A short synthesis of (±)-tecomanine via a Pauson-Khand-based route

Article abstract of DOI:10.1016/S0040-4020(03)00779-8

The N-carboethoxy precursor to (±)-tecomanine has been prepared in 11 steps from 2-methyl-1-buten-3-yne. The key step, Pauson-Khand cyclization of a methylated 5-aza-6-nonen-1-yne succeeds, but only in low yield, a consequence of the dialkyl substitution about the azaenyne framework. Nevertheless, the overall sequence to that point is one of the more efficient to be described.

Full text of DOI:10.1016/S0040-4020(03)00779-8

Tetrahedron 59 (2003) 5377–5381
A short synthesis of (6)-tecomanine via a
Pauson–Khand-based route
*
Denise A. Ockey, Mark A. Lewis and Neil E. Schore
Department of Chemistry, University of California, Davis, CA 95616 USA
Received 31 July 2002; revised 4 September 2002; accepted 4 September 2002
Abstract—The N-carboethoxy precursor to (^)-tecomanine has been prepared in 11 steps from 2-methyl-1-buten-3-yne. The key step,
Pauson–Khand cyclization of a methylated 5-aza-6-nonen-1-yne succeeds, but only in low yield, a consequence of the dialkyl substitution
about the azaenyne framework. Nevertheless, the overall sequence to that point is one of the more efficient to be described. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Tecomanine, 1, a substance with powerful hypoglycemic
activity, is one of a number of naturally-occurring alkaloids
with cyclopentanopyridine- or cyclopentanopiperidine-
based structures.1 First isolated by Hammouda and
Motawi,2 tecomanine has been synthesized in several
ways.3 We chose to explore the possibility that tecomanine
might be efficiently accessed via direct Pauson–Khand
cyclization of a suitably substituted alkenylalkynylamine
precursor 2, without the need to introduce the methyl groups
subsequent to cycloaddition (Fig. 1). It is well-known that
acyclic internal alkenes often fare poorly in the Pauson–
Khand process, but we hoped that recent advances in the
state of the art in Pauson–Khand chemistry would enable us
to develop conditions to overcome that problem.4 As to the
choice of group R in the substrate, that would also be
dictated by the limitations of the cyclization process. During
the course of our investigations, Whitby, et al. reported the
synthesis of tecomanine using a related zirconocene-based
cyclization strategy.3f We report herein the results of our
efforts.
Our synthesis of cyclization substrate 2 differed from that of
Whitby, et al. in several ways. Theirs utilized addition of a
1,2-butadienylaluminum reagent to paraformaldehyde to
obtain 2-methyl-3-butyn-1-ol. The tosylate of the latter was
then coupled with N-methyl-2-buten-1-amine, which had
been obtained as an E/Z mixture by alkylation of
N-methyltrifluoroacetamide with crotyl chloride.
We instead chose to protect the terminal carbon of
2-methylbutenyne, allowing a sequence of epoxidation,
ring opening, and displacement to give the protected
2-methyl-3-butyn-1-amine 7 in 35% overall yield
(Scheme 1).
The method of Nussbaumer and Stu¨tz5 for reductive ring
opening of epoxide 4 using DIBAL-H was the key to
obtaining 5 with 100% regioselectivity and free of any
allenic isomer. Applying Mitsunobu’s method6 to the
conversion of 5 into the corresponding amine 7 was
similarly effective. With the latter in hand our first thought
was to prepare the N-trifluoroacetyl derivative for N-crotyl-
ation, followed by deprotection of the alkyne terminus: any
subsequent Pauson–Khand would stand little chance of
success with both an internal alkene and a silylated alkyne.
However, this route proved problematic: although partial
desilylation of 7 was observed during the N-acylation/
N-alkylation sequence, all attempts to complete the
deprotection of the alkyne terminus led to significant
formation of allenic material. Fortunately, we found that
desilylation could be carried out immediately after
N-trifluoroacetylation without complication. Subsequent
alkylation at nitrogen with crotyl chloride followed by
hydrolysis and carbamate formation gave cyclization
precursor 12 in 36% overall yield (Scheme 2).
