Palladium[ii] catalysed C(sp3)-H oxidation of dimethyl carbamoyl tetrahydrocarbazoles

Article abstract of DOI:10.1039/c3cc48545e

Dimethyl carbamoyl tetrahydrocarbazoles undergo directed oxidation using standard conditions to exclusively provide products from C(sp³)-H oxidation. This result is in contrast to recent studies on the directed C-H olefination of hydrocarbazoles, which result in selective aromatic functionalisation.

Full text of DOI:10.1039/c3cc48545e

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Palladium[II] catalysed C(sp3)–H oxidation of
dimethyl carbamoyl tetrahydrocarbazoles†
Cite this:DOI: 10.1039/c3cc48545e
Yuji Nakano and David W. Lupton*
Received 8th November 2013,
Accepted 4th December 2013
DOI: 10.1039/c3cc48545e
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Dimethyl carbamoyl tetrahydrocarbazoles undergo directed oxida-
tion using standard conditions to exclusively provide products from
C(sp3)–H oxidation. This result is in contrast to recent studies on
the directed C–H olefination of hydrocarbazoles, which result in
selective aromatic functionalisation.
The discovery of methods for directed C–H functionalisation has
enriched approaches to the synthesis of complex organic targets.1,2
While a range of directing groups have been developed, pyridyl
functionality has seen extensive application due to its robust
coordination chemistry, and ubiquity.3 In contrast, C–H functiona-
lisation using other N-heterocycles common in medicinal and
natural product chemistry has received less attention.4,5 As part of
studies on the chemistry of hydrocarbazoles6 we recently com-
menced studies on the C(sp3)–H oxidation of tetrahydrocarbazoles
using Pd[II] catalysis. It was envisaged that C(sp3)–H functionalisa-
tion should occur in favour of the more common C(sp2)–H as a
consequence of benzylic activation.7,8 If this proved to be the case
then access to C1 oxidised hydrocarbazoles, motifs found in natural
products such as kopsiyunnanine H (1), and NPY-1 antagonist 2 and
antiviral 3, should be possible (Fig. 1).9 After commencing studies
on this topic examples of the undesired C(sp2)–H functionalisation
of tetrahydrocarbazole 4 (eqn (1))12c and hexahydrocarbazole 5
(eqn (2))12b have been communicated.10–12 While the latter involves
non-benzylic substrates, the former reports the C(sp2)–H olefination
of sulfonyl tetrahydrocarbazole 4, a substrate bearing benzylic
C(sp3)–H. Remarkably, our studies demonstrate that in contrast to
the C–H olefination reaction (eqn (1)), C(sp3)–H oxidation proceeds
with exclusive selectivity for the C1 centre (eqn (3)) (Fig. 2).13
Fig. 1 Naturally occurring and medicinal C8 oxidized carbazoles.
Fig. 2 Proposed selective C(sp3)–H oxidation.
Studies commenced with N-protection of commercially available hypervalent iodonium reagents as the terminal oxidant we were
tetrahydrocarbazole with diethyl carbamoyl chloride to afford urea pleased to isolate carbazole 7a in 25% yield (Table 1, entry 1), with
containing 6a.14,15 When subjected to conditions developed by no aromatic oxidation observed. Changing from phenyliodonium bis-
Sanford in which 5 mol% Pd(OAc)2 is used in association with trifluoroacetate (PIFA) to phenyliodonium diacetate (PIDA) increased
the yield to 49% (Table 1, entry 2), while performing the reaction at
room temperature, or with either K2S2O8 or Oxones as the stoichio-
metric oxidant, gave an unsatisfactory outcome (Table 1, entries 3–5).
School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia.
E-mail: david.lupton@monash.edu; Fax: +61 3 9905 4597; Tel: +61 3 9902 0327
Increasing the catalyst loading to 10 mol% increased the yield
(Table 1, entry 6); however at higher catalyst loadings palladium
† Electronic supplementary information (ESI) available: Experimental details,
1H and 13C NMR spectra of all new compounds. See DOI: 10.1039/c3cc48545e
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Table 1 Selected reaction optimisation
Entry
mol% Pd
Oxidant (equiv.)
