Synthesis of [6,n] cis-fused ring compounds via Cr-mediated dearomatisation-ring-closing metathesis

Article abstract of DOI:10.1039/b513261d

cis-Fused [6,8], [6,7], [6,6] and [6,5] ring systems containing a cyclohexadiene ring unit, a cycloenone ring and a quaternary carbon at the ring junction were obtained in only two steps from [Cr(CO)₃(η ⁶-p-methoxyphenyl oxazoline)]. The sequence proceeds via diastereoselective addition of three C-substituents across an arene double bond, followed by allylation and ring closing metathesis (RCM). RAMP-hydrazone and (R)-isopropyloxazoline were used as chiral auxiliaries to provide, after removal of the auxiliaries, the enantiomerically highly enriched [6,7] cis-fused system. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b513261d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of [6,n] cis-fused ring compounds via Cr-mediated
dearomatisation–ring-closing metathesis
E. Peter Ku¨ndig,* Alejandro Bellido, Krishna P. Kaliappan, Andrew R. Pape and Sylvie Radix
Received 19th September 2005, Accepted 16th November 2005
First published as an Advance Article on the web 14th December 2005
DOI: 10.1039/b513261d
cis-Fused [6,8], [6,7], [6,6] and [6,5] ring systems containing a cyclohexadiene ring unit, a
cycloenone ring and a quaternary carbon at the ring junction were obtained in only two steps from
6
[Cr(CO)3(g -p-methoxyphenyl oxazoline)]. The sequence proceeds via diastereoselective addition of
three C-substituents across an arene double bond, followed by allylation and ring closing metathesis
(RCM). RAMP-hydrazone and (R)-isopropyloxazoline were used as chiral auxiliaries to provide, after
removal of the auxiliaries, the enantiomerically highly enriched [6,7] cis-fused system.
a chiral ligand at the metal center,11 or by using chiral nucleophiles
to attack prochiral complexes.12
Introduction
The regio- and stereocontrolled addition of substituents across
an arene double bond is an efficient route to alicyclic synthetic
building blocks containing unmasked functionalities, new carbon–
carbon bonds and new stereogenic centers.1 Our research in this
area has focused on Cr(CO)3(arene) complexes.2 Coordination
to the electron withdrawing Cr(CO)3 fragment enables the direct
attack of the exo face of the arene by nucleophiles.3 Subsequent
alkylation of the anionic cyclohexadienyl complex intermediate
at the metal center and reductive elimination gives a trans
cyclohexadiene.4 Depending on the nature of the electrophile
and the substituents on the arene, the reductive elimination
can be preceded by migratory CO insertion. In such a case,
enolate chemistry allows the stereospecific introduction of a third
substituent (Scheme 1).5
These methods have found applications in the synthesis of
natural products and other molecules of interest.13,14
In a preliminary communication of this work we have shown
that the Cr-mediated dearomatisation sequence could be com-
bined with ring closing metathesis to access cis-fused ring systems
bearing a Me group at one ring junction.15 The structural unit of a
cis-fused ring system with an angular Me group at the ring junction
is frequently encountered in natural products.16 Here we provide
a more detailed account of this work, including the synthesis of
highly enantiomerically enriched [6,7] ring systems.
Results and discussion
6
We chose the readily available complex [Cr(CO)3(g -p-methoxy-
phenyloxazoline)] (1)8b as substrate for our initial studies because
of the useful and varied functional groups that are implicit in
the arene. In situ generated vinyllithium was the first nucleophile
tested. Selective ortho-addition took place presumably because
coordination of the reagent to the lone pair of the oxazoline
precedes C–C-bond formation. This addition was followed by Cr
alkylation with MeI in the presence of [NBu4][Br],17 migratory CO
insertion and acetyl migration to the less substituted terminus of
the cyclohexadienyl ligand (reductive elimination) to give the cor-
responding cyclohexadiene. The quaternary center was generated
via enolate formation and diastereoselective introduction of the
angular Me group from the less hindered face. The overall yield of
88% in this transformation that involves a dearomatisation with
the chemo-, regio- and diastereoselective formation of three C–C
bonds and two stereogenic centers attests to the high efficiency of
this procedure (Scheme 2).
Next, with a second enolate formation and allylation it was
possible to obtain diene 3.18 RCM for seven-membered ring
formation with the first generation ruthenium carbene complex 8
was sluggish and yields obtained were generally below 40%. This
result can be explained by the formation of a stable 7-membered
chelate that sequesters the catalyst.19 Fortunately, the use of the
more reactive catalyst 920 circumvented this problem and the [6,7]
bicyclic system 4 was obtained in an excellent 88% yield.
Scheme 1
Nucleophilic addition proceeds with generally high regioselec-
tivity. Resonance donor substituents direct meta,6 while bulky sub-
stituents and acceptor substituents direct para.7 Finally, functional
groups that can efficiently coordinate the incoming organolithium
reagent direct ortho.8
Diasteromerically- or enantiomerically enriched products are
accessible from arenes bearing chiral auxiliaries as substituents,9
from planar chiral arene complexes,10 from complexes containing
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest
Ansermet, CH-1211, Geneva 4, Switzerland. E-mail: peter.kundig@
chiorg.unige.ch; Fax: +41 22 379 3215; Tel: +41 22 379 6093
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Scheme 2
The same procedure was used to synthesize cis-fused [6,8]
bicyclic compound 7. Starting with allyllithium in place of
vinyllithium afforded 5 in 88% yield. Allylation afforded diene 6.
In this case RCM with ruthenium catalyst 8 proceeded smoothly
giving the [6,8]-cis-fused 7 quantitatively (Scheme 2). Access to
[6,6] and [6,5] fused rings was investigated next. The most straight-
forward strategy would involve the use of a vinyl halide as elec-
trophile in the dearomatisation sequence. However, alkylation–
carbonylation of the anionic [Cr(CO)3(cyclohexadienyl)] complex
intermediate starts with an SN2 process and halides bound to
an sp2 C-fragment are therefore not suitable electrophiles for
this reaction.21 Moreover, attempts to use acyl electrophiles (acid
halides, anhydrides), failed to yield the desired products. We
therefore had recourse to stepwise formation of the required
RCM precursors 12 and 15. A first approach comprised vinyl-
lithium addition to 1, followed by reaction with ethyl iodide
and carbonylation to give 10. Deprotonation and quench with
methyl iodide then gave cyclohexadiene 11 and selenation and
elimination afforded the desired enone 12 (Scheme 3). This route
is interesting because it shows that two different electrophiles
can be used in steps 2 and 3 of the sequence. Isolation of 10
proved necessary. Without this step, product 11 was contami-
nated with its homologue, containing an angular ethyl group.
Attempts at separation of the two compounds by FC was not
successful.
A second and more efficient approach consisted in the prepa-
ration of the enone via Mannich reaction. Formation of the silyl
enol ether, followed by alkylation with Eschenmoser’s salt, N-
methylation and elimination of the quaternary amine gave enone
12 in good yield (Scheme 4).
Scheme 3
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yield only. Reduction of 15 to the allylic alcohol 17 again resulted
in a much more efficient RCM using catalyst 18 to obtain 19 in
87% yield (Scheme 6).
The relative stereochemistry in 19 was assigned by comparison
of its NMR spectra with those of its diastereoisomer 20. Previous
work has shown that reduction of 16 to 20 occurs from the
less hindered, convex face of the molecule, and this gives the
opposite relative stereochemistry than that of allylic alcohol 19
(Scheme 7).14
Scheme 4
RCM of enone 12 was attempted with the Ru catalyst 9, but
no conversion was observed. This is consistent with the fact that
electron poor dienes are less reactive in the metathesis reaction.22
To avoid this problem enone 12 was diastereoselectively reduced
under Luche conditions. The resulting alcohol 13 underwent RCM
smoothly with the first generation catalyst 8, to give the cis-
fused ring compound 14. The alcohol’s stereochemistry of the
major diastereoisomer was assigned by analogy to 19 (vide infra)
(Scheme 5).
