Conjugate additions of o-iodoanilines and methyl anthranilates to acetylenic sulfones. A new route to quinolones including first syntheses of two alkaloids from the medicinal herb Ruta chalepensis

Article abstract of DOI:10.1021/jo026595t

A novel synthesis of 2-substituted 4-quinolones was developed on the basis of the conjugate additions of appropriately ortho-substituted anilines to acetylenic sulfones followed by intramolecular acylation of the corresponding sulfone-stabilized anions. C

Full text of DOI:10.1021/jo026595t

Con ju ga te Ad d ition s of o-Iod oa n ilin es a n d Meth yl An th r a n ila tes to
Acetylen ic Su lfon es. A New Rou te to Qu in olon es In clu d in g F ir st
Syn th eses of Tw o Alk a loid s fr om th e Med icin a l Her b Ru ta
ch a lepen sis
Thomas G. Back,* Masood Parvez, and J eremy E. Wulff
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada T2N 1N4
tgback@ucalgary.ca
Received October 22, 2002
A novel synthesis of 2-substituted 4-quinolones was developed on the basis of the conjugate additions
of appropriately ortho-substituted anilines to acetylenic sulfones followed by intramolecular acylation
of the corresponding sulfone-stabilized anions. Conjugate additions of variously substituted anilines
to alkyl-substituted acetylenic sulfones generally proceeded slowly and in poor yield, especially
when the aniline contained an electron-withdrawing substituent such as an ester group. In some
cases, the reactions were enhanced by the presence of DMAP and the use of an excess of the sulfone
in aqueous DMF. N-Formylanilines proved superior to free anilines. The products were either vinyl
or allyl sulfones, depending on the conditions and the structure of the reactants. The acetylenic
sulfone exists in equilibrium with its allenic and propargylic isomers under base-catalyzed
conditions. Therefore, any of the three unsaturated sulfones can serve as the starting material for
the conjugate additions. o-Iodoanilines proved superior to methyl anthranilate derivatives and
underwent conjugate additions smoothly. The products were subjected to palladium-catalyzed
carbonylation in methanol, and the resulting methyl esters were cyclized by treatment with strong
bases such as LiHMDS or LiTMP, followed by reductive desulfonylation with aluminum amalgam.
The resulting 2-substituted 4-quinolones included the naturally occurring medicinal compounds 1
and 2 and the O-methyl derivative 3.
In tr od u ction
During the past few years, we have developed a
cyclization protocol based on the sequential application
of the above processes. Thus, conjugate additions of
amines containing chloroalkyl or ester substituents to
acetylenic sulfones, followed by intramolecular alkylation
or acylation, lead to a diverse range of nitrogen hetero-
cycles (for some examples, see Scheme 1). The required
acetylenic sulfones are readily available by the free-
radical selenosulfonation5 of the parent acetylenes, fol-
lowed by selenoxide elimination or by other methods.2a
Further functional group transformations of the adducts,
ultimately including desulfonylation, provide access to
the final products. To date, these have encompassed
variously substituted piperidines, pyrrolizidines, indoliz-
idines, and quinolizidines,6 including the dendrobatid
alkaloids (-)-pumiliotoxin C7 and indolizidines (-)-167B,
(-)-209D, (-)-209B, and (-)-207A,6b as well as the
quinolizidine alkaloid (-)-lasubine II.8
Unsaturated sulfones have proven useful in a variety
of synthetic applications.1,2 For example, the electron-
withdrawing sulfone group activates adjacent double and
triple bonds toward conjugate additions and cycloaddi-
tions.2 The resulting products are saturated or vinyl
sulfones, respectively, where deprotonation of the R- or
γ-position is facilitated by stabilization of the correspond-
ing anion by the sulfone group.3 The anions in turn react
with electrophiles, thereby permitting the introduction
of alkyl groups or other substituents. Finally, upon
completion of the desired sequence of transformations,
the sulfone group can be removed reductively, oxida-
tively, or by substitution with certain types of organo-
metallic reagents.4
* To whom correspondence should be addressed.Address general
correspondence to: Tel: (403) 220-6256. Fax: (403) 289-9488. Address
correspondence regarding X-ray structures to M.P. Tel: (403) 220-5348.
Fax: (403) 289-9488.
Despite the success of this method with both primary
and secondary alkylamines, its practical extension to
(1) For general reviews of sulfone chemistry, see: (a) Simpkins, N.
S. Sulphones in Organic Synthesis; Pergamon Press: Oxford, 1993.
(b) Patai, S.; Rappoport, Z., Stirling, C. J . M., Eds. The Chemistry of
Sulphones and Sulphoxides; Wiley: Chichester, 1988.
(2) For reviews of unsaturated sulfones, see the following references.
(a) Acetylenic and allenic sulfones: Back, T. G. Tetrahedron 2001, 57,
5263. (b) Vinyl sulfones: Simpkins, N. S. Tetrahedron 1990, 46, 6951.
(c) Dienyl sulfones: Ba¨ckvall, J . E.; Chinchilla, R.; Na´jera, C.; Yus,
M. Chem. Rev. 1998, 98, 2291.
(4) Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
(5) (a) Back, T. G.; Collins, S.; Kerr, R. G. J . Org. Chem., 1983, 48,
3077. For
a review of selenosulfonation, see: (b) Back, T. G. In
Organoselenium Chemistry - A Practical Approach; Back, T. G., Ed.;
Oxford University Press: Oxford, 1999; Chapter 9, pp 176-178.
(6) (a) Back, T. G.; Nakajima, K. Org. Lett. 1999, 1, 261. (b) Back,
T. G.; Nakajima, K. J . Org. Chem. 2000, 65, 4543.
(7) Back, T. G.; Nakajima, K. J . Org. Chem. 1998, 63, 6566.
(8) Back, T. G.; Hamilton, M. D. Org. Lett. 2002, 4, 1779.
(3) Block, E. Reactions of Organosulfur Compounds; Academic
Press: New York, 1978; Chapter 2.
10.1021/jo026595t CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/21/2003
J . Org. Chem. 2003, 68, 2223-2233
2223

Back et al.
SCHEME 1
SCHEME 2
been reported.12,13 We also include the first syntheses of
alkaloids 2 and 3,14 which were recently isolated from
the roots of Ruta chalepensis, a perennial herb collected
from the northern Saudi desert, which is used in folk
medicine as, inter alia, an antirheumatic and antispas-
modic agent.15
anilines appeared uncertain because of their considerably
lower nucleophilicity. Indeed, while several detailed
earlier studies of the conjugate additions of alkylamines
to acetylenic sulfones have appeared,1,2a,9 there are very
few known examples of such additions using aniline
derivatives.9a,f We now report a more detailed investiga-
tion of the conjugate additions of appropriately ortho-
functionalized anilines to acetylenic sulfones and the
cyclization of the products to the corresponding quino-
lones.10 Members of the latter class of compounds often
manifest interesting biological and medicinal properties.11
Among the quinolones that we prepared are three natural
products. Quinolone 1 was isolated from a marine
pseudomonad12a and possesses antibiotic and other12
biological activity. Several earlier syntheses of 1 have
Resu lts a n d Discu ssion
Con ju ga te Ad d ition s of Meth yl An th r a n ila tes to
Acetylen ic Su lfon e 5. Anthranilate esters are ap-
propriately functionalized for ring closure via intramo-
lecular acylation, providing that the initial conjugate
addition can be accomplished. We therefore investigated
the addition of methyl anthranilates 4 to the representa-
tive acetylenic sulfone 5 under various conditions, as
shown in Scheme 2 and Table 1. Methyl anthranilate (4a )
and its amide and carbamate derivatives 4c and 4d failed
to react cleanly with several acetylenic sulfones under a
variety of conditions. However, greater success was
realized with the similar reactions of the N-formyl
derivative 4b with 5 in the presence of suitable bases to
generate the corresponding anion. Typically, the anthra-
nilate and acetylenic sulfone were allowed to react in
DMF-water (10:1) in the presence of potassium carbon-
ate at room temperature. Under these conditions, 4b
afforded the corresponding conjugate addition product in
(9) (a) Strating; J .; Backer, H. J . Recl. Trav. Chim. Pays-Bas 1954,
73, 709. (b) Stirling, C. J . M. J . Chem. Soc. 1964, 5863. (c) Stirling, C.
J . M. J . Chem. Soc. 1964, 5875. (d) McMullen, C. H.; Stirling, C. J . M.
J . Chem. Soc. B 1966, 1217. (e) McDowell, S. T.; Stirling, C. J . M. J .
Chem. Soc. B 1967, 351. (f) Truce, W. E.; Brady, D. G. J . Org. Chem.
1966, 31, 3543. (g) Truce, W. E.; Markley, L. D. J . Org. Chem. 1970,
35, 3275. (h) Truce, W. E.; Onken, D. W. J . Org. Chem. 1975, 40, 3200.
(10) For preparations of quinolones from o-iodoanilines or methyl
anthranilates and other types of acetylenes or allenes, see: (a) Torii,
S.; Okumoto, H.; Xu, L. H. Tetrahedron Lett. 1991, 32, 237. (b) Kalinin,
V. N.; Shostakovsky, M. V.; Ponomaryov, A. B. Tetrahedron Lett. 1992,
33, 373. (c) Torii, S.; Okumoto, H.; Xu, L. H.; Sadakane, M.; Shosta-
kovsky, M. V.; Ponomaryov, A. B.; Kalinin, V. N. Tetrahedron 1993,
49, 6773. (d) Biere, H.; Seelen, W. Liebigs Ann. Chem. 1976, 1972. (e)
Tamura, Y.; Tsugoshi, T.; Mohri, S.; Kita, Y. J . Org. Chem. 1985, 50,
1542. (f) Doad, G. J . S.; J ordis, U.; Rudolf, M.; Sauter, F.; Scheinmann,
F. J . Chem. Res., Synop. 1986, 410.
(11) For selected reviews of quinolines, quinolones, and related
compounds, see: (a) Openshaw, H. T. In The Alkaloids; Manske, R.
H. F., Ed.; Academic Press: New York, 1967; Vol. 9, pp 223-267. (b)
Grundon, M. F. In The Alkaloids; Manske, R. H. F., Rodrigo, R., Eds.;
Academic Press: New York, 1979; Vol. 17, pp 105-198. (c) Grundon,
M. F. In The Alkaloids; Brossi, A., Ed.; Academic Press: San Diego,
1988; Volume 32, pp 341-439. (d) Radl, S.; Bouzard, D. Heterocycles
1992, 34, 2143. (e) Michael, J . P. Nat. Prod. Rep. 2001, 18, 543 and
earlier reviews by this author cited therein.
(13) (a) Chong, R. J .; Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett.
1986, 27, 5323. (b) Thomsen, I.; Torssell, K. B. G. Acta Chem. Scand.
