Oxidative Friedel-Crafts reaction and its application to the total syntheses of Amaryllidaceae alkaloids

Article abstract of DOI:10.1021/jo802728u

An oxidative Friedel-Crafts reaction involving different aromatic compounds mediated by a hypervalent iodine reagent has been performed, using polysubstituted phenols. The strategy fits within the concept of "aromatic ring umpolung", which opens up novel

Full text of DOI:10.1021/jo802728u

Oxidative Friedel-Crafts Reaction and its Application to the Total
Syntheses of Amaryllidaceae Alkaloids
Kimiaka C. Gue´rard, Cyrille Sabot, Le´anne Racicot, and Sylvain Canesi*
Laboratoire de Me´thodologie et Synthe`se de Produits Naturels, UniVersite´ du Que´bec a` Montre´al,
C.P. 8888, Succursale Centre-Ville, Montre´al, H3C 3P8, Que´bec, Canada
canesi.sylVain@uqam.ca
ReceiVed December 12, 2008
An oxidative Friedel-Crafts reaction involving different aromatic compounds mediated by a hypervalent
iodine reagent has been performed, using polysubstituted phenols. The strategy fits within the concept of
“aromatic ring umpolung”, which opens up novel opportunities in chemical synthesis. The reaction takes
place in useful yields, and allows rapid access to highly functionalized compounds containing a dienone,
a quaternary carbon center, and an aromatic ring. The product’s skeleton is present in numerous natural
products. As an illustration of the potential of this transformation, total syntheses of compounds belonging
to the Amaryllidaceae alkaloids family such as O-methyljoubertiamine, mesembrine, and its natural
derivative the dihydro-O-methylsceletenone have been achieved in eight/nine steps. The synthetic route
to these molecules features a novel and efficient transformation on the basis of a Fukuyama and
Michael-retro-Michael tandem process to produce the required nitrogen-containing ring system.
Introduction
of how this objective can be achieved is apparent in the work
of Kita,1 who has shown that phenols3 may be activated under
the influence of hypervalent iodine reagents such as iodobenzene
diacetate (DIB), an environmentally benign and inexpensive
reagent, leading to species such as 2 (Figure 1). Electrophilic
species 2 tends to react at the 4-position (cf. reaction mode b),
at least with heteronucleophiles. We have recently determined
that in a bimolecular process more hindered carbon-based
Electron-rich aromatic compounds, such as phenols and their
derivatives, normally react as nucleophiles. However, oxidative
activation1,2 can transform these aromatics into very reactive
electrophilic species, which may be intercepted with appropriate
mild nucleophiles in synthetically useful yields. An indication
(1) A key aspect of the potential of DIB is well defined in the work of Kita
et al.: (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52,
3927. (b) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J. Org.
Chem. 1991, 56, 435. (c) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita,
S.; Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684. (d) Kita,
Y.; Gyoten, M.; Ohtsubo, M.; Tohma, H.; Takada, T. Chem. Commun. 1996,
1481. (e) Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma, H.; Kita,
Y. J. Org. Chem. 1998, 63, 7698. (f) Arisawa, M.; Utsumi, S.; Nakajima, M.;
Ramesh, N. G.; Tohma, H.; Kita, Y. Chem. Commun. 1999, 469. (g) Dohi, T.;
Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.;
Caemmerer, S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787.
(2) (a) Pelter, A.; Drake, R. A. Tetrahedron Lett. 1988, 29, 4181. (b) Quideau,
S.; Looney, M. A.; Pouyse´gu, L. J. Org. Chem. 1998, 63, 9597. (c) Ciufolini,
M. A.; Canesi, S.; Ousmer, M.; Braun, N. A. Tetrahedron 2006, 62, 5318. (d)
Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem. 2007, 119,
4016. (e) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.;
Chai, D. Synthesis 2007, 24, 3759. (f) Be´rard, D.; Racicot, L.; Sabot, C.; Canesi,
S. Synlett 2008, 1076. (g) Be´rard, D.; Giroux, M. A.; Racicot, L.; Sabot, C.;
Canesi, S. Tetrahedron 2008, 64, 7537. (h) Pouyse´gu, L.; Chassaing, S.;
Dejugnac, D.; Lamidey, A. M.; Miqueu, K.; Sotiropoulos, J. M.; Quideau, S.
Angew. Chem., Int. Ed. 2008, 47, 3552.
(3) Phenols activation: (a) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang,
S.; Swenton, J. S. J. Org. Chem. 1992, 57, 2135. (b) Braun, N. A.; Ciufolini,
M. A.; Peters, K.; Peters, E. M. Tetrahedron Lett. 1998, 39, 4667. (c) Braun,
N. A.; Bray, J.; Ousmer, M.; Peters, K.; Peters, E. M.; Bouchu, D.; Ciufolini,
M. A. J. Org. Chem. 2000, 65, 4397. (d) Scheffler, G.; Seike, H.; Sorensen,
E. J. Angew. Chem., Int. Ed. 2000, 39, 4593. (e) Ousmer, M.; Braun, N. A.;
Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534. (f)
Quideau, S. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; p 539. (g) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.;
Ciufolini, M. A. Tetrahedron Lett. 2002, 43, 5193. (h) Drutu, I.; Njardarson,
J. T.; Wood, J. L. Org. Lett. 2002, 4, 493. (i) Canesi, S.; Bouchu, D.; Ciufolini,
M. A. Angew. Chem., Int. Ed. 2004, 43, 4336. (j) Quideau, S.; Pouyse´gu, L.;
Deffieux, D. Curr. Org. Chem. 2004, 8, 113. (k) Canesi, S.; Bouchu, D.; Ciufolini,
M. A. Org. Lett. 2005, 7, 175. (l) Quideau, S.; Pouyse´gu, L.; Deffieux, D. Synlett
2008, 467. (m) Liang, H.; Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299. (n)
Sabot, C.; Commare, B.; Nahi, S.; Duceppe, M. A.; Gue´rard, K. C.; Canesi, S.