Scheme 7
Having gained efficient access to [6,8], [6,7], [6,6] and [6,5]
cis-fused rings, the preparation of these compounds in enan-
tiomerically enriched form was considered. In a first approach,
complex 22, bearing a chiral oxazoline, was prepared by thermal
complexation.23 Addition of vinyllithium proceeded with good
diastereoselectivity, and trapping with methyl iodide followed by
introduction of methyl group, as previously done, gave cyclohexa-
diene 23 with a diastereoisomeric excess of 88% (Scheme 8). Prod-
uct stereochemistry reflects a transition state in which the isopropyl
substituent of the chiral auxiliary is syn to the metal fragment.8a
Allylation afforded diene 24. Using the same conditions as for
the racemic series afforded the diasteroisomerically enriched ring
compound 25. Finally, cleavage of the chiral oxazoline,24 gave the
enantiomerically enriched aldehyde 26 (Scheme 8).
Scheme 5
Following the same strategy, enone 15 was obtained starting
from methyl ketone 5. Metathesis was this time possible with
catalyst 9, but the reaction was sluggish and afforded 16 in 48%
Scheme 6
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Scheme 8
Another possibility involves the use of complex 30 containing
RAMP-hydrazone as chiral auxiliary. This complex was synthe-
sized by thermal complexation of anisaldehyde dimethyl acetal,
followed by hydrolysis of the acetal 28 and treatment with the
RAMP-hydrazone (Scheme 9).
Diastereoselectivity is interpreted as arising from the preference
of a chair-like transition state over the boat-like transition
state during addition of the chelated organolithium reagent.9
Oxidative cleavage of the hydrazone25 gave nitrile 34 in good yield
(Scheme 10).
Ring compound 33 was obtained by the same reaction se-
quence as the one used to obtain 25. In this case, 1H NMR
showed a single diastereoisomer to be formed (de > 95%).
It is worth noting that intermediates 23 and 31 should give access
to enantiomerically enriched [6,5] cis-fused systems by a similar
sequence to the one described above.
Scheme 9
Scheme 10
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In order to obtain [6,8] and [6,6] cis-fused rings, we next
turned our attention to allyllithium as incoming nucleophile.
Unfortunately, the diastereoselectivities obtained were below 15%
starting from complexes 22 and 30.
(3H, s), 1.18 (3H, s), 1.13 (3H, s); dC (50 MHz; C6D6) 206.4, 165.0,
161.1, 136.0, 119.1, 117.2, 93.5, 78.5, 67.6, 57.9, 54.8, 50.7, 31.2,
28.5, 28.3, 22.9, 20.6. HRMS (EI) on (M+) for C17H23NO3 requires
289.1678, found: 289.1670.
In conclusion, an efficient synthesis of highly functionalised cis-
fused bicyclic [6,8], [6,7], [6,6], and [6,5] ring compounds has been
achieved using arene chromium complexes as precursors. The use
of chiral auxiliaries gives access to the enantiomerically highly
enriched [6,7] bicyclic system. The application of this method to
the synthesis of bioactive natural products is currently been studied
in our laboratory.
1-[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-methyl-
6-vinyl-cyclohexa-2,4-dienyl]-pent-4-en-1-one (3)
A soln. of 2 (289 mg, 1 mmol) in THF (8 mL) was added
to freshly prepared LDA (addition of nBuLi (1.6 M, 0.7 mL,
1.12 mmol) to a soln. of diisopropylamine (200 ll, 1.43 mmol) in
THF (5 mL) at 0 ◦C) at −78 ◦C. The mixture was stirred for 2 h and
then allyl bromide (200 ll, 2.31 mmol) was added. The yellow–
brown soln. was allowed to warm to rt overnight and then a sat.
ammonium chloride soln. was added. The aq. layer was separated
and extracted with Et2O (3 × 10 mL). The organics were combined,
washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by FC (cyclohexane :
Et2O, 1 : 1) to give 3 (263 mg, 80%) as a pale yellow solid. Mp =
87–89 ◦C; mmax/cm−1 (CH2Cl2) 2972, 2939, 1705, 1607, 1571, 1461,
1378, 1263, 1039, 1002, 919; dH (200 MHz; C6D6) 6.93 (1H, d, J1,3
6.7), 6.18–5.71 (2H, m), 5.53 (1H, dd, J1,3 2, 17), 5.08–4.91 (3H,
m), 4.73 (1H, d, J1,3 6.7), 3.78 (1H, d, J1,3 9.6), 3.66 (2H, s), 2.94
(3H, s), 2.61–2.32 (4H, m), 1.49 (3H, s), 1.18 (3H, s), 1.12 (3H, s);
dC (50 MHz; C6D6) 208.1, 164.9, 160.8, 138.2, 135.2, 118.4, 117.1,
114.4, 93.5, 78.2, 67.4, 57.5, 54.5, 50.6, 42.5, 28.5, 28.3, 28.1, 20.4;
HRMS (EI) on (M+) for C20H27NO3 requires 329.1991, found:
329.1970.
Experimental
Reactions and manipulations were carried out under an atm. of
N2 using a N2–vacuum double manifold and standard Schlenk
techniques, using oven and heat gun-dried glassware. Solvents were
distilled prior to use from sodium–benzophenone ketyl (THF),
sodium (toluene) or CaH2 (CH2Cl2). Commercially available solid
chemicals were used without purification unless indicated; liquids
were flash-distilled prior to use. Degassed solns. were obtained
via three pump–freeze–thaw cycles. Flash chromatography (FC)
(silica 60, 40 lm Fluka) was performed in air under pressure
(0.2–0.3 bar). IR spectra were measured on a Perkin-Elmer 241
polarimeter with a NaCl cell. NMR spectra were measured
on Bruker 400 or 500 MHz, or Varian-XL 200 spectrometers.
Chemical shifts were referenced to solvent residual peak and
are given in ppm relative to TMS. J values are given in Hz.
Diastereoisomeric excess was measured by 1H NMR integration.
Analytical data always corresponds to the major diastereoisomer.
Optical rotations were measured at 22 ◦C on a Perkin Elmer 241-
polarimeter using quartz cell (l = 10 cm) with a Na high-pressure
lamp (k = 589 mm). High resoln. mass spectra were measured
on a VG analytical 7070E instrument (data system 11250, resoln.
7000).
1-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-4-methoxy-4a-methyl-
4a,6,7,9a-tetrahydro-benzocyclohepten-5-one (4)
A soln. of 3 (120 mg, 0.36 mmol) and 926 (17 mg, 5 mol%) in
40 mL of toluene was degassed and then heated at 80 ◦C for 2 h.
The mixture was then concentrated under reduced pressure and
the residue was purified by FC (cyclohexane : AcOEt, 7 : 3) to
give 4 (96 mg, 88%) as a brown solid. Mp = 58–59 ◦C; mmax/cm−1
(CH2Cl2) 2968, 2953, 1712, 1607, 1577, 1463, 1257, 1204, 1084,
1008; dH (200 MHz; C6D6) 6.94 (1H, d, J1,3 6.7), 6.18–6.08 (1H,
m), 5.75–5.61 (1H, m), 4.65 (1H, d, J1,3 6.7), 3.85 (1H, d, J1,3 4.7
Hz), 3.70 (1H, d, J1,2 7.9), 3.68 (1H, d, J1,2 7.9), 2.90 (3H, s), 2.53
(3H, s), 1.67–1.48 (1H, m), 1.53 (3H, s), 1.16 (3H, s), 1.13 (3H, s);
dC (50 MHz; C6D6) 207.7, 164.9, 161.7, 132.9, 127.1, 120.6, 92.6,
78.7, 67.7, 55.1, 54.7, 47.0, 45.4, 28.6, 28.5, 21.9, 21.7; HRMS (EI)
on (M+) for C18H23O3N requires 301.1677, found: 301.1670.
1-[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-methyl-
6-vinyl-cyclohexa-2,4-dienyl]-ethanone (2)
nBuLi (1.6 M in hexanes, 3.25 mL, 5.2 mmol) was rapidly added
to tetravinyltin (470 lL, 2.6 mmol) at 25 ◦C. The white suspension
was stirred for 2 h and then cooled to −78 ◦C followed by the
addition of THF (32 mL). Complex 1 (1.364 g, 4 mmol) was added
in one portion and the resulting orange soln. was stirred at this
temp. in the dark for 1 h. nBu4NBr (1.675 g, 5.2 mmol) and MeI
(1.2 mL, 20 mmol) were next added and the mixture was placed
under an atm. of CO (1.5 Bar) and warmed to rt overnight. Excess
CO was vented and volatiles were removed under reduced pressure.
The residue was dissolved in THF (40 mL), cooled to −78 ◦C
and sodium ethoxide (2.56 M, 1.5 mL, 6 mmol) was added. The
mixture was stirred for 1 h before methyl iodide (750 lL, 12 mmol)
was added and the mixture was allowed to warm to rt overnight.
