Generation and trapping of N-acyliminium ions derived from isomunchnone cycloadducts. A versatile route to functionalized heterocycles

Article abstract of DOI:10.1021/jo981624e

A series of 2-diazo-N-hept-6-enoylmalonamides were prepared and treated with a catalytic amount of rhodium(II) perfluorobutyrate. The resultant carbenoids underwent facile cyclization onto the neighboring amide carbonyl oxygen atom to generate isomunchnone-type intermediates. Subsequent 1,3- dipolar cycloaddition across the pendant olefin afforded intramolecular cycloadducts in high yield. The cascade sequence is simple, direct, and extremely tolerant of structural diversity. Exposure of these cycloadducts to Lewis acids resulted in oxabicyclic ring opening. N-Acyliminium ions of wide structural variety can be easily generated by this sequence of reactions. Different cyclization pathways become available depending on the nature of the substituent group attached to the amide nitrogen. When the tethered group is electrophilic in nature, proton loss from the initially formed N- acyliminium ion occurs rapidly to give an acyl enamide which undergoes a subsequent cyclization at the electrophilic center.

Full text of DOI:10.1021/jo981624e

556
J . Org. Chem. 1999, 64, 556-565
Gen er a tion a n d Tr a p p in g of N-Acylim in iu m Ion s Der ived fr om
Isom u1 n ch n on e Cycloa d d u cts. A Ver sa tile Rou te to F u n ction a lized
Heter ocycles†
Michael A. Brodney‡ and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received August 11, 1998
A series of 2-diazo-N-hept-6-enoylmalonamides were prepared and treated with a catalytic amount
of rhodium(II) perfluorobutyrate. The resultant carbenoids underwent facile cyclization onto the
neighboring amide carbonyl oxygen atom to generate isomu¨nchnone-type intermediates. Subsequent
1,3-dipolar cycloaddition across the pendant olefin afforded intramolecular cycloadducts in high
yield. The cascade sequence is simple, direct, and extremely tolerant of structural diversity. Exposure
of these cycloadducts to Lewis acids resulted in oxabicyclic ring opening. N-Acyliminium ions of
wide structural variety can be easily generated by this sequence of reactions. Different cyclization
pathways become available depending on the nature of the substituent group attached to the amide
nitrogen. When the tethered group is electrophilic in nature, proton loss from the initially formed
N-acyliminium ion occurs rapidly to give an acyl enamide which undergoes a subsequent cyclization
at the electrophilic center.
N-Acyliminium ions can be considered to be one of the
Of the great variety of precursors used to create N-
acyliminium ions,15-18 the most widely employed are the
R-alkoxy amides and carbamates.19 These materials are
often stable compounds that readily undergo conversion
to N-acyliminium ions under a variety of acidic condi-
tions. Typically, these versatile systems are prepared
from the partial reduction of the corresponding carbonyl
group20 or oxidation of an amine under electrochemical21
or transition metal mediated conditions.22 Subsequent
N-acyliminium ion formation by Lewis or protic acids
followed by trapping with weak carbon nucleophiles
provides an exceptionally useful method for carbon-
carbon bond formation, in both intermolecular23 and
intramolecular24 cases.
more versatile carbon electrophiles for use in carbon-
carbon bond forming reactions.1-3 They have been ex-
tensively utilized as intermediates to produce a large
variety of structurally diverse nitrogen heterocycles.4-14
† This paper is dedicated to my good friend, George R. Newkome,
on the occasion of his 60th birthday.
‡ Recepient of a Graduate Fellowship from the Organic Chemistry
Division of the American Chemical Society (1997-1998) sponsored by
Dupont Merck Pharmaceutical Co.
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10.1021/jo981624e CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/06/1999

N-Acyliminium Ions
J . Org. Chem., Vol. 64, No. 2, 1999 557
Sch em e 1
Sch em e 2
(e.g., 1) has provided us with a uniquely functionalized
cycloadduct 2 containing a “masked” N-acyliminium
ion.25-26 Because we were interested in applying the
methodology toward the synthesis of nitrogen-containing
natural products,27 we embarked on a more systematic
investigation of the cycloaddition/N-acyliminium ion cy-
clization process. In particular, we were intrigued with
the notion of changing the reaction profile of the iso-
mu¨nchnone cycloadduct whereby the initially formed
N-acyliminium ion could be channeled into a different
product distribution, as this would significantly expand
the synthetic flexibility of this cascade sequence. We
reasoned that the electronic character of the group
tethered to the amido nitrogen should dictate the course
of the reaction. When a nucleophilic center is available
(R ) Nu), cyclization onto the initially generated N-
acyliminium ion 3 will be rapid thereby leading to lactam
4. On the other hand, if the tethered group possesses a
terminal site which is electrophilic in nature (i.e., R )
El), deprotonation of 3 should occur first and this will
favor formation of product 6, arising from attack of the
nucleophilic enamide present in 5 on the electrophilic
center of the tethered amide (Scheme 1).28 This report
presents the experimental details of the conversion of
isomu¨nchnone cycloadducts to N-acyliminium ions and
the internal trapping of these intermediates as a method
to prepare complex heterocyclic systems.
Rh(II)-catalyzed reaction of several unsaturated diazo
imides to first establish the propensity of these systems
to undergo the intramolecular cycloaddition reaction.
Construction of the prerequisite diazo imides necessary
for dipole generation started with commercially available
citronellic acid (7) (Scheme 2). By means of a modified
literature procedure, 7 was converted into 3-methyl-6-
hexenoic acid (8) by ozonolysis followed by a Wittig
olefination reaction.29 Treating citronellic or 3-methyl-
6-hexenoic acid with 1,1-carbonyldiimidazole and then
quenching with benzylamine afforded the corresponding
N-benzylamides in excellent yield.26 The amides were
subjected to N-malonylation,30 and the resulting imido
esters were treated with mesyl azide in the presence of
triethylamine31 to provide diazo imides 9 and 10. A
related set of reactions was used to prepare the N-â-
tosylethylamine (TSE)32 derivatives 13 and 14 from 8 and
hexenoic acid, respectively. The advantage of the TSE
group is that it can be readily deprotected upon treatment
with base.
Formation of the isomu¨nchnone dipole proceeded
smoothly when diazo imides 9, 10, 13, and 14 were
treated with rhodium(II) perfluorobutyrate in CH2Cl2 at
25 °C. After initial generation of the rhodium carbenoid
species, intramolecular cyclization occurs on the neigh-
boring carbonyl oxygen to form the mesoionic oxazolium
ylide. This dipole is the cyclic equivalent of a carbonyl
ylide and readily undergoes 1,3-dipolar cycloaddition
across the pendant olefinic π-bond. In all four cases, the
reaction provided the internal cycloadduct 11 (90%), 12
(90%), 15 (85%), and 16 (85%) as single diastereomers
resulting from endo cycloaddition with respect to the
dipole (Scheme 2). Assignment of the stereochemistry of
Resu lts a n d Discu ssion
We began our investigations of the sequential cycload-
dition-Mannich cyclization protocol by examining the
(25) Padwa, A.; Brodney, M. A.; Marino, J . P., J r.; Osterhout, M.
H.; Price, A. J . Org. Chem. 1997, 62, 67.
(26) Padwa, A.; Marino, J . P., J r.; Osterhout, M. H. J . Org. Chem.
1995, 60, 2704. Padwa, A.; Hertzog, D. L.; Nadler, W. R. J . Org. Chem.
1994, 59, 7072. Marino, J . P., J r.; Osterhout, M. H.; Price, A. T.;
Semones, M. A.; Padwa, A. J . Org. Chem. 1994, 59, 5518. Padwa, A.;
Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.; Price, A. T. J . Org.
Chem. 1994, 59, 1418. Hertzog, D. L.; Austin, D. J .; Nadler, W. R.;
Padwa, A. Tetrahedron Lett. 1992, 33, 4731. Osterhout, M. H.; Nadler,
W. R.; Padwa, A. Synthesis 1994, 123.
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63, 44.
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1982, 47, 3049. Meth-Cohn, O.; Westwood, K. T. J . Chem. Soc., Perkin
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1994, 59, 5856.

558 J . Org. Chem., Vol. 64, No. 2, 1999
Brodney and Padwa
Sch em e 3
21 with BF3‚2AcOH afforded a 4:1 mixture of the tetra-
cyclic lactams 23 and 24. Formation of the observed
products is perfectly consistent with the sequence of
events proposed in Scheme 1. The critical step in this
transformation involves the Lewis acid assisted genera-
tion of N-acyliminium ion 22, which then undergoes
intramolecular cationic π-cyclization from the less steri-
cally congested face. Under the reaction conditions,
cationic cyclization results in the formation of a thermo-
dynamically equilibrated mixture of lactams 23 and 24.
The same ratio of products (4:1) was obtained by subject-
ing either product to the acidic conditions used to effect
cyclization. When TMSOTf was used as the Lewis acid,
the major product formed corresponded to lactam 24. The
fact that there was no interconversion of the two lactams
under these conditions suggests that the Mannich cy-
clization step is kinetically controlled. The cis stereo-
chemistry about the A/B ring junction is consistent with
related cationic π-cyclizations carried out by Mondon33
and Ishibashi34 in their synthetic approach toward the
erythrinane class of alkaloids.
In a further investigation of the sequential cycloaddi-
tion π-cyclization process for the construction of nitrogen
heterocycles, we decided to examine what effect an
electrophilic carbonyl group anchored on the tether would
have on the cyclization reaction. Toward this end, cy-
cloadduct 21 was treated with ozone at -78 °C, and this
was followed by reductive workup with dimethyl sulfide
to furnish the expected methyl ketone 25 in 89% yield.
When 25 was treated with a catalytic quantity of p-TsOH
in acetonitrile, dienyl enamide 29 was obtained in 70%
yield. No detectable quantities of the Mannich cyclized
product 27 were present in the crude reaction mixture.
In this case, proton loss from N-acyliminium ion 26
occurs in preference to Mannich cyclization. The initially
formed enamide 28 undergoes subsequent condensation
on the tethered carbonyl group to ultimately give 29
(Scheme 4).
the cycloadducts was based on a comparison of NMR
signals of related substrates synthesized in this labora-
tory whose structures had been confirmed by X-ray
crystallography. In all cases, the anti stereochemistry
exists between the oxa-bridge and the angular proton
(Ha), whereas the methyl group is in the syn relationship
to this proton. The formation of the endo cycloadduct is
in full accord with molecular mechanics calculations
which show a large ground-state energy difference be-
tween the two diastereomers.
Two additional systems involving tethered carbonyl
groups on the amide nitrogen, which further illustrate
the scope of the cascade sequence, are outlined below.
Ozonolysis of the N-butenyl cycloadduct 30 afforded
aldehyde 31, which on heating with p-TsOH in CH3CN
for 24 h gave the aromatic tricyclic lactam 34 in 64%
yield. When the reaction was carried out for a shorter
period of time (i.e., 6 h), dienyl enamide 32 was formed
in 60% yield in addition to lactam 34 (20%). Opening of
the oxabicyclic ring with acid followed by proton loss fur-
nishes an enamide that undergoes condensation with the
adjacent aldehyde carbonyl to give 32 in a manner simi-
lar to that depicted in Scheme 4. Heating a pure sample
of 32 under the acidic reaction conditions cleanly afforded
the aromatic lactam 34. We suspect that 32 is first isom-
erized to cyclohexadiene 33, which undergoes subsequent
oxidative aromatization to produce 34 (Scheme 5).
In the second example (Scheme 6), the acid-catalyzed
behavior of the homologous aldehyde 35 was studied.
