Total synthesis of the bridged indole alkaloid apparicine

Article abstract of DOI:10.1021/jo901986v

(Chemical Equation Presented) An indole-templated ring-closing metathesis or a 2-indolylacyl radical cyclization constitute the central steps of two alternative approaches developed to assemble the tricyclic ABC substructure of the indole alkaloid apparic

Full text of DOI:10.1021/jo901986v

pubs.acs.org/joc
Total Synthesis of the Bridged Indole Alkaloid Apparicine
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M.-Lluısa Bennasar,* Ester Zulaica, Daniel Sole, Tomas Roca,
Davinia Garcıa-Dıaz, and Sandra Alonso
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institut de Biomedicina (IBUB),
University of Barcelona, Barcelona 08028, Spain
bennasar@ub.edu
Received September 15, 2009
An indole-templated ring-closing metathesis or a 2-indolylacyl radical cyclization constitute the
central steps of two alternative approaches developed to assemble the tricyclic ABC substructure of
the indole alkaloid apparicine. From this key intermediate, an intramolecular vinyl halide Heck
reaction accomplished the closure of the strained 1-azabicyclo[4.2.2]decane framework of the
alkaloid with concomitant incorporation of the exocyclic alkylidene substituents.
Introduction
Apparicine (Figure 1) is a fairly widespread monoterpenoid
indole alkaloid, first isolated from Aspidosperma dasycarpon
more than 40 years ago.1,2 Its structural elucidation,2 carried
out by chemical degradation and early spectroscopic techni-
ques, revealed a particular skeleton with a bridged 1-azabi-
cyclo[4.2.2]decane framework fused to the indole ring and two
exocyclic alkylidene (16-methylene and 20E-ethylidene) sub-
stituents.3 The same arrangement was also found in vallesa-
mine4 and later in a small number of alkaloids, including 16(S)-
hydroxy-16,22-dihydroapparicine5 or ervaticine,6 which differ
from apparicine in the substitution at C-16.7
The apparicine alkaloids are biogenetically defined by the
presence of only one carbon (C-6) connecting the indole 3-
position and the aliphatic nitrogen, which is the result of the C-5
FIGURE 1. Apparicine and related alkaloids.
(1) Gilbert, B.; Duarte, A. P.; Nakagawa, Y.; Joule, J. A.; Flores, S. E.;
Brissolese, J. A.; Campello, J.; Carrazzoni, E. P.; Owellen, R. J.; Blossey, E. C.;
Brown, K. S., Jr.; Djerassi, C. Tetrahedron 1965, 21, 1141–1166.
(2) Joule, J. A.; Monteiro, H.; Durham, L. J.; Gilbert, B.; Djerassi, C.
J. Chem. Soc. 1965, 4773–4780.
(3) The E configuration of the ethylidene group was established some
years later: Akhter, L.; Brown, R. T.; Moorcroft, D. Tetrahedron Lett. 1978,
19, 4137–4140.
(4) (a) Walser, A.; Djerassi, C. Helv. Chim. Acta 1965, 48, 391–404.
(b) Atta-ur-Rahman; Alvi, A. A.; Voelter, W. Heterocycles 1987, 26, 413–419.
(5) Perera, P.; van Beek, T. A.; Verpoorte, R. J. Nat. Prod. 1984, 47, 835–
838.
excision from the original two-carbon tryptamine bridge of the
alkaloid stemmadenine.8 The fragmentation-iminium hydro-
lysis-recyclization route depicted in Scheme 1, which involves
the operation of a stemmadenine N-oxide equivalent,9 has been
proposed to rationalize this biogenetic relationship. Such a
route appears to be likely since stemmadenine itself10 and, more
(6) (a) Atta-ur-Rahman; Muzaffar, A. Heterocycles 1985, 23, 2975–2978.
(b) Kam, T.-S.; Pang, H.-S.; Choo, Y.-M.; Komiyama, K. Chem. Biodiversity
2004, 1, 646–656.
(8) Kutney, J.-P. Heterocycles 1976, 4, 429–451.
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(9) Ahond, A.; Cave, A.; Kan-Fan, C.; Langlois, Y.; Potier, P. J. Chem.
Soc., Chem. Commun. 1970, 517.
(7) For a review, see: Alvarez, M.; Joule, J. A. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 2001; Vol. 57, Chapter 4.
(10) Scott, A. I.; Yeh, C.-L.; Greenslade, D. J. Chem. Soc., Chem.
Commun. 1978, 947–948.
DOI: 10.1021/jo901986v
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Bennasar et al.
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recently, pericine (subincanadine E)11 have been transformed
in vitro into the respective C-5 nor-alkaloids (vallesamine and
apparicine) by treatment of the N-oxides with trifluoroacetic
anhydride (modified Polonovski reaction).12
reported vinyl halide Heck reactions involving (aza)cyclooctene
rings to produce strained bridged systems.20
SCHEME 2. Synthetic Strategy
SCHEME 1. Biosynthesis of Apparicine Alkaloids
Their synthetically challenging structures make apparicine
alkaloids attractive targets for synthesis. However, progress in
this area has been limited to the approach developed by Joule’s
group in the late 1970s, which allowed the construction of the
ring skeleton of apparicine (i.e., 20-deethylideneervaticine) but
proved unsuitable for the total synthesis of the alkaloid.13
We envisaged apparicine to be accessible via tricyclic ABC
substructures containing the central eight-membered ring
(e.g., azocinoindoles A, Scheme 2), from which the carbon
skeleton would be completed by inserting an ethylideneethano
unit between the aliphatic nitrogen and C-5. In particular, it was
planned that after N-alkylation with the appropriate haloalke-
nyl halide, an intramolecular Heck reaction14 upon a 2-viny-
lindole moiety would serve to close the piperidine ring and at the
same time install the requisite 20E-ethylidene and (when R2=
Me) 16-methylene appendages. It should be noted that similar
Heck couplings of vinyl halides and elaborated cycloalkenes
have proved to be useful for the assembly of the bridged core of
several indole alkaloids, including pentacyclic Strychnos alka-
loids,15 strychnine,15c,16 minfiensine,17 apogeissoschizine,18 and
ervitsine.19 However, to the best of our knowledge, there are no
The power of ring-closing metathesis (RCM)21 to synthe-
size medium-sized rings22 and our own work on RCM of
indole-containing dienes23 made it our method of choice to
assemble the indolo fused eight-membered ring of the key
intermediates A and also to install the double bond required
for the Heck reaction, either directly or after an isomeriza-
tion step. In the course of our work, an alternative approach
to A based on 2-indolylacyl radical cyclization24 and manipu-
lation of the resulting ketone was also investigated.25 This
Article deals with the development of the above indole
annulation chemistry and its application to complete the
first total synthesis of (()-apparicine.26
Resuts and Discussion
Initial Studies. We set out to study the indole-templated
RCM en route to apparicine, directly targeting 6-methylazo-
cino[4,3-b]indoles (A, R2 =Me, Scheme 2) with the trisub-
stituted 5,6-double bond functionality required for the Heck
coupling. To this end, 2-isopropenylindoles 3, which are
equipped with Boc or Ts groups at the aliphatic nitrogen
(11) Lim, K.-H.; Low, Y.-Y.; Kam, T.-S. Tetrahedron Lett. 2006, 47,
5037–5039.
(12) Potier, P. In Indole and Biogenetically Related Alkaloids; Phillipson,
J. D., Zenk, M. H., Eds; Academic Press: London, 1980; Chapter 8.
(13) (a) Scopes, D. I. C.; Allen, M. S.; Hignett, G. J.; Wilson, N. D. V.;
Harris, M.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 1977, 2376–2385.
(b) Joule, J. A.; Allen, M. S.; Bishop, D. I.; Harris, M.; Hignett, G. J.; Scopes,
D. I. C.; Wilson, N. D. V. Indole and Biogenetically Related Alkaloids;
Phillipson, J. D., Zenk, M. H., Eds.; Academic: London, 1980; pp 229-247.
(20) For related Heck processes involving more robust aryl halides, see:
(a) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998, 39, 4139–
4142. (b) Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin, K.; Lannou,
M.-I.; Runsink, J.; Raabe, G. J. Org. Chem. 2005, 70, 10538–10551. Ribelin,
T. P.; Judd, A. S.; Akritopoulou-Zanze, I.; Henry, R. F.; Cross, J. L.;
Whittern, D. N.; Djuric, S. W. Org. Lett. 2007, 9, 5119–5122.
(21) General reviews: (a) Grubbs, R. H. Ed.; Handbook of Metathesis;
Wiley-VCH: Weinheim, 2003; Vol. 2. (b) Deiters, A.; Martin, S. F. Chem. Rev.
2004, 104, 2199–2238.
(22) For reviews, see: (a) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39,
2073–2077. (b) Yet, L. Chem. Rev. 2000, 100, 2963–3007. (c) Michaut, A.;
Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740–5750.
(23) (a) Bennasar, M.-L.; Zulaica, E.; Tummers, S. Tetrahedron Lett.
2004, 45, 6283–6285. (b) Bennasar, M.-L.; Zulaica, E.; Alonso, S. Tetrahe-
€
(14) General reviews: (a) Brase, S.; de Meijere, A. In Metal-Catalyzed
Cross-Coupling Reactions; de Meijere, A.; Diederich, F., Eds; Wiley-WCH: New
York, 2004; pp 217-316. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106,
4644–4680.
