Intramolecular direct arylation in the synthesis of fluorinated carbazoles

Article abstract of DOI:10.1016/j.tet.2008.01.143

The amination of 2-chloroanilines with aryl bromides and subsequent intramolecular direct arylation can be exploited in the synthesis of a range of fluorinated carbazoles, where the fluorine substituent can be introduced via the aniline, the aryl bromide or both substrates. Depending on substitution patterns, the two steps can either be performed in tandem in one-pot under microwave heating conditions or else require a two pot approach.

Full text of DOI:10.1016/j.tet.2008.01.143

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6038e6050
www.elsevier.com/locate/tet
Intramolecular direct arylation in the synthesis of fluorinated carbazoles
*
Robin B. Bedford , Michael Betham, Jonathan P.H. Charmant, Amanda L. Weeks
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Received 24 September 2007; received in revised form 21 January 2008; accepted 22 January 2008
Available online 4 March 2008
Abstract
The amination of 2-chloroanilines with aryl bromides and subsequent intramolecular direct arylation can be exploited in the synthesis of
a range of fluorinated carbazoles, where the fluorine substituent can be introduced via the aniline, the aryl bromide or both substrates. Depending
on substitution patterns, the two steps can either be performed in tandem in one-pot under microwave heating conditions or else require a two pot
approach.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
inherent in the second reaction type and often the use of
more complex oxidants can detract from the atom economy
of the process.
Catalytic aromatic CeH activation is rapidly establishing
itself as a viable alternative to classical, transition metal-cata-
lysed cross-coupling reactions of the general type shown in
Scheme 1.1 This is not least because it obviates the need to
introduce an organometallic group onto the nucleophilic
substrate.
[cat]
+
+
Ar
Ar
H
FG
FG
H
Ar FG
Ar FG
[O]
-H2O
[cat]
H
X
base
-HX
[Pd-cat]
Scheme 2. Aromatic CeH functionalisation.
+
M
X
(base)
R
R'
R
R'
A well-developed class of reaction that proceeds via the
second methodology outlined in Scheme 2 is the synthesis
of heterocycles (and carbocycles) from ‘tethered’ biaryl sub-
strates (Scheme 3); the intramolecular direct arylation
reaction.
M = MgX, SnR3,
B(OR)2, Si(OR)3,
ZnX, etc.
Scheme 1. Cross-coupling reactions.
Two general protocols are exploited in these processes; the
first is to use oxidative coupling,2,3 and the second relies on the
oxidative addition of an organic halide (Scheme 2), the so
called direct arylation reaction. The first class of reaction is
obviously more atom-economical than the seconddproviding
that the oxidant is oxygendwhich renders the process more at-
tractive from both environmental and commercial perspectives.
However, this oxidative approach can lack the selectivity
X
A B
A
B
[cat]
base
-HX
Scheme 3. Intramolecular direct arylation.
Scheme 4 shows a generalised reaction pathway for the an-
nulation step; the crux of this is the formation of a palladacy-
clic intermediate via CeH activation. The mechanism of this
step has been the subject of recent studies and current models
favour a base-assisted deprotonation mechanism over the
* Corresponding author. Tel.: þ44 (0) 117 3317538; fax: þ44 (0) 177
9290509.
E-mail address: r.bedford@bristol.ac.uk (R.B. Bedford).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.143

R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
6039
traditional extremes of CeH oxidative addition or electro-
philic displacement.4
but careful studies revealed no special ‘microwave effect’rather
that it is simply a more convenient way of performing higher
temperature reactions. More recently Dubois and co-workers
demonstrated that intramolecular arylation can be used to pro-
duce a wide range of imidazo[2,1-a]isoindoles from N-benzyl
iodoimidazoles (Scheme 6) using microwave heating.11
X
A
B
XPd
A
B
[Pd]
oxidative
addition
base
C-H activation
-HX
I
Pd(OAc)2
N
N
P(o-tol)3
A
B
A
B
N
N
R1
R1
KOAc
DMF,
- [Pd]
reductive
R2 R2
R2 R2
Pd
palladacycle
elimination
Scheme 6. Microwave-assisted synthesis of imidazo[2,1-a]isoindoles.
Scheme 4. Generalised reaction pathway for intramolecular direct arylation.
Whilst most of the syntheses via intramolecular direct ary-
lation published to date produce five- or six-membered rings,
Leblanc and Fagnou reported an elegant formal synthesis of
allocochicine, 4, in which the annulative step yields a seven-
membered ring.12 The formation of five- and six-membered
rings proceeds via six- and seven-membered palladacyclic in-
termediates; presumably in this case a far less favourable
eight-membered palladacycle is formed.
Over 20 years ago Ames and Opalko exploited this method-
ology in the synthesis of a range of five- and six-membered
heterocycles such as dibenzofurans, carbazoles, quinolinones
and pyranones.5 This procedure was subsequently used in
the synthesis of the benzylated forms of defucogilocarcins
M and E, 1;6 and compounds 2 and 3, intermediates in the
syntheses of dioncophylline A and mastigophorene B, respec-
tively (Fig. 1).7,8
NHAc
More recently Sakamoto and co-workers employed a two-
step method for the synthesis of carbolines from bromoamino-
pyridines and iodobenzene (Scheme 5) via sequential catalytic
amination and arylation. Each step required different catalysts,
bases and conditions.9
Maes and co-workers reported a related methodology for
the synthesis of indoloquinolines possessing anti-malarial
activity.10 Microwave heating was used to facilitate the reaction
MeO
MeO
CO2Me
OMe
Allocolchicine, 4, highlighted
bond formed by C-H activation
All of the reactions described so far rely on soluble palla-
dium-based pre-catalysts, however, Fagnou and co-workers
showed that palladium hydroxide on carbon can be used to
good effect in the intramolecular arylation of both bromide
and iodide-containing substrates. They concluded that the re-
actions were not in fact catalysed by a heterogeneous catalyst,
but rather by active homogeneous species formed in situ.13
Carbazoles are important structural motifs found in pharma-
ceuticals, natural products, agrochemicals and dyes.14,15 For in-
stance, carvedilol is a beta-blocker used in the treatment of
hypertension and angina whilst carazostatin is one of a family of
carbazoles produced by bacteria that are potent free radical scav-
engers and act as anti-oxidants. Ellipticine and its derivatives, in
particular 9-hydroxyellipticine, show potent anti-tumour activity.
OMe OBn
OMe
MeO
MeO
Bn
O
O
RH2C
O
O
2
1 R = H, Me
OMe
MeO
OMe
O
O
3
Figure 1. Natural products with pyranone structures formed by CeH
activation; the bonds formed during the annulation are highlighted.
H
N
Br
Br
Pd2(dba)3/dppf
NaOtBu, toluene, Δ
O
O
N
N
OH
OMe
RHN
N
R
+
N
H
Pd(OAc)2
Na2CO3
DMF, Δ
carvedilol
R
I
OH
N
N
N
R
N
H
N
H
C7H15
Scheme 5. Synthesis of carbolines via sequential amination and CeH
activation.
R = H, ellipticine;
R = OH, 9-hydroxyellipticine
carazostatin

6040
R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
little or no aminated intermediate 7 is observed in the 1H NMR
Cl
R1
R3
spectra of the crude product mixtures obtained before isolation
of the carbazole, with the exception of the reaction shown in
entry 5 using 2,4-dimethoxy bromobenzene as substrate where
nearly 30% of the product mixture is intermediate diarylamine
7e. 3,5-Dimethoxy bromobenzene gives a reasonable amount
of the carbazole 6h (entry 8), despite the absence of ortho-sub-
N
H
7
(i)
Cl
R1
+
R3
(ii) R2 = H
(iii)
(i) R2 = alkyl
NH
R2
Br
5
1
R1
stitution, but again H NMR of the crude mixture reveals the
R3
presence of significant amounts of the non-cyclised intermedi-
ate, 7h. The other meta-disubstituted aryl bromides investi-
gated, 3,5-di-tert-butyl and 3,5-dimethyl bromobenzene,
gave poor yields of the desired carbazole with the major com-
ponent in the crude product mixtures being the aminated inter-
mediates (entries 8 and 9).
Similarly a very low yield of the carbazole 6k is obtained in
the coupling of 3,5-dimethyl bromobenzene with 2-chloro-6-
fluoroaniline (entry 11), although in this case 1H NMR of
the crude reaction mixture shows very little aminated interme-
diate either. Again ortho-substituted aryl bromides gave rea-
sonable amounts of the carbazole product using this aniline
(entries 12 and 13) as does 4-bromotoluene (entry 14). In these
cases little or no aminated intermediate is obtained.
The use of 2-chloro-5-fluoroaniline typically leads to poor
activity, even with ortho-functionalised aryl bromide sub-
strates (entries 15e17), with the exception of 1-bromonaph-
thalene (entry 18), which gives a good yield of the
carbazole. Interesting a small, but significant amount of a sec-
ond isomer, 6p, is seen in entry 15. This implies some palla-
dium migration by an as yet unknown mechanism, after
oxidative addition of the carbonechlorine bond. We have
observed a similar isomerisation previously.19
Using 1-bromonaphthalene with either 2-chloro-4-fluoro-
or 2-chloro-6-fluoroaniline yields the desired carbazoles (6g
and 6m, entries 7 and 13, respectively), but the latter reaction
also generates significant amounts of a second, incompletely
characterised product 8 (ratio 6m/8¼5:1).24 It is tempting to
conclude on the limited data in hand that this second species
is 8-fluoro-7H-benzo[k,l]acridine formed by competitive CeH
activation in the 8-position of the naphthyl group.
N
R2
6
Scheme 7. Pd-PtBu3 catalysed formation of carbazoles by sequential amina-
tion; CeH activation reactions. Conditions: (i) reflux in toluene; (ii) micro-
wave heating in toluene; (iii) reflux in 1,4-dioxane.
We have investigated producing carbazoles by exploiting
sequential catalytic amination and annulation via CeH activa-
tion, using 2-chloroanilines and aryl bromides as starting ma-
terials. This choice of precursors reflects their lower costs and
greater commercial availability compared with heavier conge-
ners. Unfortunately, the aryl chloride substrates are electroni-
cally highly deactivated, due to the presence of an ortho-amine
function, and represent a significant challenge.16,17 We found
that palladium catalysts with tri-tert-butylphosphine are suffi-
ciently reactive to overcome this problem (Scheme 7). Where
R2 is a methyl or a benzyl group then the reaction proceeds in
toluene at reflux temperature in one-pot.18 By contrast the syn-
thesis of 9-H carbazoles, that is to say when R2¼H, is more
problematic and requires either significantly higher tempera-
ture, typically obtained using microwave heating, or the split-
ting of the reaction into two steps.19 The first step is performed
in toluene whilst the second requires dioxane as the solvent.
The one-step, microwave heating processes appears to be
more suited to aryl bromides with ortho-substituents.
The replacement of a hydrogen with a fluorine atom can
have a profound influence on a molecule’s physical, chemical
and biological properties and this has been exploited in phar-
maceutical, agrochemical and materials’ production.20,21 Ac-
cordingly we were interested to see whether our carbazole
synthesis could be exploited for the synthesis of fluorinated
examples and the results of this study are reported below.22
The one-pot methodology can also be used to introduce the
fluorine atom via the aryl bromide. Thus 2-chloro-6-methyl-
aniline reacts with 2-, 3- and 4-fluorobromobenzene to generate
the desired carbazoles (entries 19e21). In the case of 3-fluoro-
bromobenzene (entry 20) the two carbazoles 6o and 6p are
formed in an approximately 1.4:1 ratio.
2. Results and discussion
2.1. One-step synthesis of fluorocarbazoles
Due to the more convenient nature of the one-step, micro-
wave heating protocol outlined in Scheme 7, we first explored
the potential of this route in the production of fluorocarbazoles
from fluorinated 2-chloranilines; the results from this study are
summarised in Table 1. The catalyst system and conditions
employed are the same as those optimised previously.19 The
phosphonium salt [HPtBu3][BF4] was used in place of the
free phosphine due to the latter’s air-sensitivity.23
When all the data are taken together it is apparent that the
one-step methodology works well for most ortho-substituted
aryl bromides but can fail for other substitution patterns.
This is particularly apparent when 3,5-dimethyl bromoben-
zene is used as a substrate. Therefore we next examined the
application of a two-step methodology, where the aminated in-
termediate is isolated first and then subjected to ring-closing.
Examining entries 1e7 it can be seen that with 2-chloro-4-
fluoroaniline as substrate reasonable yields of the desired carb-
azoles 6aeg are obtained in one-step when 2-substituted aryl
bromides are used as coupling partners. In most of these cases
2.2. Two-step synthesis of fluorocarbazoles
In the first instance we performed a brief optimisation study
on the ring-closing of the intermediate 7u, formed by the