The soln. was concentrated under reduced pressure and purified
by FC (cyclohexane : AcOEt, 6 : 4) to give 2 (1.021 g, 88%) as a
pale yellow solid. Mp = 94–97 ◦C; mmax/cm−1 (CH2Cl2) 2970, 1706,
1607, 1571, 1461, 1269, 1203, 1039, 1001; dH (200 MHz; C6D6)
6.94 (1H, d, J1,3 6.7), 5.98–5.78 (1H, m), 5.34 (1H, dd, J1,2 1.92,
J1,3 16.9), 4.95 (1H, dd, J1,2 1.92, J1,3 9.9), 4.72 (1H, d, J1,3 6.7),
3.77 (1H, d, J1,3 9.5), 3.67 (2H, s), 2.95 (3H, s), 2.02 (3H, s), 1.49
1-[6-Allyl-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-
methyl-cyclohexa-2,4-dienyl]-ethanone (5)
Complex 1 (852 mg, 2.5 mmol) was treated with allyllithium
(prepared from nBuLi and allyltin) and MeI–CO following the
procedure described for the preparation of 2. Purification by FC
(cyclohexane : AcOEt, 1 : 1) afforded 5 (668 mg, 88%) as a pale
yellow solid. Mp = 56–58 ◦C; mmax/cm−1 (CH2Cl2) 2964, 2932,
1703, 1605, 1572, 1458, 1354, 1245, 1201, 1043, 1000, 913; dH
(200 MHz; C6D6) 6.98 (1H, d, J1,3 6.7), 6.22–6.02 (1H, m), 5.09–
4.93 (2H, m), 4.77 (1H, d, J1,3 6.7), 3.71 (2H, d, J1,2 7.9), 3.44 (1H,
t, J1,3 6.4), 3.04 (3H, s), 2.47 (2H, t, J1,3 6.4), 2.03 (3H, s), 1.45
(3H, s), 1.23 (3H, s), 1.19 (3H, s); dC (50 MHz; CDCl3) 207.3,
165.3, 162.1, 136.7, 119.9, 115.4, 93.3, 78.3, 67.4, 56.6, 54.6, 44.4,
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35.7, 30.7, 28.0, 21.6; HRMS (EI) on (M+) for C18H25NO3 requires
303.1834, found: 303.1823.
1-[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-methyl-
6-vinyl-cyclohexa-2,4-dienyl]-propan-1-one (11)
NaOEt in EtOH (2.46 M, 820 lL, 2.01 mmol) was added dropwise
to a soln. of 10 (387 mg, 1.34 mmol) in THF (10 mL) at −78 ◦C. The
mixture was stirred for 1 h before MeI (125 lL, 2.01 mmol) was
added and the mixture was allowed to warm to rt overnight. The
soln. was concentrated under reduced pressure and purified by FC
(cyclohexane : Et2O, 6 : 4) to give 11 (384 mg, 95%) as a colourless
oil. mmax/cm−1 (CH2Cl2) 2974, 2934, 1706, 1654, 1607, 1570, 1456,
1378, 1246, 1039, 1003; dH (400 MHz; C6D6) 6.84 (1H, d, J1,3 6.7),
5.78 (1H, dt, J1,3 16.9, 9.7), 5.21 (1H, dd, J1,2 2.0, J1,3 16.9), 4.84,
(1H, dd, J1,2 2.0, J1,3 9.7), 4.69 (1H, d, J1,3 6.7), 3.65 (1H, d, J1,3
9.7), 3.62–3.57 (2H, m), 2.94 (3H, s), 2.34–2.16 (2H, m), 1.40 (3H,
s), 1.10 (3H, s), 1.05 (3H, s), 0.99 (3H, t, J1,3 7.0); dC (100 MHz;
C6D6) 209.3, 164.9, 135.2, 127.1, 118.5, 116.7, 93.3, 78.0, 67.2,
57.4, 54.4, 50.5, 35.9, 28.1, 27.9, 20.2, 7.8; HRMS (EI) on (M+)
for C18H25O3N requires 302.1756, found 302.1712.
1-[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-methyl-
6-allyl-cyclohexa-2,4-dienyl]-pent-4-en-1-one (6)
Diene 5 (290 mg, 0.96 mmol) was treated with LDA and allylBr
following the procedure described for the preparation of 3.
Purification by FC (cyclohexane : AcOEt, 1 : 1) gave 6 (250 mg,
76%) as a pale yellow oil. mmax/cm−1 (CH2Cl2) 2971, 2934, 1703,
1606, 1572, 1461, 1265, 1247, 1207, 1001, 916; dH (200 MHz;
C6D6) 6.94 (1H, d, J1,3 6.7), 6.22–5.98 (1H, m), 5.87–5.66 (1H, m),
5.09–4.88 (4H, m), 4.74 (1H, d, J1,3 6.7), 3.68 (2H, d, J1,2 7.9), 3.43
(1H, t, J1,3 7.1), 3.02 (3H, s), 2.58–2.29 (6H, m), 1.41 (3H, s), 1.20
(3H, s), 1.15 (3H, s); dC (50 MHz; C6D6) 209.0, 166.1, 162.6, 138.2,
137.0, 119.9, 115.8, 115.2, 93.8, 78.7, 67.7, 56.9, 54.9, 44.9, 42.1,
36.0, 28.7, 28.4, 21.9; HRMS (EI) on (M+) for C21H29NO3 requires
343.2147, found: 343.2152.
1-[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-methyl-
6-vinyl-cyclohexa-2,4-dienyl]-propenone (12)
1-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-4-methoxy-4a-methyl-
6,7,10,10a-tetrahydro-4aH-benzocycloocten-5-one (7)
Method A. NaHMDS in THF (1.0 M, 2.3 mL, 2.30 mmol)
was added dropwise to a soln. of 11 (348 mg, 1.15 mmol) in THF
(16 mL) at −78 ◦C. The mixture was stirred for 4 h and then PhSeBr
(408 mg, 1.73 mmol) was added in one portion. The mixture was
warmed to rt overnight. A sat. aq. NH4Cl soln. was added and the
mixture was extracted with Et2O. The organics were combined,
washed with brine, dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by FC (cyclohexane :
Et2O, 7 : 3) to give the product of selenation (389 mg) as a mixture
of the two diastereoisomers. They were dissolved in 5 mL of
A soln. of 6 (150 mg, 0.44 mmol) and 827 (40 mg, 10 mol%) in
CH2Cl2 (44 mL) was degassed and heated at reflux, under N2 for
17 h. The mixture was then concentrated and the residue was
purified by FC (cyclohexane : Et2O, 1 : 1) to give 7 as a brown
solid. Mp = 127–129 ◦C; mmax/cm−1 (CH2Cl2) 2969, 2934, 1703,
1606, 1573, 1455, 1378, 1248, 1204, 1045, 1007, 708; dH (200 MHz;
C6D6) 6.91 (1H, d, J1,3 6.7), 5.88–5.71 (1H, m), 5.58–5.45 (1H, m),
4.75 (1H, d, J1,3 6.7 Hz), 3.69 (1H, d, J1,2 7.9), 3.65 (1H, d, J1,2 7.9),
3.15–2.98 (3H, m), 2.95 (3H, s), 2.72–2.50 (1H, m), 2.38–2.20 (2H,
m), 2.18–1.93 (1H, m), 1.46 (3H, s), 1.17 (3H, s), 1.14 (3H, s); dC
(50 MHz; C6D6) 210.2, 165.1, 161.6, 130.8, 126.1, 121.9, 93.1, 78.6,
67.7, 55.6, 54.9, 44.9, 41.2, 29.2, 28.7, 28.5, 26.4, 21.1; HRMS (EI)
on (M+) for C19H25O3N requires 315.1834, found: 315.1814.
◦
CH2Cl2 and cooled to −78 C before dropwise addition of 30%
aq. soln. of hydrogen peroxide (200 lL, 1.70 mmol). The mixture
was stirred at 0 ◦C for 3 h and then concentrated and purified by
FC (cyclohexane : Et2O, 7 : 3) to afford 12 (160 mg, 46%) as a
white solid.
