Radical cyclization of ynamides into six- or eight-membered rings. Application to the synthesis of a protoberberine analog

Article abstract of DOI:10.1016/j.tetlet.2011.03.118

A straightforward formation of six- and eight-membered rings via the radical cyclization of specifically designed ynamides is reported. This strategy provides a protoberberine analog in only three steps by a radical cyclization cascade.

Full text of DOI:10.1016/j.tetlet.2011.03.118

Tetrahedron Letters 52 (2011) 2876–2880
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Tetrahedron Letters
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Radical cyclization of ynamides into six- or eight-membered rings.
Application to the synthesis of a protoberberine analog
Sébastien Balieu a, , Krimo Toutah a, Laura Carro a, Lise-Marie Chamoreau b, Hélène Rousselière b,
⇑
Christine Courillon a,
⇑
a Université Paris Diderot (Paris 7), ITODYS (Interfaces, Traitements, Organisation et Dynamique des Systèmes), CNRS UMR 7086, équipe de Pharmacochimie Moléculaire 15, rue
Jean Antoine de Baïf, 75205 Paris Cedex 13, France
b Université Pierre et Marie Curie (Paris 6), Institut Parisien de Chimie Moléculaire—UMR 7201 Bât. F, 4ème étage 75252 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward formation of six- and eight-membered rings via the radical cyclization of specifically
designed ynamides is reported. This strategy provides a protoberberine analog in only three steps by a
radical cyclization cascade.
Received 1 February 2011
Revised 22 March 2011
Accepted 25 March 2011
Available online 1 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Cyclization
Nitrogen heterocycles
Radicals
Ynamides
The short and efficient synthesis of new heterocyclic com-
pounds remains a challenging task for the synthetic organic chem-
ists with respect to the wealth of applications in medicinal
chemistry. Ynamide chemistry has received considerable attention
in the last five years and has been developed by exploring many
different reactivity profiles. In particular, several radical transfor-
mations of ynamides have been recently reported.1,2 Among them,
a radical 5-exo-dig/6-endo-trig cascade triggers the cyclization of a
fused-ring system with the prior formation of a five-membered
ring and therefore figures as a key-step in the preparation of nitro-
gen containing polycyclic compounds.1b Our interest in the radical
cyclization of ynamides prompted us to explore the cyclization of
compounds with an ynamide moiety in an homobenzylic position
or even further from the halogenated aromatic ring. We also dis-
close here the total synthesis of a protoberberine analog based
on the reactivity of such ynamides. This makes a short and original
one-pot access to the protoberberine skeleton compared to previ-
ous numerous synthesis3,4 of this family of biologically important
alkaloids5,6 (Scheme 1).
be the most efficient way to the desired carboxylic amides.1 These
latter amides were obtained by acylation of amines 5a–h. Amine
5a was obtained from 3-(2-bromophenyl)propanoic acid. The
transformation of the acid moiety into the amine 5a was achieved
in a classical two-step pathway described by Ban et al.8a In the case
of the amine 5b, the starting material was 2-(bromopyridin-3-
yl)methanol. The alcohol function was transformed into sulfony-
lester 2. Nucleophilic substitution of the mesylate moiety by NaCN
afforded nitrile 3. Reduction of the cyano group was unfortunately
difficult to achieve. Indeed, reaction with LiAlH4 furnished the de-
sired compound 5b in poor yield (10%)8b,c (Scheme 2). After differ-
ent optimization experiments, activation of lithium aluminium
hydride with aluminium chloride increased the yield to 50%.9
The iodonium salt 1 was efficiently synthesized in a classical
way starting from diacetate iodosobenzene via the intermediary
O
A
Diverse ynamide radical precursors 7a–h were prepared from
the corresponding amides 6a–h following Witulski’s procedure7a
which, among different existing synthetic methods,7b–f proved to
B
O
N
N
C
O
N
R
R
R
H
D
X
⇑
Corresponding authors. Fax: +33 (0)1 57 27 72 63.
E-mail addresses: sebastien.balieu@yahoo.fr (S. Balieu), christine.courillon@ulb.
Scheme 1. Radical cyclization of rings B and C to form a dehydroxoprotoberberine
ac.be (C. Courillon).
derivative.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.118

