Synthesis of azaphenanthridines via anionic ring closure

Article abstract of DOI:10.1016/j.tet.2005.08.051

A new and convergent synthesis of azaphenanthridines via an anionic ring closure is reported. Ortho-lithiation/in situ borylation of cyanopyridines produces the corresponding cyanopyridylboronic esters, which undergo a Suzuki-Miyaura cross-coupling to giv

Full text of DOI:10.1016/j.tet.2005.08.051

Tetrahedron 61 (2005) 9955–9960
Synthesis of azaphenanthridines via anionic ring closure
*
´
Henriette M. Hansen, Morten Lysen, Mikael Begtrup and Jesper L. Kristensen
Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark
Received 13 June 2005; revised 25 July 2005; accepted 11 August 2005
Available online 29 August 2005
Abstract—A new and convergent synthesis of azaphenanthridines via an anionic ring closure is reported. Ortho-lithiation/in situ borylation
of cyanopyridines produces the corresponding cyanopyridylboronic esters, which undergo a Suzuki–Miyaura cross-coupling to give the key
intermediates. Addition of lithium morpholide produces the azaphenanthridines.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Substituted azaphenanthridines have a broad spectrum of
biological activities, including antimalarial2a–c and
analgesic activity.2d Furthermore, the 8-azaphenanthridine
ring system in 3c is the backbone of the pyridoacridine
alkaloids,2e which exhibit anti-bacterial, anti-viral, anti-
cancer activity,2f thus, a short and convergent approach to
these ring systems would be highly desirable. Numerous
different approaches to azaphenanthridines have been
reported in the litterature,3 but all lack the flexibility to
produce all the targeted isomers in this study.
We have previously reported a convergent synthetic
protocol for the synthesis of 6-substituted phenanthridines
(2) from biaryl 1 (see Scheme 1).1 The reaction proceeds via
attack of a lithiated species on the cyanogroup in 1 followed
by intramolecular nucleophilic aromatic substitution of the
fluorine.
2. Results and discussion
The retrosynthetic strategy is exemplified for the synthesis
of 3a from biaryl 4a, which in turn should be accessible
from commercially available 2-chloronicotinonitrile (5a)
via a Suzuki–Miyaura cross-coupling4 (see Scheme 2).
Scheme 1. Synthesis of 6-substituted phenanthridines via anionic ring
closure.1
We were interested in expanding the scope of our approach
to the synthesis of heterocyclic phenanthridine derivatives,
and set out to investigate whether it would be possible to
synthesize the four isomeric 6-morpholinoaza-phenanthri-
dines 3a–d shown in Figure 1 using this strategy.
Scheme 2. Retrosynthetic analysis of 3a.
Indeed, coupling of 5a with the depicted 2-fluorophenyl-
boronic ester5 gave biaryl 4a in 95% isolated yield (see
Scheme 3).
Figure 1. Targeted azaphenathridines. RZmorpholine.
Keywords: Pyridines; Lithiation; Anionic ring closure.
With the desired biaryl in hand we were ready to test the
proposed ring closure. Treating 4a with lithium morpholide
at reflux yielded a 37:63 mixture of the desired azaphenan-
thridine 3a together with 6 resulting from nucleophilic
*
Corresponding author. Tel.: C45 35306487; fax: C45 35306040;
e-mail: jekr@dfuni.dk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.051

9956
H. M. Hansen et al. / Tetrahedron 61 (2005) 9955–9960
sequence of cyanopyridines.9 Submitting 2-, 3- and
4-cyanopyridine to our standard conditions for in situ
trapping with LiTMP/B(OiPr)3 produced the desired
cyanopyridylboronic esters 5b–d in 52–94% isolated yield
(see Scheme 5). In all cases, GC–MS of the crude material
showed full conversion to the desired cyanopyridylboronic
esters.
Scheme 3. Synthesis of 4a.
Scheme 4. Addition of lithium morpholide to 4a.
aromatic substitution of fluorine by lithium morpholide6
(see Scheme 4, entry 1).
Scheme 5. Synthesis of cyanopyridylboronic esters 5b–d.