B 1988, 42, 309. (c) Beifuss, U.; Ledderhose, S. Synlett 1997, 313. (d)
Buu-Hoi, N. P.; Royer, R.; Xuong, N. D.; J acquignon, P. J . Org. Chem.
1953, 18, 1209.
(14) Preliminary communication: Back, T. G.; Wulff, J . E. J . Chem.
Soc., Chem. Commun. 2002, 1710.
(12) (a) Wratten, S. J .; Wolfe, M. S.; Andersen, R. J .; Faulkner, D.
J . Antimicrob. Agents Chemother. 1977, 11, 411. (b) Moon, S.-S.; Kang,
P. M.; Yoon, K. S.; Yun, S.-J .; Park, B. B. Bull. Korean Chem. Soc.
1995, 16, 1128; via Chem. Abstr. 1996, 124, 86655f. (c) Tang, Y.; Wu,
K.; Feng, X.; Huang, L. Yaoxue Xuebao 1998, 33, 121; Chem. Abstr.
1998, 129, 245022u. (d) Reil, E.; Ho¨fle, G.; Draber, W.; Oettmeier, W.
Biochim. Biophys. Acta 1997, 1318, 291. (e) Reil, E.; Ho¨fle, G.; Draber,
W.; Oettmeier, W. Biochim. Biophys. Acta 2001, 1506, 127.
(15) El Sayed, K.; Al-Said, M. S.; El-Feraly, F. S.; Ross, S. A. J . Nat.
Prod. 2000, 63, 995.
2224 J . Org. Chem., Vol. 68, No. 6, 2003

Conjugate Additions of o-Iodoanilines and Methyl Anthranilates
TABLE 1. Ad d ition of Meth yl An th r a n ila te 4b to
Su lfon es 5, 8, a n d 9a
SCHEME 3
sulfone
reaction combined yield (%)
entry (equiv)
base
K2CO3
K2CO3-DMAP
K2CO3
K2CO3-DMAP
K2CO3-DMAP
time
and ratio of 6/7
1
2
3
4
5
5 (1.0)
5 (2.0)
8 (2.0)
8 (2.0)
9 (2.0)
4 d
2 h
4 d
2 h
1 d
20 (81:19)
57 (100:0)
18 (100:0)
60 (100:0)
51 (100:0)
a
All reactions were performed at room temperature in DMF-
water (10:1).
low yield after 4 days, isolated as a chromatographically
separable mixture of allyl and vinyl sulfones 6 and 7 in
a ratio of 81:19 (Table 1, entry 1). Each product was in
turn obtained as a mixture of unseparated geometrical
isomers. Large amounts of unreacted 4b remained, along
with decomposition products of 5. A slightly higher yield
of 27% of 6 and none of isomer 7 was obtained after 25
days, but no improvement was observed at higher tem-
peratures, with the use of other bases such as cesium
carbonate or triethylamine, or in other solvents (aqueous
methanol, ethanol, acetonitrile or HMPA, or anhydrous
DMF, THF, or acetonitrile). We observed that the addi-
tion of DMAP16 to the reaction mixture improved the rate
and yield significantly but also caused more rapid
decomposition of the acetylenic sulfone 5. Thus, an excess
of the latter was employed for optimum results (entry
2). These experiments indicate that anilines containing
an electron-withdrawing ester substituent react too
slowly with a typical acetylenic sulfone to be of practical
value. However, the enhancement of the reaction rate
and yield by DMAP (entry 2) suggest a means to partly
overcome the low reactivity of such systems.
It is noteworthy that in Table 1 the allyl sulfone 6 was
in each case the chief or sole product formed, whereas
the isomeric vinyl sulfone 7 is the expected product of
direct conjugate addition to acetylenic sulfone 5. It has
been reported that allyl sulfones can be produced from
their vinyl counterparts by base-catalyzed isomeriza-
tion.17 Thus, the predominance of 6 could be the result
of initial conjugate addition to afford 7, followed by
isomerization to 6. On the other hand, it is also known
that the equilibration of acetylenic, allenic, and propar-
gylic sulfones can be promoted by bases.2a,18 An alterna-
tive possible explanation for the dominant formation of
6 is therefore the isomerization of acetylenic sulfone 5
to its allenic counterpart 8 prior to conjugate addition.
These pathways are indicated in Scheme 3. Several
control experiments were conducted to distinguish be-
tween these possibilities. First, when 7 was subjected to
the conditions of entries 1 or 2 in Table 1, it was found
to isomerize to 6 too slowly to account for the dominant
or exclusive formation of 6 in these entries. Moreover,
an authentic sample of the allenic sulfone 8 was prepared
by selenosulfonation, base-catalyzed isomerization, and
selenoxide elimination17a and was subjected to the same
conditions. In this case, the allylic sulfone 6 was produced
in 18% and 60% yield in the absence or presence of DMAP
after 4 days and 2 h, respectively (entries 3 and 4). These
results are similar to those that were obtained with
acetylenic sulfone 5 (entries 1 and 2) and are therefore
consistent with the formation of 6 via prototropic isomer-
ization of 5 to 8 prior to the conjugate addition of 4b. We
also observed no detectable isomerization of 6 to 7, even
after prolonged reaction times. The formation of the
minor product 7 in entry 1 is therefore attributed to the
direct addition of 4b to acetylenic sulfone 5.
In the absence of DMAP, the propargylic sulfone 9
proved to be a major byproduct. When each of the triad
of isomeric sulfones 5, 8, and 9 was treated independently
with potassium carbonate in aqueous DMF, the sole
product in each case was 9, indicating that it is the
thermodynamically favored isomer. Furthermore, the
formation of 9 from acetylenic sulfone 5 required several
days to go to completion, whereas that from allenic
sulfone 8 was complete in 15 min. Since 8 is presumably
an intermediate in the overall conversion of 5 to 9, we
conclude that the isomerization of 5 to 8 is relatively slow
compared to the subsequent isomerization of 8 to 9
(Scheme 3). Unlike 5 and 8, propargylic sulfone 9
contains an unactivated triple bond and therefore cannot
undergo direct conjugate addition. To test whether it can
return to the manifold in Scheme 3 by reisomerization
back to the allenic isomer 8, we allowed 9 to react with
4b under the usual conditions and found that it afforded
a comparable yield of adduct 6 (entry 5) as had been
obtained directly from 8 (entry 4). Thus, while the
propargylic isomer 9 is the most stable sulfone, all three
isomers are in equilibrium under base-catalyzed condi-
tions and each one can be employed as the starting
material for the conjugate additions. The precise role of
(16) For a review of nucleophilic catalysis with DMAP and related
compounds, see: Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129.
(17) For examples, see: (a) Back, T. G.; Krishna, M. V.; Muralidha-
ran, K. R. J . Org. Chem. 1989, 54, 4146. (b) Block, E.; Aslam, M. J .
Am. Chem. Soc. 1983, 105, 6164. (c) Block, E.; Eswarakrishnan, V.;
Gebreyes, K. Tetrahedron Lett. 1984, 25, 5469. (d) Eisch, J . J .; Galle,
J . E. J . Org. Chem. 1979, 44, 3279. (e) Baldwin, J . E.; Adlington, R.
M.; Ichikawa, Y.; Kneale, C. J . J . Chem. Soc., Chem. Commun. 1988,
702. (f) Sva´ta, V.; Procha´zka, M.; Bakos, V. Collect. Czech. Chem.
Commun. 1978, 43, 2619. (g) Broaddus, C. D. J . Am. Chem. Soc. 1966,
88, 3863. (h) Broaddus, C. D. J . Am. Chem. Soc. 1968, 90, 5504.
(18) (a) Stirling, C. J . M. J . Chem. Soc. 1964, 5856. (b) Mackle, H.;
Steele, W. V. Trans. Faraday Soc. 1969, 65, 2073. (c) Smith, G.;
Stirling, C. J . M. J . Chem. Soc. C 1971, 1530. (d) Braverman, S.;
Mechoulam, H. Tetrahedron 1974, 30, 3883.
J . Org. Chem, Vol. 68, No. 6, 2003 2225

Back et al.
CHART 1
investigate allenic sulfones, since they are less convenient
to prepare and, in some cases, less stable than their
acetylenic isomers. However, it should be kept in mind
that, as in the case of 5 and 8, other allenic sulfones may
be formed in situ from their acetylenic counterparts and
may comprise the actual electrophiles under the condi-
tions of the conjugate additions.
Conjugate additions of anilines to acetylenic sulfones
5 and 14-16 are shown in Table 2. The optimized
addition of 4b to 5 (Table 1, entry 2) is included in Table
2 (entry 1) for comparison. As expected, higher yields of
addition products were generally obtained when the less
deactivated o-iodoanilines 10, 11a , and 11b were em-
ployed instead of o-esters 4b or 12 or o-amide 13 (i.e.,
compare entry 2 with 1, entry 4 with 3, and entry 9 with
7 or 8 in Table 2). Furthermore, the o-iodoanilines
typically produced excellent yields of adducts even in the
absence of DMAP (entries 2, 4, and 5) and even when an
ester substituent was present in the para position (entries
4 and 5). We also observed that the methoxymethyl-
substituted acetylenic sulfone 15 displayed remarkably
high reactivity compared to the alkyl-substituted ana-
logues 5, 14, and 16. Thus, 15 afforded an excellent yield
of the corresponding adduct 23, even with the doubly
deactivated aniline 12 (entry 6), whereas the alkyl-
substituted acetylenic sulfone 14 produced a much poorer
yield of adduct 20 with the same aniline (entry 3).
However, since 15 decomposed more rapidly than the
other acetylenic sulfones under similar reaction condi-
tions, a 2-fold excess was employed to compensate.
Acetylenic sulfone 15 did not isomerize to the corre-
sponding allenic sulfone at an appreciable rate in DMF-
water-potassium carbonate. This observation, together
with the exclusive formation of the vinyl sulfones 22B
and 23B (entries 5 and 6), suggests that the unusually
high reactivity is an intrinsic property of 15 itself and is
not due to its facile isomerization to a more reactive
allenic isomer. In contrast to the failure of the acetanilide
4c to react with 5, the o-iodoacetanilide 11b reacted
smoothly with 15 (Table 2, entry 5). In entries 1, 2, 4,
and 7-9, products 6, 19, 21, and 24-26, respectively,
were formed exclusively as the allyl sulfone isomers
(structures A in Table 2). Product 20 (entry 3) was
isolated as a mixture of allyl and vinyl sulfone isomers
(structures A and B, respectively) in the ratio of 70:30.
Since structural assignments (allyl vs vinyl sulfone) of
the products 22 and 23 of entries 5 and 6 were equivocal
when based only on their NMR spectra, an X-ray struc-
ture of the Z-isomer of 22 was obtained (see the Sup-
porting Information), thus confirming that it was the
vinyl sulfone (structure B). Product 23 had an NMR
spectrum similar to that of 22 and was also assigned the
vinyl sulfone structure B by analogy. Each product in
Table 2, as in the case of 6 and 7 in Table 1, was obtained
as an unseparated mixture of geometrical isomers.