Method B. TMSOTf (840 lL, 4.7 mmol) was slowly added to
a soln. of 2 (908 mg, 3.1 mmol) and NEt3 (655 lL, 4.7 mmol) in
CH2Cl2 (30 mL) at 0 ◦C. The mixture was stirred 1 h and then
filtered with ether over a pad of neutral alumina activated with
10% water. Solvents were evaporated and the oil was dissolved
in 20 mL of CH2Cl2 and added via syringe to a suspension of
Eschenmosser’s salt (1.143 g, 6.2 mmol) in 40 mL of CH2Cl2 at
1-[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-6-vinyl-
cyclohexa-2,4-dienyl]-propan-1-one (10)
nBuLi (1.6 M in hexanes, 750 lL, 1.2 mmol) was rapidly added
to tetravinyltin (110 lL, 0.6 mmol) at 25 ◦C. The white soln. was
stirred 2 h and then cooled to −78 ◦C before addition of THF
(8 mL). Complex 1 (341 mg, 1 mmol) was added in one portion
and the resulting orange soln. was stirred at this temp. in the
dark for 1 h. After this time, DMPU (1.2 mL, 10 mmol) and EtI
(800 lL, 10 mmol) were next added and the mixture was placed
under CO (1.5 Bar) and warmed up to rt overnight. Then it was
stirred at 50 ◦C for 1 h. Excess CO was vented and the volatiles were
removed under reduced pressure. The residue was purified by FC
(cyclohexane : Et2O, 6 : 4) to give the cyclohexadiene 10 (194 mg,
67%) as a pale yellow solid. Mp = 67–69 ◦C; dH (500 MHz; CDCl3)
6.77 (1H, bs), 5.86–5.80 (1H, m), 5.23 (1H, d, J1,3 5.8), 5.05 (1H,
d, J1,3 6.4), 5.01 (1H, d, J1,3 10.4), 3.97 (1H, d, J1,3 4.9), 3.95 (1H,
d, J1,2 7.9), 3.89 (1H, d, J1,2 7.9), 3.70 (3H, s), 3.06 (1H, s), 2.60–
2.47 (2H, m), 1.32 (3H, s), 1.26 (3H, s), 1.01 (3H, t, J1,3 7.2); dC
(50 MHz; CDCl3) 207.1, 161.5, 158.9, 136.2, 114.2, 94.5, 78.6,
67.1, 55.4, 55.4, 53.2, 39.1, 33.1, 28.3, 28.1, 7.7; HRMS (EI) on
(M+) for C17H23O3N requires 289.1678, found: 289.1681.
0
◦C. The mixture was stirred for 2 h and then NaOH (1 M,
4 mL, 6.2 mmol) was added and the mixture poured onto brine :
H2O (1 : 1) and extracted 3 times with CH2Cl2. The combined
organic layers were washed with brine and dried with Na2SO4.
Solvents were evaporated to obtain a grey–green oil which was
dissolved in 40 mL of CH2Cl2 and MeI (965 lL, 15.5 mmol)
was added. After 15 min a precipitate appeared and the mixture
was stirred for 1.5 h. Then 40 mL of a sat. NaHCO3 aq. soln. was
added and the mixture was extracted 3 times with CH2Cl2 and the
combined organic layers were washed with brine and dried with
Mg2SO4. Solvents were evaporated and the residue was purified
by FC (cyclohexane : AcOEt, 7 : 3) to give 12 (720 mg, 77%) as
a white solid. Mp = 87–89 ◦C; mmax/cm−1 (CH2Cl2) 2970, 2934,
1697, 1609, 1573, 1456, 1398, 1246, 1039, 1003; dH (400 MHz;
C6D6) 6.90 (1H, d, J1,3 6.7), 6.23–6.25 (2H, m), 5.77 (1H, dt, J1,3
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19.2, 9.6), 5.28 (1H, dd, J1,2 1.9, J1,3 16.9), 5.04 (1H, dd, J1,3 6.7,
5.6), 4.92 (1H, dd, J1,2 1.9, J1,3 9.6), 4.69 (1H, d, J1,3 6.7), 3.79 (1H,
d, J1,3 9.6), 3.60 (2H, m), 2.89 (3H, s) 1.50 (3H, s), 1.11 (3H, s),
1.04 (3H, s); dC (125 MHz; C6D6) 197.9, 164.8, 161.1, 136.6, 135.0,
127.5, 123.9, 119.3, 117.9, 93.8, 78.5, 67.7, 55.8, 54.8, 50.9, 28.5,
28.3, 20.4; HRMS (EI) on (M+) for C18H23O3N requires 301.1677,
found: 301.1646.
s), 1.18 (3H, s); dC (125 MHz; C6D6) 198.9, 165.3, 162.3, 137.1,
136.2, 128.3, 127.6, 124.9, 120.7, 115.6, 93.8, 78.6, 67.7, 55.6, 54.9,
45.2, 36.1, 28.2, 21.4; HRMS (EI) on (M+) for C19H25O3N requires
315.1834, found: 315.1877.
1-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-4-methoxy-4a-
methyl-4a,6,7,9a-tetrahydro-benzocyclohexen-5-one (16)
Compound 15 (129 mg, 0.41 mmol) was reacted following the
procedure described for the preparation of 4 and the residue was
purified by FC (cyclohexane : AcOEt, 6 : 4) to give 16 (57 mg,
48%) as a brown solid. Mp = 153–156 ◦C; mmax/cm−1 (CH2Cl2)
2971, 2932, 1676, 1602, 1566, 1395, 1344, 1244, 1179, 1079, 1007,
762, 706; dH (400 MHz; C6D6) 6.90 (1H, d, J1,3 6.4 Hz), 6.27–
6.25 (1H, m), 6.07 (1H, dd, J1,3 2.3, 10.2), 4.73 (1H, d, J1,3 6.6),
3.72 (1H, d, J1,2 8.1), 3.71 (1H, d, J1,2 8.1), 3.52 (1H, dd, J1,3
5.5, 10.5), 2.94 (3H, s), 2.49 (1H, ddt, J1,2 19.4, J1,3 0.8, 5.5),
2.30 (1H, ddt, J1,2 19.4, J1,3 2.6, 10.5), 1.57 (3H, s), 1.20 (3H,
s), 1.19 (3H, s); dC (100 MHz; C6D6) 195.0, 163.5, 161.4, 147.9,
129.4, 128.0, 120.9, 92.7, 78.4, 67.3, 55.0, 50.6, 42.7, 28.4, 28.2,
27.9, 18.9; HRMS (EI) on (M+) for C17H21NO3 requires 287.1521,
found: 287.1523.
1-[5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-methyl-
6-vinyl-cyclohexa-2,4-dienyl]-prop-2-en-1-ol (13)
NaBH4 (12 mg, 0.31 mmol) was added to a soln. of 12 (100 mg,
0.31 mmol) and CeCl3·7H2O (118 mg, 0.31 mmol) in MeOH
(3 mL) at 0 ◦C. The mixture was stirred for 1 h and then
concentrated and purified by FC (cyclohexane : Et2O, 1 : 1) to
give 13 (66 mg, 70%, de = 76%) as a white solid. mmax/cm−1 (Et2O)
3586, 2952, 2825, 1654, 1609, 1574, 1381, 1371, 1130, 1114, 1066;
dH (400 MHz; C6D6) 6.79 (1H, d, J1,3 6.4), 6.20–6.05 (1H, m),
5.91 (1H, dt, J1,3 19.4, 9.3), 5.70 (1H, dt, J1,2 0.9, J1,3 17.0), 5.46
(1H, dd, J1,2 2.2, J1,3 17.6), 5.16 (1H, dt, J1,2 0.9, J1,3 17.0), 5.01
(1H, dd, J1,2 2.2, J1,3 9.1), 4.65–4.63 (1H, m), 4.55 (1H, d, J1,3 6.4),
3.65 (1H, d, J1,3 9.3), 3.61 (1H, d, J1,2 7.8), 3.57 (1H, d, J1,2 7.8),
3.36–3.35 (1H, m), 2.73 (3H, s), 1.32 (3H, s), 1.11 (3H, s), 1.07
(3H, s); dC (100 MHz; C6D6) 168.2, 161.0, 135.4, 133.4, 120.8,
117.0, 116.8, 93.0, 78.0, 72.7, 67.2, 54.5, 48.6, 45.6, 28.2, 27.9,
26.8, 15.4; HRMS (EI) on (M+) for C18H25O3N requires 303.1834,
found: 303.1859.
