Regioselective Pd-catalyzed direct C1- And C2-arylations of lilolidine for the access to 5,6-dihydropyrrolo[3,2,1-ij]quino-line derivatives

Article abstract of DOI:10.3762/bjoc.15.204

The Pd-catalyzed C–H bond functionalization of lilolidine was investigated. The use of a palladium-diphosphine catalyst associated to acetate bases in DMA was found to promote the regioselective arylation at α-position of the nitrogen atom of lilolidine w

Full text of DOI:10.3762/bjoc.15.204

Regioselective Pd-catalyzed direct C1- and C2-arylations of
lilolidine for the access to 5,6-dihydropyrrolo[3,2,1-ij]quino-
line derivatives
Hai-Yun Huang, Haoran Li, Thierry Roisnel, Jean-François Soulé* and Henri Doucet*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2069–2075.
Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes, France
doi:10.3762/bjoc.15.204
Email:
Received: 04 June 2019
Accepted: 14 August 2019
Published: 29 August 2019
Jean-François Soulé* - jean-francois.soule@univ-rennes1.fr;
Henri Doucet* - henri.doucet@univ-rennes1.fr
*
Corresponding author
Associate Editor: K. Itami
§
Phone: 0033 (0)2 23 23 63 84
©
2019 Huang et al.; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
catalysis: C–C bond formation; C–H bond activation; lilolidine;
palladium
Abstract
The Pd-catalyzed C–H bond functionalization of lilolidine was investigated. The use of a palladium-diphosphine catalyst associat-
ed to acetate bases in DMA was found to promote the regioselective arylation at α-position of the nitrogen atom of lilolidine with a
wide variety of aryl bromides. From these α-arylated lilolidines, a second arylation at the β-position gives the access to α,β-diary-
lated lilolidines containing two different aryl groups. The one pot access to α,β-diarylated lilolidines with two identical aryl groups
is also possible by using a larger amount of aryl bromide. The synthesis of 5,6-dihydrodibenzo[a,c]pyrido[3,2,1-jk]carbazoles from
lilolidine via three successive direct arylations is also described. Therefore, this methodology provides a straightforward access to
several lilolidine derivatives from commercially available compounds via one, two or three C–H bond functionalization steps
allowing to tune their biological properties.
Introduction
Lilolidine (Figure 1, left), which is a commercially available ration of lilolidine derivatives is an important research area in
compound, contains a 5,6-dihydropyrrolo[3,2,1-ij]quinoline pharmaceutical chemistry.
skeleton found in several bioactive molecules. For example,
tivantinib (Figure 1, middle) exhibits MET inhibitor properties To the best of our knowledge, so far only a few methods allow
[
1]; whereas tarazepide (Figure 1, right) is being investigated the synthesis of lilolidines arylated at α- [6,7] or β- [8-13] posi-
for the treatment of gastrointestinal diseases. Other lilolidine tions of the nitrogen atom. In 2014, Chen and Tang et al. re-
derivatives also exhibit properties for the treatment of cancers ported that NH4PF6 promotes the cyclodehydration of
[
2-5]. Therefore, the discovery of simple methods for the prepa- α-aminocarbonyl compounds, leading to the formation of
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Beilstein J. Org. Chem. 2019, 15, 2069–2075.
Figure 1: Structures of lilolidine, tivantinib and tarazepide.
β-arylated 5,6-dihydropyrrolo[3,2,1-ij]quinoline derivatives [6] pyrroles and indoles [14,15], this methodology has been widely
Scheme 1a). Three α-arylated 5,6-dihydropyrrolo[3,2,1- applied for the preparation of new aryl-substituted heteroarenes
(
ij]quinoline derivatives have been prepared by Pal et al. via the [16-21]. Several results dealing with the C–H bond functionali-
cyclization of 8-arylethynyl-1,2,3,4-tetrahydroquinolines [9] zation of indoles have been reported allowing to prepare either
(
Scheme 1b). The best results were obtained using 10 mol % of α- [22-31] or β-arylated [32-37] indoles, depending on the reac-
CuI as catalyst in DMF at 100 °C.
tion conditions. However, to the best of our knowledge, no ex-
ample of regioselective α- or β-arylations via the C–H bond
The late stage C–H bond functionalization of molecules repre- functionalization of lilolidine has been reported so far
sents a powerful method for the easy screening of the biologi- (Scheme 1c).
cal properties of compounds containing a bioactive unit. Since
the seminal work by Ohta et al. on the Pd-catalyzed C–H bond Herein, we report i) on the simple access to α-arylated 5,6-
functionalization of heteroarenes such as thiophenes, furans, dihydropyrrolo[3,2,1-ij]quinolines using an air-stable Pd cata-
Scheme 1: Access to α- and β-arylated lilolidine derivatives.
