 1 H, Ha-C(1.4)], 4.84 [s, 1 H, H-
C(2)], 0.76 [s, 9 H, SiC(CH3)3], 0.17 (s, 6 H, Si-CH3).
13C NMR (100 MHz, CDCl3): d = 167.6 [CPhth(2.1)] 157.0 [C(1)],
142.6 [C(1.1)], 133.9 [CPhth(2.4)], 132.1 [CPhth(2.2)], 131.2 [C(1.3)],
123.2 [CPhth(2.3)], 116.7 [C(1.2)], 116.6 [C(1.4)], 76.8 [C(2)], 25.3
[SiC(CH3)3], 17.7 [SiC(CH3)3], –4.4 (Si-CH3).
MS (DCI, NH3): m/z (%) = 374 (25, [M + 3]+), 373 (98, [M + 2]+),
372 (12, [M + 1]+), 275 (12), 270 (19), 262 (14), 258 (17), 252 (14),
196 (13), 160 (20), 133 (15), 132 (100), 130 (17), 104 (16), 91 (17),
90 (95), 73 (17).
MS (EI, 70 eV): m/z (%) = 254 (3.3) [M]+, 256 (2.3) [M]+, 197 (7),
127 (5), 115 (8), 89 (16), 75 (11), 73 (100).
Anal. Calcd for C13H24O3Si (256.42): C, 60.89; H, 9.43. Found: C,
60.93; H, 9.58.
1-[1,2-Bis(tert-butyldimethylsiloxy)vinyloxy]buta-1,3-diene (2e)
Using 1 M NaHMDS in THF (6 mL, 6 mmol), DMPU (3.5 mL),
TBDMSCl (900 mg, 6 mmol), and 1e (1.0 g, 4.13 mmol) according
to procedure B, with purification by bulb-to-bulb distillation (150
°C/0.1 mbar) gave pure 2e as a clear colorless liquid; yield: 982 mg
(67%); Rf (hexane–Et2O, 2:1) = 0.83.
HRMS (CI, isobutane): m/z [M + H]+ calcd for C20H26NO4Si:
372.1626; found: 372.1658.
Anal. Calcd for C20H25NO4Si: C, 64.66; H, 6.78; N, 3.77. Found: C,
64.20; H, 6.68; N, 3.66.
IR: 3089 (w), 2956 (s), 2931 (s), 2887 (m), 2859 (s), 1746 (m), 1718
(m), 1656 (m), 1473 (m), 1461 (m), 1418 (m), 1391 (m), 1363 (m),
1255 (s), 1167 (vs), 994 (m), 939 (m), 923 (m), 839 (vs), 813 (m),
784 (s), 674 (w), 494 cm–1 (vw).
Methyl (1,3-Dioxo-2-phenyl-2,3,3a,4,5,7a-hexahydro-1H-iso-
indol-5-yl)acetates 3; General Procedure
N-Phenylmaleimide (250 mg, 1.44 mmol) in THF (2 mL) was heat-
ed at 60 °C under argon. The desired ketene acetal 2 (0.35 mmol)
was added in one portion and the mixture was heated 70 °C for 4 h
to 16 h. The oil bath was removed and the mixture cooled to r.t. The
mixture diluted with DME (3 mL) and 25% H2SiF6 in H2O (0.3 mL,
0.45 mmol) was added to cleave the silyl ester. The mixture was
stirred at r.t. for 0.5–1 h. The solvents were evaporated, the crude
mixture dissolved in Et2O (10 mL), washed with sat. NaHCO3
(3 × 20 mL). The aqueous phase was carefully acidified at 0 °C to
pH ~2 with concd HCl and extracted with Et2O (3 × 50 mL). The or-
ganic phase was dried (Na2SO4) and evaporated. The crude carbox-
ylic acid residue was dissolved in THF–MeOH (5:2, 10 mL) and
treated with ~0.3 M CH2N2 in Et2O soln or with commercial 2 M
TMSCHN2 in hexane soln (0.5 mL, 1 mmol). After 1 h at r.t., excess
diazomethane compound was destroyed by the addition of a few
drops of glacial AcOH and the solvents were evaporated. The crude
methyl ester was purified by flash chromatography.
3
1H NMR (400 MHz, CDCl3): d = 6.51 [dd, J(1.1,1.2) = 12.1 Hz,
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
6.22 [dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.2) = 10.9 Hz,
3J(1.3,1.4a) = 10.3 Hz, J(1.3,1.1) = 0.6 Hz, 1 H, H-C(1.3)], 5.82
4
[ddt, 3J(1.2,1.1) = 12.1 Hz, 3J(1.2,1.3) = 11.0 Hz, 4J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.7 Hz, 1 H, H-C(1.2)], 5.71 [s, 1 H, H-C(2)], 5.07
2
3
4
[ddt, J(1.4b,1.4a) = 1.8 Hz, J(1.4b,1.3) = 16.9 Hz, J(1.4b,1.2) ≈
5J(1.4b,1.1) = 0.7 Hz,
1
H, Hb-C(1.4)], 4.92 [ddt,
2J(1.4a,1.4b) = 1.8 Hz, 3J(1.4a,1.3) = 10.3 Hz, 4J(1.4a,1.2)
≈
5J(1.4a,1.1) = 0.8 Hz, 1 H, Ha-C(1.4)], 0.96 [s, 9 H, SiC(CH3)3],
0.95 [s, 9 H, SiC(CH3)3], 0.20 [s, 6 H, Si(CH3)2], 0.14 [s, 6 H,
Si(CH3)2].
