Selective synthesis of 5,6-dihydrophenanthridines, 5,6-dihydrobenzo[c][1,8] naphthyridines and their fully aromatized analogues via the Pictet-Spengler reaction mediated by peptide coupling agent propylphosphonic anhydride (T3P)

Article abstract of DOI:10.1016/j.tetlet.2012.09.034

A new method has been developed for the selective synthesis of 5,6-dihydrophenanthridines, 5,6-dihydrobenzo[ c][1,8]naphthyridines and their fully aromatized analogues via the Pictet-Spengler reaction mediated by propylphosphonic anhydride (T3P). The method, which uses less toxic and readily available T3P, generally seems to be more flexible, efficient in the preparation of 5,6-dihydrophenanthridine derivatives and complementary to conventional routes in the preparation of fused pyridines.

Full text of DOI:10.1016/j.tetlet.2012.09.034

Tetrahedron Letters 53 (2012) 6280–6287
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective synthesis of 5,6-dihydrophenanthridines,
5,6-dihydrobenzo[c][1,8]naphthyridines and their fully aromatized
analogues via the Pictet–Spengler reaction mediated by peptide coupling agent
propylphosphonic anhydride (T3P)
John Kallikat Augustine a, , Agnes Bombrun b, Padma Alagarsamy a, Anandh Jothi a
⇑
a Syngene International Ltd, Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India
b Merck Serono SA, 9 Chemin des Mines, 1202 Geneva, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2012
Revised 7 September 2012
Accepted 8 September 2012
Available online 16 September 2012
A new method has been developed for the selective synthesis of 5,6-dihydrophenanthridines, 5,6-dihy-
drobenzo[c][1,8]naphthyridines and their fully aromatized analogues via the Pictet–Spengler reaction
mediated by propylphosphonic anhydride (T3P). The method, which uses less toxic and readily available
T3P, generally seems to be more flexible, efficient in the preparation of 5,6-dihydrophenanthridine deriv-
atives and complementary to conventional routes in the preparation of fused pyridines.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dihydrophenanthridine
Dihydrobenzo[c][1,8]naphthyridine
Phenanthridine
Propylphosphonic anhydride (T3P)
Pictet–Spengler reaction
Phenanthridines and their aza and benzo analogues are fused
isoquinolines, found throughout the plant kingdom, possessing a
broad range of biological properties.1 Many phenanthridines exhi-
bit antileukemic and antiviral activities.2 They have been found in
the metabolites of plant families and their ring system is present
in many synthetic dye-stuffs.3 Benzophenanthridine derivatives
that possess significant topoisomerase I (TOP1)-targeting activity
have been identified.4 A recent study has shown that a class of
5,6-dihydrophenanthridine derivatives possess high affinity for
bradykinin B1 receptors and selectivity over bradykinin B2
receptors, making them useful in the treatment or prevention of
painful and inflammatory processes.5 Besides naturally occurring
phenanthridine alkaloids, there is a continuous demand for diver-
sity of aromatic substitution to optimize the structure activity
relationship (SAR) of novel phenanthridines as high-affinity
ligands particularly in the field of medicinal chemistry. While
traditional protocols for the preparation of phenanthridine
derivatives relied extensively on Bischler–Napieralski cyclization
methods,6 strategies involving radical,7 photochemical,8 one-pot
cascade,9 iodine-induced,10 benzyne-mediated,11 microwave-
assisted,7b,12 transition-metal-catalysed13 and the modified
Pictet–Spengler syntheses14 of the phenanthridine skeleton have
been reported.
