Intramolecular C-C coupling of 2,6-disubstituted-1-bromoaryls for dihydrophenanthridines

Article abstract of DOI:10.1016/j.tetlet.2012.06.087

The reaction of 2,6-disubstituted-1-bromoaryl imines with sodium borohydride under reflux condition leads to an intramolecular cyclization through C-Br and C-H coupling without any transition-metal catalyst, furnishing 5,6-dihydrophenanthridine and phenanthridine derivatives.

Full text of DOI:10.1016/j.tetlet.2012.06.087

Tetrahedron Letters 53 (2012) 4591–4594
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular C–C coupling of 2,6-disubstituted-1-bromoaryls
for dihydrophenanthridines
Vijay P. Singh a, Puspendra Singh a, Harkesh B. Singh a, , Ray J. Butcher b
⇑
a Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
b Department of Chemistry, Howard University, Washington, DC 20059, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2,6-disubstituted-1-bromoaryl imines with sodium borohydride under reflux condition
leads to an intramolecular cyclization through C–Br and C–H coupling without any transition-metal cat-
alyst, furnishing 5,6-dihydrophenanthridine and phenanthridine derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 10 May 2012
Revised 12 June 2012
Accepted 15 June 2012
Available online 23 June 2012
Keywords:
Intramolecular C–C coupling
Phenanthridine
Dihydrophenanthridine
Phenanthridines are important structural motifs in several nat-
ural products and alkaloids.1,2 Phenanthridine alkaloids including
nitidine and sanguinarine have been attractive molecules to syn-
thetic organic chemists and biochemists over the last few decades
due to their interesting biological properties.3–6 To date, the re-
ported phenanthridines are obtained by multistep synthetic se-
quences, which are constructed by intramolecular ring
cyclization methods.7,8 Phenanthridine (1) was obtained from phe-
nanthridone by reduction with lithium aluminum hydride
(Fig. 1).1b Haloanils when treated with potassium amides in liquid
ammonia, afforded phenanthridines via the formation of benzyne
intermediate in the cyclization step.9
Phenanthridines (1–3) have been further used to obtain highly
functionalized phenanthridines.10 Leardini and co-workers re-
ported an efficient method for the synthesis of phenanthridines
by intramolecular addition of aryl radicals to the C–N double
bond.11 Another class of biologically important phenanthridines,
such as phenanthridinone (4) has been accessed via palladium-cat-
alyzed aryl C–H activation.12
ophenanthridines (7) has been developed by ring expansion of 4-
alkylnyl-4-hydroxycyclobutenones.13a
Recently, we have investigated the addition/elimination reac-
tions (SNAr) of 2,6-disubstituted-1-bromoaryls with selenium
nucleophiles.16 The selenium compounds show unusual reactivity
and undergo facile cyclization to give selenium heterocycles 8
and 9 (Fig. 2).16b,17 In continuation, while attempting to prepare
precursors, such as sec-amines by the reduction of imines for the
synthesis of desired isoselenazolines (10)18 we obtained some
functionalized 5,6-dihydrophenanthridines (vide infra). We report
our findings in this article.
2-Bromo-3-nitrobenzaldehyde19 and 2-bromo-3-methylbenzal-
dehyde20 were treated with respective amines to prepare imines;
11a,16a 11b,18 11c,17 11d,18 and 11e–11h. Attempted reduction of
O
OMe
N
N
N
Me
N
Among phenanthridines, dihydrophenanthridines’ (5–6) skele-
ton is also found in several natural products and alkaloids.13 Gen-
erally, dihydrophenanthridines are obtained by the reduction of
phenanthridines.14 Functionalized dihydrophenanthridines have
also been obtained from amines by treatment with electrophile.15
A highly convergent route for the synthesis of a variety of dihydr-
4
2
3
1
OAc
Me
MeO
MeO
OH
OH
OH
N
MeO
MeO
R1
Me
R3
N
N
MeO
AcO
OH
R2
5
6
7a: R1 = nBu, R2 = H, R3 = OMe
b: R1 = nBu, R2 = R3 = OMe
⇑
Corresponding author.
E-mail address: chhbsia@chem.iitb.ac.in (H.B. Singh).
Figure 1. Some phenanthridines (1–4) and dihydrophenanthridines (5–7).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.087

