From the study of naturally occurring N-allylated phenazines towards new Pd-mediated transformations

Article abstract of DOI:10.1016/j.tetlet.2007.09.045

New Pd-mediated reductive heteroannulations of N-allyl diphenylamines accessible through Pd-catalyzed N-arylation and of O-allylethers are reported.

Full text of DOI:10.1016/j.tetlet.2007.09.045

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8383–8387
From the study of naturally occurring N-allylated
phenazines towards new Pd-mediated transformations
Elena Merißsor and Uwe Beifuss*
Bioorganische Chemie, Institut fu¨r Chemie, Universita¨t Hohenheim, Garbenstraße 30, D-70599, Germany
Received 18 June 2007; revised 27 August 2007; accepted 7 September 2007
Available online 12 September 2007
Abstract—New Pd-mediated reductive heteroannulations of N-allyl diphenylamines accessible through Pd-catalyzed N-arylation
and of O-allylethers are reported.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Currently we know more than 100 naturally occurring
phenazines, which, due to the diversity of their biologi-
cal activities, have gained a lot of popularity.1 Most of
them are C-substituted compounds. In addition, a small
number of naturally occurring N-alkylated and N-ally-
lated phenazine derivatives are known. Apart from the
N-alkylated phenazinones represented by the structur-
ally most simple pyocyanin 1,2 there are, in particular,
the N-allylated phenazinones like lavanducyanin (WS-
9659 B) 23 and phenazinomycin 3.4 The latter was iso-
Against this background we envisaged performing an
alternative synthesis of N-allylated phenazinones
according to the retrosynthesis depicted in Scheme 1.
The initial idea was to start the synthesis with a diphe-
nylamine E, which was to be N-allylated. The reduction
of D (X = Hal) was expected to deliver C (X = Hal),
which in turn should be transformed into B by intramo-
lecular N-arylation according to Buchwald–Hartwig.6
Alternatively, the reductive cyclization of D (X = H)
according to the method described by Holliman7 would
deliver B in one synthetic step. Deprotection of the phe-
nolic OH group, followed by oxidation, should finally
give the N-allylated phenazinone A.
ꢀ
lated by Omura et al. from the mycelial extracts of
Streptomyces sp. WK-2057.4a It exhibits in vivo antitu-
mour activity against experimental murine tumour cells
and cytotoxic activity against adriamycin resistant P388
leukaemia cells.4b The total synthesis of 3 was reported
by Kitahara, using low-yield N-allylation under high
pressure conditions.5
First, we focussed on the synthesis of the tertiary o-ni-
tro-substituted diphenylamines 4a–c and their conver-
sion into the corresponding anilines 5a–c.
Intermolecular N-arylation reactions of the Buchwald–
Hartwig type6 were used to synthesize the secondary
O
O
O
N
N
N
N
N
OR'
O
OR'
N
H
N
NH2
X
1
3
N
Me
N
R
N
R
N
R
A
B
C
2
OR'
OR'
NO2
X
NO2
X
X = Hal, H
R = Allyl
Keywords: Pd-catalysis; CO; Domino reactions; Benzoxazine;
Heterocycles.
N
N
R
H
D
E
*
Corresponding author. Tel.: +49 711 459 22171; fax: +49 711 459
22951; e-mail: ubeifuss@uni-hohenheim.de
Scheme 1. Retrosynthesis of N-allylated phenazinones.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.045

8384
E. Merißsor, U. Beifuss / Tetrahedron Letters 48 (2007) 8383–8387
R1 R2
1) NaH, Et3N
C, DME
2) 11, r.t.
R1 R2
R1 R2
4a R1 = NO2, R2 = Br
4b R1 = NO2, R2 = Cl
4c R1 = NO2, R2 = H
0
°
N
N
N
H
5a R1 = NH2, R2 = Br
5b R1 = NH2, R2 = Cl
5c R1 = NH2, R2 = H
8a R1 = NO2, R2 = Br 96 %
8b R1 = NO2, R2 = Cl 90 %
8c R1 = NO2, R2 = H 97 %
4a
4b
4c
diphenylamines 8a–c, the precursors of anilines 5a–c and
4a–c, respectively. The reactions between o-substituted
anilines 6a–e and aryl bromides 7a–d were achieved by
combining the catalyst Pd2(dba)3, the ligand rac-BIN-
AP, the base Cs2CO3 and toluene as a solvent. Under
these conditions, diphenylamines 8 were isolated with
yields ranging from 57% to 99% (Table 1).8 Reaction
times varied between 12 and 17 h.