(15) (a) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695–
1698. (b) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030–3031. (c) Mori, M.; Nakanishi, M.; Kahishima, D.; Sato, Y.
J. Am. Chem. Soc. 2003, 125, 9801–9807. (d) Martin, D. B. C.; Vanderwal,
C. D. J. Am. Chem. Soc. 2009, 131, 3472–3473.
(16) (a) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685–2686.
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dron Lett. 2005, 46, 7881–7884. (c) Bennasar, M.-L.; Zulaica, E.; Sole, D.;
Alonso, S. Tetrahedron 2007, 63, 861–866.
(b) Sole, D.; Bonjoch, J.; Garcıa-Rubio, S.; Peidro, E.; Bosch, J. Chem.;Eur.
J. 2000, 6, 655–665. (c) Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.;
Lamottke, K.; Schmidt, M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123,
9324–9337.
(24) Bennasar,M.-L.;Roca,T.InProgress in Heterocyclic Chemistry; Gribble,
G. W., Joule, J. A., Eds; Elsevier: Amsterdam, 2009; Chapter 1, pp 1-19.
(25) For a previous different approach to apparicine ABC substructures, see:
(a) Street, J. D.; Harris, M.; Bishop, D. I.; Heatley, F.; Beddoes, R. L.; Mills, O. S.;
Joule, J. A. J. Chem. Soc., Perkin Trans. 1 1987, 1599–1606. (b) See also ref 13b.
(26) For a preliminary communication, see: Bennasar, M.-L.; Zulaica,
(17) (a) Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D.
J. Am. Chem. Soc. 2008, 130, 5368–5377. (b) For a related approach, see: Shen, L.;
Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem., Int. Ed. 2008, 47, 3618–3621.
(18) Birman, V. B.; Rawal, V. H. J. Org. Chem. 1998, 63, 9146–9147.
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(19) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Synlett 2008, 667–670.
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E.; Sole, D.; Alonso, S. Chem. Commun. 2009, 3372–3374.
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and a robust MOM group at the indole nitrogen, were selected
as the starting dienes (Scheme 3). These compounds were
efficiently prepared from the known 2-chloroindole-3-carbal-
dehyde 127 by a Stille coupling with (isopropenyl)tributyl-
stannane, followed by reductive amination of aldehyde 2 with
3-butenylamine and subsequent acylation or sulfonylation of
the resulting secondary amine with di-tert-butyl dicarbonate or
tosyl chloride, respectively. Unfortunately, exposure of dienes 3
to the second-generation Grubbs catalyst B in CH2Cl2 or
toluene did not deliver the expected eight-membered ring.
Instead, carbamate 3a mainly underwent an intermolecular
metathesis reaction leading to dimer 4a, even when working
under high dilution conditions (0.007 M). Sulfonamide 3b, in
turn, led to the respective dimer 4b along with variable amounts
of the ring-contracted product 5, coming from the competitive
isomerization of the terminal double bond followed by RCM
with liberation of propene. Azepinoindole 5 was the only
isolated product (75%) when cyclization of 3b was performed
in refluxing toluene. In both cases, the use of other metathesis
catalysts, either based on ruthenium (first-generation Grubbs
or second-generation Hoveyda-Grubbs catalysts) or molybde-
num (Schrock’s catalyst) did not lead to any improvement.
Thus, the required RCM substrates 7a and 7b were uneventfully
prepared from 2-vinylindole-3-carbaldehyde 627 by reductive
amination with 3-butenylamine followed by N-acylation or
sulfonylation, as in the above isopropenyl series. As anticipated,
RCM of dienes 7a or 7b, involving two terminal monosubsti-
tuted alkene units, took place with the use of ruthenium
complex B under standard conditions (0.01 M, toluene, 60 °C
or CH2Cl2, reflux) to give azocinoindoles 8a or 8b in acceptable
yields. At this point, access to the more advanced synthetic
intermediate 9 required the manipulation of the aliphatic nitro-
gen of 8a or 8b to install the iodoalkenyl chain for eventual
cyclization. As our first attempts to induce N-desulfonylation of
8b under reductive conditions (Mg, NH4Cl, MeOH or Na/
naphthalenide, THF) proved problematic, affording the un-
changed starting product or complex reaction mixtures, we fo-
cused on the more labile carbamate function of 8a. Removal of
the Boc group under standard acidic conditions (TFA, Me3SiI,
ZnBr2) was also troublesome, leading to partial decomposition,
but the deprotection took place cleanly upon exposure of 8a to a
mild acidic protocol (1.2 M HCl in MeOH at rt). The resulting
secondary amine was directly subjected to alkylation with (Z)-2-
iodo-2-butenyl tosylate in hot acetonitrile in the presence of
K2CO3 to give 9 in 60% isolated yield over the two steps.
SCHEME 3. Attempted Direct RCM Synthesis of 6-Methyl-
1,2,3,4-tetrahydroazocino[4,3-b]indoles
SCHEME 4. Studies in the 6-Demethyl Series
We next studied the key formation of the piperidine ring by
Pd-catalyzed cyclization of the vinyl iodide upon the 2-
vinylindole moiety. Our expectation was that the initially
formed alkylpalladium intermediate C (Scheme 5), in which
no β-hydrogen is available for elimination, would be stable
enough to be reduced or trapped with a suitable quencher.
However, when 9 was subjected to a number of standard
conditions for reductive Heck reactions, thedesired tetracyclic
system D (Q = H) was never detected. The only observed
process under the phosphine-free conditions28 [Pd(OAc)2,
Because this unsuccessful result was probably due to the
presence of a geminal disubstituted terminal alkene moiety in
dienes 3, we turned our attention to more easily available 6-de-
methyl tricyclic substructures (A, R2=H, Scheme 2). These mo-
del azocinoindoles would also serve as precursors for closing the
piperidine ring of apparicine by a reductive Heck cyclization or
a tandem Heck cyclization-capture, which could also allow the
introduction of the remaining carbon atom at C-16. The imple-
mentation of this new synthetic plan is depicted in Scheme 4.
(27) Hagiwara, H.; Choshi, T.; Nobuhiro, J.; Fujimoto, H.; Hibino, S.
Chem. Pharm. Bull. 2001, 49, 881–886.
(28) (a) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667–2670. (b) Jeffery, T.
Tetrahedron 1996, 52, 10113–10130.
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K2CO3, TBACl, HCO2Na, DMF, 80 °C] previously used by
Overman17a on a related substrate was N-dealkylation. After
this unsuccessful result, a variety of palladium precatalysts
[Pd(OAc)2, Pd(PPh3)4, Pd2(dba)3], ligands (PPh3, dppe), and
cosolvents (toluene, CH3CN, THF) were examined in the
presence of Et3N or diisopropylethylamine as the potential
reductants.16b,29 Whereas short reaction times left the starting
product unchanged, prolonged heating gave low yields
(5-10%) of the unexpected tetracycle 10, coming from an
apparent 7-endo cyclization with inversion of the ethylidene
configuration.30 The yield of 10 was raised to 30% on
exposure of 9 to Pd(PPh3)4 in 1:1 THF-Et3N in a sealed tube
at 90 °C for 24 h. On the other hand, under cationic conditions
[Pd(OAc)2, PPh3, Ag2CO3, 1:1 toluene-Et3N, 90 °C] the
cyclization proceeded readily to give tetracycle 10 in 46%
isolated yield. Significantly, this result was not substantially
altered when the reaction was carried out in the presence of
HCO2Na as the reductant or KCN, K4[Fe(CN)6], TMSCN,
or tributylvinylstannane as trapping agents.
guarantee the β-elimination of the alkylpalladium intermedi-
ate arising from cyclization, thus hampering the above
undesired route. Hence, we renewed our efforts to synthesize
6-methylazocino[4,3-b]indoles (A, R2=Me, Scheme 2), once
again tackling the problem of RCM and ready to explore
new routes.
RCM-Isomerization Route to Azocinoindole 15. Given
that we were unable to directly form the trisubstituted double
bond included in the azocine ring by RCM, we decided to
change the cyclization site from the 5,6-position to the less
crowded 4,5-position by using a 3-(allylaminomethyl)-2-
allylindole such as 13 (Scheme 6) as the diene. Consequently,
the synthesis of the Heck precursor would now require an
additional isomerization step of the resulting double bond.
It was planned to install the R-methyl-substituted allyl-
type chain at the indole 2-position taking advantage of an
allylic nucleophilic substitution reaction using a suitable
organometallic derivative of indole. Thus, 1-(phenylsulfo-
nyl)indole was allowed to react with n-BuLi and CuCN, and
the intermediate organocopper derivative was treated with
(E)-4-chloro-2-pentene. The resulting indole 11 was then
converted into the RCM precursor 13 by Friedel-Crafts
formylation, reductive amination of aldehyde 12 with ally-
lamine, and the subsequent protection of the aliphatic nitro-
gen with a Boc group. The overall yield of the four steps was
58%. Satisfactorily, ring closure of diene 13 took place with
the second-generation Grubbs catalyst B under standard
conditions (0.07 M, CH2Cl2, reflux) to give the desired 6-
methylazocinoindole 14 in 80% yield.
SCHEME 5
SCHEME 6. RCM-Isomerization Route to 6-Methylazoci-
noindole 15
The formation of unusual Heck cyclization products like
10 has been previously observed31 and rationalized32 by
considering that the initial 6-exo cyclization is followed by
an intramolecular carbopalladation on the exocyclic alkene.
