Synthesis of Azulenone Skeletons by Reaction of 2-Phenyl-2-acylketenes [RCO(Ph)C=C=O] with Alkynyl Ethers: Mechanistic Aspects and Further Transformations

Article abstract of DOI:10.1021/jo9719315

A method is described for a mild and efficient synthesis of azulenone skeletons via the addition reactions of 2-phenyl-2-acylketenes with 1-alkynyl ethers. A mechanism is presented to account for both azulenone formation as well as the solvent and substrate dependency of a competitive pyrone formation. The azulenone rings have been subsequently transformed into both substituted azulenes or hydroazulenes by derivatization and/or decarboxylation of an angular carboxyl substituent or by hydrogenation.

Full text of DOI:10.1021/jo9719315

1630
J . Org. Chem. 1998, 63, 1630-1636
Syn th esis of Azu len on e Sk eleton s by Rea ction of
2-P h en yl-2-a cylk eten es [RCO(P h )CdCdO] w ith Alk yn yl Eth er s:
Mech a n istic Asp ects a n d F u r th er Tr a n sfor m a tion s
Dean G. Brown,† Thomas R. Hoye,† and Ronald G. Brisbois*,‡
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, and
Department of Chemistry, Hamline University, St. Paul, Minnesota 55104
Received October 20, 1997
A method is described for a mild and efficient synthesis of azulenone skeletons via the addition
reactions of 2-phenyl-2-acylketenes with 1-alkynyl ethers. A mechanism is presented to account
for both azulenone formation as well as the solvent and substrate dependency of a competitive
pyrone formation. The azulenone rings have been subsequently transformed into both substituted
azulenes or hydroazulenes by derivatization and/or decarboxylation of an angular carboxyl
substituent or by hydrogenation.
In tr od u ction
In the course of our investigations of acylketene/
alkynyl ether reactivity directed toward the synthesis of
γ-pyrones,5 we have observed that arylacylketenes 5 react
like diarylketenes (cf. 1) to yield azulenone derivatives
6 (Table 1). This result intrigued us because of the
potentially greater synthetic versatility offered by the
angular acyl substituent in 6 (vis-a`-vis the aryl substitu-
ent present in 4). Herein we report our initial results
on the scope of arylacylketene/alkynyl ether reactions,
as well as various transformations of the azulenone
products.
Reaction of diarylketenes 1 with alkynyl ethers 2 is
known to produce azulenone derivatives 4.1 Previous
work has focused primarily on the aromatic substituent
effects (i.e. R1 vs R2) in the competing formation of
postulated norcaradiene derivatives 3,2 which undergo
ring-opening expansion to 4. The formation of norcara-
diene derivatives 3 has been discussed as a symmetry-
allowed [πa + πa + πs2] cycloaddition.1c,3 Despite the
relative ease with which this tandem cycloaddition/
electrocyclic opening accesses azulenone derivatives, its
synthetic potential appears to have gone largely unex-
plored.4 This is likely a function of the angular aryl
moieties present in 4, which impose limits on the options
available for further modification of the azulenone skel-
eton.
2
2
Resu lts a n d Discu ssion
Su bstitu en t Effects in Keten e 5. At the outset of
our studies, the series of ketenes 5a -c, derived from
thermolysis of the diazoketones 7a -c,6 as well as the
stable ketene acid chloride 5d 7 were reacted with 1-meth-
oxy-1-butyne (2a ). The nature of the acyl moiety in 5
plays a critical role in controlling the efficiency of
azulenone 6 formation (Table 1), which is always ac-
companied by one or more competing reactions. These
include competitive pyrone formation and decarboxyla-
tion [e.g., to form PhCH2PO(OMe)2]. As judged by
independent trapping experiments with methanol, ketenes
5a and 5b (entries 1 and 2) are the sole Wolff rearrange-
ment products8 accompanying decomposition of 7a and
7b. In the case of entry 3, however, 5c is one of two
ketenes generated in approximately equal amounts be-
cause the migratory aptitudes for phenyl vs methyl are
approximately equal.9 Ketene 5c is the only one that can
give rise to 6c. The increasing selectivity for azulenone
formation vis-a`-vis pyrone formation for 5c vs 5a (entries
3 vs 1) suggested that the selectivity for azulenone
† University of Minnesota.
‡ Hamline University.
(1) (a) Nieuwenhuis, J .; Arens, J . F. Rec. Trav. Chem. 1958, 77, 761.
(b) Vieregge, H.; Bos, H. J . T.; Arens, J . F. Rec. Trav. Chem. 1959, 78,
664. (c) J enny, E. F.; Schenker, K.; Woodward, R. B. Angew. Chem.
1961, 73, 756.
(2) Teufel, H.; J enny, E. F. Tetrahedron Lett. 1971, 21, 1769.
(3) Direct evidence of norcaradienes derived from naphthylketenes
and ethoxyacetylene has been reported: Wuest, J . D. Tetrahedron
1980, 36, 2291.
(5) We have also studied the (formal) [4 + 2] cycloaddition reactions
of nonaryl substituted acylketenes with alkynyl ethers to generate
γ-pyrones. These results will be published elsewhere.
(6) Baum, J . S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
(7) Nakanishi, S.; Butler, K. Org. Prep. Proc. Intl. 1975, 7, 155-
158.
(8) For characterization of ketene 5b, see: Tomioka, H.; Komatsu,
K.; Shimizu, M. J . Org. Chem. 1992, 57, 6216.
(9) Meier, H.; Zeller, K.-P. Angew. Chem., Int. Ed. Engl. 1975, 14,
32.
(4) (a) Barton, D. H. R.; Gardner, J . N.; Petterson, R. C.; Stamm,
O. A. J . Chem. Soc. 1962, 2708. (b) Druey, J .; Schenker, K.; Woodward,
R. B. Helv. Chim. Acta 1962, 71, 600.
S0022-3263(97)01931-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/11/1998

Synthesis of Azulenone Skeletons
J . Org. Chem., Vol. 63, No. 5, 1998 1631
Ta ble 1. In flu en ce of Acyl Su bstitu en t on th e Efficien cy of Azu len on e F or m a tion
a
Reactions were performed on a ca. 10-100 mg scale in a capped culture tube behind a blast shield at the indicated bath temperature.
As judged by diagnostic 1H NMR (CDCl3) signals for vinylic protons at 5.8-6.6 ppm and GC-MS data (tR ) 9.98 min) at 274 (6, M+),
b
201 (100, M+ - CO2Et), 171 (9), and 115 (6). c No pyrone resonances were observed in the H NMR spectrum of the crude product mixture
1
for the reaction performed in CH2Cl2. The 6d :R-pyrone ratio was 6:1 when the reaction was performed in benzene.
Ta ble 2. Solven t Effect on Azu len on e vs r-P yr on e
formation increases with greater electron-withdrawing
F or m a tion
ability of the acyl moiety. Therefore, we turned to the
use of (chlorocarbonyl)phenylketene 5d . Consistent with
this hypothesis, 5d gave the highest ratio of azulenone/
pyrone formation of any of the ketenes studied (entry 4).
The 70% yield of 6d and the mild reaction conditions (0
°C) render this reaction preparatively useful.10 All
subsequent studies were therefore carried out with
ketene 5d and products derived therefrom.