The conjugate additions of anilines 11a and 11c to the
unsubstituted acetylenic sulfone 17 and the dienyl sul-
fone 18 were also investigated, and the results are shown
CHART 2
DMAP in these processes is not entirely clear. However,
the observation that the addition of 4b to authentic
allenic sulfone 8 in the absence of DMAP (entry 3)
proceeded slowly and afforded only 18% of 6 after 4 days,
compared to 60% in 2 h in the presence of DMAP (entry
4), indicates that DMAP is implicated in the conjugate
addition itself and does not merely serve to promote the
isomerization of 5 to 8.19
Con ju ga te Ad d ition s of Oth er An ilin es to Un sa t-
u r a ted Su lfon es. A series of anilines 10-13 (Chart 1)
was prepared by routine methods (see the Experimental
Section and Supporting Information). The other unsatur-
ated sulfones that were studied are shown in Chart 2.
Acetylenic sulfones 147 and 1520 were prepared by
selenosulfonation5 and selenoxide elimination of the
parent acetylenes. The synthesis of compound 16 was
achieved as indicated in our preliminary communica-
tion,14 and details are provided in the Supporting Infor-
mation. We also wished to investigate conjugate additions
to the unsubstituted acetylenic sulfone 1721 and the
dienyl sulfone 18,22 which were both available by litera-
ture methods. Apart from 8 (vide supra), we did not
(19) While one could rationalize the formation of 7 from 5 and 4b
via an addition-elimination reaction of the corresponding DMAP
adduct 35 with the conjugate base of 4b, the isomeric adduct 36, which
would be obtained from allene 8 and DMAP, and which would be
expected to lead to 6 after a similar sequence, does not contain an
activated double bond for such an addition-elimination. Thus, DMAP
may play a more complex role in these additions.
(21) (a) Bhattacharya, S. N.; J osiah, B. M.; Walton, D. R. M.
Organomet. Chem. Synth. 1970/1971, 1, 145. (b) Waykole, L.; Paquette,
L. A. Org. Synth. 1989, 67, 149. (c) Chen, Z.; Trudell, M. L. Synth.
Commun. 1994, 24, 3149.
(22) Barluenga, J .; Martinez-Gallo, J . M.; Na´jera, C.; Fan˜ana´s, F.
J .; Yus, M.; J . Chem. Soc., Perkin Trans. 1 1987, 2605.
(20) This compound was reported by: Miura, T.; Kobayashi, M. J .
Chem. Soc., Chem. Commun. 1982, 438. We obtained it similarly, but
using photochemical selenosulfonation (see ref 5b) and m-CPBA in the
selenoxide elimination step.
2226 J . Org. Chem., Vol. 68, No. 6, 2003

Conjugate Additions of o-Iodoanilines and Methyl Anthranilates
TABLE 2. Ad d ition of An ilin es to Acetylen ic Su lfon esa
product, yield (%),
and (ratio of A/B)
entry
aniline
R
R′
Z
sulfone (equiv)
R′′
n-Bu
n-Bu
Et
Et
OMe
OMe
reaction time
1
2
3
4
5
6
7
8
9
4b
10
12
11a
11b
12
4b
13
H
H
CO2Me
CHO
CHO
CHO
CHO
Ac
CHO
CHO
CHO
CHO
5 (2.0)
5 (1.0)
2 hb
8 dc
6, 57 (100:0)
19, 81 (100:0)
20, 27 (70:30)
21, 82 (100:0)
22, 89 (0:100)
23, 96 (0:100)
24, 26 (100:0)
25, 66 (100:0)
26, 79 (100:0)
I
CO2Me
CO2Me
CO2Me
CO2Me
H
CO2Me
14 (1.25)
14 (1.25)
15 (2.0)
15 (2.0)
16 (1.0)
16 (1.0)
16 (1.0)
4 dc
I
I
17 hc
10 hc
16 hc
15 hb
2 db
CO2Me
CO2Me
CONEt2
I
d
d
d
Ar(CH2)5
Ar(CH2)5
Ar(CH2)5
H
H
10
2 db
a
b
All reactions were performed in 10:1 DMF-H2O containing K2CO3. Conducted with 1 equiv of DMAP. c Conducted without DMAP.
d
Ar ) 3,4-(methylenedioxy)phenyl.
SCHEME 4
substituted derivatives (e.g., 5), permit efficient conjugate
additions even with doubly deactivated anilines such as
12.
Ca r bon yla tion s a n d Cycliza tion s. The o-iodo ad-
ducts 19, 21, and 26 were converted into the correspond-
ing esters 6, 20, and 24, respectively, in excellent yield
by palladium-catalyzed carbonylation in methanol at 27
atm (400 psi).24 Adduct 27 underwent similar carbony-
lation to afford 33. Thus, the carbonylation of o-iodo
conjugate addition products such as 19, 21, and 26
smoothly circumvents the difficulties arising from the
direct additions of electron-deficient anthranilates to
acetylenic sulfones. Esters 6, 20, and 24 were then
treated with excess LiHMDS in THF and the resulting
sulfone-stabilized anions underwent intramolecular acy-
lation,25 affording the corresponding quinolones 30-32,
respectively (Scheme 5). Diester 23 reacted more slowly
but was cyclized and simultaneously deformylated quan-
titatively with LiTMP in THF to 34. On the other hand,
diethylamide 25 failed to cyclize under a variety of
conditions, while the cyclization of 33, which requires the
formation of a vinyl anion (as opposed to an allyl anion),
was also unsuccessful. N-Formyl products 30-32 were
formed with exocyclic double bonds as single geometrical
isomers, while the deprotected 34 was obtained as the
enaminone tautomer. Quinolone 34 serves as a potential
advanced intermediate for the synthesis of the antiviral
agent virantmycin.26
in Scheme 4. Acetylene 17 reacted smoothly with the
N-Cbz aniline 11c in the absence of DMAP. In contrast
to the earlier experiment, where the N-Cbz analogue 4d
failed to react with acetylenic sulfone 5, while the
N-formyl analogue 4b gave slightly better results (entry
1 in Table 1), here the N-formyl analogue 11a gave very
poor yields in attempted additions to 17. On the other
hand, 11a and 11c produced comparable results with the
dienyl sulfone 18. The products 27-29 are potential
substrates for radical cyclization reactions.23
These experiments show that o-iodoanilines provide
enhanced reactivity and afford improved yields compared
to anthranilate esters in conjugate additions, even in the
absence of DMAP. Moreover, the use of more reactive
unsaturated sulfones (e.g., 15), compared with alkyl-
Syn th esis of Alk a loid s 1-3. The synthesis of 1-3
from quinolones 30 and 32 was completed as shown in
Scheme 6. Thus, 30 was subjected to reductive desulfo-
nylation with aluminum amalgam,27 resulting in simul-
taneous deformylation and tautomerization to the cor-
responding enaminone 1, isolated in 68% yield, thus
(23) For some reviews of radical cyclization, see: (a) Giese, B.
Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds;
Pergamon Press: Oxford, 1986; Chapter 4. (b) J asperse, C. P.; Curran,
D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. (c) Curran, D. P. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 4, Chapter 4.2. (d) Motherwell, W. B.; Crich, D. Free
Radical Chain Reactions in Organic Synthesis; Academic Press:
London, 1992, Chapter 7. (e) Malacria, M. Chem. Rev. 1996, 96, 289.
(f) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke,
K. J .; Trach, F. Org. React. (N.Y.) 1996, 48, 301. (g) Curran, D. P.;
Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH:
New York, 1996. (h) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543.
(24) Tsuji, J . Palladium Reagents and Catalysts, Wiley: Chichester,
1995; pp 188-209.
(25) For other examples of intramolecular acylations of sulfone-
stabilized anions, see: (a) Grimm, E. L.; Levac, S.; Coutu, M. L.
Tetrahedron Lett. 1994, 35, 5369. (b) Grimm, E. L.; Coutu, M. L.
Trimble, L. A. Tetrahedron Lett. 1993, 34, 7017.
(26) (a) Omura, S.; Nakagawa, A.; Hashimoto, H.; Oiwa, R.; Iwai,
Y.; Hirano, A.; Shibukawa, N.; Kojima, Y. J . Antibiot. 1980, 33, 1395.
(b) Nakagawa, A.; Iwai, Y.; Hashimoto, H.; Miyazaki, N.; Oiwa, R.;
Takahashi, Y.; Hirano, A.; Shibukawa, N.; Kojima, Y.; Omura, S. J .
Antibiot. 1981, 34, 1408.
(27) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1964, 86, 1639.
J . Org. Chem, Vol. 68, No. 6, 2003 2227

Back et al.
SCHEME 5
SCHEME 6
pound, we obtained its X-ray structure in order to de-
termine the dominant tautomer in the solid state. The
ORTEP diagram of 1 clearly confirms the presence of the
enaminone tautomer. Interestingly, 1 exists as a dimeric
species in the solid state, in which the N-H moiety of
one molecule is hydrogen-bonded to the carbonyl oxygen
atom of the other molecule (see the Supporting Informa-
tion).
Su m m a r y a n d Con clu sion s
A new methodology for the synthesis of quinolones was
developed on the basis of the conjugate additions of
suitably ortho-substituted anilines to acetylenic sulfones
followed by intramolecular acylations of the correspond-
ing sulfone-stabilized anions. The conjugate additions of
various anthranilate esters to alkyl-substituted acetylenic
sulfones, such as 5, proceed slowly and in poor yield. The
reactions were enhanced by the use of N-formyl anthra-
nilates and by the addition of DMAP with the concomi-
tant use of excess sulfone. More reactive acetylenic
sulfones such as 15 undergo conjugate addition of an-
thranilates smoothly even without DMAP. Acetylenic,
allenic, and propargylic sulfones 5, 8, and 9 were found
to equilibrate under basic conditions, with 9 being the
most stable isomer. However, even the latter, which
contains an unactivated triple bond, can be employed in
conjugate additions by its in situ isomerization to allenic
sulfone 8. In at least some cases, it appears that the
additions proceed via isomerization of the acetylenic
sulfone to the corresponding allene derivative prior to
addition of the aniline. A more generally successful
alternative to the use of deactivated anilines such as
anthranilates was also developed. It employs the more
nucleophilic o-iodoaniline analogues, which undergo con-
jugate additions to acetylenic sulfones smoothly, followed
by palladium-catalyzed carbonylation to introduce the
providing 1 from aniline 10 and acetylenic sulfone 5 in
an overall yield of 40%. Similarly, desulfonylation, de-
formylation, and tautomerization of 32 afforded the
alkaloid 2, obtained in 48% overall yield from aniline 10
and acetylenic sulfone 16. O-Methylation and aromati-
zation of 2 furnished the remaining alkaloid 3 in 75%
yield. This approach therefore provides a concise and
efficient route to these biologically interesting alkaloids.