Scheme 2. Synthesis of tertiary diphenylamines 4a–c.
2H2O as reducing agents under acidic conditions11
(37% HCl in concd CH3CO2H) did not only lead to
the reduction of the nitro group but also to N-deallyla-
tion. The o,o0-disubstituted diphenylamine 12 was
formed exclusively in a yield of 63% (Scheme 3). On
the other hand, the reaction of 1 equiv of 4a with a large
excess of N2H4ÆH2O (13 equiv) in the presence of
2.5 mol % Pd/C12 resulted in both reduction of the nitro
group and cleavage of the bromo substituent, so com-
pound 5c was isolated in 65% yield (Scheme 3).
R1
R2
R2
R1
5 mol % Pd2(dba)3
7.5 mol % rac-BINAP
+
2 eq. Cs2CO3
toluene 110 °C
NH2 Br
N
H
6
7
8
Clean conversion of 4a–b into 5a–b also failed with
various other reducing agents, including NH4OH/
(NH4)2Fe(SO4)2,13 Cu(acac)2/NaBH4,14 In/NH4Cl,15 Zn/
N
CH3CO2H,16 Fe/HCl,17 FeCl3Æ6H2O/NH2–N(CH3)2
18
N
H
H
9
NO2
10
and SmI2.19 Thus, we focussed on the reduction of 4c
to 5c and the reductive cyclization of 4c, respectively.
A classical procedure for the reductive cyclization of
o-nitrodiphenylamines to phenazines in a single step is
Holliman’s method7 using a mixture of NaBH4 and
NaOEt in excess as the reducing agent. Surprisingly,
no phenazine was formed when 4c was treated with
CO2CH3
In two cases, cyclization to the corresponding carbazoles
was observed.9 Most noticeably, the reaction between 6d
and 7b exclusively produces nitrocarbazole 9 in 90%
yield. In contrast, the reaction of 6d and 7d yields a mix-
ture of diphenylamine 8e (80%) and carbazole 10 (15%).
Then the secondary diphenylamines 8a–c were trans-
formed into the corresponding tertiary amines 4a–c by
N-allylation-with prenyl bromide 11 in yields from
90% to 97% (Scheme 2).
NO2 Br
N
NH2 Br
Zn/SnCl2 H2O (1:1)
HCl, AcOH
63%
N
H
This transformation was achieved by deprotonation of
8a–c with a slight excess of NaH in dimethoxyethane
at 0 ꢁC followed by treatment with an excess of prenyl
bromide 11 at room temperature.10
4a
4a
12
5c
NH2
N
N2H4 H2O
Pd/C/EtOH
65%
The next goal was to reduce the nitro compounds 4a–c
to the corresponding anilines 5a–c. However, unex-
pected problems occurred with the reduction of the nitro
groups of 4a and 4b. For example, treatment of 1 equiv
of 4a with 2.5 equiv of a 1:1-mixture of Zn and SnCl2Æ
Scheme 3. Reductions of 4a.
Table 1. Synthesis of diphenylamines 8a–f
Entry
6
R1
7
R2
8
Yield 8 (%)
1
2
3
4
5
6
7
a
b
c
o-NO2
o-Cl
o-H
o-Br
o-Br
a
b
b
b
c
o-Br
a
68
99
98
—
58
80
57
o-NO2
o-NO2
o-NO2
p-NO2
o-CO2CH3
o-NO2
b
c
a
d
d
d
e
—
d
eb
f
o-Br
o-Br-p-CN
d
b
a 1-Nitrocarbazole (9) was isolated in 90% yield.
b In addition, 15% of 10 was isolated.

E. Merißsor, U. Beifuss / Tetrahedron Letters 48 (2007) 8383–8387
8385
CO (5 bar)
H
N
H
N
60 mol % Pd(OAc)2
120 mol % 1,10-phen
DMF, 140 °C, 24 h
NaBH4
NaOEt
H
N
NO2
N
4c
5c
+
+
N
N
13
22%
14
10%
53%
Ph
Ph
N
8%
4c
4c
13
Ph
Ph
CO (5 bar)
Scheme 4. Reductive cyclization of 4c using NaBH4/NaOEt as a
4 mol % Pd(OAc)2
8 mol % 1,10-phen
DMF, 140 °C, 24 h
reagent.
