[Ru(TPP)CO]-catalysed intramolecular benzylic C-H bond amination, affording phenanthridine and dihydrophenanthridine derivatives

Article abstract of DOI:10.1002/chem.201200888

Shedding light on azides: [Ru(TPP)CO] (TPP=tetraphenyl porphyrin dianion), white light and O₂ were found to be a suitable catalyst combination to perform the annulation of several biaryl azides (see scheme). The high chemoselectivity of the process allows the synthesis of phenanthridines and dihydrophenanthridines in good yield and purity. Copyright

Full text of DOI:10.1002/chem.201200888

COMMUNICATION
DOI: 10.1002/chem.201200888
À
[Ru
N
G
Daniela Intrieri, Matteo Mariani, Alessandro Caselli, Fabio Ragaini, and Emma Gallo*[a]
Dedicated to Dr. Eric Rose for his inspiring contributions in this field
The scientific community is very interested in the devel-
opment of new methodologies to synthesise N-heterocycles
because of their pharmaceutical and biological properties.
Considerable effort has been applied to the development of
efficient and clean procedures that afford high-added-value
fine chemicals in a few steps and with good selectivity.[1]
Intramolecular annulation reactions of organic azides could
be a suitable strategy to respond to societyꢀs demand for en-
vironmentally benign syntheses of N-heterocycles because,
in the presence of a suitable catalytic system, an intramolec-
and only old papers[5,27] have reported on the pyrolyses of
biaryl azides, yielding phenanthridine derivatives in low
yields and selectivities. Therefore, we decided to study the
synthesis of this class of N-heterocycle, starting from 2-azido
À
biaryls and applying our expertise in intermolecular C H
aminations catalysed by ruthenium porphyrin com-
pounds.[28–31] We report, herein, the intramolecular amina-
tion of several 2-azido biaryls that have been prepared by
adapting the procedure already reported by Driver and co-
workers[8] (Scheme 1).
[2,3]
À
ular C H amination occurs with excellent selectivity.
The
sustainability and atom efficiency of the reaction is indicated
by the formation of molecular nitrogen as the only stoichio-
metric side product. It is known that azide decomposition
can also be thermally or photochemically induced[4–6] but the
reaction often requires extreme experimental conditions
and, except in a few cases,[7] low selectivities are achieved.
Recently, T. G. Driver and co-workers studied the intra-
À
molecular azide C H amination reactions in depth and
reached good to excellent reaction selectivities. Nitrogen-
based heterocycles, such as carbazoles,[8] pyrroles,[9] in-
doles,[10–13] indolines[14] and benzimidazoles,[15] were synthes-
ised by employing various catalytic systems. Among the
transition-metal complexes employed as catalysts in these
reactions, metalloporphyrins exhibited very good catalytic
Scheme 1. Synthesis of 2-azido biaryl derivatives.
À
activity for the intramolecular C H amination of organic
To test the catalytic activity of the commercially available
complex [RuACTHUGNETRNNU(G TPP)CO] (TPP=the dianion of tetraphenyl
sulfonyl, phosphoryl, sulfamoyl and aryl azides to form ben-
zosultams,[16] cyclophosphoramidates[17] 1,3-diammines[18,19]
and alkaloids,[20] respectively.
porphyrin), the intramolecular amination of 2b was per-
formed under dinitrogen by using all of the experimental
conditions listed in Table 1. We obtained a mixture of the 2-
amine biaryl (1b), carbazole (3b), dihydrophenathridine
(4b) and phenanthridine (5b) compounds formed from 2b.
It should be noted that carbazole 3b, usually obtained as
the major product by using rhodium-based catalysts,[3] was
formed only as a by-product in the presence of the rutheni-
um catalyst.