1
The H and 13C NMR spectra of 1-3 were in generally
close agreement with the reported spectra.12a,15 However,
in the 1H NMR spectrum of 2, we noted a significant
concentration dependence, particularly of the chemical
shifts of the signals at δ 7.73, 7.58, and 5.87, attributed
to H-8, H-7, and H-3, respectively.15 These chemical shifts
were also sensitive to the presence or absence of trace
acids. Similar effects were observed with quinolone 1. The
concentration and pH dependence may be the result of
changes in the equilibrium between the enaminone and
corresponding pyridinol tautomers or to changes in
intermolecular hydrogen bonding, leading to some un-
certainty about the exact structures of alkaloids 1 and
2. We note that the pyridinol structure was assigned to
the natural product 1,12a whereas 2 was reported as the
corresponding enaminone.15 Since 1 is a crystalline com-
2228 J . Org. Chem., Vol. 68, No. 6, 2003

Conjugate Additions of o-Iodoanilines and Methyl Anthranilates
1953, 1596 cm-1; 1H NMR (400 MHz) δ 7.74 (d, J ) 8.3 Hz, 2
H), 7.29 (d, J ) 8.3 Hz, 2 H), 6.14 (dt J ) 6.0, 3.0 Hz, 1 H),
5.79 (dt, J ) 6.9, 6.0 Hz, 1 H), 2.39 (s, 3 H), 2.13-2.03 (m, 2
H), 1.38-1.22 (m, 4 H), 0.84 (t, J ) 7.1 Hz, 3 H); 13C NMR
(100 MHz) δ 205.3, 144.2, 138.4, 129.6, 127.5, 101.2, 100.9,
o-ester moiety required for cyclization to the desired
quinolones. The cyclizations were effected in excellent
yield via deprotonation and intramolecular acylation of
the conjugate addition products. When used in conjunc-
tion with reductive desulfonylation, this protocol was
successfully applied to the first syntheses of the biologi-
30.3, 27.2, 21.8, 21.4, 13.6; MS (ESI) m/z (%) 523 (2 × M+
+
Na), 273 (M+ + Na); HRMS calcd for C14H18O2S 250.1028,
found 250.1039.
cally interesting Ruta chalepensis alkaloids 2 and 3 as
well as to that of the previously synthesized alkaloid 1.
1-(p-Tolu en esu lfon yl)-2-h ep tyn e (9).36 A mixture of al-
lenic sulfone 8 (105 mg, 0.419 mmol) and K2CO3 (49 mg, 0.35
mmol) in 0.5 mL of DMF-water (10:1) was stirred for 15 min.
The mixture was partitioned between ether and water, the
aqueous layer was washed with ether, and the combined
organic fractions were dried and concentrated in vacuo.
Chromatography (hexanes-ethyl acetate 6:1 to 4:1) afforded
80 mg (76%) of a 10:1 mixture of 9 and 8. Propargyl sulfone 9:
Exp er im en ta l Section
Gen er a l Meth od s. All reagents, unless otherwise noted,
were obtained from commercial sources and purified by
standard methods as necessary. Anilines 4b,28 4d ,29 10,30 11c,31
and 13,32 unsaturated sulfones 5,6b 14,7 15,20 17,21 and 18,22
as well as Se-phenyl p-tolueneselenosulfonate33 and methyl
3-iodo-4-aminobenzoate34 were prepared by literature proce-
dures. The preparations of new anilines 11a and 12, the known
aniline 11b,35 and the novel acetylenic sulfone 16 are described
in the Supporting Information. Chromatography refers to flash
chromatography on silica gel (230-400 mesh). NMR spectra
were recorded in deuteriochloroform unless otherwise indicated.
1-(p-Tolu en esu lfon yl)-1,2-h eptadien e (8). 1-Heptyne (1.05
mL, 8.00 mmol) and Se-phenyl p-tolueneselenosulfonate (2.50
g, 8.03 mmol) were dissolved in 20 mL of chloroform and
irradiated for 2 h in a Rayonet reactor equipped with six 300
nm lamps. The solvent was evaporated, and the residue was
redissolved in 20 mL of THF. Potassium tert-butoxide (1.35 g,
12.0 mmol) was added, and the mixture was stirred for 6 h at
room temperature and then partitioned between ether and
water. The aqueous layer was washed with ether, and the
combined organic layers were dried and concentrated in vacuo.
Chromatography (hexanes-ethyl acetate, 9:1-4:1) gave 1.63
g (50%) of a single geometrical isomer of the corresponding
â-(phenylseleno)allyl sulfone. Purification of the other geo-
metrical isomer was complicated by coelution with residual
vinyl sulfone.
The â-(phenylseleno)allyl sulfone intermediate was dissolved
in 30 mL of chloroform. m-CPBA (1.8 g, ca. 77% purity, 8.0
mmol) was added, and the resulting mixture was stirred for
15 min and then washed twice with 5% NaOH solution. The
aqueous layers were extracted twice with chloroform to ensure
that the partly water-soluble selenoxide was not lost. The
combined organic layers were dried and refluxed in the
presence of anhydrous MgSO4 for 90 min. The mixture was
filtered, and the filtrate was concentrated in vacuo. Chroma-
tography (hexanes-ethyl acetate, 9:1 to 4:1) gave 732 mg (73%;
37% overall from 1-heptyne) of 8 as a colorless oil: IR (film)
1
IR (film) 2234, 1596, 1324 cm-1; H NMR (200 MHz) δ 7.84
(d, J ) 8.4 Hz, 2 H), 7.36 (d, J ) 8.4 Hz, 2 H), 3.92 (t, J ) 2.5
Hz, 2 H), 2.46 (s, 3 H), 2.22-2.08 (m, 2 H), 1.50-1.23 (m, 4
H), 0.87 (t, J ) 7.0 Hz, 3 H); 13C NMR (50 MHz) δ 145.0, 135.0,
129.5, 128.8, 88.7, 67.6, 49.1, 30.2, 21.8, 21.6, 18.4, 13.5.
Con ju ga te Ad d ition of An ilin e 4b to Acetylen ic Su l-
fon e 5 (Ta ble 1, En tr y 1; Typ ica l P r oced u r e). A mixture
of aniline 4b (75 mg, 0.42 mmol), K2CO3 (58 mg, 0.42 mmol),
and sulfone 5 (105 mg, 0.419 mmol) in 0.5 mL of DMF-water
(10:1) was stirred vigorously for 4 d at room temperature. TLC
analysis then revealed the presence of a significant amount
of 4b, as well as of 9 and two new products. The mixture was
partitioned between ether and water, the aqueous layer was
washed with ether, and the combined organic fractions were
dried and concentrated in vacuo. Chromatography (hexanes-
ethyl acetate, 4:1-2:1) afforded 29 mg (16%) of 6 and 7 mg
(4%) of 7.
Ad d u ct 6. NMR analysis showed the product to be a 2:1
mixture of geometrical isomers: IR (film) 1727, 1689 cm-1; 1H
NMR (400 MHz) δ 8.34 (s, major isomer) and 8.09 (s, minor
isomer, total 1 H), 7.88-7.67 (m, 3 H), 7.62-7.22 (m, 5 H),
5.84 (t, J ) 7.6 Hz, major isomer) and 5.59 (t, J ) 7.6 Hz,
minor isomer, total 1 H), 4.22 (br s, minor isomer) and 3.70
(br s, major isomer, total 2 H), 3.78 (s, both isomers, 3 H), 2.40
(s, both isomers, 3 H), 1.88-1.68 (m, 2 H), 1.30-1.08 (m, 4
H), 0.85-0.71 (m, 3 H); 13C NMR (100 MHz, both isomers) δ
166.1, 166.0, 161.8, 161.7, 145.1, 144.7, 140.0, 137.3, 137.0,
136.3, 136.2, 135.6, 133.4, 132.6, 131.0, 130.9, 130.2, 129.9,
129.7, 129.5, 129.2, 128.3, 128.1, 128.0, 126.4, 126.1, 55.0, 54.5,
52.3, 52.2, 30.9, 30.7, 27.8, 27.2, 22.1, 22.0, 21.4, 13.6, 13.6;
MS (EI) m/z 326 (7), 280 (7), 274 (5), 246 (100); HRMS calcd
for C16H20NO3 (M+ - Ts) 274.1443, found 274.1458.
Ad d u ct 7. NMR analysis showed the product to be a 4:1
mixture of geometrical isomers: IR (film) 1726, 1701 cm-1; 1H
NMR (400 MHz, major isomer) δ 8.35 (s, 1 H), 7.94 (dd, J )
7.7, 1.5 Hz, 1 H), 7.86 (d, J ) 8.3 Hz, 2 H), 7.51 (td, J ) 7.7,
1.6 Hz, 1 H), 7.44-7.33 (m, 3 H), 6.93 (d, J ) 7.8 Hz, 1 H),
6.34 (s, 1 H), 3.85 (s, 3 H), 2.46 (s, 3 H), 2.19-2.12 (m, 2 H),
1.49-1.39 (m, 2 H), 1.22-1.09 (m, 4 H), 0.80 (t, J ) 7.0 Hz, 3
H); signals from the minor isomer were observed at δ 8.13 (s),
6.40 (s); 13C NMR (100 MHz, major isomer) δ 166.0, 161.5,
151.9, 144.8, 138.7, 135.6, 132.9, 131.0, 130.2, 128.2, 128.2,
127.6, 126.8, 122.5, 52.4, 34.6, 31.0, 26.9, 22.2, 21.6, 13.8; MS
(28) Kobayashi, K.; Nakashima, T.; Mano, M.; Morikawa, O.;
Konishi, H. Chem. Lett. 2001, 602.
(29) Aniline 4d was prepared from methyl anthranilate and benzyl
chloroformate, using an identical procedure to that given in ref 31 for
the similar protection of 11c.
(30) Hays, S. J .; Caprathe, B. W.; Gilmore, J . L.; Amin, N.;
Emmerling, M. R.; Michael, W.; Nadimpalli, R.; Nath, R.; Raser, K.
J .; Stafford, D.; Watson, D.; Wang, K.; J aen, J . C. J . Med. Chem. 1998,
41, 1060.
(31) Back, T. G.; Bethell, R. J .; Parvez, M.; Taylor, J . A. J . Org.
Chem. 2001, 66, 8599.
(32) Anthranilic acid was converted into its acyl chloride via the
procedure of: Hermecz, I.; Szilagyi, I.; Orfi, L.; Kokosi, J .; Szasz, G. J .