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Beilstein J. Org. Chem. 2019, 15, 2069–2075.
lyst associated to an inexpensive base, ii) on the sequential were observed (Table 1, entries 4–6). In order to improve the
access to α,β-diarylated 5,6-dihydropyrrolo[3,2,1-ij]quinolines conversions of the aryl bromide, the thermally more stable
containing identical or different aryl groups at α- and β-posi- PdCl(C3H5)(dppb) catalyst [39] was employed. With K2CO3
tions via two-fold Pd-catalyzed C–H bond functionalizations, and Na2CO3, the conversion of 3-bromobenzonitrile was not
iii) on the synthesis of 5,6-dihydrodibenzo[a,c]pyrido[3,2,1- improved, whereas using NaOAc, a complete conversion of the
jk]carbazoles via three successive C–H bond functionalization aryl bromide was observed (Table 1, entries 8–10). Moreover,
steps (Scheme 1c).
the regioselectivity in favor of α-arylated lilolidine was im-
proved to 93% affording 1a in 83% yield. The use of KOAc as-
sociated to PdCl(C3H5)(dppb) catalyst also afforded the regio-
Results and Discussion
Based on our previous results on the arylation of heteroaro- isomer 1a in a quite good regioselectivity and yield (Table 1,
matics [38], we initially employed 1 mol % Pd(OAc)2 catalyst entry 11). The higher conversions observed in the presence of
associated to KOAc as the base in DMA at 150 °C as the reac- acetate bases compared to carbonate bases (Table 1, entries 4–6
tion conditions to promote the coupling of lilolidine with and 8–11) might be due to an easier coordination of acetates to
3
-bromobenzonitrile (Table 1, entry 1). Under these conditions palladium which favors the concerted metallation deproton-
a mixture of the α- and β-arylated lilolidines 1a and 1b was ob- ation (CMD) mechanism [40]. The regioselectivities observed
tained in a 64:36 ratio. Then, the influence of some bases on the using acetate bases are consistent with a CMD mechanism.
regioselectivity with Pd(OAc)2 catalyst was examined. With
CsOAc a similar regioselectivity than with KOAc was obtained, Then, a set of aryl bromides was reacted with lilolidine using
whereas the use of NaOAc afforded the products 1a and 1b in 2 mol % of PdCl(C3H5)(dppb) catalyst, NaOAc or KOAc as
an 85:15 ratio, but with a moderate conversion of 3-bromoben- bases in DMA at 150 °C (Scheme 2). We initially studied the
zonitrile (Table 1, entries 2 and 3). High regioselectivities in reactivity of electron-deficient aryl bromides. Acetyl, propionyl,
favor of isomer 1a (85–90%) were also obtained using K2CO3 benzoyl and ester as para-substituents on the aryl bromides
and Na2CO3, but partial conversions of 3-bromobenzonitrile were tolerated affording the target products 2–6 in 64–77%
Table 1: Influence of the reaction conditions on the palladium-catalyzed direct coupling of lilolidine with 3-bromobenzonitrile.a
Entry
Catalyst (mol %)
Base
Conv. (%)
Ratio 1a:1b
Yield in
a (%)
1
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
PdCl(C3H5)(dppb) (2)
KOAc
100
100
65
40
0
33
0b
42
35
64:36
69:31
85:15
90:10
–
85:15
–
90:10
91:9
93:7
82:18
63
58
43
37
–
n.d.
–
n.d.
n.d.
83
68
CsOAc
NaOAc
K2CO3
Cs2CO3
Na2CO3
KOAc
K2CO3
Na2CO3
NaOAc
KOAc
1
1
0
1
100
100
aConditions: lilolidine (1.5 mmol), 3-bromobenzonitrile (1 mmol), base (2 mmol), DMA, under argon, 16 h, 150 °C, isolated yields. bIn xylene.
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Beilstein J. Org. Chem. 2019, 15, 2069–2075.