Phenanthridines and dihydrophenanthridines are impor-
tant core structures in a large class of pharmaceutical com-
pounds[21] and consequently several synthetic methods have
been developed for their preparation.[22–26] To date, azides
have not been extensively employed as the starting material
As reported in Table 1, the reaction times (compare
Table 1, entries 5 and 7) can be considerably reduced by ir-
radiating the reaction mixture with a 400 W halogen lamp;
a simultaneous decrease of the carbazole yield was ob-
served. The employment of the lamp allowed the synthesis
of an equal amount of the 4b/5b mixture (77 vs. 78%, com-
pare entries 2 and 7) but at reduced reaction temperature
(120 instead of 1808C), cutting the reaction time in half, as
[a] Dr. D. Intrieri, Dr. M. Mariani, Dr. A. Caselli, Prof. F. Ragaini,
Prof. E. Gallo
Dipartimento di Chimica
Universitꢁ degli Studi di Milano and ISTM-CNR
Via Venezian 21, I-20133 Milano (Italy)
Fax : (+39)250314405
E-mail: emma.gallo@unimi.it
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200888.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

[a]
À
Table 1. Optimisation of the intramolecular C H amination of 2b.
[Ru(TPP)CO]
T
t[b]
Yield [%][c]
[%]
[8C]
[h]
1b
3b
4b
5b
1
2
3
5
none
2
0.4
1
0.4
1
none
180
180
180
120
120
120
120
13
2
3
10
1.5
7
7
92
8
18
10
24
4
–
23
27
10
14
46
–
–
54
41
40
46
32
–
Scheme 2. Suggested route for the formation of phenanthridine.
12
31
12
11
2
6[d]
7[d]
8[d]
sumption of the azide due to the presence of air in the reac-
tion mixture. Leaving the mixture exposed to air at 1208C
in the presence of the catalyst for another two hours con-
cludes the oxidation process. To support the role of path B
in the formation of 5b, we repeated the reaction but left the
reaction mixture under a nitrogen atmosphere for 5 h after
the complete conversion of the azide starting material. Com-
plete conversion of 4b into 5b was not observed due to the
lack of air.
1
1.5
97
[a] General procedure: 2b (70.0 mg, 3.13ꢃ10À4 mol) was dissolved in 1,2-
dichlorobenzene (20 mL) under dinitrogen. [b] Time required to reach
complete conversion of 2b. [c] Determined by 1H NMR spectroscopy
with 2,4-dinitrotoluene as the internal standard. [d] The reaction mixture
was irradiated with a halogen lamp (400 W).
well as the catalyst loading. The positive effect of a halogen
lamp assumes practical importance in terms of low cost and
availability.
Considering the product distributions reported in Table 1,
entry 7, the O2 concentration (ꢀ1.3 mm) involved in path B
can either originate from impurities in the nitrogen gas em-
ployed or be introduced during the preparation of the
sample for NMR spectroscopy. To reduce the oxygen con-
tamination, the annulation reactions of 2b were carried out
under argon and at a higher biaryl azide concentration
(7.61ꢃ10À2 m instead of the 1.56ꢃ10À2 m used in the reac-
Data collected to date indicate that 1 mol% catalyst at
1208C, coupled with a halogen lamp, are the optimal condi-
tions to perform intramolecular amination reactions. In fact,
the use of a lower catalyst loading (Table 1, entry 6) was as-
sociated with the formation of a significant amount of carba-
zole by the competitive uncatalyzed reaction. As shown in
Table 1, dihydrophenanthridine (4b) and phenanthridine
(5b) are obtained in variable amounts depending on the ex-
perimental conditions and for every set of reaction condi-
tions the formation of the 2-amine biaryl compound (1b)
was observed.
1
tions reported in Table 1, entry 7). The H NMR spectrum,
run under argon after the complete consumption of 2b, re-
vealed the presence of 1b (16%), 3b (4%), 4b (60%) and
5b (17%). The employment of more strict experimental
conditions allowed the formation of a 5b/1b ratio of almost
1:1 and increased the yield of 4b due to nearly complete
suppression of path B.