Synlett 2008, 3226. N-Arylsulfonamides activation: (o) Akai, S.; Kawashita, N.;
Morita, N.; Nakamura, Y.; Iio, K.; Kita, Y. Heterocycles 2002, 58, 75. (p) Jean,
A.; Cantat, J.; Be´rard, D.; Bouchu, D.; Canesi, S. Org. Lett. 2007, 9, 2553.
10.1021/jo802728u CCC: $40.75
Published on Web 02/06/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2039–2045 2039

Gue´rard et al.
FIGURE 1. Phenol oxidative activation.
nucleophiles3p attack the presumed intermediate 2 at the least
hindered position (pathway a), resulting in the formation of
product 4. As first demonstrated by Kita, this reaction is
generally best performed in solvents such as hexafluoroisopro-
panol (HFIP). If one considers the behavior of the electrophilic
species 2, this reversal of reactivity may thus be thought of as
involving “aromatic ring umpolung”.4
FIGURE 2. Protecting groups controlling reaction selectivity.
illustrate a novel version of the Friedel-Crafts reaction that
takes place via an oxidative process, and its direct application
to the total syntheses of Amaryllidaceae alkaloids such as
O-methyljoubertiamine,12 mesembrine,14-16 or 4,5-dihydro-4′-
O-methylsceletenone.17 As an initial investigation, we decided
to test the reactivity of furan with simple polysubstituted phenols
An important aspect of this reaction is the possibility to
rapidly generate C-C bonds. While similar transformations are
known in the intramolecular mode,5 broadening the scope to
successfully achieve a similar intermolecular reaction would
open up new opportunities in chemical synthesis. In this regard,
we wished to explore the behavior of polysubstituted phenols
as potential substrates for an oxidative addition with a carbon-
based nucleophile, thus providing rapid access to dienones
containing a quaternary carbon center. A key step to the
realization of such a transformation was recently provided by
Quideau and co-workers,6 who disclosed examples of oxidative
allylation of substituted 1-naphthol in aprotic solvents with
phenyliodine bis-trifluoracetate (PIFA).7 Moreover, a unique
example of such an outstanding transformation has been
demonstrated by the transformation of 4-methyl-2,6-di-tert-
butylphenol into 4-methyl-4-phenylcyclohexa-2,5-dienone by
treatment with chlorodiphenyl-13-iodane (Ph2ICl).8 Intriguingly,
in this oxidative reaction, aromatic compounds are employed
as both the electrophilic and nucleophilic species. In a bimo-
lecular process, the erstwhile phenol displays electrophilic
character and is trapped by an electron-rich aromatic compound
in a manner consistent with the rules governing electrophilic
aromatic substitution. To accomplish an intermolecular version
of this transformation, we focused our attention toward the
reaction of electron-rich aromatic species such as furan, vera-
trole, benzodioxolone, and anisole (and their derivatives) with
polysubstituted phenols in an oxidative Friedel-Crafts process
that would lead to products such as 3. The selectivity observed
on the electrophilic species would be controlled by choosing
the appropriating protecting group at the ortho or para position
(Figure 2).
(12) (a) Stevens, R. V.; Lai, J. T. J. Org. Chem. 1972, 37, 2138. (b) Martin,
S. F.; Puckette, T. A. Tetrahedron Lett. 1978, 19, 4229. (c) Martin, S. F.; Puckette,
T. A.; Colapret, J. A. J. Org. Chem. 1979, 44, 3391. (d) Jeffs, P. W.; Cortese,
N. A.; Wolfram, J.; Gross, P. M. J. Org. Chem. 1982, 47, 3881. (e) Stephenson,
G. R.; Finch, H.; Owen, D. A.; Swanson, S. Tetrahedron 1993, 49, 5649, and
references cited herein.
(13) (a) Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2006, 8,
4755. (b) Zhang, F. M.; Tu, Y. Q.; Liu, J. D.; Fan, X. H.; Shi, L.; Hu, X. D.;
Wang, S. H.; Zhang, Y. Q. Tetrahedron 2006, 62, 9446. (c) Pearson, W. H.;
Lovering, F. E. J. Org. Chem. 1998, 63, 3607. (d) Martin, S. F.; Campbell,
C. L. J. Org. Chem. 1988, 53, 3184. (e) Overman, L. E.; Mendelson, L. T. J. Am.
Chem. Soc. 1981, 103, 5579. (f) Tam, N. T.; Cho, C. G. Org. Lett. 2008, 10,
601.
(14) For isolation: (a) Popelak, A.; Haack, E.; Lettenbauer, G.; Spingler, H.
Naturwissenschaften 1960, 47, 156. (b) Smith, E.; Hosansky, N.; Shamma, M.;
Moss, J. B. Chem. Ind. 1961, 402.
(15) For synthesis of (-)-mesembrine, see: (a) Taber, D. F.; He, Y. J. Org.