We speculated that coordination of lithium morpholide to
the pyridine nitrogen was a prerequisite for the direct
nucleophilic substitution as seen in the work by Meyers and
co-workers on nucleophilic aromatic substitution on
2-fluoro-aryloxazolines.7 If this coordination could be
impeded, perhaps the ratio between 3a and 6 would
increase. Repeating the experiment with 2 equiv of
DMPU8 did improve the ratio (see Scheme 4, entry 2) and
5 equiv of DMPU accentuated the effect even more to give a
83:17 mixture of 3a and 6 (see Scheme 4, entry 3).
Increasing the amount of DMPU did not influence the ratio
further and let to a decrease in conversion. LiCl was tried as
additive in an attempt to pre-complex the pyridine nitrogen,
preventing lithium morpholide from coordinating, and the
result was remarkable (see Scheme 4, entry 4). With 5 equiv
of LiCl the desired product was the only detectable species,
and 3a was obtained in 84% isolated yield.
2.2. Cross-coupling of cyanopyridylboronic esters
With the desired cyanopyridyl boronic esters in hand we set
out to synthesize biaryls 4b–d.
Suzuki–Miyaura coupling of pyridylboronic acids or esters
is notoriously difficult as these derivatives are prone to
deborylation.10 Indeed, under standard Suzuki–Miyaura
cross-coupling conditions we observed extensive deboryl-
ation, and the parent cyanopyridines were isolated as the
main product with only traces of the desired biaryls.
Therefore, a range of conditions and additives were tested
in order to optimize the coupling. After extensive
Having established that the proposed synthetic route to
azaphenanthridines was viable, we set out to prepare the
three biaryl precursors (4b–d) needed for the remaining
azaphenanthridines (3b–d). If the strategy shown in
Scheme 2 was to be followed this would require the
synthesis of the corresponding halocyanopyridines as these
are not commercial available. Therefore, a different
synthetic strategy was chosen.
2.1. Synthesis of cyanopyridylboronic esters
We have reported a new synthetic procedure for the
synthesis of arylboronic esters via in situ trapping of
unstable lithio-intermediates.5 Following this method,
benzonitrile was ortho-lithiated to give the corresponding
cyanoarylboronic ester. Accordingly, 4b–d were envisaged
to be prepared via a ortho-lithiation/cross-coupling
Scheme 6. Synthesis of biaryls via cross-coupling of cyanopyridylboronic
esters.

H. M. Hansen et al. / Tetrahedron 61 (2005) 9955–9960
9957
experimentation we found that addition of CuI11 in
combination with CsF12 in an aprotic solvent was crucial
for the success of the reaction. Under these conditions the
desired biaryls 4b–d were isolated in 60–80% yield (see
Scheme 6).
2.3. Synthesis of azaphenathridines
Treatment of 4b and 4c with lithium morpholide gave the
desired azaphenanthridines in excellent yields (see
Scheme 7). Compound 4b gave 3b in 95% yield and 4c
produced 3c in 97% yield.
Scheme 9. Addition of lithium morpholide to 4d.
promote the formation of intermediate 9. Running the
experiment with 5 equiv LiCl did indeed improve the ratio
between 3d and 7 to 94:6 (see Scheme 8, entry 3) and 3d
was subsequently isolated in 88% yield.
3. Conclusion
Scheme 7. Addition of lithium morpholide to 4b–c.
A short, convergent and high yielding synthetic approach to
four isomeric azaphenanthridines has been developed. We
are currently exploring the scope of this approach to the
synthesis of other heterocyclic phenanthridine systems.
The reaction of 4d with lithium morpholide gave a 80:20
mixture of the desired product 3d and a compound identified
as 7 (see Scheme 8, entry 1). The identity of 7 was
unequivocally established by synthesizing 7 in two steps
from 3-bromo-2-chloropyridine.13
4. Experimental
4.1. General
All reactions involving air- and moisture sensitive reagents
were performed under N2 using syringe-septum cap
techniques. All glassware was flame dried under vacuum
prior to use. THF was distilled from Na/Benzophenone.
LiCl was flame dried under vacuum. All other chemicals
were used as received from commercial suppliers.