When 35 was heated at reflux in dry acetonitrile in the
presence of p-TsOH for 12 h, no trace of the Mannich
cyclization product was observed. We isolated instead a
With the intramolecular isomu¨nchnone cycloadducts
on hand, we attempted to deprotect them and then attach
an appropriate olefinic tether on the amide nitrogen to
probe the facility of the Mannich cyclization reaction. The
N-benzyl protected cycloadducts 11 and 12 proved un-
suitable for our purposes because the reductive dealky-
lation conditions led to a complex of products. By means
of Weinreb’s conditions for amide deprotection,32 cycload-
duct 15 was easily converted to the unsubstituted amide
17. Quenching the initially formed anion derived from
15 with iodomethane did produce the N-methylated
amide 18, but the yields were 50% or less. Unfortunately,
all of our attempts to alkylate the anion with a variety
of alkenyl halides proved unsuccessful, and consequently
we abandoned this approach.
We decided that the simplest adjustment to our model
would be to first prepare the N-alkenyl substituted amide
and then introduce the diazo imido ester functionality.
To this end, we synthesized N-3-methyl-3-butenylamide,
starting from citronellic acid. Conversion to diazo imide
20 was accomplished by N-malonation followed by stan-
dard diazo transfer. Addition of rhodium(II) perfluorobu-
tyrate (Rh2pfb4) to a solution of 20 in CH2Cl2 at 25 °C
effected loss of nitrogen and cyclization to the isomu¨nch-
none dipole, which underwent an intramolecular cycload-
dition with the tethered alkene to give cycloadduct 21 in
94% isolated yield (Scheme 3). Subsequent treatment of
(33) Mondon, A.; Hansen, K. F.; Boehme, K.; Faro, H. P.; Nestler,
H. J .; Vilhuber, H. G.; Bo¨ttcher, K. Chem. Ber. 1970, 103, 615. Mondon,
A.; Seidel, P. R. Chem. Ber. 1971, 104, 2937. Mondon, A.; Nestler, H.
J . Chem. Ber. 1979, 112, 1329.
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Y. J . Chem. Soc., Perkin Trans. 1 1985, 605.

N-Acyliminium Ions
J . Org. Chem., Vol. 64, No. 2, 1999 559
Sch em e 4
Sch em e 7
Schultz39 have conducted selective 6-endo and 7-endo
cyclizations of aryl radicals onto hydroindole and hydro-
quinoline enamide systems and have used this reaction
as the key step for several alkaloid syntheses. Because
radical cyclizations to the enamide double bond have
excellent potential for heterocyclic synthesis, we became
interested in the possibility of using isomu¨nchnone
cycloadducts as precursors for radical cyclizations. We
are unaware of any previous examples where dipolar
cycloaddition of a mesoionic betaine has been coupled
with a subsequent radical cyclization reaction.
Sch em e 5
o-Iodophenyl diazoimide 38 was prepared starting from
hept-6-enoic acid and 2-(2-iodophenyl)ethylamine, and
this was followed by N-malonylation and diazo transfer
of the resulting amide. Rhodium(II)-catalyzed cyclization
of 38 furnished the expected isomu¨nchnone cycloadduct
39. Subsequent Lewis acid induced ring opening with
BF3‚OEt2 afforded enamide 40, which was converted to
the corresponding methyl ether 41 by treatment with
NaH/CH3I. Treatment of enamide 41 with AIBN and
Bu3SnH in refluxing benzene solution gave lactam 42 in
45% yield (Scheme 7). Attempts to minimize the dehy-
drohalogenation by slow addition of tributyltin hydride
and AIBN to the solution resulted in only minor improve-
ment of the yield. Further efforts to improve the yield
by either employing a smaller amount of AIBN or by
adding tris(trimethylsilyl)silane and AIBN slowly with
a syringe pump met with no success. Even though the
yield is modest, this transformation does reveal that the
intramolecular radical arylation of enamides derived
Sch em e 6
(35) Sato, T.; Machigashira, N.; Ishibashi, H.; Ikeda, M. Heterocycles
1992, 33, 139. Sato, T.; Nakamura, N.; Ikeda, K.; Okada, M.; Ishibashi,
H.; Ikeda, M. J . Chem. Soc., Perkin Trans 1 1992, 2399.
(36) Beckwith, A. L. J .; J oseph, S. P.; Mayadunne, T. A. J . Org.
Chem. 1993, 58, 4198. Fidalgo, J .; Castedo, L.; Domingue, D. Tetra-
hedron Lett. 1993, 34, 7317. Takano, S.; Suzuki, M.; Kijima, A.;
Ogasawara, K. Tetrahedron Lett. 1990, 31, 2315.
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70% yield of pyrrole 37. Once again we assume that the
intermediate N-acyliminium ion formed from the acid-
assisted ring opening undergoes rapid proton loss to pro-
duce an equilibrating mixture of enamides. Eventual cy-
clization of the trisubstituted enamide 36 on the aldehyde
center followed by dehydration affords pyrrole 37.
Several examples of radical cyclization to the enamide
double bond have been reported over the past few
years.35,36 Aryl radical cyclizations onto cyclic enamides
generally produce heterocycles in which the nitrogen
atom is present in the newly formed ring.37 Rigby38 and
(39) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J . Am. Chem.
Soc. 1993, 115, 7904. Schultz, A. G.; Guzzo, P. R.; Nowak D. M. J .
Org. Chem. 1995, 60, 8044. Schultz, A. G.; Holoboski, M. A.; Smyth,
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560 J . Org. Chem., Vol. 64, No. 2, 1999
Brodney and Padwa
29.0, 36.5, 40.4, 46.4, 46.7, 61.1, 123.9, 125.8, 127.2, 128.6,
from isomu¨nchnone cycloadducts can be used to prepare
complex azapolyheterocyclic systems. Further studies to
improve the yield of the 6-exo-aryl radical cyclization
reaction are now in progress.
131.3, 136.5, 167.2, 168.7, and 175.5; HRMS calcd for C22H31
NO4 373.2253, found 373.2258.
-
The above imide was subjected to the standard diazo
transfer conditions to give 3.2 g (91%) of 9 as a yellow oil: IR
(neat) 2128, 1723, 1645, and 1111 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.85 (d, 3H, J ) 6.6 Hz), 1.05-1.20 (m, 1H), 1.25-
1.40 (m, 1H), 1.30 (t, 3H, J ) 7.1 Hz), 1.56 (s, 3H), 1.66 (s,
3H), 1.95 (m, 3H), 2.31 (dd, 1H, J ) 15.8 and 7.9 Hz), 2.50
(dd, 1H, J ) 15.8 and 5.6 Hz), 4.27 (q, 2H, J ) 7.1 Hz), 4.90
(s, 2H), 5.03 (t, 1H, J ) 7.4 Hz), 7.31 (s, 3H), and 7.38 (s, 2H);
13C NMR (CDCl3, 75 MHz) δ 14.2, 17.6, 19.5, 25.4, 25.7, 29.8,
36.7, 43.3, 49.1, 61.8, 73.0, 124.2, 127.2, 127.4, 128.6, 131.4,
137.1, 160.5, 166.5, and 174.9.
In conclusion, the results presented herein demon-
strate the potential of the carbenoid cyclization/dipolar
cycloaddition/N-acyliminium ion sequence for the con-
struction of functionalized piperidines. This three-step
protocol begins with the Rh(II)-catalyzed cyclization of
an R-diazo imide to give rise to an isomu¨nchnone dipole.
This is followed by an intramolecular 1,3-dipolar cycload-
dition. N-Acyliminium ion formation is triggered by
exposure of the cycloadduct to a Lewis acid. Different
cyclization pathways become available depending on the
nature of the substituent group attached to the amide
nitrogen. We are currently investigating application of
the methodology outlined here toward the synthesis of
several alkaloid natural products.
10-Ben zyl-3,7,7-tr im eth yl-9-oxo-11-oxa -10-a za -tr icyclo-
[6.2.1.01,6]-u n d eca n e-8-ca r boxylic Acid Eth yl Ester (11).
A solution containing 2.5 g (6.3 mmol) of diazoimide 9 in 60
mL of CH2Cl2 at room temperature was treated with 5 mg of
rhodium(II) perfluorobutyrate. The reaction mixture was
stirred for 24 h at room temperature and was concentrated
under reduced pressure. The resulting residue was purified
by flash silica gel chromatography to give 2.1 g (90%) of 11 as
a white solid: mp 119-120 °C; IR (neat) 1744, 1452, and 1118
Exp er im en ta l Section
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.72-0.85 (m, 2H), 0.88
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in oven-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator, and the residue
was chromatographed on a silica gel column using an ethyl
acetate-hexane mixture as the eluent unless specified other-
wise.
Gen er a l P r oced u r e for th e Syn th esis of Dia zo Im id es.
A solution containing 5.0 mmol of the appropriate amide and
10.0 mmol of ethyl malonyl chloride in 15 mL of anhydrous
benzene was heated at reflux for 1 h. After cooling to room
temperature, the reaction was diluted with ether and washed
with 10% aqueous NaOH and brine. The organic layer was
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography on a silica
gel column. A variation of the procedure described by Taber
and co-workers31 was used to prepare the diazo imide system.
To a solution containing 2 mmol of the appropriate ketolactam
and 2.2 mmol of mesyl azide in 5 mL of CH2Cl2 was added 4.0
mmol of Et3N under N2 at room temperature. After 3 hr of
stirring, the solvent was removed under reduced pressure, and
the residue was subjected to flash chromatography on a silica
gel column.
(d, 3H, J ) 6.3 Hz), 1.04 (s, 3H), 1.18 (s, 3H), 1.37 (t, 3H, J )
7.1 Hz), 1.31-1.41 (m, 1H), 1.48 (t, 2H, J ) 14.1 Hz), 1.63-
1.70 (m, 2H), 2.06 (dd, 1H, J ) 7.3 and 1.1 Hz), 4.33 (d, 1H, J
) 15.6 Hz), 4.40 (q, 2H, J ) 7.1 Hz), 4.52 (d, 1H, J ) 15.6 Hz),
and 7.20-7.42 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 14.4, 21.1,
22.1, 26.0, 26.1, 28.3, 33.0, 36.9, 43.4, 44.9, 51.0, 61.7, 92.1,
96.3, 127.7, 128.0, 128.7, 137.0, 165.4, and 169.6. Anal. Calcd
for C22H29NO4: C, 71.13; H, 7.87; N, 3.77. Found: C, 70.88;
H, 7.80; N, 3.67.
2-Dia zo-N-ben zyl-N-(3-m eth yl-h ep t-6-en oyl)-m a lon a m -
ic Acid Eth yl Ester (10). To a solution containing 3.0 g (18
mmol) of 3-methyl-hept-6-enoic acid in 100 mL of CH2Cl2 was
added 5.1 g (32 mmol) of 1,1′-carbonyldiimidazole, and the
solution was stirred at room temperature for 2 h. The reaction
mixture was charged with 5.6 g (53 mmol) of benzylamine at
0 °C, and the solution was allowed to warm to room temper-
ature, stirred for 12 h, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 3.7 g (75%) of 3-methyl-hept-6-enoic acid
benzylamide as a colorless oil: IR (neat) 3395, 3068, 1737,
1
1367, and 1146 cm-1; H NMR (CDCl3, 300 MHz) δ 0.96 (d,
3H, J ) 6.3 Hz), 1.25-1.35 (m, 1H), 1.42-1.52 (m, 1H), 1.95-
2.13 (m, 4H), 2.19-2.26 (m, 1H), 4.45 (d, 2H, J ) 5.7 Hz),
4.90-5.03 (m, 2H), 5.71 (brs, 1H), 5.72-5.86 (m, 1H), and
7.26-7.35 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 19.4, 30.2,
31.1, 35.8, 43.3, 44.1, 114.3, 127.2, 127.6, 128.5, 138.4, 138.5,
and 172.3.