In an ongoing project we were interested in optimizing a
common preparation of substituted ethyl-7,9-dimethoxy-5,
6-dihydrophenanthridine-6-carboxylates and ethyl-7,9-dime-
thoxy-5,6-dihydrobenzo[c][1,8]naphthyridine-6-carboxylates (3,
Scheme 1). However, methods directly leading to 5,6-dihydrophe-
nanthridines and 5,6-dihydrobenzonaphthyridines are less com-
mon, and there remain many limitations such as multistep
synthetic reactions, and limited functional group tolerance.11a,15
The Pictet–Spengler strategy although quite robust in the C–N
bond formation, leads directly to fully aromatized phenanthridines
owing to in situ oxidation of dihydrophenanthridines.12b,14 There-
fore, the development of general and convenient processes using
readily accessible reagents for the selective synthesis of 5,6-
dihydrophenanthridine ring system is imperative. Accordingly we
decided to optimize the Pictet–Spengler methodology (Scheme 1)
involving endo cyclization on aryl amine substrates attached to
sufficiently activated 3,5-dimethoxyphenyl ring (1) to produce
the desired 5,6-dihydrophenanthridines (3).
Syntheses of substrates (1a–h, Table 2) suitable for cationic
-cyclization were carried out via the Suzuki coupling of 3,5-
⇑
Corresponding author. Tel.: +91 80 2808 3131; fax: +91 80 2808 3150.
E-mail addresses: john.kallikat@syngeneintl.com, john.kallikat@gmail.com
p
dimethoxybenzeneboronic acid with variety of substituted
a
(J.K. Augustine).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.034

J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 6280–6287
6281
OMe
OMe
Pictet-Spengler
R
Suzuki
Br
OMe
O
OMe
R
R
X
N
X
NH2
X
NH2
H
3
O
1
X= C, N
Scheme 1. Synthetic approach to 5,6-dihydrophenanthridines-6-carboxylates.
Table 1
Screening optimum conditions for cyclization
MeO
OMe
OHC
MeO
OMe
N
MeO
COOEt
OMe
MeO
COOEt
2a
OMe
COOEt
N
NH
NH2
+
+
Reagent
4b
3a
4a
1a
a
Entry
Reagent (1.0 equiv)
Time (h)
Temp (°C)
Yield %
3a
4a
4b
1b
2b
3c
p-TsOH
p-TsOH
AcOH
CF3COOH
MeSO3H
CF3SO3H
T3P
6
5
8
8
6
5
8
10
10
25
100
60
25
25
0
25
50
65
—
—
—
—
—
—
92
78
—
9
—
17
—
12
17
7
—
—
—
24
19
61
19
66
—
4d
5d
6d
7e
8e,f
9g,e
T3P
T3P
—
92
a
b
c
d
e
f
All the reactions were performed under nitrogen atmosphere except entry 9.
Reaction was performed in toluene.
Reaction was performed in ethanol.
Reaction was performed in 1,2-dichloromethane.
Reaction was performed in EtOAc.
0.5 equiv of T3P were used.
g
Reaction was performed under oxygen atmosphere.
2-haloaryl amines as shown in Scheme 1.16 To access the
5,6-dihydrophenanthridine-6-carboxylate (3a), substrate 1a was
treated with a fairly sensitive aldehyde 2a (1.0 equiv, 50% soln in
toluene) under traditional Pictet–Spengler conditions in the pres-
ence of p-TsOH in toluene at room temperature under nitrogen
atmosphere (Table 1, entry 1). After 6 h of reaction, however, the
fully aromatized product (4a) was isolated in 9% yield and there
was no trace of 3a in the reaction mass. Heating the reaction mix-
ture for 5 h at 100 °C gave a mixture of 4a and the decarboxylated
product 4b (Table 1, entry 2). The reaction was then screened at
temperatures between 0 and 60 °C against other traditional acids
such as AcOH (Table 1, entry 3), CF3COOH (Table 1, entry 4),
methanesulfonic acid (Table 1, entry 5) and triflic acid (Table 1, en-
try 6). To our surprise, all these protocols failed to produce the
dihydrophenanthridine 3a, but directly gave 4a and/or 4b.