Solven t Effects. Nearly all of the byproducts ob-
served for the reactions of 5a , 5c, and 5d with 2a (Table
1) were either R- or γ-pyrones.5 We explored the solvent
effect on the efficiency of formation of azulenone 8 vis-
a`-vis the R-pyrone 9 (Table 2) using (chlorocarbonyl)-
phenyl ketene (5d ) and ethoxyacetylene (2b). The ratio
of 8 to 9 can be modulated somewhat (i.e., by about a
factor of 3) by the choice of solvent. Specifically, more
polar solvents support the formation of 8 (entry 1),
whereas less polar solvents suppress formation of 8
(entries 3 and 4). For substituted analogues of ethoxy-
acetylene (2a ), the ratio of azulenone to pyrone formation
is even greater (e.g., entry 4, Table 1), occasionally even
to the exclusion of pyrone formation. Finally, the result
a
b
As determined by 1H NMR analysis. 48% isolated yield of 8.
in entry 2 is notable because it adds to the repertoire of
reactions for which Curran and co-workers have reported
R,R,R-trifluorotoluene to be an adequate, higher boiling,
less toxic substitute for dichloromethane.11
Mech a n ism . As noted above, previous reports on
diarylketene/alkynyl ether reactions have postulated
formation of an intermediate norcaradiene derivative 3
formed via a symmetry-allowed [πa + πa + πs ]
cycloaddition.1c,3 Subsequent ring-opening leads to the
azulenone products. Although our primary interest has
been the exploration of synthetic aspects of these azule-
none products 6, the substituent (Table 1) and solvent
(10) Another example that demonstrates the variety of azulenone
acid chlorides that can be prepared by this route is compound 6e
containing a functional side chain, which was prepared from the
bromopentynyl ether i and 5d . Once again, the analogous γ-pyrone
was not observed (6e/pyrone > 19:1).
2
2
2
(11) Ogawa, A.; Curran, D. P. J . Org. Chem. 1997, 62, 450.

1632 J . Org. Chem., Vol. 63, No. 5, 1998
Brown et al.
Sch em e 1
(Table 2) effects and the competing pathways to pyrone
formation invite mechanistic speculation. Perhaps in the
reactions of arylacylketenes 5 and alkynyl ethers 2 a
stepwise rather than concerted process may be operating
to lead to the norcaradiene precursor 3 (Scheme 1). We
speculate that initial attack of 2 on 5 gives rise to
zwitterionic intermediate 10.
the phenyl ring, which should be less affected by the
electronic character of the substituent R.5 In other
words, cyclization of 10a to 3 would be expected to occur
at more or less similar rates for each of the various R5
groups. The presence of the chlorine atom therefore is
envisioned to slow pyrone formation more than azulenone
formation, consistent with the observed trend in sub-
stituent effects.
Rotamers of zwitterion 10 capable of cyclization to
either azulenone (from 10a ) or pyrone (10b) products are
considered in Scheme 1. Each can exist as two enolate
geometric isomers (O-Z and O-E). Either 10a (O-Z) or
10a (O-E) could cyclize to norcaradiene intermediate 3.
γ-Pyrones 11 could arise directly via 10b(O-Z) by in-
tramolecular O-acylation. R-Pyrones 13 could arise from
cyclobutenones 12,12 formed by C-acylation within 10b.
A plausible argument can be offered to account for the
observed solvent effects. Recall that azulenone formation
was suppressed in highly nonpolar solvents (Table 2).
Rotamers 10a , the azulenone precursors, should have a
larger dipole moment than 10b, the pyrone precursors.
Thus, the equilibrium population of 10a relative to 10b
should be higher in methylene chloride than in, e.g.,
cyclohexane, consistent with the observed product ratios
(entries 1 vs 4).
Consider the effect of changing the substituent R5 in
ketene 5. The most electron-withdrawing chlorine atom
in 5d resulted in the greatest preference for the norcara-
diene/azulenone pathway compared with the ethoxy and
methyl substituents present in 5a and 5c (Table 1). The
nucleophilicity of the enolate-like character in zwitterions
10 is attenuated when R5 ) Cl. Therefore, O-acylation
of 10b(O-Z) to give γ-pyrone 11 as well as C-acylation
of 10b to give cyclobutenone/R-pyrone 12/13 should be
suppressed. On the other hand, cyclization of 10a to 3
is initiated by intramolecular, electrophilic acylation of
Rea ction s of Azu len on es 6. We have studied three
types of reactions that transform azulenones 6 into
products of further interest. These involve substitution
of the acid chloride at C(8a), deacylation of the COCl
group, and some selective hydrogenation reactions of
alkenes in the cycloheptatriene moiety.
The acid chloride in azulenones 6 was reacted with
alcohols and amines to give the corresponding ester and
amide derivatives (Table 3). This could be done either
starting from isolated 6 (entry 1) or, more conveniently,
in a one-pot procedure in which 5d is reacted sequentially
with the appropriate alkynyl ether and trapping nucleo-
phile (entries 2-6). A single-crystal X-ray structure of
azulenone 14f was obtained, providing confirmation of
the core skeletal structure of azulenones 6 and 14.13
Methyl ester 14a was the sole product isolated upon
methanolysis of 6d using triethylamine as the basic
catalyst. However, when Hu¨nig’s base was used, the
reaction solution took on an intense dark blue color. The
azulene 15 was isolated as a minor product accompanying
(12) For examples of cyclobutenones formed via alkynyl ethers and
ketenes see: (a) Wasserman, H. H.; Piper, J . U.; Dehmlow, E. V. J .
Org. Chem. 1973, 38, 1451. (b) Danheiser, R. L.; Gee, S. K.; Sard, H.
J . Am. Chem. Soc. 1982, 104, 26.
(13) The authors have deposited atomic coordinates for 14f with the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, U. K.

Synthesis of Azulenone Skeletons
J . Org. Chem., Vol. 63, No. 5, 1998 1633
Ta ble 3. P r ep a r a tion of 8a -Su bstitu ted Azu len on e
Ester s a n d Am id es
ucts. These results demonstrate that 1-acetoxy-3-
alkoxyazulene derivatives 17 are indeed accessible, in
reasonable yields, in two steps from readily available
starting materials.
As demonstrated by Barton et al.,4 azulenones can be
selectively hydrogenated to various hydroazulenone ana-
logues. Similarly, we have reduced 14a by catalytic
hydrogenation over 10% palladium on carbon to give the
hydroazulenones 18a and 19a in a 2:1 ratio. The relative
stereochemistry of the ring fusion was assigned by
comparing the experimentally determined coupling con-
stants for H(3a) with calculated values. Thus, a Monte
Carlo based conformational search using the MM2* force
field as implemented in MacroModel14 (version 6.0) was
used to generate a conformer family containing all
geometries within 50 kJ /mol of the global minimum for
each of the diastereomers. The Boltzmann weighted,
calculated, vicinal coupling constants for H(3a) matched
well the experimental values [18a : J 3a/4R(calc vs exp) )
5.3 vs 6.0 Hz and J 3a/4â(calc vs exp) ) 11.3 vs 11.5 Hz.
