Rapid synthesis of bis(hetero)aryls by one-pot Masuda borylation-Suzuki coupling sequence and its application to concise total syntheses of meridianins A and G

Article abstract of DOI:10.1039/c1ob05310h

3-(Hetero)aryl substituted indoles, 7-azaindoles, and pyrroles can be obtained in a very concise fashion via a one-pot Masuda borylation-Suzuki coupling sequence. The concise total syntheses of the marine natural products meridianins A (5) and G (4i) nice

Full text of DOI:10.1039/c1ob05310h

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Rapid synthesis of bis(hetero)aryls by one-pot Masuda borylation–Suzuki
coupling sequence and its application to concise total syntheses of meridianins
A and G†‡ §
Eugen Merkul, Elisabeth Scha¨fer and Thomas J. J. Mu¨ller*
Received 2nd December 2010, Accepted 25th February 2011
DOI: 10.1039/c1ob05310h
3-(Hetero)aryl substituted indoles, 7-azaindoles, and pyrroles
can be obtained in a very concise fashion via a one-pot
Masuda borylation–Suzuki coupling sequence. The concise
total syntheses of the marine natural products meridianins A
(5) and G (4i) nicely illustrate the utility of this methodology.
values (i.e. concentration reducing cell proliferation by 50%) of
0.18 and 0.14 mM against HCT116 (colon carcinoma) and A2780
(ovarian carcinoma), respectively. 7-Azaindole is an increasingly
important structural motif due to its strong ability to bind to
the hinge region of kinases and act as a kinase inhibitor. We
are particularly interested in investigating the structure–activity
relationship of 3-heteroaryl substituted 7-azaindoles. Therefore, a
robust and general synthetic methodology to decorate (aza)indoles
with diverse heterocyclic residues is highly desirable.
The Suzuki–Miyaura cross-coupling reaction7 is an extremely
important tool for the construction of biaryls, as emphasized by
awarding the Nobel Prize 2010 to Akira Suzuki in recognition of
the enormous utility of this Pd-catalyzed transformation. As the
nucleophilic component of this coupling, pinacol boronic esters8
are stable reagents and can be also accessed via Pd-catalyzed
approaches such as Miyaura (B2pin2/PdCl2dppf/KOAc)9 and
Masuda (HBpin/PdCl2dppf/NEt3)10 borylations. The Masuda
protocol utilizes pinacolborane,11 thus being a more elegant and
atom economical approach. The catenation of Masuda and Suzuki
reactions into a one-pot fashion has been described by several
groups pioneered by the work of Baudoin in 2000.12 However,
the strategy has never been generalized and no simple catalytic
system has been disclosed for the flexible introduction of various
heterocycles on pharmaceutically relevant heterocyclic scaffolds
such as indoles or related systems.13 Herein, we report a strikingly
simple one-pot procedure which was established to efficiently
synthesize a variety of 3-(hetero)aryl substituted (7-aza)indoles,
pyrroles, and other electron-rich (hetero)aryls.
Indoles and pyrroles belong to the most important heterocycles.
They are widespread in nature1 and represent privileged structures
found in a plethora of biologically and pharmacologically active
compounds.2 In particular, indoles with 5- or 6-membered hete-
rocyclic substituents in the 3-position have aroused considerable
attention due to a remarkable spectrum of biological activity.
For example, meridianins3 and variolins4 (Fig. 1) are small
marine alkaloids consisting of indole and 7-azaindole frameworks
connected to a 2-aminopyrimidine ring, the essential structural
element for the kinase inhibitory activity of these natural products.
Fig.
1
3-Substituted indoles as natural products and bioactive
compounds.
Recently, we synthesized some members of the meridianin
family using the carbonylative Sonogashira coupling reaction as
a key step.5 The simplified 7-azaindole analogue of variolin B
(later called meriolin 1)6 has attracted our attention because it
is very active on kinases and human cancer cell lines with IC50
N-Boc protected (aza)indolyl14 iodides 1 are easily accessible,
stable to storage and can be successfully used as valuable building
blocks in cross-coupling reactions. The direct Suzuki coupling of
1 with heteroaryl boronic acids or esters is strongly limited by
the accessibility of the latter. We reasoned that iodides 1 could be
converted to the corresponding pinacol esters15 2 and then reacted
en route with heterocyclic halides 3, which are readily available
(Scheme 1).