Figure 1. Pauson–Khand approach to tecomanine.
Keywords: alkaloid; amine; cyclopentenone; Pauson–Khand reaction;
tecomanine.
*
Corresponding author. Tel.: þ1-530-752-6263; fax: þ1-530-754-7610;
e-mail: neschore@ucdavis.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00779-8

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D. A. Ockey et al. / Tetrahedron 59 (2003) 5377–5381
Scheme 1. (a) n-BuLi, THF, then t-BuMe2SiCl, 2788C to room temperature, 12 h (90%); (b) m-ClC6H4CO3H, CH2Cl2, 08C, 12 h (75%); (c) i-Bu2AlH, THF,
-35 to 08C, 3 h (83%); (d) phthalimide, Ph3P, DEAD, THF, 08C to room temperature, 48 h (81%); (e) N2H4, EtOH, 858C, 3 h (75%).
Scheme 2. (a) (CF3CO)2O, Et2O, 08C to room temperature, 1 h (98%); (b) n-Bu4Nþ F2, THF, 658C, 4 h (72%); (c) KH, THF, 08C to room temperature, 0.5 h,
then 18-crown-6, trans-CH3CHvCHCH2Cl, 658C, 6 h (62%); (d) KOH, MeOH, 08C, 1 h (98%); (e) Et3N, THF, EtOCOCl, 08C to room temperature, 1 h
(85%).
Pauson–Khand cyclizations of allyl 3-butynyl amines have
been reported by several groups. The first, by Brown and
Pauson, described cyclization of the N-acetyl derivative of
the parent compound in 30–44% yields, with the best
conditions being heating to 708C of the silica-adsorbed
substrate.7 Bolton succeeded in cyclizing several N-tosyl
systems in yields up to 90þ%, using NMO activation of
Co2(CO)8 in CH2Cl2 both in solution and polymer
supported.8 These studies also include the only report of
attempted cyclizations of substrates with internal double
bonds prior to our work, the phenyl derivative shown in
Figure 2, below, being the best example, proceeding in 51%
yield. Though encouraging, this successful result does not
quite emulate our situation, because the Pauson–Khand
process has been found to be much more tolerant of phenyl
substitution than alkyl substitution at the reactive centers of
the substrate.4
used to give in some cases quite satisfactory yields. An
Rh-based variant is also known.14
Prior to testing carbamate 12 under Pauson–Khand
conditions we had previously attempted cyclizations of
several related substrates, including N-acetyl and N-tosyl
analogs of 12, under a variety of conditions—thermal, solid
phase, and promoted. Only in the case of tosyl derivative 13
was any enone formation observed—a 6% yield of 15 upon
treatment with Co2(CO)8 in CH2Cl2 followed by addition of
TMANO under an O2 atmosphere. Interestingly, in other
preliminary studies we found that butenyl butynyl ethers
and amines lacking the propargylic methyl substituent gave
somewhat superior results: yields in the 20–25% range were
obtained, although in the case of the ether evidence for some
reduction to the saturated cyclopentanone under Pauson–
Khand conditions was observed (IR absorption at
1727 cm21).7 In any event, after considerable experimen-
tation, cyclization of 12 itself was finally achieved upon
treatment with Co2(CO)8 and NMO in CH2Cl2, although the
16% yield of the product 14 was still disappointingly low
(Fig. 3). As this compound has been previously converted
into tecomanine, it does constitute a formal synthesis of the
Krafft,9 Alcaide and Sierra,10 Perez-Castells,11 Kotha,12 and
´
most recently Magnus13 have reported cyclizations of a
variety of allylic amines. In all cases the nitrogen is
substituted with a conjugating moiety, and any of several
promoters (amine oxides, molecular sieves, thioethers) are
Figure 2. Pauson–Khand cyclization of a phenyl-substituted allyl butynyl amine derivative.