Chem. 2005, 70, 7711. (b) Taber, D. F.; Neubert, T. D. J. Org. Chem. 2001, 66,
143. (c) Ogasawara, K.; Kamikudo, T. Chem. Commun. 1998, 783. (d)
Ogasawara, K.; Yamada, O. Tetrahedron Lett. 1998, 39, 7747. (e) Langlois, Y.;
Dalko, P. I.; Brun, V. Tetrahedron Lett. 1998, 39, 8979. (f) Denmark, S. E.;
Marcin, L. R. J. Org. Chem. 1997, 62, 1675. (g) Mori, M.; Kuroda, S.; Zhang,
C.; Sato, Y. J. Org. Chem. 1997, 62, 3263. (h) Yoshimitsu, T.; Ogasawara, K.
Heterocycles 1996, 42, 135. (i) Nemoto, H.; Tanabe, T.; Fukumoto, K. J. Org.
Chem. 1995, 60, 6785. (j) Nemoto, H.; Tanabe, T.; Fukumoto, K. Tetrahedron
Lett. 1994, 35, 6499. (k) Takano, S.; Samizu, K.; Ogasawara, K. Chem. Lett.
1990, 1239. (l) Takano, S.; Imamura, Y.; Ogasawara, K. Tetrahedron Lett. 1981,
22, 4479. (m) Strauss, H. F.; Wiechers, A. Tetrahedron Lett. 1979, 20, 4495.
(n) Arns, S.; Lebrun, M. E.; Grise, C. M.; Deniss, I.; Barriault, L. J. Org. Chem.
2007, 72, 9314. For synthesis of (+)-mesembrine, see: (o) Paul, T.; Malachowski,
W. P.; Lee, J. Org. Lett. 2006, 8, 4007. (p) Kosugi, H.; Miura, Y.; Kanna, H.;
Uda, H. Tetrahedron: Asymmetry 1993, 4, 1409. (q) Yokomatsu, T.; Iwasawa,
H.; Shibuya, S. Tetrahedron Lett. 1992, 33, 6999. (r) Meyers, A. I.; Hanreich,
R.; Wanner, K. T. J. Am. Chem. Soc. 1985, 107, 7776. (s) Yamada, S.-I.
Tetrahedron Lett. 1971, 16, 1133.
(16) For racemic synthesis of mesembrine, see: (a) Chavan, S. P.; Khobra-
gade, D. A.; Pathak, A. B.; Kalkote, U. R. Tetrahedron Lett. 2004, 45, 5263.
(b) Kulkarni, M. G.; Rasne, R. M.; Davawala, S. I.; Doke, A. K. Tetrahedron
Lett. 2002, 43, 2297. (c) Rigby, J. H.; Dong, W. Org. Lett. 2000, 2, 1673. (d)
Rajagopalan, P. Tetrahedron Lett. 1997, 38, 1893. (e) Michael, J. P.; Howard,
A. S.; Katz, R. B.; Zwane, M. I. Tetrahedron Lett. 1992, 33, 6023. (f)
Bauermeister, S.; Gouws, I. D.; Strauss, H. F.; Venter, E. M. M. J. Chem. Soc.,
Perkin Trans. 1 1991, 561. (g) Parkinson, C. J.; Pinhey, J. T. J. Chem. Soc.,
Perkin Trans. 1 1991, 1055. (h) Winkler, J. D.; Muller, C. L.; Scott, R. D. J. Am.
Chem. Soc. 1988, 110, 4831. (i) Livinghouse, T.; Hackett, S. J. Org. Chem.
1986, 51, 1629. (j) Gramain, J.-C.; Remuson, R. Tetrahedron Lett. 1985, 26,
4083. (k) Sanchez, I. H.; de Jesus Soria, J.; Larraza, M. I.; Flores, H. J.
Tetrahedron Lett. 1983, 24, 551. (l) Jeffs, P. W.; Redfearn, R.; Wolfram, J. J.
Org. Chem. 1983, 48, 3861. (m) Pinnick, H. W.; Kochlar, K. S. Tetrahedron
Lett. 1983, 24, 4785. (n) Keck, G. E.; Webb, R. R. J. Org. Chem. 1982, 47,
1302. (o) Martin, S. F.; Puckette, T. A.; Colapret, J. A. J. Org. Chem. 1979, 44,
3391. (p) Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1978, 34, 2579.
(q) Stevens, R. V.; Lesko, P. M.; Lapalme, R. J. Org. Chem. 1975, 40, 3495. (r)
Keely, S. L.; Tahk, F. C. J. Am. Chem. Soc. 1968, 90, 5584. (s) Rodriguez,
H. R.; Shamma, M. Tetrahedron 1968, 24, 6583. (t) Stevens, R. V.; Wentland,
M. P. J. Am. Chem. Soc. 1968, 90, 5580. (u) Kugita, H.; Oh-ishi, T. Tetrahedron
Lett. 1968, 9, 5445. (v) Curphey, T. J.; Kim, H. L. Tetrahedron Lett. 1968, 9,
1441. (w) Rodriguez, H. R.; Shamma, M. Tetrahedron Lett. 1965, 6, 4847.
(17) Sanchez, I. H.; Larraza, M. I.; Flores, H. J.; Rojas, I.; Alcala, R. Synth.
Commun. 1983, 13, 35.
Results and Discussion
The concept of “aromatic ring umpolung” provides new
strategic opportunities in synthetic chemistry. In this paper, we
(4) Sabot, C.; Be´rard, D.; Canesi, S. Org. Lett. 2008, 10, 4629.