At this point we decided to screen propylphosphonic anhydride
(T3P), a popular coupling reagent generally used for amide synthe-
sis17 but has found handy in many other transformations in the re-
cent years.18 It was pleasing to note that the required product 3a
was exclusively isolated in 92% yield after 8 h of reaction at room
temperature in the presence of T3P (1.0 equiv, 50% soln in EtOAc)
in EtOAc under nitrogen atmosphere (Table 1, entry 7). The above
conditions were most suitable for the transformation as an incom-
plete reaction was observed even after 10 h of heating at 50 °C in
the presence of 0.5 equiv of T3P (Table 1, entry 8). Further, it is
noteworthy that the exclusive synthesis of 4a could be achieved
by performing the reaction under oxygen atmosphere (Table 1,
entry 9).19 Likewise, the formation of 4a or 4b was not observed
under any of the reaction conditions involving T3P.
After successfully establishing the optimal conditions for 3a,
substrates 1b–h were subjected to T3P mediated Pictet–Spengler
reaction with ethyl glyoxalate (2a) to give ethyl-7,9-dimethoxy-
5,6-dihydrophenanthridine-6-carboxylates (Table 2, entries 2–6)
and ethyl-7,9-dimethoxy-5,6-dihydrobenzo[c][1,8]naphthyridine-
6-carboxylates (Table 2, entries 7 and 8) in moderate to good
yields. Besides functional group tolerance, as shown in Table 2,
the method was equally effective for N-substituted substrate 1i
giving 3i in excellent yield (Table 2, entry 9). In all cases, the crude
products obtained after workup were purified over silica column
chromatography.
The extent of the reaction was further explored by performing
the reaction between a heterocyclic substrate 1h with diverse alde-
hydes and ketones (2b–q) in the presence T3P and the results are
summarized in Table 3. As observed from Table 3, various aliphatic
aldehydes (Table 3, entries 1–3), aromatic/heteroaromatic alde-
hydes (Table 3, entries 4–10) and ketones (Table 3, entries 11–
16) reacted smoothly with 1h in EtOAc at 65 °C and produced a
range of dihydrobenzonaphthyridine derivatives. Contrary to the
optimized conditions for ethyl glyoxalate (2a), heating for 6–10 h
was essential to drive the reaction to completion for all carbonyl
compounds listed in Table 3. It is notable that the cyclic ketones
underwent smooth reaction and gave the respective spiro-phenan-
thridine derivatives in excellent yields (Table 3, entries 13–15).
Also, the reaction conditions were sufficiently mild to tolerate an

6282
J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 6280–6287
Table 2
T3P mediated 5,6-dihydrophenanthridine synthesis
OMe
OMe
O
OHC
OMe
2aO
OMe
O
R
R
N
R1
NH
R1
T3P, EtOAc, 25 oC
3a-i
O
1a-i
Entry
Substrate
Product
Yielda (%)
O
O
O
O
1
92
COOEt
NH2
N
H
3a
1a
O
O
O
O
COOEt
2
3
4
5
6
7
93
87
89
93
86
82
NH2
N
H
1b
1c
3b
O
O
F
F
F
F
F
F
O
F
F
O
COOEt
NH2
N
H
3c
O
O
F
F
O
O
O
O
COOEt
F
F
NH2
N
H
1d
3d
O
O
F
F
O
O
COOEt
NH2
N
H
F
F
1e
3e
O
O
O
O
COOEt
O2N
NH2
O2N
N
H
1f
3f
O
O
O
O
N
NH2
N
N
COOEt
H
1g
3g

J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 6280–6287
6283
Table 2 (continued)
Entry
Substrate
Product
Yielda (%)
O
O
O
O
O
O
O
O
8
9
84
96
N
NH2
N
O
N
H
COOEt
1h
3h
O
O
O
COOEt
NH
N
1i
3i
a
Isolated yields.
