One-pot synthesis of novel poly-substituted phenanthrenes

Article abstract of DOI:10.1016/j.tet.2010.02.060

A one-pot synthesis of novel poly-substituted phenanthrenes is described in this article through a Suzuki-Miyaura cross-coupling followed by a Dieckmann-Thorpe ring closure under microwave irradiation. The selection of the appropriate starting materials allowed us to introduce diversity on various positions of the phenanthrene ring system.

Full text of DOI:10.1016/j.tet.2010.02.060

Tetrahedron 66 (2010) 2803–2808
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of novel poly-substituted phenanthrenes
`
Rodrigue Yougnia, Christophe Rochais, Jana Sopkova-de Oliveira Santos,
Patrick Dallemagne , Sylvain Rault
*
´
Centre d’Etudes et de Recherche sur le Medicament de Normandie (UPRES EA 4258dFR CNRS 3038 INC3M) UFR des Sciences Pharmaceutiques,
Universite´ 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:
Received 12 January 2010
Received in revised form 12 February 2010
Accepted 15 February 2010
Available online 18 February 2010
A one-pot synthesis of novel poly-substituted phenanthrenes is described in this article through
a Suzuki–Miyaura cross-coupling followed by a Dieckmann–Thorpe ring closure under microwave ir-
radiation. The selection of the appropriate starting materials allowed us to introduce diversity on various
positions of the phenanthrene ring system.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Phenanthrene
Suzuki–Miyaura cross-coupling
Dieckmann–Thorpe
Fused ring system
Ring closure
1. Introduction
The last few years have seen significant advances in the access
towards phenanthrene rings mostly due to the development of
Phenanthrene rings have gained the interest of the scientific
community because of their occurrence in material science1 and in
numerous natural products.2 A great number of these alkaloids
exhibit interesting biological activities3 among which antitumour
activities are the most notable. These pharmacological properties
are described, for example, for tylophorine4 and antofine5 (Fig. 1),
and a number of their simplified analogues have been synthesized.6
Most of these structures are constituted by poly- methoxy-
phenanthrene ring systems substituted on the 9 and 10 positions.
transition-metal-catalysed chemistry.7 However, novel and effi-
cient synthesis methods are still needed in order to obtain these
polysubstituted systems.
This is the reason why we have recently described, in a pre-
liminary report, an efficient one-pot synthesis of 10-substituted 9-
aminophenanthrenes under microwave irradiation (Scheme 1).8
For example, to achieve the synthesis of phenanthrene 6, cya-
noboronic ester 5 was engaged in a Suzuki–Miyaura cross-
coupling with methyl 2-(2-bromophenyl) acetate 1 followed by
an intramolecular Dieckmann–Thorpe ring closure (entry 1 in
Table 1).
R1
H3CO
9
7
N
6
5
8
1
10
EWG
Br
EWG
NH2
9
NC
i
H3CO
R2
+
O
4
3
B
10
R1=R2=OCH3
tylophorine
R1=OCH3 R2=H antofine
O
2
1
: EWG=CO2CH3
: EWG=CN
5
6
: EWG=CO2CH3
: EWG=CN
Figure 1. Structure of tylophorine and antofine.
2
7
3: EWG=COCH3
4
8: EWG=COCH3
9
: EWG=CHO
: EWG=CHO
* Corresponding author. Tel.: þ33 231 566 813; fax: þ33 231 566 803.
E-mail address: patrick.dallemagne@unicaen.fr (P. Dallemagne).
Scheme 1. General synthesis of novel 10-substituted 9-aminophenanthrenes. Re-
agents and conditions: (i) Pd(PPh3)4 cat 5%, Cs2CO3 3 equiv, DMF, 150 ꢀC, MW.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.060

2804
R. Yougnia et al. / Tetrahedron 66 (2010) 2803–2808
Table 1
General synthesis of aminophenanthrenes according to Scheme 1
R'
R
R1
R'
R''
R
CN
EWG
EWG
NH2
O
R''
X
R2
B
O
1-4
5
R2
R1
6-9
Entry nꢀ
R
R0
R00
X
EWG
nꢀ
R1
R2
nꢀ
R
R0
R00
R1
R2
EWG
Time (min) Yielda (%)
1
2
3
4
5
6
7
8
1a
2
3
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br CO2CH3
Br CN
Br COCH3
Br CHO
Br CO2CH3
Br CO2CH3
Br CO2CH3
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5b
5c
5b
5b
H
H
H
H
H
H
H
H
OCH3
H
OCH3
H
OCH3
OCH3
H
H
H
H
H
H
H
H
H
CF3
H
CF3
H
H
6aa
7a
8a
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
OCH3
H
OCH3
OCH3
H
H
H
H
H
H
H
H
H
CO2CH3 20
80
85
73
65
75
76
72
65
75
60
87
80
65
63
CN
COCH3
CHO
20
55
45
4
9a
1b
1c
1d
1e
1a
1a
2
2
1b
1c
OCH3
6ba
6ca
6da
6ea
6ab
6ac
7b
7c
6bb
6cb
OCH3
CO2CH3 45
CO2CH3 50
CO2CH3 20
CO2CH3 45
CO2CH3 40
OCH3 OCH3
OCH3
H
H
H
H
H
H
OCH3 OCH3
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
OCH3
Cl
CO2CH3
9
Br CO2CH3
Br CO2CH3
Br CN
Br CN
Br CO2CH3
Br CO2CH3
10
11
12
13
14
CF3 CO2CH3 60
H
CF3 CN
H
H
CN
40
55
CO2CH3 60
CO2CH3 50
OCH3 OCH3
OCH3 OCH3
a
Isolated yield.
