Manganese-catalyzed intermolecular C-H/C-H coupling of carbonyls and heteroarenes

Article abstract of DOI:10.1039/c4cc01376j

Manganese-catalyzed intermolecular C-H/C-H coupling of carbonyls and heteroarenes has been developed. The presence of NaIO₄ as an oxidant is crucial for the catalytic reaction. These new, inexpensive reaction conditions allow the gram-scale syn

Full text of DOI:10.1039/c4cc01376j

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Manganese-catalyzed intermolecular C–H/C–H
coupling of carbonyls and heteroarenes†
Keika Hattori,a Asraa Ziadi,a Kenichiro Itamiab and Junichiro Yamaguchi*a
Cite this: Chem. Commun., 2014,
50, 4105
Received 24th January 2014,
Accepted 4th March 2014
DOI: 10.1039/c4cc01376j
www.rsc.org/chemcomm
Manganese-catalyzed intermolecular C–H/C–H coupling of carbonyls Baran and co-workers.5 However, the satisfaction of both
and heteroarenes has been developed. The presence of NaIO4 as an criteria, i.e., catalytic and intermolecular, has not been achieved
oxidant is crucial for the catalytic reaction. These new, inexpensive for the coupling of carbonyls and heteroarenes without func-
reaction conditions allow the gram-scale synthesis of a-heteroaryl tional group handles. To approach this challenge, we hypo-
carboxylic acids.
thesized that the key lies in manganese-catalyzed coupling
reactions.6 It is known that Mn(III) species can mediate intra-
The a-heteroaryl carbonyl structure has stimulated interested molecular oxidative cyclization reactions7,8 and biaryl couplings9
in organic synthesis because it is a highly prevalent motif using stoichiometric amounts or catalytic amounts of Cu(OAc)2
in pharmaceuticals and natural products.1 To date, metal- as a co-oxidant. Two decades ago, Mn-mediated intermolecular
catalyzed a-arylation of carbonyls with aryl halides has been C–H/C–H coupling of carbonyls and (hetero)arenes was reported
11
extensively studied using mainly Pd-based catalysts.2 Although by Muchowski,10 which required 2.5 equivalents of Mn(OAc)3
the introduction of six-membered aromatic rings in this manner (US$9.0 per gram).12 Based on these pioneering studies, we
is possible, the use of five-membered heteroaryl halides as envisioned that the amount of Mn can be reduced to catalytic
arylating agents presents issues in terms of substrate stability, amounts, thereby rendering the synthesis of a-heteroaryl carbonyl
difficulty of preparing (pseudo)halo heteroarene starting materials, compounds more practical. Herein, we describe the development
and sluggish reactivity when compared to six-membered systems. of a practical method for an intermolecular C–H/C–H coupling of
In an alternative synthesis pathway, the coupling between carbonyls and heteroarenes using a manganese catalyst (Scheme 1).
functionalized carbonyls and heteroarenes (including its halide
Our investigation commenced with the coupling reaction of
and organometallic derivatives) have been reported by several tri(ethoxycarbonyl)methane (1A: 1.0 equiv.) and 2-acetylpyrrole
research groups, but the carbonyl starting materials in such (2a: 2.0 equiv.) in the presence of a catalytic Mn complex (5 mol%),
reactions must be synthesized using several steps.3 Thus, various oxidants (1.2 equiv.) and NaOAc (2.0 equiv.) as shown in
a catalytic C–H/C–H coupling of carbonyls and heteroarenes Table 1 (see also ESI†). Primarily, we investigated the effect of
without pre-functionalization has attracted attention as a more oxidants. Disappointingly, representative oxidants such as Ag2CO3,
concise and greener process for the synthesis of a-heteroaryl Cu(OAc)2, K2S2O8, and benzoquinone (BQ) interfered with the
carbonyl compounds.
coupling reaction and completely shut it down (entries 1–4). When
Recently, Pd-catalyzed intramolecular C–H/C–H coupling t-butyl hydroperoxide (TBHP) or CeSO4Á4H2O was used, the corre-
between carbonyls and heteroarenes (specifically pyridines) has been sponding coupling product 3Aa was obtained, albeit in very low
reported.4 Furthermore, an intermolecular coupling of carbonyls yields (entries 5 and 6). To our great delight, the coupling reaction
and indoles/pyrroles using stoichiometric copper salts and excess proceeded smoothly to afford the desired product in 32% yield
amounts of strong bases was successfully demonstrated by when sodium periodate (NaIO4) was used as an oxidant. When Mn
complexes were systematically changed, the reactions gave 3Aa
a Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Chemistry,
Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan.