Table 3
5,6-Dihydrobenzo[c][1,8]naphthyridine synthesis
OMe
OMe
MeOOC
MeOOC
R2
R1
OMe
OMe
T3P
R2
O
+
N
NH2
1h
N
N
H
3j-y
EtOAc, 65 oC
R1
2b-q
O
O
MeOOC
MeOOC
O
N
N
H
3j
2b
O
O
CHO
N
N
N
H
2c
3k
O
CHO
MeOOC
N
H
2d
3l
O
O
CHO
MeOOC
MeOOC
O
O
N
N
N
H
2e
3m
Cl
CHO
N
H
3n Cl
2f
(continued on next page)

6284
J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 6280–6287
Table 3 (continued)
O
CHO
MeOOC
MeOOC
O
O
NC
N
N
N
H
2g
2h
CN
3o
O
O
CHO
N
H
3p
Br
N
CHO
MeOOC
O
N
N
H
2i
N
3q
Br
O
O
O
S
CHO
MeOOC
MeOOC
MeOOC
O
S
N
N
N
N
H
3r
2j
O
CHO
O
O
N
H
3s
2k
O
O
O
N
H
3t
2l
O
O
MeOOC
N
N
H
2m
3u
O
O
O
MeOOC
MeOOC
O
N
N
N
H
2n
3v
O
O
O
O
N
H
3w
2o

J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 6280–6287
6285
Table 3 (continued)
O
MeOOC
O
N
O
N
boc
N
N
H
2p
boc
3x
O
O
MeOOC
MeOOC
O
N
N
O
O
3y
COOEt
2q
O
N
N
H
3z
COOEt
a
Isolated yields.
b
Reaction took 23 h for completion and gave a mixture of 3y and 3z.
acid sensitive group (Table 3, entry 15) that can serve as handle for
further extension of the phenanthridine products. Ethyl levulinate
(2q), under the reaction conditions, gave a mixture of dihydro-
benzo[c]pyrrolo[1,2-a][1,8]naphthyridin-11-one (3y) and the Pic-
tet–Spengler product (3z) in 43% and 51% yields respectively.
Table 4
T3P mediated phenanthridine synthesis
OMe
OMe
R
CHO
Me
Me
OMe
OMe
T3P, EtOAc
N
R
NH2
O2 balloon
65 oC
1b
4c-j
Entry
Aldehyde
Product
Yielda (%)
O
O
CHO
O
2a
Me
O
1
87
COOEt
N
4c
CHO
O
O
2c
Me
Me
O
2
91
N
4d
Br
N
CHO
2i
O
3
88
N
N
4e
Br
(continued on next page)

6286
J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 6280–6287
Table 4 (continued)
Entry
Aldehyde
Product
Yielda (%)
S
O
Br
CHO
Me
2r
O
O
4
5
6
7
94
N
Br
S
4f
O
N
N
CHO
Me
2s
83
95
93
91
N
N
N
4g
CHO
O
F
Me
Me
Me
O
O
O
2t
N
F
4h
CHO
O
MeOOC
2u
N
COOMe
4i
Cl
O
CHO
8
2f
N
Cl
4j
a
Isolated yields.
Protocols allowing for efficient aromatization of the heterocycle
were then explored. The optimized conditions (Table 1, entry 9) for
obtaining fully aromatized heterocycle were generalized by reacting
substrate 1b with a variety of aldehydes in the presence T3P
(1.0 equiv) at 65 °C under oxygen atmosphere and the results are
depicted in Table 4. As summarized in Table 4, various aliphatic,
aromatic and heterocyclic aldehydes reacted smoothly with 1b to
produce a range of phenanthridine derivatives (Table 4, entries
1–8), albeit, 10–12 h of heating was necessary for optimal
conversion.
