Preparation of phenanthrenes from ortho-amino-biphenyls and alkynes via base-promoted homolytic aromatic substitution

Article abstract of DOI:10.1039/c4cc10063h

A transition-metal-free phenanthrene synthesis starting from readily accessible ortho-amino-biaryls is presented. The biarylamines are in situ transformed into the corresponding diazonium salts which upon single electron reduction give the corresponding a

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Preparation of phenanthrenes from ortho-amino-
biphenyls and alkynes via base-promoted homolytic
aromatic substitution
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Marcel Hartmanna, Constantin Gabriel Daniliuca and Armido Studera,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A transition-metal-free phenanthrene synthesis starting from
readily accessible ortho-amino-biaryls is presented. The
biarylamines are in situ transformed to the corresponding
diazonium salts which upon single electron reduction give the
corresponding aryl radicals. Addition to an alkyne and
subsequent base promoted homolytic aromatic substitution
(BHAS) provide phenanthrenes in moderate to good yields.
Figure 1 Phenanthridines and phenanthrenes from ortho-aminobiphenyl via
BHAS reactions.
Base-promoted homolytic aromatic substitution (BHAS) has
recently gained great attention for direct C-H arylation.1,2 The
BHAS reaction can also be incorporated as key step in radical
cascade processes. This has been nicely documented by several
groups for preparation of phenanthridines starting with 2-
isocyanobiphenyls (Figure 1).3-9 These 2-isocyanobiphenyls are
readily accessed from the corresponding 2-aminobiphenyls by
formylation and subsequent dehydration. We wondered
whether 2-aminobiphenyls can also serve as precursors for
preparation of phenanthrenes via a radical cascade comprising a
BHAS reaction. Phenanthrenes are important organic
compounds which have found application in medicinal
chemistry10 and in materials science.11 Various methods for
Zanardi.16 The scope was limited and yields were moderate but
these examples clearly reveal that such a cascade reaction is
feasible. However, not all aryldiazonium salts are easily
accessible and isolation or storage due to their limited stability
is problematic. Herein we report a practical method for
preparation of phenanthrenes starting from readily accessible
biaryl amines. The biaryl amines are in situ transformed to the
corresponding diazonium salts which act as radical precursors. In
the past, diazonium salts have been successfully used in radical
cyclizations17 and more recently aryldiazonium salt chemistry by
using in situ generated diazonium salts has found increased
attention.18
Reaction was optimized by using biaryl amine 1a as a radical
precursor in combination with phenyl acetylene to provide
phenanthrene 2a (Table 1). We used isoamyl nitrite for in situ
diazonium salt generation, Bu4NI as a radical initiator and tested
various bases. Reactions were conducted under argon atmosphere
at 70 °C for 24 h in acetonitrile. Since we aimed at a base-
promoted homolytic aromatic substitution process, a challenge
was to identify basic conditions for in situ diazonium salt
generation. Note that in most cases, diazonium salt formation
occurs under acidic conditions.17,18
their
preparation
such as
[4+2] benzannulation,12
cycloisomerisation13 or photocyclization14 have been reported.
In addition, Zhou and co-workers recently introduced a radical
approach to phenanthrenes by reacting biaryldiazonium salts as
aryl radical precursors with alkynes in the presence of a
photoredox catalyst.15 A similar sequence for phenanthrene
synthesis starting with diazonium salts was also disclosed by
a
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität,
Corrensstraße 40, 48149 Münster, Germany. E-Mail: studer@uni-
muenster.de.
†
Electronic Supplementary Information (ESI) available: Experimental
The initial experiment was performed by using NaOAc with
3 equiv of phenyl acetylene and phenanthrene 2a was formed in
22% yield (entry 1). By increasing the amount of radical acceptor
procedures and spectral data for all compounds. CCDC reference
numbers 1039572 (2c) and 1039573 (2g).
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to 5 equiv, isolated yield was improved to 55% (entry 2). groups phenanthrene synthesis worked well (see 2g-k).
However, with 10 equiv of phenyl acetylene a worse result was Disappointingly, BHAS onto a naphthyl moiety was low yielding
obtained (entry 3). Increasing initiator loading to 20 mol% (see 2l). For the ortho-F-biphenyl derivative yield was significantly
resulted in a lower conversion (entry 4) and lowering the amount lower (see 2m) and as expected, the meta-congener 1n reacted with
of NaOAc also afforded a worse result (entry 5). Yield was low regioselectivity and both isomers 2n and 2n’ were formed. The
increased to 62% upon switching the solvent from MeCN to structures of 2c and 2g were confirmed by X-ray analysis (see SI).
benzotrifluoride (BTF, entry 6).