E-mail: junichiro@chem.nagoya-u.ac.jp
in yields ranging from 24% to 64% (entries 7–10). Although
MnI2 (US$78.90 per gram)12 gave the best yield (64%, entry 9),
b JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa,
Nagoya 464-8602, Japan
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra for products. See
DOI: 10.1039/c4cc01376j
Scheme 1 Mn-catalyzed C–H/C–H coupling of carbonyls and heteroarenes.
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Table 1 Screening of the Mn-catalyzed C–H/C–H coupling of 1A and 2aa
Entry Mn salt
Oxidant
Additive
Yield of 3Aab/%
1
2
3
4
5
6
7
8
Mn(OAc)3Á2H2O Ag2CO3
Mn(OAc)3Á2H2O Cu(OAc)2ÁH2O
Mn(OAc)3Á2H2O BQ
—
—
—
—
—
—
—
—
0
0
0
1
9
10
32
24
64
57
9
Mn(OAc)3Á2H2O K2S2O8
Mn(OAc)3Á2H2O TBHP
Mn(OAc)3Á2H2O CeSO4Á4H2O
Mn(OAc)3Á2H2O NaIO4
MnCl2
MnI2
NaIO4
NaIO4
9
—
—
—
DMSO
Pyridine 36
PPh3
X-Phos
Cy3P
Dppe
10
11c
12
13
14
15
16
17
18
Mn(OAc)2Á4H2O NaIO4
Mn(OAc)2Á4H2O NaIO4
Mn(OAc)2Á4H2O NaIO4
Mn(OAc)2Á4H2O NaIO4
Mn(OAc)2Á4H2O NaIO4
Mn(OAc)2Á4H2O NaIO4
Mn(OAc)2Á4H2O NaIO4
Mn(OAc)2Á4H2O NaIO4
Mn(OAc)2Á4H2O NaIO4
33
72(77)d
77
37
2
Scheme 2 Substrate scope of heteroarene coupling partners. The yields
of coupling products without PPh3 are shown in parentheses. a 1 mol% of
b
Mn(OAc)2Á4H2O was used. 10 equiv. of furan was employed.
OQPPh3 55
a
Conditions: 1A (1.0 mmol), 2a (2.0 mmol), Mn salt (0.05 mmol),
the halogen atom. To our delight, the coupling reaction of 1A with
2i was conducted in the presence of only 1 mol% Mn(OAc)2Á4H2O,
giving the corresponding product in 77% yield. Benzothiophene
(2j), benzofuran (2k), and furan (2l) were applicable for this
coupling reaction to afford the products in good yields. It should
be noted that PPh3 was not needed for heteroarenes 2d, 2g, 2h,
and 2i, and actually decreased the yields slightly when 2c and 2k
were used. Unfortunately, using indole as a heteroarene gave the
corresponding product in 20% yield. Additionally, electron-rich
aromatics such as dimethoxybenzene did not react under the
present conditions.
Next, the scope of the carbonyl coupling partner was inves-
tigated with 2-iodothiophene (2i) under the optimal conditions
(Scheme 3). It was found that the carbonyl partner always
required the diester moiety, and otherwise the reactions did
not proceed at all. Substrates wherein the ethyl ester of 1A was
changed to t-butylketone (1B), phenylketone (1C), or morpholine
oxidant (1.2 mmol), NaOAc (2.0 mmol), additive (0.1 mmol), AcOH
b
c
(2.0 mL), 70 1C, 18 h. GC yield. The reaction was performed without
d
NaOAc. Isolated yield.
Mn(OAc)2Á4H2O is
a significantly less expensive catalyst
(US$0.06 per gram)11 and was therefore selected as the catalyst
of choice despite the slightly lower yield (57%, entry 10). The
addition of sodium acetate is crucial to give 3Aa in good yield
(entry 11). Consequently, various additives were tested (entries
12–18) and, from these studies, it appeared that trisubstituted
phosphines such as PPh3 (72%, entry 14) and X-Phos (77%,
entry 15) were effective in increasing the yield of 3Aa, whereas
sulfoxide (e.g., DMSO, entry 12), pyridine (entry 13), and trialkyl-
phosphine (e.g., Cy3P, entry 16) were not. Surprisingly, bidentate
phosphine (e.g., dppe, entry 17) completely shut down the
reactivity. We then assumed that trisubstituted phosphines are
being oxidized to phosphine oxides under the reaction condi-
tions, and thus added triphenylphosphine oxide. However, the
yield was the same as the reaction without additive (compare
entry 18 to entry 10), showing that unoxidized trisubstituted
phosphines are necessary to improve the yield of 3Aa.13 PPh3 is
the least expensive, and therefore, we selected it as the additive
of choice for this reaction.