1-[6-Allyl-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-
methyl-cyclohexa-2,4-dienyl]-prop-2-en-1-ol (17)
Compound 15 (98 mg, 0.31 mmol) was reacted following the
procedure described for the preparation of 13. Purification by
chromatography (cyclohexane : Et2O, 1 : 1) gave 17 (81 mg, 80%,
de = 84%) as a pale yellow oil. mmax/cm−1 (CH2Cl2) 3575, 3074,
2972, 2930, 1715, 1607, 1573, 1440, 1362, 1296, 1264, 1238, 1208,
1170, 1042, 995; dH (500 MHz; CDCl3) 6.68 (1H, d, J1,3 6.4), 6.08–
6.01 (1H, m), 5.81–5.73 (1H, m), 5.45 (1H, d, J1,3 17.0), 5.29 (1H,
d, J1,3 10.6), 5.05 (1H, d, J1,3 6.5 Hz), 4.85 (1H, d, J1,3 17.0), 4.76
(1H, d, J1,3 9.9), 4.59 (1H, d, J1,3 6.1), 3.90 (1H, d, J1,2 7.8), 3.83
(1H, d, J1,2 7.8), 3.69 (3H, s), 3.29 (1H, d, J1,3 1.6), 2.66 (1H, dd,
J1,3 3.9, 9.5), 2.34–2.29 (1H, m), 2.24–2.17 (1H, m), 1.29 (3H, s),
1.22 (3H, s), 1.11 (3H, s); dC (125 MHz; C6D6) 168.2, 162.4, 136.8,
135.3, 128.1, 121.6, 118.3, 115.0, 93.4, 78.3, 72.9, 67.3, 55.9, 43.3,
42.7, 32.2, 28.0, 27.9, 16.1; HRMS (EI) on (M+) for C19H27NO3
requires 317.1991, found: 317.1986.
4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-7-methoxy-7a-methyl-
3a,7a-dihydro-1H-inden-1-ol (14)
A soln. of 13 (445 mg, 1.46 mmol) and RCM catalyst 8 (10 mol%,
134 mg, 0.15 mmol) in CH2Cl2 (100 mL) was degassed and
then heated overnight at reflux, under N2. The mixture was then
concentrated to give a brown residue which was purified by FC
(cyclohexane : Et2O, 1 : 1) to give 14 (338 mg, 84%) as a pale yellow
solid. Mp = 107–109 ◦C; mmax/cm−1 (CH2Cl2) 3586, 2966, 2932,
2869, 1660, 1606, 1578, 1453, 1235, 1093, 1011, 814, 503 cm−1; dH
(500 MHz; C6D6) 6.97 (1H, d, J1,3 6.8) 6.11 (1H, dd, J1,3 5.7, 1.9),
6.01–5.99 (1H, m), 5.10 (1H, s), 4.73 (1H, d, J1,3 6.8), 4.19–4.17
(1H, m), 3.72 (1H, d, J1,2 7.9), 3.70 (1H, dd, J1,3 7.9), 3.02 (3H, s),
1.98 (1H, bs), 1.43 (3H, s), 1.22 (3H, s), 1.21 (3H, s); dC (125 MHz;
C6D6) 167.8, 162.7, 135.9, 132.5, 128.2, 116.2, 91.6, 81.7, 78.5,
67.5, 54.8, 51.9, 50.5, 28.5, 28.4, 20.2; HRMS (EI) on (M+) for
C16H21NO3 requires 275.1521, found: 275.1509.
5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-8-methoxy-8a-methyl-
1,4,4a,8a-tetrahydro-naphthalen-1-ol (19)
A soln. of 17 (44 mg, 0.14 mmol) and 18 (10 mol%, 11 mg,
0.014 mmol) in CH2Cl2 (30 mL) was degassed and then heated
overnight at reflux under N2. The mixture was then concentrated
to give a brown residue which was purified by FC (Et2O) to give
19 (35 mg, 87%) as a pale yellow oil. mmax/cm−1 (CH2Cl2) 3593,
3030, 2967, 2931, 1646, 1599, 1560, 1454, 1345, 1223, 1011, 811;
dH (500 MHz; C6D6) 6.95 (1H, d, J1,3 6.4), 6.04–6.01 (1H, m), 5.81–
5.77 (1H, m), 4.75 (1H, d, J1,3 6.4), 4.56 (1H, s), 3.73 (1H, d, J1,2
7.9), 3.721 (1H, d, J1,2 7.9), 3.45 (1H, dd, J1,3 10.1, 6.5), 3.02 (3H,
s), 2.70–2.62 (1H, m), 2.17–2.08 (1H, m), 1.97 (1H, s), 1.54 (3H,
s), 1.24 (3H, s), 1.21 (3H, s); dC (125 MHz; C6D6) 168.4, 162.6,
131.1, 128.9, 128.3, 123.2, 92.8, 78.5, 67.3, 64.2, 54.9, 42.6, 34.8,
30.1, 28.6, 28.5, 21.5; HRMS (EI) on (M+) for C17H23O3N requires
289.1678, found: 289.1693.
1-[6-Allyl-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-
methyl-cyclohexa-2,4-dienyl]-propanone (15)
Compound 5 (303 mg, 1 mmol) was reacted following the proce-
dure described for the preparation of 12 (Method B). Purification
by FC (cyclohexane : AcOEt, 6 : 4) gave 15 (185 mg, 59%) as
an colourless solid. Mp = 125–126 ◦C; mmax/cm−1 (CH2Cl2) 2971,
2934, 1693, 1609, 1573, 1398, 1246, 1048, 1003; dH (500 MHz;
C6D6) 7.0 (1H, d, J1,3 6.7), 6.48 (1H, dd, J1,3 16.9, 10.0), 6.36 (1H,
dd, J1,2 2.2, J1,3 16.9), 6.15–6.06 (1H, m), 5.13 (1H, dd, J1,2 2.2, J1,3
10.0), 5.05 (1H, d, J1,3 16.9), 4.97 (1H, d, J1,3 10.0), 4.79 (1H, d, J1,3
6.7), 3.74 (1H, d, J1,2 7.8), 3.67 (1H, d, J1,2 7.8), 3.53 (1H, dd, J1,3
9.0, 4.9), 3.00 (3H, s), 2.59–2.47 (2H, m), 1.58 (3H, s), 1.22 (3H,
348 | Org. Biomol. Chem., 2006, 4, 342–351
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5-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-8-methoxy-8a-methyl-
1,4,4a,8a-tetrahydro-naphthalen-1-ol (20)
m), 2.96 (3H, s), 2.65–2.30 (4H, m), 1.62 (1H, m), 1.50 (3H, s),
0.95 (3H, d, J1,3 6.6), 0.79 (3H, d, J1,3 6.6); dC (100 MHz; C6D6)
207.3, 165.6, 163.5, 136.8, 119.7, 115.6, 113.7, 93.4, 73.0, 69.7,
56.6, 54.6, 44.7, 35.7, 33.3, 30.8, 21.7, 18.7. HRMS (EI) on (M+)
for C21H29NO5 requires 343.2143, found: 343.2147; [a]2D0 +81.3
(c 1.03 in CHCl3).
Compound 16 (17 mg, 0.06 mmol) was reacted following the
procedure described for the preparation of 13. Purification by
FC (cyclohexane : AcOEt, 1 : 1) afforded 20 (16 mg, 84%) as
a pale yellow oil. mmax/cm−1 (CH2Cl2) 3560, 2927, 29854, 1602,
1566, 1462, 1235, 1181, 968; dH (400 MHz; C6D6) 6.80 (1H, d,
J1,3 6.4), 5.98–5.95 (1H, m), 5.55–5.51 (1H, m), 4.64 (1H, d, J1,3
6.4 Hz), 4.27 (1H, d, J1,3 12.1), 3.69 (1H, d, J1,2 7.9), 3.68 (1H, d,
J1,2 7.9), 3.40 (1H, d, J1,3 12.1), 3.32–3.26 (1H, m), 2.78 (3H, s),
2.65–2.58 (1H, m), 2.06–2.00 (1H, m), 1.52 (3H, s), 1.19 (3H, s),
1.17 (3H, s); dC (125 MHz; C6D6) 169.4, 161.9, 132.6, 128.9, 126.9,
124.0, 94.4, 78.6, 74.9, 67.5, 54.8, 42.8, 32.3, 30.1, 28.6, 28.5, 22.0;
HRMS (EI) on (M+) for C17H23O3N requires 289.1678, found:
289.1661.