Heterocycl. Chem. 1993, 30, 1413. Amide 13 was prepared by reacting
the acyl chloride with diethylamine, then protecting with ethyl formate
and sodium hydride via the procedure of ref 30.
(33) Back, T. G.; Collins, S.; Krishna, M. V. Can. J . Chem. 1987,
65, 38.
(34) Methyl 3-iodo-4-aminobenzoate was prepared by a variation of
the procedure of: Hill, M. L.; Raphael, R. A. Tetrahedron 1990, 46,
4587. Slow addition of the iodine monochloride reagent to the reaction
mixture afforded an improved yield of 95%.
(EI) m/z 370 (2), 326 (4), 280 (100); HRMS calcd for C16H20
-
NO3 (M+ - Ts) 274.1443, found 274.1440.
The other experiments listed in Table 1 were performed in
a similar manner, with any changes noted in the table.
Con ju ga te Ad d ition s of Oth er An ilin es to Un sa tu r a ted
Su lfon es (Ta ble 2). These reactions were performed by the
same general procedure as described above for entry 1 in Table
1. The yields of products 19-26, as well as any changes to
the general experimental conditions, are indicated in Table 2.
The properties of the products are given below.
(35) Aniline 11b has been previously prepared by a different method,
but spectroscopic data was not provided: Fagnola, M. C.; Candiani,
I.; Visentin, G.; Cabri, W.; Zarini, F.; Mongelli, N.; Bedeschi, A.
Tetrahedron Lett. 1997, 38, 2307.
(36) Sulfone 9 has been previously prepared by a different method,
but spectroscopic data was not provided: Ozawa, M.; Iwata, N.;
Kinoshita, H.; Inomata, K. Chem. Lett. 1990, 1689.
J . Org. Chem, Vol. 68, No. 6, 2003 2229

Back et al.
Ad d u ct 19 (Ta ble 2, En tr y 2). The adduct was obtained
as a pale yellow foam. NMR analysis showed the product to
be the pure allyl sulfone isomer, obtained as a 2:1 mixture of
geometrical isomers: IR (film) 1686 cm-1; 1H NMR (400 MHz)
δ 8.39 (s, major isomer) and 8.15 (s, minor isomer, total 1 H),
7.90-7.83 (m), 7.75 (d, J ) 8.3 Hz, major isomer), 7.50-7.41
(m) and 7.38-7.33 (m, total 7 H for peaks between δ 7.90 and
7.33), 7.12-7.02 (m, 1 H), 6.01 (t, J ) 7.6 Hz, major isomer)
and 5.68 (t, J ) 7.6 Hz, minor isomer, total 1 H), 4.5-4.0 (br
m, minor isomer) and 4.0-3.3 (br m, major isomer, total 2 H),
2.43 (s, both isomers, 3 H), 2.00-1.63 (m, 2 H), 1.33-1.11 (m,
4 H), 0.83 (t, J ) 7.1 Hz, major isomer), 0.77 (t, J ) 6.9 Hz,
minor isomer, total 3 H); 13C NMR (100 MHz, both isomers) δ
162.4, 161.9, 145.3, 144.8, 142.5, 140.7, 140.1, 138.6, 138.2,
137.1, 136.0, 136.0, 131.4, 131.1, 130.2, 130.1, 130.1, 130.0,
129.7, 129.4, 128.5, 128.2, 125.2, 124.7, 54.4, 54.1, 30.8, 30.7,
27.8, 27.1, 22.2, 22.1, 22.1, 21.5, 13.7, 13.6.; MS (EI) m/z 342
(44), 314 (41), 270 (63), 186 (93), 144 (99), 143 (100); HRMS
calcd for C14H17INO (M+ - Ts) 342.0355, found 342.0376.
Ad d u ct 20 (Ta ble 2, En tr y 3). The adduct was obtained
as a pale yellow foam. NMR analysis showed the product to
be a 7:3 mixture of the allyl and vinyl sulfone isomers, formed
as 2:1 and 6:1 mixtures of geometrical isomers, respectively.
Further chromatography (hexanes-ethyl acetate 4:1-2:1)
afforded the pure (E,Z)-vinyl sulfone, but the allyl sulfone could
not be completely separated from its vinyl counterparts.
Allyl sulfone: IR (film) 1727, 1690 cm-1; 1H NMR (400 MHz)
major isomer δ 8.46 (d, J ) 2.0 Hz, 1 H), 8.36 (s, 1 H), 8.16
(dd, J ) 8.3, 2.0 Hz, 1 H), 7.74 (d, J ) 8.3 Hz, 2 H), 7.37-7.31
(m, 3 H), 5.94 (t, J ) 7.7 Hz, 1 H), 3.94 (s, 3 H), 3.87 (s, 3 H),
3.76 (br s, 2 H), 2.44 (s, 3 H), 2.07 (quintet, J ) 7.6 Hz, 2 H),
1.02 (t, J ) 7.5 Hz, 3 H); minor isomer δ 8.58 (d, J ) 2.0 Hz,
1 H), 8.26 (dd, J ) 8.4, 2.0 Hz, 1 H), 8.09 (s, 1 H), 7.97 (d, J )
8.4 Hz, 1 H), 7.82 (d, J ) 8.3 Hz, 2 H), 7.37-7.31 (m, 2 H),
5.62 (t, J ) 7.6 Hz,1 H), 4.32 (br s, 2 H), 3.96 (s, 3 H), 3.88 (s,
3 H), 2.44 (s, 3 H), 1.96 (quintet, J ) 7.6 Hz, 2 H), 0.89 (t, J )
7.5 Hz, 3 H); 13C NMR (100 MHz, both isomers) δ 165.6, 165.4,
165.4, 161.8, 161.6, 145.3, 145.0, 144.4, 142.0, 140.3, 139.5,
139.5, 136.5, 134.3, 133.3, 132.6, 132.2, 130.0, 129.9, 129.8,
129.6, 129.5, 129.0, 128.6, 128.2, 128.1, 126.3, 125.8, 55.6, 54.7,
52.7, 52.6, 52.5, 52.5, 21.9, 21.8, 21.6, 21.3, 13.5, 13.2; MS (EI)
m/z 276 (94), 274 (87), 244 (100); HRMS calcd for C16H18NO5
(M+ - Ts) 304.1185, found 304.1178.
98.9, 97.3, 54.6, 54.2, 52.6, 52.5, 21.8, 21.6, 21.1, 13.3, 13.2;
MS (EI) m/z 372 (14), 344 (81), 202 (86), 156 (69), 89 (100);
HRMS calcd for C14H15INO3 (M+ - Ts) 372.0097, found
372.0109.
Ad d u ct 22 (Ta ble 2, En tr y 5). Chromatography (hexanes-
ethyl acetate, 4:1-2:1) gave 72% of the vinyl sulfone as a pale
yellow foam, which NMR analysis showed to be a pure
geometrical isomer, along with a further 17% of the vinyl
sulfone (total 89%), obtained as a 5:1 mixture of geometrical
isomers. The major isomer had: IR (film) 1726, 1699 cm-1
;
1H NMR (400 MHz) δ 8.60 (s, 1 H), 8.14 (d, J ) 8.0 Hz, 1 H),
7.94 (d, J ) 8.0 Hz, 1 H), 7.89 (d, J ) 8.1 Hz, 2 H), 7.37 (d, J
) 8.1 Hz, 2 H), 6.62 (s, 1 H), 4.15 (d, J ) 16.4 Hz, 1 H), 3.95
(s, 3 H), 3.60 (d, J ) 16.4 Hz, 1 H), 3.23 (s, 3 H), 2.45 (s, 3 H),
2.04 (s, 3 H); 13C NMR (100 MHz) δ 170.5, 164.6, 147.1, 146.2,
144.8, 141.4, 136.8, 131.7, 131.3, 130.1, 129.6, 128.1, 123.3,
101.7, 70.7, 58.6, 52.6, 23.9, 21.6; MS (EI) m/z 388 (18), 218
(100); HRMS calcd for C14H15INO4 (M+ - Ts) 388.0046, found
388.0045. Anal. Calcd for C21H22INO6S: C, 46.42; H, 4.08; N,
2.58. Found: C, 46.68; H, 3.89; N, 2.55. The X-ray structure
of the major isomer and related crystallographic data is pro-
vided in the Supporting Information and confirms that it is the
1
vinyl sulfone with the Z-configuration. H NMR signals from
the minor isomer were observed at δ 8.30 (s) and 6.76 (s).
Ad d u ct 23 (Ta ble 2, En tr y 6). The adduct was obtained
as an orange solid. NMR analysis showed the product to be
the vinyl sulfone as a 4.5:1 mixture of geometrical isomers:
1
IR (film) 1727, 1706 cm-1; H NMR (400 MHz, major isomer)
δ 8.55 (d, J ) 2.0 Hz, 1 H), 8.38 (s, 1 H), 8.17 (dd, J ) 8.2, 2.0
Hz, 1 H), 7.86 (d, J ) 8.2 Hz, 2 H), 7.39 (d, J ) 8.2 Hz, 2 H),
7.13 (d, J ) 8.2 Hz, 1 H), 6.77 (s, 1 H), 3.98-3.82 (s at δ 3.95
and 3.87 superimposed on m, total 8 H), 3.23 (s, 3 H), 2.46 (s,
3 H); signals from the minor isomer were observed at δ 8.68
(s), 8.12 (s), 6.80 (s); 13C NMR (100 MHz, major isomer) δ 165.3,
165.2, 161.2, 146.6, 145.1, 139.1, 138.0, 133.9, 132.0, 130.2,
129.7, 129.5, 128.1, 127.6, 123.3, 70.5, 58.7, 52.6, 52.5, 21.6;
MS (EI) m/z 402 (10), 338 (75), 306 (25), 246 (78), 188 (65), 91
(100); HRMS calcd for C15H16NO6 (M+ - Ts) 306.0978, found
306.0970. Anal. Calcd for C22H23NO8S: C, 57.26; H, 5.02; N,
3.04. Found: C, 56.81; H, 4.86; N, 2.70.
Ad d u ct 24 (Ta ble 2, En tr y 7). The adduct was obtained
as an off-white solid foam. NMR analysis showed the product
to be the allyl sulfone isomer as a 2:1 mixture of geometrical
isomers. The properties of this product were identical to those
of the one obtained via carbonylation of 26 (vide infra).