4.1.1. 2-(2-Fluorophenyl)nicotinonitrile (4a). A 100 mL
Schlenk-flask was charged with 2-chloro-nicotinonitrile
(5a) (1.39 g, 10 mmol), 2-(2-fluorophenyl)-5,5-dimethyl-
[1,3,2]dioxaborinane5 (2.50 g, 12.0 mmol), K3PO4 (4.25 g,
20.0 mmol), Pd(PPh3)4 (0.58 g, 5 mol%), then evacuated
and refilled with N2 three times before 1,4-dioxane (50 mL)
was added. The reaction was stirred at 80 8C overnight,
cooled to rt, evaporated on Celite and purified by FC to give
1.89 g 4a as off white crystals (95%). Mp (heptane/EtOAc)
74–76 8C. Rf (heptane/EtOAc 3:1) 0.23. 1H NMR
(300 MHz, CDCl3): d 8.86 (1H, dd, JZ5.0, 1.7 Hz), 8.08
(1H, dd, JZ7.9, 1.7 Hz), 7.58 (1H, td, JZ7.5, 1.8 Hz),
7.53–7.45 (m, 1H), 7.42 (1H, dd, JZ7.9, 5.0 Hz), 7.30 (1H,
td, JZ7.5, 1.1 Hz), 7.21 (1H, d, JZ8.3 Hz). 13C NMR
(75 MHz, CDCl3): d 159.6 (JC–FZ250 Hz), 157.1, 152.6,
140.7, 132.0 (JC–FZ8 Hz), 131.2 (JC–FZ3 Hz), 125.5
(JC–FZ14 Hz), 124.5 (JC–FZ4 Hz), 122.2, 116.4, 116.3
(JC–FZ22 Hz), 110.4. Anal. Calcd for C12H7FN2: C, 72.72;
H, 3.56; N, 14.13. Found C, 72.58; H, 3.76; N, 14.35.
Scheme 8. Addition of lithium morpholide to 4d.
Penney14 reported the synthesis of aminopyridines via the
addition of lithium amides to cyanopyridines, and we
speculate that 7 is formed in a similar fashion from the
initial adduct 8 (see Scheme 9) where the lithium
presumably is coordinated to the pyridine nitrogen. This
intermediate can then proceed via two different pathways:
(1) elimination of LiCN to produce 7, and (2) ‘decoordina-
tion’ of the lithium to the pyridine nitrogen leading to
intermediate 9, which then produces 3d via intramolecular
nucleophilic aromatic substitution of the fluorine. Penney
reported that CsF promotes the formation of aminopyridines
in the reaction, but we did not see any effect of CsF (see
Scheme 8, entry 2). Encouraged by the effect of LiCl in the
synthesis of 3a, we though that LiCl might also have an
effect on the course of this reaction as excess LiCl should

9958
H. M. Hansen et al. / Tetrahedron 61 (2005) 9955–9960
4.2. General procedure for the synthesis of 5b–5d
added and the reaction was stirred vigorously under N2 at
60 8C for 5 h. The reaction was quenched with water (4 mL/
mmol) and the water phase was extracted with EtOAc (3!
20 mL), the organic phase was dried (MgSO4), evaporated
on Celite and purified by FC.
In a flame dried 250 mL Schlenk-flask 2,2,6,6-tetramethyl-
piperidine (5.06 mL, 30 mmol) was dissolved in dry THF
(50 mL) under N2 and cooled to K30 8C before n-BuLi
(30 mmol) was added via syringe over 2 min. The mixture
was stirred at K30 8C for 5 min then cooled to K78 8C
before B(OiPr)3 (8.08 mL, 35 mmol) was added via syringe
over 2 min. The mixture was stirred at K78 8C for 5 min
before the cyanopyridine (2.60 g, 25 mmol) dissolved in dry
THF (50 mL) was added via syringe over 5 min. The
reaction was left in the dry ice bath overnight slowly
reaching rt. The reaction was quenched with glacial acetic
acid (2.0 mL, 35 mmol) followed by addition of 2,2-
dimethyl-1,3-propandiol (3.91 g, 37.5 mmol). The mixture
was stirred for 1 h at rt then poured into 10% KH2PO4(aq)
(75 mL). The water phase was extracted with CH2Cl2 (4!
50 mL) and the combined organic phase was washed with
water (4!15 mL). The organic phase was dried (MgSO4)
and evaporated to give the crude product.
