HETEROCYCLES

Communication | Special issue | Vol. 86, No. 2, 2012, pp. 1045-1054
Received, 2nd November, 2012, Accepted, 26th November, 2012, Published online, 7th December, 2012.

■ Combined Directed Metalation – Suzuki-Miyaura Cross Coupling Strategies. Synthesis of Isomeric Chromenopyridinones and Related Annulated Analogues

Ricarda E. Miller,* Roman Sommer, Hope Fan, Victor Snieckus,* and Ulrich Groth

Department of Chemistry, Queen's University, 90 Bader Lane K7L 3N6, Canada

Abstract

A general strategy encompassing a Directed ortho Metalation (DoM) – Suzuki-Miyaura cross coupling and Directed remote Metalation (DreM) sequence for the synthesis of 5H-chromeno[4,3-c]pyridin-5-ones 5a-j, 5H-chromeno[3,4-b]pyridin-5-ones 6a-j, 5H-chromeno[3,4-c]pyridin-5-ones 13a-d, 12H-benzo[7,8]chromenopyridin-12-ones 16a-c, 17a-c, and pyrido[3',4':4,5]pyrano[2,3-e]indazol-5(1H)-one analogues 18, 28 is reported. Thus, using the powerful directed metalation group properties of aryl O-carbamates 9a-h, 14a-c metalation-boronation followed by Suzuki-Miyaura coupling with 3-bromopyridine affords a variety of azabiaryls 7a-i, 8a-b, 12a-c, 15a-c which, upon DreM reaction leads to several series of chromenopyridinones 5a-j, 6a-j, 13a-d and pyridonaphthopyrones 16a-c, 17a-c. The synthesis of an unusual pyridopyranoindazolone 18 is also described.

Directed ortho metalation (DoM) and directed remote metalation (DreM), when combined with transition metal catalyzed cross coupling reactions, offer regioselective, efficient, versatile, and at times unique, strategies for distinct aromatic and heteroaromatic structural elements to be embodied in bioactive molecules and natural products.1 As implementation of such tactics, we have recently reported the synthesis of the benzopyridopyranone, schumanniophytine2 and a wide-ranging route to dibenzo- pyranones,3 which involved key DoM – Suzuki-Miyaura cross coupling – DreM sequences. In view of the interest of the chromone and dibenzopyranone motifs as bioactive molecule targets,4 and as a rational extension of the previous work,2,3 we have undertaken to establish a general protocol for the preparation of annulated- and aza-dibenzopyranones involving the conceptual framework 1 ? 2 (Scheme 1) and herewith report the synthesis of several series of derivatives encompassing the structural types 3 and 4.

For the initial studies concerning the synthesis of the 5H-chromeno[3,4-b]pyridin-5-ones 5a-j and the 5H-chromeno[4,3-c]pyridin-5-one 6a-j series (Scheme 4), the necessary azabiaryls 7a-i and 8a,b (Scheme 2) were prepared in a straightforward manner starting from aryl O-carbamates 9a-h which, in turn, were obtained from the corresponding commercially available phenols. In preparation for the O-carbamate remote anionic Fries rearrangement, the necessary avoidance of the anionic ortho Fries reaction5 was secured by a DoM – silylation sequence of 9a-d,f to furnish compounds 10a-d,f. Sequential DoM – boronation and Suzuki-Miyaura cross coupling with 3-bromopyridines and 4-halopyridines yielded azabiaryls 7a-i in good to excellent yields.6 With exception of examples 11a-b, attempts to invert the sequence for 9a-h by TES electrophile introduction after the DoM – boronation – Suzuki coupling failed under standard s-BuLi/TMEDA, t-BuLi and LDA metalation conditions. On the other hand, the introduction of the TMS electrophile to give the DoM product 10e proceeded smoothly and, not surprisingly, subsequent sequential DoM – boronation and Suzuki-Miyaura cross coupling with 4-bromopyridine and 3-chloro-4-iodopyridine afforded azabiaryls 8a-b in good to excellent yields. For the methoxy-derivatives, an inverted sequence was employed (9g,h?11a,b?7h,i), to avoid the combined two DMGs in-between-metalation effect,7 which would have resulted in the formation of a different regioisomers. In contrast to the reaction of derivatives 9a-f, the TES silylation of 11a,b to give 7h,i proved to be efficient.

The ready availability of silylated azabiaryl 8a allowed a brief excursion to broaden the synthetic scope by virtue of sequential halo-ipsodesilylation8 and Suzuki-Miyaura cross coupling chemistry (Scheme 3). Thus, treatment of 8a with bromine and ICl smoothly led to the bromo-biaryl 12a and iodo-biaryl 12b derivatives respectively and the latter, upon cross-coupling with phenylboronic acid, furnished the corresponding azateraryl 12c in 95% yield.

