Palladium catalyzed tandem alkenyl- and aryl-C-N bond formation: A cascade N-annulation route to 4-, 5-, 6- and 7-chloroindoles

Article abstract of DOI:10.1016/j.tet.2010.05.046

A series of trihalogenated alkenylbenzenes undergo consecutive palladium catalyzed inter- and intramolecular amination reactions to deliver a series of 1-functionalized mono-chloroindoles. 4-, 5-, 6- and 7-Chloroindoles can all be prepared; carbamates, anilines and amines can be employed as the N-nucleophile.

Full text of DOI:10.1016/j.tet.2010.05.046

Tetrahedron 66 (2010) 6632e6638
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium catalyzed tandem alkenyl- and aryl-CeN bond formation: a cascade
N-annulation route to 4-, 5-, 6- and 7-chloroindoles
,
,
Luke C. Henderson a y, Matthew J. Lindon b, Michael C. Willis a
*
a Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK
b Medicinal Chemistry, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 March 2010
Received in revised form 10 May 2010
Accepted 13 May 2010
Available online 20 May 2010
A series of trihalogenated alkenylbenzenes undergo consecutive palladium catalyzed inter- and intra-
molecular amination reactions to deliver a series of 1-functionalized mono-chloroindoles. 4-, 5-, 6- and
7-Chloroindoles can all be prepared; carbamates, anilines and amines can be employed as the N-
nucleophile.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Indole
Amination
1. Introduction
catalyzed reactions,10 we instigated a study to adapt our annulative
indole syntheses to target chloro-substituted indoles. In this report
Indole heterocycles are embedded in a diverse range of natural
products and medicinal agents. The structural variety of indole
targets has resulted in an extensive collection of methods for their
preparation,1 including many based on transition-metal catalysis.2
A valuable sub-set of these transition-metal catalyzed processes is
transformations that are used to functionalize an already intact
indole core.3 Although the number of reports of the direct metal
catalyzed functionalisation of CeH bonds in indoles, particularly for
the C-2 and C-3 positions, is rapidly growing,4,5 the most general
class of substrates for metal catalyzed functionalisation is haloge-
nated indoles. A corollary of this is the need for efficient routes to
halogenated indoles. Although the preparation of C-3 halogenated
indoles is usually straightforward, access to the remaining halo-
genated isomers is more challenging.1c,6
we document the realisation of this goal, and show that with the
appropriate choice of halogen substituents, trihalogenated sub-
strates can be efficiently transformed into the corresponding
mono-chloroindoles (3/4, Scheme 1).
We have recently demonstrated that a broad range of 2-(2-
haloalkenyl)-aryl halides,7 as well as the corresponding alkenyl
triflates,8 can undergo two sequential palladium catalyzed
amination reactionsdthe first intermolecular, the second intra-
moleculardto provide efficient routes to a variety of N-function-
alised indoles (1/2, Scheme 1).9 With aryl chlorides now
established as useful substrates in a wide range of transition-metal
Scheme 1. Tandem palladium-catalyzed amination routes to 1-functionalised indoles
and chloroindoles.
2. Results and discussion
One key advantage of the approach to chlorinated indoles de-
scribed in Scheme 1 is the ready availability of suitable halogenated
substrates. For example, substrates with no substituents on the
alkene (corresponding to the C-2 and C-3 positions in the indole
products, 5 Scheme 2) are available by a straightforward Wittig
* Corresponding author. Tel.: þ44 1865 285126; fax: þ44 1865 285002; e-mail
address: michael.willis@chem.ox.ac.uk (M.C. Willis).
y
Present address: School of Life and Environmental Sciences, Deakin University,
Pigdons Road, Geelong, Australia.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.046

L.C. Henderson et al. / Tetrahedron 66 (2010) 6632e6638
6633
reaction on the corresponding aldehydes 6. Substrates bearing
substituents at what will become C-2 of the indole products, 7 are
available from the corresponding 1,1-dibromo-derivatives 8 using
Suzuki chemistry; the simple aldehydes are again the key starting
materials. All of the mono-chlorinated isomers of ortho-bromo-
benzaldehyde are either commercially available, or accessible using
a bromination/oxidation sequence from the related toluene.11
With an efficient set of conditions to access the 4-chloroindole
derivative secured, we next applied the optimized conditions to the
remaining isomers of the starting materials (Table 2). Entries 1e3
demonstrate the efficient preparation of the 5-, 6- and 7-chloro
Table 2
The preparation of 5-, 6- and 7-chloroindole derivatives, and variation of the
N-coupling partnera
Scheme 2. The preparation of the tri- and tetrahalogenated starting materials. Re-
agents: (i) NBS, AIBN, CCl4; (ii) NMO, MeCN; (iii) [Ph3PCH2Br]Br, tBuOK; (iv) CBr4, PPh3,
CH2Cl2; (v) Pd2(dba)3, P(2-furyl)3, Na2CO3, Ar-B(OH)2.