4.3.1.
3-(2-Fluorophenyl)isonicotinonitrile
(4b).
Following the general procedure, 5b (1.94 g, 9.0 mmol)
yielded 1.41 g 4b as white crystals (79%). Mp (heptane/
EtOAc) 50–52 8C. Rf (heptane/EtOAc 3:1) 0.25. H NMR
1
(300 MHz, CDCl3): d 8.84 (1H, s), 8.79 (1H, d, JZ5.0 Hz),
7.65 (1H, dd, JZ5.0, 0.7 Hz), 7.56–7.48 (1H, m), 7.45 (1H,
td, JZ7.5, 1.8 Hz), 7.32 (1H, td, JZ7.5, 1.2 Hz), 7.28–7.23
(1H, m). 13C NMR (75 MHz, CDCl3): d 159.5 (JC–F
249 Hz), 151.5 (JC–FZ2 Hz), 149.4, 133.2, 131.8 (JC–F
Z
Z
8 Hz), 131.1 (JC–FZ2 Hz), 125.7, 124.8 (JC–FZ4 Hz),
122.2 (JC–FZ15 Hz), 120.5, 116.4 (JC–FZ22 Hz), 115.7.
Anal. Calcd for C12H7FN2: C, 72.72; H, 3.56; N, 14.13.
Found C, 72.42; H, 3.58; N, 13.92.
4.3.2. 4-(2-Fluorophenyl)nicotinonitrile (4c). Following
the general procedure, 5c (1.51 g, 7.0 mmol) yielded
832 mg 4c as white crystals (60%). Mp (heptane/EtOAc)
102–103 8C. Rf (heptane/EtOAc 3:1) 0.29. 1H NMR
(300 MHz, CDCl3): d 8.96 (1H, s), 8.82 (1H, d, JZ
5.2 Hz), 7.55–7.45 (3H, m), 7.30 (1H, td, JZ7.6, 1.2 Hz),
7.24 (1H, td, JZ8.8, 1.2 Hz). 13C NMR (75 MHz, CDCl3): d
4.2.1. 3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)iso-
nicotinonitrile (5b). Following the general procedure,
isonicotinonitrile yielded 4.32 g 5b as analytically pure
dark-red crystals (80%). Recrystallization from heptane/
EtOAc gave white crystals. Mp 125–127 8C. 1H NMR
(300 MHz, CDCl3): d 9.08 (1H, d, JZ0.8 Hz), 8.76 (1H, d,
JZ5.1 Hz), 7.51 (1H, dd, JZ5.1, 0.9 Hz), 3.84 (4H, s), 1.06
(6H, s). 13C NMR (75 MHz, CDCl3): d 155.9, 151.5, 126.4,
124.5, 117.1, 72.5, 31.9, 21.9. Anal. Calcd for
C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C,
61.39; H, 5.86; N, 12.98.
159.2 (JC–FZ251 Hz), 153.5, 152.6, 147.1, 132.3 (JC–F
Z
8 Hz), 130.7 (JC–FZ2 Hz), 125.0 (JC–FZ2 Hz), 124.9
(JCFZ4 Hz), 123.3 (JC–FZ14 Hz), 116.6 (JC–FZ22 Hz),
116.1, 110.1. HRMS [MCH]C calcd for C12H7FN2:
199.0672, found: 199.0643.
4.2.2. 4-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)nicotino-
nitrile (5c). Following the general procedure, nicotinonitrile
yielded 2.81 g 5c as analytically pure dark-brown crystals
(52%). Recrystallization from heptane/EtOAc gave off
white crystals. Mp 96–98 8C. 1H NMR (300 MHz,
CDCl3): d 8.88 (1H, d, JZ0.7 Hz), 8.74 (1H, d, JZ
4.9 Hz), 7.77 (1H, dd, JZ4.9, 0.7 Hz), 3.84 (4H, s), 1.05
(6H, s). 13C NMR (75 MHz, CDCl3): d 152.8, 151.3, 128.2,
117.2, 113.1, 72.3, 31.7, 21.6. Anal. Calcd for
C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C,
60.85; H, 5.80; N, 13.26.