R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
6041
Table 1
The one-pot synthesis of fluorinated carbazolesa
Entry
Chloroaniline
Aryl bromide
Product
Approx. ratio of product
to aminated intermediates
Isolated yield
of carbazole (%)
F
F
F
Cl
1
No intermediate observed
70
6a
Br
N
H
NH2
2
3
21:1
44
6b
N
H
Br
F
No intermediate observed
20 (65)b
6c
Br
N
H
OMe
OMe
OMe
OMe
F
4
5
12:1
64
62
6d
Br
N
H
OMe
OMe
OMe
F
OMe
2.5:1
6e
Br
N
H
OMe
OMe
F
Br
N
6
9:1
44
6f
H
F
7
8
9
12:1
5:2
61
6g
N
H
Br
OMe
tBu
OMe
F
53
6h
N
H
OMe
Br
OMe
tBu
tBu
F
1.5:2
1:7
21 (25)b
6i
N
tBu
Br
H
F
10
11
6
6j
N
Br
H
Cl
NH2
10
6k
N
H
F
F
12
No intermediate observed
45
56
6l
N
Br
H
F
No intermediate observed
Crude product contains second species 8
13
14
6m
N
H
Ratio of 6m/8 in crude product¼w5:1
F
F
Br
23 (65)b
7:1
6n
N
H
Br
(continued on next page)

6042
R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
Table 1 (continued)
Entry
Chloroaniline
Aryl bromide
Product
Approx. ratio of product
to aminated intermediates
Isolated yield
of carbazole (%)
6o
F
N
H
F
Cl
27 (30)b
2:1
15
Br
6p
F
NH2
6o/6p¼5:1
N
H
16
17
1:4
4:1
24 (25)b
14 (24)b
6q
F
N
H
Br
Br
6r
F
F
N
H
18
19
No intermediate observed
No intermediate observed
77
6s
N
H
Br
Cl
NH2
37 (73)b
6l
Br
F
N
H
F
No intermediate observed
6o/6p¼w1.4:1
62
6o/6p¼w1.3:1
6o
N
F
F
H
F
Br
F
F
20
6p
N
H
21
2.5:1
35 (65)b
6t
N
H
Br
a
Conditions: fluoro-2-chloroaniline (0.5 mmol), aryl bromide (0.5 mmol), Pd(OAc)2 (5 mol %), [HPtBu3][BF4], (7 mol %), NaOtBu (2.5 mmol), mn, 160 ꢀC, 3 h.
Number in parentheses refers to spectroscopic yield in crude product mixture, determined by 1H NMR (1,3,5-MeO3C6H3 internal standard).
b
Cl
Cl
the best conversion to carbazole 6u is only 61%, obtained
with tri-tert-butylphosphine in 1,4-dioxane (entry 1). Compar-
ing entries 1 and 2, it is interesting to note that the palladium
source can have a profound influence on catalyst performance.
The use of tricyclohexylphosphine, XPhos (9) or the pallada-
cyclic catalyst 10 leads to a substantial diminution in catalyst
activity as does changing the solvent or the base.
Having established the best catalyst and conditions, these
were then used in the two-step couplings shown in Scheme
9. The structure of one example (6w) was determined by
single crystal X-ray analysis and the molecule is shown in
Figure 2. Interestingly there are no NH/F hydrogen bonding
interactions apparent in the structure.
(i)
MeO
N
H
MeO
NH2
7u
5u
F
(ii)
MeO
N
H
6u
F
Scheme 8. Conditions: (i) 5u (1 mmol), 2-FC6H4Br (1 mmol), NaOtBu
(5 mmol), Pd(OAc)2 (5 mol %), [HPtBu3][BF4] (7 mol %), toluene, D, 18 h.
(ii) 7u (0.5 mmol), Pd complex (5 mol %), ligand (7 mol %), base
(2.5 mmol), solvent (3 ml), D, 18 hdsee Table 2 for catalysts, solvents and
bases.
The methodology can be extended further to allow fluorine to
be introduced both on the chloroaniline and aryl bromide sub-
strates, as demonstrated by the synthesis of carbazole 6x
(Scheme 9). In this case we see very little aminated intermediate
in the crude product mixture, butdo observe substantial amounts
of bis(4-fluorophenyl)amine (ratio of 6x/diarylamine¼1:1.1).
Next we examined the introduction of a single fluorine
atom via the chloroaniline substrate. Firstly we investigated
amination of 2-chloro-5-methoxyaniline with 2-fluorobromo-
benzene, according to Scheme 8. The results of the optimisa-
tion study are summarised in Table 2.
The aminated intermediate product 7u contains an aryl
chloride function, which is highly deactivated with respect
to oxidative addition as it contains both an ortho-amino and
para-methoxy function. Therefore it is not surprising that

R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
6043
Table 2
Optimisation of the annulation of 7u
Entry
Pd source
Phosphine
Solvent
Base
Conversiona (%)
1
2
3
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
[HPtBu3][BF4]
1,4-Dioxane
NaOtBu
61
12
2
PCy3
PCy2
Pri
4
5
12
9
9
iPr
Pri
But
But
O
PiPr2
Pd Cl 10
No ligand
2
6
Pd(OAc)2
[HPtBu3][BF4]
Toluene
DMF
1,4-Dioxane
20
0
7
8
Cs2CO3
K3PO4
NEt3
22
3
9
10
a
2
Determined by 1H NMR spectroscopy (1,3,5-MeOC6H3 internal standard).
R1
R2
Cl
R1
R2
Cl
7v: 68%
w: 75%
x: 86%
(i)
Cl
Cl
F
F
(i)
F
F
N
H
NH2
N
H
NH2
7j: 55%
r: 78%
k: 83%
5j: 4-F
r: 5-F
+
(ii)
+
k: 6-F
(ii)
Br
R1
R2
F
Br
6j: 19%
F
N
H
r: 10%
k: 16%
N
H
6v: R1 = Me; R2 = OMe; F = 1-F; 52%
w: R1 = H; R2 = H; F = 3-F; 69%
x: R1 = F; R2 = H; F = 3-F; 42%
Scheme 10. Conditions: (i) 5 (1 mmol), ArBr (1 mmol), NaOtBu (5 mmol),
Pd(OAc)2 (5 mol %), [HPtBu3][BF4] (7 mol %), toluene, D, 18 h. (ii) 7
(0.5 mmol), Pd(OAc)2 (5 mol %), [HPtBu3][BF4] (7 mol %), NaOtBu
(2.5 mmol), 1,4-dioxane, D, 18 h.
Scheme 9. Conditions: (i) 5 (1 mmol), ArBr (1 mmol), NaOtBu (5 mmol),
Pd(OAc)2 (5 mol %), [HPtBu3][BF4] (7 mol %), toluene, D, 18 h. (ii) 7
(0.5 mmol), Pd(OAc)2 (5 mol %), [HPtBu3][BF4] (7 mol %), NaOtBu
(2.5 mmol), 1,4-dioxane, D, 18 h.
mixture is the aminated intermediate 7. Clearly the 1,3-disub-
stitution pattern can be deleterious to performance and it ap-
pears that in these cases the aryl chloride does not undergo
oxidative addition. Better performance is obtained with 4-bro-
motoluene and 2-chloro-4-fluoroaniline in the production of
carbazole 6y (Scheme 11).
F
Cl
F
Cl
(i)
N
H
NH2
7y: 49%
+
(ii)
Br
F
Figure 2. Crystal structure of carbazole 6w, disorder not shown.
N
H
6y: 48%
the coupling of 3,5-dimethyl bromobenzene with 4-, 5- and
6-fluoro-2-chloroanilines (Scheme 10) as these coupling part-
ners led to very low yields of carbazoles in the one-pot method
described above.
Scheme 11. Conditions: (i) 5 (1 mmol), ArBr (1 mmol), NaOtBu (5 mmol),
Pd(OAc)2 (5 mol %), [HPtBu3][BF4] (7 mol %), toluene, D, 18 h. (ii) 7
(0.5 mmol), Pd(OAc)2 (5 mol %), [HPtBu3][BF4] (7 mol %), NaOtBu
(2.5 mmol), 1,4-dioxane, D, 18 h.
Unfortunately, whilst the aminated intermediates 7j, 7k and
7r are isolated in reasonable to good yields, conversion to the
1
carbazoles as determined by H NMR remains poor. In all
cases, the major material observed in the crude product
In summary we find that intramolecular direct arylation is
a viable synthetic route for the production of fluorinated carb-
azoles, typically in reasonable to good yields. Some