Herein we wish to report the application of this strategy to
various substrates in order to extend the scope of this reaction and
to describe the synthesis of novel and highly valuable poly-
substituted phenanthrenes.
2. Results and discussion
Our first goal was to extend the reactivity to diverse aryl bro-
mides (entries 1–4 in Table 1). The optimization work we have
previously carried out8 led to the discovery of an efficient reaction
procedure. The boronic ester 5a and the methylene activated
substrate 1a were solved in DMF and irradiated with a microwave
at 150 ꢀC using Pd(PPh3)4 as a catalyst and Cs2CO3 as a base. The
reaction was highly efficient with both the nitrile 2 and the ketone
3 (Scheme 1) and two novel phenanthrenes 7a and 8a were
obtained with 85% and 73% yields, respectively (entries 2 and 3 in
Table 1).8 In order to complete the scope of this reaction, 2-(2-
bromophenyl) acetaldehyde 4 was employed and after 45 min the
reaction afforded a 65% yield of the expected aldehyde 9a (entry 4
in Table 1).
Figure 2. X-ray structure of compound 6ba: CCDC 759470.9
To study the scope and limitations of the cascade reaction, we
examined a variety of substituted benzonitrile or aryl halides.
In the first attempt, a series of substituted phenyl acetates 1b–e
were engaged in the general procedure (entries 5–8 in Table 1) and
led to the formation of four aminoesters 6ba–ea with good yields.8
The three dimensional structure of compound 6ba was assessed by
realizing its X-ray crystallography (Fig. 2).9
In order to introduce, for the first time, some substitutions on
the second ring we decided to synthesize novel cyanoboronic
esters. In our approach 5a was obtained through ortho-lithiation
of benzonitrile (Scheme 2) according to Begtrup’s procedure.10
We tried to adapt this strategy to substituted benzonitriles, as
described by the same group.11 The lithiation was carried out on
two benzonitriles 10b,c using 1.2 equiv of LTMP as a base fol-
lowed by the addition of 1.4 equiv of triisopropylborate. In order
to stabilize the boronic species the intermediates were treated,
after acidic quench, with 1.5 equiv of pinacol. This methodology
led to the synthesis of two novel esters 5b,c with good yields
(Scheme 2).
CN
CN
R2
O
B
R1
R1
i
O
R2
5a
10a
R1=H
5b R1=OCH3 R2=H
5c
R2=H
R1=H
R2=H
10b R1=OCH3 R2=H
10c
R1=H
R2=CF3
R1=H
R2=CF3
Scheme 2. Ortho-lithiation of benzonitriles 10b,c. Reagents and conditions: (i) (a)
LTMP 0 ꢀC; (b) BuLi 0 ꢀC; (c) B(O-i-Pr)3 ꢁ78 ꢀC; (c) pinacol rt.
The influence of this novel substitution on the Suzuki–Miyaura
cross-coupling was then tested by involving these two novel esters
5b,c in the previously described one-pot reaction. Treated with
methyl 2-(2-bromophenyl) acetate 1a or the nitrile 4 the procedure

R. Yougnia et al. / Tetrahedron 66 (2010) 2803–2808
2805
afforded good to excellent yields of four novel phenanthrenes
6ab,ac and 7b,c, respectively (entries 9–12 in Table 1).
The coupling of substituted methyl ester 1b or 1c with the bo-
ronic ester 5b afforded, for the first time, 9-aminophenanthrenes
substituted on both side rings 6bb,cb with moderate yields (entries
13 and 14 in Table 1).
Despite the successful utilization of the cascade reaction, this
strategy is still dependent on the availability of the corresponding
o-cyanophenyl-boronic species. Obtained according to a directed
ortho metalation (DOM) strategy, this methodology is however less
regioselective when the starting benzonitrile is substituted on para
and meta positions by directed metalation groups (DMG).11 We
therefore decided to assess the feasibility of the reverse process,
starting from a boronic species 11 and an o-halogenated benzoni-
trile 12 (Fig. 3).
In order to test the validity of the reverse process, 11a,d were
first engaged in the one-pot reaction with o-bromobenzonitrile 12a
(Scheme 4). The corresponding phenanthrenes 6aa,da were
obtained with good yields comparable to those obtained in the
original process (entries 1 and 2 in Table 2).
R'
CO2CH3
CO2CH3
NH2
NC
Br
R3
R'
i
+
O
B
O
R3
6
11a R'=H
12a R3=H
12d
11d
R'=OCH3
R3=CH3
12e R3=OCH3
Scheme 4. Reverse general synthesis of 9-aminophenanthrenes. Reagents and con-
ditions: (i) Pd(PPh3)4 cat 5%, Cs2CO3 3 equiv, DMF, 150 ꢀC, MW.
NC
X
CO2Me
NH2
CO2Me
B(OR)2
It was impossible to synthesize 2-substituted methyl 10-ami-
nophenanthrene-9-carboxylates according to the original cascade
reaction.11 Therefore, substituted o-bromobenzonitriles 12d,e were
employed in our reverse process with 11a,d, which produced the
expected phenanthrenes 6ad,ae and 6de, for the first time, and
with good yields (entries 3–5 in Table 2).
6
11
12
Figure 3. Retrosynthetic analysis of the reverse process.