Lehrstuhl fu¨r Organische Chemie, Institut fu¨r Organische Chemie und
Makromolekulare Chemie, Heinrich-Heine-Universita¨t Du¨sseldorf, Univer-
sita¨tsstraße 1, D-40225, Du¨sseldorf, Germany. E-mail: ThomasJJ.Mueller@
uni-duesseldorf.de; Fax: +49 0211 8114324; Tel: +49 0211 8112298
According to this strategy, the iodides 1 are reacted with
pinacolborane and triethylamine as a base in 1,4-dioxane. After
completed transformation (as monitiored by TLC), methanol is
added which scavenges excess of pinacolborane. One equivalent
of mostly commercially available halide 3 is added followed by
caesium carbonate to promote the Suzuki coupling. Concurrently,
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization of compounds 1a, 1c, 1f, 1j, 2a, 4a–4u
and 5. See DOI: 10.1039/c1ob05310h
‡ Dedicated to Anna Merkul, ne´e Seifert, on the occasion of her 60th
birthday.
§ The authors cordially thank Merck Serono KGaA, Darmstadt, for the
financial support.
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Scheme 1 Synthetic concept for 3-(hetero)aryl substituted 7-azaindoles
4.
the alcoholic carbonate solution cleaves the Boc protective group,
thus directly furnishing the desired products 4 without the need
for an additional deprotection step (Scheme 2).
Scheme 2 Masuda borylation–Suzuki coupling sequence.
This methodology exemplifies sequential catalysis, since a single
Pd-precatalyst promotes both transformations.16 No exotic ligands
are required and no additional catalyst portion has to be added
in the second reaction step. The yield did not increase upon
addition of further 3 mol% Pd(PPh3)4, which performed best
for the described substrates. PdCl2(PPh3)2 was only slightly less
efficient (64% vs. 61% for 4f), but the typical precatalyst for
Masuda borylations, PdCl2dppf, failed to give the desired product
in a good yield (39% for 4f). K2CO3 can be used instead of Cs2CO3
with slightly decreased efficiency.
Interestingly, in a related approach to substituted 7-azaindolyl
pyrimidines, a stepwise protocol consisting of Miyaura boryla-
tion and Suzuki coupling with two different (!) Pd-precatalysts
was utilized, and the protective phenylsulfonyl group remained
uncleaved.17
The scope of the presented sequence is remarkable since it allows
the introduction of a great variety of different 6-membered aryl
substituents or nitrogen heterocycles (Fig. 2). Functional groups
including cyano, free hydroxy and amino groups on (hetero)aryl
halides are tolerated and give good yields. (Hetero)aromatic
iodides, bromides and chlorides (see the color code of Fig. 2) can
be reacted according to the expected oxidative addition tendency
of the halide and its position in the (hetero)cycle. Pharmacophore
motifs such as 2-aminopyrimidine, 2-aminopyridine, and even 2,6-
diaminopyridine can be introduced without difficulties. It should
be emphasized that upon using the reverse approach, i.e. the
direct coupling with heteroaryl boronic acids or pinacol esters, the
observed functional and structural diversity can hardly be realized:
especially ortho-nitrogen atom containing boronic reagents are
particularly challenging coupling partners.18 Not only indoles and
7-azaindoles but also iodo pyrroles19 can be reacted and give 2,4-
disubstituted pyrroles (4k–4n), which represent an interesting and
rare substitution pattern. Furthermore, N-Bn 4-iodo pyrazole, 3-
iodo thiophene, 2,5-disubstituted 4-iodo furan20 as well as 2-amino
5-iodo pyridine, 2-amino 5-iodo pyrimidine and electron-rich iodo
arenes can be functionalized with (hetero)aryl substituents with
Fig. 2 Scope of the Masuda borylation–Suzuki coupling sequence
(isolated yields). Color code for the applied heterocyclic halides 3: violet =
iodide, brown = bromide, green = chloride. Th = thienyl.
comparable efficiency (4o–4u). Free hydroxy and amino groups on
the substrates are well tolerated (4r–4t). The yields of the isolated
products are fair to very good and the compounds can be obtained
analytically pure by simple flash chromatography.
With this practical and versatile methodology in hand, we set
out to perform very concise total syntheses of meridianins A (5)23
and G (4i) in order to illustrate the utility in alkaloid synthesis.