4592
V. P. Singh et al. / Tetrahedron Letters 53 (2012) 4591–4594
Me
N
NO2
Se
O
N
R
Se
N
Me
Se
Se
NO2
NO2
NO2
9
10
8
Figure 2. Some selenium heterocycles 8–10.
NH
Path A
N
R
+
N
Br
R
R'
R'
H
R
R'
12a 12c
-
,
13f 13g
,
11a-11h
12e 12g
-
Major
Minor
R
H
R'
11
12 13
14
Path B
NO2 11a 12a
11b 12b
NO2 11c 12c
NO2 11d
11e 12e
_
_
_
_
_
14a
14b
14c
14d
14e
4-Me
4-OMe
4-NO2
4-Et
NO2
R
_
N
H
NO2
H
Br
Scheme 2. Plausible mechanism for the formation of compounds 12 and 13.
3,4-Me2 NO2 11f 12f 13f 14f
R'
14a 14h
-
11g 12g 13g 14g
11h 14h
2,3-
4-Me
NO2
Me
_
_
having an electron-donating methyl group in the place of –NO2
group, was treated with NaBH4, the reaction afforded only the
sec-amine based bromide (14h).
Scheme 1. Synthesis of phenanthridine, dihydrophenanthridines, and sec-amines
in the presence of NaBH4 and ethanol. Path A; reflux for 5–12 h, Path B; at room
temperature for 5 h or reflux 12 h (for 14h).
Related intramolecular C–C coupling via borohydride reduction
of dienone in THF has been reported.21 The intramolecular C–C
coupling takes place due to hydride attack and alkoxide attack
on the b-carbon atom of the enone.22 A similar intramolecular
cyclization through CAr–Cl and CAr–H coupling by iron or photo-as-
sisted intermolecular electron transfer led to the formation of 9H-
carbazole and phenanthridine.23 Based on the literature reports
and our own experimental observations, a plausible mechanism
(Scheme 2) for the formation of 12, 13, and 14 is proposed via
the common intermediate 15. At room temperature reduction,
the amide anion generated from the attack of the hydride ion ab-
stracts proton from the protic solvent ethanol to give the sec-
amine. However, the reaction of NaBH4 and ethanol at high tem-
perature results in the formation of side products NaB(OEt)4 and
H+ in significant quantities.24 The electrophilic attack of the proton
on the carbon bonded to Br (intermediate 15) leads to the forma-
imines (11) with NaBH4 in ethanol under reflux condition afforded,
unexpectedly, 5,6-dihydrophenanthridines 12 in major and (13) in
minor yield (Scheme 1 and Table 1) via intramolecular C–C cou-
pling. We were able to isolate the minor products along with the
major product in two cases. Imine 11f yielded 12f (50%) along with
13f (34%) and 11g afforded 12g (47%) and 13g (15%).
However, the reaction of 11d containing an electron-withdraw-
ing –NO2 group at the para-position of the N-phenyl ring gave only
14d. When the reduction of (11) with NaBH4 in ethanol was carried
out at the room temperature, the reaction afforded expected 14.
Interestingly, further reaction of sec-amine 14e, under reflux did
not yield the expected dihydrophenanthridine 12e. To find out
the role of ortho-NO2 group in the cyclization reaction, when 11h
Table 1
Precursors, products, and their yields in (%)
11 Yield (%)
12 Yielda (%)
13 Yielda (%)
14 Yieldb (%)
Entry
R
R0
1
2
3
4
5
6
H
4-Me
4-OMe
4-NO2
4-Ethyl
3,4-Me2
NO2
NO2
NO2
NO2
NO2
NO2
11a (83)
11b (65)
11c (64)
11d (53)
11e (78)
11f (67)
12a (63)
12b (60)
12c (47)
—
12e (75)
12f (50)
—
—
—
—
14a (80)
14b (78)
14c (82)
14d (61)
14e (85)
14f (87)
—
13f (34)
7
8
NO2
Me
11g (73)
11h (60)
12g (47)
13g (15)
14g (70)
14h (76)
4-Me
—
—
a
The products 12 and 13 were isolated at high temperature in ethanol via Path A shown in Scheme 1.
The product 14 were isolated at room temperature in ethanol via Path B shown in Scheme 1.
b