1-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)-4-methoxy-4a-methyl-
4a,6,7,9a-tetrahydro-benzocyclohepten-5-one (25)
Compound 24 (106 mg, 0.31 mmol) was reacted following the
procedure described for the preparation of 4. Purification by FC
(cyclohexane : AcOEt, 7 : 3) gave 25 (105 mg, quantitative) as
a brown oil. mmax/cm−1 (CH2Cl2) 2963, 1704, 1609, 1573, 1516,
1381, 1243, 1075, 1006; dH (200 MHz; C6D6) 6.94 (1H, d, J1,3
6.8), 6.14 (1H, ddd, J1,3 11.8, 4.7, 2.4), 5.73–5.54 (1H, m), 4.69
(1H, d, J1,3 6.8), 3.97–3.67 (4H, m), 2.91 (3H, s), 2.75–2.68 (2H,
m), 2.62–2.35 (2H, m), 1.69–1.56 (1H, m), 1.55 (3H, s), 0.95 (3H,
d, J1,3 6.7), 0.77 (3H, d, J1,3 6.7); dC (125 MHz; C6D6) 207.9,
165.2, 163.3, 133.0, 128.3, 127.2, 120.6, 92.8, 73.5, 70.3, 55.3,
54.9, 51.3, 45.6, 33.6, 22.1, 21.7, 19.2, 18.9. HRMS (EI) on (M+)
for C19H25O3N requires 315.1834, found: 315.1842; [a]2D0 +115.3
(c 1.06 in CHCl3).
p-Methoxyphenyl isopropyloxazoline chromium tricarbonyl
complex (22)
A degassed soln. of oxazoline 21 (3.00 g, 13.7 mmol), Cr(CO)6
(3.00 g, 13.7 mmol), diisobutyl ether (100 mL) and THF was
heated at reflux in the dark for 17 h. The mixture was then filtered
through Celite and concentrated under reduced pressure to give a
brown oil that was purified by FC (cyclohexane : Et2O, 7 : 3) and
then recrystallised in hexanes : Et2O to give 22 (1.625 g, 33%) as a
bright yellow solid. mmax/cm−1 (CH2Cl2) 1973, 1897; dH (500 MHz;
C6D6) 6.15 (1H, d, J1,3 6.6), 6.04 (1H, d, J1,3 6.6), 4.33–4.30 (2H,
m), 3.83–3.68 (3H, m), 2.87 (3H, s), 1.63–1.57 (1H, m), 0.95 (3H,
d, J1,3 6.6), 0.84 (3H, d, J1,3 6.6); dC (125 MHz; C6D6) 232.2, 160.4,
143.8, 94.6, 94.6, 85.3, 76.6, 76.5, 72.7, 70.7, 55.1, 32.9, 18.4, 18.3;
HRMS (EI) on (M+) for C16H17O5NCr requires 355.0516, found:
355.0512; [a]2D0 +89.2 (c 0.96 in CH2Cl2).
4-Methoxy-4a-methyl-5-oxo-5,6,7,9a-tetrahydro-4aH-
benzocycloheptene-1-carbaldehyde (26)
A soln. of the chiral oxazoline 25 (70 mg, 0.22 mmol) in 5 mL of
MeI was stirred 3 days at reflux. Excess of MeI was then evaporated
under reduced pressure. The residue was dissolved in a mixture of
THF (1.5 mL), MeOH (0.5 mL) and CH2Cl2 (1 mL) and the
soln. cooled to 0 ◦C. NaBH4 (25 mg, 0.66 mmol) was then added
and the mixture was stirred for 15 min. H2O was then added
and the soln. was extracted with Et2O. The combined organic
layers were washed with brine and dried over MgSO4. The solvent
was evaporated and the residue was dissolved in a mixture of
THF (2 mL) and H2O (1 mL) and p-toluene sulfonic acid (84 mg,
044 mmol) was added. The soln. was stirred for 1.5 h and then
extracted with Et2O. Organic layers were combined washed with
brine and dried over MgSO4. The product was concentrated and
purified by FC (cyclohexane : AcOEt, 7 : 3) to afford 26 (42 mg,
82%) as a colourless oil. Mp = 65–68 ◦C; mmax/cm−1 (CH2Cl2) 2928,
2854, 1706, 1664, 1553, 1455, 1377, 1184, 1091, 909; dH (400 MHz;
C6D6) 9.32 (1H, s), 6.10 (1H, d, J1,3 6.7), 5.72 (1H, ddd, J1,3 11.6,
4.8, J1,4 2.5), 5.51–5.45 (1H, m), 4.52 (1H, d, J1,3 6.7), 3.59–3.57
(1H, m), 2.81 (3H, s), 2.61 (1H, dd, J1,2 4.6, J1,3 1.8), 2.58 (1H,
d, J1,2 4.6), 2.27–2.18 (1H, m), 1.54–1.46 (1H, m), 1.27 (3H, s); dC
(125 MHz; C6D6) 206.6, 189.7, 169.2, 141.8, 133.6, 131.9, 127.6,
93.1, 55.6, 54.8, 45.3, 43.8, 22.0, 21.8; HRMS (EI) on (M+) for
C14H16O3 requires 232.1099, found: 232.1102; [a]2D0 +222.5 (c 1.05
in CHCl3).
[5-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)-4-methoxy-1-methyl-6-
vinyl-cyclohexa-2,4-dienyl]-ethanone (23)
Compound 22 (355 mg, 1 mmol) was reacted following the
procedure described for the preparation of 2. Purification by FC
(cyclohexane : AcOEt, 7 : 3) afforded 23 (254 mg, 84%) as a pale
yellow oil. mmax/cm−1 (CH2Cl2) 2963, 2934, 1705, 1610, 1572, 1385,
1353, 1270, 1265, 1044, 1001; dH (500 MHz; C6D6) 6.95 (1H, d,
J
1,3 6.4), 5.89 (1H, m), 5.35 (1H, d, J1,3 16.7), 4.97 (1H, d, J1,3 9.8),
4.78 (1H, d, J1,3 6.4), 3.93–3.70 (4H, m), 3.0 (3H, s), 2.0 (3H, s),
1.68–1.62 (1H, m), 1.5 (3H, s), 0.95 (3H, d, J1,3 6.6), 0.79 (3H,
d, J1,3 6.6); dC (125 MHz; C6D6) 206.7, 165.0, 162.6, 135.8, 127.7,
118.9, 117.5, 93.6, 73.1, 69.7, 58.0, 54.9, 50.8, 33.2, 30.1, 20.4,
18.9, 18.4; HRMS (EI) on (M+) for C18H25NO5 requires 303.1824
found: 303.1834; [a]2D0 +159.3 (c 1.01 in CHCl3).
1-[5-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)-2-methoxy-1-methyl-6-
vinyl-cyclohexa-2,4-dienyl]-pent-4-en-1-one (24)
1-Dimethoxymethyl-4-methoxy-benzene chromium tricarbonyl
(28)
Compound 23 (161 mg, 0.53 mmol) was reacted following the
procedure described for the preparation of 3. Purification by FC
(cyclohexane : Et2O, 8 : 2) gave 24 (146 mg, 80%) as a pale yellow
oil. mmax/cm−1 (CH2Cl2) 3048, 2963, 2904, 1705, 1605, 1571, 1462,
1384, 1274, 1253, 1158, 1082, 1044, 1002, 920; dH (200 MHz; C6D6)
6.93 (1H, d, J1,3 6.6), 6.0–5.7 (2H, m), 5.32 (1H, dd, J1,2 2.0, J1,3
17.3), 5.05–4.89 (3H, m), 4.74 (1H, d, J1,3 6.6), 3.92–3.56 (4H,
A soln. of anisaldehyde dimethyl acetal (5.6 mL, 33 mmol),
chromium hexacarbonyl (6.6 g, 30 mmol) diisobutyl ether
(100 mL) and THF (10 mL) was degassed. The soln. was heated
at reflux in the absence of light for 64 h. The mixture was
transferred to another flask and concentrated under reduced
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pressure to give a brown oil. The residue was dissolved in toluene
(3 × 20 mL), filtered through Celite and concentrated to give
28 (8.86 g, 93%) as a bright yellow solid. mmax/cm−1 (hexane)
1977, 1908, 746; dH (400 MHz; C6D6) 5.43 (2H, d, J1,3 6.9),
4.87 (1H, s), 4.45 (2H, d, J1,3 6.9), 3.15 (s, 6H), 2.98 (3H, s); dC
(100 MHz; C6D6) 233.0, 143.0, 101.0, 100.2, 93.4, 76.7, 54.8, 52.8;
HRMS (EI) on (M+) for C13H14O6Cr requires 318.0196, found:
318.0215.