The resulting cyclopropane intermediate would undergo
rearrangement, with concomitant inversion of the alkene
geometry, and final β-hydride elimination. In our case, the cy-
clopropanation-rearrangement route depicted in Scheme 5
would be fast enough to prevent the quenchers from inter-
cepting the initially formed alkylpalladium intermediate C.
It now became apparent that the presence of a 6-methyl
group in the Heck cyclization substrate was crucial to
assemble the bridged framework of apparicine, as it would
(29) Minatti, A.; Zheng, X.; Buchwald, S. L. J. Org. Chem. 2007, 72,
9253–9258.
(30) The configuration of the ethylidene substituent was established by
NOESY experiments.
(31) (a) Rawal, V. H.; Michoud, C. J. Org. Chem. 1993, 58, 5583–5584.
(b) Feutren, S.; McAlonan, H.; Montgomery, D.; Stevenson, P. J. J. Chem.
Soc., Perkin Trans. 1 2000, 1129–1137.
(32) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E. J. Am. Chem.
Soc. 1992, 114, 10091–10092.
Attention was then focused on the isomerization step.
Considering recent reports on alkene isomerizations mediated
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by suitably modified ruthenium-metathesis catalysts,33-36 we
sought to examine if such a protocol could be synthetically
useful for our purpose (Scheme 7). Unfortunately, when
azocinoindole 14 was treated with catalyst B in refluxing
toluene,35 a slow isomerization of the double bond took place
to its N-conjugated counterpart (3,4-position), providing the
enecarbamate 16 in 50% yield (not optimized). The directing
effect of the carbamate nitrogen was also decisive, although to
a lesser extent, in the ruthenium-catalyzed isomerization of
the 6-demethyl analogue 17a,23c which led to the enamide 18a
as the major product along with minor amounts of vinylindole
19a. Significantly, the influence of the heteroatom was sup-
pressed in the N-tosyl analogue 17b,23c which underwent
isomerization to afford vinylindole 19b as the only product.
Finally, no isomerization was observed upon exposure of
azocinoindoles 14 or 17 to catalyst B in hot methanol.36
examined was the N-MOM tricyclic ketone 20 (Scheme 8),
since it had already been prepared by RCM followed by
removal of the resulting double bond by hydrogenation.23c
Reaction of 20 with MeLi smoothly provided tertiary alco-
hol 21, which was subjected to several dehydration protocols
without success. Thus, the acid-catalyzed dehydration using
3 M H2SO4 in acetone or TsOH in benzene was complicated
by the competitive indole deprotection, affording low yields
of the endocyclic alkene (15). On the other hand, the use of
Martin sulfurane resulted in a cleaner dehydration to the
exocyclic alkene 22, in which the N-MOM group remained
unaffected.
SCHEME 8
SCHEME 7. Isomerization Studies
In search of a more efficient approach, we decided to
extend the above organometallic addition-dehydration se-
quence to an analogous indole unprotected ketone (i.e., 26,
Scheme 9). After unsuccessful attempts to remove the N-
MOM group of 20, the substrate was efficiently prepared by
a more direct route free of indole protecting groups, based on
an 8-endo cyclization of a 2-indolylacyl radical upon an
amino tethered alkene.24,37 The synthesis began with the
preparation of selenoester 25 as the radical precursor,
equipped with a bromovinyl chain to increase both the
efficiency and the endo regioselectivity of the ring closure.37
Thus, reductive amination of aldehyde 23 with 2-bromo-2-
propenylamine followed by standard protection of the re-
sulting secondary amine with a Boc group led to ester 24,
which was converted into 25 by phenylselenation through the
corresponding carboxylic acid.38 Treatment of selenoester 25
with n-Bu3SnH as the radical mediator and Et3B as the
initiator achieved the desired ring closure affording ketone
26 in moderate yield (54%). Finally, to our satisfaction,
reaction of 26 with methyllithium followed by dehydration
of the resulting tertiary alcohol under mild acid conditions
(TsOH, CH3CN, rt) smoothly provided the target alkene 15.
Using this alternative route, the synthesis of 15 was accom-
plished from aldehyde 23 in 26% overall yield by way of only
three isolated intermediates.
Satisfactorily, we fortuitously discovered that the double
bond of azocinoindole 14 moved into conjugation with the
aromatic ring under the basic conditions used to remove the
phenylsulfonyl group. Thus, long exposure of14to t-BuOK in
refluxing THF brought about the anticipated indole depro-
tection along with alkene isomerization, affording 15 in 90%
yield (Scheme 6). By using shorter reaction times and using
NMR spectroscopy, we found that the migration of the
double bond took place after the initial indole N-deprotection
step, which suggests that the base-induced isomerization is
only compatible with the presence of a free indole NH group.
Alternative Synthesis of 15. Although the RCM-iso-
merization route depicted in Scheme 6 allowed an efficient
synthesis of the key apparicine intermediate 15 [41% overall
yield from 2-(phenylsulfonyl)indole by way of four isolated
intermediates], we explored the possibility of installing the
trisubstituted double bond required for the Heck reaction
from a ketone carbonyl group. To this end, the first substrate
(33) For intentional post-RCM isomerizations, see: (a) Sutton, A. E.;
Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124,
13390–13391. (b) Schmidt, B. J. Org. Chem. 2004, 69, 7672–7687. For a recent
example, see: (c) Schmidt, B.; Biernat, A. Chem.;Eur. J. 2008, 14, 6135–6141.
(34) For reviews on the nonmetathetic behavior of Grubbs ruthenium
catalysts, see: (a) Schmidt, B. Eur. J. Org. Chem. 2004, 1865–1880.
(b) Alcaide, A.; Almendros, P.; Luna, A. Chem. Rev. 2009, 109, 3817–3858.
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(35) Fustero, S.; Sanchez-Rosello, M.; Jimenez, D.; Sanz-Cervera, J. F.;
~
(37) Bennasar, M.-L.; Roca, T.; Garcıa-Dıaz, D. J. Org. Chem. 2007, 72,
4562–4565.
(38) Batty, D.; Crich, D. Synthesis 1990, 273–275.
del Pozo, C.; Acena, J. L. J. Org. Chem. 2006, 71, 2706–2714.
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SCHEME 9. Radical Route to 6-Methylazocinoindole 15
vinyl iodide 27 was subjected to a specific protocol, using
Pd(OAc)2/PPh3 (0.2:0.6 equiv) and Ag2CO3 (2 equiv) in 1:1
toluene-Et3N at 80 °C for a short reaction time (1.5 h),
apparicine was obtained in a consistent, reproducible 15%
isolated yield. The 1H and 13C NMR spectroscopic data of
synthetic apparicine essentially matched those described in
the literature for the natural product.2,7,39 Additionally, the
chromatographic (TLC) behavior of synthetic apparicine
was identical to an authentic sample.
Conclusion
In summary, the first total synthesis of (()-apparicine has
been accomplished by a concise route employing a vinyl
halide Heck cyclization to close the bridged piperidine ring in
the last synthetic step. The key azocinoindole intermediate
15 has been successfully assembled by developing two alter-
native procedures, namely, an indole-templated RCM fol-
lowed by base-induced isomerization and an acyl radical
cyclization followed by ketone-alkene functional group
interconversion.
Experimental Section
Completion of the Synthesis of Apparicine. With azocinoin-
dole 15 in hand, we next sought to manipulate the aliphatic
nitrogen to install the haloalkenyl chain for the subsequent
Heck reaction. As occurred with the C-6 demethyl analogue
8a (Scheme 4), removal of the N-Boc group of 15 required a
mild acid protocol to avoid decomposition. The resulting
secondary amine proved to be highly unstable and was
directly subjected to alkylation with (Z)-2-iodo-2-butenyl
tosylate to give 27 in 30% isolated yield over the two steps
(Scheme 10). Attempts to place a phenylsulfonyl group at the
indole nitrogen of 15 in order to improve the yield were
unsucccessful.
2-Isopropenyl-1-(methoxymethyl)indole-3-carbaldehyde (2).
Tetraethylammonium bromide (0.42 g, 2.01 mmol), Bu3Sn-
(CH3)CdCH2 (1.33 g, 4.02 mmol), and Pd(PPh3)2Cl2 (42 mg,
0.06 mmol) were successively added to a solution of aldehyde 127
(0.45 g, 2.01 mmol) in DMF (30 mL), and the mixture was
stirred at 85 °C overnight. The reaction mixture was diluted with
AcOEt and washed with brine. The organic solution was dried
and concentrated, and the resulting residue was chromato-
graphed (9:1 hexanes-AcOEt) to give 2 as an oil: 0.37 g
(80%); IR (film) 3057, 2934, 1663 cm-1; 1H NMR (400 MHz)
δ 2.25 (s, 3H), 3.31 (s, 3H), 5.35 (s, 1H), 5.44 (s, 2H), 5.76 (s, 1H),
7.33 (m, 2H), 7.49 (dm, J=7.5 Hz, 1H), 8.35 (dm, J=7.5 Hz,
1H), 10.0 (s, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 25.0 (CH3),
56.3 (CH3), 75.2 (CH2), 110.4 (CH), 115.2 (C), 122.1 (CH), 123.4
(CH), 123.9 (CH2), 124.3 (CH), 125.2 (C), 133.4 (C), 136.8 (C),
153.3 (C), 186.8 (CH); ESI-HRMS [M + H]+ calcd for C14H16-
NO2 230.1175, found 230.1183.