19a : J 3a/4R(calc vs exp) ) 10.3 vs 9.2 Hz and J 3a/4â(calc
vs exp) ) 2.1 vs 2.7 Hz]. The analogue 14d , which lacks
a substituent at C(2), was similarly reduced and also gave
the hexahydro azulenones 18b and 19b, this time in a
3:1 ratio. On the basis of these and related15 results, this
methodology could serve as a convenient access to hy-
droazulenone natural products skeletons.
14a . This intriguing result demonstrated the potential
for mild removal of the angular acyl moiety in azulenones
6, rendering 1,3-hydroxy azulene derivatives accessible
in two steps from readily available precursors.
Initial attempts to deacylate azulenones 6 and obtain
free 1-hydroxyazulenes by a simple hydrolysis/decarboxy-
lation strategy were unsuccessful. Although dramatic
color changes rapidly accompanied the reaction of 6e or
8 with water, only the coupled azulene/azulenone prod-
ucts 16a and 16b were isolated. We next conducted the
Exp er im en ta l Section
Ma ter ia ls. CH2Cl2 was distilled from CaH2, diethyl ether
from sodium benzophenone. All reaction vessels were flame-
dried under vacuum and back-filled with nitrogen, and all
reactions were carried out under a N2 atmosphere. All diazo
(14) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440.
(15) In one instance, when the hydrogenation was carefully moni-
tored, the tetrahydroazulenone ii was cleanly produced, implying that
the disubstituted alkenes are reduced quickly, the trisubstituted C(3a)-
C(4) alkene slowly, and the C(2)-C(3) vinylogous ester alkene very
slowly (if at all). An additional transformation of 18b/19b is also
relevant. Gassman hydrolysis (Gassman, P. G.; Schenk, W. N. J . Org.
Chem. 1977, 42, 918) was accompanied by decarboxylation to give iii
as a single diastereomer. ii: 1H NMR (CDCl3, 200 MHz) δ 1.19-1.23
(m, 2H), 1.45 (t, 3H, J ) 7.0 Hz), 1.76-1.82 (m, 2H), 1.90-1.94 (m,
2H), 2.32-2.37 (m, 1H), 2.48-2.53 (m, 1H), 3.71 (s, 3H), 4.08-4.14 (m,
2H), 5.37 (s, 1H), and 6.59 (dd, 1H, J ) 8.9, and 5.0 Hz); LRMS (EI,
70 eV) m/z (rel int) 250 (68), 191 (52), 190 (100), 163 (26), 69 (52). iii:
1H NMR (300 MHz, CDCl3) δ 1.22-1.26 (m, 2H), 1.32-1.36 (m, 2H),
1.40 (t, 3H, J ) 7.0 Hz), 1.52-1.69 (m, 4H), 1.96-2.00 (m, 2H), 2.63
(ddd, 1H, J ) 10.5, 6.0, 3.5 Hz), 2.98 (dddd, 1H, J ) 10.5, 7.0, 3.7, 1.3
Hz), 3.96-4.02 (m, 2H), 5.26 (s, 1H); IR (CDCl3) 1711 (s), 1224 (m);
MS (EI, 70 eV): m/z (rel int) 194 (30, M+), 179 (30), 151 (25), 139 (100),
111 (24).
deacylation of 6 in the presence of trapping agents for
the transient 1-hydroxyazulene intermediates that are
implicated by the formation of products 16. Use of
DMAP/acetic anhydride (5 equiv) provided 1-acetoxy-3-
alkoxyazulenes 17a and 17b as the predominant prod-

1634 J . Org. Chem., Vol. 63, No. 5, 1998
Brown et al.
compounds were prepared using p-acetamidobenzenesulfonyl
azide as the diazo transfer reagent following the protocol of
Davies (Et3N, MeCN, 0 °C to rt, ∼4 h).6 Each has been
prepared previously by alternative methods: ethyl 2-diazoac-
etoacetate (7a ),16 dimethyl (1-diazo-2-oxo-2-phenyl)ethylpho-
sponate (7b),17 and 2-diazo-1-phenyl-1,3-butanedione (7c).18
ethyl acetate) to give 6c as a yellow oil (0.025 g, 20%): 1H NMR
(500 MHz, CDCl3) δ 1.07 (t, 3H, J ) 7.5 Hz), 2.19 (s, 3H), 2.46
(q, 2H, J ) 7.5 Hz), 4.22 (s, 3H), 6.14 (d, 1H, J ) 10.0 Hz),
6.31 (dd, 1H, J ) 10, 6.5 Hz), 6.34 (dd, 1H, J ) 11.0, 6.5 Hz),
6.44 (dd, 1H, J ) 11.0, 6.5 Hz), 6.66 (d, 1H, J ) 6.5 Hz); 13C
NMR (CDCl3, 125.69 MHz) δ 14.81, 16.71, 26.39, 58.84, 69.38,
118.76, 119.63, 127.87, 128.14, 129.61, 130.62, 133.18, 174.03,
5-Br om o-1-eth oxy-1-p en tyn e.19 To a cold (0 °C) stirred
solution of ethoxyacetylene (7.13 mmol, 0.500 g of a 50 wt %/wt
solution in hexanes) in THF was slowly added n-BuLi (7.13
mmol, 2.97 mL, 2.4 M). After 30 min, 1,3-dibromopropane
(1.43 g, 0.73 mL, 7.13 mmol, purified by passing through Al2O3)
was added. This solution was allowed to warm to room
temperature and stirred overnight. Solvent was removed in
vacuo, and the product purified by silica gel chromatography
(SiO2, 95/5 hexanes/ethyl acetate; Rf ) 0.80 in 95/5 hexanes/
ethyl acetate and 0.35 in hexanes) and then again with
hexanes as the eluent (colorless oil, 0.420 g, 31%): 1H NMR
(300 MHz, CDCl3) δ 1.35 (t, 3H, J ) 7.0 Hz), 2.00 (tt, 2H, J )
7.0, 6.6 Hz), 2.29 (t, 2H, J ) 6.6 Hz), 3.55 (t, 2H, J ) 6.6 Hz),
and 4.06 (q, 2H, J ) 7.0 Hz); IR (neat) 2258 (s) and 1224 (s)
196.97, 200.25; IR (CDCl3) 1719 (m), 1686 (s), 1585 (s) cm-1
.
Anal. Calcd for C15H16O3: C; 73.75, H: 6.60. Found: C, 73.74;
H: 6.57.
(()-2-E t h yl-1,8a -d ih yd r o-3-m et h oxy-1-oxo-8a -a zu len -
ca r boxylic Acid Ch lor id e (6d ). To a cold (0 °C) stirred
solution of chloroketene 5d 7 (0.075 g, 0.415 mmol) in CH2Cl2
(5 mL) was added 1-methoxy-1-butyne (2a , 0.052 g, 0.623
mmol) in CH2Cl2 (5 mL) over 30 min. The mixture was allowed
to stir at room temperature for 5 h, at which time the solution
had turned slightly green. The solvent was removed in vacuo
and 6d was isolated by column chromatography (SiO2, Rf )
0.30 in 70/30 hexanes/ethyl acetate) as a yellow oil (0.109 g,
70%): 1H NMR (CDCl3, 300 MHz) δ 1.10 (t, 3H, J ) 7.5 Hz),
2.50 (q, 2H, J ) 7.5 Hz), 4.25 (s, 3H), 5.92 (d, 1H, J ) 9.9 Hz),
6.40-6.57 (m, 3H), 6.69 (d, 1H, J ) 6.0 Hz); 13C NMR (CDCl3,
75.4 MHz) δ 14.54, 16.85, 59.11, 69.13, 119.96, 120.40, 126.38,
129.06, 130.15, 131.26, 132.12, 169.13, 174.34, 194.32; IR
cm-1
.