+
5c
15%
13
17%
2.5 equiv NaBH4 and a 5 N ethanolic solution of
NaOEt. Instead, a mixture of 3-isopropenyl-1-phenyl-
1,2,3,4-tetrahydroquinoxaline 13 (22%), 3-isopropyl-1-
phenyl-1,2,3,4-tetrahydroquinoxaline 14 (10%) and
amine 5c (8%) was isolated (Scheme 4).
Scheme 5. Pd-mediated N-heteroannulation of 4c.
3-isopropenyl-3,4-dihydro-2H-1,4 benzoxazine 16 in
50% yield (Scheme 6).
Despite the modest yield of 22% of 3-isopropenyl-1-phe-
nyl-1,2,3,4-tetrahydroquinoxaline 13 the conversion of
an x-nitroalkene into an alkenyl-substituted N-hetero-
cycle in a single synthetic step is of general interest as
this transformation represents a new reductive domino
process.20 In the course of our studies we tried to estab-
lish reagents and reaction conditions capable of increas-
ing the yields of the annulation products. This objective
was reached by using phosphites as the reagents.21 For
example, compound 13 was obtained in a yield of 57%
upon heating 4c with (EtO)3P under reflux. In this and
all the other cases investigated, (EtO)3P had to be used
in excess. It was this excess that triggered the search
for catalytic alternatives.
In the case of 15 the amounts of Pd(OAc)2 and 1,10-phe-
nanthroline could be reduced to 6 mol % and 12 mol %,
respectively, when the reaction was performed with CO
(10 bar) in tetrahydrofuran (138 ꢁC). Under these condi-
tions 16 was obtained in 40% yield. With ethylene glycol
as the solvent as little as 2 mol % Pd(OAc)2 and 4 mol %
1,10-phenanthroline were sufficient to catalyze the
reductive cyclization of 15 with CO (8 bar). After 24 h
at 198 ꢁC 16 was isolated in 36% yield. The remarkably
strong influence of the solvent on the course of this reac-
tion is supported by the finding that no cyclization oc-
curred in xylene (145 ꢁC, 10 bar CO), and many
products were formed (TLC) in acetonitrile (140 ꢁC,
10 bar CO).
The past years have shown that the synthesis of N-het-
erocycles can be achieved by transition metal-catalyzed
N-heteroannulations of aromatic nitro compounds in
the presence of CO.22 Particularly well known is the
Pd-catalyzed reductive N-heteroannulation of o-nitro-
styrenes to indoles.22,23 Even if this annulation can be
performed with complexes of other metals like Ru,22,24
Rh22,25 or Fe,22 it is the Pd complexes that are undoubt-
edly the most important catalysts. So we set out to inves-
tigate the reductive cyclization of x-nitroalkene 4c into
the saturated N-heterocycle 13 by Pd-catalyzed reac-
tions with CO. First we concentrated on the combina-
tion of Pd(OAc)2 as a catalyst, 1,10-phenanthroline as
a ligand and CO as a reductant. We found that reductive
cyclization of x-nitroalkene 4c can be realized in a single
step by using 60 mol % of Pd(OAc)2, 120 mol % of 1,10-
phenanthroline and CO (5 bar).26 Under these condi-
tions 1,2,3,4-tetrahydroquinoxaline 13 was isolated in
53% yield (Scheme 5). But although we managed a
reduction of Pd(OAc)2 to 4 mol % and of 1,10-phenan-
throline to 8 mol %, the product yield dropped: only
17% of 13 was formed under these conditions, accompa-
nied by 15% of the tertiary diphenylamine 5c (GC–MS)
(Scheme 5).
Finally, the Pd-catalyzed transformation of 15 with CO
(10 bar) was also examined under basic conditions with
NEt3 (10 equiv) in DMF or DMF/MeOH. Surprisingly,
2,3,3-trimethyl-7-nitro-2,3-dihydro-benzofuran 17 was
the only cyclization product formed. Yields ranged from
40% to 50% (Scheme 7).27 Formation of 17 implicates
that the cyclization proceeds without the participation
of the nitro group in 15. As a side product 2-nitrophenol
was isolated with yields of 10% and 15%, respectively. It
probably originates from deallylation of 15.