(5) (a) Vanderlaan, D. G.; Schwartz, M. A. J. Org. Chem. 1985, 50, 743. (b)
Pelter, A.; Ward, R. S.; Abd-el-Ghani, A. J. Chem. Soc., Perkin Trans. 1 1992,
2249. (c) Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn,
J. J. Org. Chem. 1996, 61, 5854. (d) Node, M.; Kodama, S.; Hamashima, Y.;
Katoh, T.; Nishide, K.; Kajimoto, T. Chem. Pharm. Bull. 2006, 54, 1662.
(6) Quideau, S.; Looney, M. A.; Pouyse´gu, L. Org. Lett. 1999, 1, 1651.
(7) (a) Varvoglis, A. HyperValent Iodine in Organic Synthesis; Academic
Press: San Diego, CA, 1997. (b) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 2008,
108, 5299.
(8) Ozanne-Beaudenon, A.; Quideau, S. Angew. Chem., Int. Ed. 2005, 44,
7065.
(9) Be´rard, D.; Jean, A.; Canesi, S. Tetrahedron Lett. 2007, 48, 8238.
(10) (a) Kato, N.; Shibayama, S.; Munakata, K.; Katayama, C. J. Chem. Soc.
D 1971, 1643. (b) Bell, H. C.; Pinhey, J. T.; Sternhell, S. Aust. J. Chem. 1979,
32, 1551.
(11) Thadani, A. N.; Huang, Y.; Rawal, V. H. Org. Lett. 2007, 9, 3873.
2040 J. Org. Chem. Vol. 74, No. 5, 2009

Total Syntheses of Amaryllidaceae Alkaloids
SCHEME 1
SCHEME 4
To explore the scope and limitations of this reaction, we
proceeded to study various electron-rich aromatic compounds
with sufficient reactivity to trap the electrophilic species 15.
Our first attempt was on anisole, an inexpensive substrate. The
reaction promoted by DIB afforded the desired compound,
together with byproduct 26, resulting from the addition of acetate
on the species 15, in a ratio (4/1) favoring 25a.10 The side
reaction was easily eliminated by using phenyliodine bis-
trifluoracetate (PIFA). Trifluoroacetic acid is a stronger acid and
a weaker nucleophile than acetic acid, which explains why
compound 25a is formed exclusively (Scheme 5).
SCHEME 2
To broaden the scope of this reaction, different phenol
derivatives were oxidized in the presence of anisole and
2-bromoanisole. The reaction occurs in good yield with alkyl-
di-tert-butylphenols such as 14. Halo-anisole and anisole display
similar behavior, as shown in the Table 1 summary.
SCHEME 3
This transformation can also be performed regioselectively
at the ortho position with compounds such as 12. However, in
this specific case DIB has to be used to afford 28. Indeed, with
PIFA the stronger trifluoroacetic acid released instantaneously
induces a dienone-phenol rearrangement to afford the biphenyl
29 in 67% yield. It is likely that the dienone-phenol rearrange-
ment occurs more rapidly with compounds such as 28 than with
25 due to the proximity of the carbonyl group (Figure 3).
Oxidative treatment of compound 14a in the presence of
benzodioxolone leads to the desired compound 30 in 64% yield
(Scheme 6). Phenol 32, which was identified as a byproduct,
had not been present in the reaction with anisole under the same
oxidative conditions and probably accounts for the difference
in yield. The formation of this product can be rationalized if
we consider that a quinone methide intermediate 15 is generated
in the media that can then be trapped by benzodioxolone in a
1,6-Michael addition process. A similar result was observed with
veratrole.
If polysubstituted phenols such as alkyl-di-tert-butylphenols
are useful for exploring the scope of such a reaction, they are
actually of low potential as starting materials for the total
synthesis of natural products. Consequently, to move away from
tert-butyl groups, we have investigated easily removable
protecting groups capable of blocking selected positions on the
aromatic ring. The choice of directing groups has to achieve
two possible results: a steric effect similar to that of a tert-
butyl, e.g., trimethysilyl, or an inductive effect such as that
induced by an electronegative halide. An interesting choice
would be the halides, which can be efficiently introduced onto
an aromatic ring and are convenient handles to generate C-C
bonds by means of palladium chemistry. This synthetic strategy
could be useful for the total synthesis of a number of natural
products. Unfortunately, oxidation of 2,6-dibromo cresol led to
inextricable byproduct. A plausible explanation is that the two
strong electron-withdrawing groups provide excessive destabi-
lization of the generated electrophilic species 15, which rapidly
decomposes. To avoid this pitfall, we studied the combination
of a halide and a TMS group as substituents. In this case, the
umpoled intermediate is sufficiently stable to afford the desired
compounds. These compounds are easily obtained from the
such as 2,4,6-trimethylphenol, 9. This example allowed us to
evaluate the feasibility and the regioselective outcome of the
process (Scheme 1).
The reaction occurs in good yield and shows interesting
selectivity (9/1) in favor of reaction at the ortho position. This
reaction is performed in HFIP, and the use of trifluoroethanol
(TFE) as the solvent in the reaction leads to addition of TFE
on the substrate. To exercise better control of the regioselectivity,
we switched to alkyl-di-tert-butylphenols as the electrophilic
precursors. The choice of these phenols seemed reasonable as
possibly allowing enhanced regiocontrol, because of the en-
hanced steric effect generated by the bulky tert-butyl groups,
as shown in Scheme 2.
The presence of halide substituents could also provide
interesting selectivity patterns due to their stereoelectronic effect.