Starting from commercially available 4-methoxy-1H-indole, the
former natural product was obtained in four steps and 54% total
yield. The one-pot Masuda borylation–Suzuki coupling sequence
was used as a key step to prepare O-Me-meridianin A (4j), which
was then demethylated by PyHCl21 in the final step (Scheme
3). It is worth mentioning that this strategy represents the first
targeted synthesis of this natural product since the sole approach
by Fresneda and Molina delivered 15% (19 mg) of meridianin
A in 5 steps from 4-benzyloxy-7-bromo-1H-indole, which is not
commercially available.22 The presented procedure23 gives also
access to other interesting hydroxylated 3-aryl and 3-heteroaryl
substituted indoles. Syntheses of further natural products can be
easily envisioned and are currently underway.
The presented sequence consisting of Masuda borylation and
Suzuki coupling is tailored to efficiently synthesize 3-(hetero)aryl
substituted (aza)indoles, many of them are biologically active
compounds. Moreover, the obtained 2,4-di(hetero)aryl substituted
pyrroles represent a new promising scaffold. The most exciting
feature of this preparatively extremely simple transformation is
the possibility to directly connect readily available heterocyclic
halides in a one-pot fashion without the need for sophisticated
catalysts, ligands or additives. Considering the huge pool of
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17 S. Huang, R. Li, P. J. Connolly, S. Emanuel and S. A. Middleton, Bioorg.
Med. Chem. Lett., 2006, 16, 4818.
18 For strategies developed for the Suzuki coupling of 2-pyridyl pinacol-
boronates, see: D. X. Yang, S. L. Colletti, K. Wu, M. Song, G. Y. Li
and H. C. Shen, Org. Lett., 2009, 11, 381; J. Z. Deng, D. V. Paone, A.
T. Ginnetti, H. Kurihara, S. D. Dreher, S. A. Weissman, S. R. Stauffer
and C. S. Burgey, Org. Lett., 2009, 11, 345.
19 For a one-pot preparation of 2-substituted N-Boc 4-iodo pyrroles, see:
E. Merkul, C. Boersch, W. Frank and T. J. J. Mu¨ller, Org. Lett., 2009,
11, 2269.
Scheme 3 Final step of the total synthesis of meridianin A.
20 For a one-pot preparation of (di)substituted (3)4-iodo furans, see: A.
S. Karpov, E. Merkul, T. Oeser and T. J. J. Mu¨ller, Chem. Commun.,
2005, 2581; A. S. Karpov, E. Merkul, T. Oeser and T. J. J. Mu¨ller, Eur.
J. Org. Chem., 2006, 2991.
21 C. R. Schmid, C. A. Beck, J. S. Cronin and M. A. Staszak, Org. Process
Res. Dev., 2004, 8, 670.
commercially available or easily accessible heteroaromatic halides,
this methodology is a quite general concept.
The full scope of the sequence as well as structure–activity
studies and the biological data of analogues based on 7-azaindole
will be reported in near future.
22 P. M. Fresneda, P. Molina and J. A. Bleda, Tetrahedron, 2001, 57, 2355.
23 Typical procedure (Compound 4j): tetrakis(triphenylphosphane)-
palladium(0) (35 mg, 0.03 mmol, 3 mol%) and tert-butyl 3-iodo-
4-methoxy-1H-indole-1-carboxylate (1c) (373 mg, 1.00 mmol) were
placed under argon atmosphere in a dry screw-cap vessel with septum.
Then, 5 mL of dry 1,4-dioxane were added and the mixture was
degassed with argon. Dry triethylamine (1.39 mL, 10.0 mmol) and
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.22 mL, 1.50 mmol) were
successively added to the mixture which was stirred at 80 ◦C (preheated
oil bath) for 3 h (monitored by TLC). Then, after cooling to
room temperature (water bath), 5 mL of dry methanol, 2-amino-
4-chloropyrimidine 3a (134 mg, 1.00 mmol) and caesium carbonate
(823 mg, 2.50 mmol) were successively added and the mixture was
stirred at 100 ◦C (preheated oil bath) overnight for 15 h. Then, after
cooling to room temperature (water bath) the solvents were removed
in vacuo and the residue was adsorbed onto CeliteꢀR and purified
chromatographically on silica gel with dichloromethane–methanol-
aqueous ammonia to give after drying in vacuo at 70 ◦C overnight
185 mg (77%) of the analytically pure compound 4j as a colorless solid,
Notes and references
1 For recent reviews, see: A. J. Kochanowska-Karamyan and M. T.
Hamann, Chem. Rev., 2010, 110, 4489; H. Fan, J. Peng, M. T. Hamann
and J.-F. Hu, Chem. Rev., 2008, 108, 264.