Figure 3. Pauson–Khand cyclizations of 12 and 13.

D. A. Ockey et al. / Tetrahedron 59 (2003) 5377–5381
5379
natural product. Unfortunately, the low yield in the final step
prevents it from being similarly efficient to syntheses
previously described.3a,b
4.1.2. 1-(tert-Butyldimethylsilyl)-3,4-epoxy-3-methyl-1-
butyne (4). A solution of 1.56 g (5.54 mmol) of MCPBA
in 5 mL of CH2Cl2 was cooled to 08C. A solution of 1.0 g of
3 (5.54 mmol) in CH2Cl2 was added via cannula. The
solution was the stirred at 08C for 30 min, then allowed to
warm to room temperature, stirred overnight, and then
treated with 10 mL of sat’d aq NaCO3. The layers were
separated, the aqueous layer was extracted with 3£10 mL of
CH2Cl2, the combined extracts dried (MgSO4) and evapor-
ated. The product was purified by column chromatography
(CH2Cl2, Rf¼0.76) to yield 0.82 g of 4 (75% yield) as a light
3. Conclusions
An efficient synthesis of 2-butenyl 2-methyl-3-butynyl
amine derivatives, potential precursors to tecomanine and
related structures via Pauson–Khand cyclization, has been
achieved. The cyclization itself proceeds only poorly,
however, a consequence of the dialkyl substitution on the
alkene cyclization component. It is thus clear that, barring
appropriate improvements in the tolerance of the process for
sterically encumbered substrates, Pauson–Khand-based
routes to targets such as these should be designed to take
advantage of the superior reactivity of the simpler allyl
analogs: tecomanine has been successfully synthesized by
methylation at the a-carbon of the cyclization products of
the latter compounds.3e
1
orange oil. H NMR d 3.10 (d, J¼5.8 Hz, 1H), 2.74 (d,
J¼5.51 Hz, 1H), 1.55 (s, 3H), 0.93 (s, 9H), 0.10 (s, 6H). 13C
NMR d 105.3, 85.6, 55.6, 47.3, 26.0, 22.9, 16.5, -4.8. Anal
for C11H20SiO: calcd C 67.28%, H 10.27%, found C
66.80%, H 10.34%.
4.1.3. 4-(tert-Butyldimethylsilyl)-2-methyl-3-butyn-1-ol
(5). A solution of 1.0 g (5.1 mmol) of 4 in 5 mL of THF
was cooled to -358C. To the solution was added 5.1 mL of
DIBAL-H (1 M in THF). The mixture was then allowed to
warm slowly over 3 h to 08C. The reaction mixture was
quenched with 1 mL of MeOH, diluted with 10 mL of Et2O,
and then poured into an equal volume of a sat’d soln of
Rochelle’s salt. The mixture was warmed to room
temperature and stirred overnight. The layers were separ-
ated, the aqueous layer extracted with 3£15 mL of Et2O, the
combined extracts dried (MgSO4) and evaporated. Purifi-
cation by column chromatography (1:1 hexane/Et2O,
Rf¼0.65) gave 0.85 g of 5 (83% yield) as a colorless liquid.
1H NMR d 3.54 (dd, 1H, J¼5.3, 10.7 Hz), 3.51 (dd, 1H,
J¼5.3, 10.7 Hz), 2.70, (m, 1H), 1.73 (bs, 1H), 1.17 (d, 3H,
J¼6.6 Hz), 0.93 (s, 9H), 0.09 (s, 6H); 13C NMR d 108.8,
84.7, 66.7, 31.4, 30.4, 26.0, 17.0, -4.5. Anal for: C11H22SiO:
calcd C 66.60%, H 11.18%, found C 66.67%, H 11.19%.