S. Balieu et al. / Tetrahedron Letters 52 (2011) 2876–2880
2877
NH2
OH
OMes
CN
a
b
c
N
Br
N
Br
N
Br
N
Br
2
3
5b
Scheme 2. Reagents and conditions: (a) MesCl, NEt3, CH2Cl2, 0 °C, 74%; (b) NaCN, DMSO, rt, 95%; (c) LiAlH4, AlCl3, THF, rt, 50%.
Table 1
Synthesis of ynamides 7 via amides 6a
O
R
O
R
O
NH2
NH
N
n
R
Cl
n
KHMDS Toluene
TfO
n
TMS
CH2Cl2
Pyridine
A
X
A
X
A
7
X
I
TMS
5
6
1
Ph
Entry
A
n
X
R
Yield 6 (%)
Yield 7 (%)
1
2
3
4
5
6
7
8
CH
CH
CH
CH
CH
CH
N
1
1
1
1
1
2
1
1
Br
Br
Br
Br
I
Br
Br
Br
CF3
CH3
6a (60)
6b (85)
6c (95)
6d (75)
6e (53)
6f (60)
6g (97)
6h (95)
7a (38)
7b (59)
7c (68)
7d (60)
7e (53)
7f (46)
7g (20)
7h (—)
Phenyl
3,5-Dimethoxyphenyl
Phenyl
CF3
CF3
N
3,5-Dimethoxyphenyl
a
KHMDS = potassium bis(trimethylsilyl)amide.
Zefirov reagent.10 All of the desired amides 6 were obtained in sat-
isfying yield (Table 1).
the other ynamides did not yield significant results. Thus, after
complete disappearance of starting ynamides, we observe numer-
ous degradation products and dehalogenated compounds. Surpris-
ingly, in the case of 7a, we observed a 6-exo-dig cyclization and the
migration of a trifluoroacetyl moiety to give the product 8 in 49%
yield (Scheme 3).
This migration has already been observed but only under ionic
conditions via an intramolecular anionic Fries rearrangement.15
The structure of 8 that we assigned by 1H NMR was confirmed
by an X-ray structure analysis (Fig. 1). This shows the delocalized
character of the enamine and highlights the hydrogen bond be-
tween the amide hydrogen and the oxygen carbonyl. This result
in the crystalline state correlates with the important shift observed
in 1H NMR for this proton (11.58 ppm).16
Addition of the deprotonated amides 6 in toluene to trimethyl-
silylethynylphenyliodonium triflate 1 afforded the ynamides 7 in
modest to fair yields.11 Unfortunately, amides 6g and 6h contain-
ing a 2-bromopyridine moiety did not react with compound 1.
We observed only a moderate conversion (20%) for amide 6g into
ynamide 7g (Table 1, entry 7), and decomposition for amide 6h
(Table 1, entry 8). The poor reactivity could be explained by the
bromine in the ortho position to the nitrogen. Indeed, bromine is
known to allow a Chichibabin reaction.12 Moreover, Newkome
et al.13 have shown that nitrile carbanions are subsequently
trapped with 2-bromopyridine to afford the SEAr products. How-
ever, we were unable to characterize any of the numerous products
formed during the reaction.
Radical cyclization was successfully conducted on ynamides 7a,
7d and 7f in benzene in the presence of tin hydride and AIBN to
give the cyclized products.14 Using these same conditions with
O
CF3
O
CF3
a
N
N
TMS
TMS
Br
7a
b
NH
N
O
O
CF3
H
TMS
CF3
8
Scheme 3. Reagents and conditions: (a) AIBN, Bu3SnH, benzene, 80 °C; (b) (i) NaOH
1 M, (ii) silica gel, 49%.
Figure 1. The X-ray crystal structure of 8.

