Reactive 4a-alkyl-4aH-carbazoles by catalytic dearomatisation, and their unusual dimerisation and dealkylation reactions

Article abstract of DOI:10.1039/b910894g

Despite their intrinsic instability, 4a-alkyl-4aH-carbazoles can be generated by a catalytic dearomatisation process; their reactivity is demonstrated by facile dealkylation and highly unusual cyclodimerisation processes.

Full text of DOI:10.1039/b910894g

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Reactive 4a-alkyl-4aH-carbazoles by catalytic dearomatisation, and their
unusual dimerisation and dealkylation reactionsw
Robin B. Bedford,*a Craig P. Butts,a Mairi F. Haddow,a Robert Osborneb
and Rosalind F. Sankeya
Received (in Cambridge, UK) 3rd June 2009, Accepted 25th June 2009
First published as an Advance Article on the web 14th July 2009
DOI: 10.1039/b910894g
Despite their intrinsic instability, 4a-alkyl-4aH-carbazoles can
be generated by a catalytic dearomatisation process; their
reactivity is demonstrated by facile dealkylation and highly
unusual cyclodimerisation processes.
Catalytic C–H activation reactions are rapidly becoming
established as powerful methods for aromatic functionalisation,
not least because they can reduce the overall number of steps
in synthetic processes.1,2 One application of this class of
reaction is in the production of carbazoles (Scheme 1) and
this has been exploited in the synthesis of various natural
products.3
Fig. 1 X-Ray crystal structure of 7a. One enantiomer only shown;
H atoms omitted for clarity; thermal ellipsoids set at 50%.
We were interested to see whether this methodology could
the presence of the carbazole, 4a, in modest spectroscopic
yield (23%).
be extended to the synthesis of 6-membered rings such as
9,10-dihydroacridanes by related benzylic C–H activation, and
accordingly examined the ring-closing reaction of intermediate
1a catalysed by Pd(OAc)2/PtBu3 (Scheme 2). Examination of
Amongst low levels of unidentified components, we
observed trace amounts of the hydrodehalogenation product
5, the etherification product 6 (B10%) and the highly unusual
dimeric 4aH-carbazole, 7a (10%), presumably produced
by cyclodimerisation of the corresponding 4a-alkyl-4aH-
carbazole monomer, 8a. The structure of 7a was determined
by NOE experiments and confirmed by single crystal X-ray
analysis (Fig. 1).wz
1
the crude product mixture by H NMR and GCMS gave no
indication of the formation of the desired 6-membered ring, 2,
or its oxidised counterpart, 3. Instead we were surprised to find
Optimisation studies revealed that changing from PtBu3 to
the carbene ligand SIPr prevented the formation of 6,
although the amount of 4a produced remained constant
(23%).4 We reasoned that the dimeric species 7a and the
carbazole 4a formed from a common intermediate, namely
the unstable 4a-methyl-4aH-carbazole 8a,5 and that decreasing
the reaction concentration should disfavour dimerisation. This
resulted in an improved yield of 4a (42%) and a slightly
improved selectivity (yield of 7a: 15%). Under these optimised
conditions, we examined the reactions of a range of precursors
1 and the results are summarised in Table 1.w
Scheme 1 Carbazole synthesis via aromatic C–H activation.
Substrate 1b (Table 1, entry 2), wherein the 4-methyl-
substitution would be expected to disfavour the dimerisation
process, gave the carbazole 4b in 62% isolated yield, against
only 8% of the dimer 7b. However, further modification of the
4-position resulted in no product formation (entries 5–7). The
highly unusual C–C bond cleavage observed was not restricted
to a methyl group; when substrates 1k and 1l were subjected to
the same reaction conditions loss of an ethyl group occurred
(Scheme 3).
Scheme 2 Conditions: (i) Pd(OAc)2 (5 mol%), PtBu3 (7 mol%) or
SIPr (14 mol%), NaOtBu (5 equiv.), toluene (3 ml), D, 18 h; (ii) 2M
HCl(aq)
.
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
UK BS8 1TS. E-mail: r.bedford@bristol.ac.uk
b Process Research and Development Department, AstraZeneca,
Avlon Works, Severn Road, Hallen, Bristol, UK BS10 7ZE
w Electronic supplementary information (ESI) available: Experimental
details and spectra. CCDC 730686. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b910894g
Initially it was thought that the formation of carbazoles 4
proceeded via catalytic C–C bond activation. However, it
subsequently transpired that loss of the alkyl group did not
occur until after the catalysis, during the acidic work-up.6
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Table 1 Preparation of carbazolesa
Table 2 Isolation of 4a-methyl-4aH-carbazolesa
Yield (%)
Yield (%)
8
7
Entry
Substrate, 1
4
7
Entry
1
Substrate, 1
1b
2
3
4
5
6
7
1b
1d
1e
1f
1h
1i
8b, 52
8b, 65c
8c, 20
0
8f, 49
8g, 31
8h, 74
7b, 4
7b, 5.5c
7c, 0
0
7f, 7
4a, 42b
4b, 62b
4a, 30b
7a, 15b
7g, 11
7h, traced
2
3
7b, 8b
1j
a
Conditions: Pd(OAc)2 (5 mol%), SIPr (14 mol%), NaOtBu
b
(3 equiv.), toluene (5 ml), D, 18 h. Reaction carried out on a 1 mmol
7a, 8.5b
scale. Spectroscopic yield determined by 1H NMR (trimethoxy-
c
d
benzene internal standard). o5%, could not be isolated cleanly.