4.3.3. 3-(2-Fluorophenyl)picolinonitrile (4d). Following
the general procedure, 5d (4.75 g, 22.0 mmol) yielded
3.49 g 4d as white crystals (80%). Mp (heptane/EtOAc) 89–
1
90 8C. Rf (heptane/EtOAc 3:1) 0.24. H NMR (300 MHz,
CDCl3): d 8.74 (1H, dd, JZ4.7, 1.2 Hz), 7.88 (1H, d, JZ
8.2 Hz), 7.60 (1H, dd, JZ7.6, 4.7 Hz), 7.55–7.43 (2H, m),
7.30 (1H, td, JZ7.6, 1.2 Hz), 7.21 (1H, d, JZ8.2 Hz). 13C
NMR (75 MHz, CDCl3): d 159.3 (JC–FZ249 Hz), 149.9,
138.7 (JC–FZ2 Hz), 136.4, 133.2, 131.7 (JC–FZ8 Hz),
131.1(JC–FZ2 Hz), 126.5, 124.7 (JC–FZ4 Hz), 123.0
(JC–FZ15 Hz), 116.5, 116.3 (JC–FZ22 Hz). Anal. Calcd
for C12H7FN2: C, 72.72; H, 3.56; N, 14.13. Found C, 72.54;
H, 3.71; N, 14.00.
4.2.3. 3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)picolino-
nitrile (5d). Following the general procedure, pyridine-2-
carbonitrile yielded 5.08 g 5d as analytically pure dark-
brown crystals (94%). Recrystallization from heptane/
EtOAc gave white crystals. Mp 47–49 8C. 1H NMR
(300 MHz, CDCl3): d 8.69 (1H, dd, JZ5.0, 1.7 Hz), 8.16
(1H, dd, JZ7.7, 1.7 Hz), 7.44 (1H, dd, JZ7.7, 5.0 Hz), 3.83
(4H, s), 1.05 (6H, s). 13C NMR (75 MHz, CDCl3): d 151.5,
142.7, 137.2, 125.6, 117.6, 72.2, 31.6, 21.5. Anal. Calcd for
C11H13BN2O2: C, 61.15; H, 6.07; N, 12.97. Found C, 60.93;
H, 6.15; N, 12.85.
4.4. General procedure for the reaction of 4a–d with
lithium morpholide
In a flame dried Schlenk-flask under N2 at rt, morpholine
(1.2 equiv) was dissolved in dry THF (2 mL/mmol). n-BuLi
(1.2 equiv) was added and the mixture was stirred for 5 min
before the biaryl (3a–d) dissolved in dry THF (1 mL/mmol)
was added. The mixture was heated to reflux for 30 min.
After cooling, the reaction was quenched with satd NH4Cl
(aq) (20 mL) and extracted with CH2Cl2. The organic phase
was dried (MgSO4), evaporated on Celite and purified by
FC.
4.3. General procedure for the synthesis of 4b–4d
A Schlenk-flask was charged with the cyanopyridylboronic
ester, 1-fluoro-2-iodobenzene (1.2 equiv), CsF (2 equiv),
CuI (0.1 equiv), Pd(PPh3)4 (0.05 equiv), evacuated and
refilled with N2 three times. 1,4-Dioxane (4 mL/mmol) was
4.4.1. 6-Morpholino-10-azaphenanthridine (3a).
Following the general procedure, with the addition of dry
LiCl (5 equiv) 4a (396 mg, 2.0 mmol) yielded 413 mg 3a as

H. M. Hansen et al. / Tetrahedron 61 (2005) 9955–9960
9959
white crystals (84%). Mp (heptane/EtOAc) 111–112 8C. Rf
(heptane/EtOAc 2:1) 0.37. H NMR (300 MHz, CDCl3): d
3:1) 0.18. 1H NMR (300 MHz, CDCl3): d 8.86 (1H, dd, JZ
4.9, 1.7 Hz), 8.04 (1H, dd, JZ7.8, 1.7 Hz), 7.45 (td, 1H, JZ
7.7, 1.7 Hz), 7.39 (1H, dd, JZ7.2, 1.7 Hz), 7.36 (1H, dd,
JZ7.7, 5.0 Hz), 7.25–7.15 (2H, m), 3.55 (4H, t, JZ4.4 Hz),
2.82 (4H, t, JZ4.4 Hz). 13C NMR (75 MHz, CDCl3): d
161.3, 152.6, 150.4, 140.1, 132.8, 130.9, 130.5, 123.9,
121.2, 119.4, 117.3, 110.9, 66.8, 51.9. Anal. Calcd for
C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found C, 72.43; H,
5.77; N, 15.54.