We elected to employ the coupling of 1,3-dihalo-(2-bromovinyl)
benzenes 9 and tert-butyl carbamate as a test platform to evaluate
suitable catalysts (Table 1). Initial reaction conditions were based
on precedent from our earlier studies; reaction of dichloro sub-
strate 9a using ligand 11 and Cs2CO3 in toluene at 110 ꢀC delivered
the desired indole 10 in a poor yield of 17% as the only product
(entry 1, Table 1). We attributed the poor mass balance to thermal
degradation of the styrene starting material under the reaction
conditions. We hoped that by moving to the bromo-chloro sub-
strate 9b we could achieve a faster reaction and limit de-
composition; reaction of substrate 9b at the lower temperature of
85 ꢀC using DME as solvent delivered the expected indole in 37%
yield (entry 2). The remainder of the optimization study employed
the bromo-chloro substrate, and explored variation of biphenyl li-
gand (11, 12 or 13),12 base (Cs2CO3, K2CO3 or K3PO4) and reaction
temperature (Table 1). The optimized conditions involved using the
dimethoxy-substituted biphenyl ligand (13) in combination with
Cs2CO3 in toluene at 110 ꢀC (entry 7).
Entry
1c
Substrate
Product
Yieldb (%)
69
2d
84
68
3e
4f
39
N
Table 1
Cl
Evaluation of reaction conditions for the formation of 4-chloroindole 10a
5d,g
87
67
OMe
6d,g
Entry
X
Ligand
Base
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
Cl
11
11
12
12
12
12
13
13
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
PhMe
DME
PhMe
PhMe
DME
PhMe
PhMe
Xylene
110
85
85
110
85
110
110
130
17
37
38
<5
15
41
66
24
7d,g
68
Br
Br
Br
Br
Br
Br
Br
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
a
Conditions: Pd2(dba)3 (2.5 mol %), ligand 13 (7.5 mol %), Cs2CO3 (2.5 equiv), N-
nucleophile (1.05 equiv), toluene 110 ꢀC, 16 h.
b
Isolated yields.
E:Z 1:9.
E:Z 1:9.
E:Z 1:8.
a
c
Dihalo substrates 9a and 9b used as a >20:1 E:Z mix of isomers. Conditions:
Pd2(dba)3 (2.5 mol %), ligand (7.5 mol %), base (2.5 equiv), tert-butyl carbamate
(1.05 equiv), 16 h.
d
e
b
f
Isolated yields.
E:Z 1:9.
g
NaOtBu used as base.

6634
L.C. Henderson et al. / Tetrahedron 66 (2010) 6632e6638
derivatives, while entry 4 illustrates that access to dichlorinated
products (5,7-dichloroindole in this example) is also possible. All of
the indole forming reactions discussed so far have featured tert-
butyl carbamate as the N-nucleophile, resulting in the formation of
N-Boc indoles; in order to assess whether different substituents
could be installed, we next evaluated a number of alternative
N-coupling partners. Combining the 6-chloroindole precursor with
p-anisidine using the conditions optimized for the carbamate
coupling produced none of the expected indole product, returning
only starting materials. However, if the base was switched from
caesium carbonate to sodium tert-butoxide, then the desired N-aryl
indole was obtained in 87% yield (entry 5). Using the stronger base
also allowed an alkylamine (p-methoxybenzylamine), and an N,N-
dialkylhydrazine (N-aminomorpholine) to be employed as coupling
partners (entries 6 and 7).
N-coupling partner allowed the original caesium carbonate re-
action conditions to be employed (Table 3). When the 4-chloro
substrate was subjected to the standard reaction conditions the
desired indole was obtained in a disappointing 34% yield. However,
exchanging the ligand to the tri-isopropyl variant, 12, and using
DME as solvent allowed the expected 4-chloroindole to be isolated
in an encouraging 71% yield (entry 1). The combination of ligand 12
and DME was used as standard for substrates featuring alkenyl-
substituents. Entries 2 and 3 illustrate that both the 5-Cl, and 6-Cl
isomers were readily accessible using the established conditions.