1-Meth oxy-5-p h en yl-1-p en tyn e.20 A flame-dried three
neck flask was fitted with a glass-paddled mechanical stirrer
and oil bubbler and charged with freshly ground Fe(NO3)3‚
9H20 (∼500 mg). The flask was cooled (-78 °C) and anhydrous
ammonia was condensed (∼300 mL). Freshly shaved sodium
(5.97 g, 26 mmol) was slowly added over 30 min. After sodium
amide was formed (∼4 h, indicated by color change from blue
to gray), chloroacetaldehyde dimethyl acetal (10.0 g, 80 mmol,
freshly distilled) was added via syringe, and the mixture was
stirred an additional 90 min. To this was added 1-bromo-3-
phenylpropane (14.33 g, 70 mmol) and the suspension stirred
for 4 h. The flask was removed from the cold bath and the
mixture was carefully quenched with saturated NH4Cl (50
mL). Pentane (300 mL) was added followed by an additional
portion of saturated NH4Cl (150 mL). The pentane layer was
removed, washed with brine, and dried over MgSO4. Removal
of pentane by careful distillation led to a yellow oil. Bulb-to-
bulb distillation (bath temp ) 60-100 °C at 12 mmHg) of this
material led to the crude alkynyl ether. Further purification
by flash chromatography (SiO2, 1% ethyl acetate in hexanes)
gave pure 1-methoxy-5-phenyl-1-pentyne (4.2 g, 32%): 1H
NMR (CDCl3, 200 MHz) δ 1.80 (tt, 2H, J ) 6.9 Hz), 2.16 (t,
2H, J ) 6.9 Hz), 2.73 (t, 2H, J ) 7.0 Hz), 3.82 (s, 3H), 7.17-
7.31 (m, 5H); 13C NMR (CDCl3, 50.32 MHz) δ 16.58, 31.19,
34.76, 35.87, 65.33, 91.37, 125.71, 128.25, 128.48, 141.95; IR
(neat) 3026 (m), 2941 (s), 2272 (s), 1244 (s) cm-1. Anal. Calcd
for C12H14O: C, 82.72; H, 8.10. Found: C, 82.70; H, 7.96.
(neat) 1795 (s), 1699 (m), 1584 (s) cm-1; HRMS calcd for C14H13
-
ClO3 264.0553, found 264.0563. Anal. Calcd for C14H13ClO3:
C, 63.52; H, 4.95. Found: C, 63.68; H, 5.05.
(()-3-Eth oxy-1,8a -d ih yd r o-1-oxo-8a -a zu len eca r boxyl-
ic Acid Ch lor id e (8) a n d 6-Ch lor o-4-eth oxy-5-p h en yl-2H-
p yr a n -2-on e (9). To a cold (0 °C) stirred solution of chlo-
roketene 5d (0.179 g, 0.99 mmol) in CH2Cl2 (5 mL) was added
ethoxyacetylene (0.166 mL of a 50 wt %/wt solution in hexanes,
1.1 mmol) in CH2Cl2 (5 mL) over 30 min. The mixture was
allowed to stir at room temperature for 5 h, at which time the
solution had turned slightly green. The solvent was removed
in vacuo and purification by column chromatography (SiO2,
Rf ) 0.25 in 70/30 hexanes/ethyl acetate) gave, in order of
elution, 9 (0.042 g, 17%) and 8 (0.128 g, 48%) as yellow oils. 9:
1H NMR (CDCl3, 300 MHz) δ 1.46 (t, 3H, J ) 7.0 Hz), 4.28 (q,
2H, J ) 7.0 Hz), 5.59 (s, 1H), 7.28-7.37 (m, 5H); 13C NMR
(CDCl3, 125.69 MHz) δ 14.27, 65.87, 85.62, 115.71, 128.18,
128.25, 130.27, 132.35, 152.05, 159.18, 161.82; IR (KBr) 1728
(s), 1617 (m), 1544 (s), 1332 (s) cm-1. Anal. Calcd for C13H11
-
ClO3: C, 62.29; H, 4.42. Found: C, 61.51; H, 4.42. 8: 1H NMR
(200 MHz, CDCl3) δ 1.50 (t, 3H, J ) 7.0 Hz), 4.15-4.29 (m,
2H), 5.41 (s, 1H), 6.03 (d, 1H, J ) 9.4 Hz), 6.48-6.58 (m, 3H),
6.81-6.84 (m, 1H); 13C NMR (125.69 MHz, CDCl3) δ 14.14,
68.52, 70.14, 103.01, 121.29, 126.67, 128.76, 129.93, 130.53,
133.26, 169.24, 180.08, 192.92; IR (neat) 1792 (m), 1694 (s),
1567 (s), cm-1. The methyl ester derivative 14d (vide infra)
gave satisfactory HRMS data.
Dim et h yl (()-2-E t h yl-1,8a -d ih yd r o-3-m et h oxy-1-oxo-
8a -a zu len ep h osp h on a te (6b). Diazophosphonate 7b (0.07
g, 0.31 mmol) was heated with 1-methoxy-1-butyne (2a , 0.100
g, 0.87 mmol) in CH2Cl2 (2 mL) at 110 °C for 5 h. Solvent
was removed in vacuo, and products were purified by flash
chromatography (SiO2, ethyl acetate, Rf ) 0.25) to give 6b as
a yellow oil (0.009 g, 10%): 1H NMR (CDCl3, 500 MHz) δ 1.14
(t, 3H, J ) 7.5 Hz), 2.50 (dq, 1H, J ) 14.0, 7.5 Hz), 2.53 (dq,
1H, J ) 14.0, 7.5 Hz), 3.70 (d, 3H, J ) 11.0 Hz), 3.72 (d, 3H,
J ) 11.0 Hz), 5.79 (dd, 1H, J ) 10.3, 5.0 Hz), 6.13-6.18 (m,
1H), 6.29-6.35 (m, 2H), 6.57 (dd, 1H, J ) 7.8, 2.5 Hz); IR
(CDCl3) 1734 (s), 1696 (s), 1592 (s), 1035 (m) cm-1; HRMS (EI)
calcd for C15H19O5P 310.0971, found 310.0975.
(()-2-(3-Br om op r op yl)-3-eth oxy-1,8a -d ih yd r o-1-oxo-8a -
a zu len ca r boxylic Acid Ch lor id e (6e). To a cold (0 °C)
stirred solution of chloroketene 5d (0.123 g, 0.684 mmol) in
CH2Cl2 (5 mL) was added 1-ethoxy-5-bromo-1-pentyne (0.156
g, 0.82 mmol) in CH2Cl2 (5 mL) over 30 min. The mixture
was allowed to stir at room temperature for 5 h, at which time
the solution had turned slightly green. MPLC (80/20 hexanes/
ethyl acetate, Rf ) 0.25 in 1:1 hexanes/ ethyl acetate) provided
6e (0.127 g, 50%) as a yellow oil: 1H NMR (CDCl3, 300 MHz)
δ 1.48 (t, 3H, J ) 7.0 Hz), 2.08-2.11 (m, 2H), 2.53-2.72 (m,
2H), 3.44 (t, 2H, J ) 6.2 Hz), 4.51-4.63 (m, 2H), 5.90 (d, 1H,
J ) 9.3 Hz), 6.44-6.49 (m, 1H), 6.49-6.59 (m, 3H), 6.76 (d,
1H, J ) 5.8 Hz); 13C NMR (CDCl3, 125.69 MHz) δ 13.92, 15.34,
22.20, 33.27, 61.67, 67.70, 115.39, 116.75, 118.56, 118.70,
126.87, 128.45, 131.86, 135.41, 167.25, 174.06, 197.68; IR
(CDCl3) 1733 (s), 1694 (m), 1583 (s) cm-1; HRMS (EI) calcd
for C16H16BrCO2 (M+ loss of ClCO) 309.0335, found 309.0333.