13C NMR (100 MHz, CDCl3): d = 147.6 [C(1.1)], 146.4 [C(1)],
132.3 [C(1.3)], 113.6 [C(1.4)], 111.9 [C(1.2)], 111.1 [C(2)], 25.8
[SiC(CH3)3], 25.5 [SiC(CH3)3], 18.3 [SiC(CH3)3], 18.1
[SiC(CH3)3], –4.5 [Si(CH3)2], –5.3 [Si(CH3)2].
Methyl (1,3-Dioxo-2-phenyl-2,3,3a,4,5,7a-hexahydro-1H-iso-
indol-5-yl)acetate (3a)
MS (ESI): m/z = 413.0 [M – H + 58]–.
Using N-phenylmaleimide (100.0 mg, 0.577 mmol) diluted in THF
(2 mL) and 2a (262.6 mg, 1.16 mmol) according to the general pro-
cedure, with purification by flash chromatography (CH2Cl2–Et2O–
hexane, 7:1:2) gave a colorless oil that crystallized (CH2Cl2–hex-
ane) to give pure 3a as a white powder; yield: 121.5 mg (70%);
mp 109–109.5 °C; Rf (CH2Cl2–Et2O–hexane, 7:1:2) = 0.26.
2-[2-(Buta-1,3-dienyloxy)-2-(tert-butyldimethylsiloxy)vinyl]-
1H-isoindole-1,3(2H)-dione (2f)
Using 1 M LHMDS in THF (20 mL, 20 mmol), HMPA (14 mL),
TBDMSCl (3.0 g, 20 mmol), and 1f (3.9 g, 15 mmol), diluted in 2-
MeTHF/THF (1:2, 45 mL) according to procedure A or B. Before
quenching, MeI (1.6 mL, 25 mmol) diluted in THF (5 mL) was add-
ed, after 0.5 h at –108 °C, pentane (140 mL) was added, and finally
the reaction was quenched with H2O (50 mL). After extraction and
evaporation, the crude yellow oil was crystallized (pentane) to give
pure 2f as yellow crystals; yield: 2.44 g (43%); mp 92–93 °C; Rf
(hexane–Et2O, 2:1) = 0.30.
IR: 3064 (vw), 3032 (w), 3003 (vw), 2952 (w), 2907 (w), 2875 (w),
2854 (w), 1728 (s), 1713 (s), 1597 (w), 1502 (w), 1493 (w), 1454
(w), 1435 (w), 1401 (m), 1384 (m), 1359 (w), 1325 (w), 1278 (w),
1261 (m), 1247 (w), 1227 (w), 1202 (s), 1186 (m), 1166 (s), 1129
(w), 1079 (w), 1062 (w), 1029 (w), 996 (w), 823 (w), 754 (m), 712
(w), 696 (m), 576 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 7.49–7.44 [m, 2 H, HPh-C(2.2III)],
7.41–7.36 [m, 1 H, HPh-C(2.2IV)], 7.28–7.25 [m, 2 H, HPh-C(2.2II)],
6.06 [ddd, 3J(2.7,2.6) = 10.0 Hz, 3J(2.7,2.7a) = 3.6 Hz,
4J(2.7,2.5) = 2.6 Hz, 1 H, H-C(2.7)], 5.93 [dt, 3J(2.6,2.7) = 10.0 Hz,
3J(2.6,2.5) ≈ 4J(2.6,2.7a) = 2.2 Hz, 1 H, H-C(2.6)], 3.70 [s, 3 H, H-
C(1¢)], 3.52 [dq, 3J(2.7a,2.3a) = 8.8 Hz, 3J(2.7a,2.7) ≈ 4J(2.7a,2.6) ≈
5J(2.7a,2.5) = 3.0 Hz, 1 H, H-C(2.7a)], 3.21 [ddd, 3J(2.3a,Ha-
2.4) = 11.2 Hz, 3J(2.3a,2.7a) = 8.6 Hz, 3J(2.3a,Hb-2.4) = 6.1 Hz, 1 H,
H-C(2.3a)], 2.75–2.67 [m, 1 H, H-C(2.5)], 2.44–2.32 [m, 3 H, Ha,b-
IR: 3104 (w), 3030 (w), 2958 (m), 2932 (m), 2886 (w), 2860 (m),
2715 (vw), 2504v (w), 2258 (vw), 1961 (vw), 1923 (vw), 1782 (m),
1762 (m), 1718 (s), 1680 (s), 1656 (s), 1611 (w), 1469 (m), 1400 (s),
1366 (s), 1340 (m), 1288 (w), 1258 (m), 1217 (s), 1173 (m), 1135
(s), 1114 (s), 1088 (m), 1071 (w), 1037 (m), 1008 (s), 995 (m), 985
(m), 924 (m), 884 (s), 844 (m), 826 (m), 812 (m), 787 (m), 722 (s),
681 (m), 614 (w), 559 (w), 530 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 7.85–7.83 [m, 2 H, HPhth-C(2.3)],
3
7.71–7.69 [m, 2 H, HPhth-C(2.4)], 6.69 [dd, J(1.1,1.2) = 12.0 Hz,
2
3
5
5
4J(1.1,1.3) ≈ J(1.1,1.4a) ≈ J(1.1,1.4b) = 0.6 Hz, 1 H, H-C(1.1)],
C(2), Hb-C(2.4)], 1.39 [ddd, J(Ha-2.4,Hb-2.4) = 12.9 Hz, J(Ha-
2.4,2.3a) = 11.2 Hz, 3J(Ha-2.4,2.5) = 9.7 Hz, 1 H, Ha-C(2.4)].