On the other hand, to favour the oxidation of 4b into 5b,
we performed the intramolecular amination of 2b by using
the experimental conditions described for Table 1, entry 7
but the reaction was exposed to air from the beginning. The
1H NMR spectrum of the crude mixture registered after the
complete consumption of the azide showed the presence of
5b (17%), 4b (66%), 1b (10%) and 3b (traces). Only if the
reaction mixture was left to stir at 1208C for a further 2 h
was 4b completely transformed into 5b, indicating that the
Our previous study on the intermolecular benzylic amina-
tion of hydrocarbons by aryl azides[32] indicated that the first
À
step of the C H amination was the formation of a benzylic
amine that yields the corresponding imine through a reaction
with another azide molecule. The stoichiometric by-products
of this second step are the anilines. If we envisage a similar
mechanism for the intramolecular amination, we should
obtain equal amounts of phenanthridine (5b) and 2-amine
biaryl (1b), and considering complete azide conversion, the
remainder of the material must form dihydrophenathridine
(4b). On the other hand, the formation of a 1b/5b ratio
smaller than one indicated the presence of a competitive ox-
idation mechanism (see Table 1, entry 2). Taking into ac-
count that the oxidation of 4b to 5b could be due to
À
oxidation is a slower process than the C H amination. The
decrease in the yield of 5b (the yield decreased from 30 to
17% by running the reaction in air rather than under a N2
atmosphere) could be due to a different reaction rate of
path A with respect to path B (Scheme 2). Moreover,
path A may even be inhibited by dioxygen and therefore
the formation of 5b should be mainly due to path B.[32]
The role of ruthenium in the conversion of 4b into 5b
was confirmed by stirring a ruthenium-free mixture of the
oxygen[26] and promoted by [Ru
ACTHNUTRGNE(UNG TPP)CO], a catalytic mix-
ture containing both heterocyclic compounds was left to stir
at 1208C and directly exposed to air for 2 h by simply re-
moving the flask stopper. Complete conversion of 4b into
5b was observed. This experimental result indicates that the
phenanthridine formation is probably due to the two mecha-
nisms indicated in Scheme 2, paths A and B. We suggest
that, with the dehydrogenation of 4b to form 5b being a fa-
vourable process, it can commence before complete con-
1
two compounds in air at 1208C for 7 h. The H NMR spec-
tra registered at the beginning and end of the reaction
showed an unvaried product distribution, indicating that, for
the oxidation process of 4b to 5b to occur, a catalytic
&
2
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

À
[RuACHTUNGTRENNUNG(TPP)CO]-Catalysed Intramolecular C H Amination
COMMUNICATION
À
Table 2. The [Ru
G
amount of [RuACHTUNGTRENNUNG(TPP)CO] is required. It is worth
azido biaryls (2a–2i).[a]
noting that despite the fact that the dehydrogena-
tion of 4b into 5b is known to be a relatively
straightforward process, to the best of our knowl-
edge, it usually takes place in the presence of a hy-
drogen acceptor[26,33] or strong oxidants.[34] [Ru-
t
Dihydrophenanthridine
Yield Phenanthridine
[%][c]
[h][b]
1
1.5
ACHTUNGTRENNUNG(TPP)CO], on the other hand, catalyses this reac-
tion by employing atmosphere O2 as the oxidant.
To study the scope of the reaction, we performed
the
2
3
4
1
4b 46
5b 32[c] (78)[d]
À
C H intramolecular amination of the 2-azido biar-
yls 2a–2i (Scheme 1) by using the optimal experi-
mental conditions (Table 1, entry 7). To follow the
formation of heterocyclic compounds 4 and 5, we
1
4c 85
–
–
–
–
–
1
first performed a H NMR analysis after the com-
plete consumption of the azide and then again after
stirring the reaction for an additional 2 h in air at
1208C, without irradiating with the halogen lamp.
The experimental results listed in Table 2 indicate
that [RuACHTUNGTRENNUNG(TPP)CO] can be considered to be a com-
petent catalyst for a tandem reaction in which an
1.5
4d
–
5d 48[c]
5
6
7
1
4e 38
4 f 85
4g 24
5e 52[c] (90)[d]
À
intramolecular C H amination is followed by an
oxidation process. This reaction afforded good to
excellent yields of the phenanthridine by using the
[RuACHTUNGTRENNUNG(TPP)CO]/white-light/O2 combination.