These atoms are efficiently introduced onto aromatic rings. In
addition, bromo or iodo substituents may be useful handles to
subsequently generate C-C bonds by means of palladium
chemistry. The selectivity observed with alkyl substituents may
be explained by considering that resonance form 20 is a weak
contributor to the overall delocalized system and provides the
more accessible position. In addition, alkyls are known to be
electron-donor groups, whereas halides are electron-withdrawing
(Scheme 3).
An interesting tricyclic product was observed upon treatment
of compound 22 with furan. This transformation occurs via a
formal [2+3] cycloaddition, as we have earlier reported,9 but
for the first time, the substitution occurs at the para position. A
possible mechanism is described in Scheme 4.
J. Org. Chem. Vol. 74, No. 5, 2009 2041

Gue´rard et al.
SCHEME 5
TABLE 1. Oxidative Addition with Anisole Derivatives
TABLE 2. Oxidative Addition of Polysubstituted Phenols
entry
R
X
yield
entry
R
R1
X
Y
yield
a
b
c
d
Me
Me
Et
H
Br
H
H
80
82
70
73
a
b
c
d
e
f
CH2CH2OTBDPS
CH2CH2OTBDPS
CH2CH2OTBDPS
CH2CH3
CH2CHdCH2
CH2CH2OMs
Br
Cl
Cl
Br
Br
Br
Br
H
H
H
H
H
H
I
H
H
Br
H
H
37
38
52
43
42
41
44
Bu
Br
H
g
CH2CH2NMeNs
FIGURE 3. Dienone-phenol rearrangement.
SCHEME 6
FIGURE 4. Regioselective addition of 3-azido-anisole.
SCHEME 7
pensates for the moderate yields. Skeletons afforded by this
transformation could lead to the highly functionalized cores
found in numerous natural products such as the family of
Amaryllidaceae alkaloids. Intriguingly, this reaction seems to
occur equally with a very electron-withdrawing halide such as
chloride 35b or with 35c. The selectivity observed with
3-bromoanisole 35c has been verified by NMR NOE analysis.
A remarkable, and useful, aspect of this transformation is the
fact that the oxidation can be performed in the presence of an
azide functionality (Figure 4). Indeed treatment of compound
33a in the presence of 3-azido-anisole 36 affords compound
37 in 29% yield. The regioselectivity observed has been checked
by NMR NOE analysis.
corresponding dibromophenols.11 However, such protected
phenols are not compatible with an oxidant such as PIFA,
probably due to the high acidity generated in the medium, and
in such cases, DIB has to be used despite the presence of a
small amount of a byproduct such as 26 resulting from the
addition of acetic acid on the electrophilic species (∼15%). To
evaluate the scope of this reaction, different moderately nu-
cleophilic functionalities were introduced on the side chain and
different substituted anisoles were used. Numerous spectator
functionalities such as alcohols, sulfonamides, and alkenes are
compatible with the reaction conditions. A summary of repre-
sentative experiments appears in Table 2.
This transformation takes place in the presence of these
numerous functional groups, and although the efficiency of this
transformation with such substituents calls for improvement
[37-52%], the reaction outcome, i.e., the production of
structural complex compounds containing functional groups
from readily available simple starting materials, easily com-
Despite the low yield observed, this example constitutes a
rare example of a Friedel-Crafts reaction on a substrate
containing an azide group. If this transformation is optimized,
the stability of such functionality with respect to the reaction
conditions could open up multiple opportunities for subsequent
synthetic transformations, with potential applications in the total
synthesis of natural products. Moreover, a treatment of such
polysubstituted phenols with veratrole leads to the desired
compound. Indeed, the oxidation of compound 33g has gener-
2042 J. Org. Chem. Vol. 74, No. 5, 2009

Total Syntheses of Amaryllidaceae Alkaloids
FIGURE 6. Amaryllidaceae alkaloids.
compound 35a or 46 in the presence of TBAF leads in good yield
to the bicyclic compound 47 with complete regioselectivity
regarding the alkene containing the silyl group, the latter being
subsequently removed under the reaction conditions (Scheme 9).
This oxidative Friedel-Crafts reaction allows rapid access
to functionalized synthons containing a quaternary carbon center,
a dienone, and an aromatic moiety, and different functionalities
can be present on the side chain. Such an intermediate could
afford some opportunity for total synthesis. Numerous natural
products with such structures are known in the literature. The
most well-known belong to the family of Amaryllidaceae
alkaloids such as O-methyljoubertiamine,12 48, crinnine,13 49,
mesembrine,14-16 50, and its related analogues, 4,5-dihydro-
4′-O-methylsceletenone,17 51 (Figure 6).
As an illustration of the potential of this method, we have
synthesized two alkaloids of this family. Mesembrine and
O-methyljoubertiamine are alkaloids present in Sceletium tor-
tuosum. They have been shown to be very potent serotonin
reuptake inhibitors, active at very low doses. Interest in
Mesembrine alkaloids has recently been renewed with the
discovery of several analogues found in various sceletium
species. Extracts of these Southwest Africa plants are used as
pharmacological drugs. The 4,5-dihydro-4′-O-methylsceleten-
one, 51, is a simpler natural derivative of mesembrine isolated
from a. cordifolia. Starting from the available 2-(4-hydrox-
yphenyl)ethanol 52, dibromination with NBS was carried out
to produce 53 in 91% yield. This latter was treated with HMDS
followed by BuLi and TMSCl to give the tri-TMS product 54
in 87% yield. At this point, deprotection of the aliphatic and
more nucleophilic alcohol present in the side chain was
quantitatively achieved by treatment of 54 with PPTS in ethanol.
The free alcohol on 55 was then transformed into a leaving
group with MsCl and triethylamine to generate 56 in 92% yield
(Scheme 10).