Firstly, methyl [o-(boronic ester)phenyl] acetates 11 were syn-
thesized. Our first approach was to test a bromine-lithium ex-
change strategy12 on bromine ester 1a followed by in situ trapping
with triisopropylborate at ꢁ78 ꢀC. Unfortunately, this strategy only
led to dehalogenated structures. An alternative strategy was then
applied to the bromine esters 1 (Scheme 3), where 1a,d were
engaged in a palladium-catalysed cross-coupling reaction with
bis(pinacolato)diboron, developed by Miyaura,13 which led to the
boronic esters 11a,d with quantitative yields.
3. Conclusion
In summary, we have demonstrated that a cascade of Suzuki–
Miyaura coupling Dieckmann–Thorpe ring closures is an efficient
and fast method for the synthesis of functionalized phenanthrenes.
This one-pot procedure appears to be robust and applicable to the
synthesis of multiple substituted phenanthrenes according to the
original or reverse process. The reactivity of the highly function-
alized compounds obtained through this route will be reported in
due course.
R'
R'
CO2CH3
i
CO2CH3
O
4. Experimental
4.1. General
Br
B
O
1a
R'=H
11a
R'=H
1d R'=OCH3
11d R'=OCH3
All commercial solvents and reagents were used as received
except tetrahydrofurane, which was distilled over Na/benzophe-
none under argon. Flash chromatography was undertaken on
silica gel (SDS AAC 60, 70–200) or on neutral alumina gel (Merck 90,
63–200). IR spectra were recorded on KBr disks with a Perkin–
Scheme 3. Synthesis of boronic esters 11a,d. Reagents and conditions: KOAc,
PdCl2(dppf), bis(pinacolato)diboron, CH2Cl2.
Table 2
General synthesis of aminophenanthrenes according to Scheme 4
NC
R3
R'
CO2CH3
R'
Br
CO2CH3
O
B
12
O
NH2
11
6
R3
Entry
Starting
materials
nꢀ
R0
R3
Time
(min)
Yielda
(%)
1
2
3
4
5
11a
11d
11a
11a
11d
12a
12a
12d
12e
12e
6aa
6da
6ad
6ae
6de
H
OCH3
H
H
OCH3
H
H
CH3
OCH3
OCH3
25
40
40
50
40
85
80
70
77
83
a
Isolated yield.

2806
R. Yougnia et al. / Tetrahedron 66 (2010) 2803–2808
Elmer BX FTIR apparatus. 1H and 13C NMR spectra were recorded,
respectively, at 400 and 100 MHz with a Jeol Lambda 400 NMR
COCH3); 13C NMR (100 MHz, CDCl3)
d 202.85 (CO), 143.45, 132.75,
131.02, 129.13, 127.00, 126.97, 125.64, 125.43, 124.60, 123.55, 123.49,
122.92, 122.12, 112.93, 32.02; HRMS (EI) calcd for C16H13NO
235.0997, found 235.10073.
spectrometer. Chemical shifts
d are reported in parts per million
with the solvent resonance as the internal standard; coupling
constants J are given in hertz. Multiplicity is given as follows: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet). The
microwave reactions were performed using a Biotage Initiator
Microwave oven using 2–5 mL sealed vials. Temperature was
measured with an IR-sensor and reaction times are given as hold
times. LC/MS (ESI) analyses were undertaken with a Waters alliance
2695 as separating module using the following gradient: A (95%)/B
(5%) to A (5%)/B (95%) in 10 min. The final conditions were held for
3 min before returning to initial conditions for 1 min. Initial con-
ditions were then maintained for 5 min (A: H2O, B: CH3CN; each
containing HCOOH: 0.1%; Column: C18 Xterra MSC118/2.1–50 mm).
MS detection was performed with a Micromass ZMD 2000 by
positive ESI. EIMS and HRMS (EI) were performed at 70 eV with
a JEOL JMS GCMate. Melting points were determined on Kofler
melting point apparatus.
4.2.4. 10-Aminophenanthrene-9-carbaldehyde (9a). Yellow oil;
method (a) 65%; IR (KBr)
1730(CO), 1630, 1609, 1410, 1262, 1123, 1100, 1075, 743, 703 cmꢁ1
1H NMR (400 MHz, CDCl3)
n 3375, 3192(NH2), 2958, 2925, 2855,
;
d
10.78 (s, CHO), 8.56 (d, J¼7.8 Hz, 1H,
H4), 8.43 (d, J¼7.8 Hz, 1H, H5), 8.24 (d, J¼7.8 Hz, 1H, H8), 7.93 (d,
J¼7.8 Hz,1H, H1), 7.70 (t, J¼7.8 Hz,1H, H3), 7.56 (t, J¼7.8 Hz,1H, H2),
7.48 (m, 3H, NH2, H6), 7.36 (t, J¼7.8 Hz, 2H, H7); 13C NMR (100 MHz,
CDCl3)
d 190.36 (CO), 149.54, 134.14, 132.23, 130.86, 130.40, 128.83,
128.13, 127.00, 123.72, 123.63, 123.52, 123.27, 122.21, 119.19; HRMS
(EI) calcd for C15H11NO 221.08405, found 221.08464.