LDA metalation of 7b-i under previously developed conditions3b,5a followed by treatment with conc. HCl:EtOH (1:1) mixture led to results shown in Scheme 4 and Table 2. Since pyridine ring C-H acidity is difficult to predict for 7 in view of inherent O-carbamate and pyridine nitrogen coordination effects and biaryl rotational barriers,9 formation of mixtures of isomeric products resulting from C-2 and C-4 deprotonation – remote anionic Fries rearrangement was expected. Furthermore, protodesilylation during the acid-catalyzed lactonization step was anticipated. Thus, for t-Bu and Ph-azabiaryls 7b and 7g, besides equal amounts of the two expected isomers 5a - 6a and 5c - 6c, the protodesilylated products 5b and 6b and 5d and 6d, respectively were isolated, the former pair in about 50% yield while the latter products in less than 10% yields. For the fluoro-derivative 7d, the [3,4-b]-isomer 6j was obtained exclusively, albeit in low yield which may be due to competing benzyne formation10 and polymerization reactions.

For chloro (7e) or fluoro (7f) pyridine, bearing only one remote metalation site, the formation of single regioisomers 5e and 5f was expected and observed, however, in low yields due to formation of an unidentified black material suggesting competitive formation of reactive intermediate pyridyne species.11 As for the above cases 5b - 6b and 5d - 6d, the formation of the desilylated isomer of 5e was observed; however, this was not the case for 5f. Most interestingly, for 7h,i bearing 3-methoxy groups, the exclusive formation of the isomer 5g,h was observed.12 The 4-methoxy biaryl (7c) led to the formation of both isomers with isomer 6i being favored.

The 4-azabiaryl O-carbamates 8a and 12a,c were also subjected to the same LDA metalation conditions followed by lactonization (HCl or HOAc) to furnish chromenopyridinones 13a-d (Scheme 5, Table 3). For 8a, depending on the lactonization conditions, two different products 13a and 13b were obtained, with 13a being the result of protodesilylation, a result which was not observed under the EtOH/HCl conditions. The yields of products 13a-d were again found to be very low for halogen-substituted pyridines due to formation of unidentified black material suggesting competitive formation of reactive pyridyne species as discussed above.11

With these results in hand, the synthesis of more complex pyridonaphthopyrones was undertaken (Scheme 6). Thus the 6-OMe and the 6-Cl pyridyl naphthalene O-carbamates 14a-c, prepared from commercially available 1-naphthol, 4-chloronaphthalen-1-ol and 4-methoxynaphthalen-1-ol, were subjected to metalation-boronation which, upon Suzuki-Miyaura cross-coupling with 3-bromopyridine gave the coupled products 15a-c in good to excellent yield.13

The DreM – lactonization sequence on 15a-c, carried out under the standard LDA conditions, afforded pyridonaphthopyrones 16a-c and 17a-c. The yields and isomer distribution of products, while random and not rationalized without additional data, are undoubtedly related to the electronic nature of the substituent and the O-carbamate and pyridyl ring rotational barrier effects of the naphthalenylpyridines 15a-c. Thus, with the reasonable assumption of high yielding lactonization, the lowest combined yields of products are for the substituted DreM products of 15b, to give the single isomer 17b in 31% yield, and 15c, to give 16c,17c in a combined 38% yield. The low yield for the chloro derivatives 16c,17c may be due to competitive benzyne formation and further decomposition as well known to occur under LDA conditions for their simple aromatic counterpart compounds.11 The through-bond electronic effect of the OMe groups on the pyridyl C-2' vs C-4' C-H acidity, favoring isomer 16b over 17b is difficult to appreciate without calculational data but is supported by a different study.13

To extend the scope of the DoM – Suzuki-Miyaura cross coupling – DreM strategy, the synthesis of a pyrazole-annulated pyridochromone 18 variant was undertaken (Scheme 7). α-Bromination of 19 gave the corresponding α-brominated cyclohexanone,14 whose conversion by HBr elimination as well as other direct oxidative means to 20a proved to be unsuccessful.13 However, bromination conditions using CuBr2 (2 equiv)15 and dehydrobromination with Li2CO3/LiBr in DMF16 afforded phenol 20a (69% yield, over two steps) which, upon carbamoylation, gave the desired O-carbamate 21 in good overall yield. DoM reaction followed by quench with triisopropyl borate and further treatment with pinacol provided the ortho-B-pinacolate 22 in 86% yield,13 which was subjected to Suzuki-Miyaura cross coupling with 3-bromopyridine to furnish the pyridoindazole 23 in 99% yield. However, and perhaps not surprisingly in view of the higher acidity of indazole C-3 H over pyridine C-2/C-4 hydrogens,17 treatment with LDA as well as other bases (s-BuLi, LiTMP) failed to induce either of the potential DreM reactions, resulting instead in the formation of the ring cleavage product 24 in quantitative yield. To overcome this impasse, an alternative, non-DreM approach was undertaken. Thus the bis α-bromination product of 19 was converted into the ortho-bromophenol 20b,13 which was acylated to 25 and the latter was subjected to a Stille cross coupling with the requisite ortho-stannylated benzamide 26 to give the azabiayl 27 in good overall yield (64%, four steps from cyclohexanone 19). Lactonization (conc. HCl, EtOH 1:1) to give 28, followed by de t-butylation (H2SO4) afforded the interesting pyridopyranoindazolone 18 in 66% yield.