SCHEME 10. Completion of the Synthesis of Apparicine
3-[N-(3-Butenyl)-N-(tert-butoxycarbonyl)aminomethyl]-2-iso-
propenyl-1-(methoxymethyl)indole (3a). 3-Butenylamine (0.24
mL, 2.60 mmol), NaBH(OAc)3 (0.82 g, 3.90 mmol), and AcOH
(0.08 mL, 1.36 mmol) were successively added to aldehyde 2
(0.30 g, 1.30 mmol) in CH2Cl2 (10 mL), and the resulting mixture
was stirred at rt overnight. The reaction mixture was partitioned
between CH2Cl2 and 10% aqueous Na2CO3 and extracted with
CH2Cl2. The organic extracts were dried and concentrated to
give the crude secondary amine (0.30 g). This compound was
dissolved in MeOH (10 mL) and treated with (t-BuOCO)2O
(0.45 g, 2.06 mmol) and Et3N (0.58 mL, 4.12 mmol). After the
mixture was heated at reflux for 4 h, the solvent was removed,
and the residue was diluted with CH2Cl2 and washed with 1 N
HCl and brine. The organic solution was dried and concen-
trated, and the residue was chromatographed (8:2 hexanes-
AcOEt) to give carbamate 3a as a pale yellow oil: 0.33 g (65%);
IR (film) 1689, 1462, 1415 cm-1; 1H NMR (400 MHz) δ 1.53 (br
s, 9H), 2.12 (s, 3H), 2.13 (m, 2H), 3.10 (m, 2H) 3.26 (s, 3H), 4.66
(s, 2H), 4.96 (m, 2H), 5.15 (s, 1H), 5.38 (s, 2H), 5.60 (s, 1H), 5.65
(m, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.40 (d,
The stage was now set for the completion of the synthesis
by intramolecular coupling of the vinyl iodide and the
trisubstituted alkene. A variety of experimental conditions
were screened, including different solvents, palladium pre-
catalysts, and additives, resulting only in the recovery of the
starting material or decomposition products. However, the
critical closure of the strained 1-azabicyclo[4.2.2]decane
framework with concomitant incorporation of the exocyclic
alkylidene substituents took place under cationic conditions,
although loss of material was still extensive. Thus, when
ꢁ
ꢀ
(39) (a) Massiot, G.; Zeches, M.; Thepenier, P.; Jacquier, M.-J.; Le Men-
Olivier, L.; Delaude, C. J. Chem. Soc., Chem. Commun. 1982, 768–769.
(b) van Beek, T. A.; Verpoorte, R.; Kinh, Q. Planta Med. 1985, 51, 277–279.
(c) Atta-ur-Rahman; Fatima, T.; Mehrum-Nisa; Ijaz, S.; Crank, G.; Wasti
Planta Med. 1987, 53, 57–59.
8364 J. Org. Chem. Vol. 74, No. 21, 2009

Bennasar et al.
JOCArticle
J=7.8 Hz, 1H), 7.75 (m, 1H); 13C NMR (100.6 MHz) δ 24.5
(CH3), 28.5 (3CH3), 32.6 (CH2), 39.7 (CH2), 44.2 (CH2), 55.7
(CH3), 74.7 (CH2), 79.2 (C), 109.8 (CH), 116.1 (CH2), 120.1 (C),
120.4 (CH), 121.5 (CH2), 122.4 (CH), 122.5 (CH), 127.9 (C),
135.5 (CH), 135.6 (C), 136.9 (C), 141.3 (C), 155.7 (C); ESI-HR-
MS [M + H]+ calcd for C23H33N2O3 385.2485, found 385.2477.
3-[N-(3-Butenyl)-N-(tosyl)aminomethyl]-2-isopropenyl-1-(me-
thoxymethyl)indole (3b). Aldehyde 2 (0.25 g, 1.09 mmol) was
allowed to react as above with 3-butenylamine and NaBH-
(OAc)3. The resulting secondary amine (0.25 g) was dissolved
in CH2Cl2 (12 mL) and treated with TsCl (0.20 g, 1.05 mmol)
and Et3N (0.15 mL, 1.05 mmol) at rt overnight. The reaction
mixture was diluted with CH2Cl2 and washed with 1 N HCl and
brine. The organic solution was dried and concentrated, and the
resulting residue was chromatographed (9:1 hexanes-AcOEt)
to give sulfonamide 3b as a pale yellow solid: 0.29 g (60%); mp
88 °C (Et2O); IR (KBr) 1463, 1332, 1158 cm-1; 1H NMR (400
MHz) δ 1.92 (m, 2H), 2.06 (s, 3H), 2.44 (s, 3H), 3.04 (m, 2H),
3.28 (s, 3H), 4.48 (s, 2H), 4.70 (dm, J=17 Hz, 1H), 4.78 (dm,
J=10 Hz, 1H), 5.09 (s, 1H), 5.36 (s, 2H), 5.40 (m, 1H), 5.53 (br s,
1H), 7.14 (t, J=7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.33 (m,
2H), 7.43 (d, J=8 Hz, 1H), 7.78 (m, 3H); 13C NMR (100.6 MHz)
δ 21.5 (CH3), 24.5 (CH3), 32.9 (CH2), 43.4 (CH2), 46.7 (CH2),
55.7 (CH3), 74.7 (CH2), 107.1 (C), 109.8 (CH), 116.3 (CH2),
120.1 (CH), 120.7 (CH), 121.9 (CH2), 122.7 (CH), 127.3 (2 CH),
127.7 (C), 129.2 (2 CH), 134.8 (CH), 135.2 (C), 136.9 (2C), 141.4
(C), 143.0 (C); ESI-HRMS [M+H]+ calcd for C25H31N2O3S
439.2049, found 439.2039; [M + Na]+ calcd for C25H30Na-
N2O3S 461.1869, found 461.1866. Anal. Calcd for C25H30N2-
O3S: C, 68.46; H, 6.88; N, 6.38. Found: C, 68.22; H, 6.43;
N, 6.25.
3-[N-(3-Butenyl)-N-(tert-butoxycarbonyl)aminomethyl]-1-(me-
thoxymethyl)-2-vinylindole (7a). 3-Butenylamine (0.39 mL,
4.20 mmol), NaBH(OAc)3 (1.33 g, 6.30 mmol), and AcOH
(0.12 mL, 2.10 mmol) were successively added to aldehyde 61
(0.45 g, 2.10 mmol) in CH2Cl2 (13 mL), and the resulting mixture
was stirred at rt overnight. The reaction mixture was partitioned
between CH2Cl2 and 10% aqueous Na2CO3 and extracted with
CH2Cl2. The organic extracts were dried and concentrated to
give the crude secondary amine (0.50 g). This compound was
dissolved in MeOH (20 mL) and treated with (t-BuOCO)2O
(0.52 g, 2.40 mmol) and Et3N (0.68 mL, 4.85 mmol). After the
mixture was heated at reflux for 4 h, the solvent was removed,
and the residue was dissolved in CH2Cl2 and washed with 1 N
HCl and brine. The organic solution was dried and concen-
trated, and the residue was chromatographed (9:1 hexanes-
AcOEt) to give carbamate 7a as a pale yellow oil: 0.55 g (70%);
IR (film) 1687 cm-1; 1H NMR (400 MHz) δ 1.54 (br s, 9H), 2.19
(br s, 2H), 3.10 (m, 2H), 3.11 (s, 3H), 4.79 (br s, 2H), 4.94 (s, 1H),
4.96 (dd, J=8.4 and 1.6 Hz, 1H), 5.46 (s, 2H), 5.64 (d, J=12 Hz,
1H), 5.65 (masked, 1H), 5.70 (d, J=17 Hz, 1H), 6.90 (dd, J=17
and 12 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H),
7.44 (d, J=8 Hz, 1H), 7.45 (br m, 1H); 13C NMR (100.6 MHz) δ
28.5 (3 CH3), 32.7 (CH2), 39.4 (CH2), 44.3 (CH2), 55.7 (CH3),
74.4 (CH2), 79.4 (C), 109.4 (CH), 111.9 (C), 116.2 (CH2), 119.9
(CH), 120.6 (CH), 120.7 (CH2), 123.0 (CH), 125.2 (CH), 127,9
(C), 135.7 (CH), 136.6 (C), 137.7 (C), 155.6 (C); ESI-HRMS
[M+Na]+ calcd for C22H30N2O3Na 393.2148, found 393.2139.