4.2.5. Methyl
(6ba). Orange solid; method (a) 75%; mp 155–157 ꢀC; IR (KBr)
3306 (NH2), 3207, 1634 (CO), 1617, 1598, 1507, 1435, 1366, 1248, 1217,
1177, 1032, 862, 855, 763 cmꢁ1; 1H NMR (400 MHz, CDCl3)
8.57 (d,
10-amino-6-methoxyphenanthrene-9-carboxylate
n
3421,
d
4.2. General one-pot procedure
J¼7.8 Hz,1H, H4), 8.22 (d, J¼8.8 Hz,1H, H8), 7.96 (d, J¼6,8 Hz,1H, H1),
7.91 (d, J¼2,9 Hz, 1H, H5), 7,71 (dd, J¼8.8, 7.8 Hz, 1H, H3), 7.63 (t,
J¼6.8 Hz,1H, H2), 7.17(dd,J¼8.8,2.9 Hz,1H, H7),6.14(s, 2H, NH2),4.03
4.2.1. Methyl 10-amino-9-phenanthrene-carboxylate (6aa). Method
(a) To a solution of aryl bromide 1a (0.37 mmol) in 2 mL dioxane
were added cyanoboronic ester 5a (0.41 mmol), Pd(PPh3)4
(5 mol %) and Cs2CO3 (1.11 mmol). The mixture was irradiated at
150 ꢀC for 20 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 corre-
sponding phenanthrene 6aa with 80% yield.
(s, 3H, CO2CH3), 3.97 (s, 3H, OCH3).13C NMR (100 MHz, CDCl3)
d170.37
(CO), 155.89, 144.06, 132.10, 128.70, 127.16, 126.94, 126.65, 124.82,
124.75, 123.52, 122.14, 116.49, 104.77, 103.14, 55.46, 51.73; HRMS (EI)
calcd for C17H15NO3, 281.10518, found 281.10598.
4.2.6. Methyl 10-amino-6,7-dimethoxyphenanthrene-9-carboxylate
(6ca). Orange solid; method (a) 76%; mp 139–141 ꢀC; IR (KBr)
n
3450 (NH2), 2917, 2849, 1732 (CO), 1610, 1462, 1376, 1261, 1234,
Method (b) The same procedure was applied to the aryl bromide
12a and the boronic ester 13a to afford the expected phenanthrene
6aa with 85% yield after 25 min.
1079, 967, 799, 759, 720, 699 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d
8.48 (d, J¼8.8 Hz, 1H, H4), 7.92 (d, J¼7.8 Hz, 1H, H1), 7.86 (s, 1H,
H5), 7.83 (s, 1H, H8), 7.69 (t, J¼6.8 Hz, 1H, H3), 7.56 (dd, J¼7.8,
Orange solid; mp 68–70 ꢀC; IR (KBr)
n
3459, 3352 (NH2), 1672
(CO),1597,1431,1302,1225,1149,1092, 742, 730, 717 cmꢁ1; 1H NMR
(400 MHz, CDCl3)
6.8 Hz, 1H, H2), 6.20 (s, 2H, NH2), 4.06 (s, 3H, CO2CH3), 4.05 (s, 3H,
OCH3), 4.01 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3)
d 170.24 (CO),
d
8.64 (d, J¼8.0 Hz, 1H, H4), 8.51 (d, J¼8.0 Hz, 1H,
149.43, 146.55, 144.89, 132.18, 128.74, 125.78, 125.61, 123.43, 123.02,
122.19, 119.59, 106.97, 103.73, 102.70, 55.92, 55.63, 51.65; HRMS (EI)
calcd for C18H17NO4 311.11573, found 311.11661.
H5), 8.26 (d, J¼8.0 Hz, 1H, H8), 7.94 (d, J¼8.0 Hz, 1H, H1), 7.71 (t,
J¼8.0 Hz, 1H, H3), 7.61 (t, J¼8.0 Hz, 1H, H2), 7,53 (t, J¼8.0 Hz, 1H,
H6), 7.40 (t, J¼8.0 Hz, 1H, H7), 6.30 (s, 2H, NH2), 4.04 (s, 3H,
CO2CH3); 13C NMR (100 MHz, CDCl3)
d
169.38 (CO), 144.56, 131.57,
4.2.7. Methyl
(6da). Orange solid, method (a) 72%; method (b) 80%; mp 85–87 ꢀC;
IR (KBr) 3444, 3329 (NH2), 2947, 1668 (CO), 1599, 1581, 1433, 1307,
1225, 1184, 1174, 1095, 1041, 849, 774, 714 cmꢁ1; 1H NMR (400 MHz,
CDCl3)
10-amino-7-methoxyphenanthrene-9-carboxylate
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.
Using method (a) and/or method (b) the following compounds
were prepared according to the time described in Table 1 and Table
2, respectively.
n
d
8.52 (d, J¼7.8 Hz, 1H, H4), 8.41 (d, J¼8,8 Hz, 1H, H5), 7.90 (d,
J¼8.8 Hz,1H, H1), 7.80 (d, J¼2.9 Hz,1H, H8), 7.68 (dd, J¼7.8, 6.8 Hz,1H,
H3), 7.54 (t, J¼7.8 Hz, 1H, H2), 7.03 (dd, J¼8.8, 2.9 Hz, 1H, H6), 6.31 (s,
2H, NH2), 4.03 (s, 3H, CO2CH3), 3.97 (s, 3H, OCH3); 13C NMR (100 MHz,
4.2.2. 10-Amino-9-cyanophenanthrene (7a). White solid; method
CDCl3) d 170.40 (CO), 158.82, 146.56, 132.84, 132.18, 129.10, 125.79,
124.11, 123.07, 123.01, 121.94, 119.62, 112.37, 107.79, 102.20, 55.20,
51.66; HRMS (EI) calcd for C17H15NO3 281.10518, found 281.10568.