Vinyl sulfone: IR (film) 1726, 1704 (sh) cm-1; 1H NMR (400
MHz) major isomer δ 8.56 (s, 1 H), 8.33 (s, 1 H), 8.13 (d, J )
8.2 Hz, 1 H), 7.84 (d, J ) 8.0 Hz, 2 H), 7.38 (d, J ) 8.0 Hz, 2
H), 6.96 (d, J ) 8.2 Hz, 1 H), 6.42 (s, 1 H), 3.96 (s, 3 H), 3.89
(s, 3 H), 2.47 (s, 3 H), 2.14 (t, J ) 7.6 Hz, 2 H), 1.56-1.43 (m,
2 H), 0.83 (t, J ) 7.3 Hz, 3 H); signals from the minor isomer
were observed at δ 8.69 (s) and 6.45 (s); 13C NMR (100 MHz)
major isomer δ 165.5, 165.4, 161.1, 150.9, 145.1, 139.2, 138.3,
133.6, 132.1, 130.2, 129.8, 129.5, 127.9, 127.7, 124.3, 52.6, 52.6,
36.8, 21.6, 20.3, 13.3; MS (EI) m/z 338 (33), 244 (51), 216 (45),
Ad d u ct 25 (Ta ble 2, En tr y 8). The adduct was obtained
as an off-white solid foam. NMR analysis showed the product
to be the allyl sulfone isomer as a 4.5:1 mixture of geometrical
isomers: IR (film) 1686, 1629 cm-1; 1H NMR (200 MHz, major
isomer) δ 8.36 (s, 1 H), 7.76 (d, J ) 8.2 Hz, 2 H), 7.45-7.22
(m, 6 H), 6.74 (d, J ) 7.9 Hz, 1 H), 6.68 (d, J ) 1.5 Hz, 1 H),
6.62 (dd, J ) 7.9, 1.5 Hz, 1 H), 5.93 (s, 2 H), 5.70 (t, J ) 7.5
Hz, 1 H), 4.15-2.90 (m, 6 H), 2.54 (t, J ) 7.4 Hz, 2 H), 2.43 (s,
3 H), 2.16-1.90 (m, 2 H), 1.68-1.24 (m, 6 H), 1.19 (t, J ) 7.2
Hz, 3 H), 1.01 (t, J ) 7.1 Hz, 3 H); signals from the minor
isomer were observed at δ 8.30 (s), 7.86 (d, J ) 8.2 Hz), 5.82
(t, J ) 7.5 Hz); 13C NMR (50 MHz, both isomers) δ 167.8, 162.3,
147.3, 145.3, 144.8, 136.9, 136.6, 136.2, 136.0, 135.0, 132.3,
130.3, 129.7, 129.6, 129.6, 129.4, 128.8, 128.2, 128.0, 127.3,
120.9, 108.6, 107.9, 100.6, 54.8, 42.7, 38.7, 35.4, 31.3, 28.6, 28.1,
21.5, 13.8, 12.7; MS (EI) m/z 449 (4.5, M+ - Ts), 421 (50), 398
156 (84), 128 (72), 91 (100); HRMS calcd for C16H18NO5 (M+
Ts) 304.1185, found 304.1185.
-
Ad d u ct 21 (Ta ble 2, En tr y 4). The adduct was obtained
as a pale yellow foam. NMR analysis showed the product to
be the pure allyl sulfone isomer, obtained as a 2:1 mixture of
geometrical isomers: IR (film) 1724, 1688 cm-1; 1H NMR (400
MHz) major isomer: 8.55 (d, J ) 1.9 Hz, 1 H), 8.43 (s, 1 H),
8.08 (dd, J ) 8.2, 1.9 Hz, 1 H), 7.76 (d, J ) 8.3 Hz, 2 H), 7.46
(d, J ) 8.2 Hz, 1 H), 7.38 (d, J ) 8.3 Hz, 2 H), 6.05 (t, J ) 7.7
Hz, 1 H), 3.93 (s, 3 H), 3.66 (br s, 2 H), 2.46 (s, 3 H), 1.97
(quintet, J ) 7.6 Hz, 2 H), 1.01 (t, J ) 7.5 Hz, 3 H); minor
isomer: δ 8.58 (d, J ) 1.9 Hz,1 H), 8.19 (s, 1 H), 8.13 (dd, J )
8.3, 1.9 Hz, 1 H), 7.97 (d, J ) 8.3 Hz, 1 H), 7.85 (d, J ) 8.3 Hz,
2 H), 7.38 (d, J ) 8.3 Hz, 2 H), 5.64 (t, J ) 7.7 Hz, 1 H), 4.28
(br s, 2 H), 3.95 (s, 3 H), 2.46 (s, 3 H), 1.86 (quintet, J ) 7.6
Hz, 2 H), 0.88 (t, J ) 7.5 Hz, 3 H); 13C NMR (100 MHz, both
isomers) δ 164.8, 164.7, 162.1, 161.8, 146.9, 145.5, 145.0, 142.8,
142.0, 141.4, 140.3, 138.8, 136.3, 136.2, 131.6, 131.6, 131.2,
131.2, 130.7, 130.4, 130.1, 129.9, 128.4, 128.2, 124.8, 124.5,
(20), 348 (42), 184 (100); HRMS calcd for C27H33N2O4 (M+
Ts) 449.2440, found 449.2432.
-
Ad d u ct 26 (Ta ble 2, En tr y 9). The adduct was obtained
as a yellow solid foam. NMR analysis showed the product to
be the allyl sulfone isomer as a 2:1 mixture of geometrical
1
isomers: IR (film) 1689 cm-1; H NMR (200 MHz) δ 8.40 (s,
major isomer) and 8.18 (s, minor isomer, total 1 H), 7.95-7.75
(m, 3 H), 7.55-7.32 (m, 4 H), 7.17-7.04 (m, 1 H), 6.75-6.55
(m, 3 H), 6.01 (t, J ) 7.6 Hz, major isomer) and 5.69 (t, J )
7.5 Hz, minor isomer, total 1 H), 5.93 (s, 2 H), 4.22 (br s, minor
isomer) and 3.68 (br s, major isomer, total 2 H), 2.52 (t, J )
2230 J . Org. Chem., Vol. 68, No. 6, 2003

Conjugate Additions of o-Iodoanilines and Methyl Anthranilates
7.4 Hz, 2 H), 2.46 (s, 3 H), 1.95-1.15 (m, 8 H); 13C NMR (50
MHz, both isomers) δ 162.3, 161.8, 147.4, 145.4, 145.2, 144.8,
142.5, 140.7, 140.1, 138.5, 137.9, 136.9, 136.2, 136.1, 131.4,
131.1, 130.2, 130.1, 130.0, 129.7, 129.3, 128.5, 128.2, 125.3,
124.8, 120.9, 108.7, 108.0, 100.6, 99.7, 97.8, 54.4, 54.1, 35.3,
31.2, 28.7, 28.6, 28.5, 28.0, 27.3, 21.5; MS (EI) m/z 631 (M+,
0.9), 476 (18), 448 (20), 270 (18), 229 (61), 156 (61), 147 (100);
HRMS calcd for C22H23INO3 (M+ - Ts) 476.0723, found
476.0732.
21.6; MS (FAB) m/z 620 (7, M+ + 1), 307 (22), 154 (100); HRMS
calcd for C20H19INO4 (M+ - Ts) 464.0359, found 464.0350.
P r ep a r a tion of 6 by Ca r bon yla tion of 19. Adduct 19 (140
mg, 0.281 mmol), triethylamine (39 µL, 0.28 mmol), and Pd-
(OAc)2 (6.3 mg, 0.028 mmol) were stirred in 30 mL of methanol
at 70 °C for 2 d in a Parr high-pressure reaction vessel under
carbon monoxide at a pressure of 27 atm (400 psi). The
apparatus was cooled to room temperature and vented, and
the mixture was filtered and then concentrated in vacuo.
Chromatography (hexanes-ethyl acetate, 4:1-1:1) gave 31.0
mg (22%) of recovered 19 and 88.1 mg (73%; 94% based on
recovered starting material) of 6 as a pale yellow solid foam.
NMR analysis showed the product to be a 2:1 mixture of
geometrical isomers. The product was identical to that ob-
tained by direct addition of 4b to 5 (vide supra).
P r ep a r a tion of 20 by Ca r bon yla tion of 21. Adduct 21
was converted into 20 in 94% yield as in the preceding
procedure: pale yellow solid foam. NMR analysis showed the
product to be a 2:1 mixture of geometrical isomers. The product
was identical to that obtained by direct addition of 12 to 14
(vide supra).
P r ep a r a tion of 24 by Ca r bon yla tion of 26. Adduct 26
was treated as in the preparation of 6 to afford 14% of
recovered 26 and 82% (95% based on recovered starting
material) of 24 as an off-white solid foam. NMR analysis
showed the product to be a 2:1 mixture of geometrical
isomers: IR (film) 1727, 1687 cm-1; 1H NMR (200 MHz) δ 8.36
(s, major isomer) and 8.12 (s, minor isomer, total 1 H), 7.94-
7.24 (m, 8 H), 6.75-6.56 (m, 3 H), 5.92 (s, major isomer) and
5.91 (s, minor isomer, total 2 H), 5.86 (t, J ) 7.5 Hz, major
isomer) and 5.61 (t, J ) 7.5 Hz, minor isomer, total 1 H), 4.27
(s, minor isomer) and 3.72 (s, major isomer, total 2 H), 3.82
(s, both isomers, 3 H), 2.56-2.43 (s at δ 2.44 superimposed on
m, total 5 H), 2.01-1.77 (m, 2 H), 1.70-1.13 (m, 6 H); 13C NMR
(50 MHz, both isomers) δ 166.1, 166.0, 161.8, 161.7, 147.4,
147.3, 145.4, 145.3, 145.1, 144.7, 140.1, 137.1, 136.8, 136.4,
136.2, 136.0, 135.6, 133.5, 132.6, 131.1, 131.0, 130.2, 129.9,
129.7, 129.5, 129.5, 129.1, 128.3, 128.1, 126.5, 126.4, 120.8,
108.6, 107.9, 100.6, 55.1, 54.5, 52.4, 52.2, 35.4, 31.2, 28.7, 28.5,
28.1, 27.5, 21.5; MS (EI) m/z 504 (1.5), 408 (21), 380 (94), 357
(29), 348 (36), 184 (72), 147 (100); HRMS calcd for C24H26NO5
(M+ - Ts) 408.1811, found 408.1792.
Con ju ga te Ad d ition of An ilin e 11c to Acetylen ic Su l-
fon e 17. Aniline 11c (500 mg, 1.22 mmol), K2CO3 (168 mg,
1.22 mmol), and sulfone 17 (329 mg, 1.83 mmol) were stirred
for 6 h in 5 mL of 10:1 DMF-water. The mixture was diluted
with dichloromethane, filtered, and concentrated in vacuo.