6.26 (dddd, 3J(1.3,1.4b) = 16.9 Hz, 3J(1.3,1.2) = 11.0 Hz,
3J(1.3,1.4a) = 10.3 Hz, J(1.3,1.1) = 0.6 Hz, 1 H, H-C(1.3)], 6.02
4
13C NMR (100 MHz, CDCl3): d = 177.8 [C(2.3)], 175.5 [C(2.1)],
172.1 [C(1)], 134.2 [C(2.6)], 131.7 [CPh(2.2I)], 129.1 [CPh(2.2III)],
128.6 [CPh(2.2IV)], 126.3 [CPh(2.2II)], 121.3 [C(2.7)], 51.8 [C(1¢)],
3
3
4
(ddt, J(1.2,1.1) = 12.0 Hz, J(1.2,1.3) = 11.0 Hz, J(1.2,1.4a) ≈
4J(1.2,1.4b) = 0.7 Hz, 1 H, H-C(1.2)], 5.19 [ddt, 2J(1.4b,1.4a) = 1.6
Synthesis 2007, No. 15, 2379–2387 © Thieme Stuttgart · New York

PAPER
High Stereoselectivity of the Tandem Sequence Diels–Alder Reaction/Ireland–Claisen Rearrangement
2385
40.7 [C(2.7a)], 39.6 [C(2)], 38.9 [C(2.3a)], 30.7 [C(2.5)], 19.8
[C(2.4)].
(vw), 719 (w), 678 (w), 631 (w), 621 (m), 581 (m), 567 (m), 534
(m), 511 (w), 456 (vw), 437 cm–1 (vw).
MS (DCI): m/z (%) = 299 (9) [M]+, 239 (9), 92 (38), 91 (35), 79
(17), 77 (24), 74 (100), 44 (13).
1H NMR (400 MHz, CDCl3): d = 7.52–7.47 [m, 2 H, HPh-C(2.2III)],
7.43–7.38 [m, 1 H, HPh-C(2.2IV)], 7.33–7.30 [m, 2 H, HPh-C(2.2II)],
6.25 [dt, 3J(2.7,2.6) = 10.3 Hz, 3J(2.7,2.7a) ≈ 4J(2.7,2.5) ≈ 2.0 Hz, 1
H, H-C(2.7)], 6.02 [dt, 3J(2.6,2.7) = 10.3 Hz, 3J(2.6,2.5) ≈
4J(2.6,2.7a) ≈ 3.1 Hz, 1 H, H-C(2.6)], 3.62 [s, 3 H, H3-C(1¢)], 3.50
[dq,3J(2.7a,2.3a) = 8.8 Hz, 3J(2.7a,2.7) ≈ 4J(2.7a,2.6) ≈ 5J(2.7a,2.5) ≈
3.1 Hz, 1 H, H-C(2.7a)], 3.26 [ddd, 3J(2.3a,Ha-2.4) = 12.0 Hz,
Anal. Calcd for C17H17NO4 (299.32): C, 68.22; H, 5.72; N, 4.68.
Found: C, 68.21; H, 5.89; N, 4.45.
Methyl 2-(1,3-Dioxo-2-phenyl-2,3,3a,4,5,7a-hexahydro-1H-
isoindol-5-yl)propanoate (3b)
3
3J(2.3a,2.7a) = 8.8 Hz, J(2.3a,Hb-2.4) = 6.1 Hz, 1 H, H-C(2.3a)],
Using N-phenylmaleimide (349.6 mg, 2.02 mmol) and 2b (766.5
mg, 3.19 mmol) according to the general procedure, with purifica-
tion by flash chromatography (CH2Cl2–Et2O–hexane, 7:1:2) gave a
colorless oil that crystallized (CH2Cl2–hexane) to give pure 3b as a
white powder; yield: 486.9 mg (77%); mp 102–102.5 °C; Rf
(CH2Cl2–Et2O–hexane, 7:1:2) = 0.29.
2.64–2.58 [m, 1 H, H-C(2.5)], 2.34–2.28 [m, 1 H, Hb-C(2.4)], 2.29
[d, 3J(2,2.5) = 3.4 Hz, 1 H, H-C(2)], 1.53 [dt*, 2J(Ha-2.4,Hb-2.4) ≈
3
3
12.2 Hz, J(Ha-2.4,2.3a) ≈ J(Ha-2.4,2.5) ≈ 11.2 Hz, 1 H, Ha-
C(2.4)], 1.08 [s, 9 H, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 177.87 [C(2.1)], 175.52 [C(2.3)],
173.38 [C(1)], 133.80 [C(2.6)], 131.68 [CPh(2.2I)], 129.10
[CPh(2.2III)], 128.54 [CPh(2.2IV)], 126.32 [CPh(2.2II)], 120.51
[C(2.7)], 58.95 [C(2)], 51.00 C(1¢)], 40.38 [C(2.7a)], 39.47
[C(2.3a)], 33.64 [C(3)], 32.89 [C(2.5)], 31.66 [C(2.4)], 28.18
[C(3¢)].