4
5
6
7
4b, 61b
4c, 0c
4d, 0
7b, 1b
7c, 0
7d, 0
7e, 0
Indeed, prior to work-up, the reactions produced 4a-alkyl-
4aH-carbazoles, 8, via a proposed catalytic dearomatisation
process (see below). Whilst these 4a-alkyl-4aH-carbazoles are
highly reactive, they can be isolated provided they have a
substituent in the 4-position (Table 2). To the best of our
knowledge, this is the first isolation of such simple 4a-alkyl-
4aH-carbazoles; previously these species have either only been
postulated as reactive intermediates in flash-vacuum pyrolysis
and photolytic reactions, or have been electronically stabilised
by benzannulation.5,7,8
4e, 0
The isolated 4a-methyl-4aH-carbazole 8b is a bright yellow
gum that undergoes slow cyclodimerisation in the pure state at
room temperature to give 7b, irrespective of whether it is
stored in the light or the dark. By contrast, solutions of 8b
appear to be stable. Interestingly, when 8b was photolysed, it
did not dimerise to 7b, but rather it underwent a previously
reported5 skeletal rearrangement to give the cyclopenta[b]-
quinoline 9 via consecutive aza-di-p-methane and [1,5]-H shift
processes (Scheme 4).
8
9
4f, 49
7f, 6
4g, 28
4h, 53
7g, 5
10
7h, traced
Conditions: (i) Pd(OAc)2 (5 mol%), SIPr (14 mol%), NaOtBu
a
b
(3 equiv.), toluene (5 ml), D, 18 h; (ii) 2M HCl(aq)
.
Spectroscopic
yield determined by H NMR (trimethoxybenzene internal standard).
1
c
d
Hydrodehalogenated product was the main product (24%). o5%,
Scheme 4 Rearrangement reactions of 8b.
could not be isolated cleanly.
In all cases of dimerisation to compounds 7, only one isomer
was observed, namely the ‘head-to-head’ dimer with exo
geometry across the cyclobutane ring. This is a sterically
hindered isomer, which implies that the reaction is not
concerted, but rather that one of the bonds forms first to
generate the least hindered diradical intermediate, which
undergoes rotation about the newly formed bond and ring
closure. By contrast the reported 4aH-carbazole 8m, which is
Scheme 3 Conditions: Pd(OAc)2 (5 mol%), SIPr (14 mol%), NaOtBu
(3 equiv.), toluene (5 ml), D, 18 h. Conversion determined using 1H
NMR (trimethoxybenzene internal standard).
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electronically stabilised by benzannulation, was prepared in
88% yield from 1m according to the standard catalytic
reaction and showed no tendency to dimerise on standing.9
after all, but rather through a catalytic dearomatisation/
H-shift manifold via highly unstable intermediates of the type
13—a possibility that we are currently exploring.
In summary we have developed a novel synthesis of
4a-alkyl-4aH-carbazoles by catalytic dearomatisation. Whilst
these carbazoles are reactive with respect to both unusual
dealkylation and dimerisation processes, representative
examples can be isolated. We are currently exploring the
scope, limitations and mechanisms of this class of reaction,
particularly with regard to the role such mechanisms may play
in ‘C–H activation’ reactions.
With regards to the mechanism of cyclisation, two possible
pathways are shown in Scheme 5. In the first instance,
oxidative addition generates species 10, which can then either
undergo a Heck-type process, through intermediate 11, or a
catalytic dearomatisation process via intermediate 12.
We thank the EPSRC and AZ for funding, and Johnson
Matthey for the loan of Pd salts.
Notes and references
z Crystal data for 7a: C28H26N2, M = 390.51, orthorhombic, a =
13.0545(3), b = 13.7865(3), c = 23.0330(5) A, V = 4145.38(16) A3,
T = 100(2) K, space group P212121, Z = 8, m = 0.073 mmꢁ1, rcalc
1.352 g cmꢁ3, Rint = 0.0624 (for 71 694 measured reflections), R1
=
=
0.0411 [for 4599 unique reflections with 42s(I)], wR2 = 0.1149 (for all
5253 unique reflections), 2ymax = 55.21, highest residual = 0.290 eAꢁ3
.
Crystals were mounted on a glass fibre on a Bruker Apex II diffractometer
and measured using Mo radiation (l = 0.71073 A). The structure was
solved using direct methods (XS) and refined using XL. CCDC 730686.