When the 7-chloro substrate was subjected to the reaction condi-
tions none of the desired indole was obtained; however, the cor-
responding alkyne (14), resulting from elimination of HBr, was
isolated in 78% yield (entry 4). A further coupling of the same
substrate but employing the less sterically demanding ethyl-
carbamate was similarly unsuccessful (73% of the alkyne isolated).
The final two examples serve to demonstrate that alternative C-2
groups can also be incorporated, with both a 3-furyl, and an ethyl
ester substituent being successfully incorporated. The ester sub-
stituent was introduced into the substrate using a Br-substituted
Horner/Wadsworth/Emmons olefination reaction on the corre-
sponding aldehyde.
The final variation explored was extension of the chemistry to
allow the formation of C-1 substituted indole products. As shown in
Scheme 2, a variety of aryl-substituted substrates were readily
accessible using Suzuki chemistry; a 4-methoxyphenyl group was
used as a standard substituent to allow the regioisomeric chloro-
substrates to be evaluated. Employing tert-butyl carbamate as the
Table 3
The preparation of C-2 functionalised mono-chloroindolesa
3. Conclusion
We have established that a cascade palladium catalysed inter/
intramolecular amination process can be applied to trihalogenated
alkenylbenzenes to allow access to synthetically useful mono-
chloroindole derivatives. The approach removes the issue of
selective chlorination of indole derivatives, to that of the prepa-
ration of suitably halogenated benzene derivatives. The strategy
allows the ready preparation of 4-, 5-, 6- and 7-chlorinated
indoles.
Entry
1
Substrate
Yieldb (%)
71
2
3
75
81
4. Experimental section
4.1. General information
All reactions were performed under an inert atmosphere of ni-
trogen, in oven dried glassware. Palladium catalysts and ligands
werepurchasedfromAldrich Chemical Companyor StremChemical.
tert-Butyl 4-chloro-1H-indole-1-carboxylate (10, Table 1, entry 7),13
tert-butyl 5-chloro-1H-indole-1-carboxylate (Table 2, entry 1),13
tert-butyl 6-chloro-1H-indole-1-carboxylate (Table 2, entry 2)14
and tert-butyl 7-chloro-1H-indole-1-carboxylate (Table 2, entry
3)14 are known compounds and as such data is not included below.
4c
0
Cl
O
4.2. General procedure (A) for the Wittig derived synthesis of
vinyl bromide substrates; exemplified by the preparation of 1-
bromo-2-[(E)-2-bromovinyl]-3-chlorobenzene (Table 1, entry
2 substrate)
5
61
61
Br
Cl
Potassium tert-butoxide (560 mg, 5.0 mmol) was added to
a suspension of (methylbromo)triphenylphosphonium bromide
(2.2 g, 5.0 mmol) in THF (25 mL) cooled to ꢁ78 ꢀC and the sus-
pension stirred for 40 min. 2-Bromo-6-chlorobenzaldehyde (1.0 g,
4.6 mmol) was added as a solid to the suspension and the reaction
slowly warmed to room temperature over 12 h. The crude product
was poured into petrol (100 mL), filtered through Celite and the
Celite washed repeatedly with petrol (3ꢂ50 mL). The crude
6
a
Conditions: 5a (1.0 equiv), amine (2.0 equiv), Pd(OAc)2 (5 mol %), ligand (12 mol
%), Cs2CO3 (2.2 equiv), toluene, 110 ꢀC, 6 h. Substrate 5a was used as a >20:1 mix-
ture of Z/E isomers.
b
Isolated yields.
c
Alkyne 14 isolated in 78% yield.

L.C. Henderson et al. / Tetrahedron 66 (2010) 6632e6638
6635
solution was reduced in vacuo to give a pale yellow solid, which was
13 (10.5 mg, 25.5
m
mol) and alkene 9b (100 mg, 0.34 mmol) and
purified by flash chromatography (SiO2, 25% petrol/hexane) to give
the vinyl bromide as a white crystalline solid (604 mg, 30%, E:
Z>20:1); mp 40e42 ꢀC; nmax (thin film, cmꢁ1) 3080, 2962, 1473,
897; 1H NMR (400 MHz, CDCl3) 7.52 (dd, J¼8.0, 1.2 Hz, 1H), 7.38 (dd,
J¼8.0,1.2 Hz,1H), 7.12 (d, J¼14.2 Hz,1H), 7.08 (dd, J¼8.0, 8.0 Hz,1H),
6.88 (d, J¼14.2 Hz, 1H); 13C NMR (100 MHz, CDCl3), 134.6, 133.8,
132.7, 131.7, 129.3, 129.2, 123.9, 114.5; MS (FIþ) 296, 298, 294; HRMS
for C8H579Br81Br35Cl predicted 293.8447, found 293.8447.