6044
R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
substitution patterns still prove problematic with the current
methodology and strategies to address these shortcomings
will be investigated further.
4.4 Hz, 1H, Ar H), 7.83 (dd, J¼9.8, 2.7 Hz, 1H, Ar H), 7.94
(br s, 1H, NH); 13C NMR (100 MHz, CDCl3) d 16.63 (s,
CH3), 20.37 (s, CH3), 108.28 (d, J¼24.0 Hz, CH), 110.93
(d, J¼9.0 Hz, CH), 112.77 (d, J¼24.0 Hz, CH), 117.42 (s,
C), 120.96 (s, CH), 121.33 (s, C), 124.92 (d, J¼9.0 Hz, C),
126.80 (s, CH), 131.05 (s, C), 135.78 (s, C), 139.99 (s, C),
157.50 (d, J¼232.0 Hz, CF); 19F NMR (282.65 MHz,
CDCl3) d ꢂ124.54 (dt, J¼9.1, 4.5 Hz); HRMS (EI) calcd for
C14H12FN [Mþ]: 213.0954, found: 231.0961. Anal. Calcd
for C14H12FN: C, 78.85; H, 5.67; N, 6.57. Found: C, 78.95;
H, 5.74; N, 7.10.
3. Experimental
3.1. General experimental conditions
All reactions and preparations were carried out under a dry
nitrogen atmosphere, either in a glove box or using standard
Schlenk techniques with anhydrous solvents. Microwave reac-
tions were performed using a Biotage AB Initiator (300 W;
software version 1.1) with autochanger (8 positions) using
Biotage 5 ml sealed vials. XPhos (9) was purchased from
SigmaeAldrich and palladacycle 10 was prepared according
to a literature procedure.25
3.2.3. 3-Fluoro-8-methoxy-9H-carbazole, 6c (Table 1,
entry 3)
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 2-bro-
motoluene (0.06 ml, 0.50 mmol) gave the product as a light
brown powder: 22 mg (20%); Rf 0.78 (CHCl3); mp 102.1e
1
3.2. General method for microwave-assisted, one-pot
synthesis of fluorocarbazoles
103.8 ꢀC; H NMR (400 MHz, CDCl3) d 4.01 (s, 3H, OMe),
6.91 (d, J¼7.8 Hz, 1H, Ar H), 7.36 (dd, J¼8.8, 4.4 Hz, 1H,
Ar H), 7.15 (m, 2H, Ar H), 7.62 (d, J¼8.0 Hz, 1H, Ar H),
7.70 (dd, J¼9.0, 2.7 Hz, 1H, Ar H), 8.22 (br s, 1H, NH);
13C NMR (100 MHz, CDCl3) d 55.50 (s, CH3), 106.08 (s,
C), 106.09 (d, J¼23.3 Hz, CH), 111.43 (d, J¼9.2 Hz, CH),
112.91 (s, CH), 113.53 (d, J¼25.9 Hz, CH), 119.75 (s, CH),
123.95 (s, CH), 124.11 (d, J¼9.0 Hz, C), 130.92 (s, C),
135.44 (s, C), 145.74 (s, C), 157.40 (d, J¼234 Hz, CF); 19F
NMR (282.65 MHz, CDCl3) d ꢂ124.47 (dt, J¼9.3, 3.7 Hz);
HRMS (EI) calcd for C13H10FNO [Mþ]: 215.0746, found:
215.0751. Anal. Calcd for C13H10FNO$H2O: C, 66.94; H,
4.32; N, 6.00. Found: C, 67.86; H, 4.96; N, 5.97.26
NaOtBu (0.240 g, 2.5 mmol), Pd(OAc)2 (0.006 g,
0.025 mmol) and [HPtBu3][BF4] (0.010 g, 0.035 mmol) were
suspended in toluene (3 ml) in a 5 ml microwave vial. The ap-
propriate 2-chloroaniline (0.50 mmol) and aryl bromide
(0.50 mmol) were then added and the vial sealed. The reaction
was then heated in the microwave reactor at 160 ꢀC for 3 h,
allowed to cool and then quenched by addition of HCl(aq)
(2 M, 3 ml). The organic phase was extracted with CH2Cl2
(2ꢁ20 ml), dried (MgSO4), then filtered and the solvent
removed under reduced pressure. The crude product mixture
was then subjected to column chromatography (SiO2).
3.2.4. 3-Fluoro-5,8-dimethoxy-9H-carbazole, 6d (Table 1,
entry 4)
3.2.1. 3-Fluoro-8-methyl-9H-carbazole, 6a (Table1, entry 1)
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 2-bro-
motoluene (0.06 ml, 0.50 mmol) gave the product as a light
grey powder: 70 mg (70%); Rf 0.88 (CHCl3); mp 120.6e
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 1-
bromo-2,5-dimethoxybenzene (0.08 ml, 0.50 mmol) gave the
product as a dark brown oil: 78 mg, (64%); Rf 0.73 (CHCl3);
1H NMR (400 MHz, CDCl3) d 3.96 (s, 3H, OMe), 4.02 (s, 3H,
OMe), 6.50 (d, J¼8.3 Hz, 1H, Ar H), 6.79 (d, J¼8.6 Hz, 1H,
Ar H), 7.12 (dd, J¼8.2, 2.6 Hz, 1H, Ar H), 7.31 (dd, J¼8.8,
2.6 Hz, 1H, Ar H), 7.99 (dd, J¼9.4, 2.6 Hz, 1H, Ar H), 8.25
(br s, 1H, NH); 13C NMR (100 MHz, CDCl3) d 55.70 (s,
CH3), 56.06 (s, CH3), 99.03 (s, CH), 106.57 (s, CH), 108.63
(d, J¼24.0 Hz, CH), 110.81 (d, J¼9.0 Hz, CH), 112.84 (d,
J¼25.0 Hz, CH), 113.75 (s, C), 123.52 (d, J¼10.0 Hz, C),
132.04 (s, C), 134.93 (s, C), 140.21 (s, C), 150.45 (s, C),
157.55 (d, J¼233.0 Hz, CF); 19F NMR (282.65 MHz, CDCl3)
d ꢂ124.46 (dt, J¼9.1, 4.5 Hz); HRMS (EI) calcd for
C14H12FNO2 [Mþ]: 245.0852, found: 245.0847. Anal. Calcd
for C14H12FNO2: C, 68.56; H, 4.93; N, 5.71. Found: C, 68.33;
H, 5.01; N, 5.91.
1
122.8 ꢀC; H NMR (400 MHz, CDCl3) d 2.55 (s, 3H, Me),
7.15 (m, 2H, Ar H), 7.25 (d, J¼8 Hz, 1H, Ar H), 7.37 (dd,
J¼8.6, 4.2 Hz, 1H, Ar H), 7.71 (dd, J¼9.0, 2.4 Hz, 1H, Ar
H), 7.87 (d, J¼7.8 Hz, 1H, Ar H), 7.93 (br s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 16.79 (s, CH3), 106.06 (d,
J¼23.7 Hz, CH), 111.18 (d, J¼9.2 Hz, CH), 113.42 (d,
J¼25.2 Hz, CH), 118.12 (s, CH), 119.59 (s, CH), 119.99 (s,
C), 122.57 (s, CH), 124.37 (d, J¼9.0 Hz, C), 135.65 (s, C),
139.91 (s, C), 157.50 (d, J¼234.0 Hz, CF); 19F NMR
(282.65 MHz, CDCl3) d ꢂ124.35 (dt, J¼9.1, 4.6 Hz);
HRMS (EI) calcd for C13H10FN [Mþ]: 199.0797, found:
199.0792. Anal. Calcd for C13H10FN: C, 78.37; H, 5.06; N,
7.03. Found: C, 77.75; H, 5.40; N, 7.86.
3.2.2. 3-Fluoro-5,8-dimethyl-9H-carbazole, 6b (Table 1,
entry 2)
3.2.5. 3-Fluoro-6,8-dimethoxy-9H-carbazole, 6e (Table 1,
entry 5)
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 1-
bromo-2,4-dimethoxybenzene (0.07 ml, 0.50 mmol) gave the
product as a dark brown oil: 76 mg (62%); Rf 0.80 (CHCl3);
1H NMR (400 MHz, CDCl3) d 3.92 (s, 3H, OMe), 3.96
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 2-
bromo-p-xylene (0.07 ml, 0.50 mmol) gave the product as
a dark brown powder: 47 mg (44%); Rf 0.86 (CHCl3); mp
1
84.8e87.2 ꢀC; H NMR (400 MHz, CDCl3) d 2.52 (s, 3H,
Me), 2.81 (s, 3H, Me), 7.16 (m, 2H, Ar H), 7.38 (dd, J¼8.8,