V. P. Singh et al. / Tetrahedron Letters 53 (2012) 4591–4594
4593
works like
a NAD(P)H model for biomimetic asymmetric
hydrogenation.25
The identities of dihydrophenanthridine derivatives 12 and
phenanthridine 13 were established by spectroscopic methods
such as IR, 1H & 13C NMR, and HRMS (please see Supplementary
data). The molecular structures of 12a, 12g, and 13g were unam-
biguously confirmed by single crystal X-ray crystallographic stud-
ies26 (Fig. 3). The structure was solved by direct method and
refined by a full-matrix least-squares procedure on F2 for all
reflections in SHELXL-97 software.27 In summary, an efficient
methodology for the high yield and facile synthesis of dihydrophe-
nanthridines from Schiff’s bases has been developed. The advanta-
ges of this methodology include easy access to the starting
materials and one-pot procedure for the C–C bond formation with-
out any transition-metal catalyst. The cyclization reactions of
imines having electron-withdrawing para-substituents (e.g., NO2)
at the N-phenyl ring and electron-donating substituents (e.g.,
Me) in place of NO2 in another ring are not viable.
Acknowledgments
HBS is grateful to the Department of Science and Technology
(DST), New Delhi, for funding. P.S. thanks the Indian Institute of
Technology, Bombay for a Post Doctoral Fellowship and V.P.S.
wishes to thank IIT Bombay for a teaching assistantship.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.06.087. These data include MOL files and InChiKeys of the
most important compounds described in this article.
References and notes
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Figure 3. Molecular structures of 12a (a), 12g (b), and 13g (c) shown with 25% (for
12a) or 50% (for 12g and 13g) probability displacement ellipsoids drawn from
ORTEP. The disordered NO2 group (for 13g) is omitted for clarity.
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tion of dihydrophenanthridines via intermediates 16 and 17. The
reducing reagent, NaBH4, and solvent ethanol play crucial roles in
the cyclization reaction. The role played by NaBH4/NaB(OEt)4 is
corroborated by attempting the cyclization in the absence of
NaBH4. When 14e was refluxed in ethanol in the absence of NaBH4,
no cyclization was observed. Since NaBH4 is the source of hydride
ion and which also acts as a base, the cyclization reaction of sec-
amine was attempted with NaH. The reaction gave a red intracta-
ble mixture, which could not be purified and characterized. Also
when the sec-amine was refluxed with bases Et3N/NaOH, only
the starting material was recovered. Attempted catalytic cycliza-
tion of 14e with Pd(OAc)2/Ag2SO4 in AcOH under reflux condition
did not lead to the corresponding dihydrophenanthridine.
In order to understand the mechanism of the formation of phe-
nanthridines 13f and 13g, the reduction of 11g under reflux was
monitored by TLC for 12 h. It was found that the reaction (for prod-
uct 12) was almost complete in 1 h and there was no significant
change in the intensity of the red spot for 12 up to 12 h. However,
the intensity of the minor product 13, which appeared after 1 h (a
faint yellow spot) increased with time up to 12 h. Therefore, we
presume that the minor product is obtained by the aerial oxidation
of 12. The formation of 13 is favored in the cases where N-aryl ring
is electron rich and also aromatization of phenanthridine ring may
be the driving force for the oxidation. Recently, Zhou et al. reported
that the conversion of phenanthridine into dihydrophenanthridine
is a reversible reaction and in the presence of hydrogen gas it
21. Kasturi, T. R.; Raju, G. J. J. Chem. Soc., Chem. Commun. 1982, 167.

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V. P. Singh et al. / Tetrahedron Letters 53 (2012) 4591–4594
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23. Guastavino, J. F.; Rossi, R. A. J. Org. Chem. 2012, 77, 460.
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(b) Davis, R. E.; Gottbrath, J. A. J. Am. Chem. Soc. 1962, 84, 895.
25. Chen, Q.-A.; Gao, K.; Duan, Y.; Ye, Z.-S.; Shi, L.; Yang, Y.; Zhou, Y.-G. J. Am. Chem.
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7.3710(2) Å; c = 18.1991(5) Å;
T = 123(2) K;
calcd = 1.423 Mg/m3; GOF = 1.034; R1 = 0.0432, wR2 = 0.1200 for
[I > 2 (I)]; R1 = 0.0474, wR2 = 0.1247 for all data. Of the 4429 reflections that
were collected, 2591 were unique (Rint = 0.0227). Crystal data for 13g:
17H10N2O2; Mr = 274.27; monoclinic; P21/n; a = 8.7715(6) Å; b =
10.8310(6) Å; c = 13.1005(9) Å; V =
= 90o; b = 93.581(6)o;
1242.17(14) Å3; T = 123(2) K; calcd = 1.467 Mg/m3; GOF = 1.036; R1 = 0.0705,
wR2 = 0.1969 for [I > 2 (I)]; R1 = 0.0814, wR2 = 0.2162 for all data. Of the 7346
a = c
= 90o; b = 98.336(3)o; V = 1289.90(6) Å3;
q
r
C
a = c
26. Crystal data for 12a:
7.7355(2) Å; b = 13.8253(3) Å;
2174.11(8) Å3; T = 295(2) K; calcd = 1.382 Mg/m3; GOF = 1.063; R1 = 0.0413,
wR2 = 0.1175 for [I > 2 (I)]; R1 = 0.0462, wR2 = 0.1218 for all data. Of the 14911
reflections that were collected, 2288 were unique (Rint = 0.0321). Crystal data
for 12g: 17H12N2O2; Mr = 276.29; monoclinic; P21/c; a = 9.7183(3) Å; b =
C
13H10N2O2; Mr = 226.23; orthorhombic; Pbcn; a =
q
c = 20.3291(4) Å; = b = V =
a
c
= 90o;
r
q
reflections that were collected, 2551 were unique (Rint = 0.0654).
27. Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Determination;
University of Göttingen: Germany, 1997.
r
C