Scheme 2: Synthesis of α-arylated lilolidine derivatives.
yields. The structure of 2 was confirmed by X-ray analysis. A marketed drugs contain these units. Therefore, the reactivity of
lower yield of 7 was obtained for the reaction of 4-bromobenz- 3- and 4-bromo-substituted pyridines, 3-bromoquinoline and
aldehyde with lilolidine due to the formation of degradation 4-bromoisoquinoline for the α-arylation of lilolidine was also
products. Good yields in 8 and 9 were obtained from 4-chloro- studied. In all cases, the desired N-containing coupling prod-
and 4-carbonitrile-substituted aryl bromides. In all cases, with ucts 16–19 were obtained in high regioselectivities and in
these para-substituted aryl bromides, high regioselectivities in 58–74% yields.
favor of the α-arylations were observed. The meta-substituted
3
-bromoacetophenone and methyl 3-bromobenzoate also Then, the one-pot synthesis of α,β-di(hetero)arylated 5,6-
afforded the α-arylated lilolidines 10 and 11 with high regiose- dihydropyrrolo[3,2,1-ij]quinolines was attempted (Scheme 3).
lectivities. Conversely, with the more sterically hindered aryl The use of a larger amount of aryl bromides (3 equiv) provided
source 2-bromobenzonitrile, a mixture of α- and β-arylated lilo- the target diarylated lilolidines 20–22 in good yields. Under
lidine derivatives was obtained (ratio α:β 69:31). The reactivity these conditions, the mono-arylated lilolidines were detected in
of two electron-rich aryl bromides was also examined. With very low yields by GC–MS analysis of the crude mixtures. The
4
-tert-butylbromobenzene and 4-bromoanisole, the target prod- structure of 20 was confirmed by X-ray diffraction.
ucts 13 and 14 were obtained with high regioselectivities, but in
low yields due to a partial conversion of these aryl bromides. It As α-arylated lilolidines can be easily obtained under the reac-
should be mentioned that the use of aryl chlorides instead of tion conditions shown in Scheme 2, the synthesis of α,β-diary-
aryl bromides did not allow to improve the regioselectivities or lated 5,6-dihydropyrrolo[3,2,1-ij]quinolines containing two dif-
the reaction yields. With 4-chlorobenzonitrile, product 2 was ferent aryl groups at α- and β-positions via sequential Pd-cata-
obtained in 80% regioselectivity and in 38% yield; whereas the lyzed C–H bond functionalization steps was studied
use of 2-chlorobenzonitrile afforded 12 in 62% regioselectivity (Scheme 4). The reaction of 1 equiv of 4-(5,6-dihydro-
and in 34% yield. In both cases, partial conversions of the aryl pyrrolo[3,2,1-ij]quinolin-2-yl)benzonitrile 2 and 1.5 equiv of a
chlorides were observed.
set of aryl bromides using again 2 mol % PdCl(C3H5)(dppb)
catalyst associated to KOAc provided the desired diarylated
Pyridines and quinoline heterocycles are very important struc- lilolidines 23–26 in 55–87% yields. The structure of 23 was
tures in pharmaceutical chemistry as more than 100 currently confirmed by X-ray diffraction.
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Beilstein J. Org. Chem. 2019, 15, 2069–2075.
Scheme 3: Synthesis of α,β-di(hetero)arylated lilolidine derivatives.
Scheme 5: Synthesis of 5,6-dihydrodibenzo[a,c]pyrido[3,2,1-
jk]carbazoles via successive direct arylations.
Scheme 4: Synthesis of α,β-diarylated lilolidine derivatives via succes-
sive direct arylations.
ation strategy was also effective for the synthesis of the
carbazole 29 from the pyridine α-substituted lilolidine 17.
Finally, the synthesis of 5,6-dihydrodibenzo[a,c]pyrido[3,2,1-
jk]carbazoles via β-arylation of the previously obtained Conclusion
α-arylated lilolidines followed by an intramolecular Pd-cata- The late stage Pd-catalyzed C–H bond functionalization allows
lyzed direct arylation was examined (Scheme 5). The reaction to prepare (di)arylated lilolidine derivatives in only one or two
of compound 2 with 1,2-dibromobenzene in the presence of steps. The α-arylated lilolidines were generally obtained in high
2
mol % PdCl(C3H5)(dppb) catalyst and KOAc as base afforded regioselectivities and in good yields using aryl bromides as
the desired carbazole 27 in moderate yield after 16 h due to a easily available aryl sources, acetates as inexpensive bases and
partial conversion of 2. However, the use of a longer reaction PdCl(C3H5)(dppb) as air-stable catalyst. The reaction tolerated
time (48 h) allowed to reach an almost complete conversion of a wide variety of useful functional groups such as nitrile,
2
, and the carbazole 27 was isolated in 62% yield. A slightly formyl, acetyl, propionyl, benzoyl, esters, chloro, or aceto-
lower yield in the carbazole 28 was obtained from (4-(5,6- nitrile on the aryl bromide and the heteroaryl bromides 3- or
dihydropyrrolo[3,2,1-ij]quinolin-2-yl)phenyl)(phenyl)methan- 4-bromopyridines and 3-bromoquinoline. From these α-arylated
one 5 and 1,2-dibromobenzene. This sequential C–H bond aryl- lilolidines, a second Pd-catalyzed direct arylation at β-position
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Beilstein J. Org. Chem. 2019, 15, 2069–2075.