With the optimal conditions in hand, we investigated the
scope of C–H/C–H coupling of tri(ethoxycarbonyl)methane (1A)
with various five-membered heteroarenes (Scheme 2). When
the C2-substituent of the pyrrole was changed from acetyl (2a) to
methoxycarbonyl (2b) and cyano (2c), the coupling proceeded well
to give the corresponding products in good yields. Unsubstituted
thiophene (2d) performed well (68% yield), and C2-alkylated
thiophenes such as methyl (2e) and ethyl (2f) thiophenes also gave
the products in excellent yields. In the case of C2-halogenated
thiophenes such as chloro (2g), bromo (2h), and iodo (2i)
thiophenes, these reactions worked very well without loss of Scheme 3 Substrate scope of carbonyls.
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Areas ‘‘Molecular Activation Directed toward Straightforward
Synthesis’’ (25105720 to J.Y.) from MEXT. ITbM is supported
by the World Premier International Research Center (WPI)
Initiative, Japan.
Notes and references
1 For selected examples, see: (a) J. M. Muchowski, Adv. Med. Chem., 1992,
1, 109; (b) A. Sato, T. Morishita, T. Shiraki, S. Yoshioka, H. Horikoshi,
H. Kuwano, H. Hanzawa and T. Hata, J. Org. Chem., 1993, 58, 7632;
(c) A. R. Carroll, E. Hyde, J. Smith, R. J. Quinn, G. Guymer and P. I. Forster,
J. Org. Chem., 2005, 70, 1096; (d) L. Bhattacharyya, S. K. Chatterjee, S. Roy
and D. P. Chakraborty, J. Indian Chem. Soc., 1989, 66, 140.
2 For selected examples and reviews, see: (a) T. Satoh, Y. Kawamura,
M. Miura and M. Nomura, Angew. Chem., Int. Ed. Engl., 1997, 36,
1740; (b) M. Palucki and S. L. Buchwald, J. Am. Chem. Soc., 1997,
119, 11108; (c) B. C. Hamann and J. F. Hartwig, J. Am. Chem. Soc.,
1997, 119, 12382; (d) D. A. Culkin and J. F. Hartwig, Acc. Chem. Res.,
2003, 36, 234; (e) C. C. C. Johansson and T. J. Colacot, Angew. Chem.,
Int. Ed., 2010, 49, 676.
3 For selected examples, see: (a) M. Prats, C. Galvez, Y. Gasanz and
A. Rodriguez, J. Org. Chem., 1992, 57, 2184; (b) J. L. Wood, B. M. Stoltz,
H.-J. Dietrich, D. A. Pflum and D. T. Petsch, J. Am. Chem. Soc., 1997, 119,
9641; (c) A. Boularot, C. Giglione, S. Petit, Y. Duroc, R. Alves de Sousa,
V. Larue, T. Cresteil, F. Dardel, I. Artaud and T. Meinnel, J. Med. Chem.,
2007, 50, 10; (d) Y. Cai, S.-F. Zhu, G.-P. Wang and Q.-L. Zhou, Adv. Synth.
Catal., 2011, 353, 2939; (e) Q. Tang, X. Chen, B. Tiwari and Y. R. Chi,
Org. Lett., 2012, 14, 1922.
4 C. Dey and E. P. Ku¨ndig, Chem. Commun., 2012, 48, 3064.
5 (a) P. S. Baran, J. M. Richter and D. W. Lin, Angew. Chem., Int. Ed.,
2005, 44, 609; (b) J. M. Richter, B. W. Whitefield, T. J. Maimone,
D. W. Lin, M. P. Castroviejo and P. S. Baran, J. Am. Chem. Soc., 2007,
129, 12857.
6 For selected examples of Mn-catalyzed direct C–C or C–heteroatom
bond formation, see: (a) Y. Kuninobu, Y. Nishina, T. Takeuchi and
K. Takai, Angew. Chem., Int. Ed., 2007, 46, 6518; (b) Y.-C. Teo,
F.-F. Yong, C.-Y. Poh, Y.-K. Yan and G.-L. Chua, Chem. Commun., 2009,
6258; (c) N. Yoshikai, S. Zhang, K. Yamagata, H. Tsuji and E. Nakamura,
J. Am. Chem. Soc., 2009, 131, 4099; (d) J. Y. Kim, S. H. Cho, J. Joseph and
S. Chang, Angew. Chem., Int. Ed., 2010, 49, 9899; (e) B. Zhou, H. Chen and
C. Wang, J. Am. Chem. Soc., 2013, 135, 1264.
Scheme 4 Addition of radical scavengers.
amide (1D) were tolerated albeit in moderate yields. Using
diethyl 2-methylmalonate (1E) as the carbonyl partner, the
coupling reaction proceeded to give the product in 46% yield.
