An expedient one-pot synthesis of novel 10-substituted 9-aminophenanthrenes

Article abstract of DOI:10.1016/j.tetlet.2009.07.124

An efficient synthesis of 9,10-disubstituted phenanthrenes is described in this Letter. These novel useful building blocks were obtained in a one-pot reaction including Suzuki-Miyaura cross-coupling followed by a Dieckmann-Thorpe ring closure under microw

Full text of DOI:10.1016/j.tetlet.2009.07.124

Tetrahedron Letters 50 (2009) 5704–5708
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expedient one-pot synthesis of novel 10-substituted 9-aminophenanthrenes
*
Christophe Rochais, Rodrigue Yougnia, Patrick Dallemagne , Sylvain Rault
Centre d’Etudes et de Recherche sur le Médicament de Normandie (UPRES EA 4258—FR CNRS 3038 INC3M), UFR des Sciences Pharmaceutiques,
Université de Caen Basse-Normandie, Boulevard Becquerel, 14032 Caen cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 9,10-disubstituted phenanthrenes is described in this Letter. These novel useful
building blocks were obtained in a one-pot reaction including Suzuki–Miyaura cross-coupling followed
by a Dieckmann–Thorpe ring closure under microwave irradiation. The selection of the appropriate
reagents and the optimal reaction conditions to isolate the intermediate biphenyl compound or the final
substituted phenanthrenes in high yields will be discussed in this Letter.
Received 15 June 2009
Revised 13 July 2009
Accepted 22 July 2009
Available online 26 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Phenanthrene
Suzuki–Miyaura cross-coupling
Ring closure
Dieckmann–Thorpe
Fused ring system
1. Introduction
A second reaction has been used to afford a,b-diphenyl-b-ami-
noethanol by reduction of the corresponding o-quinone mono-
oxime (route 2).11 A third route introduced an aryl group on
position 10 by coupling with an aryllead triacetate (route 3).12
More recently the synthesis of 10-aryl-9-aminophenanthrenes
has been reported by reaction of the anion of 9-aminophenan-
threne with aryl halides (route 4).13 All these syntheses are intro-
ducing the diversity from an already prepared phenanthrene ring
system. Only two routes described the formation of the amino sub-
stituent according to a nitrile cyclization. The acidic ring closure of
2-biphenylylacetonitrile (route 5) leading to novel 10-alkyl-9-
aminophenanthrenes was exposed in the first one.14 More recently
during his work concerning Directed ortho-Metalation (DoM),
Snieckus group has studied the synthesis of various 9-aminophe-
nanthrenes from the corresponding 2-cyano-20-methyl biaryls.15
Starting from 9-phenanthrols a 10-methoxy 9-aminophenanthrene
(route 6) was synthesized in two steps using lithium diethyl amide
as a base.
Considering the experience of our laboratory in the synthesis of
functionalized heterocycles,16 we have designed a two-step syn-
thesis (route 7) of novel 10-substituted-9-aminophenanthrenes.
During the preparation of this work, a paper has described a similar
strategy9b that however has never been exploited toward the syn-
thesis of aminophenanthrene. Moreover, our strategy will offer the
opportunity to access novel o-aminoesters of phenanthrene, which
could be used as a very useful building block according to the great
reactivity of anthranilic acid.17
Phenanthrene rings are extensively present in natural prod-
ucts,1 which possess interesting biological activity such as antima-
larial2 or cytotoxic activity.3 These systems have also been studied
and developed for their important properties either in materials
science4 or in medicinal chemistry.5
Many routes have been explored toward these useful cycles.