Meth yl (()-2-Eth yl-1,8a -d ih yd r o-3-m eth oxy-1-oxo-8a -
a zu len eca r boxyla te (14a ). To a cold (0 °C) stirred solution
of azulene 6d (0.80 g, 0.45 mmol) in CH2Cl2 (5 mL) was added
MeOH (0.015 g, 0.49 mmol), followed by DMAP (0.050 g, 0.40
mmol). This solution was stirred at room temperature for an
additional 90 min. The solvents were then removed in vacuo,
and the resultant green oil was subjected to column chroma-
(()-1-(8a H )-2-E t h yl-3-m et h oxy-8a -(1-oxoet h yl)a zu le-
n on e (6c). 2-Diazobenzoylacetone (7c, 0.100 g, 0.53 mmol)
was heated with 1-methoxy-1-butyne (2a , 0.100 g, 1.06 mmol)
in CH2Cl2 (2 mL) at 110 °C for 5 h. Solvent was removed in
vacuo and the residue was purified by MPLC (80/20 hexanes/
(16) Saba, A. Synth. Commun. 1994, 24, 695.
(17) Regitz, M.; Martin, R. Tetrahedron 1985, 41, 819.
(18) Regitz, M.; Liedhegener, A. Chem. Ber. 1966, 99, 3128.
(19) See Pons, J .-M.; Kocienski, P. Tetrahedron Lett. 1989, 30, 1833
for a general procedure for alkylation of lithioethoxyacetylene.
(20) For a general procedure for in situ generation and alkylation
of alkoxy acetylides, see: Newman, M. S.; Geib, J . R.; Stalick, W. M.
Org. Prep. Proc. Intl. 1972, 4, 89.

Synthesis of Azulenone Skeletons
J . Org. Chem., Vol. 63, No. 5, 1998 1635
tography (Rf ) 0.25 in 70/30 hexanes/ethyl acetate) to give 14a
as a yellow oil (0.076 g, 65%): 1H NMR (CDCl3, 300 MHz) δ
1.05 (t, 3H, J ) 7.5 Hz), 2.49 (q, 2H, J ) 7.5 Hz), 3.57 (s, 3H),
4.19 (s, 3H), 5.95 (d, 1H, J ) 10.0 Hz), 6.33 (dd, 1H, J ) 10.0,
5.5 Hz), 6.41 (dd, 1H, J ) 10.5, 6.0 Hz), 6.44 (dd, 1H, J ) 11.0,
5.5 Hz), 6.60 (d, 1H, J ) 6.0 Hz); 13C NMR (CDCl3, 75.4 MHz)
δ 14.8, 16.9, 52.9, 59.1, 61.5, 118.6, 120.1, 127.1, 128.7, 128.9,
131.8, 131.9, 168.8, 173.8, 197.3; IR (neat) 1746 (s), 1696 (s),
1585 (s), 1362 (s), 1340 (s), 1232 (s) cm-1; HRMS (EI) calcd
for C15H16O4 260.1048, found 260.1028.
Meth yl (()-1,8a -Dih yd r o-3-m eth oxy-1-oxo-2-p r op yl-8a -
a zu len eca r boxyla te (14b). To a cold (0 °C) stirred solution
of chloroketene 5d (0.400 g, 2.2 mmol) in CH2Cl2 (15 mL) was
added 1-methoxy-1-pentyne (0.281 g, 2.8 mmol) in CH2Cl2 (5
mL) over 30 min. The mixture was allowed to stir at room
temperature for 5 h, at which time dry MeOH was added
(0.073 g, 0.092 mL, 2.3 mmol). The mixture was cooled again
(0 °C), and to this solution was added pyridine (0.183 g, 0.187
mL, 2.3 mmol) followed by DMAP (ca. 20 mg). The mixture
was stirred at room temperature for an additional 90 min. The
volatiles were then removed in vacuo, and the resultant green
oil was subjected to column chromatography (Rf ) 0.25 in 70/
30 in hexanes/ethyl acetate) to give 14b as a yellow oil (0.35
g, 58%): 1H NMR (CDCl3, 300 MHz) δ 0.92 (t, J ) 3H, 7.3
Hz), 1.42-1.58 (m, 2H), 2.41-2.46 (m, 2H), 3.58 (s, 3H), 4.18
(s, 3H), 5.94 (d, 1H, J ) 10.0 Hz), 6.33 (dd, 1H, J ) 10.0, 5.0
Hz), 6.41-6.48 (m, 2H), 6.50 (d, 1H, J ) 6.0 Hz); 13C NMR
(CDCl3, 75.47 MHz) δ 13.83, 23.58, 25.19, 52.82, 58.59, 61.16,
118.42, 118.64, 126.95, 128.54, 128.75, 131.68, 131.90, 168.05,
174.25, 197.44; IR (neat) 1746 (s), 1695 (s), 1585 (s), 1365 (s),
1335 (s), 1232 (s) cm-1. Anal. Calcd for C16H18O4: C, 71.31;
H, 6.34. Found: C, 71.11; H, 6.44.
Met h yl (()-1,8a -Dih yd r o-2-(3-p h en ylp r op yl)-3-m et h -
oxy-1-oxo-8a -a zu len eca r boxyla te (14c). To a cold (0 °C)
stirred solution of chloroketene 5d (0.200 g, 1.10 mmol) in CH2-
Cl2 (15 mL) was added 1-methoxy-5-phenyl-1-pentyne (0.270
g, 1.55 mmol) in CH2Cl2 (5 mL) over 30 min. The mixture
was allowed to stir at room temperature for 5 h, at which time
dry MeOH was added (0.070 g, 2.2 mmol). The mixture was
cooled again (0 °C), and to this solution was added DMAP
(0.161 g, 1.31 mmol). The mixture was stirred at room
temperature for an additional 90 min. The volatiles were then
removed in vacuo, and the resultant green oil was subjected
to column chromatography (Rf ) 0.25 in 70/30 in hexanes/ethyl
acetate) to give 14c as a yellow oil (0.135 g, 35%): 1H NMR
(CDCl3, 300 MHz) δ 1.81 (m, 2H), 2.47 (t, 2H, J ) 8.0 Hz),
2.64 (t, 2H, J ) 7.5 Hz), 3.58 (s, 3H), 4.01 (s, 3H), 5.94 (d, 1H,
J ) 10.0 Hz), 6.32 (dd, 1H, J ) 5.5, 10.0 Hz), 6.42 (dd, 1H, J
) 10.0, 5.5 Hz), 6.45 (dd, 1H, J ) 10.0, 6.0 Hz), 6.58 (d, 1H, J
) 5.5 Hz), 7.16-7.25 (m, 5H); 13C NMR (125.69 MHz, CDCl3)
δ 22.78, 31.68, 35.46, 52.82, 58.79, 61.13, 118.28, 118.54,
125.86, 126.88, 128.30, 128.40, 128.55, 128.70, 131.78, 131.79,
141.68, 167.96, 174.23, 197.39; IR (CDCl3) 1746 (s), 1694 (s),
1584 (s), 1231 (m) cm-1. Anal. Calcd for C22H22O4: C, 75.41;
H, 6.33. Found: C, 74.93; H, 6.24.