1.5
2.5
–
–
It should be noted that the annulation of the
azide 2a under ruthenium catalysis afforded phen-
anthridine 5a in 47% yield (Table 2, entry 1),
whereas in the presence of a rhodium catalyst the
corresponding carbazole[8] was the major reaction
product. The compound 4a was not detected in the
1H NMR spectrum recorded under nitrogen after
5g 48[c] (72)[d]
1
8
9
3
1
4h 85
5h 10[c] (95)[d]
complete consumption of the azide. The H NMR
spectrum revealed the presence of aniline 1a and
carbazole 3a in 31 and 20% yield, respectively. This
result suggests that the annulation of 2a should
mainly occur through path A (Scheme 2) in which
the dihydrophenanthridine formed immediately
reacts with the azide, yielding equimolar amounts
of 5a and 1a.[32] The fast dehydrogenation of 4a is
responsible for the formation of the rest of 5a and
explains the absence of 4a in the reaction mixture.
The same behaviour was observed for the annula-
tion of 2d, showing, as expected, a favourable dehy-
drogenation process for dihydrophenanthridines
containing two hydrogen atoms at the six position.
This trend is less marked if an electron-withdrawing
group is present at the two position of the starting
4i
98
–
–
[a] General procedure for catalytic reactions: [RuACTHNUTRGNEUNG
(TPP)CO] (2.0 mg, 2.70ꢃ10À6 mol)
in 1,2-dichlorobenzene (20 mL) at 1208C under N2 and halogen-lamp irradiation
(400 W); molar ratio: catalyst/azide=1:100. [b] Time required to reach complete con-
1
version of the azide. [c] Determined by H NMR spectroscopy, with 2,4-dinitrotoluene
as the internal standard, after the complete consumption of azide. [d] Determined by
1H NMR spectroscopy, with 2,4-dinitrotoluene as the internal standard, after oxidation
by atmospheric oxygen. Isolated yields are reported in the Supporting Information.
derivative 4 (Table 2, entry 7). Dihydrophenanthridine was
found to be the unique reaction product only when the de-
hydrogenation process was impossible (Table 2, entries 3, 6
and 9). In all other cases, a dihydrophenanthridine/phen-
anthridine mixture was initially obtained and the further ox-
idation process allowed the complete transformation of 4
into 5 (Table 2, entries 2, 5, 7 and 8). The high yield of 4h
obtained for the annulation of 2h (Table 2, entry 8) is proba-
bly due to a synergic effect of the CF3 and CH3 groups pres-
ent at the two and six positions, respectively. In all experi-
ments reported in Table 2 the rest of the material consisted
of the aniline and carbazole corresponding to the azide em-
ployed (see the Supporting Information for yields).
In conclusion, we have presented a convenient three-step
methodology to form dihydrophenanthridines and phenan-
thridines from commercially available anilines and boronic
acids. The reported methodology presents several practical
advantages. Firstly, only 1 mol% of commercially available
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

E. Gallo et al.
À
[5] G. Smolinsky, J. Am. Chem. Soc. 1961, 83, 2489–2493.
[RuACHTUNGTRENNUNG(TPP)CO] catalyses an intramolecular C H amination,
[6] B. C. G. Soderberg, Curr. Org. Chem. 2000, 4, 727–764.
[7] Z. Shi, Y. Ren, B. Li, S. Lu, W. Zhang, Chem. Commun. 2010, 46,
3973–3975.
[8] B. J. Stokes, B. Jovanovic, H. J. Dong, K. J. Richert, R. D. Riell,
T. G. Driver, J. Org. Chem. 2009, 74, 3225–3228.
[9] W. G. Shou, J. Li, T. Guo, Z. Lin, G. Jia, Organometallics 2009, 28,
6847–6854.
