Gold-facilitated '6-exo-dig' intramolecular cyclization of 2-[(2-nitrophenyl)ethynyl]phenylacetic acids: General access to 5H-benzo[b]carbazole-6,11-diones

Article abstract of DOI:10.1055/s-0029-1218362

The preliminary results of a regiospecific synthesis of (Z)-1 -(2-nitrobenzylidene)isochroman-3-ones by gold(I)-catalyzed cycloisomerization of phenylethynylacetic acids under mild conditions is described. These novel lactones proved to be suitable starti

Full text of DOI:10.1055/s-0029-1218362

LETTER
3107
Gold-Facilitated ‘6-Exo-dig’ Intramolecular Cyclization of
2-[(2-Nitrophenyl)ethynyl]phenylacetic Acids: General Access to
5H-Benzo[b]carbazole-6,11-diones
G
eneral
Access
t
r
H
-Ben
i
z
o[
b
]c
s
arbazole-
t
6,11-di
i
ones an O. Salas,a Francisco J. Reboredo,b Juan C. Estévez,b Ricardo A. Tapia,a Ramón J. Estévez*b
a
Departamento de Química Orgánica, Facultad de Química, Pontifícia Universidad Católica de Chile, 782043 Santiago, Chile
Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax +34(981)591014; E-mail: ramon.estevez@usc.es
b
Received 13 August 2009
the basic reaction conditions, spontaneously rearranged to
the corresponding 2-(2-nitrophenyl)-1H-indene-1,3(2H)-
diones. Secondly, the nitro group provides the amino
functionality required to generate the indole subunit of
Abstract: The preliminary results of a regiospecific synthesis of
(Z)-1-(2-nitrobenzylidene)isochroman-3-ones by gold(I)-catalyzed
cycloisomerization of phenylethynylacetic acids under mild condi-
tions is described. These novel lactones proved to be suitable start-
ing materials for a new, general access to 5H-benzo[b]carbazole- these targets 4.
6,11-diones.
O
Z
H
Key words: alkynes, annulations, fused-ring systems, gold(I) chlo-
ride, indoles, lactones, nitro compounds, quinones
O
O
n
n
n
O
Z
+
Alkynes are compounds of growing interest in organic
synthesis due to their ease of preparation and their use in
the construction of heterocycles through the intramolecu-
lar heteroannulation of carboxylic acids, amides, alcohols
and amines to a carbon–carbon triple bond.1 In recent
times, this process has been widely applied in natural
product synthesis for the generation of indoles from o-
amino-diphenylacetylenes,2 benzofurans from o-hydrox-
ydiphenylacetylenes,3 phthalides 2 (n = 0) and isocou-
marins 2 (n = 1) from 2-(phenylethynyl)benzoic acids (1,
n = 0), etc.4 In fact, in the intramolecular cyclization of
these benzoic acids, both the ‘5-exo-dig’ and the ‘6-endo-
dig’ closures are allowed by Baldwin’s rules5 and both
closure modes have been observed (Scheme 1). This route
allowed regiocontrolled access to (Z)-3-benzylidene-
isobenzofuran-1(3H)-ones (2; n = 0, X = H, Z = O) and 3-
phenyl-1H-isochromen-1-ones (3; n = 0, X = H), respec-
tively, although sometimes mixtures of both compounds
were obtained.6 The regioselectivity of this process is
greatly influenced by the reaction conditions and the na-
ture of the substituents on the two aromatic rings. Several
methods have been reported to promote this intramolecu-
lar reaction, including an efficient lactonization using pal-
ladium(II) acetate or gold(I) chloride as the catalyst.6c,d
X
X
X
1
2
3
n = 0,1; X = H, NO2
Z = O, NMe
N
H
4
Scheme 1
Surprisingly, very little chemistry concerning 2-[2-(phe-
nylethynyl)phenyl]acetic acids has been reported. In fact,
at present, only a few intramolecular heteroannulations of
compounds 1 (n = 1, X = H, Z = O) have been reported
and they provide mixtures of lactones 2 (n = 1, X = H,
Z = O) and 3 (n = 1, X = H), resulting from 6-exo-dig and
7-endo-dig closures, respectively.6c,d In addition, a re-
giospecific 6-exo-dig cyclization of N-methyl 2-[2-(phe-
nylethynyl)phenyl]acetamide (1, n = 1, X = H, Z = NMe)