Met h yl (()-3-E t h oxy-1,8a -d ih yd r o-1-oxo-8a -a zu len e-
ca r boxyla te (14d ). To a cold (0 °C) stirred solution of
chloroketene 5d (0.778 g, 4.3 mmol) in CH2Cl2 (50 mL) was
added ethoxyacetylene (0.391 g of a 50 wt %/wt solution in
hexanes, 5.59 mmol) in CH2Cl2 (5 mL) over 30 min. The
mixture was stirred at room temperature for 5 h, at which
time dry MeOH was added (0.206 g, 6.45 mmol MeOH),
followed by Et3N (6.45 mmol, 0.652 g, 0.898 mL, 1.5 equiv)
and DMAP (ca. 50 mg). This was stirred at room temperature
for an additional 90 min. The volatiles were then removed in
vacuo, and the resultant green oil was subjected to column
chromatography (Rf ) 0.45 in 70/30 hexanes/ethyl acetate) to
give 14d as a yellow solid (mp 116-118 °C, 0.250 g, 25%): 1H
NMR (CDCl3, 200 MHz) δ 1.47 (t, 3H, J ) 7.0 Hz), 3.61 (s,
3H), 4.17-4.21 (m, 2H), 5.37 (s, 1H), 6.00 (d, 1H, J ) 9.8 Hz),
6.35-6.48 (m, 3H), 6.90 (d, 1H, J ) 5.0 Hz); 13C NMR (75.42
MHz, CDCl3) δ 14.19, 52.39, 62.27, 68.11, 102.74, 119.95,
127.15, 128.38, 128.44, 131.0, 132.85, 167.93, 179.86, 196.23;
IR (KBr) 1722 (m), 1689 (s), 1561 (s), 1031 (m) cm-1; HRMS
(EI) calcd for C14H14O4 246.0892, found 246.0889.
(4-Nitr oph en yl)m eth yl (()-2-Eth yl-1,8a-dih ydr o-3-m eth -
oxy-1-oxo-8a -a zu len eca r boxyla te (14e). To a cold (0 °C)
stirred solution of chloroketene 5d (0.350 g, 1.93 mmol) was
added 1-methoxy-1-butyne (2a , 0.163 g, 1.93 mmol) in CH2-
Cl2 (5 mL) over 30 min. The mixture was stirred at room
temperature for 5 h, at which time p-nitrobenzyl alcohol (0.236
g, 1.54 mmol) in CH2Cl2 (5 mL) was added, followed by DMAP
(0.235 g, 1.93 mmol). This was stirred at room temperature
for 3 h and the solvent removed in vacuo. The black residue
was subjected to chromatography (SiO2, 80/20 ethyl acetate/
hexanes, Rf ) 0.15 in 75/25 hexanes/ethyl acetate) to give 14e
(0.200 g, 27%) as a yellow solid (mp 135-137 °C): 1H NMR
(CDCl3, 300 MHz) δ 1.07 (t, 3H, J ) 7.5 Hz), 2.49 (q, 2H, J )
7.5 Hz), 4.20 (s, 3H), 5.13 (s, 2H), 5.97 (d, 1H, J ) 9.0 Hz),
6.34-6.41 (m, 3H), 6.61 (d, 1H, 6.0 Hz), 7.37 (d, 2H, J ) 8.6
Hz), 8.14 (d, 2H, J ) 8.6 Hz); 13C NMR (75.47 MHz, CDCl3) δ
14.38, 16.80, 58.94, 60.97, 65.49, 118.75, 119.92, 123.62,
126.73, 127.72, 128.71, 128.93, 131.57, 143.17, 147.52, 167.19,
174.04, 196.83; IR (CDCl3) 1739 (s), 1695 (s), 1585 (s), 1524
(s), 1348 (s) cm-1. Anal. Calcd for C21H19NO6: C: 66.14, H:
5.02, N: 3.67. Found: C, 66.05; H, 5.23, N, 3.49.
N-(4-Br om op h en yl) (()-2-Eth yl-1,8a -d ih yd r o-3-m eth -
oxy-1-oxo-8a -a zu len eca r boxa m id e (14f). To a cold (0 °C)
stirred solution of chloroketene 5d (0.300 g, 1.63 mmol) was
added 1-methoxy-1-butyne (2a , 0.139 g, 1.66 mmol) in CH2-
Cl2 (5 mL) over 30 min. The mixture was stirred at room
temperature for 5 h, at which time 4-bromoaniline (0.236 g,
1.54 mmol) in CH2Cl2 (5 mL) was added, followed by Et3N
(0.254 mL, 0.184 g, 1.82 mmol) and DMAP (0.060 g, 0.49
mmol). This mixture was stirred at room temperature for 3 h
and the solvent removed in vacuo. The residue was subjected
to chromatography (SiO2, 70/30 ethyl acetate/hexanes, Rf )
0.15 in 75/25 hexanes/ethyl acetate) to give 14f as a light
yellow solid [0.230 g, 35%, needles, mp 135-137 °C
(CH2Cl2/pentane)]: 1H NMR (300 MHz, CDCl3) δ 1.10 (t, 3H,
J ) 7.5 Hz), and 2.50 (q, 2H, J ) 7.5 Hz), 4.23 (s, 3H), 6.05-
6.09 (m, 1H), 6.37-6.39 (m, 1H), 6.52-6.61 (m, 1H), 6.77 (d,
1H, J ) 6.6 Hz), 7.35-7.78 (m, 5H), 7.78 (s, 1H); 13C NMR
(300 MHz, CDCl3) δ 14.84, 16.77, 58.97, 68.92, 109.97, 116.74,
119.45, 122.16, 126.03, 129.73, 130.51, 130.55, 131.76, 132.07,
136.81, 164.28, 174.26, 199.05; IR (CDCl3) 1687 (s), 1581 (s),
1516 (s) cm-1; HRMS (CI) calcd for C20H18BrNO3 [M + H]+
400.0548, found 400.0554.