1-(2-Methoxy-5-[(2-methoxymethyl-pyrrolidin-1-ylimino)-methyl]-
1-methyl-6-vinyl-cyclohexa-2,4-dienyl)-pent-4-en-1-one (32)
Compound 31 (299 mg, 0.9 mmol) was reacted following the
procedure described for the preparation of 3. Purification by FC
(cyclohexane : AcOEt, 7 : 3) afforded 32 (247 mg, 76%) as a
pale yellow oil. mmax/cm−1 (CH2Cl2) 2976, 2932, 1702, 1633, 1565,
1458, 1337, 1240, 1152, 1119, 1005, 918, 812; dH (400 MHz;
C6D6) 6.82 (1H, s), 5.98–5.77 (2H, m), 5.75 (1H, d, J1,3 6.6),
5.25 (1H, dd, J1,2 1.8, J1,3 17.0), 5.01 (1H, dd, J1,2 2.2, J1,3 17.0),
4.92–4.86 (3H, m), 3.78 (1H, d, J1,3 9.8), 3.60–3.50 (2H, m), 3.32
(1H, dd, J1,3 9.1, 6.8), 3.07 (3H, s), 3.03 (3H, s), 2.98–2.89 (1H,
m), 2.71–2.40 (m, 5H), 1.74–1.55 (3H, m), 1.51 (3H, s), 1.47–
1.36 (1H, m); dC (125 MHz; C6D6) 209.8, 161.3, 138.8, 137.0,
132.6, 130.4, 120.2, 116.6, 114.6, 114.3, 95.0, 75.1, 63.5, 58.9,
58.0, 54.6, 50.3, 43.1, 28.9, 27.2, 22.3, 20.6; HRMS (EI) on (M+)
for C22H32O3N2 requires 372.2413, found: 372.2421; [a]2D0 +114.4
(c 0.70 in CHCl3).
4-Methoxy-benzaldehyde chromium tricarbonyl (29)
2 M HCl (35 mL) was added to a soln. of 28 (8.65 g, 27 mmol)
in THF (35 mL) at rt. The mixture immediately became red and
was stirred overnight. The soln. was brought to pH 7 with sat.
NaHCO3 soln. The aq. layer was separated and then extracted
with Et2O (3 × 50 mL). The organics were combined, washed
with brine, dried over MgSO4 and concentrated under reduced
pressure to give 29 (7.07 g, 96%) as a red oil. mmax/cm−1 (hexane)
1990, 1932, 1706, 746; dH (400 MHz; C6D6) 8.89 (1H, s), 5.36 (2H,
d, J1,3 6.2), 4.25 (2H, d, J1,3 6.2), 2.93 (3H, s); dC (100 MHz; C6D6)
230.4, 185.7, 144.2, 94.2, 90.9, 76.4, 54.9; HRMS (EI) on (M+) for
C11H8O5Cr requires 271.9776, found: 271.9778.
1-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)-4-methoxy-4a-methyl-
4a,6,7,9a-tetrahydro-benzocyclohepten-5-one (33)
Compound 32 (78 mg, 0.21 mmol) was reacted following the
procedure described for the preparation of 4. Purification by FC
(cyclohexane : AcOEt, 7 : 3) afforded 33 (64 mg, 89%) as a brown
oil. mmax/cm−1 (CH2Cl2) 2978, 2878, 1699, 1635, 1569, 1453, 1376,
1337, 1236, 1172, 1116, 1070, 1010, 744; dH (500 MHz; C6D6) 6.97
(1H, s), 6.12–6.08 (1H, m), 5.85 (1H, d, J1,3 6.6), 5.75–5.70 (1H,
m), 4.92 (1H, d, J1,3 6.6), 3.94–3.93 (1H, m), 3.57–3.54 (1H, m),
3.58 (1H, dd, J1,2 8.8, J1,3 3.4), 3.42 (1H, dd, J1,2 8.8, J1,3 6.6), 3.15
(3H, s), 3.10 (3H, s), 3.04–3.00 (1H, m), 2.88–2.83 (1H, m), 2.80–
2.73 (1H, m), 2.69–2.62 (2H, m), 2.46–2.40 (1H, m), 1.75–1.64
(3H, m), 1.72 (3H, s), 1.49–1.43 (1H, m); dC (125 MHz; C6D6)
208.7, 161.3, 133.3, 131.9, 126.5, 121.0, 93.6, 75.1, 63.2, 58.9, 54.8,
48.6, 46.2, 45.6, 27.2, 27.1, 22.4, 22.2, 21.6; HRMS (EI) on (M+)
for C20H28O3N2 requires 344.2100, found: 344.2109; [a]2D0 +193.4
(c 0.67 in CHCl3).
(4-Methoxy-benzylidene)-(2-methoxymethyl-pyrrolidin-1-yl)-
amine chromium tricarbonyl (30)
R-1-Amino-2-(methoxymethyl)pyrrolidine (340 lL, 2.55 mmol)
was added to a soln. of 29 (660 mg, 2.43 mmol) in Et2O (10 mL)
˚
and stirred over 4 A molecular sieves (1.8 g) for 18 h at rt.
The mixture was filtered through Celite and concentrated under
reduced pressure to give a yellow oil. The residue was crystallised
(Et2O–hexane) to give 30 (623 mg, 67%) as a very fine yellow
powder. mmax/cm−1 (hexane) 1971, 1903, 746; dH (400 MHz; C6D6)
6.36 (1H, s), 5.66 (1H, dd, J1,3 6.8, 1.3), 5.59 (1H, dd, J1,3 6.8, 1.3),
4.70 (1H, dd, J1,3 7.0, 2.2), 4.66 (1H, dd, J1,3 7.0, 2.2), 3.76–3.74
(1H, m), 3.66 (1H, d, J1,2 4.6), 3.48 (1H, d, J1,2 4.6), 3.27 (3H, s),
3.05 (3H, s), 2.96–2.87 (1H, m), 2.68–2.60 (1H, m), 1.84–1.68 (3H,
m), 1.57–1.44 (1H, m); dC (100 MHz; C6D6) 233.9, 141.6, 124.1,
90.9, 78.3, 77.8, 74.4, 62.8, 58.6, 54.8, 47.9, 26.7, 21.9; HRMS (EI)
on (M+) for C17H20O5N2Cr requires 384.0777, found 384.0780; [a]2D0
+7.5 (c 0.86 in CHCl3).
4-Methoxy-4a-methyl-5-oxo-5,6,7,9a-tetrahydro-4aH-
benzocycloheptene-1-carbonitrile (34)
A soln. of hydrazone 33 (41 mg, 0.12 mmol) in 0.3 mL of a MeOH :
phosphate buffer pH 7 (1 : 1) mixture was added dropwise to a
soln. of magnesium monoperoxyphthalate hexahydrate (MMPP)
(77 mg, 0.16 mmol) in 1 mL of MeOH : phosphate buffer at
0 ◦C. The mixture was stirred for 15 min and then H2O was added.
The soln. was extracted with Et2O. The combined organic layers
were washed with an aq. soln. of NaHCO3 and dried over MgSO4.
34 (25 mg, 91%) was obtained as a yellow oil after purification by
FC (cyclohexane : AcOEt, 7 : 3). mmax/cm−1 (CH2Cl2) 3062, 2936,
2850, 2203, 1708, 1639, 1563, 1454, 1380, 1275, 1253, 1075, 1005,
907, 808, 762; dH (500 MHz; C6D6) 6.14 (1H, dd, J1,3 6.6, 3.9),
5.55–5.51 (2H, m), 4.32 (1H, d, J1,3 6.6), 2.81 (3H, s), 2.73–2.69
(1H, m), 2.65 (1H, ddd, J1,2 15.0, J1,3 6.6, J1,4 4.8), 2.42 (1H, ddd,
J1,2 15.0, J1,3 10.1, J1,4 4.8), 2.18–1.99 (1H, m), 1.70–1.50 (1H, m),
1.23 (3H, s); dC (125 MHz; C6D6) 205.8, 164.9, 137.2, 131.1, 128.8,
119.3, 104.2, 92.9, 55.2, 54.9, 45.6, 43.4, 23.1, 21.4; HRMS (EI)
on (M+) for C14H15NO2 requires 229.1106, found: 229.1103; [a]2D0
+82.6 (c 0.53 in CHCl3).