IR: 3055 (vw), 3023 (vw), 2986 (vw), 2960 (vw), 2907 (vw), 2875
(vw), 1775 (vw), 1708 (s), 1644 (vw), 1600 (vw), 1503 (w), 1458
(vw), 1437 (vw), 1384 (m), 1355 (w), 1302 (vw), 1284 (vw), 1274
(vw), 1253 (vw), 1228 (w), 1197 (m), 1180 (m), 1170 (w), 1149
(w), 1138 (w), 1123 (vw), 1069 (vw), 1055 (vw), 1033 (vw), 991
(vw), 824 (vw), 753 (w), 709 (w), 700 (w), 692 (vw), 586 cm–1 (vw).
MS (ESI): m/z = 378.3 [M + Na]+.
1H NMR (400 MHz, CDCl3): d = 7.49–7.45 [m, 2 H, HPh-C(2.2III)],
7.41–7.37 [m, 1 H, HPh-C(2.2IV)], 7.29–7.26 [m, 2 H, HPh.-C(2.2II)],
6.07 [ddd, 3J(2.7,2.6) = 10.1 Hz, 3J(2.7,2.7a) = 3.6 Hz,
4J(2.7,2.5) = 2.5 Hz, 1 H, H-C(2.7)], 5.89 [dt, 3J(2.6,2.7) = 10.1 Hz,
3J(2.6,2.5) ≈ 4J(2.6,2.7a) = 2.1 Hz, 1 H, H-C(2.6)], 3.70 [s, 3 H, H-
C(1¢)], 3.52 [dq, 3J(2.7a,2.3a) = 8.3 Hz, 3J(2.7a,2.7) ≈ 4J(2.7a,2.6) ≈
5J(2.7a,2.5) = 3.2 Hz, 1 H, H-C(2.7a)], 3.19 [ddd, 3J(2.3a,Ha-
HRMS: m/z [M + Na]+ calcd for C21H25NNaO4: 378.16758; found:
378.16763.
Methyl (1,3-Dioxo-2-phenyl-2,3,3a,4,5,7a-hexahydro-1H-iso-
indol-5-yl)(methoxy)acetate (3d)
Using N-phenylmaleimide (350.6 mg, 2.02 mmol) and 2d (758.6
mg, 2.96 mmol) according to the general procedure, with purifica-
tion by flash chromatography (CH2Cl2–Et2O–hexane, 7:1:2) gave
an colorless oil that crystallized (CH2Cl2–hexane) to give pure 3d as
a white powder; yield: 441.6 mg (66%); mp 124.5 °C; Rf (CH2Cl2–
Et2O–hexane, 7:1:2) = 0.20.
3
2.4) = 11.5 Hz, 3J(2.3a,2.7a) = 8.6 Hz, J(2.3a,Hb-2.4) = 6.0 Hz, 1
H, H-C(2.3a)], 2.60–2.53 [m, 1 H, H-C(2.5)], 2.48 [quint,
3J(2,3) = 3J(2,2.5) = 7.1 Hz, 1 H, H-C(2)], 2.27 [ddd, 2J(Hb-2.4,Ha-
3
3
2.4) = 12.8 Hz, J(Hb-2.4,2.3a) = 5.5 Hz, J(Hb-2.4,2.5) = 4.5 Hz,
2
3
1 H, Hb-C(2.4)], 1.41 [ddd, J(Ha-2.4,Hb-2.4) = 12.7 Hz, J(Ha-
2.4,2.3a) = 11.5 Hz, 3J(Ha-2.4,2.5) = 10.1 Hz, 1 H, Ha-C(2.4)],
1.18 [d, 3J(3,2) = 7.0 Hz, 3 H, H-C(3)].
IR: 3067 (vw), 3044 (vw), 3009 (vw), 2963 (vw), 2936 (vw), 2882
(vw), 2860 (vw), 2830 (vw), 1733 (s), 1709 (s), 1597 (vw), 1501
(w), 1454 (w), 1444 (vw), 1391 (m), 1341 (vw), 1325 (w), 1302 (w),
1289 (w), 1274 (m), 1243 (w), 1230 (w), 1202 (m), 1186 (m), 1165
(w), 1117 (m), 1082 (w), 1031 (vw), 1055 (vw), 1014 (w), 988 (vw),
976 (w), 824 (w), 756 (w), 694 (m), 581 (w), 493 cm–1 (vw).
13C NMR (100 MHz, CDCl3): d = 178.0 [C(2.1)], 175.5 [C(2.3)],
175.3 C((1)], 133.7 [C(2.6)], 131.7 [CPh(2.2I)], 129.1 [CPh(2.2III)],
128.6 [CPh(2.2IV)], 126.4 [CPh(2.2II)], 121.5 [C(2.7)], 51.8 [C(1¢)],
43.4 [C(2)], 40.8 [C(2.7a)], 39.0 [C(2.3a)], 36.6 [C(2.5)], 26.7
[C(2.4)],13.7 [C(3)].