(a) 85%; mp 177–179 ꢀC; IR (KBr)
n
3451, 3369 (NH2), 2200 (CN),
1641, 1579, 1499, 1457, 1415, 1249, 746, 719 cmꢁ1 1H NMR
(400 MHz, CDCl3)
;
d
8.67 (d, J¼7.8 Hz, 1H, H4), 8.53 (d, J¼7.8 Hz, 1H,
H5), 8.01 (d, J¼7.8 Hz, 1H, H8), 7.91 (d, J¼7.8 Hz, 1H, H1), 7.80 (t,
J¼7.8 Hz, 1H, H3), 7.68 (dd, J¼7.8, 6.8 Hz, 1H, H2), 7.63 (dd, J¼7.8,
6.8 Hz,1H, H6), 7.50 (t, J¼6.8 Hz,1H, H7), 5.27 (s, 2H, NH2); 13C NMR
4.2.8. Methyl
(6ea). Yellowsolid; method (a) 80%; mp 107–109 ꢀC; IR (KBr)
3462, 3369 (NH2), 2947,1673 (CO),1616,1433,1248,1205, 757 (CCl),
748, 732 cmꢁ1 1H NMR (400 MHz, CDCl3)
10-amino-8-chlorophenanthrene-9-carboxylate
n
(100 MHz, CDCl3)
d
148.17, 132.47, 129.83, 129.73, 128.38, 127.16,
;
d
8.60 (d, J¼7.8 Hz, 1H,
124.83, 124.50, 123.99, 123.72, 122.72, 122.46, 121.74, 117.86, 87.00;
HRMS (EI) calcd for C15H10N2 218.08439, found 218.08534.
H4), 8.43 (d, J¼7.8 Hz, 1H, H5), 7.94 (d, J¼7.8 Hz, 1H, H1), 7.72 (t,
J¼7.8 Hz, 1H, H3), 7.66 (t, J¼7.8 Hz, 1H, H2), 7.44 (d, J¼7.8 Hz, 1H,
H7), 7.34 (t, J¼7.8 Hz, 1H, H6), 5.73 (s, 2H, NH2), 3.92 (s, 3H,
4.2.3. 1-(10-Aminophenanthren-9-yl)ethanone (8a). White solid;
CO2CH3); 13C NMR (100 MHz, CDCl3)
d 170.48 (CO), 143.87, 133.60,
method (a) 73%; mp 142–144 ꢀC; IR (KBr)
n
3427, 3289 (NH2), 1605
(CO), 1551, 1508, 1492, 1421, 1227, 748, 726 cmꢁ1 1H NMR
(400 MHz, CDCl3)
132.86, 132.00, 130.60, 129.40, 129.13, 127.95, 127.54, 124.38, 123.90,
123.80, 122.01, 121.26, 51.16; HRMS (EI) calcd for C16H12NO2Cl
285.05564, found 285.05486.
;
d
8.62 (d, J¼7.8 Hz, 1H, H4), 8.50 (d, J¼7.8 Hz, 1H,
H5), 7.95 (d, J¼7.8 Hz, 1H, H1), 7.75 (d, J¼7.8 Hz, 1H, H8), 7.72 (dd,
J¼7.8, 6.8 Hz, 1H, H3), 7.62 (t, J¼7.8 Hz, 1H, H2), 7.50 (t, J¼6.8 Hz, 1H,
H6), 7.42 (dd, J¼7.8, 6.8 Hz, 1H, H7), 6.62 (s, 2H, NH2)2.66 (s, 3H,
4.2.9. Methyl
10-amino-1-methoxyphenanthrene-9-carboxylate
3461,
(6ab). Yellow solid; method (a) 75%; mp 89–91 ꢀC; IR (KBr)
n

R. Yougnia et al. / Tetrahedron 66 (2010) 2803–2808
2807
3363(NH2), 2942, 1670 (CO), 1588, 1433, 1289, 1254, 1224, 1201,
1086, 1014, 759, 657 cmꢁ1 1H NMR (400 MHz, CDCl3)
8.39 (d,
J¼8.8 Hz, 1H, H5), 8.23 (d, J¼8.8 Hz, 1H, H4), 8.12 (d, J¼7.8 Hz, 1H,
H8), 7.96 (s, 2H, NH2), 7.57 (dd, J¼8.8, 7.8 Hz, 1H, H3), 7.44 (dd,
J¼8.8, 6.8 Hz, 1H, H6), 7.28 (t, J¼6.8 Hz, 1H, H7), 7.03 (d, J¼7.8 Hz,
1H, H2), 4.00 (s, 3H, OCH3), 3.99 (s, 3H, OCH3); 13C NMR (100 MHz,
135.13, 128.91, 126.74, 121.38, 118.33, 116.10, 114.37, 107.15, 106.25,
104.68, 56.30, 55.87, 55.55, 51.32; HRMS (EI) calcd for C19H19NO5
341.12629, found 341.12731.
;
d
4.2.15. Methyl
(6ad). Colourless oil; method (b) 70%; IR (KBr)
2948, 2922, 1711 (CO), 1682, 1615, 1435, 1231, 1090, 769, 749,
726 cmꢁ1 1H NMR (400 MHz, CDCl3)
10-amino-2-methylphenanthrene-9-carboxylate
n
3447, 3373 (NH2),
CDCl3)
d 170.68 (CO), 158.91, 149.02, 135.66, 131.64, 129.12, 127.47,
124.88, 124.24, 123.35, 122.41, 116.57, 115.11, 108.34, 100.11, 56.38,
51.42; HRMS (EI) calcd for C17H15NO3 281.10518, found 281.10505.