Table 1 Optimization studies.
entry
HCCPh
(equiv)
Bu4NI
(mol%)
base
(equiv)
solvent
yielda
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3.0
5.0
10.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
10
10
10
20
10
10
10
10
10
10
10
10
10
5
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (1.1)
NaOAc (1.1)
CsOAc (1.1)
MeCN
MeCN
MeCN
MeCN
MeCN
BTF
BTF
BTF
dioxane
BTF
BTF
22
55b
34
32
48
62
46
60
14
54c
60d
78b
72
66
55e
39
-
-
-
-
-
-
-
-
-
5.0
Figure 2 Substrate scope (variation of the aminobiphenyl component)
10.0
15.0
10.0
10.0
10.0
BTF
BTF
BTF
BTF
We next investigated the scope with respect to the alkyne radical
acceptor. Electronic effects exerted by the para-substituent of the
aryl acetylene are weak and phenanthrenes 2o-r were isolated in 69-
80% yield. Ortho and meta-substituents at the aryl moiety were
tolerated (2s,t), the naphthyl derivative worked well (2u) and also 2-
pyridyl acetylene provided the targeted product 2v in good yield.
10
-
BTF
aYield determined by 1H NMR analysis using an internal standard. bIsolated
yield. cWith 1 equiv of isoamyl nitrite. dWith 3 equiv of isoamyl nitrite. etert-
butyl nitrite instead of isoamyl nitrite was used.
CsOAc as a base provided 2a in only 46% (entry 7). Interestingly,
we found that external base is not needed rendering the overall
process even more economic (entry 8). Dioxane was not a suitable
solvent (entry 9) and 1.5 equiv of isomamyl nitrite was found to be
optimal for that cascade (entries 10 and 11). Yield was further
improved to 78% if 10 equiv of radical acceptor is added (entry 12).
A further increase of the radical acceptor concentration (15 equiv) or
decreasing the initiator loading to 5 mol% did not provide a better
t
result (entries 13, 14). The yield dropped to 55% by using BuONO
for diazonium salt formation (entry 15). Without any initiator, 2a
was obtained in 39% (entry 16). Initiation likely occurred by traces
of transition metals. An experiment under optimized conditions at
lager scale (1 mmol) provided 2a in 68% yield.
Under optimized conditions (Table 1, entry 12) various
aminobiphenyls19 1b-n were reacted with phenylacetylene to give
the corresponding phenanthrenes 2b-n in moderate to good yield
(Figure 2). Preparation of the biphenyls 1b-n is described in the
Supporting Information. We first investigated the effect of
substituent at the arene moiety of the biaryl where the BHAS
reaction occurs. Aminobiphenyls carrying electron-donating groups
at the para-position worked well and phenanthrenes 2c-f were
isolated in 69-85% yield. Electronic effects at the para-position are
not important since also for systems carrying electron withdrawing
Figure 3 Substrate scope (variation of the alkyne component)
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Enyne 1w was a substrate and also the cyclopropyl derivative 1x 6439; (f) H. Jiang, Y. Cheng, R. Wang, M. Zheng, Y. Zhang and S. Yu,
underwent addition/cyclization (see 2x). For the latter, products Angew. Chem. Int. Ed., 2013, 52, 50.
derived from cyclopropane ring-opening were not identified. This is
4
R = aryl: (a) M. Tobisu, K. Koh, T. Furukawa and N. Chatani,
likely due to the fact that ring-opening is reversible and the BHAS Angew. Chem. Int. Ed., 2012, 51, 11363; (b) Z. Xia, J. Huang, Y. He, J.
reaction can only occur on the cyclized vinyl radical. The electron- Zhao, J. Lei and Q. Zhu, Org. Lett., 2014, 16, 2546; (c) L. Gu, C. Jin, J.
poor methyl propiolate provided phenanthrene 2y in 48% yield. If Liu, H. Ding and B. Fan, Chem. Comm., 2014, 50, 4643.
ethynyltrimethylsilane is used as an acceptor, initial addition of the
aryl radical was not fully regioselective and the cascade provided the Chem. Commun., 2014, 50, 12892; (b) X. Sun and S. Yu, Org, Lett.,
two inseparable regioisomers 2z and 2z’ in 47% combined yield. 2014, 16, 2938; (c) B. Zhang, C. Mück-Lichtenfeld, C. G. Daniluc and A.