[10] K. Sun, S. Liu, P. M. Bec, T. G. Driver, Angew. Chem. 2011, 123,
1740–1744; Angew. Chem. Int. Ed. 2011, 50, 1702–1706.
[11] B. J. Stokes, S. Liu, T. G. Driver, J. Am. Chem. Soc. 2011, 133, 4702–
4705.
[12] M. Shen, B. E. Leslie, T. G. Driver, Angew. Chem. 2008, 120, 5134–
5137; Angew. Chem. Int. Ed. 2008, 47, 5056–5059.
[13] B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey, T. G. Driver, J.
Am. Chem. Soc. 2007, 129, 7500–7501.
[14] K. Sun, R. Sachwani, K. J. Richert, T. G. Driver, Org. Lett. 2009, 11,
3598–3601.
[15] M. Shen, T. G. Driver, Org. Lett. 2008, 10, 3367–3370.
[16] J. V. Ruppel, R. M. Kamble, X. P. Zhang, Org. Lett. 2007, 9, 4889–
4892.
which is followed by an oxidation process in a tandem reac-
tion. Furthermore, the use of an ordinary halogen lamp
speeds up the reaction and renders the procedure feasible in
any laboratory and at a low cost. Finally, the formation of
molecular nitrogen as the by-product associated with the
use of molecular oxygen for the dihydrophenanthridine oxi-
dation grants this method sustainability.
Considering that porphyrins are potent photosensitisers
(PS) capable of transforming 3O2 into 1O2 by irradiation
with visible light,[35] the influence of the catalyst/white-light
combination on the decomposition of the azide N3 group de-
serves a more in-depth investigation. Moreover, because of
the great importance of the use of oxygen as a “green” oxi-
dising species, further work will be devoted to clarifying the
mechanism of the dihydrophenanthridine oxidation.
[17] H. Lu, J. Tao, J. E. Jones, L. Wojtas, X. P. Zhang, Org. Lett. 2010, 12,
1248–1251.
[18] H. Lu, H. Jiang, Y. Hu, L. Wojtas, X. P. Zhang, Chem. Sci. 2011, 2,
2361–2366.
Experimental Section
General procedure for catalytic reactions: In a typical reaction, the cata-
lyst (2.0 mg, 2.70·10À6 mol) and 2-azido biaryl (2.70·10À4 mol) were dis-
solved in 1,2-dichlorobenzene (20 mL) under a N2 atmosphere. The re-
sulting solution was heated at 1208C by using a pre-heated oil bath, and
irradiated with a halogen lamp (400 W). The consumption of 2-azido
biaryl was monitored by IR spectroscopy measuring the characteristic N3
absorbance in the range 2120–2127 cmÀ1. The reaction was considered
finished when the azide absorbance was below 0.03 (by using a 0.5 mm
thick cell). The solution was then evaporated to dryness and analysed by
1H NMR spectroscopy with 2,4-dinitrotoluene as the internal standard.
To isolate phenanthridines 5, the reaction was left stirring while it was ex-
posed to air at 1208C for an additional two hours after complete con-
sumption of the azide. The reaction mixture was evaporated to dryness
and the residue purified by flash column chromatography (see the Sup-
porting Information for more experimental details).
[19] H. Lu, H. Jiang, L. Wojtas, X. P. Zhang, Angew. Chem. 2010, 122,
10390–10394; Angew. Chem. Int. Ed. 2010, 49, 10192–10196.
[20] Y. Liu, J. Wei, C.-M. Che, Chem. Commun. 2010, 46, 6926–6928.
[21] M. A. Lynch, O. Duval, A. Sukhanova, J. Devy, S. P. MacKay, R. D.
Waigh, I. Nabiev, Bioorg. Med. Chem. Lett. 2001, 11, 2643–2646.
[22] R. T. McBurney, A. M. Z. Slawin, L. A. Smart, Y. Yu, J. C. Walton,
Chem. Commun. 2011, 47, 7974–7976.