This was extended to other malonate derivatives, including a
cyano-containing (1F: 73%) and chloro-containing alkyl chain
(1G: 54%).
As the presence of a radical scavenger suppressed the
Mn-catalyzed C–H/C–H coupling of 1A and 2a (Scheme 4), we
assume that the reaction proceeds via a radical mechanism.14
For example, when this reaction was performed under oxygen,
the yield of 3Aa was only 8% yield; similar effects were observed
upon addition of TEMPO (12% yield) and galvinoxyl (19% yield).
The reaction mechanism remains unclear, but these experiments
support a radical pathway for this coupling reaction.
Finally, a gram-scale synthesis of a-heteroaryl carbonyls was
performed (Scheme 5). 20 mmol of 1A was coupled with 2a
under our optimized conditions, followed by hydrolysis and
decarboxylation of 3Aa. Thereafter, acid–base extraction of the
crude product afforded 2.3 g of pure a-heteroaryl carboxylic
acid 4Aa without column chromatography (67% yield overall).
In summary, we have developed a practical intermolecular
C–H/C–H coupling of carbonyls and heteroarenes catalyzed by
manganese.15 The oxidant, sodium periodate, is a readily avail-
able, inexpensive oxidant. This method tolerates a wide range of
heteroarenes to furnish the a-heteroaryl carbonyl products
(18 examples, including various carbonyl partners). A gram-scale
C–H/C–H coupling demonstrated that the reaction could be
applied to the practical synthesis of a-heteroaryl carboxylic acids.
Further modifications of the Mn catalyst to achieve a broad scope
for the carbonyl partner are ongoing in our laboratory.
7 For selected examples of Mn-mediated intramolecular oxidative
cyclization, see: (a) B. B. Snider, Chem. Rev., 1996, 96, 339; (b) D. R.
Artis, I.-S. Cho and J. M. Muchowski, Can. J. Chem., 1992, 70, 1838;
(c) J. Magolan and M. A. Kerr, Org. Lett., 2006, 8, 4561; (d) J. Magolan,
C. A. Carson and M. A. Kerr, Org. Lett., 2008, 10, 1437; (e) V. Bhat,
L. A. MacKay and V. H. Rawal, Org. Lett., 2011, 13, 3214.
8 Very recently, Oisaki and Kanai reported a Mn-catalyzed intra-
molecular oxidative cyclization of diesters and indoles with oxygen
as terminal oxidants. K. Oisaki, J. Abe and M. Kanai, Org. Biomol.
Chem., 2013, 11, 4569.
9 For selected examples of Mn-mediated biaryl coupling, see: (a) A. S.
¨
Demir, O. Reis and M. Emrullahoglu, Tetrahedron, 2002, 58, 8055;
¨
(b) A. S. Demir, O. Reis and M. Emrullahoglu, J. Org. Chem., 2003, 68, 578.
10 (a) I.-S. Cho and J. M. Muchowski, Synthesis, 1991, 567. For a similar
type of reaction, see: (b) C.-P. Chuang and S.-F. Wang, Tetrahedron
Lett., 1994, 35, 1283.
11 Muchowski and co-workers actually use 2.5 equivalents of
Mn(OAc)2Á4H2O and employed an in situ oxidation procedure with
KMnO4 in order to address the problem of cost of Mn(OAc)3.
12 Based on current prices from Sigma-Aldrich, Inc.
This work was supported by the Funding Program for Next
Generation World-Leading Researchers from JSPS (220GR049
to K.I.), a Grant-in-Aid for Scientific Research on Innovative
13 Almost immediately after starting the reaction (5 min), it was
determined that Ph3P was completely oxidized to Ph3PQO. There-
fore, we assume that the role of Ph3P might be to quench some
peroxides such as peracetic acid that is slightly produced from
AcOH and NaIO4.
14 (a) A. Citterio, R. Santi, T. Fiorani and S. Strologo, J. Org. Chem.,
1989, 54, 2703; (b) Z.-Q. Cong and H. Nishino, Synthesis, 2008, 2686.
15 One example of intermolecular C–H/C–H coupling of indole with
dimethyl 2-methylmalonate is shown in ref. 8. However, we could
not reproduce the reported reaction. Additionally, although we
applied their conditions to the coupling between 1A and 2a, the
product was obtained only in trace amounts.
Scheme 5 Gram-scale synthesis of a-heteroaryl carboxylic acid 4Aa.
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Chem. Commun., 2014, 50, 4105--4107 | 4107