5
6
.
.
Zhang, H.; Wu, W.; Feng, C.; Liu, Z.; Bai, E.; Wang, X.; Lei, M.;
Cheng, H.; Feng, H.; Shi, J.; Wang, J.; Zhang, Z.; Jin, T.; Chen, S.;
Hu, S.; Zhu, Y. Eur. J. Med. Chem. 2017, 135, 12–23.
doi:10.1016/j.ejmech.2017.04.036
Ji, X.-M.; Zhou, S.-J.; Deng, C.-L.; Chen, F.; Tang, R.-Y. RSC Adv.
2014, 4, 53837–53841. doi:10.1039/c4ra11168k
gave rise to α,β-diarylated lilolidines with two different aryl
units. The one pot access to α,β-diarylated lilolidines with
two identical aryl groups was also possible by using a larger
amount of aryl bromide. The synthesis of 5,6-dihydrodi-
benzo[a,c]pyrido[3,2,1-jk]carbazoles from lilolidine via three
successive direct C–H bond arylations also proceed nicely. 7. Ghorai, J.; Reddy, A. C. S.; Anbarasan, P. Chem. – Eur. J. 2016, 22,
1
6042–16046. doi:10.1002/chem.201604111
Therefore, this methodology provides a straightforward access
to a wide variety of α- and β-(hetero)aryl-substituted lilolidines
allowing to tune or modify their biological properties.
8
9
.
.
Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853–2856.
doi:10.1021/ol0201052
Layek, M.; Dhanunjaya Rao, A. V.; Gajare, V.; Kalita, D.;
Barange, D. K.; Islam, A.; Mukkanti, K.; Pal, M. Tetrahedron Lett. 2009,
5
0, 4878–4881. doi:10.1016/j.tetlet.2009.06.041
Supporting Information
Supporting information features experimental procedures,
products characterizations, copies of 1H and 13C NMR
spectra of all products and CCDC numbers of products 2,
1
1
0.Wang, C.; Huang, Y. Org. Lett. 2013, 15, 5294–5297.
doi:10.1021/ol402523x
1.Wang, J.; Wang, M.; Chen, K.; Zha, S.; Song, C.; Zhu, J. Org. Lett.
2016, 18, 1178–1181. doi:10.1021/acs.orglett.6b00310
12.Panferova, L. I.; Smirnov, V. O.; Levin, V. V.; Kokorekin, V. A.;
Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2017, 82, 745–753.
doi:10.1021/acs.joc.6b02344
2
0 and 23.
1
1
1
3.Xu, C.; Xu, J. J. Org. Chem. 2018, 83, 14733–14742.
doi:10.1021/acs.joc.8b02203
Supporting Information File 1
Experimental procedures and NMR spectra of compounds
4.Akita, Y.; Inoue, A.; Yamamoto, K.; Ohta, A.; Kurihara, T.; Shimizu, M.
Heterocycles 1985, 23, 2327–2333. doi:10.3987/r-1985-09-2327
5.Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.;
Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951–1958.
doi:10.3987/com-90-5467
1
–29.
[
https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-204-S1.pdf]
1
1
6.Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205.
doi:10.1246/cl.2007.200
7.Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269–10310.
doi:10.1016/j.tet.2009.10.015
Acknowledgments
We thank China Scholarship Council for a fellowships to HH
and HL.
18.Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed. 2009, 48,
792–9826. doi:10.1002/anie.200902996
9.Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014,
56, 17–117. doi:10.1002/adsc.201300922
9
1
2
ORCID® iDs
3
Thierry Roisnel - https://orcid.org/0000-0002-6088-4472
Jean-François Soulé - https://orcid.org/0000-0002-6593-1995
Henri Doucet - https://orcid.org/0000-0002-1410-3663
0.Gensch, T.; James, M. J.; Dalton, T.; Glorius, F.