5
R = perfluoroalkyl: (a) J.-J. Cao, X. Wang, S.-Y. Wang and S.-J. Ji,
The suggested mechanism for the radical phenanthrene synthesis is Studer, Angew. Chem. Int. Ed., 2013, 52, 10792; (d) B. Zhang and A.
presented in Figure 4. The biaryl amine is first converted to the Studer, Org. Lett. 2014, 16, 3990.
corresponding diazonium salt with isoamyl nitrite. Initiation of the
6
R = CO2R’: (a) C. Pan, J. Han, H. Zhang and C. Zhu, J. Org. Chem.,
chain occurs by SET reduction of the diazonium salt with Bu4NI20 to 2014, 79, 5374; (b) G. Wang, S.-Y. Chen and X.-Q. Yu, Tetrahedron
generate aryl radical A.21 Addition of A to the alkyne provides vinyl Lett., 2014, 55, 5338; (c) X. Li, M. Fang, P. Hu, G. Hong, Y. Tang and X.
radical B which cyclizes to the arene to give cyclohexadienyl radical Xu, Adv. Synth. Catal., 2014, 356, 2103.
C. Deprotonation22 of C by the alcoholate derived from isoamyl
7
R = POR2: (a) J.-J. Cao, T.-H. Zhu, Z.-Y. Gu, W.-J. Hao, S.-Y. Wang
nitrite generates radical anion D which is eventually oxidized to and S.-J. Ji, Tetrahedron, 2014, 70, 6985; (b) Y. Li, G. Qiu, Q. Ding and
phenanthrene 2. In this step an electron is formally liberated which J. Wu, Tetrahedron, 2014, 70, 4652; (c) B. Zhang, C. G. Daniliuc and A.
then reduces the diazonium salt documenting the role of the electron Studer, Org. Lett. 2014, 16, 250.
as a catalyst in this cycle.23,24
8
R = acyl: (a) J. Liu, C. Fan, H. Yin, C. Qin, G. Zhang, X. Zhang, H.
Yi and A. Lei, Chem. Comm., 2014, 50, 2145; (b) D. Leifert, C. G.
Daniliuc and A. Studer, Org. Lett., 2013, 15, 6286.
9
R = SR’: H. Fang, J. Zhao, P. Qian, J. Han and Y. Pan, Asian J. Org.
Chem., 2014, , 12.
3
10 (a) L. Wei, A. Brossi, R. Kendall, K. F. Bastow, S. L. Morris-
Natschke, Q. Shi and K.-H. Lee, Bioorg. Med. Chem., 2006, 14, 6560; (b)
P. Dalta, M. D. Kalluri, K. Basha, A. Bellary, R. Kashirsagar, Y.
Kanekar, S. Upadhyay, S. Singh and V. Rajagopal, British Journal of
Pharmacology 2010, 160, 1158.
11 (a) K. Pelzer, L. Greenman, G. Gidofalvi and D. A. Mazzioti, J. Phys.
Chem. A., 2011, 115, 5632; (b) Y. Morita, S. Suzuki, K. Sato and T.
Takui, Nature Chemistry, 2011,
3, 197; (c) Y. Matsuo, Y. Sato, M.
Hashigushi, K. Matsuo and E. Nakamura, Adv. Func. Mater., 2009, 19
,
2224.
12 (a) Z. Shi, S. Ding, Y. Cui and N. Jiao, Angew. Chem., Int. Ed., 2009,
48, 7895; (b) C. Wang, S. Rakshit and F. Glorius, J. Am. Chem. Soc.,
2010, 132, 14006; (c) A. Matsumoto, L. Ilies and E. Nakamura, J. Am.
Chem. Soc., 2011, 133, 6557; (d) F. Ye, Y. Shi, L. Zhou, Q. Xiao, Y.
Zhang and J. Wang, Org. Lett., 2011, 13, 5020.
Figure 4 Suggested mechanism
In summary, we have developed a novel method for the preparation
of phenanthrenes. Starting materials are readily prepared and
reactions are easy to conduct. TBAI is used as a cheap and
commercially available chain initiator. Substrate scope is broad and
product phenanthrenes are obtained in moderate to good yields.
We thank Carolin Gerleve for conducting some experiments.
13 (a) V. Mamane and A. Fürstner, J. Org. Chem., 2002, 67, 6264; (b)
Y.-L. Liu, Y. Liang, S.-F- Pi, X.-C- Huang and J.-H. Li, J. Org. Chem.,
2009, 74, 3199; (c) Y. Kwon, H. Cho and S. Kim, Org. Lett., 2013, 15
,
920.