FIGURE 5. Plausible approach.
ated compound 38, and a similar result has been observed with
benzodioxolone (Scheme 7).
Mechanistically, we propose that the aromatic ring approaches
the generated electrophilic species as illustrated in the next figure.
We envisage that an orbital overlap due to a π-stacking interaction
could explain the obtained results. In the case of the intermediate
15, we believe that the steric crowding between the tert-butyl group
and the second methoxy group of veratrole could perturb the
approach and explain the formation of compounds such as 32
(Scheme 6). In the case of species 40, the methoxy group may be
located above the unhindered halide and the lack of this steric
interaction would explain the absence of a compound such as 32.
In the case of anisole, since there are no steric interactions, only
the desired reaction occurs (Figure 5).
We were interested in testing different silyl groups less fragile
than a TMS in order to obtain yields close to those presented
in Table 1. The corresponding polysubstituted phenols such as
43 or 45 are easily afforded by a retro-Brook rearrangement
(Scheme 8). Unfortunately, these groups behave similarly to
the TMS group in the reaction. The differences in yields between
the di-tert-butyl and silyl polysubstituted phenols can be
rationalized if we consider that the tert-butyl group is a better
electron-donor group than silyl. The electron-donor effect
generated by tert-butyl stabilizes the electrophilic species 15,
and consequently limits the formation of byproduct, but
unfortunately this group is not easily removable.
However the presence of a silyl group leads to interesting
opportunities for chemical transformation. Indeed, treatment of
At this point, in order to introduce the necessary nitrogen moiety,
an SN2 reaction was performed between 56 and the corresponding
SCHEME 8
SCHEME 9
J. Org. Chem. Vol. 74, No. 5, 2009 2043

Gue´rard et al.
SCHEME 10
SCHEME 11
SCHEME 12
SCHEME 13
anion of N-methyl-p-nosylamide, generated in DMF with sodium
hydride. This reaction proceeded in 88% yield; the phenol
protecting O-TMS group was then removed in the same pot.
Nosylamide or Fukuyama’s sulfonamide18 was chosen because it
is known to be easily cleaved under mild reaction conditions.
Compound 33g, when treated with anisole or veratrole in oxidative
conditions, led to the corresponding dienone 57 and 58. While this
process occurs in reasonable yield with anisole (42%), unfortunately
oxidation of compound 33g with veratrole only gave compound
58 in low yield (Scheme 11).
From these key compounds total syntheses of these natural
products were efficiently accomplished via an unprecedented
transformation afforded by treatment of compounds 57 or 58
with K2CO3 and thiophenol (Fukuyama’s condition).18 This
novel transformation, occurring in good yield (71% yield), takes
place via six successive distinct steps: (1) a nucleophilic
aromatic substitution (SNAr) deprotection leads to the corre-
sponding free amine; (2) the free amine reacts via a Michael
process to afford the bicyclic compound 61; (3) desylilation
followed by (4) addition of thiophenol leads to compound 62;
(5) substitution of the bromide by an SN2 process occurs to
generate 63; and (6) a final retro-Michael reaction produces 59
(X ) H) or 60 (X ) OMe) (Scheme 12). This method provides
rapid and efficient access to the main core of these alkaloids
and may be assimilated to a Fukuyama and Michael-retro-
Michael tandem process.
Total syntheses of mesembrine and 4,5-dihydro-4′-O-meth-
ylsceletenone were completed by treatment of compounds 59
and 60 with Raney Nickel in ethanol to reduce the alkene and
remove the thio-ether, forming the desired natural product in
86% yield. These syntheses represent a first application of this
new transformation and demonstrate its utility in chemical
synthesis. In addition, the conversion of 4,5-dihydro-4′-O-
methylsceletenone, 51, into O-methyljoubertiamine, 48, may be
achieved by treatment with iodomethane12a (Scheme 13).
Conclusions
In summary, a novel transformation involving an oxidative
(18) Review: Kan, T.; Fukuyama, T. Chem. Commun. 2004, 105.
Friedel-Crafts reaction on a variety of polysubstituted phenols
2044 J. Org. Chem. Vol. 74, No. 5, 2009

Total Syntheses of Amaryllidaceae Alkaloids
3a-(4-Methoxyphenyl)-1-methyl-5-(phenylthio)-1,2,3,3a,7,7a-
hexahydro-6H-indol-6-one (59). To a solution of 57 (24 mg, 0.04
mmol) in degassed acetonitrile (1 mL) was added K2CO3 solid (28
mg, 0.2 mmol) and thiophenol (22 mg, 0.2 mmol). The solution
was stirred overnight and filtrated directly on silica (ethyl
acetate-hexane-NEt3, 49:49:2) to afford 59 (11 mg, 0.03 mmol,
71%) as a pale yellow oil. IR υ (cm-1) 2920, 1603, 1506, 1248;
1H NMR (300 MHz, acetone-d6) δ 7.47 (d, J ) 7.6 Hz, 2H), 7.40
(t, J ) 7.6 Hz, 2H), 7.32 (t, J ) 7.6 Hz, 1H), 7.30 (d, J ) 8.8 Hz,
2H), 6.92 (d, J ) 8.8 Hz, 2H), 6.33 (s, 1H), 3.78 (s, 3H), 3.20 (td,
J ) 9.4, 2.9 Hz, 1H), 2.69 (br, 1H), 2.63 (dd, J ) 15.8, 2.3 Hz,
1H), 2.56 (dd, J ) 15.8, 2.3 Hz, 1H), 2.52 (t, J ) 8.8 Hz, 1H),
2.36 (td, J ) 8.8, 2.9 Hz, 1H), 2.27 (s, 3H), 2.02 (m, 1H); 13C
NMR (150 MHz, acetone-d6) δ 194.2, 160.5, 151.5, 137.0, 135.2,
135.0, 134.4, 131.3, 129.7, 129.6, 115.8, 75.0, 57.1, 56.5, 54.4,
41.0, 40.4, 38.5. HRMS (ESI) calcd for C22H24NO2S (M + H)+
366.1528, found 366.1523.