to the corresponding derivative 2 (n = 1, X = H,
Z = NMe) has been reported.7
As part of our continued interest in nitro compounds, we
recently reported a synthesis of indoles 4 from 2-[(2-nitro-
phenyl)ethynyl]benzoic acids (1; n = 0, X = NO2, Z = O)
by a route in which the nitro group plays a critical role.6a
Firstly, it promotes the stereocontrolled 5-exo-dig cycliza-
tion that leads to (Z)-3-(2-nitrobenzylidene)isobenzo-
furan-1(3H)-ones 2 (n = 0, X = NO2, Z = O) which, under
As a first contribution to a synthetic program on the chem-
istry of diphenyl acetylenes 1, we report here our prelim-
inary results on the application of these compounds to the
preparation of 2-phenylnaphthoquinones 9. This work re-
sulted in the development of a novel, general, and effi-
cient synthesis of 5H-benzo[b]carbazole-6,11-diones 10,
a class of indole quinones with well-known antitumor ac-
tivity (Scheme 2).8
SYNLETT 2009, No. 19, pp 3107–3110
x
x
.x
x
.2
0
0
9
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1218362; Art ID: D21809ST
© Georg Thieme Verlag Stuttgart · New York

3108
C. O. Salas et al.
LETTER
Our present study was carried out with model compounds 5H-benzo[b]carbazole-6,11-dione 10a via nitrophenyl-
7a and 7b, which were easily obtained by Sonogashira naphthoquinone 9a.8b This constitutes a novel approach to
coupling reactions. For example, Sonogashira coupling of the synthesis of these highly functionalized indole quino-
o-iodophenylacetic acid ester 5a with TMS-acetylene and nes 10, but is of limited scope because of restricted access
subsequent removal of the TMS group by treatment with to the required 2-{2-[2-(2-nitrophenyl)acetyl]phenyl}ace-
TBAF, provided the phenylacetylene derivative 6a,9,10 tic acids 8.
which, when subjected to a second Sonogashira reaction
On the basis of the results discussed above, lactone 2a was
reacted with sodium methoxide in methanol in order to
transform it into the known ester 8a. However, under
these reaction conditions, 2a spontaneously underwent a
mixed Claisen condensation and subsequent oxidation to
provide naphthoquinone 9a directly.
with commercial o-bromonitrobenzene, afforded the de-
sired phenylethynylphenylacetic acid ester 7a.11 This
compound was then subjected to basic hydrolysis in order
to transform it into the phenylacetate derivative 1a. How-
ever, attempts to promote the direct cyclization of the lat-
ter compound to the key lactone 2a by intramolecular
In order to establish the significance of this novel route, a
attack of the carboxylate group on the acetylenic function-
second model substrate (7b) was studied, which was eas-
ality failed; only unreacted starting material was recov-
ily obtained by a double Sonogashira coupling protocol
ered. Nevertheless, satisfactory results were obtained
similar to that used for its analogue 7a. Transformation of
7b into 1b was followed by the cycloisomerization of the
when compound 1a was allowed to react with 10 mol%
solution of K2CO3 in acetonitrile in the presence of a cat-
potassium salt of 1b promoted by AuCl, as described
above. This led to the expected lactone 2b, which, upon
treatment with sodium methoxide in methanol, furnished
the desired the nitrophenylnaphthoquinone 9b. Finally,
9b was easily converted into 5H-benzo[b]carbazole-6,11-
dione 10b by reduction of the nitro group to an amino
group with NaBH4, a process that was followed by a spon-
taneous heteroannulation and further oxidation.
alytic amount of AuCl.6b Under these conditions, the de-
sired lactone 2a formed as the only regioisomer12 as a
result of a regiospecific 6-exo-dig cycloisomerization,
which was probably facilitated by the strong resonance ef-
fect of the nitro group.