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S. Balieu et al. / Tetrahedron Letters 52 (2011) 2876–2880
OMe
OMe
O
O
O
N
OMe
OMe
a
N
N
TMS
TMS
TMS
Br
OMe
MeO
7d
N
O
N
H
O
N
O
b
TMS
MeO
TMS
MeO
H
OMe
OMe
MeO
OMe
9
Scheme 4. Reagents and conditions: (a) AIBN, Bu3SnH, benzene, 80 °C; (b) (i) NaOH 1 M, (ii) silica gel, 30%.
Figure 2. The X-ray crystal structure of 9.
In the case of ynamide 7d, the product obtained resulted from a
The major product of the reaction resulted from an 8-endo-dig
cyclization and was confirmed by an X-ray structure analysis of
10 in 29% yield (Fig. 3).19
6-exo-dig followed by a 6-endo-trig cyclization to afford compound
9 in 30% yield (Scheme 4).17
The X-ray structure analysis of 9 was further proof that the syn-
thesis of polycyclic compounds via radical cascade cyclizations is
possible (Fig. 2).
Thus, this reaction also provides access to unsaturated eight-
membered rings contributing to the few already reported examples
of 8-endo-dig cyclization in the literature. In 1999, Reissig et al. de-
scribed the first use of SmI2 in radical cyclization.20a The authors
then used the ketyl radical anion to synthesize benzannulated cyclo-
octene.20b More recently, Rosas and co-workers described the syn-
thesis of oxocin-4-one by an 8-endo-dig cyclization under ionic
conditions.20c Finally, Echavarren and co-workers obtained Indo-
loazocine through a gold catalysis complex.20d,e
These results show the reactivity of homobenzylic ynamides
under radical conditions leading to the closure of a six-membered
ring. Lengthening the carbon chain between the brominated
aromatic ring and the nitrogen atom by one supplementary carbon
atom allowed us to isolate an eight-membered ring via a rarely
reported 8-endo-dig cyclization process. Moreover, we have
In only three steps, our synthetic path has allowed to isolate a
new protoberberin analog 9. These results support the observation
that in the case of an aromatic ring with a two carbon side chain,
the cyclization of ynamides is 6-exo-dig. This selectivity is in agree-
ment with other 6-exo-dig cyclizations reported in the literature
that show 6-exo-dig cyclizations are more favored over their com-
petitive endo-dig ones.18 We observed the loss of the trimethylsilyl
moiety in both cases. This is probably due to the acidic nature of
the silica gel, which weakens the carbon silicon bond in the exo
position.
Radical cyclization also occurred with ynamide 7f possessing a
three carbon side chain (Scheme 5).