2-Dia zo-N -b e n zyl-N -(3,7-d im e t h yl-oct -6-e n oyl)-m a l-
on a m ic Acid Eth yl Ester (9). To a solution containing 3.0 g
(18 mmol) of citronellic acid (7) in 100 mL of CH2Cl2 was added
4.3 g (26 mmol) of 1,1′-carbonyldiimidazole, and the solution
was stirred at room temperature for 2 h. To this mixture was
added 4.7 g (44 mmol) of benzylamine at 0 °C, and the solution
was allowed to warm to room temperature, stirred for 12 h,
and concentrated under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 3.9 g (70%)
of 3,7-dimethyl-oct-6-enoic acid benzylamide as a white solid:
N-Malonylacylation was carried out on the above amide in
the normal manner to give 1.6 g (90%) of N-benzyl-N-(3-
methyl-hept-6-enoyl)-malonamic acid ethyl ester as a colorless
oil: IR (neat) 3068, 2968, 1737, 1694, 1630, and 1026 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.85 (d, 3H, J ) 6.8 Hz), 1.10-
1.15 (m, 1H), 1.25-1.40 (m, 1H), 1.29 (t, 3H, J ) 7.2 Hz), 1.94-
2.06 (m, 3H), 2.32 (dd, 1H, J ) 16.4 and 7.5 Hz), 2.49 (dd,
1H, J ) 16.4 and 5.4 Hz), 3.92 (s, 2H), 4.21 (q, 2H, J ) 7.2
Hz), 4.89-5.02 (m, 2H), 5.02 (s, 2H), 5.69-5.78 (m, 1H), and
7.19-7.45 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 19.4,
29.0, 31.0, 35.5, 43.7, 46.4, 46.8, 61.2, 114.4, 125.9, 127.3,
128.8, 136.5, 138.3, 167.2, 168.8, and 175.4; HRMS calcd for
1
mp 43-44 °C; IR (neat) 3288, 1559, 1455, and 1018 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.97 (d, 3H, J ) 6.3 Hz), 1.05-1.20
(m, 1H), 1.25-1.40 (m, 1H), 1.59 (s, 3H), 1.67 (s, 3H), 1.95 (m,
3H), 2.24 (m, 2H), 4.45 (dd, 2H, J ) 5.7 and 1.2 Hz), 5.09 (t,
1H, J ) 7.1 Hz), 5.72 (brs, 1H), and 7.26-7.35 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 17.6, 19.5, 25.4, 25.6, 30.4, 36.9, 43.5,
44.4, 124.3, 127.4, 127.7, 128.6, 131.4, 138.4, and 172.3.
N-Malonylacylation was carried out on the above amide in
the normal manner to give 3.5 g (93%) of N-benzyl-N-(3,7-
dimethyl-oct-6-enoyl)malonamic acid ethyl ester as a colorless
C
20H27NO4 345.1940, found 345.1945.
The above imide was subjected to the standard diazo
transfer conditions to give 1.1 g (88%) of 10 as a yellow oil:
1
IR (neat) 2128, 1709, 1645, and 1452 cm-1; H NMR (CDCl3,
300 MHz) δ 0.86 (d, 3H, J ) 6.6 Hz), 1.10-1.30 (m, 1H), 1.30-
1.41 (m, 1H), 1.30 (t, 3H, J ) 6.9 Hz), 1.94-2.04 (m, 3H), 2.31
(dd, 1H, J ) 15.8 and 7.9 Hz), 2.50 (dd, 1H, J ) 15.8 and 5.6
Hz), 4.27 (q, 2H, J ) 7.1 Hz), 4.90 (s, 2H), 4.93-5.00 (m, 2H),
5.67-5.81 (m, 1H), 7.31 (s, 3H), and 7.38 (s, 2H); 13C NMR
(CDCl3, 75 MHz) δ 14.2, 19.4, 29.5, 31.0, 35.6, 43.1, 49.1, 61.7,
73.0, 114.3, 127.1, 127.4, 128.5, 137.0, 138.4, 160.3, 166.4, and
174.7.
oil: IR (neat) 3060, 1701, and 1154 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 0.85 (d, 3H, J ) 6.8 Hz), 1.05-1.20 (m, 1H), 1.25-
1.40 (m, 1H), 1.29 (t, 3H, J ) 7.2 Hz), 1.55 (s, 3H), 1.66 (s,
3H), 1.85-1.95 (m, 2H), 1.95-2.05 (m, 1H), 2.30 (dd, 1H, J )
15.8 and 7.9 Hz), 2.49 (dd, 1H, J ) 15.8 and 5.6 Hz), 3.92 (s,
2H), 4.21 (q, 2H, J ) 6.9 Hz), 5.03 (m, 3H), and 7.19-7.45 (m,
5H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 17.4, 19.4, 25.2, 25.5,

N-Acyliminium Ions
J . Org. Chem., Vol. 64, No. 2, 1999 561
10-B e n zy l-9-o x o -11-o x a -10-a za -t r ic y c lo [6.2.1.01,6]-
u n d eca n e-8-ca r boxylic Acid Eth yl Ester (12). A solution
of 0.9 g (2.3 mmol) of diazoimide 10 in 30 mL of CH2Cl2 at
room temperature was treated with 3 mg of rhodium(II)
perfluorobutyrate. The reaction mixture was stirred for 12 h
at room temperature and was concentrated under reduced
pressure. The resulting residue was purified by flash silica gel
chromatography to give 0.70 g (90%) of 12 as a white solid:
) 7.2 Hz), 1.45-1.56 (m, 2H), 1.63-1.76 (m, 2H), 1.89-1.99
(m, 2H), 2.20 (dd, 2H, J ) 12.8 and 7.1 Hz), 2.45 (s, 3H), 3.23-
3.61 (m, 4H), 4.33 (dq, 2H, J ) 7.2 and 2.1 Hz), 7.39 (d, 2H, J
) 8.2 Hz), and 7.79 (d, 2H, J ) 8.2 Hz); 13C NMR (CDCl3, 75
MHz) δ 14.1, 21.6, 22.0, 28.1, 32.1, 33.0, 33.8, 35.5, 36.6, 41.3,
54.3, 62.1, 85.8, 97.6, 127.9, 130.1, 135.5, 145.3, 165.4, and
171.2. Anal. Calcd for C22H29NO6: C, 60.67; H, 6.71; N, 3.22.
Found: C, 60.75; H, 6.69; N, 3.22.
1
mp 96-97 °C; IR (neat) 1745, 1716, 1403, and 1239 cm-1; H
3-Me t h yl-9-oxo-11-oxa -10-a za -t r icyclo[6.2.1.01,6]u n -
d eca n e-8-ca r boxylic Acid Eth yl Ester (17). To a solution
containing 0.2 g (0.5 mmol) of cycloadduct 15 in 20 mL of THF
at -78 °C was added 0.08 g (0.7 mmol) of potassium tert-
butoxide. The reaction mixture was stirred for 2 h, poured into
2 mL of water, extracted with ether, and dried over Na2SO4.
The resulting residue was concentrated under reduced pres-
sure and purified by flash silica gel chromatography to give
0.06 g (50%) of 17 as a white solid: mp 154-155 °C; IR (neat)
1750, 1721, and 1110 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.96
(d, 3H, J ) 6.6 Hz), 1.01-1.09 (m, 1H), 1.24-1.29 (m, 1H),
1.36 (t, 3H, J ) 7.2 Hz), 1.24-1.29 (m, 1H), 1.40-1.45 (m, 1H),
1.65-1.81 (m, 2H), 1.89-2.11 (m, 2H), 2.32-2.39 (m, 2H), 4.33
(m, 2H), and 6.29 (brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.4,
22.1, 28.5, 32.3, 33.4, 36.1, 36.8, 43.5, 62.3, 86.7, 94.6, 166.1,
and 173.9. Anal. Calcd for C13H19NO4: C, 61.64; H, 7.56; N,
5.54. Found: C, 61.56; H, 7.50; N, 5.54.
NMR (CDCl3, 300 MHz) δ 0.71-0.85 (m, 1H), 0.91 (d, 3H, J )
6.6 Hz), 1.14-1.28 (m, 1H), 1.38 (t, 3H, J ) 7.2 Hz), 1.43-
1.51 (m, 2H), 1.54-1.64 (m, 2H), 1.72-1.86 (m, 2H), 2.12-
2.26 (m, 2H), 4.33 (d, 1H, J ) 15.6 Hz), 4.40 (m, 2H), 4.50 (d,
1H, J ) 15.6 Hz), and 7.25-7.40 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 14.4, 22.2, 28.3, 32.3, 33.4, 36.1, 36.9, 41.5, 43.3,
62.2, 86.3, 97.6, 127.8, 127.9, 128.9, 136.9, 166.2, and 171.2.
Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found:
C, 69.75; H, 7.32; N, 4.05.
2-Dia zo-N-(3-m eth yl-h ep t-6-en oyl)-N-[2-(tolu en e-4-su l-
fon yl)eth yl]-m a lon a m ic Acid Eth yl Ester (13). To a solu-
tion containing 1.9 g (13 mmol) of 3-methyl-hept-6-enoic acid
in 100 mL of CH2Cl2 was added 2.6 g (16 mmol) of 1,1′-
carbonyldiimidazole, and the solution was stirred at room
temperature for 2 h. To this mixture was added 4.0 g (20.0
mmol) of â-tosylethylamine32 at 0 °C, and the solution was
allowed to warm to room temperature, stirred for 12 h, and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 3.0 g (70%) of
3-methyl-hept-6-enoic acid [2-(toluene-4-sulfonyl)ethyl]amide
as a yellow oil: IR (neat) 2910, 1730, and 1630 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.93 (d, 3H, J ) 6.0 Hz), 1.22-1.30 (m,
1H), 1.37-1.48 (m, 1H), 1.91-2.19 (m, 5H), 2.46 (s, 3H), 3.23-
3.27 (m, 2H), 3.65-3.71 (m, 2H), 4.93-5.05 (m, 2H), 5.73-
5.87 (m, 1H), 6.23 (brs, 1H), 7.38 (d, 2H, J ) 8.3 Hz), and 7.77
(d, 2H, J ) 8.3 Hz); 13C NMR (CDCl3, 75 MHz) δ 19.5, 29.8,
30.2, 31.2, 33.4, 35.8, 44.0, 55.5, 114.5, 127.9, 130.2, 136.0,
138.6, 145.2, and 173.1.
3,10-Dim et h yl-9-oxo-11-oxa -10-a za -t r icyclo[6.2.1.01,6]-
u n d eca n e-8-ca r boxylic Acid Eth yl Ester (18). To a solution
of 0.5 g (1.2 mmol) of cycloadduct 15 in 50 mL of THF at -78
°C was added 0.19 g (1.7 mmol) of potassium tert-butoxide.