4. Experimental
4.1. General
Solvents were purified and dried according to standard
procedures. All reactions were carried out under an
atmosphere of dry N2, unless indicated otherwise. All
NMR spectra were recorded at 298 K in CDCl3 at 300 MHz
(1H) or 75 MHz (13C). High resolution mass spectrometry
was provided by Dr Robert Barkley at the Mass Spec-
trometry Facility at the University of Colorado at Boulder.
Column chromatography was done using flash techniques
with silica gel (60–200 mesh) as the solid phase. Radial
chromatography was done on a Chromatotron using plates
of either 1, 2, or 4 mm film thickness. The solid phase used
was silica gel 60 PF, and compounds were visualized by
UV. Capillary gas chromatography was done on a Shimadzu
14A GC using a DB-101 column with a flame ionization
detector (FID) detector. Conditions: initial temperature
1508C; hold time 2.0 min; ramp 58/min; final temperature
2408C; hold time 5.0 min.
4.1.4. N-[4-(tert-Butyldimethylsilyl)-2-methyl-3-
butynyl]phthalimide (6). To
a solution of 0.74 g
(5.04 mmol) of phthalimide in 10 mL of THF was added
1.32 g of PPh3 and 1.0 g of 5. The mixture was cooled to
08C, and 0.97 mL (5.04 mmol) of diethyl azodicarboxylate
in 5 mL of THF was added dropwise. The mixture was
warmed to room temperature and stirred in the dark for 48 h.
The solvent evaporated, and the product was purified by
column chromatography (CH2Cl2, Rf¼0.66) to yield 1.34 g
of 6 (81% yield) as a yellow liquid. 1H NMR d 7.84 (dd, 2H,
J¼2.2, 5.5 Hz), 7.72 (dd, 2H, J¼2.9, 5.5 Hz), 3.83 (dd, 1H,
J¼8.4, 13.6 Hz), 3.62 (dd, 1H, J¼7.4, 13.2 Hz), 3.12 (m,
1H), 1.20 (d, 3H, J¼6.6 Hz), 0.78 (s, 9H), -0.03 (s, 6H); 13C
NMR d 168.0, 133.9, 132.0, 123.2, 108.0, 83.3, 42.8, 25.8,
18.3, 16.2, 8.3, -4.8; HRMS for C19H25NO2Si (Mþ): calcd
327.1655, found 327.1646.
4.1.1. 4-(tert-Butyldimethylsilyloxy)-2-methyl-1-buten-3-
yne (3).15 A solution of 2.0 g (29.4 mmol) of 2-methyl-1-
buten-3-yne in 10 mL of THF was cooled to 2788C. To the
cooled solution was added 11.74 mL of n-BuLi (2 M in
THF) dropwise. The mixture was stirred at 2788C for
30 min. To the cooled solution was added a solution of
4.43 g of tert-butyldimethylsilyl chloride (29.4 mmol) in
10 mL of THF. The reaction was allowed to warm slowly to
room temperature and was stirred for 12 h. The reaction was
quenched with 100 mL of water, the layers separated, the
aqueous layer extracted with 4£100 mL of pentane, and the
combined organic layers dried (MgSO4) and evaporated.
The product was purified by column chromatography
(pentane, Rf¼0.93) to yield 4.77 g of 3 (90% yield) as a
pale yellow oil. 1H NMR d 5.34 (s, 1H), 5.24 (s, 1H), 1.89 (s,
3H), 0.95 (s, 9H), 0.12 (s, 6H). 13C NMR d 127.0, 122.6,
107.1, 91.3, 26.1, 23.4, 16.6, -4.6. HRMS for C11H20Si
(Mþ): calcd 180.1334, found 180.1333.