S. Balieu et al. / Tetrahedron Letters 52 (2011) 2876–2880
2879
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CF3
O
CF3
a
N
N
TMS
Br
TMS
7f
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Yamagishi, M. J. Cell Biol. 1962, 15, 589–592; (c) Krey, A. K.; Hahn, F. E. Science
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b
O
CF3
O
CF3
N
N
TMS
TMS
10
Scheme 5. Reagents and conditions: (a) AIBN, Bu3SnH, benzene, 80 °C; (b) (i) NaOH
1 M, (ii) silica gel, 29%.
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11. General procedure for the formation of ynamides: KHMDS (5.36 mL, 2.68 mmol,
0.5 M solution in toluene) was added to a solution of amide (2.42 mmol) in
anhydrous toluene (90 mL) at room temperature. The reaction mixture was
heated to 80 °C for 2 h. Phenyl-trimethylsilyl ethynyl iodonium triflate
(3.03 mmol) was then added. After 30 min the resulting mixture was cooled
to room temperature, quenched with 12 g of silica, then concentrated and the
residue was purified by flash chromatography (petroleum ether/diethylether
90:10).
12. Hauser, C. R.; Weiss, M. J. J. Org. Chem. 1949, 14, 310–321.
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14. General procedure for radical cyclization: Tributyltin hydride (0.88 mmol) and
AIBN (0.22 mmol) were added to a degassed solution of ynamide (0.44 mmol)
in benzene (30 mL). The reaction mixture was refluxed until TLC indicated that
the starting material had completely reacted, then cooled to room
temperature. 1 M aq NaOH (30 mL) was added and the resulting mixture
was stirred for 30 min then extracted with ethyl acetate (2 Â 40 mL), dried
over MgSO4 and concentrated. The residue was purified by flash
chromatography (petroleum ether/ethyl acetate: 97:3) to afford the cyclized
products.
Figure 3. The X-ray crystal structure of 10.
extended our methodology to a radical cyclization cascade to effi-
ciently access a new protoberberine analog.
Acknowledgments
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16. 3-(3,4-Dihydroisoquinolin-1(2H)-ylidene)-1,1,1-trifluoro-3-(trimethylsilyl)
propan-2-one 8: 1H NMR (400 MHz, CDCl3) d 11.58 (br s, 1H), 7.75 (d, J = 8.0 Hz,
1H), 7.51 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 8.4 Hz, 1H), 5.98 (s, 1H), 3.61 (qt,
J = 7.6 Hz, 2H), 3.00 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 176.10 (q,
J = 33 Hz, CO), 162.38, 136.62, 132.65, 128.43, 127.63, 127.56, 126.18, 115.55
(q, J = 287 Hz, CF3), 83.83, 38.90, 27.57; 19F NMR (376 MHz, CDCl3) d À76.79; IR
The authors wish to thank Professor Max Malacria and his
group for generous procurement of reagents and friendly support.
S.B. wishes to thank Dr. Karen Plé for her generous contribution to
this work and Dr. Guillaume Anquetin for his help.
(KBr)
12H10NONaF3: calcd 264.0612; found 264.0616, CCDC 772462 contains the
m
(cmÀ1): 3052, 2984, 1619, 1582, 1564, 1264, 737; HRMS (ESI) for
Supplementary data
C
supplementary crystallographic data for this molecule.
17. 10,12-Dimethoxy-5H-isoquinolino[3,2-a]isoquinolin-8(6H)-one 9: 1H NMR
(400 MHz, CDCl3) d 7.88 (dd, J = 7.2 Hz, J = 1.4 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H),
7.37 (s, 1H), 7.36-7.23 (m, 3H), 6.70 (d, J = 1.4 Hz, 1H), 4.43 (t, J = 8.0 Hz, 2H),
3.98 (s, 3H), 3.97 (s, 3H), 3.05 (t, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d
161.43, 159.27, 155.97, 134.76, 134.51, 130.68, 128.62, 124.84, 122.61, 102.86,
99.05, 97.39, 55.81, 55.73, 39.87, 28.57; HRMS (ESI) for C19H7NO3Na: calcd
330.1106; found 330.1103. CCDC 772463 contains the supplementary
crystallographic data for this molecule.
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.118.
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19. 2,2,2-Trifluoro-1-(1-(trimethylsilyl)-5,6-dihydrobenzo[d]azocin-3(4H)-yl) ethanone
10:1HNMR(400 MHz,CDCl3)d7.26–7.12(m,4H),6.86(d,J = 1.6 Hz,1H),3.73(td,
J = 13.6 Hz, J = 4.4 Hz, 1H), 3.47 (td, J = 10.4 Hz, J = 2.8 Hz, 1H), 2.80 (t, J = 2.0 Hz,

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S. Balieu et al. / Tetrahedron Letters 52 (2011) 2876–2880
1H), 2.78 (t, J = 4.0 Hz, 1H), 2.63 (td, J = 12.8 Hz, J = 4.0 Hz, 1H), 2.05 (m, 1H), 1.43
20. (a) Dinesh, C. U.; Reissig, H.-U. Angew. Chem., Int. Ed. 1999, 38, 789–791; (b)
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(m, 1H), 0.16 (s, 9H); 13C NMR (100 MHz, CDCl3) d 155.78 (q, J = 36 Hz), 137.88,
137.57, 129.90, 129.86, 129.16, 128.63, 127.73, 127.45, 125.82, 115.45 (q,
J = 286 Hz, CF3), 42.28, 30.99, 26.95, À0.58; 19F NMR (376 MHz, CDCl3) d À68.69;
HRMS (ESI) for C16H20NOF3NaSi: calcd 350.1164; found 350.1167. CCDC 772464
contains the supplementary crystallographic data for this molecule.