Angew. Chem., Int. Ed. 2018, 57, 2296–2306.
doi:10.1002/anie.201710377
2
2
2
2
1.Mao, S.; Li, H.; Shi, X.; Soulé, J.-F.; Doucet, H. ChemCatChem 2019,
11, 269–286. doi:10.1002/cctc.201801448
2.Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72,
References
1
2
.
.
Remsing Rix, L. L.; Kuenzi, B. M.; Luo, Y.; Remily-Wood, E.;
Kinose, F.; Wright, G.; Li, J.; Koomen, J. M.; Haura, E. B.;
Lawrence, H. R.; Rix, U. ACS Chem. Biol. 2014, 9, 353–358.
doi:10.1021/cb400660a
1
476–1479. doi:10.1021/jo061979v
3.Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007,
3, 1970–1980. doi:10.1016/j.tet.2006.12.068
6
4.Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1473–1476.
doi:10.1002/anie.200704619
5.Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428–7431.
doi:10.1021/jo801371w
Huang, W.-S.; Li, F.; Dalgarno, D. C.; Gong, Y.; Ishchenko, A. V.;
Kohlmann, A.; Shakespeare, W. C.; West, A. V.; Xu, Y.;
Youngsaye, W.; Zhang, Y.; Zhou, T.; Zhu, X. Preparation of
2
2
2
2
2
3
2-anilino-4-heteroarylpyrimidine compounds for inhibition of mutant
EGFR and mutant HER2 kinase. PCT Int. Appl. WO2015175632A1,
Nov 19, 2015.
6.Joucla, L.; Batail, N.; Djakovitch, L. Adv. Synth. Catal. 2010, 352,
2929–2936. doi:10.1002/adsc.201000512
3
4
.
.
Wei, Y.; Li, Y.; Zhang, G.; Qui, G.; Hu, S.; Chen, L.; Li, S.; Zhang, Q.
Preparation of (substituted phenyl) (substituted pyrimidine) amino
deriv. as anticancer drugs. PCT Int. Appl. WO2016029839A1, March 3,
7.Liang, Z.; Yao, B.; Zhang, Y. Org. Lett. 2010, 12, 3185–3187.
doi:10.1021/ol101147b
8.Zhou, J.; Hu, P.; Zhang, M.; Huang, S.; Wang, M.; Su, W.
Chem. – Eur. J. 2010, 16, 5876–5881. doi:10.1002/chem.201000529
9.Wang, L.; Yi, W.-b.; Cai, C. Chem. Commun. 2011, 47, 806–808.
doi:10.1039/c0cc01666g
2016.
Zhu, Y.; Liu, Z.; Feng, C.; Hu, S.; Chen, H.; Bai, E.; Wang, J.; Shi, J.
Deuterated 3-(4,5-substituted pyrimidinamine) phenyl derivative useful
in treatment of cancer and its preparation. PCT Int. Appl.
WO2018050108A1, March 22, 2018.
0.Lu, G.-p.; Cai, C. Synlett 2012, 23, 2992–2996.
doi:10.1055/s-0032-1317702
2
074

Beilstein J. Org. Chem. 2019, 15, 2069–2075.
3
3
3
1.Wu, M.; Luo, J.; Xiao, F.; Zhang, S.; Deng, G.-J.; Luo, H.-A.
Adv. Synth. Catal. 2012, 354, 335–340. doi:10.1002/adsc.201100603
2.Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm. Bull. 1989,
37, 1477–1480. doi:10.1248/cpb.37.1477
3.Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R.
Tetrahedron Lett. 2007, 48, 2415–2419.
doi:10.1016/j.tetlet.2007.01.173
3
3
3
3
3
3
4.Cusati, G.; Djakovitch, L. Tetrahedron Lett. 2008, 49, 2499–2502.
doi:10.1016/j.tetlet.2008.02.130
5.Bellina, F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529–5535.
doi:10.1021/jo8007572
6.Ackermann, L.; Barfüßer, S. Synlett 2009, 808–812.
doi:10.1055/s-0028-1087951
7.Cornella, J.; Lu, P.; Larrosa, I. Org. Lett. 2009, 11, 5506–5509.
doi:10.1021/ol902304n
8.Zhao, L.; Bruneau, C.; Doucet, H. ChemCatChem 2013, 5, 255–262.
doi:10.1002/cctc.201200521
9.Cantat, T.; Génin, E.; Giroud, C.; Meyer, G.; Jutand, A.
J. Organomet. Chem. 2003, 687, 365–376.
doi:10.1016/s0022-328x(03)00791-5
4
0.Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.;
DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676–14681.
doi:10.1021/ja107159b
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