The reaction mixture was stirred for 2 h at -45 °C, and then
0.7 g (5 mmol) of methyl iodide was added. After 15 min of
stirring at -45 °C, the reaction was allowed to warm to room
temperature and was stirred for an additional 6 h. The solution
was poured into 20 mL of H2O, extracted with ether, washed
with brine, and dried over Na2SO4. The resulting residue was
concentrated under reduced pressure and purified by flash
silica gel chromatography to give 0.12 g (40%) of 18 as a white
solid: mp 87-88 °C; IR (neat) 1751, 1726, 1241, and 1111
N-Malonylacylation was carried out on the above amide in
the normal manner to give 0.89 g (88%) of N-(3-methyl-hept-
6-enoyl)-N-[2-(toluene-4-sulfonyl)-ethyl]malonamic acid ethyl
ester as a white solid: mp 79-80 °C; IR (neat) 1735, 1708,
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.99 (d, 3H, J ) 6.6 Hz),
0.95-1.09 (m, 1H), 1.26-1.31 (m, 1H), 1.35 (t, 3H, J ) 7.2
Hz), 1.24-1.29 (m, 1H), 1.44-1.53 (m, 1H), 1.65-1.77 (m, 2H),
1.84-1.99 (m, 2H), 2.18-2.27 (m, 2H), 2.75 (s, 3H), and 4.30-
4.43 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 14.4, 22.3, 25.2,
28.3, 32.2, 33.5, 35.6, 37.1, 40.1, 62.2, 86.4, 97.1, 166.2, and
171.2. Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92; N, 5.24.
Found: C, 62.97; H, 7.87; N, 5.27.
1
1697, and 1139 cm-1; H NMR (CDCl3, 300 MHz) δ 0.94 (d,
3H, J ) 6.6 Hz), 1.21-1.33 (m, 1H), 1.25 (t, 3H, J ) 7.2 Hz),
1.37-1.49 (m, 1H), 1.99-2.15 (m, 3H), 2.32 (dd, 1H, J ) 16.9
and 7.8 Hz), 2.46 (s, 3H), 2.59 (dd, 1H, J ) 16.4 and 5.7 Hz),
3.39 (dd, 2H, J ) 7.8 and 6.6 Hz), 3.79 (s, 2H), 4.07 (dd, 2H,
J ) 9.0 and 6.0 Hz), 4.16 (q, 2H, J ) 7.2 Hz), 4.95-5.05 (m,
2H), 5.73-5.86 (m, 1H), 7.39 (d, 2H, J ) 8.2 Hz), and 7.79 (d,
2H, J ) 8.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.0, 19.5, 21.6,
29.1, 31.1, 35.7, 38.6, 43.7, 46.1, 53.9, 61.3, 114.7, 127.9, 130.1,
135.8, 138.3, 145.3, 167.1, 168.7, and 174.5; HRMS calcd for
2-Dia zo-N-h ep t-6-en oyl-N-[2-(tolu en e-4-su lfon yl)eth yl]-
m a lon a m ic Acid Eth yl Ester (14). To a solution containing
7.5 g (59 mmol) of hept-6-enoic acid in 250 mL of CH2Cl2 was
added 12 g (70 mmol) of 1,1′-carbonyldiimidazole, and the
solution was stirred at room temperature for 2 h. The reaction
mixture was charged with 15.0 g (74.9 mmol) of â-tosylethy-
lamine at 0 °C. The solution was allowed to warm to room
temperature, stirred for 12 h, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 8.6 g (60%) of hept-6-enoic acid [2-(toluene-
4-sulfonyl)ethyl] amide as a white solid: mp 63-64 °C; IR
(neat) 2926, 1651, and 1536 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.40 (quint, 2H, J ) 7.8 Hz), 1.62 (quint, 2H, J ) 7.2 Hz),
2.03-2.10 (m, 2H), 2.16 (t, 2H, J ) 7.8 Hz), 2.46 (s, 3H), 3.26
(m, 2H), 3.67 (dd, 2H, J ) 11.4 and 5.7 Hz), 4.93-5.04 (m,
2H), 5.72-5.86 (m, 1H), 7.38 (d, 2H, J ) 8.2 Hz), and 7.77 (d,
2H, J ) 8.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 21.7, 25.0, 28.5,
36.3, 55.5, 114.8, 128.0, 130.2, 136.1, 138.5, 145.2, and 173.3.
N-Malonylacylation was carried out on the above amide in
the normal manner to give 5.9 g (87%) of N-hept-6-enoyl-N-
[2-(toluene-4-sulfonyl)ethyl]-malonamic acid ethyl ester as a
white solid: mp 68-69 °C; IR (neat) 2940, 1737, 1712, and
C
22H31NSO6 437.1872, found 437.1872.
The above compound was subjected to the standard diazo
transfer conditions to give 0.6 g (85%) of 13 as a yellow oil:
1
IR (neat) 2143, 1716, 1645, and 1445 cm-1; H NMR (CDCl3,
300 MHz) δ 0.88 (d, 3H, J ) 6.6 Hz), 1.19-1.27 (m, 1H), 1.31
(t, 3H, J ) 7.2 Hz), 1.35-1.41 (m, 1H), 1.99-2.08 (m, 3H),
2.30 (dd, 1H, J ) 15.5 and 7.8 Hz), 2.45 (s, 3H), 2.50 (dd, 1H,
J ) 15.5 and 6.1 Hz), 3.45 (t, 2H, J ) 6.6 Hz), 3.96 (t, 2H, J
) 6.6 Hz), 4.27 (q, 2H, J ) 7.2 Hz), 4.91-5.02 (m, 2H), 5.70-
5.83 (m, 1H), 7.39 (d, 2H, J ) 8.2 Hz), and 7.79 (d, 2H, J )
8.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.3, 19.6, 21.7, 30.0,
31.2, 35.8, 40.7, 43.2, 54.7, 62.2, 114.6, 128.0, 130.1, 136.1,
138.5, 145.1, 160.1, 166.6, and 174.2.
3-Meth yl-9-oxo-10-[2-(tolu en e-4-su lfon yl)eth yl]-11-oxa -
10-aza-tr icyclo-[6.2.1.01,6]u n decan e-8-car boxylic Acid Eth -
yl Ester (15). A solution of 0.5 g (1.1 mmol) of diazo imide 13
in 20 mL of CH2Cl2 at room temperature was treated with 3
mg of rhodium(II) perfluorobutyrate. The reaction mixture was
stirred for 6 h at room temperature and was then concentrated
under reduced pressure. The resulting residue was purified
by flash silica gel chromatography to give 0.4 g (85%) of 15 as
a white solid: mp 154-155 °C; IR (neat) 1752, 1724, 1452,
and 1139 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.99 (d, 3H, J )
6.3 Hz), 0.90-1.08 (m, 1H), 1.21-1.31 (m, 1H), 1.32 (t, 3H, J
1
1026 cm-1; H NMR (CDCl3, 300 MHz) δ 1.25 (t, 3H, J ) 7.1
Hz), 1.41 (quint, 2H, J ) 7.8 Hz), 1.64 (quint, 2H, J ) 7.2 Hz),
2.08 (dt, 2H, J ) 7.2 and 6.9 Hz), 2.45 (s, 3H), 2.60 (t, 2H, J
) 6.9 Hz), 3.39 (dd, 2H, J ) 8.1 and 6.9 Hz), 3.78 (s, 2H), 4.08
(t, 2H, J ) 7.5 Hz), 4.16 (q, 2H, J ) 7.1 Hz), 4.95-5.05 (m,
2H), 5.72-5.85 (m, 2H), 7.38 (d, 2H, J ) 8.4 Hz), and 7.78 (d,
2H, J ) 8.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.2, 21.8, 24.0,

562 J . Org. Chem., Vol. 64, No. 2, 1999
Brodney and Padwa
28.2, 33.5, 36.6, 38.7, 46.2, 54.1, 61.5, 115.0, 128.0, 130.3,
136.0, 138.3, 145.5, 167.3, 168.9, and 175.2; HRMS calcd for
(neat) 2140, 1726, 1700, and 1654 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.92 (d, 3H, J ) 6.6 Hz), 1.16-1.24 (m, 1H), 1.24-
1.36 (m, 1H), 1.28 (t, 3H, J ) 7.2 Hz), 1.57 (s, 3H), 1.65 (s,
3H), 1.73 (s, 3H), 1.94-2.04 (m, 3H), 2.31 (dd, 1H, J ) 15.7
and 8.1 Hz), 2.30 (t, 2H, J ) 8.0 Hz), 2.51 (dd, 1H, J ) 15.7
and 5.4 Hz), 3.75 (t, 2H, J ) 8.0 Hz), 4.24 (q, 2H, J ) 7.2 Hz),
4.69 (s, 1H), 4.77 (s, 1H), and 5.06 (t, 1H, J ) 6.9 Hz); 13C
NMR (CDCl3, 75 MHz) δ 14.4, 17.8, 19.8, 22.5, 25.6, 25.8, 30.2,
37.0, 37.5, 43.4, 45.2, 61.9, 112.6, 124.4, 131.6, 142.4, 160.5,
166.7, and 174.6.
3,7,7-Tr im eth yl-10-(3-m eth yl-bu t-3-en yl)-9-oxo-11-oxa -
10-aza-tr icyclo-[6.2.1.01,6]u n decan e-8-car boxylic Acid Eth -
yl Ester (21). A solution containing 1.7 g (4.5 mmol) of
diazoimide 20 in 100 mL of CH2Cl2 at room temperature was
treated with 5 mg of rhodium(II) perfluorobutyrate. The
reaction mixture was stirred for 6 h at room temperature and
was then concentrated under reduced pressure. The resulting
residue was purified by flash silica gel chromatography to give
1.5 g (94%) of 21 as a white solid: mp 90-91 °C; IR (neat)
1751, 1728, and 1113 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.89-
0.92 (m, 1H), 0.97 (d, 3H, J ) 6.6 Hz), 1.04 (s, 3H), 1.20 (s,
3H), 1.34 (t, 3H, J ) 7.1 Hz), 1.30-1.38 (m, 1H), 1.43-1.47
(m, 1H), 1.51-1.57 (m, 1H), 1.68-1.74 (m, 3H), 1.77 (s, 3H),
2.17-2.26 (m, 3H), 3.23-3.41 (m, 2H), 4.36 (q, 2H, J ) 7.1
Hz), 4.80 (s, 1H), and 4.73 (s, 1H); 13C NMR (CDCl3, 75 MHz)
δ 14.6, 21.1, 22.4, 22.6, 26.4, 26.6, 28.5, 33.2, 36.9, 37.8, 38.6,
44.8, 51.7, 61.8, 92.1, 96.0, 112.5, 142.5, 165.5, and 169.4. Anal.
Calcd for C20H31NO4: C, 68.74; H, 8.94; N, 4.01. Found: C,
68.64; H, 8.91; N, 3.98.