Interest in lactone 2a lies in its structural relationship to
ketoester 8a, which was previously converted by us into
a)
TMS
R2
o-bromonitrobenzene
PdCl2(PPh3)2
CuI, Et3N
COX
PdCl2(PPh3)2
R2
R1
R2
R1
CuI, Et3N
COOMe
COOMe
R1
THF, r.t., 2–10 h
THF, r.t., 12 h
b) TBAF, CH2Cl2
r.t., 20 min
I
O2N
6a R1 = OMe, R2 = H (70%)
6b R1, R2 = OMe (49%)
5a R1 = OMe, R2 = H
5b R1, R2 = OMe
7a X = OMe, R1 = OMe, R2 = H (72%)
7b X = OMe, R1, R2 = OMe (47%)
2 N NaOH
MeOH
r.t., 12 h
1a X = OH ,R1 = OMe, R2 = H (83%)
1b X = OH, R1, R2 = OMe (81%)
R3O
O
O
R2
O
O
O
R2
R1
OH
R2
R1
R1
MeONa, MeOH
r.t., 24 h
AuCl, K2CO3
MeCN, r.t., 12 h
O
O2N
O2N
O2N
9a R1 = OMe, R2 = H (79%)
9b R1, R2 = OMe (67%)
2a R1 = OMe, R2 = H (50%)
2b R1, R2 = OMe (52%)
8a R1 = OMe, R2 = H
8b R1, R2 = OMe
O
R1
R2
NaBH4, i-PrOH
r.t., 6 h
10a R1 = OMe, R2 = H (98%)
10b R1, R2 = OMe (99%)
N
H
O
Scheme 2
Synlett 2009, No. 19, 3107–3110 © Thieme Stuttgart · New York

LETTER
General Access to 5H-Benzo[b]carbazole-6,11-diones
3109
L. A.; Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron
2002, 58, 3015. (d) Cruces, J.; Estevez, J. C.; Castedo, L.;
Estevez, R. J. Tetrahedron Lett. 2001, 42, 4825.
In summary, we report here a novel nitro-group mediated
6-exo-dig regiocontrolled heteroannulation of 2-[2-(phe-
nylethynyl)phenyl]acetic acids to (Z)-1-(2-nitroben-
zylidene)isochroman-3-ones, which should be of general
interest. These complex lactones proved to be suitable
starting materials for general access to highly functional-
ized 5H-benzo[b]carbazole-6,11-diones.
(e) Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron
Lett. 1993, 34, 6479. For other recent contributions, see:
(f) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.;
Fagnou, K. J. Org. Chem. 2008, 73, 5022. (g) Mal, D.;
Senapati, B. K.; Pahari, P. Tetrahedron 2007, 63, 3768.
(h) Miguel del Corral, J. M.; Castro, M. A.; Gordaliza, M.;
Martin, M. L.; Gamito, A. M.; Cuevas, C.; San Feliciano, A.
Bioorg. Med. Chem. 2006, 14, 2816. (i) Bernardo, P. H.;
Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Smith, G. D.;
Waring, P.; Wilkes, B. A. J. Med. Chem. 2004, 47, 4958.
(9) All new compounds gave satisfactory analytical and
spectroscopic data. Selected physical and spectroscopic data
follow. Compound 6a: oil; IR (NaCl): 3282 (C≡CH), 2106
(C≡C), 1736 (C=O) cm–1; 1H NMR (CDCl3): d = 3.29 (s,
1 H, CH), 3.52 (s, 2 H, CH2), 3.66 (s, 3 H, OCH3), 3.85 (s,
3 H, OCH3), 6.82 (d, J = 8.5 Hz, 1 H, ArH), 7.21 (dd, J = 8.5
Hz, 1 H, ArH), 7.35 (d, J = 2.0 Hz, 1 H, ArH); 13C NMR
(CDCl3): d = 39.8 (CH2), 52.0 (OCH3), 55.8 (OCH3), 80.0
(CH), 81.2 (C), 110.6 (ArH), 111.1 (Ar), 125.9 (Ar), 131.0
(ArH), 134.7 (ArH), 159.6 (Ar), 171.8 (C=O); MS:
Work is currently in progress on a systematic study of this
kind of alkyne heteroannulation in order to further estab-
lish its scope and limitations prior to its application to the
preparation of wide sets of 5H-benzo[b]carbazole-6,11-
diones and related compounds, including ellipticine and
analogues with powerful antitumoral properties.13,14
Acknowledgment
We thank the Spanish Ministry of Science and Education and Xunta
de Galicia for financial support, and the latter for a grant to F.J.R.