CO (5 bar)
60 mol % Pd(OAc)2
120 mol % 1,10-phen
DMF, 140 °C, 24 h
NO2
O
H
N
50%
O
15
15
16
16
CO (10 bar)
6 mol % Pd(OAc)2
12 mol % 1,10-phen
THF, 138 °C, 24 h
40%
In order to find out whether this new one-step Pd-med-
iated N-heteroannulation of x-nitroalkenes can also be
applied to the synthesis of other heterocycles, we turned
our attention to the conversion of allyl 2-nitrophenyl
ethers. Reaction of 3,3-dimethylallyl-2-nitrophenyl ether
15 with CO (5 bar, 140 ꢁC) in the presence of 60 mol %
Pd(OAc)2 and 120 mol % 1,10-phenanthroline produced
CO (8 bar)
2 mol % Pd(OAc)2
4 mol % 1,10-phen
ethylene glycol,198
°C, 24 h
15
16
36%
Scheme 6. Synthesis of benzoxazine 16.

8386
E. Merißsor, U. Beifuss / Tetrahedron Letters 48 (2007) 8383–8387
In summary, new Pd-mediated reductive hetero-
CO (10 bar)
6 mol % Pd(OAc)2
DMF, NEt3, 140
NO2
NO2
O
annulations have been achieved starting from N-allyl
diphenylamines and O-allylethers yielding saturated
heterocycles.
°C, 24 h
O
50%
15
17
17
Acknowledgements
CO (10 bar)
5 mol % PdCl2(PhCN)2
DMF/MeOH, NEt3, 140
We thank Dr. J. Conrad, Ms. S. Mika, Dr. R. Frank
and Ms. I. Klaiber for recording of NMR, UV and
MS spectra.
°C, 24 h
15
40%
Scheme 7. Synthesis of benzofuran 17.
References and notes
1. (a) Beifuss, U.; Tietze, M. Top. Curr. Chem. 2005, 244,
77; (b) Laursen, J. B.; Nielsen, J. Chem. Rev. 2004, 104,
1663.
Currently, we can only speculate on the mechanism of
the Pd-mediated reductive N-heteroannulation of x-
nitroalkenes with CO.28
2. see Ref. 1 and references cited therein.
3. (a) Imai, S.; Furihata, K.; Hayakawa, Y.; Noguchi, T.;
Seto, H. J. Antibiot. 1989, 47, 1196; Nakayama, O.; Yagi,
M.; Tanaka, M.; Kiyoto, S.; Okuhara, M.; Kohsaka, M.
J. Antibiot. 1989, 47, 1221; (b) Nakayama, O.; Shigematsu,
N.; Katayama, A.; Takase, S.; Kiyoto, S.; Hashimoto, M.;
Kohsaka, M. J. Antibiot. 1989, 47, 1230.
We assume that the process starts with the metal-medi-
ated deoxygenation of 4c and 15, respectively. Reaction
of the nitro group with CO would first yield A leading to
the metal-bound nitrosamine B and the formation of
CO2. Repeated insertion of CO would give the metal-
lacyclobutanone C, which in turn decomposes to yield
the metal-bound nitrene D and CO2. A formal intramo-
lecular [2+2] cycloaddition between the Pd-bound nit-
rene and the alkene would give tricycle E. The next
step involves the formation of the bicyclic intermediate
F by means of b-hydride elimination. Finally, reductive
elimination would not only deliver products 13 and 16,
respectively, but also regenerate the Pd(0) catalyst
(Scheme 8).
ꢀ
4. (a) Funayama, S.; Eda, S.; Komiyama, K.; Omura, S.;
Tokunaga, T. Tetrahedron Lett. 1989, 30, 3151; (b)
ꢀ
Omura, S.; Eda, S.; Funayama, S.; Komiyama, K.;
Takahashi, Y.; Woodruff, H. B. J. Antibiot. 1989, 47,
1037.
5. Kinoshita, Y.; Kitahara, T. Tetrahedron Lett. 1997, 38,
4993.
6. Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131.
7. Challand, S. R.; Herbert, R. B.; Holliman, F. G. J. Chem.
Soc., Chem. Commun. 1970, 1423.
8. Tietze, M.; Iglesias, A.; Merisor, E.; Conrad, J.; Klaiber,
I.; Beifuss, U. Org. Lett. 2005, 7, 1549.
9. For a review see: (a) Kno¨lker, H. J. Curr. Org. Chem.
2004, 1, 309; (b) Bedford, R. B.; Cazin, C. S. J. Chem.
Commun. 2002, 2310.
10. Mohri, K.; Suzuki, K.; Usui, M.; Isobe, K.; Tsuda, Y.
Chem. Pharm. Bull. 1995, 43, 159.
11. Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G.
Synthesis 1996, 1076.
O
Pd
O
NO2
Pd(0)
CO
N
O
- CO2
X
X
A
4c
15
12. Black, D. St. C.; Rothnie, N. E. Aust. J. Chem. 1983, 36,
1141.
Pd
N
Pd O
N
O
13. Boojamra, C. G.; Burow, K. M.; Thompson, L. A.;
Ellman, J. A. J. Org. Chem. 1997, 62, 1240.
14. Murphy, J. A.; Rasheed, F.; Gastaldi, S.; Ravishanker, T.;
Lewis, N. J. Chem. Soc., Perkin Trans. 1 1997, 1549.
15. Banik, B. K.; Banik, I.; Samajdar, S.; Wilson, M.
Heterocycles 2004, 63, 283.
16. Tomlinson, M. L. J. Chem. Soc. 1939, 158.
17. Mahood, S. A.; Schaffner, P. V. L. Org. Synth. Coll. 1943,
2, 160.
CO
O
- CO2
X
X
B
D
F
C
E
H
Pd
Pd
N
N
β
-hydride
2 + 2
elimination
18. Boothroyd, S. R.; Kerr, M. A. Tetrahedron Lett. 1995, 36,
2411.
X
X
19. Banik, B. K.; Mukhopadhyay, C.; Venkatraman, M. S.;
Becker, F. F. Tetrahedron Lett. 1998, 39, 7243.
20. Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino
Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
2006.
21. (a) Merißsor, E.; Conrad, J.; Klaiber, I.; Mika, S.; Beifuss,
U. Angew. Chem., Int. Ed. 2007, 46, 3353; (b) Merißsor, E.;
Conrad, J.; Klaiber, I.; Mika, S.; Beifuss, U. Synlett 2007,
2033.
PdH
N
H
N
reductive
elimination
- Pd(0)
X
X
13 X = NPh
16 X = O
Scheme 8. Possible reaction mechanism for the Pd-mediated N-
heteroannulation.
22. For a review see: So¨derberg, B. C. G. Curr. Org. Chem
2000, 4, 727.

E. Merißsor, U. Beifuss / Tetrahedron Letters 48 (2007) 8383–8387
8387
23. (a) So¨derberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62,
5838; (b) Tollari, S.; Cenini, S.; Gianella, E. J. Mol. Catal.
1994, 87, 203; (c) Akazome, M.; Kondo, T.; Watanabe, Y.
Chem. Lett. 1992, 769.
24. (a) Tollari, S.; Cenini, S.; Ragaini, F.; Cassar, L. J. Chem.
Soc., Chem. Commun. 1994, 1741; (b) Crotti, C.;
Cenini, S.; Ragaini, F.; Porta, F. J. Mol. Catal. 1992,
72, 283.
N2 followed by CO. The system was pressurized with CO
(5 bar) and heated at 140 ꢁC for 24 h. The reaction mixture
was cooled to rt, the catalyst filtered off and washed with
H2O. Extraction with EtOAc (3 · 50 mL) was followed by
drying of the organic phase over MgSO4 and removal of
the solvent under reduced pressure. The residue was
purified by flash column chromatography (PE/
EtOAc = 20:1).
25. Ucciani, E.; Bonfand, A. J. Chem. Soc., Chem. Commun.
1981, 82.
26. General procedure for the cyclization reaction with CO. A
Berghof PTFE liner was charged with (0.166 g,
0.589 mmol) 4c dissolved in 5 mL DMF and inserted into
27. The conversion of a dimethylallyl phenyl ether into a
dihydrobenzofuran has been reported to proceed with a
low yield in the absence of a transition metal catalyst: (a)
Buchi, G.; Leung, J. C. J. Org. Chem. 1986, 51, 4813; For
¨
a related process, see: (b) Evans, C. M.; Kirby, A. J. J.
Am. Chem. Soc. 1982, 104, 4705.
a
Berghof pressure reactor HR-100. A mixture of
Pd(OAc)2 (80 mg, 0.356 mmol) and 1,10-phenanthroline
(128 mg, 0.71 mmol) dissolved in 50 mL DMF was added.
The reactor system was sealed and purged three times with
28. (a) Scott, T. L.; So¨derberg, B. C. G. Tetrahedron Lett.
2002, 43, 1621; (b) So¨derberg, B. C. G.; Wallace, J. M.;
Tamariz, J. Org. Lett. 2002, 4, 1339.