2-(3-Br om op r op yl)-3-et h oxy-1-a zu len yl (()-2-(3-Br o-
m op r op yl)-3-et h oxy-1,8a -d ih yd r o-1-oxo-8a -a zu len eca r -
boxyla te (16a ). To a cold (0 °C) stirred solution of azulenone
acid chloride 6e (0.032 g, 0.08 mmol) in CH2Cl2 (10 mL) was
added Et3N (0.015 mL, 0.010 g, 0.10 mmol) and DMAP (0.001
g, 0.008 mmol). The mixture was stirred for 5 min and H2O
(0.015 mL, 0.86 mmol) added. After several minutes the
reaction color turned deep blue. The mixture was stirred at
room temperature for 5 h, the volatiles were removed in vacuo,
and the product was purified by chromatography (SiO2, Rf )
0.30 in 70/30 hexanes/ethyl acetate) to give 16a as a blue oil
(0.019 g, 70%): 1H NMR (CDCl3, 300 MHz) δ 1.41 (t, 3H, J )
6.9 Hz), 1.47 (t, 3H, J ) 6.9 Hz), 2.10-2.15 (m, 4H), 2.67-
2.77 (m, 3H), 3.38 (t, 2H, J ) 6.7 Hz), 3.45 (t, 2H, J ) 6.5 Hz),
3.71-3.73 (m, 1H), 4.09 (q, 2H, J ) 6.9 Hz), 4.55-4.58 (m,
2H), 6.09 (d, 1H, J ) 9.8 Hz), 6.44-6.47 (m, 1H), 6.61 (m, 2H),
6.77-6.81 (m, 1H), 6.86 (t, 2H, J ) 9.7 Hz), 7.38 (t, 1H, J )
9.8 Hz), 7.71 (d, 1H, J ) 9.7 Hz), 8.14 (d, 1H, J ) 9.6 Hz).21
3-Eth oxy-1-a zu len yl (()-3-Eth oxy-1,8a -d ih yd r o-1-oxo-
8a -a zu len eca r boxyla te (16b). To a cold (0 °C) stirred
solution of azulenone acid chloride 8 (0.070 g, 0.27 mmol) in
CH2Cl2 (10 mL) was added H2O (0.010 g, 0.55 mmol). The
mixture was stirred for 20 min, followed by the addition of
(21) Upon GC-MS analysis, this compound underwent thermal
cleavage to a smaller fragment to which we assign structure iv on the
basis of the its mass spectral data: LRMS 228 (35), 199 (100), 171
(83), 115 (24).

1636 J . Org. Chem., Vol. 63, No. 5, 1998
Brown et al.
Et3N (0.034 g, 0.046 mL, 0.33 mmol) and DMAP (ca. 5 mg).
After several minutes the reaction color turned deep blue. The
mixture was stirred at room temperature for 5 h, the volatiles
were removed in vacuo, and the product was purified by
chromatography (SiO2, 80/20 hexanes/ethyl acetate, Rf ) 0.25
in 70/30 hexanes/ethyl acetate) to give 16b as a blue oil (0.026
g, 45%): 1H NMR (CDCl3, 500 MHz) δ 1.43 (t, 3H, J ) 7.0 Hz),
1.50 (t, 3H, J ) 7.0 Hz), 4.14 (q, 2H, J ) 7.0 Hz), 4.19-4.34
(m, 2H), 5.44 (s, 1H), 6.19 (d, 1H, J ) 10.0 Hz), 6.48 (dd, 1H,
J ) 10.0, 5.5 Hz), 6.56-6.61 (m, 2H), 6.64 (t, 1H, J ) 9.5 Hz),
6.83 (dd, 1H, J ) 5.0, 2.5 Hz), 7.14 (s, 1H), 7.27 (t, 2H, J )
10.0 Hz), 7.78 (d, 1H, J ) 9.5 Hz), 8.12 (d, 1H, J ) 9.0 Hz);
13C NMR (CDCl3, 125.69 MHz) δ 14.19, 14.95, 62.48, 66.44,
68.21, 99.98, 109.26, 119.10, 119.17, 119.56, 120.22, 121.71,
127.13, 128.66, 128.80, 131.00, 133.10, 133.75, 134.15, 139.86,
140.50, 145.06, 165.80, 179.95, 195.83; IR (CDCl3) 1745 (m),
1695 (s), 1565 (s), 1032 (m) cm-1; UV [EtOH, λmax (log ꢀ)] 222
(3.4), 240 (4.13), 286 (4.28), 360 (3.49), and 368 (3.41) nm;
HRMS (FAB) calcd for C25H22O5 402.1467, found 402.1473.
2-E t h yl-3-m et h oxy-1-a zu len yl E t h a n oa t e (17a ). To a
cold (0 °C) stirred solution of azulenone acid chloride 6d (0.040
g, 0.15 mmol) in CH2Cl2 (5 mL) was added acetic anhydride
(0.078 g, 0.75 mmol), the mixture was stirred for 20 min, and
DMAP (0.021 g, 0.18 mmol) was added in one portion. The
reaction mixture quickly turned deep blue in color and was
stirred for 3 h. Solvent was removed in vacuo, and products
were purified by chromatography (SiO2, Rf ) 0.20 in 90/10
hexanes/ethyl acetate) to give 17a (0.28 g, 77%) as a blue oil:
1H NMR (CDCl3, 300 MHz): δ 1.30 (t, 3H, J ) 7.5 Hz), 2.44
(s, 3H), 2.83 (q, 2H, J ) 7. 5 Hz), 3.99 (s, 3H), 6.86 (t, 1H, J
) 9.6 Hz), 6.90 (t, 1H, J ) 9.3 Hz), 7.41 (t, 1H, J ) 9.9 Hz),
7.86 (t, 1H, J ) 9.6 Hz), 8.21 (t, 1H, J ) 9.6 Hz); 13C NMR
(CDCl3, 75.44 MHz): δ 13.46, 18.38, 20.64, 63.51, 120.67,
121.02, 122.15, 123.54, 130.71, 131.72, 132.70, 135.80, 137.76,
143.65, 169.93; IR (neat) 1767 (s), 1575 (m), 1198 (s) cm-1; UV
[EtOH, λmax (log ꢀ)] 240 (4.24), 284 (4.80), 336 (3.50), and 352
(3.67) nm. Anal. Calcd for C15H16O3: C, 73.75; H, 6.60.
Found: C, 74.02; H, 6.66.
3-Eth oxy-1-a zu len yl Eth a n oa te (17b). To a cold (0 °C)
stirred solution of chloroketene 5d (0.098 g, 1.08 mmol) in CH2-
Cl2 (15 mL) was added ethoxyacetylene (0.075 mL of a 50 wt
%/wt solution in hexanes, 5.59 mmol) in CH2Cl2 (5 mL) over
30 min, and the mixture was stirred for 6 h. The reaction was
cooled to 0 °C and acetic anhydride (2.71 mmol, 0.276 g, 5
equiv) added. After a few minutes, DMAP (0.55 mmol, 0.068
g, 1.01 equiv) was added in one portion, and the mixture
turned bright blue. This was stirred for an additional 2 h,
adsorbed onto SiO2, and chromatographed (SiO2, 90/10 hex-
anes/ethyl acetate) to provide 17b as a blue oil (Rf ) 0.25 in
90/10 hexanes/ethyl acetate, 0.050 g, 40%): 1H NMR (CDCl3,
300 MHz) δ 1.47 (t, 3H, J ) 7.0 Hz), 2.38 (s, 3H), 4.20 (q, 2H,
J ) 7.0 Hz), 6.60 (t, 1H, J ) 9.9 Hz), 6.67 (t, 1H, J ) 9.6 Hz),
7.28 (t, 1H, J ) 9.9 Hz), 7.90 (d, 1H, J ) 9.9 Hz), 8.16 (d, 1H,
J ) 9.0 Hz); 13C NMR (CDCl3, 75.44 MHz) δ 14.98, 21.02,
66.44, 109.34, 118.83, 118.92, 119.56, 121.69, 132.75, 133.80,
134.25, 139.91, 145.26, 169.23; IR (CDCl3) 1755 (s), 1581 (s),
1514 (s), 1374 (s), 1358 (s), 1219 (s), 1207 (s) cm-1; UV [EtOH,
by the addition of MeOH (0.031 mL, 0.024 g, 0.07 mmol). The
reaction was stirred for 12 h, and the volatiles were then
removed in vacuo. The resultant blue oil was subjected to
column chromatography (Rf ) 0.25 in 70/30 hexanes/ ethyl
acetate) to give 15 as a blue oil (0.015 g, 10%): 1H NMR
(CDCl3, 300 MHz) δ 1.30 (t, 3H, J ) 7.5 Hz), 2.86 (q, 2H, J )
7.5 Hz), 3.95 (s, 3H), 3.98 (s, 3H), 6.91 (t, 1H, J ) 9.8 Hz),
6.92 (t, 1H, J ) 9.8 Hz), 7.44 (t, 1H, J ) 10.0 Hz), 7.96 (d, 1H,
J ) 9.5 Hz), 8.21 (d, 1H, J ) 9.4 Hz).