;
d
8,53 (d, J¼7.8 Hz, 1H, H4),
8.47 (d, J¼7.8 Hz, 1H, H5), 8.24 (d, J¼7.8 Hz, 1H, H8), 7.72 (s, 1H, H1),
7.54 (d, J¼7.8 Hz, 1H, H3), 7.46 (t, J¼7.8 Hz, 1H, H6), 7.39 (t, J¼7.8 Hz,
4.2.10. Methyl
boxylate (6ac). Yellow solid; method (a) 60%; mp 143–145 ꢀC; IR
(KBr) 3445, 3372 (NH2), 2957, 2921, 1714 (CO), 1687, 1621, 1292,
1159, 1119, 1079, 1000, 774, 752 cmꢁ1 1H NMR (400 MHz, CDCl3)
10-amino-3-(trifluoromethyl)phenanthrene-9-car-
1H, H7), 6.27 (s, 2H, NH2), 4.03 (s, 3H, CO2CH3), 2.58 (s, 3H, CH3); 13
C
NMR (100 MHz, CDCl3) d 170.64 (CO), 154.52, 136.62, 133.85, 133.71,
n
130.62, 130.26, 126.87, 125.50, 125.40, 124.26, 123.47, 123.27, 122.33,
121.74, 51.69, 21.74; HRMS (EI) calcd for C17H15NO2 265.11027,
found 265.10938.
;
d
8.88 (s, 1H, H4), 8.50 (d, J¼8.8 Hz, 1H, H5), 8.23 (d, J¼8.8 Hz, 1H,
H8), 8.03 (d, J¼8.8 Hz, 1H, H1), 7.79 (d, J¼8.8 Hz, 1H, H2), 7.55 (dd,
J¼8.8, 6.8 Hz, 1H, H6), 7.44 (t, J¼6.8 Hz, 1H, H7), 6.17 (s, 2H, NH2),
4.2.16. Methyl
(6ae). Orange solid; method (b) 77%; mp 117–119 ꢀC; IR (KBr)
3444, 3362 (NH2), 2951, 2927, 1684 (CO), 1617, 1433, 1261, 1224,
1040, 826 cmꢁ1; 1H NMR (400 MHz, CDCl3)
10-amino-2-methoxyphenanthrene-9-carboxylate
4.05 (s, 3H, CO2CH3). 13C NMR (100 MHz, CDCl3)
d
170.03 (CO),
n
144.20, 132.84, 132.31, 131.47, 130.9, 128.92, 128.15, 125.70, 124.86,
123.94, 123.00, 122.60, 120.90, 120.85, 104.97, 51.96; HRMS (EI)
calcd for C17H12NO2F3 319.08199, found 319.08265.
d
8.53 (d, J¼8.8 Hz, 1H,
H4), 8.40 (d, J¼7.8 Hz, 1H, H5), 8.21 (d, J¼7.8 Hz, 1H, H8), 7.45 (t,
J¼6.8 Hz, 1H, H6), 7.37 (dd, J¼8.8, 7.8 Hz, 1H, H7), 7.31 (dd, J¼2.9,
8.8 Hz, 1H, H3), 7.25 (d, J¼2.9 Hz, 1H, H1), 6.10 (s, 2H, NH2), 4.03 (s,
4.2.11. 10-Amino-1-methoxyphenanthrene-9-carbonitrile
(7b). Yellow solid; method (a) 87%; mp 220–222 ꢀC; IR (KBr)
n
3H, CO2CH3), 3.95 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
d 170.46
3466, 3350 (NH2), 2944, 2196 (CN), 1621, 1603, 1584, 1575, 1246,
(CO), 158.57, 144.75, 131.96, 130.87, 129.40, 126.68, 126.30, 125.49,
125.16, 123.43, 121.98, 119.16, 118.17, 103.82, 55.48, 51.30; HRMS (EI)
calcd for C17H15NO3 281.10518, found 281.10618.
1170, 1087, 1013, 740 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
8.54 (d,
J¼8.8 Hz, 1H, H5), 8.35 (d, J¼7.8 Hz, 1H, H4), 7.73 (d, J¼8.8 Hz, 1H,
H4), 7.70 (m, 2H, H8, H3), 7.57 (dd, J¼7.8, 6.8 Hz, 1H, H6), 7.36 (t,
J¼7.8 Hz, 1H, H7), 7.32 (s, 2H, NH2), 7.27 (d, J¼8.8 Hz, 1H, H2), 4.03
4.2.17. Methyl 10-amino-2,7-dimethoxyphenanthrene-9-carboxylate
(6de). Orange solid; method (b) 83%; mp 149–151 ꢀC; IR (KBr)
n
(s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6)
d
158.23, 151.21,
134.60, 130.84, 130.66, 128.82, 124.00, 123.31, 123.06, 121.95, 118.29,
116.27, 112.82, 109.30, 81.34, 56.55; HRMS (EI) calcd for C16H12N2O
248.09495, found 248.09389.