1
9.08 (1H, dd, JZ4.1, 1.8 Hz), 8.96 (1H, dd, JZ8.2, 1.8 Hz),
8.43 (1H, dd, JZ8.2, 1.8 Hz), 7.94 (1H, d, JZ8.2 Hz), 7.73
(1H, td, JZ8.2, 1.2 Hz), 7.56 (1H, t, JZ7.6 Hz), 7.53 (1H,
dd, JZ8.2, 4.1 Hz), 4.00 (4H, t, JZ4.7 Hz), 3.51 (4H, t, JZ
4.7 Hz). 13C NMR (75 MHz, CDCl3): d 159.2, 152.3, 151.0,
145.4, 134.1, 130.5, 127.9, 125.4, 123.8, 123.6, 121.6,
116.3, 67.1, 51.9. Anal. Calcd for C16H15N3O: C, 72.43; H,
5.70; N, 15.85. Found C, 72.44; H, 5.90; N, 15.86.
4.4.6. 3-(2-Fluorophenyl)-2-morpholinopyridine (7). A
25 mL flask was charged with 3-bromo-2-chloropyridine
(962 mg, 5.0 mmol), morpholine (871 mg, 10 mmol),
K2CO3 (1.66 g, 12 mmol) and DMF (20 mL). The reaction
was stirred overnight at 130 8C. After cooling to rt the
reaction was poured into satd NH4Cl (aq) (50 mL) and Et2O
(50 mL). The DMF-water phase was extracted with Et2O
(3!20 mL) and the combined organic phase was dried
(MgSO4), evaporated on Celite and purified by FC to give
840 mg 3-bromo-2-morpholinopyridine as white crystals
(70%). Mp 94–95 8C. Rf (heptane/EtOAc 3:1) 0.42. 1H
NMR (300 MHz, CDCl3): d 8.22 (1H, dd, JZ4.7, 1.6 Hz),
7.78 (1H, dd, JZ7.7, 1.6 Hz), 6.78 (1H, dd, JZ7.7, 4.7 Hz),
3.89–3.84 (4H, m), 3.36–3.31 (4H, m). 13C NMR (75 MHz,
CDCl3): d 159.0, 146.3, 142.2, 118.6, 112.7, 66.8, 49.9.
Anal. Calcd for C9H11BrN2O: C, 44.47; H, 4.56; N, 11.52.
Found C, 44.47; H, 4.47; N, 11.44.
4.4.2.
6-Morpholino-9-azaphenanthridine
(3b).
Following the general procedure, 4b (991 mg, 5.0 mmol)
yielded 1.27 g 3b as yellow crystals (95%). Mp (heptane/
EtOAc) 124–125 8C. Rf (heptane/EtOAc 3:1) 0.16. 1H NMR
(300 MHz, CDCl3): d 9.97 (1H, s), 8.80 (1H, d, JZ5.9 Hz),
8.54 (1H, dd, JZ8.2, 1.8 Hz), 7.95 (1H, dd, JZ8.2, 1.2 Hz),
7.90 (1H, dd, JZ5.9, 1.2 Hz), 7.70 (1H, td, JZ7.0, 1.2 Hz),
7.57 (1H, td, JZ8.2, 1.8 Hz), 4.01 (4H, t, JZ4.7 Hz), 3.54
(4H, t, JZ4.7 Hz). 13C NMR (75 MHz, CDCl3): d 158.1,
147.5, 145.7, 143.9, 129.6, 129.0, 128.7, 125.77, 124.9,
121.2, 120.5, 118.4, 67.0, 51.4. Anal. Calcd for C16H15N3O:
C, 72.43; H, 5.70; N, 15.85. Found C, 72.21; H, 5.66; N,
15.68.
4.4.3.