Chromatography (hexanes-ethyl acetate, 3:1-2:1) gave 646
mg (90%) of 27 as a bright yellow foam. NMR analysis showed
the product to be a 5:1 mixture of Z and E geometrical
isomers: IR (film) 1725 cm-1 1H NMR (400 MHz, major
;
isomer) δ 8.29 (d, J ) 1.8 Hz, 1 H), 7.98 (dd, J ) 8.2, 1.8 Hz,
1 H), 7.46 (d, J ) 8.5 Hz, 1 H), 7.33 (d, J ) 10.6 Hz, 1 H),
7.32-7.13 (m, 9 H), 5.73 (d, J ) 10.6 Hz, 1 H), 5.26-5.12 (m,
2 H), 3.92 (s, 3 H), 2.38 (s, 3 H); signals from the minor isomer
were observed at δ 8.52 (d, J ) 1.8 Hz), 8.39 (d, J ) 13.6 Hz),
8.05 (dd, J ) 8.2, 1.8 Hz), 7.70 (d, J ) 8.3 Hz), 5.06 (d, J )
13.6 Hz); 13C NMR (100 MHz, major isomer) δ 164.7, 152.8,
144.6, 143.8, 140.2, 138.6, 134.5, 134.2, 131.4, 131.2, 129.6,
129.3, 128.4, 127.9, 126.3, 111.9, 99.2, 69.5, 52.4, 21.4; MS (EI)
m/z 591 (0.6), 560 (1), 436 (14), 390 (37), 264 (46), 204 (63),
114 (77), 91 (100); HRMS calcd for C18H15INO4 (M+ - Ts)
436.0046, found 436.0069.
Con ju ga te Ad d ition of An ilin e 11a to Dien yl Su lfon e
18. A mixture of aniline 11a (128 mg, 0.421 mmol), K2CO3 (58
mg, 0.42 mmol), and sulfone 18 (105 mg, 0.504 mmol) was
stirred for 4 d at room temperature in 0.5 mL of 10:1 DMF-
water. The mixture was then partitioned between ether and
water, the aqueous layer was washed with ether, and the
combined organic fractions were dried and concentrated in
vacuo. Chromatography (hexanes-ethyl acetate, 4:1-1:1) gave
19.4 mg of recovered 11a , 12.8 mg of recovered 18, and 145
mg (67%; 79% based on recovered 11a ) of 28 as a bright yellow
foam. NMR analysis showed the product to be an 8:1 mixture
of E and Z geometrical isomers: IR (film) 1724, 1681 cm-1
;
1H NMR (400 MHz, major isomer) δ 8.60 (d, J ) 1.9 Hz, 1 H),
8.12 (s, 1 H), 8.07 (dd, J ) 8.1, 1.9 Hz, 1 H), 7.66 (d, J ) 8.3
Hz, 2 H), 7.32 (d, J ) 8.3 Hz, 2 H), 7.22 (d, J ) 8.1 Hz, 1 H),
5.69 (dt, J ) 15.4, 6.5 Hz, 1 H), 5.55 (dt, J ) 15.4, 7.3 Hz, 1
H), 4.32-4.25 (br m, 2 H), 3.96 (s, 3 H), 3.73 (d, J ) 7.3 Hz, 2
H), 2.46 (s, 3 H); signals from the minor isomer were observed
at δ 8.29 (s), 5.78 (m); 13C NMR (100 MHz, major isomer) δ
164.5, 161.9, 145.8, 144.8, 141.3, 135.4, 133.4, 131.7, 130.6,
129.7, 129.7, 128.2, 121.2, 99.0, 59.3, 52.6, 47.2, 21.5; MS (EI)
m/z 358 (9), 330 (77), 288 (31), 202 (100); HRMS calcd for
P r ep a r a tion of 33 by Ca r bon yla tion of 27. Adduct 27
was converted into 33 as in the case of 6 to afford 73% of 33
as a yellow solid foam, obtained exclusively as the E isomer:
1
IR (film) 1727, 1623 cm-1; H NMR (400 MHz) δ 8.70 (d, J )
2.0 Hz, 1 H), 8.43 (d, J ) 13.7 Hz, 1 H), 8.25 (dd, J ) 8.2, 2.0
Hz, 1 H), 7.66 (d, J ) 8.3 Hz, 2 H), 7.38-7.07 (m, 8 H), 5.36-
4.99 (br m, 2 H), 5.05 (d, J ) 13.7 Hz, 1 H), 3.96 (s, 3 H), 3.58
(br s, 3 H), 2.40 (s, 3 H); 13C NMR (50 MHz) δ 165.0, 163.6,
152.2, 143.6, 141.9, 140.2, 139.0, 134.8, 134.7, 133.6, 131.4,
130.2, 129.6, 128.6, 128.5, 128.3, 128.1, 127.0, 110.3, 69.3, 52.7,
52.5, 21.5; MS (EI) m/z 523 (M+, 0.3), 389 (7), 324 (10), 91 (100);
HRMS calcd for C20H18NO6 (M+ - Ts) 368.1134, found 368.1110.
C
13H13INO3 (M+ - Ts) 357.9940, found 357.9909.
Con ju ga te Ad d ition of An ilin e 11c to Dien yl Su lfon e
18. A mixture of aniline 11c (173 mg, 0.421 mmol), K2CO3 (58
mg, 0.42 mmol), and sulfone 18 (105 mg, 0.503 mmol) was
stirred for 4 d at room temperature in 0.5 mL of 10:1 DMF-
water. The mixture was then partitioned between ether and
water. The aqueous layer was washed with ether, and the
combined organic fractions were dried and concentrated in
vacuo. Chromatography (hexanes-ethyl acetate, 4:1-1:1) gave
37.1 mg of recovered 11c, 15.9 mg of recovered 18, and 163
mg (63%; 80% based on recovered 11c) of 29 as a bright yellow
foam, obtained as the pure E-isomer: IR (film) 1712 cm-1; 1H
NMR (400 MHz) δ 8.53 (d, J ) 1.9 Hz, 1 H), 7.99 (dd, J ) 8.2,
1.9 Hz, 1 H), 7.65 (d, J ) 8.2 Hz, 2 H), 7.46-7.15 (m, 7 H),
7.14 (d, J ) 8.2 Hz, 1 H), 5.81-5.70 (m, 1 H), 5.50 (dt, J )
15.4, 7.4 Hz, 1 H), 5.10 (br s, 2 H), 4.51 (dd, J ) 15.4, 5.6 Hz,
1 H), 3.93 (s, 3 H), 3.78 (dd, J ) 15.4, 7.1 Hz, 1 H), 3.74 (d, J
) 7.4 Hz, 2 H), 2.43 (s, 3 H); 13C NMR (50 MHz) δ 164.8, 154.1,
147.2, 144.8, 140.8, 135.9, 135.5, 134.6, 130.8, 130.4, 129.7,
128.3, 127.9, 127.7, 120.6, 118.6, 99.9, 67.8, 59.5, 52.5, 51.3,
4-Qu in olon e 30. Ester 6 (662 mg, 1.54 mmol) was dissolved
in 15 mL of THF. The solution was cooled to -78 °C, and
LiHMDS (11.5 mL, 0.267 M, 3.07 mmol) was added. The
resulting red solution was stirred for 70 min at -78 °C, and
the reaction was quenched with saturated (NH4)2SO4 solution.
The mixture was partitioned between ether and dilute (NH4)2-
SO4 solution. The aqueous layer was washed with ether, and
the combined organic fractions were dried and concentrated
in vacuo. Chromatography (hexanes-ethyl acetate, 2:1) gave
473 mg (77%) of a single geometrical isomer of 30 as a white
solid: mp 149-152 °C; IR (film) 1682 cm-1 1H NMR (400
;
MHz) δ 8.67 (br s, 1 H), 8.49-8.08 (br s, 1 H), 8.00 (d, J ) 7.5
Hz, 1 H), 7.71 (d, J ) 8.1 Hz, 2 H), 7.64 (t, J ) 7.5 Hz, 1 H),
7.34 (d, J ) 8.1 Hz, 2 H), 7.25 (t, J ) 7.5 Hz, 1 H), 5.97 (t, J
) 7.6 Hz, 1 H), 4.97 (s, 1 H), 2.44 (s, 3 H), 2.22-1.85 (m, 2 H),
1.42-1.21 (m, 4 H), 0.89 (t, J ) 6.7 Hz, 3 H); 13C NMR (100
MHz) δ 182.8, 161.3, 145.9, 136.3, 134.6, 129.8, 129.2, 128.0,
125.0, 122.1, 71.6, 30.8, 26.4, 22.2, 21.6, 13.7; MS (EI) m/z 276
J . Org. Chem, Vol. 68, No. 6, 2003 2231

Back et al.
(42), 248 (100); MS (ESI) m/z 420 (M+ + Na); HRMS calcd for
68.4, 59.5, 52.3, 21.6; MS (EI) m/z 337 (30), 336 (85), 306 (100);
HRMS calcd for C20H18NO4 (M+ - SO2H) 336.1236, found
336.1250. Anal. Calcd for C20H19NO6S: C, 59.84; H, 4.77; N,
3.49. Found: C, 59.69; H, 4.82; N, 3.37.
C
21H23NO3S (M+ - CO) 369.1399, found 369.1373. Anal. Calcd
for C22H23NO4S: C, 66.48; H, 5.83; N, 3.52. Found: C, 66.37;
H, 5.62; N, 3.52.
4-Qu in olon e 31. Ester 20 (68.3 mg, 0.149 mmol) was
dissolved in 2 mL of THF. The solution was cooled to -78 °C,
and LiHMDS (2.00 mL, 0.148 M, 0.296 mmol) was added. The
resulting red solution was stirred for 60 min at -78 °C, and
the reaction was quenched with saturated (NH4)2SO4 solution.
The mixture was partitioned between ether and water. The
aqueous layer was washed with ether, and the combined
organic fractions were dried and concentrated in vacuo.