Table 5
Screening electronic parameters of the amine
R1
R1
R2
R2
R3
OHC
Br
R3
T3P, EtOAc
NH2
N
O2, 65 oC, 8-17 h
1
4k-n
Br
Next, in an attempt to probe the electronic requirements of
T3P mediated phenanthridine synthesis, substrates with varied
electron densities (Table 5, entries 1–4) were reacted with 4-
bromobenzaldehyde in the presence of T3P at 65 °C under oxygen
atmosphere. While substrates 1a and 1j gave the respective phe-
nanthridines in excellent yields within 8 h of reaction (Table 5,
entries 1 and 2), 17 h of heating was required for 1k to produce
4m regioselectively in 87% yield. However, substrate 1l failed to
produce the desired phenanthridine (4n) even after prolonged
heating. These results reveal that the reaction is limited to elec-
tron rich substrates.
Entry
Substrate
R1
R2
R3
Product
Yield (%)
1
2
3
4
1a
1j
1k
1l
OMe
OMe
OMe
H
H
OMe
H
OMe
OMe
H
4k
4l
4m
4n
95
96
87a
0b
H
H
a
Exclusive formation of 4m was observed.
Reaction did not proceed beyond imine formation.
b
A likely involvement of T3P during the initiation of reaction
between amine (1) and carbonyl partner (2) enhances the rate of
formation of Schiff’s base.18k The ‘open’ hydrated T3P produced
during the process activates the imine towards cyclization
leading to dihydrophenanthridines 3 (see, Supplementary data
Scheme 2). When the carbonyl partner is an aldehyde, prolonged
heating in the presence of oxygen leads to fully aromatized
phenanthridines 4.
In conclusion, a new method has been developed for the selec-
tive synthesis of 5,6-dihydrophenanthridines, 5,6-dihydrobenzo

J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 6280–6287
6287
[c][1,8]naphthyridines20,21 and their fully aromatized analogues22
via the T3P mediated Pictet–Spengler reaction. The method, which
uses less toxic and readily available T3P, generally seems to be
more flexible, efficient in the preparation of 5,6-dihydrophenan-
thridine derivatives and complementary to conventional routes
in the preparation of fused pyridines.
Melanie, F.; Schmitz, K.; Lender, A. Tetrahedron Lett. 2007, 48, 1421; (d)
Crawforth, J. M.; Paoletti, M. Tetrahedron Lett. 2009, 50, 4916; (e) Augustine, J.
K.; Atta, R. N.; Ramappa, B. K.; Boodappa, C. Synlett 2009, 3378; (f) Augustine, J.
K.; Vairaperumal, V.; Narasimhan, S.; Alagarsamy, P.; Radhakrishnan, A.
Tetrahedron 2009, 65, 9989; (g) Vasantha, B.; Hemantha, H. P.; Sureshbabu,
V. V. Synthesis 2010, 2990; (h) Augustine, J. K.; Kumar, R.; Bombrun, A.; Mandal,
A. B. Tetrahedron Lett. 2011, 52, 1074; (i) Augustine, J. K.; Bombrun, A.; Mandal,
A. B.; Alagarsamy, P.; Atta, R. N.; Selvam, P. Synthesis 2011, 1477; (j) Desroses,
M.; Wieckowski, K.; Stevens, M.; Odell, L. R. Tetrahedron Lett. 2011, 52, 4417;
(k) Augustine, J. K.; Bombrun, A.; Venkatachaliah, S. Tetrahedron Lett. 2011, 52,
6814; (l) Augustine, J. K.; Bombrun, A.; Ramappa, B.; Boodappa, C. Tetrahedron
Lett. 2012, 53, 4422; (m) Augustine, J. K.; Bombrun, A.; Vijaykumar, P.
Tetrahedron Lett. 2012, 53, 5030.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
09.034.
19. Although aromatization was observed while allowing the reaction mixture
open to air for longer hours, maintaining a balloon of oxygen allowed a clean
and more rapid reaction.