the solution was heated to 110 ꢀC for 16 h. The solution was
allowed to cool to room temperature then filtered through
a Celite pad, followed by repeated washing of the Celite with
DCM (3ꢂ50 mL). The filtrate was then reduced to dryness under
reduced pressure. The crude product was purified via flash
chromatography (SiO2, 5% Et2O/petrol) to give the indole as
a yellow oil (56 mg, 66%); nmax (thin film/cmꢁ1) 3155, 3122, 2980,
2933, 1744, 1531, 1474, 1426, 1345, 1148; 1H NMR (400 MHz,
CDCl3) 8.07 (dd, J¼8.6, 8.6 Hz, 1H), 7.64 (d, J¼3.8 Hz, 1H), 7.24 (m,
2H), 6.70 (d, J¼3.8 Hz, 1H), 1.68 (s, 9H); 13C NMR (100 MHz,
CDCl3) 149.4, 132.7, 129.2, 126.4, 126.0, 124.8, 122.4, 113.7, 105.3,
84.2, 28.1; MS (FIþ) 251, 253; HRMS (FIþ) predicted for
C13H1435ClO2 251.0716, found 251.0713.
4.2.1. 1-Bromo-2-[(Z)-2-bromovinyl]-4-chlorobenzene (Table 2, entry
1 substrate). Prepared and purified according to General procedure
A, using 2-bromo-5-chlorobenzaldehyde11 (0.50 g, 2.30 mmol),
potassium tert-butoxide (307 mg, 2.30 mmol) and (methylbromo)
triphenylphosphonium bromide (1.20 g, 2.74 mmol) to give the
vinyl bromide as a clear oil (376 mg, 56%, E/Z 1:9); nmax (thin film/
cmꢁ1) 3083, 2977, 2866, 1547, 1581, 1319, 1038; 1H NMR (400 MHz,
CDCl3) 7.77 (d, J¼2.4 Hz, 1H), 7.53 (d, J¼8.4 Hz, 1H), 7.18 (dd, J¼8.4,
2.4 Hz, 1H), 7.14 (d, J¼8.0 Hz, 1H), 6.65 (d, J¼8.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) 136.5, 133.6, 131.3, 130.2, 129.5,126.9,121.5,110.6;
MS (EIþ) 296, 294, 298; HRMS for C8H579Br81Br35Cl predicted
293.8447, found 293.8441.
4.3.1. tert-Butyl 5,7-dichloro-1H-indole-1-carboxylate (Table 2, entry
4). Prepared using General procedure B, employing 1-bromo-2-
[(Z)-2-bromovinyl]-4,6-dichlorobenzene (98 mg, 0.3 mmol), ligand
13 (9.2 mg, 22.5
m
mol), caesium carbonate (244 mg, 0.75 mmol),
mol) and tert-butyl carbamate (39 mg,
Pd2(dba)3 (6.9 mg, 7.5
m
0.33 mmol) to give the indole as a yellow oil (33 mg, 39%); nmax (thin
film/cmꢁ1) 2930, 1759, 1739, 1448, 1319, 1152; 1H NMR (400 MHz,
CDCl3) 7.58 (d, J¼3.6 Hz,1H), 7.46 (d, J¼1.8 Hz,1H), 7.33 (d, J¼1.8 Hz,
1H), 6.52 (d, J¼3.6 Hz, 1H), 1.66 (s, 9H); 13C NMR (125 MHz, CDCl3)
148.4, 134.6, 130.67, 130.64, 128.5, 126.1, 120.9, 119.2, 106.3, 84.8,
27.9; MS (ESIþ) 308, 310; HRMS (ESIþ) predicted for
C13H13N35Cl35ClNaO2 308.0213, found 308.0216.