Temp. (1C)
Yielda (%)
1
2
3
4
5
6
7
8
5
5
5
5
5
10
20
0
PhI(OCOCF3)2 (1.1)
PhI(OAc)2 (1.1)
PhI(OAc)2 (1.1)
K2S2O8 (2.0)
100
100
rt
100
100
100
100
100
25
49
8
—
—
65
50
—
Table 2 C(sp3)–H oxidation of various tetrahydrocarbazoles 6db–dja
Oxone (2.0)
PhI(OAc)2 (1.1)
PhI(OAc)2 (1.1)
PhI(OAc)2 (1.1)
a
Isolated yield following column chromatograph.
deposition was observed and the isolated yield was decreased
(Table 1, entry 7). In the absence of the palladium[II] catalyst the
reaction failed to occur (Table 1, entry 8).
Modification of the directing group was examined with a variety
of urea (6b–d), carbamate (6e), and amide (6f–h) functionalities
(eqn (5)). Although there was little difference in the outcome when
the urea N-substituent was varied, dimethyl carbamoyl 6d gave the
highest yield of the product (i.e. 7d). The yield of hydrocarbazole 7d
could be further improved to 86% using 2 equivalents of PIDA.
Unfortunately, Boc-protected tetrahydrocarbazole 6e, which could
potentially serve as a useful protecting and directing group, failed
to afford the expected product 7e. In contrast pivaloyl-protected
substrate 6h gave the oxidized material 7h in a similar yield to that
observed with ureas 6a–d.
a
Isolated yield following column chromatography.
releasing or withdrawing functionality in the 6-position had little
effect on the reaction outcome with products 7db–dg formed in good
yields. In addition the reaction conditions are compatible with aryl
halides with 6dd, de, dh and di providing the expected products
without loss of the halogen. Finally, substitution in the C5 position, as
in 6dh, and in the C7 position (6di and dj) provided the expected
product in good yield.
C(sp3)–H oxidation of dimethyl carbamoyl 6d was investi-
With suitable conditions identified for the C(sp3)–H oxidation the gated on a multigram scale and found to provide the expected
generality of the reaction was investigated by examining the nature product 7d in comparable yield (80%, 2.17 g cf. 86%, 118 mg).
of the alcohol. Exchanging methanol for ethanol or benzyl alcohol In addition deprotection using reported conditions was viable,
gave the expected ethers 8d and 9d in good yields, while allyl alcohol affording carbazole 11 in a 58% isolated yield (Scheme 1).15
gave a modest yield of ether 10d (eqn (6)). This latter result may
occur as a consequence of decomposition pathways involving the
readily oxidized allyl functionality. The success of benzyl alcohol was
pleasing since product 9d could be readily deprotected under
hydrogenolytic conditions.
Next the sensitivity of the reaction to modifications about the
aromatic ring was investigated (Table 2). Substituents were introduced
to perturb the electronic environment of tetrahydrocarbazole. In all
cases selective C(sp3)–H oxidized products were identified in yields
Scheme 1 Multi-gram synthesis of carbazole 7d and deprotection to
provide indole 11.
ranging from 51 to 86%. Specifically, introduction of electron
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The use of carbamoyl protected tetrahydrocarbazoles in the
directed C(sp3)–H oxidation has been examined. In contrast to
alternate examinations of the functionalisations of hydrocarba-
zoles these studies gave materials arising solely from aliphatic
C–H oxidation. The generality of this reaction is broad with
respect to tetrahydrocarbazoles; however the reaction is not suited
to alternate ring sizes and non-cyclic structures.
Financial support from the Australian Research Council
through the Discovery and Future Fellowship programs is
acknowledged.
Fig. 3 Substrates poorly suited to the C–H oxidation.
Notes and references
1 For general reviews on catalytic directed C(sp3)–H functionalisation
see: R. Jazzar, J. Hilce, A. Renaudat, J. Sofack-Kreutzer and
O. Baudoin, Chem.–Eur. J., 2010, 16, 2654.
Surprisingly, variation of the tetrahydrocarbazole ring system
to nonannulated substrates (12), or substrates bearing alternate
ring sizes (13 and 14), failed to provide the expected products
with unreacted starting materials isolated in all cases (Fig. 3).
Presumably this sensitivity can be attributed to subtle conforma-
tional changes within substrates 12–14 that limit the viability of
the C–H insertion (eqn (8) and (9)).