Two main routes are usually described to generate the appropriate
structure I (Fig. 1). The first one deals with the synthesis of a stil-
bene II, suitable for an intramolecular aryl–aryl bond formation
(connection B then A). Many mechanisms have been recently ex-
plored in that aim including oxidative coupling.6 The second and
reverse route (connection A then B) requests the preparation of
substituted biphenyls III which were finally submitted to an intra-
molecular ring closure. If the synthesis of 2,20-biphenyl III has been
extensively studied,7 the development of transition-metal-cata-
lyzed cross-coupling has conducted to huge improvement in their
access.8 This novel methodology has recently allowed highly effi-
cient one-pot synthesis of substituted phenanthrenes.9
Despite these recent advances, novel syntheses are needed,
especially to create more diversity on the phenanthrene ring sys-
tem. This is notably the case of 10-substituted 9-aminophenan-
threne ring systems which have been rarely described. Most of
the examples exposed their access through the reduction of their
nitro analog (route 1, Fig. 2).10
In our approach, a Suzuki–Miyaura cross-coupling between
partner 1 and o-cyanoboronic ester 2 will first form the appropri-
ate biphenyl compound (route 6). The second step will be to realize
* Corresponding author. Tel.: +33 231 566 813; fax: +33 231 566 803.
E-mail address: patrick.dallemagne@unicaen.fr (P. Dallemagne).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.124

C. Rochais et al. / Tetrahedron Letters 50 (2009) 5704–5708
5705
R
R
R1
R1
R1
B
R2
A
II
I
III
Figure 1. Main routes toward 9-substituted phenanthrenes.
a nitrile cyclization again but with the anion of an activated meth-
ylene present on the second aryl group according to a Dieckmann–
Thorpe mechanism. Furthermore, this procedure will introduce on
the phenanthrene ring system more diversity with the presence for
the first time of an electron-withdrawing group in position 10.
Having demonstrated the feasibility and the efficiency of our
strategy, we then decided to optimize it in a one-pot cascade reac-
tion. Our first attempt was to add one more equivalent of base in
the Suzuki reaction and to increase the reaction time (entry 1 in
Table 1). Unfortunately, if the expected phenanthrene 4a was iso-
lated, the yield remains very low and the corresponding biphenyl
compound 3a would remain as the major product. Dieckmann–
Thorpe ring closures are usually realized in protic solvent. Addition
of MeOH in the reaction mixture did not improve the reaction (en-
try 2 in Table 1). The use of toluene in place of dioxane did not
make any difference (entry 3).
2. Results and discussion
In order to verify the validity of our strategy, the two steps were
evaluated individually. The requested boronic ester 2 was obtained
from an ortho-lithiation of benzonitrile (Scheme 1).18 The latter
was involved in a Suzuki–Miyaura reaction with methyl 2(2-
bromophenyl)acetate 1a under microwave irradiation to afford in
good yield and in 5 min the expected biphenyl 3a.19 The reaction
has been run under standard conditions in dioxane using Pd(PPh3)4
as a catalyst and cesium carbonate as a base. Biphenyl 3a was then
submitted to a Dieckmann–Thorpe ring closure in methanol using
potassium carbonate as a base to afford, after 20 min under micro-
wave irradiation, the expected aminoester 4a in 85% yield.20
However, a one-pot two-step method brought many improve-
ments. After 5 min under classical Suzuki conditions, 200 lL of
MeOH was added to the closed reactor and the heating was pro-
longed for 20 min (entry 4). For the first time these conditions
led to the expected phenanthrene 4a with good conversion and
in high yield. Addition of EtOH instead of MeOH led to the same
reactivity but to a side transesterification reaction. These results
were encouraging and proved the great influence of protic solvent
on the final ring closing reaction.
O
R
R'
N
NO2
R'=H,OH
Route 2 (R = OH)
Route 1 (R = Br, Alkyl...)
RPb(OAc)3
+
NH2
R
Route 7 (R = EWG)
R
NC
Route 3 (R = Ar
)
NH2
(RO)2B
X
1
2
Route 4 (R = Ar)
NH–
RX
+
Route 5 (R = Alkyl)
Route 6 (R = OMe)
R
CN
R
CN
Figure 2. Principal synthesis of 10-substituted 9-aminophenanthrenes.