[23] A. M. Linsenmeier, C. M. Williams, S. Brꢄse, J. Org. Chem. 2011, 76,
9127–9132.
[24] M. E. Budꢅn, V. B. Dorn, M. Gamba, A. B. Pierini, R. A. Rossi, J.
Org. Chem. 2010, 75, 2206–2218.
[25] N. D. Ca’, E. Motti, A. Mega, M. Catellani, Adv. Synth. Catal. 2010,
352, 1451–1454.
[26] G. Maestri, M.-H. Larraufie, E. Derat, C. Ollivier, L. Fensterbank,
E. Lacote, M. Malacria, Org. Lett. 2010, 12, 5692–5695.
[27] G. Smolinsky, J. Am. Chem. Soc. 1960, 82, 4717–4719.
[28] D. Intrieri, A. Caselli, F. Ragaini, P. Macchi, N. Casati, E. Gallo,
Eur. J. Inorg. Chem. 2012, 569–580.
Acknowledgements
[29] D. Intrieri, A. Caselli, F. Ragaini, S. Cenini, E. Gallo, J. Porphyrins
Phthalocyanines 2010, 14, 732–740.
We express our thanks to Dr. Nicolas Raoul for contributing to this work
and MIUR for financial support.
[30] S. Fantauzzi, E. Gallo, A. Caselli, F. Ragaini, N. Casati, P. Macchi, S.
Cenini, Chem. Commun. 2009, 3952–3954.
[31] S. Fantauzzi, A. Caselli, E. Gallo, Dalton Trans. 2009, 5434–5443.
[32] F. Ragaini, A. Penoni, E. Gallo, S. Tollari, C. L. Gotti, M. Lapadula,
E. Mangioni, S. Cenini, Chem. Eur. J. 2003, 9, 249–259.
[33] Q.-A. Chen, K. Gao, Y. Duan, Z.-S. Ye, L. Shi, Y. Yang, Y.-G. Zhou,
J. Am. Chem. Soc. 2012, 134, 2442–2448.
À
Keywords: azides
porphyrins · ruthenium
·
C H amination
·
heterocycles
·
[34] R. Sanz, Y. Fernꢆndez, M. P. Castroviejo, A. Pꢅrez, F. J. FaÇanꢆs,
Eur. J. Org. Chem. 2007, 62–69.
[35] M. Ethirajan, Y. Chen, P. Joshi, R. K. Pandey, Chem. Soc. Rev. 2011,
40, 340–362.
[1] S. Minakata, Acc. Chem. Res. 2009, 42, 1172–1182.
[2] S. Cenini, F. Ragaini, E. Gallo, A. Caselli, Curr. Org. Chem. 2011,
15, 1578–1592.
[3] B. J. Stokes, T. G. Driver, Eur. J. Org. Chem. 2011, 4071–4088.
[4] J. S. Swenton, T. J. Ikeler, B. H. Williams, J. Am. Chem. Soc. 1970,
92, 3103–3109.
Received: March 15, 2012
Revised: June 14, 2012
Published online: && &&, 0000
&
4
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

À
[RuACHTUNGTRENNUNG(TPP)CO]-Catalysed Intramolecular C H Amination
COMMUNICATION
Heterocycle Formation
D. Intrieri, M. Mariani, A. Caselli,
F. Ragaini, E. Gallo* ........ &&&& — &&&&
[Ru
ACHTUNGTNER(NUNG TPP)CO]-Catalysed Intra-
À
AHCTUNGTRENGNmUN olecular Benzylic C H Bond Amina-
tion, Affording Phenanthridine and
Dihydrophenanthridine Derivatives
Shedding light on azides: [Ru-
ACHTUNGTRENNUNG(TPP)CO] (TPP=tetraphenyl porphy-
rin dianion), white light and O2 were
found to be a suitable catalyst combi-
nation to perform the annulation of
several biaryl azides (see scheme). The
high chemoselectivity of the process
allows the synthesis of phenanthridines
and dihydrophenanthridines in good
yield and purity.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!