4.1.5. 4-(tert-Butyldimethylsilyl)-2-methyl-3-butyn-1-
amine (7). A solution of 1.0 g (3.05 mmol) of 6 in 10 mL
of 95% EtOH was treated with 6.1 mL of a 1.0 M solution of
hydrazine hydrate in 95% ethanol. The mixture was refluxed
for 3 h, cooled to 08C, and made slightly acidic. Sat’d aq
NaHCO3 was added and the mixture was extracted with
3£20 mL of Et2O. The combined extracts were washed with
sat’d aq NaHCO3 and brine, and dried (KOH). The solvent
was evaporated and the product purified by column
chromatography (20% EtOH in Et2O, Rf¼0.59) to give

5380
D. A. Ockey et al. / Tetrahedron 59 (2003) 5377–5381
0.45 g of 7 (75% yield) as a colorless liquid. 1H NMR d 2.73
(dd, 1H, J¼5.9, 11.8 Hz), 2.63 (dd, 1H, J¼7.6, 11.8 Hz),
2.52 (m, 1H), 1.50 (br s, 2H), 1.17 (d, 3H, J¼7.1 Hz), 0.92
(s, 9H), 0.09 (s, 6H); 13C NMR d 110.3, 83.8, 48.0, 31.3,
A solution of 0.80 g (6.8 mmol) of 10 in 5 mL of MeOH was
cooled to 08C and treated with 2 pellets of solid KOH. After
warming to room temperature and stirring for 1 h, the layers
were separated and the aqueous phase extracted with
5£5 mL of Et2O, and the combined extracts dried
(MgSO4). Evaporation and column chromatography (1:1
hexane/Et2O, Rf¼0.36) gave 0.44 g of 11 (94% yield) as a
26.0, 18.1, 16.4, -4.5; FTIR (neat): 3369, 3293, 2163 cm21
.
4.1.6. N-[4-(tert-Butyldimethylsilyl)-2-methyl-3-
butynyl]trifluoroacetamide (8). To a solution of 1.0 g
(5.06 mmol) of 7 in 5 mL of Et2O was added dropwise at
08C a solution of 1.07 mL (7.59 mmol) of trifluoroacetic
anhydride in 3 mL of Et2O. The mixture was brought to
room temperature, stirred for 1 h, and cooled to 08C, at
which point 2.0 mL of water was added and the mixture
stirred for 5 min. Sat’d aq NaHCO3 was added, the layers
separated, the aqueous layer extracted with 3£10 mL of
Et2O, and the combined extracts dried (MgSO4). Evapor-
ation and column chromatography (1:1 hexane/Et2O,
Rf¼0.74) gave 1.45 g of 8 (98% yield) as a colorless liquid.
1H NMR d 6.72 (br s, 1H), 3.54 (m, 1H), 3.21 (m, 1H), 2.78
(m, 1H), 1.20 (d, 3H, J¼7.0 Hz), 0.90 (s, 9H), 0.05 (s, 6H);
13C NMR d 107.5, 85.9, 44.3, 27.2, 26.0, 18.2, 16.3, -4.6;
FTIR (neat): 2169, 1722 cm21; HRMS for C13H22F3NOSi
(Mþ): calcd 293.1423, found 293.1433. Anal for C13H22F3-
NOSi: calcd C 53.22%, H 7.56%, found C 53.34%, H
7.62%.
1
colorless liquid. H NMR d 5.60 (m, 2H), 3.20 (d, 2H,
J¼4.8 Hz), 2.80 (m, 4H), 2.10 (d, 1H, J¼2.2 Hz), 1.70 (d,
3H, J¼6.6 Hz), 1.20 (d, 3H, J¼6.3 Hz); 13C NMR d 130.0,
126.9, 105.1, 87.8, 70.0, 54.9, 51.5, 26.8, 18.7; FTIR (film):
3309, 2112, 968 cm21; HRMS for C9H15N (Mþ): calcd
137.1204, found 137.1207.