6-Morpholino-8-azaphenanthridine
(3c).
Following the general procedure, except the mixture was
heated at reflux for 24 h, 4c (793 mg, 4.0 mmol) yielded
1.03 g 3c as yellow crystals (97%). Mp (heptane/EtOAc)
134–136 8C. Rf (heptane/EtOAc 3:1) 0.29. 1H NMR
(300 MHz, CDCl3): d 9.48 (1H, s), 8.83 (1H, d, JZ
5.3 Hz), 8.36 (1H, d, JZ7.6, 1.2 Hz), 8.27 (1H, d, JZ
5.9 Hz,), 7.92 (1H, dd, JZ8.2, 1.2 Hz), 7.72 (1H, td, JZ7.0,
1.2 Hz), 7.51 (1H, td, JZ8.2, 1.2 Hz), 4.01 (4H, t, JZ
4.7 Hz), 3.57 (4H, t, JZ4.7 Hz). 13C NMR (75 MHz,
CDCl3): d 159.0, 150.0, 148.2, 145.2, 140.4, 131.2, 128.7,
125.4, 122.6, 120.5, 116.0, 115.9, 67.0, 52.0. HRMS [MC
H]C calcd for C16H15N3O: 266.1293, found: 266.1293.
A Schlenk-flask was charged with 3-bromo-2-morpholino-
pyridine (729 mg, 3.0 mmol), 2-(2-fluorophenyl)-5,5-
dimethyl-[1,3,2]dioxaborinane5 (811 mg, 3.9 mmol),
Pd(PPh3)4 (104 mg, 3 mol%) and evacuated and refilled
with N2 three times. Toluene (15 mL), EtOH (3 mL), 2 M
K2CO3 (aq) (3 mL) was added and the reaction was stirred
at 100 8C for 3 h. After cooling the mixture was poured into
water (30 mL) and the water phase was extracted with
CH2Cl2 (3!20 mL), dried (MgSO4), evaporated on Celite
and purified on FC to give 642 mg 7 as a colourless oil
1
(83%). Rf (heptane/EtOAc 3:1) 0.27. H NMR (300 MHz,
4.4.4.
6-Morpholino-7-azaphenanthridine
(3d).
CDCl3): d 8.28 (1H, dd, JZ4.8, 1.8 Hz), 7.54–7.47 (2H, m),
7.38–7.29 (1H, m), 7.20 (1H, m), 7.16 (1H, m), 6.94 (1H,
dd, JZ7.5, 4.9 Hz), 3.59 (4H, t, JZ4.7 Hz), 3.13 (4H, t, JZ
4.7 Hz). 13C NMR (75 MHz, CDCl3): d 159.5, 159.2
(JC–FZ248 Hz), 147.0, 140.7, 130.7 (JC–FZ3 Hz), 129.6
(JC–FZ8 Hz), 127.1 (JC–FZ15 Hz), 124.5 (JC–FZ4 Hz),
121.4, 116.7, 116.4 (JC–FZ22 Hz), 66.9, 49.4. Anal. Calcd
for C15H15FN2O: C, 69.75; H, 5.85; N, 10.85. Found C,
69.38; H, 5.84; N, 10.23.
Following the general procedure, with the addition of dry
LiCl (5 equiv) 4d (198 mg, 1.0 mmol) yielded 233 mg 3d as
yellow crystals (88%). Mp (heptane/EtOAc) 104–105 8C. Rf
1
(heptane/EtOAc 3:1) 0.20. H NMR (300 MHz, CDCl3): d
8.89 (1H, dd, JZ4.1, 1.8 Hz), 8.77 (1H, dd, JZ8.8, 1.8 Hz),
8.27 (1H, dd, JZ8.2, 1.2 Hz), 7.89 (1H, d, JZ8.2 Hz),
7.66–7.60 (2H, m), 7.43 (1H, td, JZ7.0, 1.2 Hz), 4.03 (8H,
m). 13C NMR (75 MHz, CDCl3): d 157.2, 148.1, 143.5,
137.7, 130.9, 130.0, 129.6, 128.0, 124.6, 124.3, 121.8,
121.0, 67.2, 50.3. Anal. Calcd for C16H15N3O: C, 72.43; H,
5.70; N, 15.85. Found C, 72.15; H, 5.53; N, 15.75.