MS (DCI): m/z (%) = 314 (32) [M + 1]+, 313 (39) [M]+, 282 (32),
254 (37), 253 (100), 119 (14), 107 (18), 106 (51), 105 (22), 91 (43),
88 (80), 79 (58), 78 (13), 77 (40), 57 (12).
1H NMR (400 MHz, CDCl3): d = 7.48–7.42 [m, 2 H, HPh-C(2.2III)],
7.39–7.35 [m, 1 H, HPh-C(2.2IV)], 7.27–7.25 [m, 2 H, HPh-C(2.2II)],
6.12 [ddd, 3J(2.7,2.6) = 10.0 Hz, 3J(2.7,2.7a) = 3.7 Hz,
4J(2.7,2.5) = 2.7 Hz, 1 H, H-C(2.7)], 5.92 [dt, 3J(2.6,2.7) = 10.1 Hz,
3J(2.6,2.5) ≈ 4J(2.6,2.7a) = 2.3 Hz, 1 H, H-C(2.6)], 3.78 [s, 3 H, H-
C(2¢)], 3.75 [d, 3J(2,2.5) = 5.3 Hz, 1 H, H-C(2)], 3.50 [dq,
3J(2.7a,2.3a) = 8.7 Hz, 3J(2.7a,2.7) ≈ 4J(2.7a,2.6) ≈ 5J(2.7a,2.5) = 2.9
Anal. Calcd for C18H19NO4 (313.35): C, 69.00; H 6.11; N 4.47.
Found: C, 69.26; H, 6.18; N, 4.38.
3
Hz, 1 H, H-C(2.7a)], 3.38 [s, 3 H, H-C(1¢)], 3.15 [ddd, J(2.3a,Ha-
2.4) = 11.2 Hz, 3J(2.3a,2.7a) = 8.6 Hz, 3J(2.3a,Hb-2.4) = 6.3 Hz, 1 H,
H-C(2.3a)], 2.70–2.64 [m, 1 H, H-C(2.5)], 2.20 [ddd, 2J(Hb-2.4,Ha-
2.4) = 13.2 Hz, 3J(Hb-2.4,2.3a) = 6.3 Hz, 3J(Hb-2.4,2.5) = 4.4 Hz, 1
H, Hb-C(2.4)], 1.67 [ddd, 2J(Ha-2.4,Hb-2.4) = 13.2 Hz, 3J(Ha-
2.4,2.3a) = 11.1 Hz, 3J(Ha-2.4,2.5) = 9.9 Hz, 1 H, Ha-C(2.4)].
Methyl 2-(1,3-Dioxo-2-phenyl-2,3,3a,4,5,7a-hexahydro-1H-
isoindol-5-yl)-3,3-dimethylbutanoate (3c)
Using N-phenylmaleimide (250 mg, 1.44 mmol) and 2c (100 mg,
0.35 mmol) according to the general procedure, with purification by
flash chromatography (CH2Cl2) gave a colorless oil that was crys-
tallized (CH2Cl2–hexane) to give pure 3c as a white powder; yield:
66 mg (53%); mp 164–166 °C; Rf (hexane–EtOAc, 98:2) = 0.83.
Monocrystals were obtained by recrystallization (CH2Cl2–hexane).
13C NMR (100 MHz, CDCl3): d = 177.7 [C(2.3)], 175.3 [C(2.1)],
171.5 [C(1)], 131.7 [CPh.(2.2I)], 131.2 [C(2.6)], 129.1 [CPh(2.2III)],
128.5 [CPh(2.2IV)], 126.3 [CPh(2.2II)], 122.5 [C(2.7)], 82.6 [C(2)],
58.8 [C(2¢)], 52.1 [C(1¢)], 40.6 [C(2.7a)], 38.6 [C(2.3a)], 37.3
[C(2.5)], 24.9 [C(2.4)].
MS (DCI): m/z (%) = 329 (8) [M]+, 297 (31), 270 (29), 265 (21), 226
(35), 120 (11), 119 (15), 118 (10), 105 (11), 104 (58), 103 (60), 92
(14), 91 (100), 89 (34), 79 (89), 78 (15), 77 (59), 75 (45), 65 (12),
45 (11).
IR: 3100 (vw), 3070 (vw), 3049 (w), 2989 (m), 2962 (s), 2921 (m),
2907 (m), 2866 (m), 2554 (vw), 2336 (vw), 1974 (vw), 1899 (vw),
1778 (m), 1708 (vs), 1593 (m), 1491 (s), 1468 (m), 1452 (m), 1468
(m), 1440 (m), 1434 (m), 1397 (s), 1376 (vs), 1271 (s), 1249 (m),
1230 (m), 1215 (s), 1179 (vs), 1168 (s), 1148 (vs), 1137 (s), 1090
(m), 1077 (m), 1065 (m), 1023 (w), 992 (m), 978 (m), 942 (m), 922
(vw), 903 (w), 849 (w), 819 (m), 810 (m), 780 (w), 757 (s), 732
Anal. Calcd for C18H19NO5 (329.35): C, 65.64; H, 5.81; N, 4.25.
Found: C, 65.39; H, 5.95; N, 4.27.