2 For a recent minireview on indole alkaloid marine natural products as
a source of drug leads, see: W. Gul and M. T. Hamann, Life Sci., 2005,
78, 442.
3 M. D. Lebar and B. J. Baker, Aust. J. Chem., 2010, 63, 862; A. M.
Seldes, M. F. R. Brasco, L. H. Franco and J. A. Palermo, Nat. Prod.
Res., 2007, 21, 555; L. H. Franco, E. Bal de Kier Joffe´, L. Puricelli,
M. Tatian, A. M. Seldes and J. A. Palermo, J. Nat. Prod., 1998, 61,
1130.
4 N. B. Perry, L. Ettouati, M. Litaudon, J. W. Blunt, M. H. G. Munro, S.
Parkin and H. Hope, Tetrahedron, 1994, 50, 3987; G. Trimurtulu, D. J.
Faulkner, N. B. Perry, L. Ettouati, M. Litaudon, J. W. Blunt, M. H. G.
Munro and G. B. Jameson, Tetrahedron, 1994, 50, 3993; Recent review
on variolins and related alkaloids: S. R. Walker, E. J. Carter, B. C. Huff
and J. C. Morris, Chem. Rev., 2009, 109, 3080.
5 A. S. Karpov, E. Merkul, F. Rominger and T. J. J. Mu¨ller, Angew. Chem.,
Int. Ed., 2005, 44, 6951.
6 A. Echalier, K. Bettayeb, Y. Ferandin, O. Lozach, M. Cle´ment, A.
Valette, F. Liger, B. Marquet, J. C. Morris, J. A. Endicott, B. Joseph
and L. Meijer, J. Med. Chem., 2008, 51, 737.
7 M. Prieto, E. Zurita, E. Rosa, L. Muoz, P. Lloyd-Williams and E. Giralt,
J. Org. Chem., 2004, 69, 6812; N. Miyaura and A. Suzuki, Chem. Rev.,
1995, 95, 2457; N. Miyaura, T. Yanagi and A. Suzuki, Synth. Commun.,
1981, 11, 513.
◦
1
mp 221–222 C. H NMR (DMSO-d6, 500 MHz): d (ppm) 3.87 (s, 3
H), 6.27 (s, 2 H, NH2), 6.63 (d, J = 6.9 Hz, 1 H), 7.06–7.12 (m, 2 H),
7.26 (dd, J = 5.4 Hz, J = 0.9 Hz, 1 H), 7.85 (d, J = 2.5 Hz, 1 H), 8.15 (d,
J = 5.4 Hz, 1 H), 11.6 (br, 1 H, NH). 13C NMR (DMSO-d6, 125 MHz):
d (ppm) 55.0 (CH3), 101.2 (CH), 105.5 (CH), 109.7 (CH), 114.4 (Cquat),
115.4 (Cquat), 122.7 (CH), 127.5 (CH), 138.8 (Cquat), 153.2 (Cquat), 157.0
(CH), 161.8 (Cquat), 163.2 (Cquat). EI MS (m/z (%)): 240 (M+, 50), 239
(M+ - H, 21), 211 (M+ - CH3O + H, 20), 202 (M+ - C2H2N + 2 H,
+
+
-1
˜
11), 58 (CH4N3 , 41), 43 (C2H3O , 100). IR (KBr): n 3465 (m) cm ,
3313 (m), 3165 (m), 1644 (m), 1624 (m), 1575 (s), 1555 (s), 1506 (s),
1459 (s), 1414 (m), 1320 (m), 1245 (m), 1088 (m), 733 (m). Anal. calcd
for C13H12N4O (240.3): C 64.99, H 5.03, N 23.32. Found: C 64.86, H
4.85, N 23.25. Synthesis of meridianin A (5): pyridinium hydrochloride
(1.18 g, 10.0 mmol) was placed in a dry screw-cap vessel under argon
atmosphere. Then, 4j (120 mg, 0.50 mmol) was added and the mixture
was heated to 210 ◦C (preheated oil bath). After 0.5 h the mixture
was cooled to 50 ◦C (preheated oil bath) and methanol was added to