4.1.10. Ethyl N-[(E)-2-Butenyl]-N-(2-methyl-3-butynyl)-
carbamate (12). A solution of 0.32 g (2.3 mmol) of 11 and
0.32 mL (2.3 mmol) of Et3N in 5 mL of THF was treated
dropwise at 08C with a solution of 0.18 mL (2.3 mmol) of
ethyl chloroformate in 5 mL of THF. The mixture was
stirred for 1 h and allowed to warm to room temperature.
Water was added, the layers were separated and the aqueous
phase extracted with 3£10 mL of Et2O, and the combined
extracts dried (MgSO4). Evaporation and column chroma-
tography (1:1 hexane/Et2O, Rf¼0.61) gave 0.41 g of 12
1
(85% yield) as a colorless liquid. H NMR d 5.60 (m, 1H),
5.40 (m, 1H), 4.17 (q, 2H, J¼7.1 Hz), 4.1–3.8 (m, 2H),
3.4–3.2 (m, 2H), 2.80 (m, 1H), 2.02 (d, 1H, J¼2.1 Hz), 1.70
(d, 3H, J¼6.7 Hz), 1.23 (t, 3H, J¼7.0 Hz), 1.19 (d, 3H,
J¼7.2 Hz); 13C NMR d 156.5, 128.1, 126.4, 86.8, 69.4,
61.2, 51.7, 50.9, 49.7, 44.3, 25.3, 18.2, 17.6, 14.6; FTIR
(film): 2114, 1701 cm21; HRMS for C12H19NO2 (Mþ):
calcd 209.1365, found 209.1424.
4.1.7. N-[2-Methyl-3-butynyl]trifluoroacetamide (9). To
a solution of 1.17 g (4.00 mmol) of 8 in 5 mL of THF was
added 6.0 mL (6.0 mmol) of 1.0 M tetrabutylammonium
fluoride in THF. The mixture was heated to 408C for 3 h.
After cooling to 08C and acidification, sat’d aq NaHCO3
was added, the layers separated, the aqueous layer extracted
with 3£15 mL of Et2O, and the combined extracts dried
(MgSO4). Evaporation and column chromatography (1:1
hexane/Et2O, Rf¼0.52) gave 0.52 g of 9 (72% yield) as a
4.1.11. N-[(E)-2-Butenyl]-N-(2-methyl-3-butynyl)-p-
toluenesulfonamide (13). A solution of 0.42 g (2.2 mmol)
of p-toluenesulfonyl chloride in 2 mL of pyridine was
treated dropwise at 08C with a solution of 0.30 g (2.2 mmol)
of 11 in 1 mL of pyridine. The mixture was stirred for 1.5 h
at 08C, treated with 2 mL of water, the layers separated, the
aqueous phase extracted with 3£5 mL of Et2O, and the
combined extracts dried (MgSO4). Evaporation and column
chromatography (1:1 hexane/Et2O, Rf¼0.65) gave 0.50 g of
13 (78% yield) as a colorless liquid. 1H NMR d 7.70 (d, 2H,
J¼8.1 Hz), 7.40 (d, 2H, J¼8.1 Hz), 5.60 (m, 1H), 5.20 (m,
1H), 3.80 (d, 2H, J¼6.6 Hz), 3.15 (m, 2H), 2.80 (m, 1H),
2.48 (s, 3H), 2.04 (d, 1H, J¼2.2 Hz), 1.60 (d, 3H,
J¼6.3 Hz), 1.21 (d, 3H, J¼6.6 Hz); 13C NMR d 143.1,
137.0, 129.5, 129.4, 127.1, 125.3, 86.3, 69.7, 52.1, 51.7,
50.8, 25.7, 18.1, 17.4; FTIR (film): 3290, 2114, 1599,
1161 cm21; HRMS for C16H21NO2S (Mþ): calcd 291.1293,
found 291.1291.