3-[N-(3-Butenyl)-N-(tosyl)aminomethyl]-1-(methoxymethyl)-
2-vinylindole (7b). Aldehyde 6 (0.45 g, 2.10 mmol) was allowed to
react as above with 3-butenylamine (0.39 mL, 4.20 mmol) and
NaBH(OAc)3 (1.33 g, 6.30 mmol). The resulting secondary
amine was dissolved in CH2Cl2 (30 mL) and treated with TsCl
(0.48 g, 2.52 mmol) and Et3N (0.36 mL, 2.52 mmol) at rt
overnight. The reaction mixture was diluted with CH2Cl2 and
washed with 1 N HCl and brine. The organic solution was dried
and concentrated, and the resulting residue was chromato-
graphed (8:2 hexanes-AcOEt) to give sulfonamide 7b as a white
solid: 0.58 g (65%); mp 105 °C (Et2O); IR (KBr) 1335, 1462,
1598 cm-1; 1H NMR (400 MHz) δ 1.90 (m, 2H), 2.45 (s, 3H),
3.01 (m, 2H), 3.30 (s, 3H), 4.57 (s, 2H, CH2), 4.68 (d, J=17 Hz,
1H), 4.76 (d, J=12 Hz, 1H), 5.38 (m, 1H), 5.45 (s, 2H), 5.60 (d,
J=12 Hz, 1H), 5.73 (d, J = 18 Hz, 1H), 6.80 (dd, J = 18 and 12
Hz, 1H), 7,12 (t, J=7.5 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.34 (d,
J=8 Hz, 2H), 7.43 (d, J=8 Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.78
(d, J=8 Hz, 2H); 13C NMR (100.6 MHz) δ 21.5 (CH3), 33.1
(CH2), 42.9 (CH2), 46.9 (CH2), 55.7 (CH3), 74.4 (CH2), 109.0
(C), 109.4 (CH), 116.4 (CH2), 119.8 (CH), 120.8 (CH), 121.7
(CH2), 123.3 (CH), 124.7 (CH), 127.3 (2CH), 129.7 (2CH), 127.8
(C), 134.8 (CH), 136.5 (C), 137.1 (C), 137.6 (C), 143.2 (C). Anal.
Calcd for C24H28N2O3S: C, 67.80; H, 6.63; N, 6.58; S; 7.68.
Found: C, 67.62; H, 6.65; N, 6.52; S, 7.70.
2-(tert-Butoxycarbonyl)-7-(methoxymethyl)-1,2,3,4-tetrahy-
droazocino[4,3-b]indole (8a). The second-generation Grubbs
catalyst (33 mg, 10 mol %) was added under Ar to a solution
of diene 7a (150 mg, 0.40 mmol) in toluene (40 mL), and the
resulting mixture was heated at 60 °C for 2.5 h. The reaction
mixture was concentrated, and the residue was chromato-
graphed (9:1 hexanes-AcOEt) to give azocinoindole 8a as a co-
lorless oil: 97 mg (70%); IR (film) 1689 cm-1; 1H NMR (CDCl3,
400 MHz, assignment aided by gHSQC, mixture of rotamers) δ
1.30 and 1.44 (2 s, 9H, Boc), 2.48 (m, 2H, 4-H), 3.19 and 3.21 (2s,
3H, OCH3), 3.59 and 3.68 (2 apparent t, J=5.6 Hz, 2H, 3-H),
4.62 and 4.64 (2s, 2H, 1-H), 5.37 and 5.40 (2s, 2H, OCH2), 6.09
(m, 1H, 5-H), 6.63 (m, 1H, 6-H), 7.13 (t, J=7.6 Hz, 1H, 10-H),
7.22 (m, 1H, 9-H), 7.35 and 7.39 (2d, J=8 Hz, 1H, 8-H), 7.56 and
7.70 (2 d, J=8 Hz, 1H, 11-H); 13C NMR (100.6 MHz, assign-
ments aided by gHSQC, major rotamer) δ 28.4 (3CH3), 28.6
(CH2, C-4), 43.2 (CH2, C-1), 45.8 (CH2, C-3), 55.4 (CH3), 73.8
(CH2), 79.4 (C), 109.2 (CH, C-8), 112.3 (C), 118.7 (CH, C-11),
119.8 (CH, C-10), 120.6 (CH, C-6), 122.5 (CH, C-9), 127.0 (C),
132.5 (CH, C-5), 132.6 (C), 137.4 (C), 156.2 (C); ESI-HRMS
[M + H]+ calcd for C20H27N2O3 343.2016, found 343.2005;
[M+Na]+ calcd for C20H26N2O3Na 365.1835, found 365.1837.
7-(Methoxymethyl)-2-tosyl-1,2,3,4-tetrahydroazocino[4,3-b]-
indole (8b). The second-generation Grubbs catalyst (24 mg,
7 mol %) was added under Ar to a solution of diene 7b (170
mg, 0.40 mmol) in CH2Cl2 (30 mL), and the resulting mixture
was heated at reflux overnight. The reaction mixture was con-
centrated, and the residue was chromatographed (8:2 hexanes-
AcOEt) to give azocinoindole 8b as a white solid: 103 mg (65%);
mp 154 °C (Et2O); IR (KBr) 1157, 1330, 1462 cm-1; 1H NMR
(400 MHz) δ 2.30 (m, 2H), 2.37 (s, 3H), 3.16 (s, 3H), 3.36 (m,
2H), 4.47 (s, 2H), 5.30 (s, 2H, CH2), 6.07 (m, 1H), 6.58 (d, J=11
Hz, 1H), 7.19 (d, J = 8 Hz, 2H), 7.22 (m, 1H), 7.26 (m, 1H), 7.42
(d, J=7.6 Hz, 1H), 7.65 (d, J=8 Hz, 2H), 7.84 (d, J=8 Hz, 1H);
13C NMR (100.6 MHz) δ 21.4 (CH3), 28.8 (CH2), 43.4 (CH2),
45.5 (CH2), 55.6 (CH3), 74.3 (CH2), 109.4 (CH), 110.8 (C), 119.6
(CH), 120.2 (CH), 120.6 (CH), 122.9 (CH), 127.2 (2CH), 129.5
(2CH), 127.4 (C), 133.5 (CH), 135.3 (C), 137.0 (C), 137.3 (C),
142.9 (C). Anal. Calcd for C22H24N2O3S. 2/3H2O: C, 64.67; H,
6.25; N, 6.86. Found: C, 64.19; H, 6.47; N, 6.49.
2-(2-Iodo-2-(Z)-butenyl)-7-(methoxymethyl)-1,2,3,4-tetrahi-
droazocino[4,3-b]indole (9). A solution of carbamate 8a (0.31 g,
0.90 mmol) in 1.2 M HCl in MeOH (3.7 mL) was stirred at rt for
18 h. The reaction mixture was basified with 20% NH4OH and
concentrated. The residue was partitioned between CH2Cl2 and
H2O and extracted with CH2Cl2. The organic extracts were
dried and concentrated to give the crude secondary amine
(0.18 g). K2CO3 (0.16 g, 1.15 mmol) and (Z)-2-iodo-2-butenyl
tosylate15a,16c (0.26 g, 0.74 mmol) were added to a solution of the
above material (0.18 g, 0.74 mmol) in acetonitrile (20 mL),
and the resulting mixture was stirred at 70 °C for 1.5 h. The
solvent was removed, and the residue was dissolved in Et2O
and washed with H2O. The organic solution was dried and con-
centrated to give the crude product. After chromatography
J. Org. Chem. Vol. 74, No. 21, 2009 8365

Bennasar et al.
JOCArticle
(9:1 hexanes-AcOEt) the pure tertiary amine 9 was obtained as
a yellow oil: 0.23 g (60%); IR (film) 1323, 1461, 1659 cm-1; 1H
NMR (400 MHz) δ 1.81 (d, J = 6.4 Hz, 3H), 2.30 (m, 2H), 2.79
(m, 2H), 3.23 (s, 3H), 3.32 (br s, 2H), 4.04 (br s, 2H), 5.44 (s, 2H),
5.80 (q, J = 6.4 Hz, 1H), 6.12 (m, 1H), 6.56 (d, J = 11.2 Hz, 1H),
7.15 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 8
Hz, 1H), 7.57 (d, J = 8 Hz, 1H); 13C NMR (100.6 MHz) δ 21.7
(CH3), 26.9 (CH2), 47.6 (CH2), 49.3 (CH2), 55.9 (CH3), 65.4
(CH2), 74.5 (CH2), 109.4 (CH), 110.5 (C), 110.6 (C), 117.9 (CH),
118.8 (CH), 120.3 (CH), 122.5 (CH), 129.0 (C), 131.8 (CH),
135.6 (CH), 136.0 (C), 137.3 (C); ESI-HRMS [M + H]+ calcd
for C19H24N2OI 423.0927, found 423.0941.