Additional thanks are given to FONDECYT (Research Grants
11085027 and 1060592) for financial support.
m/z (%) = 205 (100) [M + 1]+. Compound 6b: mp 81–83 °C
(CH2Cl2–MeOH); IR (NaCl): 3250 (CºCH), 2070 (CºC),
1722 (C=O) cm–1; 1H NMR (CDCl3): d = 3.24 (s, 1 H, CH),
3.69 (s, 3 H, OCH3), 3.79 (s, 2 H, CH2), 3.85 (s, 3 H, OCH3),
3.87 (s, 3 H, OCH3), 6.79 (s, 1 H, ArH), 6.98 (s, 1 H, ArH);
13C NMR (CDCl3): d = 38.4 (CH2), 51.3 (OCH3), 55.2
(OCH3), 55.3 (OCH3), 79.8 (CH), 81.3 (C), 112.1 (ArH),
113.6 (Ar), 114.3 (ArH), 129.4 (Ar), 147.1 (Ar), 149.1 (Ar),
171.0 (C=O); MS: m/z (%) = 235 (100) [M + 1]+. Compound
7a: mp 87–88 °C (CH2Cl2–MeOH); IR (NaCl): 2205 (C≡C),
1725 (C=O), 1565 (NO2), 1344 (NO2) cm–1; 1H NMR
(CDCl3): d = 3.70 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 3.94
(s, 2 H, CH2), 6.83 (d, J = 8.5 Hz, 1 H, ArH), 6.86 (s, 1 H,
ArH), 7.43 (t, J = 8.5 Hz, 1 H, ArH), 7.546 (m, 2 H, 2 ×
ArH), 7.70 (d, J = 9.1 Hz, 1 H, ArH), 8.08 (d, J = 8.2 Hz, 1
H, ArH); 13C NMR (CDCl3): d = 40.2 (CH2), 52.6 (OCH3),
55.8 (OCH3), 87.7 (C), 96.1 (C), 113.5 (ArH), 115.3 (Ar),
116.1 (ArH), 119.6 (Ar), 125.2 (ArH), 128.6 (ArH), 133.3
(ArH), 134.8 (ArH), 134.9 (Ar), 139.1 (Ar), 160.9 (Ar),
171.9 (C=O); MS: m/z (%) = 326 (53) [M + 1]+, 207 (100).
Compound 7b: mp 142–145 °C (CH2Cl2–MeOH); IR
(NaCl): 2201 (C≡C), 1724 (C=O), 1565 (NO2), 1337 (NO2)
cm–1; 1H NMR (CDCl3): d = 3.71 (s, 2 H, CH2), 3.92 (s, 6 H,
2 × OCH3), 3.94 (s, 3 H, OCH3), 6.84 (s, 1 H, ArH), 7.08 (s,
1 H, ArH), 7.46 (t, J = 7.3 Hz, 1 H, ArH), 7.60 (t, J = 7.3 Hz,
1 H, ArH), 7.73 (d, J = 7.3 Hz, 1 H, ArH), 8.09 (d, J = 7.3
Hz, 1 H, ArH); 13C NMR (CDCl3): d = 39.2 (CH2), 52.1
(OCH3), 55.9 (OCH3), 56.0 (OCH3), 87.7 (C), 95.7 (C),
112.6 (ArH), 114.6 (ArH), 118.9 (Ar), 124.7 (ArH), 128.2
(ArH), 130.5 (Ar), 132.8 (ArH), 134.4 (ArH), 147.8 (Ar),
148.8 (Ar), 150.2 (Ar), 171.7 (Ar), 179.2 (C=O); MS: m/z
(%) = 356 (0.6) [M + 1]+, 17 (100). Compound 1a: mp 152–
154 °C (CH2Cl2); IR (NaCl): 2204 (CºC), 1703 (C=O), 1564
(NO2), 1337 (NO2) cm–1; 1H NMR (acetone-d6): d = 3.85 (s,
3 H, OCH3), 3.97 (s, 2 H, CH2), 6.93 (dd, J = 8.8, 2.5 Hz, 1
H, ArH), 7.03 (d, J = 2.5 Hz, 1 H, ArH), 7.48 (t, J = 7.3 Hz,
1 H, ArH), 7.63 (t, J = 7.3 Hz, 1 H, ArH), 7.77 (m, 2 H,
ArH), 8.10 (d, J = 7.3 Hz, 1 H, ArH); 13C NMR (acetone-d6):
d = 41.0 (CH2), 56.8 (OCH3), 89.3 (C), 97.3 (C), 114.6
(ArH), 116.6 (Ar), 118.0 (ArH), 120.3 (Ar), 126.5 (ArH),
130.7 (ArH), 134.0 (Ar), 135.1 (ArH), 135.8 (ArH), 136.3
(ArH), 141.5 (Ar), 162.6 (Ar), 173.1 (C=O); MS: m/z (%) =
312 (22) [M + 1]+, 282 (100). Compound 1b: mp 163–
165 °C (CH2Cl2); IR (NaCl): 2204 (C≡C), 1710 (C=O), 1566
References and Notes
(1) (a) Huang, Q.; Larock, R. C. Org. Lett. 2002, 4, 2505.