R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
6045
1
(s, 3H, OMe), 6.59 (d, J¼2.1 Hz, 1H, Ar H), 7.03 (d,
J¼2.0 Hz, 1H, Ar H), 7.12 (dt, J¼8.0, 2.0 Hz, 1H, Ar H),
7.33 (dd, J¼8.0, 2.1 Hz, 1H, Ar H), 7.64 (dd, J¼9.1, 2.5 Hz,
1H, Ar H), 8.06 (br s, 1H, NH); 13C NMR (100 MHz,
CDCl3) d 55.68 (s, CH3), 56.11 (s, CH3), 93.91 (s, CH),
98.12 (s, CH), 105.87 (d, J¼24.0 Hz, CH), 111.73 (d,
J¼9.0 Hz, CH), 113.55 (d, J¼26.0 Hz, CH), 123.02 (s, C),
124.15 (d, J¼9.0 Hz, C), 126.23 (s, C), 136.00 (s, C),
146.36 (s, C), 157.25 (d, J¼230 Hz, CF); 19F NMR
(282.65 MHz, CDCl3) d ꢂ124.85 (dt, J¼9.1, 4.5 Hz);
HRMS (EI) calcd for C14H12FNO2 [Mþ]: 245.0852, found:
245.0845. Anal. Calcd for C14H12FNO2$0.5H2O: C, 66.60;
H, 4.79; N, 5.55. Found: C, 66.36; H, 4.95; N, 5.66.
product as a black oil: 65 mg (53%); Rf 0.33 (CHCl3); H
NMR (400 MHz, CDCl3) d 3.87 (s, 3H, OMe), 4.01 (s, 3H,
OMe), 6.29 (d, J¼1.7 Hz, 1H, Ar H), 6.47 (d, J¼1.7 Hz, 1H,
Ar H), 7.00 (m, 1H, Ar H), 7.22 (dd, J¼8.7, 4.0 Hz, 1H, Ar
H), 7.84 (dd, J¼9.5, 3.8 Hz, 1H, Ar H), 7.89 (br s, 1H, NH);
13C NMR (100 MHz, CDCl3) d 55.54 (s, CH3), 55.74 (s,
CH3), 86.81 (s, CH), 91.17 (s, CH), 106.93 (s, C), 107.70 (d,
J¼25.0 Hz, CH), 110.02 (d, J¼10.0 Hz, CH), 111.13 (d,
J¼25.0 Hz, CH), 123.50 (d, J¼10.0 Hz, C), 134.94 (s, C),
142.63 (s, C), 156.73 (s, C), 157.76 (d, J¼232.0 Hz, CF),
160.79 (s, C); 19F NMR (282.65 MHz, CDCl3) d ꢂ124.52 (br
s); HRMS (EI) calcd for C14H12FNO2 [Mþ]: 245.0852, found:
245.0854. Anal. Calcd for C14H12FNO2: C, 68.56; H, 4.93; N,
5.71. Found: C, 68.43; H, 5.23; N, 6.19.
3.2.6. 3-Fluoro-8-phenyl-9H-carbazole, 6f (Table 1,
entry 6)
3.2.9. 3-Fluoro-5,7-di-tert-butyl-9H-carbazole, 6i (Table 1,
entry 9)
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 2-bro-
mobiphenyl (0.09 ml, 0.50 mmol) gave the product as an or-
ange oil: 58 mg (44%); Rf 0.75 (1:1 CHCl3/hexane); 1H
NMR (400 MHz, CDCl3) d 7.16 (dt, J¼8.8, 2.4 Hz, 1H, Ar
H), 7.33 (d, J¼8.0 Hz, 2H, Ar H), 7.45 (m, 2H, Ar H), 7.56
(t, J¼7.8 Hz, 2H, Ar H), 7.69 (d, J¼8.0 Hz, 2H, Ar H), 7.75
(dd, J¼8.9, 2.6 Hz, 2H, Ar H), 8.02 (d, J¼7.8 Hz, 1H, Ar
H), 8.26 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3)
d 106.21 (d, J¼24.0 Hz, CH), 111.34 (d, J¼9.0 Hz, CH),
113.90 (d, J¼26.0 Hz, CH), 119.92 (d, J¼24.0 Hz, CH),
123.52 (d, J¼4.0 Hz, C), 124.18 (d, J¼10.0 Hz, C), 125.42
(s, C), 126.37 (s, CH), 127.78 (s, CH), 128.43 (s, CH),
129.07 (s, CH), 129.41 (s, CH), 135.84 (s, C), 138.43 (s, C),
138.91 (s, C), 157.64 (d, J¼234.0 Hz, CF); 19F NMR
(282.65 MHz, CDCl3) d ꢂ124.13 (dt, J¼9.1, 4.5 Hz);
HRMS (EI) calcd for C18H12FN [Mþ]: 261.0954, found:
261.0946. Anal. Calcd for C18H12FN$H2O: C, 77.40; H,
4.33; N, 5.01. Found: C, 77.34; H, 4.40; N, 5.87.
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 1-
bromo-3,5-di-tert-butylbenzene (0.14 g, 0.50 mmol) gave the
product as a dark brown gum: 31 mg (21%); Rf 0.75
1
(CHCl3); H NMR (400 MHz, CDCl3) d 1.41 (s, 9H, Me),
1.66 (s, 9H, Me), 6.89 (s, 2H, Ar H), 7.09e7.15 (m, 1H, Ar
H), 7.32e7.36 (m, 1H, Ar H), 7.99 (dd, J¼11.6, 2.3 Hz,
1H), 8.11 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3)
d 31.54 (s, CH3), 35.52 (s, C), 35.84 (s, C), 105.97 (s, CH),
110.75 (d, J¼9 Hz, C), 111.86 (d, J¼26 Hz, CH), 112.34 (s,
CH), 115.00 (s, CH), 116.09 (d, J¼23 Hz, CH), 119.70 (d,
J¼8 Hz, C), 122.99 (d, J¼10 Hz, C), 136.39 (s, C), 142.41
(s, C), 146.39 (s, C), 157.01 (d, J¼232 Hz, CF); 19F NMR
(282.65 MHz, CDCl3) d ꢂ124.56 (dt, J¼8.2, 4.5 Hz);
HRMS (EI) calcd for C20H24FN [Mþ]: 297.1893, found:
297.1894. Anal. Calcd for C20H24FN$1.2H2O: C, 75.30; H,
7.58; N, 4.39. Found: C, 75.45; H, 8.17; N, 4.82.
3.2.10. 3-Fluoro-5,7-dimethyl-9H-carbazole, 6j (Table 1,
entry 10)
3.2.7. 3-Fluoro-11H-benzo(a)carbazole, 6g (Table 1,
entry 7)
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 5-
bromo-m-xylene (0.07 ml, 0.50 mmol) gave the product as
a yellow powder: 6 mg (6%); Rf 0.78 (CHCl3); mp 110.5e
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 2-bro-
monaphthalene (0.07 ml, 0.50 mmol) gave the product as
a dark brown powder: 72 mg (61%); Rf 0.85 (CHCl3); mp
1
112.8 ꢀC; H NMR (400 MHz, CDCl3) d 2.48 (s, 3H, Me),
1
214.9e216.3 ꢀC; H NMR (400 MHz, CDCl3) d 7.18 (m, 1H,
2.79 (s, 3H, Me), 6.84 (s, 1H, Ar H), 7.07 (s, 1H, Ar H),
7.11 (m, 1H, Ar H), 7.31 (dd, J¼8.8, 4.3 Hz, 1H, Ar H),
7.77 (d, J¼9.8, 2.4 Hz, 1H, Ar H), 7.94 (br s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 20.66 (s, CH3), 22.14 (s, CH3),
98.16 (d, J¼39 Hz, C), 108.16 (d, J¼24 Hz, CH), 108.75 (s,
CH), 110.81 (d, J¼9 Hz, CH), 112.51 (d, J¼26 Hz, CH),
118.11 (s, C), 122.92 (s, CH), 124.78 (s, C), 133.44 (s, C),
136.06 (s, C), 136.92 (s, C), 161.44 (d, J¼241.2 Hz, CF);
19F NMR (282.65 MHz, CDCl3) d ꢂ124.85 (dt, J¼9.9,
4.5 Hz); HRMS (EI) calcd for C14H12FN [Mþ]: 213.0954,
found: 213.0949. Anal. Calcd for C14H12FN$0.4H2O: C,
76.27; H, 5.49; N, 6.35. Found: C, 75.91; H, 5.41; N, 6.49.
Ar H), 7.56 (m, 4H, Ar H), 7.75 (s, 1H, Ar H), 8.06 (m, 3H,
Ar H), 8.71 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3)
d 105.45 (d, J¼24.0 Hz, CH), 111.72 (d, J¼9.0 Hz, CH),
112.89 (d, J¼26.0 Hz, CH), 118.32 (s, C), 119.31 (s, CH),
120.39 (s, CH), 120.58 (s, CH), 121.22 (s, C), 124.76 (d,
J¼10.0 Hz, C), 125.68 (s, CH), 125.80 (s, CH), 129.17 (s,
CH), 132.71 (s, C), 134.87 (s, C), 136.25 (s, C), 158.00 (d,
J¼235.0 Hz, CF); 19F NMR (282.65 MHz, CDCl3) d ꢂ123.65
(dt, J¼9.1, 3.7 Hz); HRMS (EI) calcd for C16H10FN [Mþ]:
235.0797, found: 235.0793. Anal. Calcd for C16H10FN: C,
81.69; H, 4.28; N, 5.95. Found: C, 80.85; H, 4.36; N, 6.33.26
3.2.8. 3-Fluoro-5,7-dimethoxy-9H-carbazole, 6h (Table 1,
entry 8)
3.2.11. 1-Fluoro-5,7-dimethyl-9H-carbazole, 6k (Table 1,
entry 11)
2-Chloro-4-fluoroaniline (0.06 ml, 0.50 mmol) and 1-
bromo-3,5-dimethoxybenzene (0.11 g, 0.50 mmol) gave the
2-Chloro-6-fluoroaniline (0.06 ml, 0.50 mmol) and 5-
bromo-m-xylene (0.07 ml, 0.50 mmol) gave the product as