In summary, the combined DoM – Suzuki-Miyaura – DreM strategy1-3 has been extended to effective and general syntheses of new heterocyclic systems 5H-chromeno[4,3-c]pyridin-5-ones and 5H-chromeno[3,4-b]pyridin-5-ones (5a-j, 6a-j, Scheme 4), 5H-chromeno[3,4-c]pyridin-5-ones (13a-d, Scheme 5), 12H-benzo[7,8]chromenopyridin-12-ones (16a-c, 17a-c, Scheme 6), and pyrido[3',4':4,5]pyrano[2,3-e]indazol-5(1H)-one analogues (18, 28, Scheme 7). While occurring in modest yields, the DreM reaction provides a method for intramolecular carbamoyl translocation to the alternate ring of a biaryl or azabiaryl. Alternative, direct cross coupling with more highly substituted benzamide or aryl boronic acid partners may be of lower efficacy due to steric requirements.18 In the course of this work, new DoM chemistry of an indazole 4-O-carbamate (21, Scheme 7) has been achieved. Complete synthetic studies with bioactivity data will be published in due course.

ACKNOWLEDGEMENTS
We thank the Graduate School Chemical Biology Konstanz for scientific encouragement and financial support. RM is also grateful for a fellowship from the Studienstiftung des Deutschen Volkes (German National Academic Foundation). VS is grateful to NSERC Canada Discovery Grant (DG) program for continuing support.

References

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4. Schumanniophytine: central and autonomic depressant potentially antiviral agent. a) P. J. Houghton, In The Alkaloids; ed. by A. Brossi, Academic Press, London, 1987, Vol. 31, 67–100; b) P. J. Houghton, T. Z. Woldemariam, A. I. Khan, A. Burke, and N. Mahmood, Antivir. Res., 1994, 25, 235; CrossRef Chromones: c) Anti-HCV: J. Neyts, E. DeClercq, R. Singha, Y. H. Chang, A. R. Das, S. K. Chakraborty, S. Ching Hong, S. Tsay, M.-H. Hsu, and J. Ru Hwu, J. Med. Chem., 2009, 52, 1486; CrossRef d) Antibacterial: V. S. V. Satyanarayana, P. Sreevani, A. Sivakumar, and V. Vijayakumar, ARKIVOC, 2008, 17, 221.
5. TES rather than TMS protection was required due to an interesting α-deprotonation-carbamoyl migration reaction observed for the latter derivative, see W. Wang and V. Snieckus, J. Org. Chem., 1992, 57, 424; CrossRef S.-I. Mohri, M. Stefinovic, and V. Snieckus, J. Org. Chem., 1997, 62, 7072. CrossRef
6. Representative example: To a solution of s-BuLi (4.89 mL, 6.86 mmol) was added a solution of TMEDA (0.790 g, 6.85 mmol) in THF (60 mL) at -78 °C and the whole was stirred for 10 min, before O-carbamate 10e (2.00 g, 6.23 mmol, in 3.0 mL THF) was added. After 1 h at -78 °C, B(Oi-Pr)3 (2.32 g, 16.2 mmol) was added, the mixture was stirred for an additional 30 min, warmed to 0 °C, and acidified (< pH 5, 1 M aq HCl), and the whole was extracted (EtOAc), dried (MgSO4) and concentrated. To the crude residue, 4-bromopyridine hydrochloride (1.21 g, 6.23 mmol), [Pd(PPh3)4] (0.140 g, 0.121 mmol), Na2CO3 (1.32 g, 12.5 mmol), degassed DME (20 mL) and degassed Na2CO3 (16 mL, 2 M aq solution) was added and the mixture was heated at 90 °C for 12 h, water was added, and the whole was extracted with EtOAc, dried and concentrated. Flash column chromatography (pet ether/EtOAc 1/1) followed by recrystallization (MeOH) yielded 2.28 g (5.72 mmol, 92%) of compound 8b as a colourless solid; mp 86-89 °C (MeOH); IR (ATR) cm-1: 1702; 1H-NMR (CDCl3, 400 MHz, 293K) δ 0.15 (s, 9H), 0.71 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H), 1.19 (s, 9H), 3.06 (br s, 2H), 3.32 (q, J = 7.2 Hz, 2H), 7.15 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 6.0 Hz, 2H), 7.38 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 6.0 Hz, 2H) ppm; 13C-NMR (CDCl3, 100 MHz, 293K) δ -0.71, 12.6, 13.9, 31.4, 34.5, 41.1, 41.4, 123.9, 127.1, 128.7, 131.8, 132.7, 146.8, 147.9, 149.6, 151.7, 153.3 ppm; LRMS (70 eV), m/z (%) = 398(40)[M+], 100(100)[CONEt2+]; Anal. Cacld for C23H34N2O2Si requires: C 69.30, H 8.60, N 7.03. Found: C 68.98, H 8.38, N 6.74.
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13. Metalation-electrophile quench reactions with other electrophiles as well as the anionic Fries rearrangement of 21 occur smoothly providing a hitherto unexplored DoM playground. These reactions as well as an alternative route to isomeric pyridonaphthopyrones 16a-c, 17a-c will be reported in a full account of our studies.
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