and electron-rich aromatic compounds has been carried out. The
synthetic potential of this reaction has been illustrated by the
synthesis of natural compounds belonging to the Amaryllidaceae
alkaloids family. This transformation fits within the concept of
“aromatic ring umpolung” and demonstrates the potential of such
an approach. Further applications on more elaborate natural
products based on this transformation are under study in our
laboratories and will be disclosed in due course.
Experimental Section
Oxidative Process: General Procedure. To a stirred solution
of phenol (0.1 mmol) in HFIP (0.5 mL) at 0 °C was added anisole
or one of its derivatives (0.9 mmol, 9 equiv) or furan (0.7 mmol,
7 equiv), followed by addition of DIB or PIFA (Table 1) (0.15
mmol, 1.5 equiv) dissolved in HFIP (0.2 mL), over 20 s. The
solution was stirred for another 2 min and quenched with sat. aq
NaHCO3 (2 mL). The aqueous phase was extracted with EtOAc (3
× 5 mL), and the combined organic layers were washed with brine
(5 mL), dried over Na2SO4, and concentrated. The crude product
was purified by chromatography (n-hexane:dichloromethane or
n-hexane:ethylacetate as required).
3a-(3,4-Dimethoxyphenyl)-1-methyl-5-(phenylthio)-1,2,3,3a,7,7a-
hexahydro-6H-indol-6-one (60). The same procedure was used
with compound 58 (12.5 mg, 0.02 mmol) to afford 60 (5.8 mg,
0.014 mmol, 73%) as a pale yellow oil: IR υ (cm-1) 2922, 1606,
1
1501, 1242; H NMR (600 MHz, acetone-d6) δ 7.47 (d, J ) 7.6
Hz, 2H), 7.40 (t, J ) 7.6 Hz, 2H), 7.33 (t, J ) 7.6 Hz, 1H), 6.92
(d + s, J ) 8.2 Hz, 2H), 6.88 (d, J ) 8.8 Hz, 1H), 6.33 (s, 1H),
3.81 (s, 3H), 3.79 (s, 3H), 3.20 (td, J ) 9.4, 2.9 Hz, 1H), 2.73 (br,
1H), 2.63 (d, J ) 17.0 Hz, 1H), 2.60 (d, J ) 17.0 Hz, 1H), 2.52 (t,
J ) 8.2 Hz, 1H), 2.39 (td, J ) 8.8, 2.9 Hz, 1H), 2.27 (s, 3H), 2.02
(m, 1H); 13C NMR (150 MHz, CDCl3) δ 194.3, 151.5, 151.3, 150.3,
135.2, 135.0, 134.5, 131.3, 129.7, 120.8, 113.7, 112.7, 74.8, 57.1,
57.1, 57.0, 54.7, 41.0, 40.5, 38.7; HRMS (ESI) calcd for
C23H26NO3S (M + H)+ 396.1633, found 396.1641.
N-{2-[3-Bromo-4-hydroxy-5-(trimethylsilyl)phenyl]ethyl}-N-
methyl-4-nitrobenzenesulfonamide (33g). To a solution of N-
methyl-p-nosylamide (1.85 g, 8 mmol, 4 equiv) in dry DMF (7
mL) was added sodium hydride (60%, 320 mg, 8 mmol), then the
solution was stirred during 30 min after the end of the gas evolution.
Compound 56 (880 mg, 2 mmol) in dry THF (2 mL) was added
dropwise and the resulting mixture was stirred at room temperature
for 3 h. The reaction was quenched by addition of a saturated
solution of NH4Cl (10 mL) followed by the addition of ethyl acetate
(30 mL). The organic layer was washed with brine (2 × 10 mL),
tehn aqueous layers were combined and washed with ethyl acetate
(2 × 20 mL). The combined organic layers were dried over sodium
sulfate, filtered, and then concentrated. The crude mixture was
purified by chromatography (SiO2, hexanes/ethyl acetate, 83:12).
A white solid was obtained, 33g (854 mg, 1.76 mmol, 88%). Mp
161 °C; IR υ (cm-1) 3496, 2941, 1529, 1347, 1244, 1161, 1077;
1H NMR (300 MHz, CDCl3) δ 8.33 (d, J ) 8.8 Hz, 2H), 7.88 (d,
J ) 8.8 Hz, 2H), 7.20 (s, 1H), 7.06 (s, 1H), 5.63 (s, 1H), 3.30 (t,
J ) 7.0 Hz, 2H), 2.84 (s, 3H), 2.78 (t, J ) 7.0 Hz, 2H), 0.30 (s,
9H); 13C NMR (150 MHz, CDCl3) δ 154.9, 149.8, 144.0, 134.8,
132.8, 130.8, 128.2, 127.4, 124.2, 110.3, 51.8, 34.8, 33.5, -1.2;
HRMS (ESI) calcd for C18H24BrN2O5SSi (M + H)+ 487.0359,
found 487.0355.