1
colorless liquid. H NMR d 6.60 (br s, 1H), 3.58 (m, 1H),
3.24 (m, 1H), 2.79 (m, 1H), 2.17 (d, 1H, J¼2.2 Hz), 1.23 (d,
3H, J¼7.0 Hz); 13C NMR d 117.6, 84.7, 70.6, 65.7, 44.2,
25.9, 25.5; FTIR (film): 3313, 2119, 1711 cm21; HRMS for
C7H8F3NO (Mþ): calcd 179.0558, found 179.0565.
4.1.8. N-[(E)-2-Butenyl]-N-[2-methyl-3-butynyl]tri-
fluoroacetamide (10). To
a suspension of 0.15 g
(3.7 mmol) of KH in 3 mL of THF was added dropwise at
08C a solution of 0.66 g (3.7 mmol) of 9 in 2 mL of THF.
The mixture was stirred for 30 min, warmed to room
temperature, treated with a solution of 0.51 mL (5.2 mmol)
of crotyl chloride and 20 mg of 18-crown-6 in 2 mL of THF,
and heated to reflux for 6 h. After cooling to 08C, 2 mL of
water was added, the solution was made acidic, sat’d aq
NaHCO3 was added, the layers separated, the aqueous layer
extracted with 3£15 mL of Et2O, and the combined extracts
dried (MgSO4). Evaporation and column chromatography
(4:1 hexane/Et2O, Rf¼0.63) gave 0.60 g of 10 (70% yield)
as a colorless liquid. 1H NMR d 5.75 (m, 1H), 5.40 (m, 1H),
4.15 (d, 2H, J¼6.8 Hz), 3.50 (m, 1H), 3.25 (m, 1H), 3.00 (m,
1H), 2.10 (d, 1H, J¼2.2 Hz), 1.75 (d, 3H, J¼6.9 Hz), 1.20
(d, 3H, J¼6.9 Hz); 13C NMR d 131.2, 124.8, 105.0, 86.0,
70.0, 50.8, 50.54, 50.45, 24.0, 18.4, 17.6; FTIR (film): 3313,
2116, 1697, 966 cm21; HRMS for C11H14F3NO (Mþ): calcd
233.1027, found 233.1035.
4.1.12. Ethyl (4R p,7S p,7aS p)-4,7-Dimethyl-6-oxo-
1,2,3,4,7,7a-hexahydro-6H-2-pyrindine-2-carboxylate
(14).3b To a solution of 0.42 g (0.124 mmol) of Co2(CO)8 in
0.30 mL of freshly distilled CH2Cl2 was added a solution of
0.241 g (0.124 mmol) of 12 in 0.30 mL of CH2Cl2. The
solution was allowed to stir for 2 h, cooled to 08C, and
treated with a solution of 0.090 g (0.77 mmol) of NMO in
0.30 mL of CH2Cl2. The mixture was warmed to room
temperature and stirred overnight, at which time the reaction
appeared to be complete by TLC, and the solvent was
evaporated. The residue was taken up in a small amount of
4.1.9. N-(2-Methyl-3-butynyl)-(E)-2-buten-1-amine (11).

D. A. Ockey et al. / Tetrahedron 59 (2003) 5377–5381
5381
3. (a) Imanishi, T.; Yagi, N.; Hanaoka, M. Tetrahedron Lett.
1981, 22, 667–670. (b) Imanishi, T.; Yagi, N.; Hanaoka, M.
Chem. Pharm. Bull. 1983, 31, 1243–1253. (c) Kametani, T.;
Suzuki, Y.; Ban, C.; Honda, T. Heterocycles 1987, 26,
1491–1493. (d) Miyashita, M.; Tanaka, D.; Shiratani, T.; Irie,
H. Chem. Pharm. Bull. 1992, 40, 1614–1615. (e) Vidari, G.;
Tripolini, M.; Novella, P.; Allegrucci, P.; Garlaschelli, L.
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Whitby, R. J.; Coote, S. J. Synthesis 1998, 552–556.
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refs. therein.