20. Representative procedure for the T3P mediated synthesis of Ethyl-5,6-
dihydrophenanthridine-6-carboxylates (3a–i): To
a
mixture of 30,50-
References and notes
dimethoxy-5-(trifluoromethoxy)biphenyl-2-amine (1d) (1.0 g, 0.003 mol) and
ethyl glyoxalate (2a) (0.65 g, 0.003 mol, 50% soln in toluene) in EtOAc (10 mL)
was added T3P (2.02 g, 0.003 mol, 50% soln in EtOAc). The resulting reaction
mixture was stirred at room temperature for 8 h under nitrogen atmosphere.
When the reaction was completed as confirmed by TLC, the mixture was
diluted with water and extracted with ethyl acetate (2 ꢀ 25 mL). The combined
organic phase was washed with saturated NaHCO3 solution (1 ꢀ 20 mL) and
brine. The organic phase was dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The crude product was passed through a small plug of
1. (a) Shamma, M. In The Isoquinoline Alkaloids: Chemistry and Pharmacology;
Academic Press, 1972; (b) Simánek, V. In The Alkaloids. Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: Orlando, 1985; Vol. 26, p 229;
(c) Keene, B. R. T.; Tissington, P. Adv. Heterocycl. Chem. 1971, 13, 315.
2. Taira, Z.; Matsumoto, M.; Ishida, S.; Icikawa, T.; Sakiya, Y. Chem. Pharm. Bull.
1994, 42, 1556.
3. (a) Zimmermann, H. W. Angew. Chem., Int. Ed. Engl. 1986, 25, 115; (b) Martin, S.
F. In The Alkaloids. Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, p 251.
4. Li, D.; Makhey, D. B.; Zhao, B.; Sim, S.-P.; Liu, A.; Li, L. F.; LaVoie, E. J. Proc. Am.
Assoc. Cancer Res. 2001, 42, 720.
5. Éles, J.; Beke, G.; Vágó, I.; Bozó, E.; Huszár, J.; Tarcsay, A.; Kolok, S.; Schmidt, E.;
Vastag, M.; Hornok, K.; Farkas, S.; Domány, G.; Keseru, G. M. Bioorg. Med. Chem.
Lett. 2012, 22, 3095.
6. (a) Mamalis, P.; Petrow, V. J. Chem. Soc. 1950, 703; (b) Buuï-Ho, N. P.; Jaquignon,
P.; Long, C. T. J. Chem. Soc. 1957, 505; (c) Bartram, C. A.; Harrison, D.; Short, W. F.
J. Chem. Soc. 1958, 1158; (d) Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med.
Chem. 1988, 31, 774.
7. (a) Leardini, R.; Tundo, A.; Zanardi, G.; Pedulli, G. F. Synthesis 1985, 107; (b)
Katrizky, A. L.; Yang, B. J. Heterocycl. Chem. 1996, 33, 607; (c) Rosa, A. M.; Lobo,
A. M.; Branco, S. P.; Pereira, A. M. D. L. Tetrahedron 1997, 53, 269; (d) Nakanishi,
T.; Suzuki, M.; Mashiba, A.; Ishikawa, K.; Yokotsuka, T. J. Org. Chem. 1998, 63,
silica
to
afford
ethyl-7,9-dimethoxy-2-(trifluoromethoxy)-5,6-
dihydrophenanthridine-6-carboxylate (3d) as pale yellow solid: Yield 1.12 g
(89%); mp 107.2–109 °C; IR (KBr): 3351, 1716, 1606, 1131 cmꢁ1; MS (ESI-APCI,
positive mode) 398 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): dH = 7.70 (d,
J = 2.2 Hz, 1H), 7.04-7.01 (dd, J = 8.7, 1.4 Hz, 1H), 6.94-6.91 (m, 2H), 6.80 (d,
J = 8.7 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 5.16 (d, J = 1.2 Hz, 1H), 3.98-3.89 (q, 2H),
3.84 (s, 3H), 3.79 (s, 3H), 1.03 (t, 3H); 13C NMR (DMSO-d6, 400 MHz): dC = 171.6,
160.4, 156.8, 143.6, 139.9, 131.7, 121.9, 120.0, 117.0, 115.4, 111.4, 99.0, 98.4,
60.3, 55.8, 55.5, 51.0, 13.9.