1-(2-Methoxy-5-[(2-methoxymethyl-pyrrolidin-1-ylimino)-methyl]-
1-methyl-6-vinyl-cyclohexa-2,4-dienyl)-ethanone (31)
Compound 30 (768 mg, 2 mmol) was reacted following the
procedure described for the preparation of 2. Purification by FC
(cyclohexane : AcOEt, 7 : 3) afforded 31 (483 mg, 73%) as a pale
yellow oil. mmax/cm−1 (CH2Cl2) 2976, 2931, 1704, 1667, 1634, 1567,
1458, 1352, 1240, 1111, 1002; dH (400 MHz; C6D6) 6.99 (1H, s),
6.08 (1H, dt, J1,3 18.3, 9.8), 5.92 (1H, d, J1,3 6.6), 5.44 (1H, dd, J1,2
2.2, J1,3 18.3), 5.10 (1H, dd, J1,2 2.2, J1,3 9.8), 5.03 (1H, dd, J1,3 6.6),
3.95 (1H, d, J1,3 9.8), 3.78–3.72 (2H, m), 3.49 (1H, dd, J1,3 9.1, 6.7),
3.24 (3H, s), 3.19 (3H, s), 3.12–3.06 (1H, m), 2.78–2.74 (1H, m),
2.28 (3H, s), 1.86–1.75 (3H, m), 1.67 (3H, s), 1.57–1.49 (1H, m); dC
(125 MHz; C6D6) 207.8, 161.3, 137.4, 132.7, 130.4, 120.2, 116.5,
94.7, 75.1, 63.1, 58.9, 58.1, 54.6, 49.2, 47.1, 31.7, 27.1, 22.3, 20.6;
HRMS (EI) on (M+) for C19H28O3N2 requires 332.2099, found:
332.2074; [a]2D0 +230.8 (c 0.57 in CHCl3).
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15 E. P. Ku¨ndig, A. Bellido, K. P. Kaliappan, A. R. Pape and S. Radix,
Synlett, 2003, 2407.
References
16 See for example: a) Occidentalol: (a) D.S. Watt and E. J. Corey, Tetra-
hedron. Lett, 1972, 46, 4651; (b) Tubipofurans: ref. 14; (c) Dolastanes:
G. Mehta and N. Krishnamurthy, Tetrahedron Lett., 1987, 28, 5945;
(d) Taxol: K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G. Nantermet,
R. K. Guy, C. F. Claiborne, J. Renaud, E. A. Couladouros, K.
Paulvannan and E. J. Sorensen, Nature, 1994, 367, 630.
17 We have found earlier that a polar additive, HMPA or, preferably,
because non-carcinogenic, DMPU, after the nucleophilic addition reac-
tion gives a higher product yield because it increases the efficiency of the
electrophile addition step.5,9 We now find that addition of [nBu4N][Br]
in place of a cosolvent also works. Li–ammonium metathesis results in a
looser ion-pair and this increases nucleophilicity of the cyclohexadienyl
intermediate. The advantage of using [nBu4N][Br] rather than DMPU
is that it makes product isolation often easier.
18 Diene 3 was also obtained in 73% yield from complex 1 without
isolation of 2 and using NaHMDS as a base. However mono-allylation
proved somewhat tricky and was found to depend on the batch of the
bottle of NaHMDS in THF used.
19 (a) A. Fu¨rstner and K. Langemann, J. Am. Chem. Soc., 1997, 119, 9130;
(b) A. K. Ghosh, J. Cappiello and D. Shin, Tetrahedron Lett., 1998, 39,
4651.
1 Transition Metal Arene p-Complexes in Organic Synthesis and Catalysis,
ed. E. P. Ku¨ndig, Topics in Organometallic Chemistry, vol. 7, Springer
Verlag, Berlin, Heidelberg, New York, 2004.
2 (a) A. R. Pape, K. P. Kaliappan and E. P. Ku¨ndig, Chem. Rev., 2000,
100, 2917; (b) E. P. Ku¨ndig and S. H. Pache, Sci. Synth., 2003, 2, 153.
3 M. F. Semmelhack, J. H. T. Hall, R. Farina, M. Yoshifuji, G. Clark, T.
Bargar, K. Hirotsu and J. Clardy, J. Am. Chem. Soc., 1979, 101, 3535.
4 E. P. Ku¨ndig, J. A. F. Cunningham, P. Paglia, D. P. Simmons and
G. Bernardinelli, Helv. Chim. Acta, 1990, 73, 386.
5 E. P. Ku¨ndig, A. Ripa, R. Liu and G. Bernardinelli, J. Org. Chem.,
1994, 59, 4773.
6 (a) M. F. Semmelhack, G. R. Clark, R. Farina and M. Saeman, J. Am.
Chem. Soc., 1979, 101, 217; (b) A. J. Pearson, A. V. Gontcharov and P. D.
Woodgate, Tetrahedron Lett., 1996, 37, 3087; (c) M. F. Semmelhack and
H.-G. Schmalz, Tetrahedron Lett., 1996, 37, 3089.
7 M. F. Semmelhack, J. L. Garcia, D. Cortes, R. Farina, R. Hong and
B. K. Carpenter, Organometallics, 1983, 2, 467.
8 (a) E. P. Ku¨ndig, D. Amurrio, R. Liu and A. Ripa, Synlett, 1991, 657;
(b) E. P. Ku¨ndig, A. Ripa, R. Liu, D. Amurrio and G. Bernardinelli,
Organometallics, 1993, 12, 3724.
9 (a) E. P. Ku¨ndig, A. Ripa and G. Bernardinelli, Angew. Chem., Int. Ed.
Engl., 1992, 31, 1071; (b) G. Bernardinelli, S. Gillet, E. P. Ku¨ndig, R.
Liu, A. Ripa and L. Saudan, Synthesis, 2001, 2040.
10 S. E. Gibson and H. Ibrahim, Chem. Commun., 2002, 2465.
11 (a) E. P. Kundig, A. Quattropani, M. Inage, A. Ripa, C. Dupre,
A. F. Cunningham, Jr. and B. Bourdin, Pure Appl. Chem., 1996, 68,
97; (b) G. Bernardinelli, A. Cunningham, C. Dupre, E. P. Ku¨ndig, D.
Stussi and J. Weber, Chimia, 1992, 46, 126.
20 (a) M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999,
1, 953; (b) J. Huang, E. D. Stevens, S. P. Nolan and J. L. Petersen,
J. Am. Chem. Soc., 1999, 121, 2674; (c) L. Ackermann, A. Fu¨rstner, T.
Weskamp, F. J. Kohl and W. A. Herrmann, Tetrahedron Lett., 1999, 40,
4787.
21 E. P. Ku¨ndig, A. F. Cunningham, Jr., P. Paglia, D. P. Simmons and G.
Bernardinelli, Helv. Chim. Acta, 1990, 73, 386.
22 A. K. Chatterjee, T.-L. Choi, D. P. Sanders and R. H. Grubbs, J. Am.
Chem. Soc., 2003, 125, 11360.
12 D. Amurrio, K. Khan and E. P. Ku¨ndig, J. Org. Chem., 1996, 61,
2258.
23 Ent-21 has also been prepared via arene exchange in
[Cr(CO)3(naphthalene)]: E. P. Ku¨ndig and S. Radix, unpublished
results.
24 M. Reuman and A. I. Meyers, Tetrahedron, 1985, 41, 837.
25 D. Enders and A. Plant, Synlett, 1994, 1054.
26 L. Jafarpour and S. P. Nolan, Organometallics, 2000, 19, 2055.
27 A. Fu¨rstner, O. Guth, A. Du¨ffels, G. Seidel, M. Liebl, B. Gabor and R.
Mynott, Chem. Eur. J., 2001, 22, 4811.
13 H.-G. Schmalz, B. Gotov and A. Bo¨ttcher, in Transition Metal Arene
p-Complexes in Organic Synthesis and Catalysis, ed. E. P. Ku¨ndig,
Topics in Organometallic Chemistry, vol. 7, Springer Verlag, Berlin,
Heidelberg, New York, 2004, p. 157.
14 (a) E. P. Ku¨ndig, R. Cannas, M. Laxmisha, R. Liu and S. Tchertchian,
J. Am. Chem. Soc., 2003, 125, 5642; (b) E. P. Ku¨ndig, M. Laxmisha,
R. Cannas, S. Tchertchian and R. Liu, Helv. Chim. Acta, 2005, 88,
1063.
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The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 342–351 | 351
©