6046
R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
a grey powder: 11 mg (10%); Rf 0.59 (1:1 CHCl3/hexane); mp
for C16H10FN: C, 81.69; H, 4.28; N, 5.95. Found: C, 81.40; H,
4.54; N, 6.51.26
1
112.5e114.4 ꢀC; H NMR (400 MHz, CDCl3) d 2.49 (s, 3H,
Me), 2.81 (s, 3H, Me), 6.88 (s, 1H, Ar H), 7.13 (dd, J¼8.0,
4.0 Hz, 1H, Ar H), 7.11 (d, J¼4.0 Hz, 1H, Ar H), 7.13 (s,
1H, Ar H), 7.87 (m, 1H, Ar H), 8.10 (br s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 20.61 (s, CH3), 21.94 (s, CH3),
100.00 (s, C), 108.74 (s, CH), 109.92 (s, C), 110.09 (d,
J¼18.1 Hz, CH), 117.88 (s, CH), 119.47 (d, J¼3.1 Hz, CH),
123.16 (s, CH), 133.17 (s, C), 136.73 (s, C), 139.59 (s, C),
140.20 (s, C), 160.73 (d, J¼220.0 Hz, CF); 19F NMR
(282.65 MHz, CDCl3) d ꢂ135.63 (dd, J¼8.2, 8.0 Hz);
HRMS (EI) calcd for C14H12FN [Mþ]: 213.0954, found:
213.0958. Anal. Calcd for C14H12FN: C, 78.85; H, 5.67; N,
6.57. Found: C, 79.30; H, 5.91; N, 6.98.
3.2.14. 1-Fluoro-6-methyl-9H-carbazole, 6n (Table 1,
entry 14)
2-Chloro-6-fluoroaniline (0.06 ml, 0.50 mmol) and 4-bro-
motoluene (0.06 ml, 0.50 mmol) gave the product as a cream
powder: 23 mg (23%); Rf 0.55 (1:1 CHCl3/hexane); mp
1
165.5e167.9 ꢀC; H NMR (400 MHz, CDCl3) d 2.53 (s, 3H,
Me), 7.13 (m, 2H, Ar H), 7.28 (d, J¼8.0 Hz, 1H, Ar H),
7.36 (d, J¼8.0 Hz, 1H, Ar H), 7.80 (d, J¼8.0 Hz, 1H, Ar
H), 7.86 (s, 1H, Ar H), 8.08 (br s, 1H, NH); 13C NMR
(100 MHz, CDCl3) d 21.51 (s, CH3), 100.00 (s, C), 110.82
(d, J¼12.1 Hz, CH), 110.92 (s, CH), 115.97 (d, J¼3.0 Hz,
CH), 119.51 (d, J¼6.0 Hz, CH), 120.59 (s, CH), 123.52 (s,
C), 126.82 (s, C), 127.99 (s, CH), 129.44 (s, C), 137.89 (s,
C), 149.22 (d, J¼241.0 Hz, CF); 19F NMR (282.65 MHz,
CDCl3) d ꢂ135.22 (dd, J¼7.6, 7.4 Hz); HRMS (EI) calcd
for C13H10FN [Mþ]: 199.0797, found: 199.0793. Anal. Calcd
for C13H10FN: C, 78.37; H, 5.06; N, 7.03. Found: C, 78.76; H,
5.51; N, 7.56.26
3.2.12. 1-Fluoro-8-methyl-9H-carbazole, 6l. Method a
(Table 1, entry 12)
2-Chloro-6-fluoroaniline (0.06 ml, 0.50 mmol) and 2-bro-
motoluene (0.06 ml, 0.50 mmol) gave the product as a brown
powder: 45 mg (45%); Rf 0.93 (CHCl3); mp 100.8e102.3 ꢀC;
1H NMR (400 MHz, CDCl3) d 2.58 (s, 3H, Me), 7.12e7.26
(m, 3H, Ar H), 7.28 (d, J¼8.0 Hz, 1H, Ar H), 7.83 (dd,
J¼8.0, 1.8 Hz, 1H, Ar H), 7.92 (d, J¼7.8 Hz, 1H, Ar H),
8.09 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3) d 16.94
(s, CH3), 110.86 (d, J¼12.1 Hz, CH), 116.22 (s, CH),
118.33 (s, CH), 119.79 (s, C), 120.24 (s, CH), 120.35 (d,
J¼12.0 Hz, CH), 122.86 (s, C), 127.16 (s, CH), 127.47 (d,
J¼3.1 Hz, C), 139.10 (s, C), 140.01 (s, C), 149.32 (d, J¼
241.0 Hz, CF); 19F NMR (282.65 MHz, CDCl3) d ꢂ135.07
(dd, J¼15.6, 6.5 Hz); HRMS (EI) calcd for C13H10FN
[Mþ]: 199.0797, found: 199.0795. Anal. Calcd for
C13H10FN: C, 78.37; H, 5.06; N, 7.03. Found: C, 78.03; H,
5.18; N, 7.28.
3.2.15. 2-Fluoro-8-methyl-9H-carbazole, 6o and 4-fluoro-8-
methyl-9H-carbazole, 6p. Method a (Table 1, entry 15)
2-Chloro-5-fluoroaniline (0.06 ml, 0.50 mmol) and 2-bro-
motoluene (0.06 ml, 0.50 mmol) gave the product as pink
crystals: 27 mg (27%); Rf 0.75 (CHCl3); mp 116.0e
1
117.8 ꢀC; H NMR (400 MHz, CDCl3) d 2.55 (s, 3H, Me),
6.96 (dt, J¼8.0, 2.5 Hz, 1H, Ar H), 7.12 (dd, J¼9.5, 2.3 Hz,
1H, Ar H), 7.18 (d, J¼7.5 Hz, 1H, Ar H), 7.21 (d,
J¼8.0 Hz, 1H, Ar H), 7.87 (d, J¼7.5 Hz, 1H, Ar H), 7.96
(dd, J¼8.6, 5.4 Hz, 1H, Ar H), 7.99 (br s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 16.92 (s, CH3), 97.56 (d,
J¼26.0 Hz, CH), 107.79 (d, J¼24.0 Hz, CH), 117.64 (s,
CH), 119.84 (s, C), 120.13 (s, CH), 120.36 (s, C), 121.42 (d,
J¼10.0 Hz, CH), 122.54 (s, C), 126.20 (s, CH), 138.00 (s,
C), 140.01 (s, C), 161.97 (d, J¼240.0 Hz, CF); 19F NMR
(282.65 MHz, CDCl3) d ꢂ115.69 (dt, J¼10.4, 5.5 Hz);
HRMS (EI) calcd for C13H10FN [Mþ]: 199.0797, found:
199.0797. Anal. Calcd for C13H10FN: C, 78.37; H, 5.06; N,
7.03. Found: C, 77.96; H, 5.50; N, 7.48.26 Data for 6p are
given below.
Method b (Table 1, entry 20): 2-chloro-6-methylaniline
(0.06 ml, 0.50 mmol) and 1-bromo-3-fluorobenzene (0.06 ml,
0.50 mmol) gave a mixture of 6o and 6p (ratio 1.3:1) as a beige
powder: 62 mg (62%); Rf 0.75 (CHCl3); 6o data as above; 6p:
1H NMR (400 MHz, CDCl3) d 2.56 (s, 3H, Me), 6.91 (dd,
J¼9.1, 8.0 Hz, 1H, Ar H), 7.21 (m 1H, Ar H), 7.23 (d,
J¼8.1 Hz, 1H, Ar H), 7.28 (m, 1H, Ar H), 7.33 (dt, J¼8.1,
3.2 Hz, 1H, Ar H), 8.03 (br s, 1H, NH), 8.06 (d, J¼7.9 Hz,
1H, Ar H); 13C NMR (100 MHz, CDCl3) d 105.41 (d,
J¼19.2 Hz, CH), 106.60 (d, J¼3.8 Hz, CH), 112.46 (d, J¼
20.8 Hz, C), 119.63 (s, C), 120.35 (s, CH), 120.64 (d,
J¼3.1 Hz, CH), 126.39 (d, J¼8.5 Hz, CH), 126.74 (s, CH),
138.45 (s, C), 139.97 (d, J¼12.3 Hz, C), 141.62 (d,
J¼10.8 Hz, CH), 158.69 (d, J¼248.2 Hz, CH); 19F NMR
(282.65 MHz, CDCl3) d ꢂ119.40 (dd, J¼9.4, 4.5 Hz);
Method b (Table 1, entry 19): 2-chloro-6-methylaniline
(0.06 ml, 0.50 mmol) and 1-bromo-2-fluorobenzene (0.06 ml,
0.50 mmol) gave product as a light cream powder: 37 mg
(37%); data as above.
3.2.13. 1-Fluoro-11H-benzo(a)carbazole, 6m (Table 1,
entry 13)
2-Chloro-6-fluoroaniline (0.06 ml, 0.50 mmol) and 2-bro-
monaphthalene (0.07 ml, 0.50 mmol) gave the product as
a dark green powder: 66 mg (56%); Rf 0.85 (CHCl3); mp
1
143.8e145.2 ꢀC; H NMR (400 MHz, CDCl3) d 7.14e7.24
(m, 2H, Ar H), 7.54e7.63 (m, 2H, Ar H), 7.68 (d,
J¼8.5 Hz, 1H, Ar H), 7.87 (d, J¼7.6 Hz, 1H, Ar H), 8.01
(d, J¼7.6 Hz, 1H, Ar H), 8.10 (d, J¼8.5 Hz, 1H, Ar H),
8.14 (d, J¼8.1 Hz, 1H, Ar H), 8.90 (br s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 109.91 (d, J¼16.0 Hz, CH),
115.63 (d, J¼3.0 Hz, CH), 118.53 (d, J¼3.1 Hz, CH),
119.32 (s, CH), 120.26 (d, J¼6.2 Hz, CH), 120.72 (d,
J¼21.8 Hz, CH), 121.18 (s, C), 125.68 (s, CH), 125.88 (s,
CH), 126.72 (d, J¼12.4 Hz, C), 127.99 (d, J¼12.4 Hz, C),
129.08 (s, CH), 132.71 (s, C), 135.23 (s, C), 139.07 (s, C),
149.45 (d, J¼243.0 Hz, CF); 19F NMR (282.65 MHz,
CDCl3) d ꢂ134.67 (dd, J¼10.2, 4.8 Hz); HRMS (EI) calcd
for C16H10FN [Mþ]: 235.0797, found: 235.0802. Anal. Calcd