8-H yd r oxy-3,9,9,13-t et r a m et h yl-7-oxo-6-a za -t r icyclo-
[8.4.0.01,6]tetr a d ec-3-en e-8-ca r boxylic Acid Eth yl Ester
(23). To a solution of 0.3 g (0.9 mmol) of cycloadduct 21 in 20
mL of CH2Cl2 at room temperature was added 1.6 mL (8.6
mmol) of BF3‚2AcOH complex. The reaction mixture was
stirred at 25 °C for 10 h and then quenched with 2 mL of
ethanol. The solution was taken up in 50 mL of CH2Cl2 and
extracted with water. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The resulting residue was analyzed by NMR spectroscopy and
shown to consist of a 4:1 ratio of 23 and 24 (vide infra) by
integration of the appropriate methyl signals. Flash silica gel
chromatography afforded 0.24 g (75%) of 23 as a white solid:
mp 110-111 °C; IR (neat) 1746, 1720, and 1234 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.92 (s, 3H), 0.97 (s, 3H), 0.99-1.09 (m,
2H), 1.05 (s, 3H), 1.30 (t, 3H, J ) 7.2 Hz), 1.34-1.44 (m, 1H),
1.68 (s, 3H), 1.87-1.91 (m, 1H), 2.16-2.22 (d, 1H, J ) 16.8
Hz), 2.23 (dd, 1H, J ) 12.1 and 2.1 Hz), 2.28 (dd, 1H, J ) 12.1
and 4.5 Hz), 2.54 (d, 1H, J ) 17.7 Hz), 3.46 (d, 1H, J ) 18.2
Hz), 4.16-4.28 (m, 2H), 4.23 (q, 2H, J ) 7.3 Hz), 4.27 (s, 1H),
4.98 (d, 1H, J ) 18.2 Hz), and 5.38 (s, 1H); 13C NMR (CDCl3,
75 MHz) δ 14.4, 20.5, 21.0, 22.7, 23.8, 24.7, 29.2, 34.0, 35.6,
38.4, 39.2, 43.5, 46.3, 58.9, 62.2, 81.7, 117.6, 131.4, 168.1, and
172.1. Anal. Calcd. for C20H31NO4: C, 68.74; H, 8.94; N, 4.01,
found C, 68.74; H, 8.90; N, 4.02.
8-H yd r oxy-3,9,9,13-t et r a m et h yl-7-oxo-6-a za t r icyclo-
[8.4.0.01,6]tetr a d ec-2-en e-8-ca r boxylic Acid Eth yl Ester
(24). When the above reaction was carried out using 0.3 g (0.9
mmol) of cycloadduct 21 in 20 mL of CH2Cl2 together with 2.1
g (10 mmol) of TMSOTf as the Lewis acid at 25 °C for 10 h,
the major product (75%) obtained from silica gel chromatog-
raphy of the reaction mixture corresponded to azatricyclic 24
which was obtained as a white solid: mp 113-114 °C; IR (neat)
1744, 1633, 1457, and 1243 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.78 (s, 3H), 0.90-0.93 (m, 6H), 0.95-1.07 (m, 2H), 1.29 (t,
3H, J ) 7.2 Hz), 1.61 (m, 5H), 1.86 (m, 2H), 2.13 (dd, 1H, J )
11.5 and 2.7 Hz), 2.30 (m, 1H), 2.46 (dd, 1H, J ) 11.5 and 2.7
Hz), 3.32 (dt, 1H, J ) 12.5 and 5.4 Hz), 4.21 (m, 2H), 4.35 (s,
1H), 4.50 (dd, 1H, J ) 13.3 and 6.9 Hz), and 5.83 (s, 1H); 13C
NMR (CDCl3, 75 MHz) δ 14.4, 18.9, 20.7, 22.8, 23.6, 23.8, 28.8,
29.1, 35.4, 36.5, 38.9, 46.0, 50.0, 60.3, 62.0, 81.7, 125.8, 132.0,
169.7, and 171.8. Anal. Calcd for C20H31NO4: C, 68.74; H, 8.94;
N, 4.01. Found: C, 68.70; H, 8.92; N, 3.99.
C
21H29NSO6 423.1715, found 423.1715.
The above compound was subjected to the standard diazo
transfer conditions to give 4.9 g (85%) of 14 as a yellow oil:
1
IR (neat) 2140, 1717, 1653, and 780 cm-1; H NMR (CDCl3,
300 MHz) δ 0.88 (d, 3H, J ) 6.6 Hz), 1.19-1.27 (m, 1H), 1.31
(t, 3H, J ) 7.2 Hz), 1.35-1.41 (m, 1H), 1.99-2.08 (m, 3H),
2.30 (dd, 1H, J ) 15.5 and 7.8 Hz), 2.45 (s, 3H), 2.50 (dd, 1H,
J ) 15.5 and 6.1 Hz), 3.45 (t, 2H, J ) 6.6 Hz), 3.96 (t, 2H, J
) 6.6 Hz), 4.27 (q, 2H, J ) 7.2 Hz), 4.91-5.02 (m, 2H), 5.70-
5.84 (m, 1H), 7.39 (d, 2H, J ) 8.2 Hz), and 7.79 (d, 2H, J )
8.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.1, 21.5, 24.4, 28.1,
33.2, 35.6, 40.3, 54.4, 62.0, 72.7, 114.6, 127.8, 129.9, 135.8,
138.3, 145.1, 160.0, 166.2, and 174.6.
9-Oxo-10-[2-(t olu en e-4-su lfon yl)et h yl]-11-oxa -10-a za -
tr icyclo[6.2.1. 01,6]u n d eca n e-8-ca r boxylic Acid Eth yl Es-
ter (16). A solution of 5.0 g (11 mmol) of diazo imide 14 in
120 mL of CH2Cl2 at room temperature was treated with 5
mg of rhodium(II) perfluorobutyrate. The reaction mixture was
stirred for 20 h at room temperature and was then concen-
trated under reduced pressure. The resulting residue was
purified by flash silica gel chromatography to give 4.0 g (85%)
of 16 as a white solid: mp 144-145 °C; IR (neat) 1749, 1722,
and 1145 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.99 (d, 3H, J )
6.3 Hz), 0.90-1.08 (m, 1H), 1.21-1.31 (m, 1H), 1.32 (t, 3H, J
) 7.2 Hz), 1.45-1.56 (m, 2H), 1.63-1.76 (m, 2H), 1.89-1.99
(m, 2H), 2.20 (dd, 2H, J ) 12.8 and 7.1 Hz), 2.45 (s, 3H), 3.20-
3.61 (m, 4H), 4.33 (dq, 2H, J ) 7.2 and 2.1 Hz), 7.38 (d, 2H, J
) 8.4 Hz), and 7.79 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 75
MHz) δ 14.3, 21.5, 21.8, 24.5, 27.5, 32.7, 34.0, 36.9, 42.0, 54.6,
62.3, 85.9, 97.3, 128.2, 130.3, 135.7, 145.5, 165.7, and 171.5.
Anal. Calcd for C21H27NO6: C, 59.84; H, 6.46; N, 3.32, found
C, 59.81; H, 6.42; N, 3.25.
2-Dia zo-N-(3,7-d im eth yl-oct-6-en oyl)-N-(3-m eth yl-bu t-
3-en yl)-m a lon a m ic Acid Eth yl Ester (20). To a solution
containing 5.0 g (35 mmol) of citronellic acid (7) in 125 mL of
benzene was added 15.6 g (123 mmol) of oxalyl chloride and
0.14 mL (1.8 mmol) of DMF. The solution was stirred at room
temperature for 2 h and concentrated under reduced pressure.
The resulting oil was taken up in 20 mL of CH2Cl2 and was
added to a solution of 3.6 g (42 mmol) of 3-methyl-but-3-
enylamine40 in 150 mL of CH2Cl2 at 0 °C. The solution was
allowed to warm to room temperature, stirred for 12 h, and
concentrated under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 3.6 g (44%) of
3,7-dimethyl-oct-6-enoic acid-N-(3-methyl-but-3-enyl)-amide as
a clear oil: IR (neat) 2927, 1645, and 1551 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.93 (d, 3H, J ) 6.3 Hz), 1.17-1.24 (m,
1H), 1.30-1.41 (m, 1H), 1.59 (s, 3H), 1.68 (s, 3H), 1.74 (s, 3H),
1.86-2.03 (m, 4H), 2.15-2.20 (m, 1H), 2.21 (t, 2H, J ) 6.8
Hz), 3.39 (t, 2H, J ) 6.6 Hz), 4.74 (s, 1H), 4.82 (s, 1H), 5.06-
5.11 (m, 1H), and 5.39 (brs, 1H); 13C NMR (CDCl3, 75 MHz) δ
17.7, 19.6, 22.1, 25.6, 30.5, 37.0, 37.1, 37.6, 44.6, 112.2, 124.5,
131.4, 142.7, and 172.7.
N-Malonylacylation was carried out on the above amide in
the normal manner to give 2.2 g (73%) of N-(3,7-dimethyl-oct-
6-enoyl)-N-(3-methyl-but-3-enyl)-malonamic acid ethyl ester as
a colorless oil: IR (neat) 1743, 1699, and 1140 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.95 (d, 3H, J ) 6.6 Hz), 1.18-1.28 (m,
1H), 1.27 (t, 3H, J ) 7.2 Hz), 1.32-1.39 (m, 1H), 1.60 (s, 3H),
1.68 (s, 3H), 1.79 (s, 3H), 1.97-2.10 (m, 3H), 2.27 (t, 2H, J )
7.7 Hz), 2.36 (dd, 1H, J ) 16.2 and 8.1 Hz), 2.57 (dd, 1H, J )
16.2 and 5.4 Hz), 3.79 (t, 2H, J ) 7.7 Hz), 3.81 (s, 2H), 4.18 (q,
2H, J ) 7.2 Hz), 4.74 (s, 1H), 4.82 (s, 1H), and 5.06-5.11 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 17.7, 19.8, 22.6, 25.5,
25.7, 29.5, 36.9, 36.9, 43.2, 43.9, 46.5, 61.2, 112.5, 124.2, 131.6,
142.1, 167.4, 168.7, and 175.3; HRMS calcd for C20H33NO4
351.2409, found 351.2415.
The above compound was subjected to the standard diazo
transfer conditions to give 1.8 g (94%) of 20 as a yellow oil; IR
The minor component (18%) isolated from the above column
chromatographic separation corresponded to compound 23.
Heating a sample of either 23 or 24 in the presence of
(40) Leonard, N. J .; Hecht, S. M.; Skoog, F.; Schmitz, R. Y. Proc.
Natl. Acad. Sci. U.S.A. 1968, 59, 15.

N-Acyliminium Ions
J . Org. Chem., Vol. 64, No. 2, 1999 563
BF3‚2AcOH in CH2Cl2 for 18 h afforded the same thermody-
namic mixture of isomers (i.e., 23:24 ) 4:1). The ratio was
determined by NMR analysis of the appropriate methyl
signals.
2H), 4.12 (q, 2H, J ) 7.2 Hz), 5.01-5.09 (m, 3H), and 5.69-
5.78 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.2, 17.7, 19.8,
25.6, 25.8, 29.5, 33.3, 36.9, 43.8, 44.0, 46.6, 61.2, 117.8, 124.2,
131.7, 134.2, 167.4, 168.8, and 175.3; HRMS calcd for C19H31
NO4 337.2253, found 337.2249.
-
3,7,7-Tr im et h yl-9-oxo-10-(3-oxo-b u t yl)-11-oxa -10-a za -
tr icyclo[6.2.1. 01,6]u n d eca n e-8-ca r boxylic Acid Eth yl Es-
ter (25). A solution containing 0.25 g (0.7 mmol) of cycloadduct
21 in 30 mL of 1:1 CH2Cl2/MeOH mixture was cooled to -78
°C, and ozone was bubbled through the solution for 30 min.