Chromatography (hexanes-ethyl acetate, 2:1) gave 49.8 mg
(78%) of a single geometrical isomer of 31 as an off-white
solid: mp 167-170 °C dec; IR (film) 1722, 1690 cm-1; 1H NMR
(200 MHz) δ 8.70 (br s, 1 H), 8.63 (t, J ) 1.2 Hz, 1 H), 8.36-
8.22 (m, 2 H), 7.68 (d, J ) 8.2 Hz, 2 H), 7.34 (d, J ) 8.2 Hz, 2
H), 6.00 (t, J ) 7.7 Hz, 1 H), 5.01 (s, 1 H), 3.93 (s, 3 H), 2.43
(s, 3 H), 2.20-1.99 (m, 2 H), 1.02 (t, J ) 7.5 Hz, 3 H); 13C
NMR (50 MHz) δ 182.2, 165.2, 161.3, 146.1, 143.9, 136.8, 136.3,
134.4, 129.9, 129.8, 129.1, 126.8, 121.8, 120.6, 71.4, 52.3, 21.7,
20.4, 13.3; MS (EI) m/z 334 (47), 306 (100); HRMS calcd for
Alk a loid 1. Mercuric chloride (120 mg, 0.44 mmol) was
dissolved in 6 mL of 2:1 methanol-THF. Thin strips of
aluminum metal (50 mg, 1.9 mg atom) were added, and the
mixture was stirred for 5 min, whereupon keto sulfone 30 (99.9
mg, 0.251 mmol) was added in one portion. The mixture was
stirred for 90 min at room temperature and allowed to settle,
and the supernatant liquid was decanted and diluted with
dichloromethane. It was washed with 10% HCl solution, and
the aqueous layer was neutralized with saturated NaHCO3
solution, and extracted three times with dichloromethane. The
combined organic layers were dried and evaporated. Chroma-
tography (chloroform-methanol, 40:1-10:1) gave 36.5 mg
(68%) of 1 as a white solid: mp 141-142 °C (from 1:1 benzene/
hexanes) (lit.12a mp 141-142 °C); IR (film) 1638, 1594, 1550,
1
1503 cm-1; H NMR (400 MHz) δ 8.37 (dd, J ) 8.1, 1.2 Hz, 1
H), 7.81 (d, J ) 8.1 Hz, 1 H), 7.58 (td, J ) 7.6, 1.2 Hz, 1 H),
7.33 (t, J ) 7.6 Hz, 1 H), 6.25 (s, 1 H), 2.70 (t, J ) 7.8 Hz, 2
H), 1.79-1.63 (m, 2 H), 1.32-1.16 (m, 4 H), 0.79 (t, J ) 7.0
Hz, 3 H); 13C NMR (100 MHz) δ 178.8, 155.4, 140.7, 131.7,
125.2, 124.9, 123.6, 118.6, 108.1, 34.3, 31.3, 28.7, 22.3, 13.8;
MS (EI) m/z (%) 215 (2, M+), 184 (29), 172 (79), 158 (99), 130
(100); HRMS calcd for C14H17NO 215.1310, found 215.1321.
The spectra were in agreement with the literature.12a The
X-ray structure of 1 iand related data are provided in the
Supporting Information.
Ru ta ch a lepen sis Alk a loid 2. Keto sulfone 32 (57.5 mg,
0.108 mmol) was subjected to the preceding procedure to afford
25.6 mg (68%) of 2 as a white solid: mp 156-157 °C (from
dichloromethane) (lit.15 mp 163 °C); IR (film) 1635, 1594, 1548,
1501 cm-1; 1H NMR (200 MHz) δ 12.35 (br s, 1 H), 8.36 (dd, J
) 8.1, 1.3 Hz, 1 H), 7.73 (d, J ) 8.0 Hz, 1 H), 7.58 (ddd, J )
8.0, 7.0, 1.3 Hz, 1 H), 7.31 (ddd, J ) 8.1, 7.0, 1.0 Hz, 1 H);
6.67 (d, J ) 7.9 Hz, 1 H), 6.59 (d, J ) 1.5 Hz, 1 H), 6.52 (dd,
J ) 7.9, 1.5 Hz, 1 H), 6.27 (s, 1 H), 5.87 (s, 2 H), 2.71 (t, J )
7.7 Hz, 2 H), 2.41 (t, J ) 7.5 Hz, 2 H), 1.80-1.63 (m, 2 H),
1.54-1.38 (m, 2 H), 1.38-1.15 (m, 4 H); 13C NMR (100 MHz)
δ 178.8, 155.5, 147.4, 145.4, 140.7, 136.3, 131.7, 125.1, 124.9,
123.5, 120.9, 118.7, 108.7, 108.0, 108.0, 100.6, 35.5, 34.3, 31.4,
29.1, 29.0, 28.8; MS (EI) m/z 349 (0.8, M+), 184 (19), 172 (100);
HRMS calcd for C22H23NO3 349.1678, found 349.1699. Anal.
Calcd for C22H23NO3: C, 75.62; H, 6.63; N, 4.01. Found: C,
75.46; H, 6.13; N, 3.98. The spectra were in agreement with
those reported15 for the natural product.
Ru ta ch a lepen sis Alk a loid 3. Sodium bicarbonate (15.5
mg, 0.185 mmol) and dimethyl sulfate (17.4 µL, 0.184 mmol)
were added to a solution of 2 (32.2 mg, 0.0922 mmol) in 5 mL
of THF. The mixture was stirred at room temperature for 1 h
and then refluxed for 17 h. The mixture was then partitioned
between brine and ether. The aqueous layer was washed with
ether, and the combined organic fractions were dried and
concentrated in vacuo. Chromatography (hexanes-ethyl ac-
etate, 4:1-2:1) gave 13.9 mg of 2 as a yellow oil. Elution of
the column with dichloromethane-methanol, 10:1, followed
by rechromatography of the product with chloroform-metha-
nol, 40:1, gave another 11.2 mg of 2 (total yield, 75%) as a
yellow oil: IR 1595, 1503, 1485, 1246 cm-1; 1H NMR (200 MHz)
δ 8.14 (dd, J ) 8.2, 1.5 Hz, 1 H), 7.98 (d, J ) 8.4 Hz, 1 H),
7.66 (ddd, J ) 8.4, 6.9, 1.5 Hz, 1 H), 7.44 (ddd, J ) 8.2, 6.9,
1.2 Hz, 1 H), 6.72 (d, J ) 7.7 Hz, 1 H), 6.67 (d, J ) 1.5 Hz, 1
H), 6.63 (s, 1 H), 6.61 (dd, J ) 7.7, 1.5 Hz, 1 H), 5.92 (s, 2 H),
4.04 (s, 3 H), 2.92 (t, J ) 7.9 Hz, 2 H), 2.53 (t, J ) 7.4 Hz, 2
H), 1.90-1.25 (m, 8 H);13C NMR (50 MHz) δ 164.1, 162.3,
148.7, 147.4, 145.3, 136.6, 129.6, 128.2, 124.7, 121.5, 121.0,
120.0, 108.8, 108.0, 100.6, 99.7, 55.5, 39.9, 35.6, 31.6, 30.0, 29.4,
29.0; MS (EI) m/z 363 (2, M+), 306 (2), 228 (6), 186 (100);
HRMS calcd for C23H25NO3 363.1834, found 363.1861. The
spectra were in agreement with those reported15 for the
natural product.
C
21H21NO5S (M+ - CO) 399.1140, found 399.1151. Anal. Calcd
for C22H21NO6S: C, 61.81; H, 4.95; N, 3.28. Found: C, 61.80;
H, 4.88; N, 3.29. See the Supporting Information for the X-ray
structure of 31.
4-Qu in olon e 32. Ester 24 (1.043 g, 1.850 mmol) was
dissolved in 15 mL of THF. The solution was cooled to -78
°C, and LiHMDS (13.9 mL, 0.267 M, 3.71 mmol) was added.
The resulting red solution was stirred for 70 min at -78 °C,
and the reaction was quenched with saturated (NH4)2SO4
solution. The mixture was partitioned between ether and
dilute (NH4)2SO4 solution. The aqueous layer was washed with
ether, and the combined organic fractions were dried and
concentrated in vacuo. Chromatography (hexanes-ethyl ac-
etate, 2:1) gave 928 mg (94%) of a single geometrical isomer
of 32 as a white solid foam: IR (film) 1684 cm-1; 1H NMR (200
MHz) δ 8.66 (br s, 1 H), 8.21 (br s, 1 H), 8.00 (d, J ) 7.7 Hz,
1 H), 7.78-7.58 (m, 3 H), 7.40-7.20 (m, 3 H), 6.72 (d, J ) 7.7
Hz, 1 H), 6.65 (s, 1 H), 6.60 (d, J ) 7.7 Hz, 1 H), 5.96 (t, J )
7.7 Hz, 1 H), 5.93 (s, 2 H), 4.95 (s, 1 H), 2.51 (t, J ) 7.5 Hz, 2
H), 2.43 (s, 3 H), 2.22-1.91 (m, 2 H), 1.69-1.20 (m, 6 H); a
10% nOe was observed between the proton at C-3 (δ 4.95 ppm)
and the allylic side chain protons (δ 2.2 ppm), indicating the
E geometry; 13C NMR (50 MHz) δ 182.8, 161.2, 147.4, 145.8,
145.4, 136.3, 136.1, 134.6, 129.8, 129.2, 128.0, 125.0, 122.0,
120.9, 108.7, 108.0, 100.7, 71.7, 35.4, 31.3, 28.6, 28.5, 26.7, 21.6;
MS (EI) m/z 348 (7), 276 (38), 248 (100); HRMS calcd for
C
29H29NO5S (M+ - CO) 503.1767, found 503.1756. Anal. Calcd
for C30H29NO6S: C, 67.78; H, 5.50; N, 2.63. Found: C, 68.34;
H, 5.66; N, 2.73.
4-Qu in olon e 34. 2,2,6,6-Tetramethylpiperidine (364 µL,
2.16 mmol) was dissolved in 5 mL of THF. The solution was
cooled to -78 °C, and tert-butyllithium (1.06 mL, 1.7 M, 1.8
mmol) was added dropwise. The solution was removed from
the cooling bath, stirred at room temperature for 30 min, and
then cooled back to -78 °C. A solution of diester 23 (332 mg,
0.719 mmol) in 3 mL of THF was added via cannula. The deep
red solution was slowly warmed to room temperature and
stirred for 3 days. The mixture was diluted with dichlo-
romethane, quenched with water, and washed with 10% HCl
solution. The aqueous layer was washed with dichloromethane,
and the combined organic layers were dried and concentrated
in vacuo to afford 289 mg (100%) of 34 as a homogeneous oil
(NMR, TLC) that crystallized from dichloromethane and ether
to provide 34 as an off-white solid: mp 246-247 °C; IR (film)
1
1722, cm-1; H NMR (400 MHz) δ 9.91 (br s, 1 H, exchanged
D2O), 8.86 (d, J ) 1.8 Hz, 1 H), 8.22 (dd, J ) 8.6, 1.8 Hz, 1 H),
7.99 (d, J ) 8.2 Hz, 2 H), 7.46 (d, J ) 8.6 Hz, 1 H), 7.27 (d, J
) 8.2 Hz, 2 H), 5.26 (s, 2 H), 3.88 (s, 3 H), 3.66 (s, 3 H), 2.38
(s, 3 H); 13C NMR (100 MHz) δ 173.0, 165.7, 152.9, 144.1, 140.1,
139.0, 133.5, 129.1, 128.9, 128.3, 127.3, 125.6, 118.3, 118.2,
2232 J . Org. Chem., Vol. 68, No. 6, 2003

Conjugate Additions of o-Iodoanilines and Methyl Anthranilates
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation of compounds 11a ,b, 12, and 16, X-ray data for
compounds 1, 22, and 31, and copies of 1H and 13C NMR
spectra of new compounds and of alkaloids 1-3. This material
is available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC)
for financial support. J .E.W. thanks NSERC and the
Alberta Heritage Foundation for Medical Research for
Graduate Scholarships.
J O026595T
J . Org. Chem, Vol. 68, No. 6, 2003 2233