R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
6047
HRMS (EI) calcd for C13H10FN [Mþ]: 199.0797, found:
199.0792. Anal. Calcd for C13H10FN: C, 78.37; H, 5.06; N,
7.03. Found: C, 78.77; H, 5.28; N, 7.56.
J¼40.0 Hz, CH), 128.94 (s, CH), 131.95 (s, C), 135.10 (d,
J¼3.1 Hz, C), 138.66 (d, J¼12 Hz, C), 141.72 (s, C), 161.35
(d, J¼240.1 Hz, CF); 19F NMR (282.65 MHz, CDCl3)
d ꢂ116.61 (dt, J¼9.6, 5.7 Hz); HRMS (EI) calcd for
C16H10FN [Mþ]: 235.0797, found: 235.0793. Anal. Calcd
for C16H10FN: C, 81.69; H, 4.28; N, 5.95. Found: C, 81.57;
H, 4.66; N, 6.35.
3.2.16. 2-Fluoro-6-methyl-9H-carbazole, 6q (Table 1,
entry 16)
2-Chloro-5-fluoroaniline (0.06 ml, 0.50 mmol) and 4-bro-
motoluene (0.06 ml, 0.50 mmol) gave the product as a silver
powder: 24 mg (24%); Rf 0.74 (CHCl3); mp 210.6e
3.2.19. 3-Fluoro-8-methyl-9H-carbazole, 6t (Table 1,
entry 21)
1
212.5 ꢀC; H NMR (400 MHz, CDCl3) d 2.52 (s, 3H, Me),
6.94 (dd, J¼8.0, 2.4 Hz, 1H, Ar H), 7.07 (dd, J¼9.6, 2.3 Hz,
1H, Ar H), 7.21 (d, J¼8.0 Hz, 1H, Ar H), 7.30 (d,
J¼8.0 Hz, 1H, Ar H), 7.81 (br s, 1H, Ar H), 7.93 (dd,
J¼8.5, 5.4 Hz, 1H, Ar H), 7.96 (br s, 1H, NH); 13C NMR
(100 MHz, CDCl3) d 21.40 (s, CH3), 97.44 (d, J¼26.3 Hz,
CH), 105.20 (d, J¼18.1 Hz, C), 107.56 (d, J¼24.0 Hz, CH),
110.14 (s, C), 110.36 (s, CH), 120.05 (s, CH), 121.22 (d,
J¼9.8 Hz, CH), 123.14 (d, J¼20.3 Hz, C), 126.72 (d,
J¼32.4 Hz, C), 126.91 (s, CH), 129.54 (d, J¼18.1 Hz, C),
162.12 (d, J¼240.0 Hz, CF); 19F NMR (282.65 MHz,
CDCl3) d ꢂ115.78 (dt, J¼10.2, 5.7 Hz); HRMS (EI) calcd
for C13H10FN [Mþ]: 199.0797, found: 199.0793. Anal. Calcd
for C13H10FN: C, 78.37; H, 5.06; N, 7.03. Found: C, 78.01; H,
5.10; N, 7.84.26
2-Chloro-6-methylaniline (0.06 ml, 0.50 mmol) and 1-
bromo-4-fluorobenzene (0.06 ml, 0.50 mmol) gave the product
as a beige powder: 35 mg (35%); Rf 0.74 (CHCl3); mp 98.0e
1
102.1 ꢀC; H NMR (400 MHz, CDCl3) d 2.56 (s, 3H, Me),
7.14 (dd, J¼8.0, 4.0 Hz, 1H, Ar H), 7.17 (d, J¼8.0 Hz, 1H,
Ar H), 7.24 (d, J¼8.0 Hz, 1H, Ar H), 7.37 (dd, J¼8.8,
4.2 Hz, 1H, Ar H), 7.71 (dd, J¼9.0, 2.6 Hz, 1H, Ar H), 7.87
(d, J¼7.8 Hz, 1H, Ar H), 7.92 (br s, 1H, NH); 13C NMR
(100 MHz, CDCl3) d 16.94 (s, CH3), 106.19 (d, J¼24.0 Hz,
CH), 111.31 (d, J¼9.0 Hz, CH), 113.55 (d, J¼25.0 Hz, CH),
118.23 (s, CH), 119.70 (s, CH), 120.11 (s, C), 122.65 (s, C),
124.44 (s, C), 127.01 (s, CH), 135.77 (s, C), 140.03 (s, C),
157.61 (d, J¼234.0 Hz, CF); 19F NMR (282.65 MHz,
CDCl3) d ꢂ124.35 (dt, J¼10.2, 4.5 Hz); HRMS (EI) calcd
for C13H10FN [Mþ]: 199.0797, found: 199.0789. Anal. Calcd
for C13H10FN: C, 78.37; H, 5.06; N, 7.03. Found: C, 78.26; H,
5.38; N, 6.65.
3.2.17. 2-Fluoro-5,7-dimethyl-9H-carbazole, 6r (Table 1,
entry 17)
2-Chloro-5-fluoroaniline (0.06 ml, 0.50 mmol) and 5-
bromo-m-xylene (0.07 ml, 0.50 mmol) gave the product as
a purple powder: 15 mg (14%); Rf 0.74 (CHCl3); mp 111.7e
3.3. General method for thermal synthesis of aminated
intermediates
1
114.2 ꢀC; H NMR (400 MHz, CDCl3) d 2.48 (s, 3H, Me),
2.79 (s, 3H, Me), 6.85 (s, 1H, Ar H), 6.95 (dd, J¼8.0, 2.5 Hz,
1H, Ar H), 7.06 (s, 1H, Ar H), 7.08 (dd, J¼8.0, 4.0 Hz, 1H, Ar
H), 7.97 (br s, 1H, NH), 8.00 (dd, J¼8.7, 5.4 Hz, 1H, Ar H);
13C NMR (100 MHz, CDCl3) d 20.61 (s, CH3), 21.88
(s, CH3), 97.31 (d, J¼26.4 Hz, CH), 103.77 (d, J¼25.7 Hz,
C), 107.48 (d, J¼24.1 Hz, CH), 108.54 (s, CH), 117.11 (s, C),
123.10 (d, J¼9.8 Hz, CH), 123.21 (s, CH), 124.24 (s, C),
130.72 (s, C), 132.70 (s, C), 135.84 (s, C), 161.56 (d,
J¼240.7 Hz, CF); 19F NMR (282.65 MHz, CDCl3) d ꢂ117.03
(dd, J¼13.6, 9.1 Hz); HRMS (EI) calcd for C14H12FN [Mþ]:
213.0954, found: 213.0946. Anal. Calcd for C14H12FN: C,
78.85; H, 5.67; N, 6.57. Found: C, 78.53; H, 6.03; N, 7.04.
NaOtBu (0.480 g, 5.0 mmol), Pd(OAc)2 (0.012 g,
0.05 mmol) and [HPtBu3][BF4] (0.020 g, 0.070 mmol) were
suspended in toluene (6 ml). The appropriate 2-chloroaniline
(1.0 mmol) and the aryl bromide (1.0 mmol) were then added
under nitrogen. The reaction was then heated at reflux for 18 h,
allowed to cool and then quenched by addition of HCl(aq)
(2 M, 3 ml). The organic phase was extracted with CH2Cl2
(2ꢁ40 ml), dried (MgSO4), then filtered and the solvent
removed under reduced pressure. The crude product mixture
was then subjected to column chromatography (SiO2).
3.3.1. (2-Chloro-5-methoxyphenyl)-(2-fluorophenyl)-
amine, 7u
3.2.18. 2-Fluoro-11H-benzo(a)carbazole, 6s (Table 1,
entry 18)
2-Chloro-5-methoxyaniline
1.0 mmol) and 1-bromo-2-fluorobenzene (0.12 ml, 1.0 mmol)
hydrochloride
(0.194 g,
2-Chloro-5-fluoroaniline (0.06 ml, 0.50 mmol) and 2-bro-
monaphthalene (0.07 ml, 0.50 mmol) gave the product as
a off-white powder: 90 mg (77%); Rf (CHCl3); mp 223.6e
225.8 ꢀC; 1H NMR (400 MHz, CDCl3) d 7.05 (dt, J¼9.1,
2.3 Hz, 1H, Ar H), 7.28 (dd, J¼9.0, 2.2 Hz, 1H, Ar H), 7.53
(dt, J¼9.0, 2.1 Hz, 1H, Ar H), 7.60 (dt, J¼7.5, 1.3 Hz, 1H,
Ar H), 7.67 (d, J¼8.5 Hz, 1H, Ar H), 8.01 (m 2H, Ar H),
8.09 (m, 2H, Ar H), 8.79 (br s, 1H, NH); 13C NMR
(100 MHz, CDCl3) d 97.58 (d, J¼26.9 Hz, CH), 108.24 (d,
J¼24.1 Hz, CH), 118.00 (s, CH), 118.77 (s, CH), 120.12 (s,
CH), 120.54 (s, CH), 120.67 (s, C), 120.81 (s, C), 125.34 (d,
gave the product as a brown oil: 214 mg (85%); Rf 0.85
1
(CHCl3); H NMR (400 MHz, CDCl3) d 3.74 (s, 3H, OMe),
6.12 (br s, 1H, NH), 6.41 (dd, J¼8.8, 2.8 Hz, 1H, Ar H),
6.79 (d, J¼2.8 Hz, 1H, Ar H), 6.96e7.02 (m, 1H, Ar H),
7.08 (dd, J¼8.0, 4.0 Hz, 1H, Ar H), 7.14 (dd, J¼8.0, 4.0 Hz,
1H, Ar H), 7.27 (d, J¼8.8 Hz, 1H, Ar H), 7.38 (dt, J¼8.0,
2.0 Hz, 1H, Ar H); 13C NMR (100 MHz, CDCl3) d 55.54
(s, CH3), 102.25 (s, CH), 106.33 (s, CH), 114.49 (s, C),
116.13 (d, J¼19.3 Hz, CH), 120.69 (d, J¼1.9 Hz, CH),
123.10 (d, J¼7.5 Hz, CH), 124.55 (d, J¼3.7 Hz, CH),
129.79 (d, J¼11.8 Hz, C), 130.22 (s, CH), 140.32 (s, C),