5706
C. Rochais et al. / Tetrahedron Letters 50 (2009) 5704–5708
CO2Me
NC
CO2Me
CO2Me
NH2
i
ii
O
+
CN
B
Br
O
1a
2
3a
4a
Scheme 1. Reagents and conditions: (i) Pd(PPh3)4 5%, Cs2CO3 2 equiv, dioxane, MW 120 °C, 5 min, 90% yield; and (ii) MeOH, K2CO3, MW 20 min, 85%.
CO2Me
NC
CO2Me
CO2Me
NH2
CO2
H
i
O
+
+
+
CN
B
NH2
Br
O
1a
2
3a
4a
5a
Scheme 2. Reagents and conditions: (i) 1a 0.01 mol, Pd cat, 5%, 2 1.1 equiv, base 3 equiv, solvent 2 mL, MW. See Table 1 for details.
Table 1
Derivative 4a produced via Scheme 2
Entry
Pd
Base
Solvent
Time (min)
T (°C)
Yield (%)
3a
4a
5a
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuOK
K3PO4
Dioxane
50
50
50
25
50
20
20
50
20
20
120
120
120
120
120
150
200
120
150
150
80
86
90
2
45
0
9
0
0
84
5
14
10
80
35
85
0
0
0
16
Dioxane/MeOHa
Toluene/MeOHa
Dioxane then MeOHa
DMF
DMF
DMF
DMF
DMF
DMF
60
10
a
Toluene/MeOH 10/1.
R
EWG
NC
EWG
NH2
i
O
B
+
R
Br
O
1a-g
2
4a-g
Scheme 3. Reagents and conditions: (i) 1a–g 0.01 mol, Pd(PPh3)4 cat, 5%, 2 1.1 equiv, Cs2CO3 3 equiv, DMF 2 mL, MW.
Table 2
Derivative 4a produced via Scheme 2
Entry
Pd
Base
Heating
Solvent
Time (min)
T (°C)
Yield (%)
3a
4a
5a
1
2
3
4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Microwave
DMF
DMF
DMF
DMF
25
150
150
150
150
0
45
25
15
85
35
35
0
Oil bath, sealed tube
Oil bath, sealed tube
Oil bath, round-bottomed flask
120
240
24 h
25
DMF was then used (entry 5) and led after 50 min at 120 °C to
4a in 35% yield. If the temperature was increased to 150 °C, 4a
was obtained as the major product after 20 min in 85% yield (entry
6). These conditions appear to be the best to achieve both the cou-
pling and the ring closure in that series.21 Indeed heating the reac-
tion mixture to 200 °C led this time to the saponified ester 5a

C. Rochais et al. / Tetrahedron Letters 50 (2009) 5704–5708
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Table 3
9-Aminophenanthrene derivatives 4a–g produced via Scheme 3
Entry
Starting material
Product
Time (min)
45
Yield (%)
75
MeO
CO2Me
CO2Me
NH2
1
1b
1c
1d
1e
1f
4b
4c
4d
4e
4f
MeO
MeO
Br
OMe
CO2Me
Br
CO2Me
2
3
4
5
6
50
20
20
20
20
72
76
80
85
88
NH2
OMe
MeO
CO2Me
Br
MeO
MeO
CO2Me
NH2
Cl
CO2Me
Cl
CO2Me
NH2
Cl
CN
Br
CN
NH2
COMe
Br
COMe
NH2
1g
4g
(entry 7). We then decided to explore the influence of the catalyst
or the base (entry 8–10), with the evidence of better conditions
when Pd(PPh3)4 and Cs2CO3 were used.
efficient to easily obtain amino nitrile phenanthrene 4f. Indeed this
compound was isolated in an efficient one-pot procedure and 85%
yield, compared to the longer previously described sequence.10
Very good yields were also obtained starting from another acti-
vated methylene compound, 1-(2-bromophenyl)propan-2-one 1g
(entry 6).
Following this study we have also explored the nature and the
influence of the thermal activation (Table 2). After 2 h at 150 °C
in an oil bath and in a sealed tube most of the starting material
has been converted, but only 35% of 4a was obtained. Extension
of the reaction time mostly produced the saponified compound
5a (entry 3 in Table 2). Pressure conditions appear to be relevant
in our case. If the reaction is run in a round-bottomed flask, only
a small trace of the biphenyl 3a is isolated after 24 h.