2 For a reviews on C–H activation in total synthesis see: (a) L. McMurray,
F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885;
(b) D. Y. K. Chen and S. W. Youn, Chem.–Eur. J., 2012, 18, 9452.
3 For general reviews on palladium catalyzed directed C–H functio-
nalisation see: (a) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc.
Chem. Res., 2012, 45, 788; (b) C.-J. Li, Acc. Chem. Res., 2009, 42, 335;
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heterocycles see: (a) J.-J. Li, R. Giri and J.-Q. Yu, Tetrahedron, 2008,
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´
C–H oxidation using Carretero and Arrayas’ pyridine sulfonyl
directing group was investigated with tetrahydrocarbazole 4.12c Using
the conditions developed in this study (Table 2), the reaction failed to
afford any oxidised product; however increasing the stoichiometry of
the oxidant provided a complex mixture of oxidised materials that
were inseparable. Subsequent removal of the directing group allowed
the C(sp3)–H oxidised product 15 to be isolated in 21% yield16 with a
trace of the C(sp3)–H oxidised product 16. Mechanistically both
oxidation and olefination commence with Pd(II) C–H insertion which
is presumed to be turnover limiting.3i,17 The difference in outcomes
indicates that with these substrates this may not be the case, and
implicates a reversible C–H insertion. Further investigations are
required to allow this difference in outcome to be fully appreciated.
6 For other studies from our group on the derivatisation of carbazoles
see: (a) C. J. Gartshore and D. W. Lupton, Angew. Chem., Int. Ed.,
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7 W. D. Jones, Inorg. Chem., 2005, 44, 4475.
8 For examples of selective sp3 functionalisation with Pd(II) when the
C–H is allylic see: M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2008,
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9 For examples see: (a) R. DiFabio, R. Giovannini, B. Bertani,
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To examine the possibility that acetate 17 is an intermediate in
the C(sp3)–H etherification, 17 was prepared13a and subjected to the
reaction conditions, or methanol at 100 1C. In both cases this led to
rapid conversion to ether 7d (eqn (11)). In addition when the
conversion of carbazole 6d - 7d (eqn (6)) was monitored by TLC
analysis rapid formation of acetate 17 was observed, which subse-
quently provided 7d.
11 For arylation of carbazoles see: J.-H. Chu, C.-C. Wu, D.-H. Chang,
Y.-M. Lee and M.-J. Wu, Organometallics, 2013, 32, 272.
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X. Huang, J. You and F. Song, Chem. Commun., 2013, 49, 8830. For
olefination of carbazoles which are selective for C(sp2)–H centres with
hexahydrocarbazoles see: (b) L.-Y. Jiao and M. Oestreich, Org. Lett.,
2013, 15, 5374. For olefination of carbazoles which are selective for
C(sp2)–H centres with tetrahydrocarbazoles see: (c) B. Urones,
´
R. G. Arrayas and J. C. Carretero, Org. Lett., 2013, 15, 1120. For directed
methylation of indolines see: (d) S. R. Neufeldt, C. K. Seigerman and
M. S. Sanford, Org. Lett., 2013, 15, 2302.
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13 For alternate synthesis of oxidised tetrahydrocarbazoles see:
(a) H. Zaimoku, T. Hatta, T. Taniguchi and H. Ishibashi, Org. Lett.,
2012, 14, 6088; (b) K. Higuchi, M. Tayu and T. Kawasaki, Chem.
Commun., 2011, 47, 6728.
Angew. Chem., Int. Ed., 2009, 48, 1830. For Suzuki–Miyaura with this
directing group see: (c) T. Nishikata, A. R. Abela, S. Huang and
B. H. Lipshutz, J. Am. Chem. Soc., 2010, 132, 4978.
15 For the C2 Rh[III] catalyzed C2 alkenylation of protected indoles see:
D. J. Schipper, M. Hutchinson and K. Fagnou, J. Am. Chem. Soc.,
2010, 132, 6910.
´
14 (a) C. E. Houlden, C. D. Bailey, J. G. Ford, M. R. Gagne, G. C. Lloyd
Jones and K. I. Booker-Milburn, J. Am. Chem. Soc., 2008, 130, 10066;
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´
Tyler, M. R. Gagne, G. C. Lloyd-Jones and K. I. Booker-Milburn, 17 K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2009, 131, 9651.
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