(b) Larock, L. C. Pure Appl. Chem. 1999, 71, 1435.
(2) (a) Hiroya, K.; Suzuki, N.; Yasuhara, A.; Egawa, Y.;
Kasano, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
2000, 4339; and references cited therein. (b) Zhang, H.;
Larock, R. C. J. Org. Chem. 2002, 67, 9318. (c) Kirsch, G.;
Hesse, S.; Comel, A. Curr. Org. Synth. 2004, 1, 47.
(d) Reboredo, F. J.; Treus, M.; Estévez, J. C.; Castedo, L.;
Estévez, R. J. Synlett 2003, 1603.
(3) Larock, R. C.; Yum, E. K.; Refvick, M. D. J. Org. Chem.
1998, 63, 7652.
(4) (a) Mehta, S.; Waldo, J. P.; Larock, R. C. J. Org. Chem.
2009, 74, 1141. (b) Le Bras, G.; Hamze, A.; Messaoudi, S.;
Provot, O.; Le Calvez, P.-B.; Brion, J.-D.; Alami, M.
Synthesis 2008, 1607. (c) Kim, S.; Yamamoto, K.; Hayashi,
K.; Chiba, K. Tetrahedron 2008, 64, 2855. (d) Hellal, M.;
Bourguignon, J.-J.; Bihel, F. J.-J. Tetrahedron Lett. 2008,
49, 62. (e) Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.;
van de Weghe, P. Tetrahedron 2007, 63, 9979.
(f) Kanazawa, C.; Terada, M. Tetrahedron Lett. 2007, 48,
933. (g) Uchiyama, M.; Ozawa, H.; Takuma, K.;
Matsumoto, Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T.
Org. Lett. 2006, 8, 5517.
(5) (a) Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L.
J. Org. Chem. 1977, 42, 3846. (b) Johnson, C. D. Acc.
Chem. Res. 1993, 26, 476.
(6) (a) Reboredo, F. J.; Treus, M.; Estevez, J. C.; Castedo, L.;
Estevez, R. J. Synlett 2002, 999. (b) Uchiyama, M.; Ozawa,
H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.;
Sakamoto, T. Org. Lett. 2006, 24, 5517. (c) Marchal, E.;
Uriac, P.; Legouin, B.; Toupet, L.; van de Weghe, P.
Tetrahedron 2007, 63, 9979. (d) Brady, M. G. A.; Kariuki,
B.; Knight, D. W.; Mohammed, F. K. Tetrahedron Lett.
2009, 50, 1385.
(7) Yu, Y.; Stephenson, A.; Mitchell, D. Tetrahedron Lett.
2006, 47, 3811.
(8) For our contributions on these targets, see: (a) Fernandez,
M.; Barcia, C.; Estevez, J. C.; Estevez, R. J.; Castedo, L.