Synthesis 2007, No. 15, 2379–2387 © Thieme Stuttgart · New York

2386
N. Soldermann et al.
PAPER
Methyl (1,3-Dioxo-2-phenyl-2,3,3a,4,5,7a-hexahydro-1H-iso-
indol-5-yl)(hydroxy)acetate (3e)
4J(2.7,2.5) = 3.1 Hz, 1 H, H-C(2.7)], 4.77 [d, 3J(2,2.5) = 8.9 Hz, 1
H, H-C(2)], 3.74 [s, 3 H, H-C(1¢)], 3.53 [dq, 3J(2.7a,2.3a) = 8.6 Hz,
4
5
Using N-phenylmaleimide (291 mg, 1.68 mmol) and 2e (200 mg,
0.56 mmol) according to the general procedure. In this case after
cleavage of the silyl ester with H2SiF6, the carboxylic acid was ex-
tracted with sat. NaHCO3–Et2O. The aqueous phase was carefully
acidified to pH ~2 with concd HCl and extracted with Et2O. After
evaporation, the crude carboxylic acid was diluted in THF (4 mL)
and MeOH (2 mL) and treated with 1 M TBAF in THF (0.6 mL, 0.6
mmol) to cleave the silyl ether. After 2 h at r.t., the reaction was di-
luted with Et2O (10 mL) and poured into aq 1 M HCl and extracted
with Et2O (2 × 10 mL). The combined organic phases were dried
(Na2SO4) and evaporated. The crude carboxylic acid residue was
dissolved in THF–MeOH (5:2, 10 mL) and treated with ~0.3 M
CH2N2 in Et2O or with commercial 2 M TMSCHN2 in hexane (0.5
mL, 1 mmol). After 1 h at r.t., the excess diazomethane reagent was
destroyed by addition of a few drops of glacial AcOH and the sol-
vents were evaporated. Purification by flash chromatography
(CH2Cl2–EtOAc, 82: 18) gave pure 3e as a yellow viscous oil; yield:
71 mg (40%); Rf (CH2Cl2–EtOAc, 8:2) = 0.35.
3J(2.7a,2.7) ≈ J(2.7a,2.6) ≈ J(2.7a,2.5) = 3.1 Hz, 1 H, H-C(2.7a)],
3.38–3.30 [m, 1 H, H-C(2.5)], 3.18 [ddd, 3J(2.3a,Ha-2.4) = 12.8 Hz,
3
3J(2.3a,2.7a) = 8.6 Hz, J(2.3a,Hb-2.4) = 5.8 Hz, 1 H, H-C(2.3a)],
2
3
2.27 [dddd, J(Hb-2.4,Ha-2.4) = 12.6 Hz, J(Hb-2.4,2.3a) = 5.8 Hz,
3J(Hb-2.4,2.5) = 3.8 Hz, J(Hb-2.4,2.6) = 1.2 Hz, 1 H, Hb-C(2.4)],
4
1.24 [q, 2J(Ha-2.4,Hb-2.4) ≈ J(Ha-2.4,2.3a) ≈ J(Ha-2.4,2.5) = 12.3
3
3
Hz, 1 H, Ha-C(2.4)].
13C NMR (100 MHz, CDCl3): d = 177.5 [C(2.3)], 175.2 [C(2.1)],
168.4 [C(1)], 167.5 [CPhth.(2I)], 134.5 [CPhth(2IV)], 132.4 [C(2.6)],
131.5, 131.4 [CPhth(2II), CPh(2.2I)], 129.1 [CPh(2.2III), 128.6
[CPh(2.2IV)], 126.4 [CPh(2.2II)], 123.8 [CPhth(2III)], 122.0 [C(2.7)],
54.2 [C(2)], 52.9 [C(1¢)], 40.8 [C(2.7a)], 38.9 [C(2.3a)], 34.7
[C(2.5)], 27.5 [C(2.4)].
MS (DCI): m/z (%) = 444 (11) [M]+, 297 (14), 266 (18), 265 (100),
237 (19), 219 (27), 218 (38), 190 (30), 187 (43), 160 (39), 150 (83),
132 (31), 130 (39), 119 (25), 118 (49), 105 (22), 104 (55), 92 (14),
91 (81), 90 (11), 79 (39), 78 (18), 77 (71), 76 (44), 65 (12), 44 (14).
Anal. Calcd for C25H20N2O6 (444.44): C, 67.56; H 4.54; N, 6.30.
Found: C, 67.28; H, 4.70; N, 6.02.
IR: 3472 (s), 3036 (m), 2953 (m), 2332 (vw), 2251 (vw), 1710 (vs),
1598 (m), 1542 (w), 1500 (s), 1456 (m), 1443 (m), 1380 (s), 1317
(m), 1182 (s), 1141 (m), 1117 (m), 1027 (w), 1003 (w), 981 (m), 904
(w), 843 (vw), 819 (m), 799 (w), 755 (m), 722 (m), 693 (s), 621 (w),
581 (w), 525 (vw), 504 (w), 489 (vw), 408 cm–1 (vw).