The solution was quenched with 0.3 mL (3.6 mmol) of dimethyl
sulfide and warmed to room temperature. After 6 h of stirring
at 25 °C, the solution was added to 10 mL of water, extracted
with ethyl acetate, and dried over Na2SO4. The solution was
concentrated under reduced pressure, and the resulting resi-
due was purified by flash silica gel chromatography to give
0.23 g (89%) of ketone 25 as a white solid: mp 103-104 °C;
The above compound was subjected to the standard diazo
transfer conditions to give 1.8 g (90%) of 2-diazo-N-but-3-enyl-
N-(3,7-dimethyl-oct-6-enoyl)-malonamic acid ethyl ester as a
yellow oil: IR (neat) 2134, 1720, 1699, and 1121 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.91 (d, 3H, J ) 6.8 Hz), 1.14-1.23 (m,
1H), 1.27 (t, 3H, J ) 6.0 Hz), 1.31-1.40 (m, 1H), 1.57 (s, 3H),
1.65 (s, 3H), 1.91-2.03 (m, 3H), 2.26-2.39 (m, 3H), 2.51 (dd,
1H, J ) 15.5 and 5.4 Hz), 3.70 (t, 2H, J ) 7.8 Hz), 4.23 (q, 2H,
J ) 6.8 Hz), 5.01-5.10 (m, 3H), and 5.67-5.81 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 14.5, 17.8, 19.6, 25.6, 25.9, 30.2, 34.9,
38.5, 42.9, 47.1, 62.4, 73.1, 118.5, 124.8, 132.1, 134.9, 161.0,
166.9, and 174.6.
IR (neat) 1751, 1718, and 1116 cm-1 1H NMR (CDCl3, 300
;
10-Bu ten yl-3,7,7-tr im eth yl-9-oxo-11-oxa-10-aza-tr icyclo-
[6.2.1.01,6]-u n d eca n e-8-ca r boxylic Acid Eth yl Ester (30).
A solution of 1.8 g (5.0 mmol) of the above diazo imide in 100
mL of CH2Cl2 at room temperature was treated with 5 mg of
rhodium(II) perfluorobutyrate. The reaction mixture was
stirred for 8 h at room temperature and was concentrated
under reduced pressure. The resulting residue was purified
by flash silica gel chromatography to give 1.48 g (90%) of 30
as a white solid: mp 77-78 °C; IR (neat) 1750, 1725, and 1112
MHz) δ 0.91-0.95 (m, 1H), 0.97 (d, 3H, J ) 6.9 Hz), 1.03 (s,
3H), 1.16 (s, 3H), 1.34 (t, 3H, J ) 7.1 Hz), 1.47-1.61 (m, 3H),
1.66-1.74 (m, 3H), 2.12-2.20 (m, 1H), 2.16 (s, 3H), 2.64 (ddd,
1H, J ) 18.1, 8.4, and 5.4 Hz), 2.91 (ddd, 1H, J ) 18.1, 8.4,
and 6.3 Hz), 3.30 (ddd, 1H, J ) 14.6, 8.5, and 5.5 Hz), 3.5 (ddd,
1H, J ) 14.6, 8.5, and 6.6 Hz), and 4.37 (q, 2H, J ) 7.1 Hz);
13C NMR (CDCl3, 75 MHz) δ 14.3, 20.8, 22.0, 26.1, 26.3, 28.2,
30.1, 32.8, 34.9, 36.3, 42.7, 44.6, 50.9, 61.6, 91.7, 96.3, 165.1,
169.8, and 206.6. Anal. Calcd for C19H29NO5: C, 64.93; H, 8.32;
N, 3.99, found C, 64.89; H, 8.30; N, 3.97.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.89-0.97 (m, 1H), 0.98
(d, 3H, J ) 6.6 Hz), 1.04 (s, 3H), 1.20 (s, 3H), 1.35 (t, 3H, J )
7.2 Hz), 1.38-1.46 (m, 2H), 1.51-1.62 (m, 2H), 1.67-1.79 (m,
2H), 2.20-2.33 (m, 3H), 3.16-3.40 (m, 2H), 4.37 (q, 2H, J )
7.2 Hz), 5.06-5.14 (m, 2H), and 5.71-5.84 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 14.5, 21.0, 22.3, 26.3, 26.6, 28.4, 33.1, 34.1,
36.9, 39.4, 44.8, 51.5, 61.8, 92.0, 96.0, 117.5, 134.8, 165.4, and
169.4. Anal. Calcd for C19H29NO4: C, 68.02; H, 8.73; N, 4.16.
Found: C, 68.04; H, 8.65; N, 4.11.
2-Hydr oxy-1,1,7,8-tetr am eth yl-3-oxo-2,3,6,8,9,10-h exah y-
dr o-1H,5H-pyr ido[3,2,1-ij]qu in olin e-2-car boxylic Acid Eth -
yl Ester (29). A solution containing 0.1 g (0.3 mmol) of ketone
25 in 30 mL of acetonitrile was treated with 4 mg of p-
toluenesulfonic acid. The mixture was heated at reflux for 10
h, and the solution was concentrated under reduced pressure.
The crude residue was subjected to flash silica gel chroma-
tography to give 0.7 g (78%) of 29 as a white solid: mp 93-94
3,7,7-Tr im eth yl-9-oxo-10-(3-oxo-p r op yl)-11-oxa -10-a za -
tr icyclo[6.2.1.0 1,6]-u n d eca n e-8-ca r boxylic Acid Eth yl Es-
ter (31). A solution of 0.7 g (2.1 mmol) of cycloadduct 30 in 75
mL of CH2Cl2 was cooled to -78 °C, and ozone was bubbled
through the solution for 30 min. The solution was quenched
with 0.8 mL (10.4 mmol) of dimethyl sulfide, and the mixture
was warmed to room temperature. After 4 h of stirring, the
solution was added to 10 mL of H2O, extracted with ethyl
acetate, and dried over Na2SO4. The solution was concentrated
under reduced pressure, and the resulting residue was purified
by flash silica gel chromatography to give 0.6 g (85%) of 31 as
°C; IR (neat) 3419, 1741, 1672, and 1232 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.94 (s, 3H), 0.95 (d, 3H, J ) 6.0 Hz),
1.16 (t, 3H, J ) 6.9 Hz), 1.23 (s, 3H), 1.64-1.67 (m, 2H), 1.79
(s, 3H), 2.03-2.15 (m, 2H), 2.26-2.37 (m, 2H), 2.84-2.89 (m,
1H), 3.02 (dt, 1H, J ) 12.3 and 4.5 Hz), 4.09 (q, 2H, J ) 6.9
Hz), 4.47 (s, 1H), and 4.58 (ddd, 1H, J ) 12.3, 6.0, and 1.5
Hz); 13C NMR (CDCl3, 75 MHz) δ 14.1, 17.3, 18.4, 18.8, 20.4,
21.6, 28.1, 28.6, 30.6, 39.2, 39.9, 61.6, 78.8, 122.4, 125.5, 126.5,
127.3, 167.1, and 169.5. Anal. Calcd for C19H27NO4: C, 68.44;
H, 8.16; N, 4.20. Found: C, 68.32; H, 8.19; N, 4.14.
2-Dia zo-N-bu t-3-en yl-N-(3,7-d im eth yl-oct-6-en oyl)-m a -
lon a m ic Acid Eth yl Ester . To a solution containing 4.0 g
(28 mmol) of citronellic acid (7) in 125 mL of CH2Cl2 was added
6.8 g (42 mmol) of 1,1′-carbonyldiimidazole, and the solution
was stirred at room temperature for 1 h. To this reaction
mixture was added 6.0 g (56 mmol) of but-3-enylamine41 in
100 mL of CH2Cl2. The solution was allowed to warm to room
temperature, stirred for 12 h, and concentrated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 2.5 g (40%) of 3,7-dimethyl-oct-6-enoic acid
but-3-enyl-amide as a clear oil: IR (neat) 3292, 1640, and 1552
1
an clear oil: IR (neat) 2955, 1749, 1726, and 1111 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.89-0.93 (m, 1H), 0.97 (d, 3H, J )
6.6 Hz), 1.01 (s, 3H), 1.13 (s, 3H), 1.22 (t, 1H, J ) 7.2 Hz),
1.32 (t, 3H, J ) 7.2 Hz), 1.46-1.47 (m, 1H), 1.50-1.54 (m, 1H),
1.66-1.67 (m, 1H), 1.70-1.71 (m, 1H), 1.72-1.81 (m, 1H),
2.05-2.20 (m, 1H), 2.64 (t, 1H, J ) 6.9 Hz), 2.70 (t, 1H, J )
6.3 Hz), 2.82 (t, 1H, J ) 7.2 Hz), 2.88 (t, 1H, J ) 7.2 Hz), 4.37
(q, 2H, J ) 7.2 Hz), and 9.75 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 14.5, 21.0, 22.2, 26.3, 26.5, 28.4, 33.0, 33.6, 36.5, 43.6,
44.8, 51.1, 61.9, 91.9, 96.4, 165.2, 170.0, and 200.0; HRMS
calcd for C18H27NO5 337.1889, found 337.1888.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.93 (d, 3H, J ) 6.3 Hz),
2-H yd r oxy-1,1,8-t r im e t h yl-3-oxo-2,3,6,7-t e t r a h yd r o-
1H,5H-p yr id o[3,2,1-ij]qu in olin e-2-ca r boxylic Acid Eth yl
Ester (34). A solution containing 0.1 g (0.3 mmol) of aldehyde
31 in 30 mL of acetonitrile was treated with 4 mg of p-
toluenesulfonic acid. The reaction mixture was refluxed for 24
h, and the solution was concentrated under reduced pressure.
The crude residue was then subjected to flash silica gel
chromatography to afford 60 mg (64%) of 34 as a white solid:
1.15-1.26 (m, 1H), 1.30-1.42 (m, 1H), 1.60 (s, 3H), 1.68 (s,
3H), 1.86-2.06 (m, 4H), 2.18 (dd, 1H, J ) 12.5 and 4.8 Hz),
2.26 (q, 2H, J ) 6.6 Hz), 3.33 (m, 2H), 5.01-5.13 (m, 3H), 5.42
(brs, 1H), and 5.70-5.83 (m, 1H); 13C NMR (CDCl3, 75 MHz)
δ 17.7, 19.6, 25.6, 25.8, 30.6, 34.0, 37.0, 38.5, 44.6, 117.1, 124.5,
131.5, 135.5 and 172.7.
N-Malonylacylation was carried out on the above amide in
the normal manner gave 2.3 g (85%) of N-but-3-enyl-N-(3,7-
dimethyl-oct-6-enoyl)-malonamic acid ethyl ester as a colorless
1
mp 88-89 °C; IR (neat) 1744, 1662, and 1457 cm-1; H NMR
(CDCl3, 300 MHz) δ 0.96 (t, 3H, J ) 7.2 Hz), 1.14 (s, 3H), 1.46
(s, 3H), 1.91-1.97 (m, 1H), 2.05-2.11 (m, 1H), 2.23 (s, 3H),
2.71 (dt, 2H, J ) 7.6 and 5.2 Hz), 3.31-3.40 (m, 1H), 3.92-
4.02 (m, 2H), 4.45 (s, 1H), 4.55 (dt, 1H, J ) 14.1 and 4.2 Hz),
6.90 (d, 1H, J ) 7.6 Hz), and 7.00 (d, 1H, J ) 7.0 Hz); 13C
NMR (CDCl3, 75 MHz) δ 14.0, 19.8, 21.5, 24.7, 25.0, 40.4, 41.4,
53.6, 61.9, 79.2, 122.1, 123.9, 125.5, 130.8, 134.1, 135.9, 167.7,
and 169.4. Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N,
4.41. Found: C, 68.19; H, 7.34; N, 4.44.
oil: IR (neat) 3079, 1744, 1699, and 1029 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 0.89 (d, 3H, J ) 6.6 Hz), 1.14-1.26 (m,
1H), 1.20 (t, 3H, J ) 7.2 Hz), 1.26-1.36 (m, 1H), 1.54 (s, 3H),
1.62 (s, 3H), 1.89-2.04 (m, 3H), 2.25-2.35 (m, 3H), 2.52 (dd,
1H, J ) 16.2 and 5.4 Hz), 3.71 (q, 2H, J ) 7.5 Hz), 3.75 (s,
(41) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida, Z. J . Am.