Met h yl (()-(3a a ,8a b )- a n d (()-(3a a ,8a a )-2-E t h yl-
1,3a ,4,5,6,7,8,8a -octa h yd r o-3-m eth oxy-1-oxo-8a -a zu len e-
ca r boxyla te (18a a n d 19a ). Methyl ester 14a (0.165 g, 0.66
mmol) was dissolved in ethanol, and 10% Pd/C was added to
this solution. The reaction flask was fitted with a balloon filled
with H2, and the mixture was stirred for 24 h. The mixture
was filtered through Celite and the solvent was removed in
vacuo to provide crude diastereomers (0.150 g, crude 2:1).
Chromatographic purification (SiO2, 70/30 hexanes/ethyl ace-
tate) provided analytical samples of each. Major 18a : 1H NMR
(CDCl3, 500 MHz) δ 1.01 (t, 3H, J ) 7.5 Hz), 1.05-1.09 (m,
1H), 1.25 (ddd, J ) 1H, 13.8, 12.0, 5.5 Hz), 1.36 (ddd, 1H, J )
12.5, 12.0, 12.0 Hz), 1.62-1.69 (m, 2H), 1.81-1.97 (m, 3H),
1.93-1.96 (m, 1H), 2.35 (q, 2H, J ) 7.5 Hz,), 2.70 (ddd, J )
1H, 13.8, 5.0, 3.0 Hz), 2.98 (dd, 1H, J ) 11.5, 6.0 Hz), 3.65 (s,
3H), 4.13 (s, 3H); 13C NMR (CDCl3, 75.44 MHz) δ 14.96, 16.33,
23.28, 24.90, 26.11, 27.77, 48.75, 52.23, 58.80, 63.66, 115.98,
170.09, 184.04, 200.91; IR (CDCl3) 1733 (w), 1608 (s), 1347
(m) cm-1
. Anal. Calcd for C15H22O4: C, 67.64; H, 8.32.
Found: C, 67.04; H, 8.05. Minor 19a : 1H NMR (300 MHz,
CDCl3) δ 1.01 (t, 3H, J ) 7.5 Hz), 1.40-1.57 (m, 7H), 1.84-
1.95 (m, 2H), 2.30 (q, 2H, J ) 7.5 Hz), 2.33-2.39 (m, 1H), 3.42
(dd, J ) 1H, J ) 9.15, 2.7 Hz), 3.68 (s, 3H), 4.09 (s, 3H); 13C
NMR (CDCl3, 75.44 MHz) δ 14.35, 15.78, 25.30, 27.15, 28.81,
30.62, 31.22, 48.13, 52.75, 57.99, 63.33, 118.87, 172.65, 185.62,
201.75; IR (CDCl3) 1734 (w), 1616 (s) cm-1. Anal. Calcd for
C
15H22O4: C, 67.64; H, 8.32. Found: C, 67.07; H, 8.16.
Meth yl (()-(3a R,8a â)- a n d (()-(3a R,8a R)-(()-3-Eth oxy-
1,3a ,4,5,6,7,8,8a -oct a h yd r o-1-oxo-8a -a zu le n e ca r b oxy-
la te (18b a n d 19b). Methyl ester 14d (0.060 g, 0.2 mmol)
was hydrogenated according to the same procedure as for 14a .
The products (∼3:1 ratio of diastereomers by 1H NMR analysis
of the crude product mixture) were purified by MPLC (SiO2,
70:30 hexanes/ethyl acetate) to give a fraction containing a
2.5:1 ratio of major/minor diastereomers and a later fraction
containing a 9:1 ratio of major/minor diastereomers (60 mg
total recovery, 99% yield). Major 18b: 1H NMR (500 MHz,
CDCl3) δ 1.08-1.16 (m, 1H), 1.29-1.39 (m, 3H), 1.43 (t, J )
7.5 Hz, 3H), 1.61-1.66 (m, 1H), 1.67-1.71 (m, 1H), 1.83-1.94
(m, 2H), 2.01-2.10 (m, 1H), 2.71 (ddd, 1H, J ) 14.0, 5.0, 3.5
Hz), 3.12 (ddd, 1H), J ) 11.7, 5.8, 1.5 Hz), 3.70 (s, 3H), 4.04-
4.11 (m, 2H), 5.18 (d, J ) 1.5 Hz, 1H); 13C NMR (125.69 Hz,
CDCl3) δ 14.05, 22.59, 24.87, 26.00, 27.80, 31.94, 49.43, 52.40,
64.75, 68.00, 100.56, 170.01, 191.57, 199.99; IR (CDCl3) 1733
(s), 1688 (s), 1583 (s) cm-1. Anal. Calcd for C14H20O4: C, 66.64;
H, 7.99. Found: C, 66.78; H, 7.76. Minor 19b: 1H NMR (500
MHz, CDCl3) δ 1.43 (t, J ) 7.0 Hz, 3H), 1.60-2.01 (m, 9H),
2.27-2.32 (m, 1H), 3.53 (ddd, 1H, J ) 9.5, 3.5, 1.0 Hz), 3.71
(s, 3H), 4.04-4.14 (m, 2H), 5.25 (d, J ) 1.5 Hz, 1H).
λmax (log ꢀ)] 236 (4.06), 286 (4.51), 360 (3.56), 378 (3.51). Anal.
Calcd for C14H14O3: C, 73.03; H, 6.13. Found: C, 73.10; H,
5.82.
Ack n ow led gm en t. This work was supported by an
NSF-Presidential Faculty Fellowship to R.G.B. (CHE
9350393). We thank Dr. Victor G. Young, J r. (University
of Minnesota) for the X-ray crystallographic analysis.
2-Eth yl-3-m eth oxy-1-a zu len yl Meth yl Ca r bon a te (15).
To a cold (0 °C) stirred solution of azulenone 6d (0.100 g, 0.05
mmol) in CH2Cl2 (5 mL) were added ethyl diisopropylamine
(0.05 mmol, 0.071 g, 0.095 mL, 1 equiv) and DMAP (0.002
mmol, 0.013 g, 0.2 equiv). This was stirred for 10 min followed
J O9719315