6048
R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
154.61 (d, J¼243.6 Hz, CF), 159.33 (s, C); 19F NMR
(282.65 MHz, CDCl3) d ꢂ128.90 (dt, J¼12.4, 6.5 Hz);
HRMS (EI) calcd for C13H11ClFNO [Mþ]: 251.0513, found:
251.0508.
d 2.28 (s, 6H, Me), 5.78 (br s, 1H, NH), 6.66 (s, 1H, Ar H),
6.70 (s, 2H, Ar H), 6.88 (ddd, J¼9.0, 8.0, 2.9 Hz, 1H, Ar
H), 7.12 (dd, J¼8.2, 2.9 Hz, 1H, Ar H), 7.22 (dd, J¼9.1,
5.3 Hz, 1H, Ar H); 13C NMR (100 MHz, CDCl3) d 21.25 (s,
CH3), 114.35 (d, J¼21.8 Hz, CH), 116.78 (d, J¼25.5 Hz,
CH), 117.00 (s, CH), 117.60 (d, J¼8.1 Hz, CH), 122.43 (d,
J¼10.6 Hz, C), 124.16 (s, CH), 136.91 (d, J¼3.1 Hz, C),
139.32 (s, C), 142.05 (s, C), 156.27 (d, J¼241.7 Hz, CF);
19F NMR (282.65 MHz, CDCl3) d ꢂ126.85 (dt, J¼8.2,
5.5 Hz); HRMS (CI) calcd for C14H13ClFN [MþþH]:
250.0799, found: 250.0803.
3.3.2. (2-Chloro-5-methoxy-4-methylphenyl)-
(2-fluorophenyl)amine, 7v
2-Chloro-5-methoxy-4-methylaniline (0.12 ml, 1.0 mmol)
and 2-bromofluorobenzene (0.12 ml, 1.0 mmol) gave the prod-
1
uct as a brown oil: 181 mg (68%); Rf 0.80 (CHCl3); H NMR
(400 MHz, CDCl3) d 2.06 (s, 3H, Me), 3.64 (s, 3H, OMe), 5.90
(br s, 1H, NH), 6.69 (s, 1H, Ar H), 6.76e6.87 (m, 1H, Ar H),
6.96 (dt, J¼8.0, 2.1 Hz, 1H, Ar H), 7.03 (m, 1H, Ar H), 7.04
(s, 1H, Ar H), 7.19 (dt, J¼8.0, 1.8 Hz, 1H, Ar H); 13C NMR
(100 MHz, CDCl3) d 15.26 (s, CH3), 55.53 (s, CH3), 100.78
(s, CH), 114.21 (s, C), 115.83 (d, J¼19.3 Hz, CH), 118.40
(d, J¼1.9 Hz, CH), 120.88 (s, C), 121.65 (d, J¼7.5 Hz, CH),
124.36 (d, J¼3.7 Hz, CH), 130.97 (d, J¼11.3 Hz, CH),
130.98 (s, CH), 137.22 (s, C), 153.78 (d, J¼242.4 Hz, CF),
156.95 (s, C); 19F NMR (282.65 MHz, CDCl3) d ꢂ130.47
(m); HRMS (CI) calcd for C14H13ClFNO [MþþH]:
266.0748, found: 266.0741.
3.3.6. (2-Chloro-5-fluorophenyl)-(3,5-dimethylphenyl)-
amine, 7r
2-Chloro-5-fluoroaniline (0.12 ml, 1.0 mmol) and 5-bromo-
m-xylene (0.13 ml, 1.0 mmol) gave the product as a brown oil:
195 mg (78%); Rf (CHCl3); 1H NMR (400 MHz, CDCl3)
d 2.32 (s, 6H, Me), 6.10 (br s, 1H, NH), 6.47 (ddd, J¼8.7,
7.9, 2.9 Hz, 1H, Ar H), 6.76 (s, 1H, Ar H), 6.82 (s, 2H, Ar
H), 6.93 (dd, J¼11.1, 2.9 Hz, 1H, Ar H), 7.26 (dd, J¼8.8,
5.7 Hz, 1H, Ar H); 13C NMR (100 MHz, CDCl3) d 21.33 (s,
CH3), 101.83 (d, J¼28.0 Hz, CH), 106.32 (d, J¼24.2 Hz,
CH), 115.55 (d, J¼3.1 Hz, C), 119.31 (s, CH), 125.76 (s,
CH), 130.38 (d, J¼10.6 Hz, CH), 139.56 (s, C), 140.42 (s,
C), 142.36 (d, J¼11.2 Hz, C), 162.37 (d, J¼243.6 Hz, CF);
19F NMR (282.65 MHz, CDCl3) d ꢂ113.26 (ddd, J¼11.2,
7.5, 5.9 Hz); HRMS (CI) calcd for C14H13ClFN [MþþH]:
250.0799, found: 250.0802.
3.3.3. (2-Chlorophenyl)-(3-fluorophenyl)amine, 7w
2-Chloroaniline (0.11 ml, 1.0 mmol) and 4-bromofluoro-
benzene (0.11 ml, 1.0 mmol) gave the product as a brown
oil: 166 mg (75%); Rf 0.90 (CHCl3); 1H NMR (400 MHz,
CDCl3) d 5.82 (br s, 1H, NH), 6.96e7.26 (m, 3H, Ar H),
7.30 (d, J¼8.5 Hz, 2H, Ar H), 7.38 (m, 1H, Ar H), 7.45 (d,
J¼8.0 Hz, 1H, Ar H); 13C NMR (100 MHz, CDCl3)
d 114.83 (s, C), 116.21 (d, J¼16.6 Hz, CH), 120.12 (s, CH),
123.38 (d, J¼6.0 Hz, CH), 123.61 (s, C), 127.57 (s, CH),
129.78 (s, CH), 131.46 (s, CH), 141.27 (d, J¼4.5 Hz, C),
154.33 (d, J¼253.5 Hz, CF); 19F NMR (282.65 MHz,
CDCl3) d ꢂ130.47 (dt, J¼9.1, 4.5 Hz); HRMS (EI) calcd for
C12H9ClFN [Mþ]: 221.5962, found: 221.5957.
3.3.7. (2-Chloro-6-fluorophenyl)-(3,5-dimethylphenyl)-
amine, 7k
2-Chloro-6-fluoroaniline (0.12 ml, 1.0 mmol) and 5-bromo-
m-xylene (0.13 ml, 1.0 mmol) gave the product as a brown oil:
207 mg (83%); Rf (CHCl3); 1H NMR (400 MHz, CDCl3)
d 2.22 (s, 6H, Me), 5.60 (s, 1H, NH), 6.61 (s, 2H, Ar H),
6.63 (s, 1H, Ar H), 7.03 (ddd, J¼9.0, 8.1, 2.9 Hz, 1H, Ar
H), 7.22 (dd, J¼9.1, 2.9 Hz, 1H, Ar H), 7.27 (dd, J¼8.0,
5.5 Hz, 1H, Ar H); 13C NMR (100 MHz, CDCl3) d 21.31 (s,
CH3), 109.94 (d, J¼16.2 Hz, CH), 115.55 (d, J¼21.1 Hz,
CH), 118.87 (s, CH), 123.05 (d, J¼11.2 Hz, CH), 124.15 (s,
CH), 127.78 (d, J¼9.3 Hz, C), 136.24 (d, J¼3.1 Hz, C),
138.66 (s, C), 146.17 (s, C), 161.47 (d, J¼253.5 Hz, CF);
19F NMR (282.65 MHz, CDCl3) d ꢂ120.60 (dd, J¼9.1,
5.5 Hz); HRMS (CI) calcd for C14H13ClFN [MþþH]:
250.0799, found: 250.0803.
3.3.4. (2-Chloro-4-fluorophenyl)-(3-fluorophenyl)amine, 7x
2-Chloro-4-fluoroaniline (0.12 ml, 1.0 mmol) and 4-bromo-
fluorobenzene (0.11 ml, 1.0 mmol) gave the product as a dark
green oil: 207 mg (86%); Rf 0.90 (CHCl3); 1H NMR
(400 MHz, CDCl3) d 5.78 (br s, 1H, NH), 6.86 (dt, J¼8.2,
3.0 Hz, 1H, Ar H), 6.98e7.08 (m, 5H, Ar H), 7.12 (dd, J¼8.6,
2.9 Hz, 1H, Ar H); 13C NMR (100 MHz, CDCl3) d 114.48 (d,
J¼22.3 Hz, CH), 116.26 (d, J¼22.3 Hz, CH), 116.46 (s, C),
116.91 (d, J¼25.4 Hz, CH), 121.90 (d, J¼10.8 Hz, C), 122.42
(d, J¼7.7 Hz, CH), 123.30 (d, J¼7.7 Hz, CH), 137.85 (d,
J¼36.9 Hz, C), 156.24 (d, J¼241.3 Hz, CF), 158.98 (d,
J¼241.3 Hz, CF); 19F NMR (282.65 MHz, CDCl3) d ꢂ120.05
(m), ꢂ122.63 (dt, J¼8.0, 5.0 Hz); HRMS (CI) calcd for
C12H8ClF2N [MþþH]: 240.0392, found: 240.0397.
3.3.8. (2-Chloro-4-fluorophenyl)-(4-methylphenyl)amine, 7y
2-Chloro-4-fluoroaniline (0.12 ml, 1.0 mmol) and 4-bromo-
toluene (0.12 ml, 1.0 mmol) gave the product as a brown oil:
115 mg (49%); Rf 0.85 (CHCl3); 1H NMR (400 MHz,
CDCl3) d 2.35 (s, 3H, Me), 5.84 (br s, 1H, NH), 6.87 (dt,
J¼8.0, 4.0 Hz, 1H, Ar H), 7.04 (d, J¼8.0 Hz, 2H, Ar H),
7.12e7.18 (m, 4H, Ar H); 13C NMR (100 MHz, CDCl3)
d 20.84 (s, CH3), 114.39 (d, J¼22.3 Hz, CH), 116.35 (d,
J¼7.7 Hz, CH), 116.80 (d, J¼26.1 Hz, CH), 120.50 (s, CH),
121.65 (d, J¼10.0 Hz, C), 130.12 (s, CH), 132.47 (s, C),
137.58 (d, J¼2.3 Hz, C), 139.30 (s, C), 155.98 (d,
3.3.5. (2-Chloro-4-fluorophenyl)-(3,5-dimethylphenyl)-
amine, 7j
2-Chloro-4-fluoroaniline (0.12 ml, 1.0 mmol) and 5-bromo-
m-xylene (0.13 ml, 1.0 mmol) gave the product as a brown oil:
137 mg (55%); Rf (CHCl3); 1H NMR (400 MHz, CDCl3)