4.2.2. 1-Bromo-2-[(Z)-2-bromovinyl]-5-chlorobenzene (Table 2,
entry 2 substrate). Prepared using General procedure A, employing
2-bromo-4-chlorobenzaldehyde15 (0.50 g, 2.30 mmol), potassium
tert-butoxide (307 mg, 2.74 mmol) and (methylbromo)triphenyl-
phosphonium bromide(1.20 g, 2.74 mmol) to give the vinyl bromide as
a white solid (367 mg, 55%, E/Z 1:9); mp 44e46 ꢀC; nmax (thin film/
cmꢁ1) 3081, 2979, 2866, 1540, 1582, 1316; 1H NMR (200 MHz, CDCl3)
7.73 (d, J¼8.4 Hz,1H),7.63(d,J¼2.2 Hz,1H), 7.33 (dd, J¼8.4, 2.2 Hz,1H),
7.15 (d, J¼8.2 Hz,1H), 6.62 (d, J¼8.2 Hz,1H);13CNMR(100 MHz, CDCl3)
134.5, 133.6, 132.3, 131.3, 131.1, 127.2, 124.0, 110.0; MS (FIþ) 296, 298,
294; HRMS for C8H579Br81Br35Cl predicted 293.8447, found 293.8456.
4.3.2. 6-Chloro-1-(4-methoxyphenyl)-1H-indole (Table 2, entry
5). Prepared using General procedure B, employing 1-bromo-2-
[(Z)-2-bromovinyl]-5-chlorobenzene (0.10 mg, 0.34 mmol), sodium
tert-butoxide (82 mg, 0.85 mmol), Pd2dba3 (10.5 mg, 8.5
ligand 13 (7.7 mg, 25.5 mol) and p-methoxyaniline (46 mg,
0.37 mmol) in toluene (0.68 mL) to give the indole as a yellow solid
after purification by flash chromatography (SiO2, 5% Et2O/petrol),
(76 mg, 87%); mp 49e51 ꢀC; nmax (thin film/cmꢁ1) 3001, 2932, 2835,
1517, 1463, 1249; 1H NMR (400 MHz, CDCl3), 7.60 (d, J¼8.4 Hz, 1H),
7.45 (d, J¼1.6 Hz, 1H), 7.39 (d, J¼9.2 Hz, 2H), 7.28 (d, J¼3.2 Hz, 1H),
7.15 (dd, J¼8.4, 1.6 Hz, 1H), 7.07 (d, J¼9.2 Hz, 2H), 6.64 (d, J¼3.2 Hz,
1H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) 158.5, 136.7, 132.1,
129.0, 128.1, 127.4, 126.0, 121.8, 120.7, 114.8, 110.3, 102.9, 55.6; MS
(CIþ) 258, 260; HRMS (CIþ) predicted for C15H13NO35Cl 258.0686,
found 258.0688.
mmol),
m
4.2.3. 1-Bromo-2-[(Z)-2-bromovinyl]-6-chlorobenzene (Table 2, en-
try 3 substrate). Prepared using General procedure A, employing
2-bromo3-chlorobenzaldehyde (410 mg, 1.88 mmol), potassium
tert-butoxide (255 mg, 2.30 mmol) and (methylbromo)triphenyl-
phosphonium bromide (1 g, 2.30 mmol) to give the vinyl bromide as
a clear oil (34 mg, 68%, E:Z 1:8); nmax (thin film/cmꢁ1); 3086, 2978,
2866, 1541, 1577, 1316; 1H NMR (400 MHz, CDCl3) 7.60 (dd, J¼8.0,
1.2 Hz, 1H), 7.45 (dd, J¼8.0, 1.2 Hz, 1H), 7.29 (dd, J¼8.0, 8.0 Hz, 1H),
7.20 (d, J¼8.0 Hz, 1H), 6.63 (d, J¼8.0 Hz, 1H); 13C NMR (CDCl3,
100 MHz) 137.7,135.2,132.7,129.8,128.6,127.6,123.6,110.1; MS (EIþ)
296; Predicted for C8H579Br81Br35Cl 293.8447, found 293.8443.