Synlett 2004, 267. (b) Barcia, J. C.; Cruces, J.; Estevez, J. C.;
Estevez, R. J.; Castedo, L. Tetrahedron Lett. 2002, 43,
5141. (c) Cruces, J.; Martinez, E.; Treus, M.; Martinez,
Synlett 2009, No. 19, 3107–3110 © Thieme Stuttgart · New York

3110
C. O. Salas et al.
LETTER
(NO2), 1337 (NO2) cm–1; 1H NMR (CDCl3): d = 3.92 (s, 2 H,
CH2), 3.92 (s, 6 H, 2 × OCH3), 6.89 (s, 1 H, ArH), 7.10 (s, 1
H, ArH), 7.48 (t, J = 7.3 Hz, 1 H, ArH), 7.63 (t, J = 7.3 Hz,
1 H, ArH), 7.77 (d, J = 7.3 Hz, 1 H, ArH), 8.10 (d, J = 7.3
Hz, 1 H, ArH); 13C NMR (CDCl3/DMSO-d6): d = 39.9
(CH2), 55.4 (OCH3), 55.5 (OCH3), 87.4 (C), 95.4 (C), 112.5
(ArH), 114.3 (Ar), 114.3 (ArH), 118.6 (Ar), 124.3 (ArH),
128.0 (ArH), 130.8 (Ar), 132.7 (ArH), 134.2 (ArH), 147.4
(Ar), 148.4 (Ar), 149.8 (Ar), 173.6 (C=O); MS: m/z (%) =
342 (0.6) [M + 1]+, 33 (100). Compound 2a: mp 141–142 °C
(CH2Cl2); IR (NaCl): 1764 (C=O), 1514 (NO2), 1307 (NO2)
cm–1; 1H NMR (CDCl3): d = 3.85 (s, 2 H, CH2), 3.87 (s, 3 H,
OCH3), 6.68 (s, 2 H, ArH and CH), 6.91 (dd, J = 8.8 Hz, 1
H, ArH), 7.39 (t, J = 8.5 Hz, 1 H, ArH), 7.61 (m, 2 H, 2 ×
ArH), 7.97 (dd, J = 8.2 Hz, 1 H, ArH), 8.04 (dd, J = 8.0 Hz,
1 H, ArH); 13C NMR (CDCl3): d = 35.0 (CH2), 55.5 (OCH3),
101.1 (CH), 111.8 (ArH), 114.7 (ArH), 120.0 (Ar), 124.6
(ArH), 126.6 (ArH), 127.7 (ArH), 128.5 (Ar), 130.5 (Ar),
132.1 (ArH), 132.8 (ArH), 148.1 (Ar), 148.6 (Ar), 161.6
(Ar), 165.0 (C=O); MS: m/z (%) = 312 (50) [M + 1]+, 282
(100). Compound 2b: mp 163–165 °C (CH2Cl2); IR (NaCl):
1736 (C=O), 1518 (NO2), 1292 (NO2) cm–1; 1H NMR
(CDCl3): d = 3.85 (s, 2 H, CH2), 3.93 (s, 3 H, OCH3), 3.96 (s,
3 H, OCH3), 6.63 (s, 1 H, CH), 6.68 (s, 1 H, ArH) 7.09 (s, 1
H, ArH), 7.40 (t, J = 7.2 Hz, 1 H, ArH), 7.63 (t, J = 7.9 Hz,
1 H, ArH), 8.00 (d, J = 8.2 Hz, 1 H, ArH), 8.06 (d, J = 8.2
Hz, 1 H, ArH); 13C NMR (CDCl3/DMSO-d6): d = 34.2
(CH2), 56.1 (2 × OCH3), 101.2 (CH), 106.9 (ArH), 109.4
(ArH), 112.6 (Ar), 119.5 (Ar), 121.8 (Ar), 124.7 (ArH),
127.7 (ArH), 128.5 (Ar), 132.2 (ArH), 132.9 (ArH), 148.7
(Ar), 149.0 (Ar), 151.3 (Ar), 165.0 (C=O); MS: m/z (%) =
342 (0.6) [M + 1]+, 33 (100). Compound 9a: mp 205–206 °C
(MeOH); IR (NaCl): 3331 (OH), 1675 (C=O), 1637 (C=O),
1525 (NO2), 1356 (NO2) cm–1; 1H NMR (DMSO-d6): d =
4.03 (s, 3 H, OCH3), 7.41 (dd, J = 8.7 Hz, 1 H, ArH), 7.62–
7.74 (m, 3 H, ArH), 7.80 (m, 1 H, ArH), 8.09 (d, J = 8.7 Hz,
1 H, ArH), 8.19 (d, J = 8.3 Hz, 1 H, ArH); 13C NMR
5 H, ArH + OH), 7.66 (m, 1 H, ArH), 8.17 (dd, J = 8.2 Hz, 1
H, ArH); 13C NMR (CDCl3): d = 57.0 (OCH3), 57.1 (OCH3),
108.2 (ArH), 109.6 (ArH), 119.6 (Ar), 123.9 (Ar), 125.0
(ArH), 126.2 (Ar), 128.3 (Ar), 129.9 (ArH), 133.0 (ArH),
133.4 (ArH), 149.5 (Ar), 152.0 (Ar), 153.4 (Ar), 155.2 (Ar),
180.8 (C=O), 182.6 (C=O); MS: m/z (%) = 356 (29) [M +
1]+, 309 (100).