21. Representative procedure for the T3P mediated synthesis of 5,6-dihydro-
benzonaphthyridines (3j-z): To
a
mixture of methyl-6-amino-5-(3,
5-dimethoxyphenyl)nicotinate (1h) (1.0 g, 0.003 mol) and tetrahydropyran-4-
one (2o) (0.35 g, 0.003 mol) in EtOAc (10 mL) was added T3P (2.22 g,
0.003 mol, 50% soln in EtOAc). The resulting reaction mixture was stirred at
65 °C for 7 h under nitrogen atmosphere. When the reaction was completed as
confirmed by TLC, the mixture was diluted with water and extracted with ethyl
acetate (2 ꢀ 25 mL). The combined organic phase was washed with saturated
NaHCO3 solution (1 ꢀ 20 mL) and brine. The organic phase was dried over
anhydrous Na2SO4 and evaporated under reduced pressure. The crude product
was passed through a small plug of silica to afford 1.2 g (94%) of methyl-7,9-
dimethoxy-20,30,5060-tetrahydro-5H-spiro[benzo[c][1,8]naphthyridine-6,40-
pyran]-2-carboxylate (3w) as white solid: mp 215.1–216.7 °C; IR (KBr): 3381,
1701, 1609, 1237 cmꢁ1; MS (ESI-APCI, positive mode) 371 [M+H]+; 1H NMR
(DMSO-d6, 400 MHz): dH = 8.49 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 6.98 (d,
J = 1.4 Hz, 1H), 6.62 (d, J = 1.2 Hz, 1H), 3.99–3.93 (m, 2H), 3.85 (s, 3H), 3.83 (s,
3H), 3.80 (s, 3H), 3.66-3.62 (m, 2H), 2.82–2.74 (m, 2H), 1.52-1.49 (m, 2H); 13C
NMR (DMSO-d6, 400 MHz): dC = 165.5, 159.7, 157.7, 156.1, 150.6, 130.5, 130.1,
118.5, 114.4, 111.6, 100.4, 98.8, 61.4, 55.7, 55.3, 54.3, 51.5, 36.2.
´
4235; (e) Buden, M. E.; Dorn, V. B.; Gamba, M.; Pierini, A. B.; Rossi, R. A. J. Org.
Chem. 2010, 75, 2206.
8. (a) Kessar, S. V.; Grupta, Y. P.; Dhingra, K.; Sharma, G. S.; Narula, S. Tetrahedron
Lett. 1977, 18, 1459; (b) Alonso, R.; Campos, P. J.; Garcia´, B.; Rodrig´uez, M. A.
Org. Lett. 2006, 8, 3521.
9. (a) Wang-Ge, S.; Yun-Yun, Y.; Yan-Guang, W. J. Org. Chem. 2006, 71, 9241; (b)
Youn, S. W.; Bihn, J. H. Tetrahedron Lett. 2009, 50, 4598.
10. Moreno, I.; Tellitu, I.; Etayo, J.; SanMartin, R.; Dominguez, E. Tetrahedron 2001,
57, 5403.
11. (a) Kessar, S. V.; Gopal, R.; Singh, M. Tetrahedron 1973, 29, 167; (b) Nakanishi,
T.; Suzuki, M. Org. Lett. 1999, 1, 985; (c) Pawlas, J.; Begtrup, M. Org. Lett. 2002, 4,
2687; (d) Sanz, R.; Ferna´ndez, Y.; Castroviejo, M. P.; Pe´rez, A.; Fan~ana´s, F. J.
Eur. J. Org. Chem. 2007, 8, 62.