dissolve the residue. The solvents were removed in vacuo and the residue
was adsorbed onto CeliteꢀR and purified chromatographically on silica
gel with dichloromethane–methanol–aqueous ammonia to give after
drying in vacuo at 70 ◦C overnight 96 mg (85%) of the analytically
pure meridianin A (5) as◦a bright yellow fine crystalline solid, mp 264–
276 ◦C. (Lit.:3,22 164–168 C). 1H NMR (DMSO-d6, 500 MHz): d (ppm)
6.39 (dd, J = 7.9 Hz, J = 0.9 Hz, 1 H), 6.76 (s, 2 H, NH2), 6.82 (dd, J =
8.2 Hz, J = 0.9 Hz, 1 H), 7.00 (t, J = 7.9 Hz, 1 H), 7.14 (d, J = 5.4 Hz,
1 H), 8.14 (d, J = 5.4 Hz, 1 H), 8.25 (d, J = 3.2 Hz, 1 H), 11.8 (br, 1 H,
NH), 13.62 (s, 1 H, OH). 13C NMR (DMSO-d6, 125 MHz): d (ppm)
102.3 (CH), 104.3 (CH), 105.5 (CH), 113.7 (Cquat), 114.3 (Cquat), 124.4
(CH), 128.4 (CH), 139.2 (Cquat), 152.0 (Cquat), 158.4 (CH), 160.4 (Cquat),
161.7 (Cquat). EI MS (m/z (%)): 226 (M+, 100), 225 (M+ - H, 13), 209
(M+ - OH, 2), 197 (M+ - COH, 6), 185 (M+ - CH2N2 + H, 18), 158
8 C. E. Tucker, J. Davidson and P. Knochel, J. Org. Chem., 1992, 57,
3482.
9 T. Ishiyama, M. Murata and N. Miyaura, J. Org. Chem., 1995, 60, 7508.
10 M. Murata, T. Oyama, S. Watanabe and Y. Masuda, J. Org. Chem.,
2000, 65, 164; M. Murata, S. Watanabe and Y. Masuda, J. Org. Chem.,
1997, 62, 6458.
11 For a method for practical large-scale preparation of pinacolborane,
see: T. Kikuchi, Y. Nobuta, J. Umeda, Y. Yamamoto, T. Ishiyama and
N. Miyaura, Tetrahedron, 2008, 64, 4967.
12 For reported one-pot Masuda borylation–Suzuki coupling sequences,
ˇ
see: P.-E. Broutin, I. Cernˇa, M. Campaniello, F. Leroux and F. Colobert,
Org. Lett., 2004, 6, 4419; M. Penhoat, V. Levacher and G. Dupas, J.
Org. Chem., 2003, 68, 9517; O. Baudoin, D. Gue´nard and F. Gue´ritte,
J. Org. Chem., 2000, 65, 9268.
13 For a sequence applied in a bisindole synthesis using XPhos, see: H. A.
Duong, S. Chua, P. B. Huleatt and C. L. L. Chai, J. Org. Chem., 2008,
73, 9177.
14 B. Witulski, N. Buschmann and U. Bergstra¨ßer, Tetrahedron, 2000, 56,
8473.
15 For a direct Ir-catalyzed borylation of N-Boc protected heterocycles,
see: V. A. Kallepalli, F. Shi, S. Paul, E. N. Onyeozili, R. E. Maleczka
Jr. and M. R. Smith III, J. Org. Chem., 2009, 74, 9199.
16 T. J. J. Mu¨ller, Top. Organomet. Chem., 2006, 19, 149.
+
-1
˜
(M - C3H4N2, 6). IR (KBr): n 3429 (m) cm , 3342 (m), 1638 (m), 1593
(s), 1562 (m), 1532 (m), 1469 (m), 1444 (m), 1401 (m), 1321 (m), 1227
(m), 719 (m). Anal. calcd for C12H10N4O (226.2): C 63.71, H 4.46, N
24.76. Found: C 63.48, H 4.61, N 24.72.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3139–3141 | 3141
©