In order to widen the scope of our reaction, various substituted
ortho-bromophenylacetates were first introduced in our optimized
one-pot procedure. For two compounds, 1b and 1c, the presence of
the methoxy group induced longer reaction time in order to reach
total consumption of the starting material (entries 3 and 4 in Table
3). Good results were also obtained from the dimethoxy analog 1d
(entry 3). The good yield obtained from dichlorophenylacetate 1e
proved that the bromine atom could be easily replaced by a chlo-
rine atom in the Suzuki–Miyaura cross-coupling reaction (entry 4).
We have decided to study the replacement of the electron-with-
drawing group. If particular care is needed to control the reaction
with the ester group (4a–4e), the reaction appears to be really
3. Conclusion
In conclusion, we have demonstrated that our one-pot sequence
could be an efficient method to synthesize highly functionalized
aminophenanthrenes. This synthesis, consisting of a Suzuki cross-
coupling and a subsequent Dieckmann–Thorpe cyclization, ap-
pears to be a fast and effective method to access interesting phen-
anthrene building blocks. The use of the latter and the application
of this methodology to various novel heterocycles will be reported
in due time.
References and notes
1. For
a review of bioactive natural products containing phenanthrene
skeleton see: Kovács, A.; Vasas, A.; Hohmann, J. Phytochemistry 2008, 69,
1084–1110.

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C. Rochais et al. / Tetrahedron Letters 50 (2009) 5704–5708
2. Nodiff, E. A.; Saggiomo, A. J.; Shinbo, M.; Chen, E. H.; Otomasu, H.; Kondo, Y.;
Kikuchi, T.; Verma, B. L.; Matsuura, S. J. Med. Chem. 1972, 15, 775–780.
3. Lee, C.-L.; Chang, F.-R.; Yen, M.-H.; Yu, D.; Liu, Y.-N.; Bastow, K. F.; Morris-
Natschke, S. L.; Wu, Y.-C.; Lee, K. H. J. Nat. Prod. 2009, 72, 210–213.
4. Machado, A. M.; Munaro, M.; Martins, T. D.; Davila, L. Y. A.; Giro, R.; Caldas, M.
J.; Atvars, T. D. Z.; Akcelrud, L. C. Macromolecules 2006, 39, 3398–3407.
5. Lin, J.-C.; Yang, S.-C.; Hong, T.-M.; Yu, S. L.; Shi, Q.; Wei, L.; Chen, H. Y.; Yang, P.
C.; Lee, K. H. J. Med. Chem. 2009, 52, 1903–1911.
6. Wang, K.; Lu, M.; Yu, A.; Zhu, X.; Wang, Q. J. Org. Chem. 2009, 74, 935–938.
7. Buntrock, R. E.; Taylor, E. C. Chem. Rev. 1968, 68, 209–227.
8. For an extensive review of metal-transition-catalysed aryl–aryl bond formation
see: Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238.
9. (a) Zhao, Y. B.; Mariampillai, B.; Candito, D. A.; Laleu, B.; Li, M.; Lautens, M.
Angew. Chem., Int. Ed. 2009, 48, 1849–1852; (b) Kim, Y. H.; Lee, H.; Kim, Y. J.;
Kim, B. T.; Heo, J. N. J. Org. Chem. 2008, 73, 495–501.
cyanoboronic ester 2 (95 mg, 0.41 mmol), Pd(PPh3)4 (14 mg, 5%), and Cs2CO3
(241 mg, 0.74 mmol). The mixture was irradiated at 120 °C for 5 min using a
microwave reactor. The reaction mixture was then diluted with EtOAc, filtrated
on a small pad of Celite, and concentrated under vacuum. The crude mixture
was then purified by column chromatography (DCM/CyHex 7/3) to afford an
orange oil in 90% yield. IR (KBr) 2951, 2225 (CN), 1732 (CO), 1434, 1247, 1211,
1007, 759, 744 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.0 Hz, 1H), 7.71
.