´
´
12. (a) Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008, 6, 263; (b)
Kohno, K.; Azuma, S.; Choshi, T.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2009,
50, 590.
22. Representative procedure for the T3P mediated synthesis of phenanthridines
(4c–m): To
a
mixture of 30,50-dimethoxy-5-methylbiphenyl-2-amine (1b)
(1.0 g, 0.004 mol) and 4-bromo thiophene-2-carboxaldehyde (2r) (0.78 g,
0.004 mol) in EtOAc (10 mL) was added T3P (2.6 g, 0.004 mol, 50% soln in
EtOAc). The resulting reaction mixture was stirred at 65 °C for 11 h under
oxygen balloon. When the reaction was completed as confirmed by LCMS, the
mixture was diluted with water and extracted with ethyl acetate (2 ꢀ 25 mL).
The combined organic phase was washed with saturated NaHCO3 solution
(1 ꢀ 20 mL) and brine. The organic phase was dried over anhydrous Na2SO4
and evaporated under reduced pressure. The crude product was recrystallized
with acetonitrile to afford 1.59 g (94%) of 6-(4-bromothiophen-2-yl)-7,9-
dimethoxy-2-methylphenanthridine (4f) as white solid: mp 139.4–141 °C; IR
(KBr): 2361, 2336, 1607, 1345, 1197 cmꢁ1; MS (ESI-APCI, positive mode) 416
[M+2]+; 1H NMR (CDCl3, 400 MHz): dH = 8.19 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H),
7.55–7.53 (m, 2H), 7.28 (t, J = 1.4 Hz, 1H), 7.13 (d, J = 1.4 Hz, 1H), 6.63 (d,
J = 2.2 Hz, 1H), 4.05 (s, 3H), 3.73 (s, 3H), 2.62 (s, 3H); 13C NMR (CDCl3,
400 MHz): dC = 162.2, 158.9, 149.2, 141.8, 137.1, 136.8, 131.0, 129.7, 129.5,
122.9, 122.3, 121.8, 112.0, 108.4, 99.4, 94.9, 55.6, 55.4, 22.0.
13. (a) Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett. 1988, 29, 5463; (b) Hilt, G.;
Hess, W.; Schmidt, F. Eur. J. Org. Chem. 2005, 2526; (c) Luo, Y.; Mei, Y.; Zhang, J.;
Lua, W.; Tang, J. Tetrahedron 2006, 62, 9131; (d) Shabashov, D.; Daugulis, O. J.
Org. Chem. 2007, 72, 7720; (e) Donaldson, L. R.; Haigh, D.; Hulme, A. N.
Tetrahedron 2008, 64, 4468; (f) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2010, 12,
3682; (g) Peng, J.; Chen, T.; Chen, C.; Li, B. J. Org. Chem. 2011, 76, 9507.
14. Mandadapu, A. K.; Saifuddin, M.; Agarwal, P. K.; Kundu, B. Org. Biomol. Chem.
2009, 7, 2796.
15. Meseroll, L. M. N.; McKee, J. R.; Zanger, M. Synth. Commun. 2011, 41, 2557.
16. Reagents and conditions for Suzuki coupling: PdCl2(PPh3)2, Na2CO3, 70 °C,
DMF, 2 h.
17. (a) Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed. Engl. 1980, 19, 133; (b)
Escher, R.; Bünning, P. Angew. Chem., Int. Ed. Engl. 1986, 25, 277; (c)
LlanesGarcía, A. L. Synlett 2007, 1328; (d) Schwarz, M. Synlett 2000, 1369.
18. (a) Meudt, A.; Scherer, S.; Nerdinger, S. PCT Int. Appl. WO 2005070879, 2005;
Chem. Abstr. 2005, 143, 172649.; (b) Meudt, A., Scherer, S., Böhm, C. PCT Int.
Appl. WO 2005123632, 2005; Chem. Abstr. 2005, 144, 69544.; (c) Zumpe, F. L.;