References and notes
4.4.5. 2-(2-Morpholinophenyl)nicotinonitrile (6). A 5 mL
vial for septum capping was charged with 4d (180 mg,
0.91 mmol) and morpholine (3 mL, 35 mmol), capped and
heated in a Biotage Initiatore microwave system for 1 h at
225 8C. After cooling, the reaction was poured into satd
NH4Cl (aq) (15 mL) and CH2Cl2 (15 mL) and the organic
phase was washed with satd NH4Cl (aq) (2!15 mL) and the
water phase was back extracted with CH2Cl2 (10 mL). The
combined organic phases were dried (MgSO4), evaporated
on Celite and purified by FC to give 186 mg 6 as a white
solid (78%). Mp (Et2O) 133–134 8C. Rf (heptane/EtOAc
´
1. Lysen, M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org. Lett.
2002, 257.
2. (a) Roseman, K. A.; Gould, M. M.; Linfield, W. M.; Edwards,
B. E. J. Med. Chem. 1970, 13, 230. (b) Loy, M.; Joullie, M. M.
J. Med. Chem. 1973, 16, 549. (c) Yapi, A. D.; Mustofa, M.;
Valentin, A.; Chavignon, O.; Teulade, J. C.; Mallie, M.;
Chapat, J. P.; Blache, Y. Chem. Pharm. Bull. 2000, 48, 1886.
(d) Hinschberger, A.; Butt, S.; Lelong, V.; Boulouard, M.;
Dumuis, A.; Dauphin, F.; Bureau, R.; Pfeiffer, B.; Renard, P.;

9960
H. M. Hansen et al. / Tetrahedron 61 (2005) 9955–9960
Rault, S. J. Med. Chem. 2003, 46, 138. (e) Molinski, T. F.
Chem. Rev. 1993, 93, 1825. (f) Marshall, K. M.; Barrows, L. R.
Nat. Prod. Rep. 2004, 21, 731.
appeared describing the lithiation of cyanopyridines, see:
ˆ
Cailly, T.; Fabis, F.; Lemaıtre, S.; Bouillon, A.; Rault, S.
Tetrahedron Lett. 2005, 46, 135.
3. For an extensive list of references to the synthesis of
phenanthridines in general see: Patra, P. K.; Suresh, J. R.;
Ila, H.; Junjappa, H. Tetrahedron 1998, 54, 10167.
4. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981,
11, 513. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457.
10. For a recent review of heterocyclic boronic acids see: Tyrrell,
E.; Brookes, P. Synthesis 2004, 4, 469.
11. Recently the addition of CuI was reported to be crucial in the
coupling of other pyridylboronic derivatives: (a) Hodgson,
P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685. (b)
Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004, 45,
6239.
´
5. (a) Kristensen, J. L.; Lysen, M.; Vedsø, P.; Begtrup, M. Org.
´
Lett. 2001, 1435. (b) Kristensen, J. L.; Lysen, M.; Vedsø, P.;
Begtrup, M. Org. Synth. 2005, 81, 134.
12. Fluoride activation in Suzuki–Miyaura couplings, see: Wright,
S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994,
59, 6095.
6. When 4a was heated in neat morpholine at 225 8C for 1 h, 6
was produced in 78% isolated yield, see Section 4 for details.
7. (a) Meyers, A. I.; Williams, B. E. Tetrahedron Lett. 1978, 3,
223. (b) For a review, see: Reuman, M.; Meyers, A. I.
Tetrahedron 1985, 41, 837.
13. Alternative synthesis of 7 from 3-bromo-2-chloropyridine, see
Section 4 for details.
8. DMPUZN,N0-dimethyl-N,N0-propyleneurea, see: Seebach,
D.; Mukhopadhyay, T. Helv. Chim. Acta 1982, 65, 385.
9. At that time there was only a single report in the in the
literature describing an unselective ortho-lithiation of
3-cyanopyridine: Pletnev, A. A.; Tian, Q.; Larock, R. C.
J. Org. Chem. 2002, 67, 9276. Recently a more general study
14. Penney, J. M. Tetrahedron Lett. 2004, 45, 2667.