1 For a recent review see: D. Alberico, M. E. Scott and M. Lautens,
Chem. Rev., 2007, 107, 174.
2 For recent overviews, see: (a) Catalytic Aromatic C–H Activation
(Symposium in Print), Tetrahedron, 2008, 64, 5963–6138;
(b) Handbook of C–H Transformations, ed. G. Dyker, Wiley-VCH,
Weinheim, 2005.
3 (a) R. B. Bedford and C. S. J. Cazin, Chem. Commun., 2002, 2310;
(b) R. B. Bedford and M. Betham, J. Org. Chem., 2006, 71, 9403;
(c) R. B. Bedford, M. Betham, J. P. H. Charmant and A. L. Weeks,
Tetrahedron, 2008, 64, 6038.
Scheme 5 Proposed mechanism of ring-closure. Co-ligands omitted
for clarity.
A significant delineation between these two potential
mechanisms is in the role of the base. In the Heck-type
reaction, the base would merely serve to deprotonate the
‘PdHX’ product, whilst in the dearomatisation route, the base
would play an intimate role in the mechanism, specifically
deprotonation of the nitrogen atom in 10, which would act as
the trigger for the dearomatisation. It is telling that the range
of bases that could be used in the reaction was rather limited:
NaOAc, Cs2CO3 and Cy2NMe all showed no reactivity,
despite the fact that all are commonly employed in Heck
reactions. This strongly militates against a Heck-type process
and consequently we favour the dearomatisation mechanism.
Our current hypothesis for the dealkylation step is activa-
tion of the alkyl group to nucleophilic attack by protonation
of the nitrogen or coordination to a Lewis acid, but it must be
stressed that this is highly tentative; as yet, we have been
unable to trace the fate of the alkyl leaving group using GC,
GC-MS, 1H or 13C NMR experiments (the latter under closed
conditions); these studies are ongoing.10
4 For ease of handling 1,3-bis(2,6-diisopropylphenyl)-2-pentafluoro-
phenyl)imidazolidine was used as the SIPr source. See:
R. B. Bedford, M. Betham, M. E. Blake, R. M. Frost,
P. N. Horton, M. B. Hursthouse and R.-M. Lopez-Nicolas, Dalton
´ ´
Trans., 2005, 2774.
5 8a has been reported as a transient intermediate in the flash vacuum
pyrolysis and photolysis of 1-phenyl-1H-benzo[d][1,2,3]triazole:
(a) J. J. Kulagowski, C. J. Moody and C. W. Rees, J. Chem. Soc.,
Chem. Commun., 1982, 548; (b) J. J. Kulagowski, C. J. Moody and
C. W. Rees, J. Chem. Soc., Perkin Trans. 1, 1985, 2725.
6 Interestingly, when pure isolated 8b is reacted with 2M HCl(aq)
under the same conditions as those during workup, but in the
absence of palladium, only B20% is converted to the dimer 4b.
This may indicate some role for the palladium—possibly as a Lewis
acid coordinating to the nitrogen. Water is not necessary for the
dealkylation step; quenching a crude catalytic reaction with
TMSCl gives complete conversion of 8b to 4b under anhydrous
conditions.
7 (a) J. J. Kulagowski, G. Mitchell, C. J. Moody and C. W. Rees,
J. Chem. Soc., Chem. Commun., 1985, 650; (b) J. J. Kulagowski, C. J.
Moody and C. W. Rees, J. Chem. Soc., Perkin Trans. 1, 1985, 2733.
8 During the preparation if this manuscript, Buchwald and co-
workers reported the preparation of chiral, benzannulation-
stabilised 4aH-carbazoles from naphthyl precursors via asymmetric
An interesting aspect of the catalytic dearomatisation reaction
is the notional relationship of product 8 with intermediate 13
proposed in the Graebe–Ullmann synthesis of carbazoles from
N-arylbenzotriazines (Scheme 6).11 This raises the intriguing
possibility that the reactions such as those shown in Scheme 1
may not proceed by metal-mediated C–H bond ‘activation’
Pd-catalysed dearomatisation. See: J. Garcıa-Fortanet, F. Kessler
´
and S. L. Buchwald, J. Am. Chem. Soc., 2009, 131, 6676.
9 The UV/Vis spectrum of the reactive carbazole 8b shows a
substantial red shift of the chromophore compared with the
stabilised product 8m: see the ESIw for the spectra.
10 We disfavour a radical pathway as this would yield multiple products,
particularly N–Me carbazoles (see ref. 5), which we do not observe. In
addition, we see no evidence of methane in 1H or 13C NMR spectra of
crude quenched mixtures under closed system conditions, suggesting
that the formation of a methyl radical followed by hydrogen
abstraction from the medium does not occur.
11 C. Graebe and F. Ullmann, Justus Liebigs Ann. Chem., 1896, 291, 16.
Scheme 6 Graebe–Ullman carbazole synthesis.
4834 | Chem. Commun., 2009, 4832–4834
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