14 (a) W. F. Kiesman and F. W. Wassmundt, J. Org. Chem., 1995, 60
,
Notes and references
95; (b) A. G. Neo, C. López, V. Romero, B. Antelo, J. Delamano, A.
Pérez, D. Fernández, J. F. Almeida, L. Castedo and G. Tojo, J. Org.
Chem., 2010, 75, 6764; (c) K. Hamza, R. Abu-Reziq, D. Avnir and J.
1
2
A. Studer and D. P. Curran, Angew. Chem. Int. Ed., 2011, 50, 5018.
(a) T. L. Chan, Y. Wu, P. Y. Choy, F. Y. Kwong, Chem. Eur. J.,
Blum, Org. Lett., 2004, 6, 925.
2013, 19, 15802; (b) C.-L. Sun, Z.-J. Shi, Chem. Rev., 2014, 114, 9219.
R = alkyl: (a) Z.-Q. Zhu, T.-T. Wang, P. Bai and Z.-Z. Huang, Org.
15 T. Xiao, X. Dong, Y. Tang and L. Zhou, Adv. Synth. Catal., 2012,
354, 3195.
3
Biomol. Chem., 2014, 12, 31, 5839; (b) Z. Li, F. Fan, J. Yang and Z.-Q.
Liu, Org. Lett., 2014, 16, 3396; (c) Z. Xu, C. Yan and Z.-Q. Liu, Org.
Lett., 2014, 16, 5670; (d) Q. Dai, J.-T. Yu, X. Feng, Y. Jiang, H. Yang
and J. Cheng, Adv. Synth. Catal., 2014, 356, 16; (e) J.-J. Cao, T.-H. Zhu,
16 R. Leardini, D. Nanni, A. Tundo and G. Zanardi, Synthesis, 1988,
333.
17 (a) P. Han, J. Zhou, C.-C. Zhang, K. Chen and Z.-T. Du,
Heterocycles, 2014, 89, 2151; (b) H. Jasch, Y. Landais and M. R.
Heinrich, Chem. Eur. J., 2013, 19, 8411; (c) W. Fu, F. Xu, Y. Fu, M.
S.-Y. Wang, Z.-Y. Gu, X. Wang and S.-J. Ji, Chem. Comm., 2014, 50
,
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Zhu, J. Yu, C. Xu and P. Zou, J. Org. Chem., 2013, 78, 12202; (d) S.
Tang, P. Zhou and Y.-C. Wang, Eur. J. Org. Chem., 2014, 3656.
18 (a) F. P. Crisόstomo, T. Martin and R. Carillo, Angew. Chem. Int.
Ed., 2014, 53, 2181; (b) Review: F. Mo, G. Dong, Y. Zhang and J. Wang,
Org. Biomol. Chem., 2013, 11, 1582.
19 Aminobiphenyls were prepared by Pd-coupling reactions, see
Supporting Information. Alternatively, such compounds can also be
accessed by radical ortho-arylation of anilines, see: (a) H. Jasch, J.
Scheumann and M. R. Heinrich, J. Org. Chem., 2012, 77, 10699; (b) J.
Hofmann, H. Jasch and M. R. Heinrich, J. Org. Chem., 2014, 79, 2314.
20 (a) P. Finkbeiner and B. J. Nachtsheim, Synthesis, 2013, 45, 979; (b)
X.-F. Wu, J.-L. Gong and X. Qi, Org. Biomol. Chem. 2014, 12, 5807.
21 Recent examples on in situ diazonium salt generation: (a) N.
Chernyak and S. L. Buchwald, J. Am. Chem. Soc., 2012, 134, 12466; (b)
B. Bayarmagnai, C. Matheis, E. Risto and L. J. Goossen, Adv. Synth.
Catal., 2014, 356, 2343; (c) M. Hartmann and A. Studer, Angew. Chem.
Int. Ed. 2014, 53, 8180; (d) Review: L. He, G. Qiu, Y. Gao and J. Wu,
Org. Biomol. Chem., 2014, 12, 6965.
22 Calculated relative acidity of
C (R = Me) with respect to ortho-iodo
benzoic acid is -4.7 (DFT PW6B95-D3/def2-TZVP).
23 A. Studer, D. P. Curran, Nature Chem., 2014, 765.
24 Alternatively, the electron transfer can occur from cyclohexadienyl
radical
C to the diazonium salt followed by deprotonation.
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