Chem. Soc. 1988, 110, 3994.

564 J . Org. Chem., Vol. 64, No. 2, 1999
Brodney and Padwa
2-Hydr oxy-1,1,8-tr im eth yl-3-oxo-2,3,6,8,9,10-h exah ydr o-
1H,5H-p yr id o[3,2,1-ij]qu in olin e-2-ca r boxylic Acid Eth yl
Ester (32). A solution containing 0.1 g (0.3 mmol) of aldehyde
31 in 30 mL of acetonitrile was treated with 5 mg of p-
toluenesulfonic acid. The solution was heated at reflux for 6
h, and the solution was evaporated under reduced pressure.
The crude residue was subjected to flash silica gel chroma-
tography to afford 0.02 g (20%) of lactam 34 and 0.06 g (60%)
of 32 as a white solid: mp 67-68 °C; IR (neat) 3419, 1739,
1.47-1.60 (m, 2H), 1.68-1.76 (m, 2H), 2.17-2.22 (m, 1H),
3.86-3.89 (m, 2H), 4.38 (q, 2H, J ) 7.2 Hz), 5.16-5.30 (m,
2H), and 5.69-5.82 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.4,
20.9, 22.2, 26.2, 26.4, 28.3, 32.9, 36.6, 42.2, 44.7, 51.3, 61.8,
92.1, 96.0, 118.1, 133.2, 165.4, and 169.1; HRMS calcd for
C
18H27O4N 321.1940, found 321.1941.
A solution of 0.5 g (1.6 mmol) of the above cycloadduct in
35 mL of CH2Cl2 was cooled to -78 °C, and ozone was bubbled
through the solution for 20 min. The solution was quenched
with 0.6 mL (7.8 mmol) of dimethyl sulfide and was warmed
to room temperature. After 6 h of stirring at 25 °C, this
solution was added to 10 mL of H2O and extracted with ethyl
acetate, and the extracts were dried over Na2SO4. The solution
was concentrated under reduced pressure, and the resulting
residue was purified by flash silica gel chromatography to give
0.4 g (83%) of 35 as a clear oil: IR (neat) 1748, 1732, and 1116
1670, and 1112 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.97 (s,
;
3H), 1.04 (d, 3H, J ) 7.2 Hz), 1.17 (t, 3H, J ) 6.9 Hz), 1.21 (s,
3H), 1.45-1.55 (m, 1H), 1.65-1.75 (m, 1H), 2.11-2.24 (m, 2H),
2.27-2.32 (m, 2H), 2.34-2.46 (m, 1H), 2.96-3.06 (m, 1H), 4.10
(dq, 2H, J ) 6.9 and 2.7 Hz), 4.44 (s, 1H), 4.57 (ddd, 1H, J )
12.5, 5.3, and 2.1 Hz), and 5.58 (d, 1H, J ) 3.6 Hz); 13C NMR
(CDCl3, 75 MHz) δ 14.1, 18.8, 19.7, 21.8, 24.3, 29.2, 33.2, 39.4,
39.9, 61.7, 79.1, 105.6, 118.3, 124.1, 126.7, 134.4, 167.3, and
169.5. Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.42; H, 7.97; N, 4.24.
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.94 (d, 3H, J ) 6.6 Hz),
0.87-0.90 (m, 1H), 0.96-0.99 (m, 1H), 1.08 (s, 3H), 1.17-1.23
(m, 1H), 1.26 (s, 3H), 1.36 (t, 3H, J ) 7.2 Hz), 1.37-1.42 (m,
1H), 1.69-1.80 (m, 2H), 1.89 (dd, 1H, J ) 12.3 and 6.0 Hz),
2.13-2.19 (m, 1H), 4.10 (s, 2H), 4.39 (q, 2H, J ) 7.2 Hz), and
9.57 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.5, 20.9, 22.1, 26.2,
26.4, 28.4, 32.9, 36.5, 44.8, 49.5, 50.9, 61.9, 92.1, 96.3, 165.0,
169.8, and 196.8; HRMS calcd for C17H25NO5 323.1733, found
323.1731.
N-Allyl-2-d ia zo-N-(3,7-d im eth yl-oct-6-en oyl)-m a lon a m -
ic Acid Eth yl Ester . To a solution containing 4.0 g (28 mmol)
of citronellic acid (7) in 125 mL of CH2Cl2 was added 6.8 g (42
mmol) of 1,1′-carbonyldiimidazole, and the solution was stirred
at room temperature for 2 h. The reaction mixture was then
charged with 3.2 g (56 mmol) of freshly distilled allylamine at
0 °C. The solution was allowed to warm to room temperature,
stirred for 10 h, and concentrated under reduced pressure. The
residue was subjected to flash silica gel chromatography to
give 4.6 g (78%) of 3,7-dimethyl-oct-6-enoic acid allyl amide
5-Hydr oxy-6,6,9-tr im eth yl-4-oxo-5,6,6a,7,8,9-h exah ydr o-
4H-p yr r olo-[3,2,1-ij]qu in olin e-5-ca r boxylic Acid Eth yl
Ester (37). A solution containing 0.1 g (0.3 mmol) of aldehyde
35 in 30 mL of acetonitrile was treated with 6 mg of p-
toluenesulfonic acid. The mixture was heated at reflux for 12
h, and the solution was concentrated under reduced pressure.
The crude residue was subjected to flash silica gel chroma-
tography to give 0.07 g (70%) of 37 as a colorless oil: IR (neat)
1743, 1715, and 1251 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.79
(t, 3H), 1.11 (s, 3H), 1.18 (d, 3H, J ) 6.9 Hz), 1.25 (t, 3H, J )
7.2 Hz), 1.28-1.38 (m, 1H), 1.69-1.73 (m, 1H), 1.84-1.91 (m,
1H), 2.05-2.21 (m, 1H), 2.59-2.66 (m, 1H), 2.94-3.00 (m, 1H),
4.10 (bs, 1H), 4.20-4.31 (m, 2H), 6.23 (d, 1H, J ) 3.3 Hz), and
7.20 (dd, 1H, J ) 3.3 and 0.9 Hz); 13C NMR (CDCl3, 75 MHz)
δ 14.3, 17.4, 21.0, 21.1, 24.0, 29.1, 33.1, 39.2, 44.9, 62.8, 83.2,
113.6, 116.4, 127.1, 130.5, 167.4, and 169.9; HRMS calcd for
as a colorless oil: IR (neat) 3289, 1653, and 1110 cm-1 1H
;
NMR (CDCl3, 300 MHz) δ 0.86 (d, 3H, J ) 6.0 Hz), 1.08-1.18
(m, 1H), 1.24-1.35 (m, 1H), 1.52 (s, 3H), 1.59 (s, 3H), 1.86-
1.96 (m, 4H), 2.10-2.20 (m, 1H), 3.79 (dt, 1H, J ) 5.6 and 1.0
Hz), 4.99-5.13 (m, 2H), 5.67-5.82 (m, 1H), and 6.40 (brs, 1H);
13C NMR (CDCl3, 75 MHz) δ 17.7, 19.6, 25.5, 25.7, 30.5, 37.0,
41.9, 44.3, 116.0, 124.4, 131.4, 134.6, and 172.7.
N-Malonylacylation was carried out on the above amide in
the normal manner to give 6.6 g (88%) of N-allyl-N-(3,7-
dimethyl-oct-6-enoyl)-malonamic acid ethyl ester as a colorless
oil: IR (neat) 1742, 1702, and 1190 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 0.93 (d, 3H, J ) 6.6 Hz), 1.17-1.26 (m, 1H), 1.27
(t, 3H, J ) 7.1 Hz), 1.33-1.39 (m, 1H), 1.59 (s, 3H), 1.67 (s,
3H), 1.70-1.73 (m, 1H), 1.95-2.09 (m, 2H), 2.36 (dd, 1H, J )
16.4 and 8.4 Hz), 2.56 (dd, 1H, J ) 16.4 and 2.3 Hz), 3.86 (s,
2H), 4.19 (q, 2H, J ) 7.7 Hz), 4.35-4.45 (m, 2H), 5.05-5.10
(m, 1H), 5.17-5.23 (m, 2H), and 5.78-5.90 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 14.3, 17.9, 19.9, 25.7, 25.9, 29.5, 37.0, 43.9,
46.1, 46.6, 61.5, 116.6, 124.4, 131.9, 132.7, 167.6, 168.6 and
175.6; HRMS calcd for C18H29NO4 323.2096, found 323.2082.
The above compound was subjected to the standard diazo
transfer conditions to give 4.5 g (70%) of N-allyl-2-diazo-N-
(3,7-dimethyl-oct-6-enoyl)-malonamic acid ethyl ester as a
yellow oil: IR (neat) 2128, 1720, 1695, and 1320 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.87 (d, 3H, J ) 6.9 Hz), 1.10-1.19 (m,
1H), 1.23 (t, 3H, J ) 7.2 Hz), 1.28-1.36 (m, 1H), 1.52 (s, 3H),
1.60 (s, 3H), 1.57-1.63 (m, 1H), 1.86-1.99 (m, 1H), 2.27 (dd,
1H, J ) 15.9 and 7.8 Hz), 2.47 (dd, 1H, J ) 15.9 and 5.7 Hz),
4.19 (q, 2H, J ) 7.2 Hz), 4.22-4.30 (m, 2H), 4.99-5.03 (m,
1H), 5.09-5.22 (m, 2H), and 5.73-5.84 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 14.5, 17.9, 19.9, 25.7, 25.9, 29.9, 37.1, 43.2,
48.2, 62.0, 72.9, 117.4, 124.5, 131.7, 133.4, 160.7, 166.4, and
175.0.
3,7,7-Tr im et h yl-9-oxo-10-(2-oxo-et h yl)-11-oxa -10-a za -
tr icyclo-[6.2.1. 01,6]u n d eca n e-8-ca r boxylic Acid Eth yl Es-
ter (35). A solution of 3.4 g (9.8 mmol) of the above diazo imide
in 60 mL of CH2Cl2 at room temperature was treated with 5
mg of rhodium(II) perfluorobutyrate. The reaction mixture was
stirred for 24 h at room temperature and was concentrated
under reduced pressure. The resulting residue was purified
by flash silica gel chromatography to give 2.8 g (87%) of 10-
allyl-3,7,7-trimethyl-9-oxo-11-oxa-10-aza-tricyclo[6.2.1.01,6]-
undecane-8-carboxylic acid ethyl ester as a colorless oil: IR
(neat) 1754, 1722, 1403, and 1114 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.82-0.89 (m, 1H), 0.95 (d, 3H, J ) 6.3 Hz), 1.05 (s,
3H), 1.21 (s, 3H), 1.31-1.43 (m, 2H), 1.35 (t, 3H, J ) 7.2 Hz),
C
17H23NO4 305.1627, found 305.1625.