3460, 3353 (NH2), 2921, 1669 (CO), 1609, 1576, 1567, 1428, 1246,
1216, 1050, 1038, 1012, 869, 801 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
8.44 (d, J¼9.8 Hz, 1H, H4), 8.32 (d, J¼8.8 Hz, 1H, H5), 7.75 (d,
J¼2.0 Hz, 1H, H8), 7.31 (dd, J¼8.8, 2.0 Hz, 1H, H6), 7.24 (d, J¼2.9 Hz,
1H, H1), 7.01 (dd, J¼9.8, 2.9 Hz, 1H, H3), 6.20 (s, 2H, NH2), 4.04 (s,
3H, CO2CH3), 3.96 (s, 3H, OCH3) 3.92 (s, 3H, OCH3); 13C NMR
4.2.12. 10-Amino-3-(trifluoromethyl)phenanthrene-9-carbonitrile
(7c). Beige solid; method (a) 80%; mp 209–211 ꢀC; IR (KBr)
n
3460,
3365 (NH2), 2948, 2209 (CN), 1652, 1592, 1433, 1311, 1231, 1176,
1166, 1120, 747 cmꢁ1; 1H NMR (400 MHz, CDCl3)
8.91 (s, 1H, H4),
(100 MHz, CDCl3)
d 170.47 (CO), 158.11, 157.89, 145.77, 130.89,
d
127.03, 124.72, 124.30, 123.51, 119.87, 118.50, 112.57, 107.77, 103.70,
103.25, 55.54, 55.23, 51.70; HRMS (EI) calcd for C18H17NO4
311.11573, found 311.11653.
8.52 (d, J¼8.8 Hz, 1H, H5), 8.02 (d, J¼7.8 Hz, 2H, H1, H8), 7.87 (d,
J¼8.8 Hz, 1H, H2), 7.68 (t, J¼6.8 Hz, 1H, H6), 7.52 (dd, J¼8.8, 6.8 Hz,
1H, H7), 6.17 (s, 2H, NH2); 13C NMR (100 MHz, CDCl3)
d 147.27,
132.27, 131.46, 131.13, 130.10, 129.32, 125.25, 124.47, 124.35, 123.12,
123.08, 122.73, 121.20, 121.10, 117.15, 92.40; HRMS (EI) calcd for
C16H9F3N2 286.07177, found 286.07152.
4.3. Ortho-lithiation procedure
4.3.1. 2-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzonitrile (5b). In a dry Schlenk flask under N2 2,2,6,6- tetra-
methylpiperidine (0.12 mmol) was dissolved in dry THF (25 mL)
and the mixture was cooled to ꢁ10 ꢀC before n-BuLi (0.12 mmol)
was added over 2 min. The mixture was stirred for 10 min before
cooling to ꢁ78 ꢀC. At ꢁ78 ꢀC, B(O-i-Pr)3 (0,14 mmol) was added
over 2 min and stirred for 5 min at ꢁ78 ꢀC before the benzonitrile
10b (0.1 mmol) dissolved in dry THF (10 mL) was added drop-wise
over 5 min. The reaction was left in the dry ice bath overnight,
slowly reaching room temperature. The reaction was quenched
with glacial acetic acid (0.14 mmol) followed by addition of pinacol
(0.15 mmol). The mixture was stirred for 1 h at room temperature
and then transferred to a separating funnel with CH2Cl2 (75 mL)
and washed with aqueous KH2PO4 (10 w/v %) (4ꢂ60 mL). The
combined water phase was back-extracted once with CH2Cl2
(15 mL), the combined organic phase was dried over MgSO4, and
the solvents were evaporated to give the crude cyanoarylboronic
4.2.13. Methyl 10-amino-1,6-dimethoxyphenanthrene-9-carboxylate
(6bb). Orange solid; method (a) 65%; mp 98–100 ꢀC; IR (KBr)
n
3491, 3375 (NH2), 3002, 2953, 1657 (CO), 1583, 1563, 1492, 1285,
1263, 1228, 1211, 1174, 1085, 1053, 1022, 817, 750 cmꢁ1 1H NMR
(400 MHz, CDCl3)
;
d
8.14 (d, J¼8.8 Hz, 1H, H4), 8.08 (d, J¼8.8 Hz, 1H,
H8), 7.81 (s, 2H, NH2), 7.80 (d, J¼2.9 Hz, 1H, H5), 7.56 (dd, J¼8.8,
7.8 Hz, 1H, H3), 7.12 (dd, J¼8.8, 2.9 Hz, 1H, H7), 7.02 (d, J¼7.8 Hz, 1H,
H2), 4.02 (s, 3H, CO2CH3), 3.98 (s, 3H, OCH3), 3.94 (s, 3H, OCH3); 13
C
NMR (100 MHz, CDCl3) d 170.58(CO), 158.96, 155.22, 147.60, 135.02,
128.85, 126.47, 125.92, 125.35, 116.82, 116.60, 115.55, 108.43, 105.52,
100.17, 56.36, 55.45, 51.37; HRMS (EI) calcd for C18H17NO4
311.11573, found 311.11700.
4.2.14. Methyl 10-amino-1,6,7-trimethoxyphenanthrene-9-carboxyl-
ate (6cb). Colourless oil; method (a) 63%; IR (KBr)
2924, 2853,1668 (CO),1594, 1517,1464,1376,1261,1164,1088,1024,
789 cmꢁ1 1H NMR (400 MHz, CDCl3)
n 3445 (NH2),
ester as a yellow solid with 98% yield; mp 110–112 ꢀC; IR (KBr)
3003, 2985, 2953, 2225 (CN), 1576, 1455, 1351, 1329, 1275, 1042,
849, 802, 750, 678 cmꢁ1 1H NMR (400 MHz, CDCl3)
7.51 (dd,
n
;
d
8.05 (d, J¼8.8 Hz, 1H, H4),
7.87 (s, 2H, NH2), 7.76 (s, 1H, H5), 7.69 (s, 1H, H8), 7.55 (dd, J¼8.8,
7.8 Hz, 1H, H3), 6.96 (d, J¼7.8 Hz, 1H, H2), 4.04 (s, 3H, CO2CH3), 4.03
(s, 3H, OCH3), 4.00 (s, 3H, OCH3), 3.98 (s, 3H, OCH3). 13C NMR
;
d
J¼7.8, 6.8 Hz, 1H, H4), 7.40 (d, J¼6.8 Hz, 1H, H5), 7.05 (d, J¼7.8 Hz,
1H, H3), 3.90 (s, 3H, OCH3), 1.34 (s, 12H); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d
170.41 (CO), 159.12, 149.68, 148.43, 145.93,
d 161.63, 133.03, 127.31, 115.93, 113.43, 105.95, 84.68, 55.99, 24.70

2808
R. Yougnia et al. / Tetrahedron 66 (2010) 2803–2808
(the quaternary carbon bonded to the boron was missing); HRMS
(EI) calcd for C14H18 BNO3 259.13796, found 259.13719.