12-(Z)-Ethylidene-7-(methoxymethyl)-1,2,3,6-tetrahydro-2,66-
ethanoazocino[4,3-b]indole (10). Method A. Pd(PPh3)4 (12 mg,
0.010 mmol) was added under Ar to a solution of amine 9 (45
mg, 0.107 mmol) in 1:1 THF-Et3N (5 mL), and the mixture was
heated at 90 °C in a sealed tube for 24 h. The solvent was
removed, and the residue was partitioned between CH2Cl2 and a
saturated aqueous NaHCO3 solution and extracted with CH2-
Cl2. The organic extracts were dried and concentrated, and the
residue was chromatographed (hexanes and 8:2 hexanes-
AcOEt) to give 10 as a yellow oil: 10 mg (30%); 1H NMR (400
MHz, assignment aided by gCOSY and gHSQC) δ 1.53 (d, J=
7.2 Hz, 3H, dCHCH3), 3.23 (s, 3H, OCH3), 3.67 (d, J=19.2 Hz,
1H, 3-H), 3.86 (dt, J=19.2, 3, and 2.2 Hz, 1H, 3-H), 3.89 (d, J=
17.6 Hz, 1H, 13-H), 3.95 (d, J=17.6 Hz, 1H, 13-H), 4.24 (d, J=
9.2 Hz, 1H, 6-H), 4.28 (d, J=17.2 Hz, 1H, 1-H), 4.41 (d, J=17.2
Hz, 1H, 1-H), 5.34 (qt, J=7.2 and 2.2 Hz, 1H, dCHCH3), 5.45
(d, J=11.6 Hz, 1H, OCH2), 5.50 (d, J=11.6 Hz, 1H, OCH2),
5.59 (dt, J=10.4 and 3 Hz, 1H, 4-H), 6.07 (ddt, J=10.4, 9.2, and
3 Hz, 1H, 5-H), 7.08 (t, J=7.6 Hz, 1H, 10-H), 7.16 (t, J=7.6 Hz,
1H, 9-H), 7.36 (d, J=8.4 Hz, 1H, 8-H), 7.39 (d, J=8 Hz, 1H,
11-H); 13C NMR (100.6 MHz, assignment aided by gHSQC) δ
13.0 (dCHCH3), 44.0 (CH, C-6), 52.5 (CH2, C-1), 53.0 (CH2, C-
13), 56.0 (OCH3), 57.0 (CH2, C-3), 73.5 (OCH2), 109.0 (CH, C-
8), 112.4 (C), 118.0 (CH, C-11), 118.5 (CH, dCHCH3), 120.0
(CH, C-10), 121.5 (CH, C-9), 127.0 (C), 129.0 (CH, C-5), 132.0
(CH, C-4), 136.9 (C), 139.0 (C), 143.1 (C); ESI-HRMS [M +
H]+ calcd for C19H23N2O 295.1804, found 295.1803.
Method B. Pd(OAc)2 (2 mg, 0.009 mmol), PPh3 (7 mg, 0.027
mmol), and Ag2CO3 (50 mg, 0.18 mmol) were added under Ar to
a solution of amine 9 (40 mg, 0.095 mmol) in 1:1 toluene-Et3N
(5 mL), and the resulting mixture was heated at 90 °C for 1 h 45
min. The solvent was removed, and the residue was partitioned
between CH2Cl2 and a saturated aqueous NaHCO3 solution
and extracted with CH2Cl2. The organic extracts were dried and
concentrated, and the residue was chromatographed (hexanes
and 8:2 hexanes-EtOAc) to give 10: 13 mg (46%).
2-(1-Methyl-2-(E)-butenyl)-1-(phenylsulfonyl)indole (11). n-
BuLi (1.6 M in hexane, 5.83 mL, 9.33 mmol) was slowly added
to a cooled (0 °C) solution of 1-(phenylsulfonyl)indole (2 g, 7.78
mmol) in THF (20 mL), and the solution was stirred at 0 °C for 2
h and then cooled to -78 °C. CuCN (0.84 g, 9.38 mmol) was
added and the reaction mixture was allowed to warm to rt (2-
3 h) and then cooled again to -78 °C. (E)-4-Chloro-2-pentene
(0.98 g, 9.38 mmol) was added, and the stirring was continued at
rt for 12 h. The reaction mixture was diluted with 20% NH4OH
and extracted with CH2Cl2. The organic extracts were dried and
concentrated, and the resulting residue was chromatographed
(hexanes and 95:5 hexanes-AcOEt) to give indole 11 as an oil:
2.15 g (85%); IR (neat) 1448, 1367, 1173 cm-1; 1H NMR (400
MHz, signals due to a minor isomer are omitted) δ 1.45 (d, J=
6.8 Hz, 3H), 1.67 (d, J=6.0 Hz, 3H), 4.34 (m, 1H), 5.52 (m, 1H),
5.66 (m, 1H), 6.49 (s, 1H), 7.24-7.50 (m, 6H), 7.72 (m, 2H), 8.23
(d, J=8.4 Hz, 1H); 13C NMR (100.6 MHz) δ 17.9 (CH3), 21.7
(CH3), 35.0 (CH), 108.6 (CH), 115.3 (CH), 120.3 (CH), 123.7
(CH), 124.0 (CH), 124.9 (CH), 126.2 (2CH), 129.0 (2CH), 129.9
(C), 133.5 (CH), 134.0 (CH), 137.5 (C), 139.0 (C), 147.1 (C);
ESI-HRMS [M + H]+ calcd for C19H20NO2S 326.1209, found
326.1212.
2-(1-Methyl-2-(E)-butenyl)-1-(phenylsulfonyl)indole-3-carbal-
dehyde (12). Indole 11 (1 g, 3.07 mmol) in CH2Cl2 (20 mL) was
added to a cooled (- 78 °C) solution of TiCl4 (1 M in CH2Cl2,
6.15 mL, 6.15 mmol) and Cl2CHOCH3 (0.55 mL, 6.15 mmol) in
CH2Cl2 (10 mL), and the resulting mixture was stirred at -78 °C
for 4 h. The reaction mixture was diluted with H2O, basified with
a saturated aqueous Na2CO3 solution, and extracted with
CH2Cl2. The organic extracts were dried and concentrated,
and the residue was chromatographed (hexanes and 95:5
hexanes-AcOEt) to give aldehyde 12 as an amorphous solid:
0.83 g (76%); IR (film) 1666, 1449, 1382, 1174 cm-1; 1H NMR
(400 MHz) δ 1.47 (d, J = 6.8 Hz, 3H), 1.61 (dm, J = 6.4 Hz, 3H),
4.76 (m, 1H), 5.40 (m, 1H), 5.61 (dm, J=15 Hz, 1H), 7.37 (m,
2H), 7.49 (m, 2H), 7.62 (m, 1H), 7.82 (d, J=7.8 Hz, 2H), 8.32 (m,
2H), 10.45 (s, 1H); 13C NMR (100.6 MHz) δ 17.7 (CH3), 22.5
(CH3), 33.8 (CH), 114.7 (CH), 119.3 (C), 122.1 (CH), 125.2
(CH), 125.7 (CH), 125.9 (CH), 126.3 (C), 126.5 (2CH), 129.6
(2CH), 133.1 (CH), 134.4 (CH), 136.4 (C), 139.4 (C), 155.3 (C),
187.5 (CH); ESI-HRMS [M + H]+ calcd for C20H20NO3S
354.1158, found 354.1165.
3-[N-Allyl-N-(tert-butoxycarbonyl)aminomethyl]-2-(1-methyl-
2-(E)-butenyl)-1-(phenylsulfonyl)indole (13). Allylamine (0.21
mL, 2.83 mmol), NaBH(OAc)3 (0.90 g, 4.25 mmol), and AcOH
(0.08 mL, 1.41 mmol) were successively added to aldehyde 12
(0.50 g, 1.41 mmol) in CH2Cl2 (17 mL), and the resulting mixture
was stirred at rt overnight. The reaction mixture was partitioned
between CH2Cl2 and 10% aqueous Na2CO3 and extracted with
CH2Cl2. The organic extracts were dried and concentrated to
give the crude secondary amine (540 mg). This compound
was dissolved in MeOH (5 mL) and treated with (t-BuOCO)2O
(0.54 g, 2.47 mmol) and Et3N (0.70 mL, 4.94 mmol). After the
mixture was heated at reflux for 5 h, the solvent was removed,
and the residue was diluted with CH2Cl2 and washed with 2 N
HCl and brine. The organic extracts were dried and concen-
trated to give the crude product. After chromatography
(hexanes and 95:5 hexanes-AcOEt) diene 13 was obtained as
a pale yellow oil: 0.63 g (90%); IR (film) 1690, 1450, 1368,
1173 cm-1; 1H NMR (400 MHz) δ 1.21 (d, J = 7.2 Hz, 3H), 1.42
(s, 9H), 1.52 (d, J = 6.4 Hz, 3H), 3.38 (br s, 2H), 4.44 (m, 1H),
4.57 (m, 2H), 4.83 (dd, J=17.2 and 1.5 Hz, 1H), 4.92 (dd, J =
10.4 and 1.5 Hz, 1H), 5.28 (m, 1H), 5.44 (dm, J = 15.2 Hz, 1H),
5.50 (m, 1H), 7.20 (m, 2H), 7.32 (m, J = 2H), 7.43 (m, 2H), 7.60
(dm, J = 8.4 Hz, 2H), 8.18 (d, J = 8.4 Hz, 1H); 13C NMR
(100.6 MHz) δ 18.1 (CH3), 20.1 (CH3), 28.6 (3CH3), 33.5 (CH),
40.0 (CH2), 46.8 (CH2), 80.1 (C), 115.4 (CH2), 115.6 (CH), 117.2
(C), 119.7 (CH), 123.9 (CH), 124.7 (CH), 125.2 (CH), 126.5
(2CH), 129.2 (C), 129.3 (2CH), 132.8 (CH), 133.8 (CH), 133.9
(CH), 137.1 (C), 139.7 (C), 142.9 (C), 156.1 (CO); ESI-HRMS
[M + Na]+ calcd for C28H34N2O4NaS 517.2131, found 517.2144.