Mesembrine (50). To a solution of 60 (5.5 mg, 0.014 mmol) in
a melange of EtOH/ethyl acetate (1 mL, 2:1) was added a small
amount of Ni (Raney) at 0 °C until the reaction was completed as
indicated by TLC (SiO2, hexanes/ethyl acetate, 1/3). The mixture
was filtered, and then concentrated under vacuo. Purification of the
resulting crude product by column chromatography (ether) afforded
50 (3.5 mg, 0.012 mmol, 86%) as a yellow oil identical with the
1
natural product. IR υ (cm-1) 2926, 1719, 1519, 1455, 1254; H
NMR (600 MHz, C6D6) δ 6.75 (d, J ) 2.3 Hz, 1H), 6.69 (dd, J )
8.8, 2.3, 1H), 6.60 (d, J ) 8.8, 1H), 3.48 (s, 3H), 3.45 (s, 3H),
2.85 (td, J ) 8.2, 2.3 Hz, 1H), 2.69 (t, J ) 3.5 Hz, 1H), 2.48 (d,
J ) 15,8, 2.9 Hz, 1H), 2.35 (m, 1H), 2.31 (dd, J ) 15.8, 3.5 Hz,
1H), 2.06 (s, 3H), 2.04 (m, 2H), 1.93-1.69 (m, 4H); HRMS (ESI)
calcd for C17H24NO3 (M + H)+ 290.1756, found 290.1751.
4,5-Dihydro-4′-O-methylsceletenone (51). The same procedure
was used as with 59 (7.3 mg, 0.02 mmol) to afford 51 (4.5 mg,
0.17 mmol, 87%) as a yellow oil identical with the natural product.
IR υ (cm-1) 2924, 1716, 1455; 1H NMR (600 MHz, C6D6) δ 7.00
(d, J ) 8.8 Hz, 2H), 6.80 (d, J ) 8.8, 2H), 3.37 (s, 3H), 2.82 (td,
J ) 8.2, 2.3 Hz, 1H), 2.60 (t, J ) 3.5 Hz, 1H), 2.44 (dd, J ) 15.8,
2.9 Hz, 1H), 2.33 (m, 1H), 2.22 (dd, J ) 15.8, 3.5 Hz, 1H), 2.04
(s, 3H), 2.00 (m, 2H), 1.90-1.66 (m, 4H); HRMS (ESI) calcd for
C16H22NO2 (M + H)+ 260.1651, found 260.1645.
N-{2-[3-Bromo-1-(4-methoxyphenyl)-4-oxo-5-(trimethylsilyl)-
cyclohexa-2,5-dien-1-yl]ethyl}-N-methyl-4-nitrobenzenesulfona-
mide (57). Pale yellow oil; IR υ (cm-1) 2921, 1650, 1530, 1348,
1
1247, 1164; H NMR (300 MHz, CDCl3) δ 8.38 (d, J ) 8.8 Hz,
2H), 7.91 (d, J ) 8.8 Hz, 2H), 7.29 (d, 1H, J ) 2.3 Hz, 1H), 7.17
(d, 1H, J ) 8.2 Hz, 2H), 7.03 (d, 1H, J ) 2.3 Hz, 1H), 6.91 (d, J
) 8.8, Hz, 2H), 3.81 (s, 3H), 2.99 (m, 1H), 2.89 (m, 1H), 2,83 (s,
3H), 2.48 (m, 2H), 0.22 (s, 9H); 13C NMR (150 MHz, CDCl3) δ
181.1, 160.4, 159.3, 152.3, 150.1, 143.2, 139.7, 129.3, 128.3, 127.4,
125.2, 124.5, 114.7, 55.3, 50.7, 46.8, 35.9, 35.7, 1.5; HRMS (ESI)
calcd for C25H30BrN2O6SSi (M + H)+ 593.0777, found 593.0781.
N-{2-[3-Bromo-1-(3,4-dimethoxyphenyl)-4-oxo-5-(trimethyl-
silyl)cyclohexa-2,5-dien-1-yl]ethyl}-N-methyl-4-nitrobenzene-
sulfonamide (58). Pale yellow oil; IR υ (cm-1) 2923, 1650, 1533,
Acknowledgment. The authors thank the Donors of the
Petroleum Research Fund (ACS PRF), administered by the
American Chemical Society, for support of this research. We
are also very grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) and to the provincial
government of Quebec (FQRNT).
1
1344, 1245; H NMR (300 MHz, CDCl3) δ 8.38 (d, J ) 8.8 Hz,
2H), 7.91 (d, J ) 8.8 Hz, 2H), 7.29 (d, 1H, J ) 2.3 Hz, 1H), 7.03
(d, 1H, J ) 2.3 Hz, 1H), 6.87 (d, J ) 8.8, Hz, 1H), 6.82 (d, J) 8.8
Hz, 1H), 6.71 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 2.98 (m, 1H),
2.89 (m, 1H), 2,83 (s, 3H), 2.48 (m, 2H), 0.22 (s, 9H); 13C NMR
(150 MHz, CDCl3) δ 181.0, 160.2, 152.1, 149.5, 149.0, 143.2,
139.7, 129.6, 128.3, 125.2, 124.5, 118.6, 111.6, 109.4, 55.9, 50.9,
46.9, 35.9, 29.6, -1.5; HRMS (ESI) calcd for C26H32BrN2O7SSi
(M + H)+ 623.0883, found 623.0881.
Supporting Information Available: 1H and 13C NMR data
for all compounds are provided. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO802728U
J. Org. Chem. Vol. 74, No. 5, 2009 2045