(10) PdCl2(PPh3)2 (0.22 mmol) was added under argon to a
degassed mixture of CuI (0.22 mmol) and o-iodophenyl-
acetic acid ester 5a or 5b (3.6 mmol) in anhydrous THF (20
mL). After 5 min stirring, Et3N (5 mL) was first added, then
TMS-acetylene (3.60 mmol) was slowly added and the
resulting mixture was stirred at room temperature for 1.5 h
for 6a or 12 h for 6b. The solids were filtered off through a
Celite pad, the solvents were removed in vacuo, and the
crude oil was poured into water and extracted with
methylene chloride. The pooled organic liquids were washed
with brine, dried over anhydrous sodium sulfate and
concentrated to dryness in vacuo. Compound 6a or 6b were
isolated by flash column chromatography.
(11) PdCl2(PPh3)2 (0.16 mmol) was added under argon to a
degassed mixture of CuI (0.16 mmol) and o-bromonitro-
benzene (2.8 mmol) in anhydrous THF (20 mL). After 5 min
stirring, Et3N (5 mL) was first added, then a solution of 6a or
6b (3.85 mmol) in anhydrous THF (10 mL) was slowly
added and the resulting mixture was stirred at room
temperature for 12 h. The solids were filtered off through a
Celite pad, the solvents were removed in vacuo and the
filtrate was concentrated to dryness in vacuo. Compound 7a
or 7b were isolated by flash column chromatography.
(12) In a flask containing 1a or 1b (1.00 equiv) and K2CO3 (0.10
equiv), acetonitrile (2 mL/0.4 mmol) was added under argon.
The solution was purged with argon three times and then
AuCl (0.10 equiv) was added. After stirring at room
temperature for 12 h, the reaction mixture was filtered
through a Celite pad and liquids from the filtrate were
removed under reduced pressure. Flash column chroma-
tography of the crude material allowed compound 2a or 2b
to be isolated.
(DMSO-d6): d = 57.0 (OCH3), 109.2 (ArH), 113.8 (Ar),
115.1 (Ar), 119.8 (ArH), 123.3 (ArH), 126.8 (Ar), 127.9
(ArH), 131.7 (ArH), 134.0 (ArH), 136.0 (ArH), 147.5 (Ar),
149.4 (Ar), 161.8 (Ar), 176.3 (Ar), 178.9 (C=O), 184.1
(C=O); MS: m/z (%) = 326 (100) [M + 1]+. Compound 9b:
mp 266–268 °C (MeOH); IR (NaCl): 3349 (OH), 1642
(C=O), 1525 (NO2), 1337 (NO2) cm–1; 1H NMR (CDCl3):
d = 4.03 (s, 3 H, OCH3), 4.05 (s, 3 H, OCH3), 7.52–7.58 (m,
(13) Ferlin, M. G.; Marzano, C.; Gandin, V.; Dall’Acqua, S.;
Dalla Via, L. ChemMedChem 2009, 4, 363; and references
therein.
(14) Ashcroft, W. R.; Dalton, L.; Beal, M. G.; Humphrey, G. H.;
Joule, J. A. J. Chem. Soc., Perkin Trans. 1 1983, 2409.
Synlett 2009, No. 19, 3107–3110 © Thieme Stuttgart · New York