2-(tert-Butoxycarbonyl)-6-methyl-7-(phenylsulfonyl)-1,2,3,6-
tetrahydroazocino[4,3-b]indole (14). The second-generation
Grubbs catalyst (24 mg, 7 mol %) was added under Ar to a
solution of diene 13 (200 mg, 0.40 mmol) in CH2Cl2 (5.7 mL),
and the resulting mixture was heated at reflux for 4.5 h. The
reaction mixture was concentrated, and the residue was chro-
matographed (9:1 hexanes-AcOEt) to give azocinoindole 14 as
a white foam: 146 mg (80%); IR (KBr) 1689, 1450, 1370, 1172
cm-1 1H NMR (400 MHz, assignments aided by gHSQC and 1H
gCOSY, mixture of rotamers) δ 1.42 (br s, 9H, Boc), 1.47 (br s,
3H, CH3), 2.85 (m, 1H, 3-H), 3.81 and 4.03 (2m, 1H, 3-H), 4.37
(br s, 1H, 1-H), 4.65 (m, 1H, 6-H), 4.89 and 5.01 (2m, 1H, 1-H),
5.44 (br s, 1H, 4-H), 5.80 (br d, J=11 Hz, 1H, 5-H), 7.29 (m, 3H),
7.38 (t, J=7.6 Hz, 2H), 7.51 (t, J=7.6 Hz, 1H), 7.67 (d, J=
7.6 Hz, 2H), 8.28 (d, J=7.8 Hz, 1H); 13C NMR (100.6 MHz,
assignments aided by gHSQC) δ 24.3 (CH3), 28.4 (3CH3), 32.5
(CH, C-6), 37.0 (CH2, C-1), 38.0 (CH2, C-3), 79.90 (C), 115.6
8366 J. Org. Chem. Vol. 74, No. 21, 2009

Bennasar et al.
JOCArticle
(CH, C-8), 118.7 (CH, C-11), 118.9 (C), 121.0 (CH, C-4), 123.8
(CH, C-10), 124.8 (CH, C-9), 126.0 (2CH, Ph), 129.2 (2CH, Ph),
130.8 (C), 133.8 (CH, Ph), 136.9 (C), 137.6 (CH, C-5), 138.8 (C),
142.2 (C), 155.0 (CO); ESI-HRMS [M + H]+ calcd for C25H29-
N2O4S 453.1842, found 453.1851; [M + Na]+calcd for C25H28-
N2O4NaS 475.1662, found 475.1670.
reaction mixture was stirred at rt for 2 h with dry air constantly
supplied by passing compressed air through a short tube of
Drierite. Then, additional n-Bu3SnH (0.50 mL, 1.89 mmol) and
Et3B (1 M in hexanes, 1.90 mmol) were added, and the reaction
mixture was stirred under dry air at rt for 2 h. The reaction
mixture was concentrated, and the resulting residue was parti-
tioned between hexanes and acetonitrile. The polar layer was
washed with hexanes and concentrated to give the crude pro-
duct. Flash chromatography (8:2 hexanes-AcOEt) gave ketone
26 as an orange solid: 0.64 g (54%); 1H NMR (400 MHz,
assignment aided by gHSQC, mixture of rotamers) δ 1.30 and
1.50 (2s, 9H, Me), 1.96 and 2.04 (2m, 2H, 4-H), 2.97 (m, 2H, 5-
H), 3.48 and 3.62 (2m, 2H, 3-H), 4.88 and 5.01 (2s, 2H, 1-H),
7.16 (t, J = 7.2 Hz, 1H, 10-H), 7.35 (ddd, J = 8.4, 7.2, 0.9 Hz,
1H, 9-H), 7.41 (d, J = 8.4 Hz, 1H, 8-H), [7.72 (d, J = 8.4 Hz),
and 7.77 (d, J = 8 Hz), 1H, 11-H], 9.42 and 9.47 (2s, 1H, NH);
13C NMR (CDCl3, 100.6 MHz, gHSQC, mixture of rotamers) δ
23.9 and 25.1 (CH2, C-4), 28.3 (CH3), 38.7 and 39.5 (CH2, C-5),
42.5 and 42.6 (CH2, C-1), 43.0 and 46.1 (CH2, C-3), 80.3 (C),
112.1 (CH, C-8), 117.3 and 119.3 (C), 120.3 and 120.7 (CH, C-
10), 120.9 (CH, C-11), 126.4 and 126.6 (CH, C-9), 127.5 and
127.8 (C), 132.7 and 133.9 (C), 135.8 and 136.0 (C), 155.1 and
155.2 (C), 192.7 and 193.4 (C); ESI-HRMS [M + Na]+ calcd for
C18H22N2NaO3 337.1522, found 337.1524. Anal. Calcd for
C18H22N2O3.1/2 H2O C, 66.85; H, 7,17; N, 8.66. Found: C,
67.24; H, 7.00; N, 8.33.
Methyl 3-[N-(2-Bromo-2-propenyl)-N-(tert-butoxycarbonyl)-
aminomethyl]indole-2-carboxylate (24). A solution of methyl 3-
formylindole-2-carboxylate (23, 2.34 g, 11.52 mmol), 2-bromo-
2-propenylamine (1.88 g, 13.82 mmol), NaBH(OAc)3 (7.32 g,
35.0 mmol), and AcOH (1.32 mL, 23.0 mmol) in anhydrous
CH2Cl2 (100 mL) was stirred at rt overnight. The reaction
mixture was washed with a saturated aqueous Na2CO3 solution.
The solvent was removed, and the resulting residue (3.72 g,
crude secondary amine) was dissolved in anhydrous dioxane
(100 mL) and treated with (t-BuOCO)2O (3.92 g, 17.96 mmol) at
rt overnight. The reaction mixture was diluted with H2O and
concentrated. The residue was partitioned between Et2O and
brine and extracted with Et2O. The organic extracts were dried
and concentrated and the crude product was chromatographed
(85:15 hexanes-AcOEt) to give 24 as a white solid: 3.71 g (76%);
1H NMR (300 MHz, major rotamer) δ 1.49 (s, 9H), 3.89 (s, 2H),
3.96 (s, 3H), 5.11 (s, 2H), 5.49 (s, 1H), 5.57 (s, 1H), 7.16 (ddd,
J=1.5, 6.6, 8.1 Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.40 (d, J=8.4
Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.87 (s, 1H); 13C NMR (100.6
MHz, major rotamer) δ 28.2 (CH3), 39.1 (CH2), 52.0 (CH3), 52.6
(CH2), 80.2 (C), 111.7 (CH), 115.1 (CH2), 118.8 (C), 120.8 (CH),
122.0 (CH), 124.8 (C), 125.9 (CH), 127.6 (C), 129.6 (C), 136.0
(C), 155.2 (C), 162.6 (C); ESI-HRMS [M + Na]+ calcd for
C19H23BrN2NaO4 445.0733, found 445.0738. Anal. Calcd for
C19H23BrN2O4: C, 53.91; H, 5.48; N, 6.62. Found: C, 53.85; H,
5.46; N, 6.56.
2-(tert-Butoxycarbonyl)-6-methyl-1,2,3,4-tetrahydroazocino-
[4,3-b]indole (15). From Azocinoindole 14. t-BuOK (0.55 g, 4.90
mmol) was added to a solution of 14 (0.22 g, 0.49 mmol) in THF
(14 mL), and the resulting solution was heated at reflux for 48 h.
The reaction mixture was partitioned between a saturated
aqueous NH4Cl solution and Et2O and extracted with Et2O.
The organic extracts were dried and concentrated to give
azocinoindole 15 as a yellow foam: 138 mg (90%). An analytical
sample was obtained by chromatography (hexanes and 8:2
Se-Phenyl 3-[N-(2-Bromo-2-propenyl)-N-(tert-butoxycarbo-
nyl)aminomethyl]-indole-2-carboselenoate (25). A solution of
carboxylic ester 24 (2.30 g, 5.44 mmol) and LiOH H2O (0.27 g,
3
1
6.43 mmol) in a 3:1 mixture of THF-H2O (45 mL) was stirred
at 65 °C overnight. The reaction mixture was concentrated,
acidified with 1 N HCl, and extracted with CH2Cl2. The com-
bined organic extracts were dried and concentrated to give the
crude carboxylic acid (2.20 g). A suspension of this material in
anhydrous CH2Cl2 (40 mL) was treated with Et3N (1.50 mL,
10.88 mmol). After 15 min at rt, the mixture was concentrated to
give the corresponding triethylammonium salt. In another flask,
tributylphosphine (6.70 mL, 27.16 mmol) was added under Ar to
a solution of PhSeCl (5.20 g, 27.16 mmol) in anhydrous THF
(40 mL) and the mixture was stirred at rt for 10 min (yellow
solution). Theabovetriethylammonium saltin THF (40 mL) was
added to this solution, and the resulting mixture was stirred
overnight. The reaction mixture was partitioned between Et2O
and H2O and extracted with Et2O. The organic extracts were
dried and concentrated and the crude product was chromato-
graphed (hexanes and 9:1 hexanes-AcOEt) to give 25 as a yellow
solid: 2.68 g (90%); 1H NMR (300 MHz, major rotamer) δ 1.51
(s, 9H), 3.93 (s, 2H), 5.13 (s, 2H), 5.44 (s, 1H), 5.54 (s, 1H), 7.18
(m, 1H), 7.39 (m, 2H), 7.46 (m, 3H), 7.62 (m, 2H), 7.94 (d,
J = 7.8 Hz, 1H), 8.83 (s, 1H); 13C NMR (75.4 MHz, major
rotamer) δ 28.3 (CH3), 39.8 (CH2), 53.0 (CH2), 80.5 (C), 112.1
(CH), 115.8 (CH2), 118.4 (C), 121.3 (CH), 122.4 (CH), 125.0 (C),
126.8 (CH), 127.8 (C), 129.4 (CH), 129.5 (CH), 132.8 (C), 136.3
(CH), 136.4 (C), 155.2 (C), 184.1 (C), (one missing quaternary
carbon); HRMS [M + Na]+ calcd for C24H25BrN2NaO3Se
571.0105, found 571.0102. Anal. Calcd for C24H25BrN2O3Se:
C, 52.57; H, 4.60; N, 5.11. Found: C, 52.57; H, 4.52; N, 5.11.
