Studies toward Labeling Cytisine with [11C]Phosgene
SCHEME 3. Dir ected Lith ia tion -Allyla tion of
mide 11a with tributyltin hydride catalyzed by pal-
ladium(0) afforded the (Z)-bromoalkene 8a in 82% yield.31
The same reduction conditions applied to diiodide 11b
led, under optimized conditions, to a mixture of products
from which the expected (Z)-iodoalkene 8b could be
isolated with 39% yield. The moderate yield obtained in
this case was due to over-reduction: reduced terminal
alkene 13 was produced in 43% yield. Attempts to
improve selectivity and yield for our substrate by chang-
ing the ligand of palladium [binap, dppp, dppf, P(o-tolyl)3
instead of PPh3]32 resulted mainly in the recovery of
starting material 11b. It is worth noting that we obtained
the (Z)-iodoalkene 8b from (Z)-bromoalkene 8a via a
recently developed copper-mediated substitution under
Buchwald’s conditions.33 The reaction was completely
stereoselective and could find wide application in the
future. Treatment of dibromoalkene 11a with n-butyl-
lithium and quenching the reaction with iodine afforded
the terminal iodoalkyne 12 with an average overall yield
of 95%.34 The same alkyne 12 was obtained with a
moderate 40% yield in one step from aldehyde 10 using
iodoform, triphenylphosphine, and an excess of t-BuOK
according to a described procedure.30 Moreover, purifica-
tion of the product from phosphorus-based side products
was quite difficult, and these conditions cannot be
recommended here. Reduction of iodoalkyne 12 to (Z)-
iodoalkene 8b was performed in 73% yield with diimide
using o-nitrobenzenesulfonylhydrazide (o-NBSH) in com-
bination with Et3N.35 Finally, removal of the Boc group
led to the target precursors 3a and 3b. Under the most
efficient synthetic sequence, gram quantities of pip-
eridines 3a and 3b were obtained with an overall yield
of 61% and 53%, respectively.
Boc-p ip er id in ea
a
Reagents and conditions: (a) s-BuLi, THF, -78 °C, with or
without sparteine or TMEDA; (b) 7, -78 to +20 °C, 15 h.
generated from precursor 3, which reacts with phosgene.
The second approach (route B) uses the N-benzylated
precursor 4, which undergoes an halogen-metal ex-
change reaction followed by condensation-debenzylation
with phosgene. The final strategy tested (route C) starts
from carbamoyl chloride 5, prepared by reaction of
phosgene with precursor 3, and which reacts with the
anion, formed via an halogen-metal exchange reaction,
to cyclize into lactam 2.
Syn t h esis of P r ecu r sor 3. A convergent approach
was first tried in order to prepare the common precursor
3 (Scheme 3). It was based on Beak’s methodology to
functionalize N-Boc-piperidines via a directed lithiation
R to nitrogen and subsequent alkylation with an electro-
phile.22 All attempts to metalate N-Boc-piperidine 6 with
sec-butyllithium (with or without sparteine, TMEDA,
followed or not by a transmetalation step with CuCN‚
2LiCl23) then trapping the anion with (Z)-3-bromo-1-
iodopropene24 7 failed to give the 2-alkylated piperidine
8b, direct precursor of 3b (X ) I). Boc-protected piperi-
dine 6 was quantitatively recovered with small amounts
of alkene 7.
Then we turned to a linear strategy starting from 2-(2-
hydroxyethyl)piperidine 9 (Scheme 4). Protection of the
secondary amine with a Boc group and Swern oxidation
of the primary alcohol gave aldehyde 10 (80% overall
yield). Using o-iodoxybenzoic acid (IBX),25 the oxidation
step was performed with a higher yield (95%) and under
more convenient experimental conditions.26 Thus, the
crude aldehyde 10 was used without purification in the
further steps. Wittig olefination27 with bromomethyl-
triphenylphosphonium bromide afforded an inseparable
mixture 70/30 of Z/E bromo alkenes 8a . Therefore, to
obtain selectively the (Z)-halogenoalkenes 8, the following
synthetic sequences were carried out.
Cycliza tion Stu d ies Usin g P h osgen e. To have a
reference sample of lactam 2 we focused our research first
on using a palladium cross-coupling reaction described
for synthesizing amides from carbamoyl chlorides and tin
derivatives.36 However, the intramolecular version of this
cross-coupling reaction required some adjustments. At-
tempts to transform bromoalkene piperidine 8a into a
(Z)-tributyltin alkene derivative failed [t-BuLi, THF, -78
°C followed by Bu3SnCl or (Bu3Sn)2, Pd(PPh3)4, toluene,
reflux]. The bulkiness of the tributyltin group probably
prevented its introduction on a cis position of a double
bond. Only the reduced terminal alkene 13 was detected
in the crude mixture. Therefore, bromine-tin exchange
was tried using a trimethyltin group. The palladium-
mediated conditions ([(Me3Sn)2, Pd(PPh3)4], toluene, re-
Dibromo olefination28 of aldehyde 10 furnished the
dibromoalkene 11a 29 or the diiodoalkene 11b under
modified conditions.30 Selective reduction of the dibro-
1
flux) resulted in complete conversion as shown by the H
NMR of the crude product but purification on silica gel
(22) (a) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg, K. B.
J . Am. Chem. Soc. 2002, 124, 1889-1895. (b) Beak, P.; Lee, W. K. J .
Org. Chem. 1993, 58, 1109-1117 and references therein.
(23) (a)Dehmel, F.; Abarbri, M.; Knochel, P. Synlett 2000, 345-346.
(b) Knochel, P.; Singer, R. P. Chem. Rev. 1993, 93, 2117-2188.
(24) (a) Piers, E.; Renaud, J .; Rettig, S. J . Synthesis 1998, 590-
602. (b) Marek, L.; Alexakis, A.; Normant, J .-F. Tetrahedron Lett. 1991,
32, 532-5332.
(25) (a) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G.
J . Org. Chem. 1995, 60, 7272-7276. (b) Frigerio, M.; Santagostino,
M.; Sputore, S. J . Org. Chem. 1999, 64, 4537-4538 and references
therein.
(26) More, J . D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
(27) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
(28) Ramirez, F.; Desai, N. B.; McKelvie, N. J . Am. Chem. Soc. 1962,
84, 1745-1747.
(29) Ikeda, M.; Kugo, Y.; Sato, T. J . Chem. Soc., Perkin Trans. 1
1996, 1819-1824.
(30) Michel, P.; Rassat, A. Tetrahedron Lett. 1999, 40, 8579-8581.
(31) Uenishi, J .; Kawahama, R.; Yonemitsu, O.; Tsuji, J . J . Org.
Chem. 1998, 63, 8965-8975.
(32) binap: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; dppp: 1,3-
bis(diphenylphosphino)propane; dppf: 1,1′-bis(diphenylphosphino)-
ferrocene.
(33) Buchwald, S. L.; Klapars, A. J . Am. Chem. Soc. 2002, 124,
14844-14845.
(34) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-
3772.
(35) (a) Myers, A. G.; Zheng, B.; Movassaghi, M, J . Org. Chem. 1997,
62, 7507. (b) Wang, Y.-G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615-
4618. When using disodium azodicarboxylate in acetic acid as diimide
precursor, the reduction, which gave 8b in 89% yield, went to
completion in about 1 month by slowly adding 100 equiv of reagent.
Moreover, this result was difficult to reproduce.
(36) J ousseaume, B.; Kwon, H.; Verlhac, J .-B.; Denat, F.; Dubac, J .
Synlett 1993, 117-118.
J . Org. Chem, Vol. 69, No. 11, 2004 3789