2-Dia zo-N-h ep t-6-en oyl-N-[2-(2-iod op h en yl)eth yl]-m a -
lon a m ic Acid Eth yl Ester (38). To a solution containing 1.9
g (14.4 mmol) of hept-6-enoic acid in 175 mL of CH2Cl2 was
added 2.4 g (15 mmol) of 1,1′-carbonyldiimidazole, and the
solution was stirred at room temperature for 2 h. The reaction
mixture was charged with 3.6 g (15 mmol) of 2-(2-iodo-phenyl)-
ethylamine. The solution was stirred for 8 h and concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography to give 4.0 g (77%) of hept-6-enoic
acid [2-(2-iodophenyl)ethyl] amide as a white solid: mp 38-
39 °C; IR (neat) 3281, 1645, and 1552 cm-1; 1H NMR (CDCl3,
300 MHz) δ 1.29-1.39 (m, 2H), 1.53-1.63 (m, 2H), 2.00 (q,
2H, J ) 6.9 Hz), 2.10 (t, 2H, J ) 7.5 Hz), 2.90 (t, 2H, J ) 6.9
Hz), 3.46 (q, 2H, J ) 6.6 Hz), 4.92 (m, 2H), 5.67 (bs, 1H), 5.69-
5.80 (m, 1H), 6.84-6.89 (m, 1H), 7.15-7.24 (m, 2H), and 7.77
(d, 1H, J ) 8.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 25.3, 28.7,
33.6, 36.7, 39.6, 40.4, 100.8, 114.9, 128.6, 128.7, 130.2, 138.6,
139.8, 141.8, and 173.2. Anal. Calcd for C15H20NOI: C, 50.43;
H, 5.64; N, 3.92. Found: C, 50.56; H, 5.70; N, 3.91.
N-Malonylacylation was carried out on the above amide in
the normal manner to give 4.9 g (97%) of N-hept-6-enoyl-N-
[2-(2-iodo-phenyl)ethyl]-malonamic acid ethyl ester as a color-
less oil: IR (neat) 1737, 1694, 1630, and 1190 cm-1; H NMR
1
(CDCl3, 300 MHz) δ 1.24 (t, 3H, J ) 7.2 Hz), 1.30 (quint, 2H,
J ) 7.5 Hz), 1.52 (quint, 2H, J ) 7.5 Hz), 1.99 (dd, 2H, J )
14.1 and 6.9 Hz), 2.44 (t, 2H, J ) 7.2 Hz), 2.99 (t, 2H, J ) 7.2
Hz), 3.79 (s, 2H), 3.86 (t, 2H, J ) 7.5 Hz), 4.16 (q, 2H, J ) 7.2
Hz), 4.89-4.98 (m, 2H), 5.66-5.79 (m, 1H), 6.89-6.92 (m, 1H),
7.25-7.26 (m, 2H), and 7.77 (d, 1H, J ) 7.8 Hz); 13C NMR
(CDCl3, 75 MHz) δ 14.3, 24.1, 28.4, 33.6, 36.6, 39.7, 44.6, 46.7,
61.4, 100.5, 114.9, 128.9, 129.0, 131.0, 138.4, 139.7, 141.2,
167.5, 169.0, and 176.0; HRMS calcd for C20H26NO4I 471.0908,
found 471.0899.

N-Acyliminium Ions
J . Org. Chem., Vol. 64, No. 2, 1999 565
The above compound was subjected to the standard diazo
was added 0.12 g (0.8 mmol) of iodomethane, and the mixture
was stirred at room temperature for 3h. The mixture was
quenched with 5 mL of H2O and extracted with CH2Cl2. The
organic extracts were dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude residue was sub-
jected to flash silica gel chromatography to give 0.16 g (60%)
of 41 as a colorless oil: IR (neat) 1730, 1673, 1460, and 1253
transfer conditions to give 4.6 g (90%) of 38 as a yellow oil:
1
IR (neat) 2135, 1737, 1652, and 1588 cm-1; H NMR (CDCl3,
300 MHz) δ 1.25 (t, 3H, J ) 7.2 Hz), 1.36 (quint, 2H, J ) 7.5
Hz), 1.60 (quint, 2H, J ) 7.5 Hz), 2.01 (dd, 2H, J ) 14.2 and
7.5 Hz), 2.49 (t, 2H, J ) 7.5 Hz), 3.02 (t, 2H, J ) 7.5 Hz), 3.83
(t, 2H, J ) 7.5 Hz), 4.21 (q, 2H, J ) 7.2 Hz), 4.89-4.99 (m,
2H), 5.68-5.82 (m, 1H), 6.85-6.90 (m, 1H), 7.19-7.23 (m, 2H),
and 7.77 (d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3, 75 MHz) δ
14.5, 24.6, 28.6, 33.7, 36.1, 40.5, 46.3, 62.0, 77.5, 100.5, 114.8,
128.8, 128.9, 131.1, 138.6, 139.7, 141.1, 160.6, 166.5, and 175.7.
10-[2-(2-Iodop h en yl)eth yl]-9-oxo-11-oxa -10-a za tr icyclo-
[6.2.1.01,6]-u n d eca n e-8-ca r boxylic Acid Eth yl Ester (39).
A solution containing 0.6 g (1.3 mmol) of diazoimide 38 in 50
mL of CH2Cl2 at room temperature was treated with 5 mg of
rhodium(II) perfluorobutyrate. The reaction mixture was
stirred for 12 h at room temperature and was then concen-
trated under reduced pressure. The resulting residue was
purified by flash silica gel chromatography to give 0.51 g (86%)
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.24 (t, 3H, J ) 7.2 Hz),
1.46-1.64 (m, 3H), 1.96-1.99 (m, 3H), 2.04-2.09 (m, 1H), 2.36
(d, 1H J ) 16.2 Hz), 2.61 (d, 1H, J ) 16.2 Hz), 2.96 (t, 2H, J
) 7.5 Hz), 3.47 (s, 3H), 3.61-3.71 (m, 1H), 3.75-3.87 (m, 1H),
3.99-4.13 (m, 1H), 4.17-4.31 (m, 2H), 6.83-6.88 (m, 1H),
7.18-7.27 (m, 2H), 7.75 (d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3,
75 MHz) δ 14.4, 22.2, 22.9, 25.6, 29.3, 35.1, 39.7, 41.7, 54.9,
61.8, 80.6, 100.6, 112.3, 128.6, 128.5, 130.8, 131.1, 139.5, 142.0,
166.4, and 169.6; HRMS calcd for C21H26NO4I 483.0906, found
483.0898.
2-Met h oxy-3-oxo-1,2,3,4,5,10,11,12,13,13a -d eca h yd r o-
3a -a za -ben zo[d ]p h en a n th r en e-2-ca r boxylic Acid Eth yl
Ester (42). To a flask containing 0.09 g (0.2 mmol) of the above
methyl ether 41 in 30 mL of benzene at room temperature
was added 0.07 g (0.2 mmol) of Bu3SnH and 10 mg of AIBN
over a 2 h period, and the mixture was heated at reflux for 12
h. The reaction mixture was quenched with 2 mL of a
saturated KF solution and extracted with ethyl acetate. The
organic extracts were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.03 g
(45%) of 42 as a white solid: mp 132-133 °C; IR (neat) 2935,
of 39 as a clear oil: IR (neat) 1740, 1695, 1644, and 1062 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.19-1.28 (m, 2H), 1.37 (t, 3H,
J ) 6.9 Hz), 1.56-1.66 (m, 1H), 1.79-1.81 (m, 3H), 1.85-1.96
(m, 2H), 2.01-2.07 (m, 1H), 2.09-2.14 (m, 1H), 2.23 (dd, 1H,
J ) 12.6 and 7.2 Hz), 2.93-3.01 (m, 2H), 3.25-3.35 (m, 1H),
3.39-3.48 (m, 1H), 4.38 (dq, 2H, J ) 7.1 and 2.7 Hz), 6.90-
6.96 (m, 1H), 7.26-7.33 (m, 2H), and 7.81 (d, 1H, J ) 7.5 Hz);
13C NMR (CDCl3, 75 MHz) δ 14.4, 21.7, 24.8, 27.7, 32.8, 37.1,
40.2, 40.3, 42.4, 62.3, 86.1, 97.1, 100.4, 128.8, 128.9, 130.7,
139.7, 141.2, 166.2, and 171.6; HRMS calcd for C20H24O4NI:
469.0752, found 469.0766.
1730, and 1628 cm-1 1H NMR (CDCl3, 400 MHz) δ 0.86 (t,
;
3-Hydr oxy-1-[2-(2-iodoph en yl)eth yl]-2-oxo-1,2,3,4,5,6,7,8-
octa h yd r o-qu in olin e-3-ca r boxylic Acid Eth yl Ester (40).
To a flask containing 2.0 g (4.3 mmol) of the cycloadduct 39 in
50 mL of CH2Cl2 at 0 °C was added 1.2 g (8.5 mmol) of BF3‚
OEt2, and the solution was stirred at 0 °C for 1 h. The reaction
mixture was quenched with 4 mL of H2O and extracted with
CH2Cl2. The organic extracts were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude residue
was subjected to flash silica gel chromatography to give 1.9 g
(97%) of 40 as a colorless oil: IR (neat) 3416, 1730, 1666, and
3H, J ) 7.2 Hz), 1.35-1.43 (m, 1H), 1.47-1.54 (m, 1H), 1.61-
1.68 (m, 2H), 1.80-1.86 (m, 2H), 1.94 (d, 1H, J ) 11.1 Hz),
2.14 (dq, 1H, J ) 13.6 and 4.6 Hz), 2.29-2.45 (m, 3H), 2.81
(dd, 1H, J ) 17.2 and 6.0 Hz), 3.23 (dt, 1H, J ) 17.2 and 9.6
Hz), 3.47-3.56 (m, 1H), 3.58 (s, 3H), 3.85-3.99 (m, 2H), 4.73
(ddd, 1H, J ) 13.6, 9.2, and 2.0 Hz), 7.07-7.18 (m, 3H), and
7.52 (d, 1H), J ) 8.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 13.7,
21.4, 25.2, 27.0, 30.1, 35.2, 36.6, 39.4, 39.5, 55.3, 61.1, 61.7,
81.5, 124.6, 126.2, 127.0, 130.7, 136.3, 140.5, 166.2, and 170.8;
HRMS calcd for C21H27NO4 357.1939, found 357.1933.
1
1467 cm-1; H NMR (CDCl3, 300 MHz) δ 1.24 (t, 3H, J ) 7.2
Hz), 1.28-1.50 (m, 2H), 1.60-1.69 (m, 1H), 1.73-1.78 (m, 1H),
1.93-2.04 (m, 3H), 2.09-2.19 (m, 1H), 2.37 (d, 1H, J ) 15.6
Hz), 2.61 (d, 1H, J ) 15.9 Hz), 2.94-3.10 (m, 2H), 3.57-3.66
(m, 1H), 3.98-4.07 (m, 1H), 4.19 (dq, 2H, J ) 7.1 and 2.4 Hz),
4.59 (s, 1H), 6.88-6.94 (m, 1H), 7.25-7.29 (m, 2H), and 7.80
(d, 1H, J ) 8.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.3, 22.1,
22.8, 25.5, 29.3, 35.1, 39.6, 42.2, 61.9, 73.8, 100.6, 114.4, 128.6,
128.7, 130.7, 131.4, 139.6, 141.5, 168.8, and 170.1. Anal. Calcd
for C20H24NO4I: C, 51.18; H, 5.15; N, 2.98. Found: C, 51.19;
H, 5.16; N, 2.95.
1-[2-(2-Iodoph en yl)eth yl]-3-m eth oxy-2-oxo-1,2,3,4,5,6,7,8-
octa h yd r o-qu in olin e-3-ca r boxylic Acid Eth yl Ester (41).
To a flask containing 0.3 g (0.6 mmol) of alcohol 40 in 25 mL
of THF at 0 °C was added 0.02 g (0.8 mmol) of NaH, and the
mixture was stirred for 45 min at 0 °C. To the reaction mixture
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health for generous support of
this work. Use of high-field NMR spectrometers used
in these studies was made possible through equipment
grants from the NIH and NSF.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for new compounds lacking analyses (15 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
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J O981624E