2-(tert-Butoxycarbonyl)-6-oxo-1,2,3,4,5,6-hexahydroazocino-
[4,3-b]indole (26). n-Bu3SnH (2.50 mL, 9.42 mmol) and Et3B
(1 M in hexanes, 9.50 mmol) were added to a solution of phenyl
selenoester 25 (2.07 g, 3.78 mmol, previously dried azeotropi-
cally with anhydrous C6H6) in anhydrous C6H6 (135 mL). The
hexanes-AcOEt); IR (film) 3321, 1670 cm-1; H NMR (400
MHz, assignments aided by gHSQC, mixture of rotamers) δ
1.35 and 1.45 (2s, 9H, Boc), 2.13 (s, 3H, CH3), 2.37 (m, 2H, 4-H),
3.60 (m, 2H, 3-H), 4.64 (br s, 2H, 1-H), 5.69 and 5.75 (2t, J=8
Hz, 1H, 5-H), 7.15 (m, 2H, 9-H, 10-H), 7.28 and 7.31 (2 d, J=8
Hz, 1H, 8-H), 7.56 and 7.62 (2d, J = 8 Hz, 1H, 11-H), 7.85 and
7.89 (2 br s, 1H, NH); 13C NMR (100.6 MHz, assignments aided
by gHSQC,) δ 22.7 and 22.8 (CH3), 28.4 and 28.5 (3CH3, Boc),
28.7 (CH2, C-4), 43.4 and 43.5 (CH2, C-1), 46.0 and 46.7 (CH2,
C-3), 79.1 and 79.3 (C), 110.3 and 110.4 (CH, C-8), 110.8 and
111.0 (C), 118.5 and 119.0 (CH, C-11), 119.3 and 119.4 (CH, C-
10), 122.1 and 122.2 (CH, C-9), 126.5 and 127.1 (CH, C-5), 127.2
and 127.3 (C), 128.9 and 129.5 (C), 132.8 and 133.4 (C), 135.7
and 135.9 (C), 156.1 and 156.5 (C); ESI-HRMS calcd for
C19H24N2O2 312.1837, found 312.1837.
From Ketone 26. Ketone 26 (0.52 g, 1.66 mmol) in anhydrous
THF (35 mL) was added under Ar to a cooled (-10 °C) solution
of MeLi (1.6 M in Et2O, 10.40 mL, 16.60 mmol) in anhydrous
THF (35 mL). After stirring at rt for 2 h, the reaction mixture
was quenched with ice-water and extracted with AcOEt. Con-
centration of the organic extracts gave the crude carbinol
(0.45 g). p-Toluenesulfonic acid monohydrate (25 mg,
0.13 mmol) was added to a suspension of the above material
in acetonitrile (25 mL), and the mixture was stirred at rt for 1 h.
The reaction mixture was concentrated, and the resulting resi-
due was dissolved in CH2Cl2 and washed with a saturated
aqueous Na2CO3 solution. Concentration of the organic solu-
tion gave 15: 0.36 g (70%).
2-(2-Iodo-2-(Z)-butenyl)-6-methyl-1,2,3,4-tetrahydroazocino-
[4,3-b]indole (27). A solution of carbamate 15 (224 mg,
0.72 mmol) in 1.2 M HCl in MeOH (3.2 mL) was stirred at rt
for 4.5 h. 20% NH4OH was added and the organic solvent was
removed. The residue was partitioned between CH2Cl2 and H2O
J. Org. Chem. Vol. 74, No. 21, 2009 8367

Bennasar et al.
JOCArticle
and extracted with CH2Cl2. The organic extracts were dried and
concentrated to give the secondary amine (127 mg), which was
directly used in the next step. Diisopropylethylamine (0.15 mL,
0.89 mmol) and (Z)-2-iodo-2-butenyl tosylate15a,16c (230 mg,
0.65 mmol) were added to a solution of the above amine (127
mg, 0.59 mmol) in 1:1 CH2Cl2-acetonitrile (21 mL). After the
reaction mixture was stirred at rt for 2 h, MeNH2 (2 M in
MeOH, 1.5 mL, 3 mmol) was added and the stirring was
continued for 1 h. The reaction mixture was diluted with CH2Cl2
and washed with a saturated aqueous NaHCO3 solution. The
organic solution was dried and concentrated, and the residue
was chromatographed (hexanes and 9:1 hexanes-EtOAc) to
give pure tertiary amine 27 (yellow oil): 70 mg (30%); IR (film)
3408, 2923, 1612, 1460, 742 cm-1; 1H NMR (400 MHz) δ 1.79
(dd, J = 6.2 and 1.2 Hz, 3H), 2.11 (s, 3H), 2.14 (br s, 2H), 2.77
(br s, 2H), 3.35 (br s, 2H), 3.99 (br s, 2H), 5.81 (q, J = 6.2 Hz,
1H), 5.85 (t, J = 7.8 Hz, 1H), 7.15 (m, 2H), 7.33 (d, J = 7.6 Hz,
1H), 7.57 (d, J = 7.6 Hz, 1H), 7.95 (br s, 1H); 13C NMR (100.6
MHz) δ 21.7 (CH3), 22.5 (CH3), 26.0 (CH2), 48.0 (CH2), 50.6
(CH2), 65.3 (CH2), 110.1 (C), 110.5 (CH), 110.6 (C), 118.9 (CH),
119.5 (CH), 121.9 (CH), 126.9 (C), 128.8 (C), 130.0 (CH), 131.3
(CH), 135.8 (C), 136.1 (C); ESI-HRMS [M þ H]þ calcd for
C18H22IN2 393.0822, found 393.0831.
chromatography (SiO2, 0.5% Et2O-diethylamine) gave pure
(()-apparicine as an amorphous solid: 6.6 mg (15%); 1H NMR
(CDCl3, 400 MHz, assignments aided by gHSQC) δ 1.46 (dd,
J=6.8 and 2.4 Hz, 3H, 18-H), 1.89 (ddt, J=13.6, 6.8, and 2.4 Hz,
1H, 14-H), 2.16 (dddd, J=13.6, 11.2, 8, and 5.6 Hz, 1H, 14-H),
3.07 (dddd, J=13.2, 11.2, 6.8, and 1.2 Hz, 1H, 3-H), 3.20 (d, J=
16 Hz, 1H, 21-H), 3.42 (ddd, J = 13.2, 8, and 2 Hz, 1H, 3-H),
3.82 (dt, J=16 and 2 Hz, 1H, 21-H), 3.92 (broad s, 1H, 15-H),
4.28 (d, J=17.8 Hz, 1H, 6-H), 4.51 (d, J = 17.8 Hz, 1H, 6-H),
5.25 (q, J=6.8 Hz, 1H, 19-H), 5.26 (s, 1H, 17-H), 5.39 (s, 1H, 17-
H), 7.06 (ddd, J = 7.6, 7.2, and 1.2 Hz, 1H, 10-H), 7.18 (ddd,
J = 8, 7.2, and 1.2 Hz, 1H, 11-H), 7.28 (d, J=8 Hz, 1H, 12-H),
7.42 (d, J = 7.6 Hz, 1H, 9-H), 7.84 (broad s, 1H, NH); 13C NMR
(CDCl3, 100.6 MHz, assignment aided by gHSQC) δ 12.6 (CH3,
C-18), 29.6 (CH2, C-14), 41.2 (CH, C-15), 45.3 (CH2, C-3), 54.2
(CH2, C-6), 54.3 (CH2, C-21), 110.2 (CH, C-12), 111.5 (C, C-7),
112.2 (CH2, C-17), 118.6 (CH, C-9), 119.3 (CH, C-10), 120.1
(CH, C-19), 123.0 (CH, C-11), 129.0 (C, C-8), 131.3 (C, C-20),
135.6 (C, C-16), 137.4 (C, C-13), 145.2 (C, C-2); ESI-HRMS
[M þ H]þ calcd for C18H21N2 265.1699, found 265.1705.
Acknowledgment. We thank the Ministerio de Ciencia e
ꢀ
Innovacion, Spain, for financial support (project CTQ2006-
(()-Apparicine. Pd(OAc)2 (7.6 mg, 0.034 mmol), PPh3 (26 mg,
0.10 mmol) and Ag2CO3 (93 mg, 0.34 mmol) were added
under Ar to a solution of amine 27 (65 mg, 0.17 mmol) in 1:1
toluene-Et3N (17 mL) and the mixture was heated at 80 °C for
1.5 h. The solvent was removed, and the residue was partitioned
between CH2Cl2 and a saturated aqueous NaHCO3 solution
and extracted with CH2Cl2. The organic extracts were dried and
concentrated, and the resulting residue was chromatographed
(SiO2, flash, CH2Cl2 to 9:1 CH2Cl2-MeOH). An additional
00500/BQU) and the University of Barcelona for a predocto-
ral grant to S.A. We are grateful to Professor John A. Joule
for an authentic sample of apparicine.
Supporting Information Available: General protocols, addi-
tional experimental procedures and characterization data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
8368 J. Org. Chem. Vol. 74, No. 21, 2009