R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
6049
J¼241.1 Hz, CF); 19F NMR (282.65 MHz, CDCl3) d ꢂ128.69
(dt, J¼9.1, 5.0 Hz); HRMS (CI) calcd for C13H11ClFN
[MþþH]: 236.6856, found: 236.6860.
3.4.3. 3-Fluoro-9H-carbazole, 6w
(2-Chlorophenyl)-(4-fluorophenyl)amine (0.111 g, 0.5 mmol)
gave the product as white crystals: 59 mg (69%). Crystals of
6w suitable for X-ray analysis were grown from a concentrated
CH2Cl2 solution. Rf 0.70 (CH2Cl2); mp 201.1e203.4 ꢀC; H
1
3.4. General method for thermal cyclisation of aminated
product to fluorinated carbazole
NMR (400 MHz, CDCl3) d 7.15 (dt, J¼9.0, 2.6 Hz, 1H, Ar
H), 7.23 (m, 1H, Ar H), 7.33 (dd, J¼8.7, 4.2 Hz, 1H, Ar H),
7.43 (m, 2H, Ar H), 7.72 (dd, J¼8.9, 2.6 Hz, 1H, Ar H),
7.98 (br s, 1H, NH), 8.01 (d, J¼7.8 Hz, 1H, Ar H); 13C
NMR (100 MHz, CDCl3) d 106.12 (d, J¼10.1 Hz, CH),
110.85 (d, J¼4.1 Hz, CH), 111.12 (s, CH), 113.58 (d,
J¼18.9 Hz, CH), 119.50 (s, CH), 120.55 (s, CH), 123.18 (s,
C), 126.44 (s, CH), 135.98 (s, C), 141.35 (s, C), 157.68 (d,
J¼252.0 Hz, CF); 19F NMR (282.65 MHz, CDCl3)
d ꢂ124.36 (dt, J¼9.0, 4.5 Hz); HRMS (CI) calcd for
C12H8FN [MþþH]: 186.0719, found: 186.0727. Anal. Calcd
for C12H8FN: C, 77.82; H, 4.35; N, 7.56. Found: C, 78.25;
H, 4.78; N, 7.65.
NaOtBu (0.240 g, 2.5 mmol), Pd(OAc)2 (0.006 g,
0.025 mmol) and [HPtBu3][BF4] (0.010 g, 0.035 mmol) were
suspended in 1,4-dioxane (3 ml). The appropriate aminated in-
termediate 7 (0.50 mmol) was then added. The reaction was
then stirred at reflux temperature for 18 h, allowed to cool
and then quenched by addition of HCl(aq) (2 M, 3 ml). The
organic phase was extracted with CH2Cl2 (2ꢁ20 ml), dried
(MgSO4), then filtered and the solvent removed under reduced
pressure. The crude product mixture was then subjected to
column chromatography (SiO2). Compounds 6j, 6r and 6k
prepared by this method where not isolated, rather the conver-
sion to product was determined by 1H NMR spectroscopy
using 1,3,5-trimethoxybenzene as an internal standard.
3.4.4. 3,6-Difluoro-9H-carbazole, 6x
(2-Chloro-4-fluorophenyl)-(4-fluorophenyl)amine (0.120 g,
0.5 mmol) gave the product as a off-white powder: 43 mg
(42%); Rf 0.70 (CHCl3); mp 198.9e200.8 ꢀC; 1H NMR
(400 MHz, CDCl3) d 7.17 (td, J¼8.8, 2.6 Hz, 2H, Ar H),
7.35 (dd, J¼8.8, 4.2 Hz, 2H, Ar H), 7.66 (dd, J¼8.8, 2.6 Hz,
2H, Ar H), 7.98 (br s, 1H, NH); 13C NMR (100 MHz,
CDCl3) d 106.14 (d, J¼23.6 Hz, CH), 111.50 (d, J¼8.7 Hz,
CH), 114.41 (d, J¼25.5 Hz, CH), 119.45 (d, J¼7.6 Hz, C),
136.87 (s, C), 157.44 (d, J¼236.1 Hz, CF); 19F NMR
(282.65 MHz, CDCl3) d ꢂ124.06 (dt, J¼9.9, 6.2 Hz);
HRMS (CI) calcd for C16H10FN [MþþH]: 204.0625, found:
204.0616; Anal. Calcd for C12H7F2N: C, 70.93; H, 3.47; N,
6.89. Found: C, 71.23; H, 3.42; N, 6.66.
3.4.1. 1-Fluoro-7-methoxy-9H-carbazole, 6u
(2-Chloro-5-methoxyphenyl)-(2-fluorophenyl)amine (0.126 g,
0.50 mmol) gave the product as off-white powder: 61 mg,
(57%); Rf 0.85 (CHCl3); mp 149.2e151.9 ꢀC; 1H NMR
(400 MHz, CDCl3) d 3.90 (s, 3H, OMe), 6.87 (dd, J¼8.6,
2.3 Hz, 1H, Ar H), 6.94 (d, J¼2.2 Hz, 1H, Ar H), 7.03e7.14
(m, 2H, Ar H), 7.71 (d, J¼8.0 Hz, 1H, Ar H), 7.91 (d,
J¼8.6 Hz, 1H, Ar H), 8.14 (br s, 1H, NH); 13C NMR
(100 MHz, CDCl3) d 55.73 (s, CH3), 95.01 (s, CH), 100.00
(s, C), 108.91 (s, CH), 109.02 (d, J¼12.0 Hz, CH), 110.02
(s, C), 115.21 (s, CH), 119.93 (d, J¼5.0 Hz, CH), 121.47 (s,
CH), 131.05 (s, C), 150.22 (s, C), 159.63 (s, C), 165.23 (d,
J¼214.0 Hz, CF); 19F NMR (282.65 MHz, CDCl3)
d ꢂ135.49 (dd, J¼10.2, 4.5 Hz); HRMS (EI) calcd for
C13H10FNO [Mþ]: 215.0746, found: 215.0751. Anal. Calcd
for C13H10FNO: C, 72.55; H, 4.68; N, 6.51. Found: C,
72.51; H, 4.77; N, 6.89.
3.4.5. 3-Fluoro-6-methyl-9H-carbazole, 6y
(2-Chloro-4-fluorophenyl)-(4-methylphenyl)amine (0.118 g,
0.50 mmol) gave the product as a brown powder: 48 mg
(48%); Rf 0.68 (CHCl3); mp 153.1e155.3 ꢀC; 1H NMR
(400 MHz, CDCl3) d 2.52 (s, 3H, Me), 7.13 (dt, J¼8.9,
2.5 Hz, 1H, Ar H), 7.26 (s, 1H, Ar H), 7.29 (d, J¼8.0 Hz,
1H, Ar H), 7.31 (d, J¼8.0 Hz, 1H, Ar H), 7.68 (dd, J¼9.0,
2.5 Hz, 1H, Ar H), 7.81 (s, 1H, Ar H), 7.91 (br s, 1H, NH);
13C NMR (100 MHz, CDCl3) d 21.48 (s, CH3), 105.95 (d,
J¼23.0 Hz, CH), 110.65 (s, CH), 111.11 (s, C), 113.50
(d, J¼26.0 Hz, CH), 120.47 (s, CH), 123.77 (d, J¼
1.9 Hz, C), 127.92 (s, CH), 128.89 (s, CH), 130.01 (s, C),
136.18 (s, C), 138.86 (s, C), 157.48 (d, J¼234.0 Hz, CF);
19F NMR (282.65 MHz, CDCl3) d ꢂ124.70 (dt, J¼8.2,
5.6 Hz); HRMS (EI) calcd for C13H10FN [Mþ]: 199.0797,
found: 199.0793. Anal. Calcd for C13H10FN: C, 78.37; H,
5.06; N, 7.03. Found: C, 78.98; H, 5.24; N, 7.57.26
3.4.2. 1-Fluoro-7-methoxy-6-methyl-9H-carbazole, 6v
(2-Chloro-5-methoxy-4-methylphenyl)-(2-fluorophenyl)-
amine (0.134 g, 0.50 mmol) gave the product as a brown pow-
der: 59 mg (52%); Rf 0.90 (CHCl3); mp 165.6e167.3 ꢀC; H
1
NMR (400 MHz, CDCl3) d 2.29 (s, 3H, Me), 3.84 (s, 3H,
OMe), 6.82 (s, 1H, Ar H), 6.94e7.06 (m, 2H, Ar H), 7.62
(dd, J¼8.0, 1.1 Hz, 1H, Ar H), 7.70 (s, 1H, Ar H), 7.98 (br
s, 1H, NH); 13C NMR (100 MHz, CDCl3) d 16.92 (s, CH3),
55.53 (s, CH3), 92.83 (s, CH), 109.63 (d, J¼16.2 Hz, CH),
115.24 (d, J¼3.7 Hz, CH), 116.39 (d, J¼3.0 Hz, C), 119.82
(d, J¼6.2 Hz, CH), 121.97 (s, CH), 127.40 (s, C), 127.26 (d,
J¼3.7 Hz, C), 131.25 (s, C), 139.61 (s, C), 149.30 (d,
J¼241.7 Hz, CF), 158.24 (s, C); 19F NMR (282.65 MHz,
CDCl3) d ꢂ135.64 (dd, J¼9.9, 5.6 Hz); HRMS (EI) calcd
for C14H12FNO [Mþ]: 229.0903, found: 229.0904. Anal.
Calcd for C14H12FNO: C, 73.35; H, 5.28; N, 6.11. Found: C,
73.92; H, 5.64; N, 6.22.
3.5. X-ray crystallographic analysis of carbazole 6w
C12H8FN,
M¼185.19,
orthorhombic,
a¼7.5282(4),
˚
3
˚
b¼19.5065(14), c¼5.7432(3) A, V¼843.38(9) A , T¼120(2) K,
space group Pnma, Z¼4, m¼0.832 mmꢂ1, Rint¼0.0442 (for

6050
R.B. Bedford et al. / Tetrahedron 64 (2008) 6038e6050
5. (a) Ames, D. E.; Bull, D. Tetrahedron 1982, 38, 383; (b) Ames, D. E.;
Opalko, A. Synthesis 1983, 235; (c) Ames, D. E.; Opalko, A. Tetrahedron
1984, 40, 1919.
2271 measured reflections), R1¼0.0343 [for 339 unique reflec-
tions with >2s(I)], wR2¼0.0756 (for all 753 unique reflections).
A single crystal of 6w was coated in high-vacuum grease and
mounted on a glass fibre. X-ray measurements were made using
an Oxford Diffraction Gemini R Ultra CCD area-detector diffrac-
6. Deshpande, P. P.; Martin, O. R. Tetrahedron Lett. 1990, 44, 6313.
}
7. Bringmann, G.; Jansen, J. R.; Reuscher, H.; Rubenacker, M.; Peters, K.; von
Schnering, H. G. Tetrahedron Lett. 1990, 31, 643; See also: Bringmann, G.;
Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977.
8. Bringmann, G.; Pabst, T.; Henschel, P.; Kraus, J.; Peters, K.; Peters, E.-M.;
Rycroft, D. S.; Connolly, J. D. J. Am. Chem. Soc. 2000, 122, 9127.
9. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999,
1505.
tometer with Cu Ka radiation (l¼1.54178 A).27 Intensities were
˚
integrated27 from several series of exposures, each exposure
covering a narrow angle in u or f. Absorption corrections were
applied, based on multiple and symmetry-equivalent measure-
ments.28 The structure was solved by direct methods and refined
by least squares on weighted F2 values for all reflections.29 All
non-hydrogen atoms were assigned anisotropic displacement pa-
rameters and refined without positional constraints. All hydrogen
atomswereconstrainedtoidealgeometriesandwereassignediso-
tropic displacementparameters equal to 1.2 timesthat oftheir par-
ent atom. Refinement proceeded smoothly to give the residuals
above. Complex neutral-atom scattering factors were used.30
The fluorine atom is disordered in exact 1:1 ratio over two sites,
bonding to C3A and its crystallographic symmetry equivalent
C3B. The other component of the disorder is a hydrogen atom
similarlydistributedoverthetwosites.Removingthemirrorplane
from the space group did not reduce this disorder. Crystallo-
graphic data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC
675115. Copies of the data can be obtained, free of charge, on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: þ44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
10. Hostyn, S.; Maes, B. U. W.; van Baelen, G.; Gulevskaya, A.; Meyers, C.;
Smits, K. Tetrahedron 2006, 62, 4676.
11. de Figueiredo, R. M.; Thoret, S.; Huet, C.; Dubois, J. Synthesis 2007, 529.
12. Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849.
13. Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578.
14. Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F., Eds.; Pergamon: Oxford, 1996.
15. For a review on the isolation and synthesis of biologically active carb-
azoles see: Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
¨
16. For a discussion, see: Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
17. For recent examples of the use of tethered aryl chloride substrates in the
arylation reactions via CeH activation see: (a) Ackermann, L.;
Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1627; (b) Campeau,
L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581;
(c) Campeau, L. C.; Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857.
18. Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2002, 2310.
19. Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403.
20. For a recent review see: Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed.
2005, 14, 214.
21. For an overview of biological effects of organofluorine chemistry, see the
special issue on Fluorine in the Life Sciences, ChemBioChem 2004, 5,
557e726.
22. Limited precedents exist for the formation of fluorinated carbazoles, see
Ref. 16.
23. For the use of [HPtBu3][BF4] as an air-stable replacement for PtBu3 in
a range of coupling reactions, see: Netherton, M. R.; Fu, G. C. Org.
Lett. 2001, 3, 4295.
Acknowledgements
24. Data for second species, 8: 8 mg (6%, impure); Rf 0.75 (CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.06 (dt, J¼9.0, 1.1 Hz, 1H, Ar H), 7.12 (t,
J¼7.8 Hz, 1H, Ar H), 7.42e7.55 (m, 2H, Ar H), 7.58 (d, J¼8.4 Hz, 1H,
Ar H), 7.75 (d, J¼7.0 Hz, 1H, Ar H), 7.94 (d, J¼7.5 Hz, 1H, Ar H),
8.04 (d, J¼8.6 Hz, 1H, Ar H), 8.12 (d, J¼8.1 Hz, 1H, Ar H), 8.79 (br s,
1H, NH); 19F NMR (282.65 MHz, CDCl3) d ꢂ134.55 (br s); MS (CI)
[MþþH]¼234.
We thank the EPSRC (PDRA for M.B., DTA for A.L.W., Ad-
vanced Research Fellowship for R.B.B.) and the Royal Society
of Chemistry (Sir Edward Frankland Fellowship to R.B.B.) for
funding and Johnson Matthey for the loan of palladium salts.
References and notes
25. Bedford, R. B.; Hazelwood, S. L.; Horton, P. N.; Hursthouse, M. B.
Dalton Trans. 2003, 4164.
26. Despite repeated attempts, we were unable to obtain better microanalyti-
cal data.
1. For an overview see: Handbook of CeH Transformations; Dyker, G., Ed.;
Wiley-VCH: Weinheim, 2005.
27. CrysAlis RED diffractometer control and data processing software version
1.171.32.5; Oxford Diffraction: Abingdon, UK, 2007.
28. SCALE3 ABSPACK; Oxford Diffraction: Abingdon, UK, 2007.
29. SHELXTL program system version 6.14; Bruker-AXS: Madison, WI,
2000e2003.
2. For recent reviews see: (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43,
3400; (b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439.
3. For recent rare examples of biaryl formation using this methodology see:
(a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172; (b) Dwight, T. A.;
Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137.
´
4. Garcıa-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2006, 128, 1066.
30. International Tables for Crystallography; Kluwer: Dordrecht, 1992;
Vol. C.