CH2Cl2 and passed through a silica plug. Purification by
radial chromatography (4:1 hexane/ethyl acetate) gave
4.7 mg of 13 (16% yield), a colorless oil, displaying NMR
and IR spectra identical to those reported.3b
4.1.13. Ethyl (4R p,7S p,7aS p)-4,7-Dimethyl-6-oxo-
1,2,3,4,7,7a-hexahydro-6H-2-pyrindine-2-carboxylate
(15). To a solution of 0.17 g (0.050 mmol) of Co2(CO)8 in
5.0 mL of freshly distilled CH2Cl2 was added a solution of
0.15 g (0.050 mmol) of 12 in 5.0 mL of CH2Cl2. The
solution was allowed to stir for 1 h, the atmosphere was
changed to O2, and a solution of 0.050 g (0.70 mmol) of
TMANO in 2.0 mL of CH2Cl2 was added slowly, dropwise.
The mixture was stirred for 2 h, at which time an additional
0.190 g (2.50 mmol) of TMANO in 5.0 mL of CH2Cl2 was
added slowly and the mixture stirred for an additional 12 h.
The mixture was passed through a silica plug, eluting with
Et2O. Purification by preparative HPLC (4:1 hexane/ethyl
acetate) gave 5.0 mg of 15 (6% yield) as a colorless oil. 1H
NMR d 7.63 (d, 2H, J¼8.1 Hz), 7.32 (d, 2H, J¼8.1 Hz),
5.86 (s, 1H), 4.22 (m, 1H), 3.77 (d, 1H, J¼11.4 Hz), 3.03
(m, 1H), 2.84 (m, 1H), 2.47 (dd, 1H, J¼3.3, 11.8 Hz), 2.43
(s, 3H), 1.98 (m, 1H), 1.87 (m, 1H), 1.38 (d, 3H, J¼7.0 Hz),
1.23 (d, 3H, J¼7.4 Hz); 13C NMR d 179.9, 143.9, 129.8,
127.2, 126.6, 105.0, 52.1, 51.9, 45.0, 44.5, 36.7, 21.5, 17.8,
4. (a) Schore, N. E. Org. React. 1991, 40, 1–90. (b) Schore, N. E.
Comprehensive Organometallic Chemistry II; Pergamon:
London, 1995; Vol. 12, pp 703–709.
5. Nussbaumer, P.; Stu¨tz, A. Tetrahedron Lett. 1992, 33,
7507–7508.
6. Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972,
94, 679–680.
7. Brown, S. W.; Pauson, P. L. J. Chem. Soc., Perkin Trans. 1
1990, 1205–1209.
8. (a) Bolton, G. L. Tetrahedron Lett. 1996, 37, 3433–3436.
(b) Bolton, G. L.; Hodges, J. C.; Rubin, J. R. Tetrahedron
1997, 53, 6611–6634.
9. Krafft, M. E.; Wilson, A. M.; Dasse, O. A.; Shao, B.; Cheung,
Y. Y.; Fu, Z.; Bonaga, L. V. R.; Mollman, M. K. J. Am. Chem.
Soc. 1996, 118, 6080–6081.
17.7, 14.4; FTIR (film): 1707, 1599 cm21
.
10. (a) Alcaide, B.; Polanco, C.; Sierra, M. A. Tetrahedron Lett.
1996, 37, 6901–6904. (b) Alcaide, B.; Polanco, C.; Sierra,
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´
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Acknowledgements
We thank the National Institutes of Health (Grant GM
26294) and the National Science Foundation (Grants CHE-
9710286 and CHE-0078191) for support of this research.
´ ´
3513–3519. (b) Perez-Serrano, L.; Perez-Serrano, P.;
´ ´
Casarrubios, L.; Domınguez, G.; Perez-Castells, J. Synlett
2000, 1303–1305.
12. Kotha, S.; Sreenivasachary, N.; Eur, J. Org. Chem. 2001,
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