Acknowledgment
1H NMR (400 MHz, CDCl3): d = 7.68–7.44 [m, 2 H, HPh-C(2.2III)],
7.43–7.38 [m, 1 H, HPh-C(2.2IV)], 7.30–7.20 [m, 2 H, HPh-C(2.2II)],
6.18 [ddd, 3J(2.7,2.6) = 10.1 Hz, 3J(2.7,2.7a) = 3.7 Hz,
4J(2.7,2.5) = 2.6 Hz, 1 H, H-C(2.7)], 6.06 [dt, 3J(2.6,2.7) = 10.2 Hz,
3J(2.6,2.5) ≈ 4J(2.6,2.7a) ≈ 2.5 Hz, 1 H, H-C(2.6)], 4.33 [d,
3J(2,2.5) = 3.5 Hz, 1 H, H-C(2)], 3.86 [s, 3 H, H3-C(1¢)], 3.55 [dq,
This work was financially supported by the Swiss National Science
Foundation and the University of Neuchâtel. Part of this manuscript
is based on the Ph.D. thesis of J.V. (Thèse de Doctorat, Université
de Neuchâtel, 1998) and of N.S. (Thèse de Doctorat, Université de
Neuchâtel, 2002). We are grateful to H. Bursian and Dr. S. Claude
(Neuchâtel) for measuring the NMR spectra.
3
4
5
3J(2.7a,2.3a) = 8.7 Hz, J(2.7a,2.7) ≈ J(2.7a,2.6) ≈ J(2.7a,2.5) ≈
3.0 Hz, 1 H, H-C(2.7a)], 3.21 [ddd, 3J(2.3a,Ha-2.4) = 10.4 Hz,
References
3
3J(2.3a,2.7a) = 8.7 Hz, J(2.3a,Hb-2.4) = 6.5 Hz, 1 H, H-C(2.3a)],
2.78–2.71 [m, 1 H, H-C(2.5)], 2.11–2.05 [m, 1 H, Hb-C(2.4)], 1.73
[ddd, 2J(Ha-2.4,Hb-2.4) = 13.3 Hz, 3J(Ha-2.4,2.3a) = 10.4 Hz,
3J(Ha-2.4,2.5) = 9.2 Hz, 1 H, Ha-C(2.4)].
13C NMR (100 MHz, CDCl3): d = 178.1 [C(2.1)], 175.4 [C(2.3)],
173.7 [C(1)], 131.7 [CPh.(2.2I)], 131.3 [C(2.6)], 129.2
[CPh.(2.2III)],128.6 [CPh.(2.2IV)], 126.4 [CPh.(2.2II)], 122.7 [C(2.7)],
72.5 [C(2)], 53.4 [C(1¢)], 40.5 [C(2.7a)], 38.4 [C(2.3a)], 37.6
[C(2.5)], 23.6 [C(2.4)].
(1) (a) Wender, P. A.; Miller, B. L. In Organic Synthesis:
Theory and Applications, Vol. 2; Hudlicky, T., Ed.; JAI
Press: Greenwich, 1993, 27. (b) Tietze, L. F.; Beifuss, U.
Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (c) Hudlicky,
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Chem. Rev. 1996, 96, 1. (i) Tietze, L. F.; Brasche, G.;
Gericke, K. Domino Reactions in Organic Synthesis; Wiley–
VCH: Weinheim, 2006.
MS (ESI): m/z = 316.0 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C17H17NNaO5: 338.09999; found:
338.10002.
(2) Neuschütz, K.; Velker, J.; Neier, R. Synthesis 1998, 227.
(3) (a) Huber, S.; Stamouli, P.; Neier, R. J. Chem. Soc., Chem.
Commun. 1985, 533. (b) Huber, S.; Stamouli, P.; Jenny, T.;
Neier, R. Helv. Chim. Acta 1986, 69, 1898. (c) Schoepfer,
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2000, 83, 2266. (e) Velker, J.; Roblin, J.-P.; Neels, A.;
Tesuro, A.; Stoeckli-Evans, H.; Klaerner, F.-G.; Gehrke, J.-
S.; Neier, R. Synlett 1999, 925.
(4) (a) Baak, M.; Rubin, Y.; Franz, A.; Stoeckli-Evans, H.;
Bigler, L.; Nachbauer, J.; Neier, R. Chimia 1993, 47, 233.
(b) Franz, A.; Eschler, P.-Y.; Tharin, M.; Stoeckli-Evans, H.;
Neier, R. Synthesis 1996, 1239. (c) Franz, A.; Eschler, P.-
Y.; Tharin, M.; Neier, R. Tetrahedron 1996, 52, 11643.
(d) Franz, A.; Eschler, P.-Y.; Tharin, M.; Neier, R. In
Electronic Conference on Trends in Organic Chemistry
(ECTOC-1) [Online]; Rzepa, H. S.; Goodman, J. M.; Leach,
C., Eds.; Royal Society of Chemistry: Cambridge, 1995, ;
Methyl (1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)(1,3-dioxo-2-
phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindol-5-yl)acetate (3f)
Using N-phenylmaleimide (257.1 mg, 1.48 mmol) and 2f (371.6
mg, 1 mmol) according to the general procedure, with purification
by flash chromatography (CH2Cl2–Et2O–hexane, 7:1:2) gave pure
3f as a white powder; yield: 289.1 mg (65%); mp 229.5–230 °C; Rf
(CH2Cl2–Et2O–hexane, 7:1:2) = 0.24.
IR: 3066 (vw), 3050 (vw), 2955 (vw), 2909 (vw), 2859 (vw), 1777
(w), 1746 (s), 1708 (s), 1611 (vw), 1599 (vw), 1503 (w), 1469 (vw),
1455 (vw), 1439 (vw), 1391 (s), 1383 (s), 1340 (w), 1281 (w), 1252
(w), 1237 (w), 1194 (m), 1181 (m), 1148 (w), 1134 (vw), 1112 (w),
1094 (w), 1073 (vw), 1020 (vw), 1010 (vw), 964 (w), 926 (vw), 902
(vw), 753 (w), 720 (m), 695 (w), 583 (vw), 560 (vw), 531 cm–1
(vw).