(t, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.40 (t,
J = 8.0 Hz, 1H), 4.04 (s, OCH3), 3.44 (dd, 2H). 13C NMR (100 MHz, CDCl3)
d = 171.53, 144.67, 138.38, 132.93, 132.39, 132.04, 130.72, 130.67, 130.00,
129.10, 127.96, 127.46, 117.84, 113.01, 52.02, 38.78. HRMS (EI) calcd for
C16H13NO2 251.09461, found 251.09554.
20. General procedure for the ring closure. Synthesis of 4a. (a) To a solution of 3a
(100 mg, 0.40 mmol) in 2 mL MeOH was added K2CO3 (55 mg, 0.44 mmol) and
the reaction mixture was irradiated at 120 °C using a microwave reactor before
concentrating under vacuum. The crude mixture was then purified by column
chromatography (DCM/CyHex 7/3) to afford an orange solid in 85% yield. Mp:
69 °C; IR (KBr) 3459, 3352 (NH2), 2944, 1672 (CO), 1597, 1431, 1302, 1225,
10. Mosby, W. J. Org. Chem. 1959, 24, 421–423.
11. Mustafa, A.; Kamel, M. J. Am. Chem. Soc. 1954, 76, 124–127.
12. Kano, T.; Ohyabu, Y.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 5365–
5373.
1149, 1092, 742, 730, 717 cmꢀ1 1H NMR (400 MHz, CDCl3)
. d 8.64 (d,
13. Tempesti, T. C.; Pierini, A. B.; Baumgardner, M. T. J. Org. Chem. 2005, 70, 6508–
6511.
14. (a) Bradsher, C. K.; Beavers, D. J.; Little, E. D. J. Am. Chem. Soc. 1954, 76, 948; (b)
Bradsher, C. K.; Little, E. D.; Beavers, D. J. J. Am. Chem. Soc. 1956, 78, 2153–2156.
15. Benesch, L.; Bury, P.; Guillaneux, D.; Houldsworth, S.; Wang, X.; Snieckus, V.
Tetrahedron Lett. 1998, 39, 961–964.
J = 8.0 Hz,1H), 8.51 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.94 (d,
J = 8.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.53 (t,
J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.30 (s, 2H, NH2), 4.04 (s, 3H, OCH3).
13C NMR (100 MHz, CDCl3) d = 169.38(CO), 144.56, 131.57, 129.58, 127.90,
126.26, 125.75, 124.52, 124.25, 123.13, 122.43, 122.27, 121.51, 120.88, 101.75,
50.69. HRMS (EI) calcd for C16H13NO2 251.09461, found 251.09501.
16. (a)Lisowski, V.;Vu, D.N.;Feng, X.;Rault, S. Synthesis2002, 6, 753–756;(b)Rochais,
C.; Lisowski, V.; Dallemagne, P.; Rault, S. Tetrahedron 2004, 60, 2267–2270.
21. General one-pot procedure. To a solution of aryl bromide 1 (0.37 mmol) in 2 mL
dioxane were added cyanoboronic ester 2 (0.41 mmol), Pd(PPh3)4 (5%), and
Cs2CO3 (1.11 mmol). The mixture was irradiated at 150 °C for 20 to 50 min
using a microwave reactor. The reaction mixture was then diluted with EtOAc,
filtrated on a small pad of Celite, and concentrated under vacuum. The crude
mixture was then purified by column chromatography (DCM/CyHex 7/3) to
afford the corresponding phenanthrene.
17. For
a review of reactivity of anthranilic acid towards the synthesis of
polycycles see: Wiklund, P.; Bergman, J. Curr. Org. Synth. 2006, 3, 379–402.
18. Kristensen, J.; Lysen, M.; Vedso, P.; Begtrup, M. Org. Lett. 2001, 3, 1435–1437.
19. General procedure for the Suzuki–Miyaura cross-coupling: Synthesis of 3a. To a
solution of aryl bromide 1a (100 mg, 0.37 mmol) in 2 mL dioxane were added