1463, 1384, 1352, 1261, 1146, 1113, 1035, 964, 802 cmꢁ1
(400 MHz, CDCl3)
7.77 (d, J¼7.8 Hz, 1H), 6.79 (dd, J¼7.8, 2.9 Hz,
1H), 6.73 (d, J¼2.9 Hz, 1H), 3.95 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 3.66
(s, 3H, OCH3), 1.29 (s, 12H); 13C NMR (100 MHz, CDCl3)
172.69
(CO), 161.78, 142.47, 137.90, 129.95, 116.10, 111.52, 83.27, 55.23,
51.80, 41.20, 21.74.
;
1H NMR
d
4.3.2. 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(tri-
fluoromethyl)benzonitrile (5c). Compound 5c was obtained
according to the same procedure and starting from 10c as a yellow
d
solid with 65% yield; mp 78–80 ꢀC; IR (KBr)
n
2988, 2235 (CN), 1610,
;
1352, 1305, 1176, 1142, 1080, 1064, 849 cmꢁ1
1H NMR (400 MHz,
References and notes
CDCl3)
d
8.14 (d, J¼2.0 Hz, 1H, H5), 7.83 (d, J¼7.8 Hz, 1H, H2), 7.78
(dd, J¼7.8, 2.0 Hz, 1H, H3), 1.40 (s, 12H); 13C NMR (100 MHz, CDCl3)
1. 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.
2. Floyd, A. J.; Dyke, S. F.; Ward, S. E. Chem. Rev. 1976, 76, 509–562.
d
133.73, 132.62, 132.58, 127.82, 127.79, 120.73, 117.69, 85.31, 24.76
(the quaternary carbon bonded to the boron was missing).
3. For
a review of bioactive natural products containing phenanthrene
skeleton see Kova´cs, A.; Vasas, A.; Hohmann, J. Phytochemistry 2008, 69,
1084–1110.
4.4. Boronic ester synthesis
4. (a) Baumgartner, B.; Erdelmeier, C. A. J.; Wright, A. D.; Rali, T.; Sticher, O. Phy-
tochemistry 1990, 29, 3327–3330; (b) Fu¨ rstner, A.; Kennedy, J. W. J. Chem.dEur.
J. 2006, 12, 7398–7410.
5. Kim, S.; Lee, Y. M.; Lee, J.; Lee, T.; Fu, Y.; Song, Y. L.; Cho, J.; Kim, D. J. Org. Chem.
2007, 72, 4886–4891.
6. Yang, X.; Shi, Q.; Liu, Y.; Zhao, G.; Bastow, K. F.; Lin, J.; Yang, S.; Yang, P.; Lee, K.
J. Med. Chem. 2009, 52, 5262–5268 and references cited.
7. (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.
4.4.1. Methyl [2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]
acetate (11a). To a solution of methyl 2-(2-bromophenyl)acetate
(1.09 mmol) in 4.3 mL of dioxane were successively added at rt bis(-
pinacolato)diboron (1.22 mmol) and potassium acetate (4.1 mmol)
The reaction mixture was then flushed twice with argon and
PdCl2(dppf) (0.07 mmol) was then added. The reaction mixture was
heated for 3 h under reflux before being cooled and diluted with Et2O.
The organic phase was washed with H2O and brine and dried
(MgSO4). The crude product was purified by silica gel chromatogra-
phy (CH2Cl2/CyHex 6/4) to afford 11a as colourless oil with 98% yield.
8. Rochais, C.; Yougnia, R.; Dallemagne, P.; Rault, S. Tetrahedron Lett. 2009, 50,
5704–5708.
9. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 759470. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336 033 or e-mail: deposit@
ccdc.cam.ac.uk.
1H NMR (400 MHz, CDCl3)
d
7.83 (d, J¼5.8 Hz, 1H), 7.38 (dd, J¼7.8,
5.8 Hz, 1H), 7.26 (dd, J¼7.8, 6.9 Hz, 1H), 7.18 (d, J¼6.9 Hz, 1H), 3.98 (s,
2H, CH2), 3.66 (s, 3H, OCH3), 1.31 (s, 12H); Other analyses are consis-
tent with the previously described product.14
10. Kristensen, J.; Lysen, M.; Vedso, P.; Begtrup, M. Org. Lett. 2001, 3,
1435–1437.
11. Lysen, M.; Hansen, H. M.; Begtrup, M.; Kristensen, J. L. J. Org. Chem. 2006, 71,
2518–2520.
12. Bouillon, A.; Lancelot, J.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58,
4369–4373.
13. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510.
14. Tsukamoto, H.; Kondo, Y. Org. Lett. 2007, 9, 4227–4230.
4.4.2. Methyl
2-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)acetate (11d). Compound 11d was obtained
according to the same procedure and starting from 11d as colour-
less oil with 85% yield; IR (KBr) n 3444, 2951, 1739 (CO), 1605, 1569,