1H NMR (400 MHz, CDCl3): d = 7.90–7.85 [m, 2 H, HPhth-C(2III)],
7.78–7.74 [m, 2 H, HPhth-C(2IV)], 7.46–7.41 [m, 2 H, HPh-C(2.2III)],
7.38–7.33 [m, 1 H, HPh-C(2.2IV)], 7.26–7.22 [m, 2 H, HPh-C(2.2II)],
3
3
4
6.24 [dt, J(2.6,2.7) = 10.1 Hz, J(2.6,Hb-2.4) ≈ J(2.6,2.7a) = 1.4
3
3
Hz, 1 H, H-C(2.6)], 6.14 [dt, J(2.7,2.6) = 10.2 Hz, J(2.7,2.7a) ≈
Synthesis 2007, No. 15, 2379–2387 © Thieme Stuttgart · New York

PAPER
High Stereoselectivity of the Tandem Sequence Diels–Alder Reaction/Ireland–Claisen Rearrangement
2387
See: http://www.ch.ic.ac.uk/ectoc/papers/39/ (accessed 12
April 2007); ISBN 084504899.
(5) (a) Seebach, D.; Amstutz, R.; Laube, T.; Schweizer, W. B.;
Dunitz, J. D. J. Am. Chem. Soc. 1985, 107, 5403. (b)Corey,
E. J.; Wright, S. T. J. Org. Chem. 1990, 55, 1670.
crystal dimensions 0.65 × 0.49 × 0.23 mm; 4709
independent reflections, 3504 observed reflections with [I >
2s(I)]; R-values [I > 2s(I)]: R1 = 0.0701, wR2 = 0.1669.
All three structures were refined with full-matrix block least
squares on F2; all non-hydrogen atoms were anisotropically
refined. Crystallographic data (excluding structure
factors)for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-118778 for 1f,
CCDC-629878 for 2f, CCDC-629879 for 3c, CCDC-629880
for 4 and CCDC-629881 for 5. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033; e-
mail: deposit@ccdc.cam.ac.uk.
(6) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(7) Crystal structure analysis of 2f: C20H25NO4Si, Mr = 371.50,
monoclinic, space group P21, a = 8.191(1), b = 23.442(2),
c = 11.342(1) Å, b = 105.12(1)°, V = 2102.4(3) Å3, Z = 4,
r
calcd = 1.174 g cm–3, T = 223(2) K, m = 1.34 cm–1,
l = 0.71073 Å, 1.65 £ q £ 26.05°, Stoe IPDS diffractometer,
crystal dimensions 0.65 × 0.40 × 0.15 mm; 7956
independent reflections, 3934 observed reflections with [I >
2s(I)]; R-values [I > 2s(I)]: R1 = 0.0658, wR2 = 0.1409.
Crystal structure analysis of 4: C24H18N2O6, Mr = 430.40,
triclinic, space group P, a = 7.894(2), b = 11.426(3),
c = 12.057(4)Å, a = 101.78(4), b = 97.43(4), c = 98.91(3)°,
V = 1037.2(5) Å3, Z = 2, rcalcd = 1.378 g cm–3, T = 293(2) K,
m = 1.01 cm–1, l = 0.71073 Å, 1.65 £ q £ 26.05°, Stoe IPDS
diffractometer, crystal dimensions 0.70 × 0.50 × 0.40 mm;
3738 independent reflections, 2453 observed reflections
with [I > 2s(I)]; R-values [I > 2s(I)]: R1 = 0.0328,
wR2 = 0.0816.
(8) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1993, 58, 5130.
(9) (a) Lutz, R. P. Chem. Rev. 1984, 84, 205. (b) Wipf, P. In
Comprehensive Organic Synthesis, Vol. 5; Trost, B. M.;
Fleming, I., Eds.; Pergamon: New York, 1991, 827.
(10) (a) Ireland, R. E.; Wipf, P.; Xiang, J. J. Org. Chem. 1991, 56,
3572. (b) Ireland, R. E.; Wipf, P.; Armstrong, J. D. J. Org.
Chem. 1991, 56, 650.
(11) Khaledy, M. M.; Kalani, M. M. Y. S.; Khuong, K. S.; Houk,
K. N.; Aviyente, V.; Neier, R.; Soldermann, N.; Velker, J.
J. Org. Chem. 2003, 68, 572.
Crystal structure analysis of 5: C24H18N2O6·CHCl3, Mr =
549.77, triclinic, space group P, a = 10.261(3), b = 11.610(3),
c = 11.818(4)Å, a = 76.81(3), b = 67.38(3), c = 87.40(2)°,
V = 1263.9(7) Å3, Z = 2, rcalcd = 1.445 g cm–3, m = 1.34 cm–1,
l = 0.71073 Å, 2.00 £ q £ 25.50°, Stoe AED2 diffractometer,
(12) Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, E. S.;
Lees, W.; Bednarski, M. D.; Whitesides, G. M. J. Org.
Chem. 1988, 53, 3457.
Synthesis 2007, No. 15, 2379–2387 © Thieme Stuttgart · New York