4.3.3. 6-Chloro-1-(4-methoxybenzyl)-1H-indole (Table 2, entry
6). Prepared using General procedure B, employing 1-bromo-2-
[(Z)-2-bromovinyl]-5-chlorobenzene (100 mg, 0.34 mmol), sodium
tert-butoxide (82 mg, 0.85 mmol), p-methoxybenzyl amine (51 mg,
4.2.4. 1-Bromo-2-[(Z)-2-bromovinyl]-4,6-dichlorobenzene (Table 2,
entry 4 substrate). Prepared using General procedure A, employing
2-bromo-3,5-dichlorobenzaldehyde16 (134 mg, 0.53 mmol), potas-
sium tert-butoxide (65 mg, 0.58 mmol) and (methylbromo)triphe-
nylphosphonium bromide (253 mg, 0.58 mmol) to give the vinyl
bromide as a white solid (98 mg, 56%, E:Z 1:9); mp 40e41 ꢀC; nmax
(thin film/cmꢁ1) 3076, 3016, 2920, 1612, 1566, 1399, 1386, 1313,
1174, 1030, 918, 819, 722, 674; 1H NMR (200 MHz, CDCl3) 7.59 (d,
J¼2.2 Hz, 1H), 7.46 (d, J¼2.2 Hz, 1H), 7.14 (d, J¼8.0 Hz, 1H), 6.67 (d,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) 138.6, 136.0, 133.1, 131.8,
129.4, 128.6, 121.9, 111.3; MS (EIþ) 330, 332, 328; HRMS (EIþ) pre-
dicted for C8H479Br79Br35Cl35Cl 327.8057, found 327.8057.
0.37 mmol), Pd2dba3 (7.7 mg, 25.5
mmol) and ligand 13 (10.5 mg,
8.5 mol) in toluene (0.68 mL) to give the desired indole as a pale
m
yellow oil after flash chromatography (SiO2, 5% Et2O/petrol),
(66 mg, 68%); nmax (thin film/cmꢁ1) 2930, 2835, 1611, 1512, 1463,
1248, 804; 1H NMR (400 MHz, CDCl3) 7.56 (d, J¼8.4 Hz, 1H), 7.31 (br
s, 1H), 7.11e7.06 (m, 4H), 6.86 (d, J¼8.8 Hz, 2H), 6.53 (d, J¼3.2 Hz,
1H), 5.21 (s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) 159.2,
136.6, 128.9, 128.8, 128.2, 127.6, 127.2,121.8,120.2,114.2,109.7,101.7,
55.3, 49.7; MS (FIþ) 271, 273; HRMS (FIþ) predicted for
C16H14NO35Cl 271.0770, found 271.0764.
4.3.4. Chloro-1-morpholin-4-yl-1H-indole (Table 2, entry 7). Pre-
pared using General procedure B, 1-bromo-2-[(Z)-2-bromovinyl]-
5-chlorobenzene (100 mg, 0.34 mmol), sodium tert-butoxide
4.3. General procedure (B) for indole formation using non-
substituted substrates; exemplified by the preparation of tert-
butyl 4-chloro-1H-indole-1-carboxylate (10, Table 1, entry 7)13
(82 mg, 0.85 mmol), Pd2dba3 (10.5 mg, 8.5
mmol), ligand 13 (7.7 mg,
25.5 mol) and N-aminomorpholine (38 mg, 0.37 mmol) in toluene
m
Toluene (0.68 mL) was added to
a
flask charged with
(0.68 mL) to give the indole as colourless crystals after purification
via flash chromatography (SiO2, 10% Et2O/petrol), (54 mg, 67%); mp
Pd2(dba)3 (7.7 mg, 8.5 mol), Cs2CO3 (273 mg, 8.5 mmol), ligand
m

6636
L.C. Henderson et al. / Tetrahedron 66 (2010) 6632e6638
182e184 ꢀC; nmax (thin film/cmꢁ1) 2916, 2850, 1458, 1113, 902; 1H
NMR (400 MHz, CDCl3) 7.59 (d, J¼2.0 Hz, 1H), 7.50 (d, J¼8.2 Hz, 1H),
7.41 (d, J¼3.4 Hz, 1H), 7.09 (dd, J¼8.2, 2.0 Hz, 1H), 6.50 (d, J¼3.4 Hz,
1H), 3.94 (t, J¼4.6 Hz, 4H), 3.16 (t, J¼4.6 Hz, 4H); 13C NMR
(100 MHz, CDCl3) 135.4, 128.2, 123.8, 121.9, 121.7, 120.7, 109.6, 101.1,
67.2, 55.5; MS (CIþ) 237, 239; HRMS (CIþ) predicted for
C12H14N2O35Cl 237.0795, found 237.0793.
were then washed with brine (2ꢂ20 mL), dried (MgSO4) and the
solvent removed under reduced pressure. The crude product was
obtained as a yellow oil and purified by flash chromatography (SiO2,
5% ether/petrol) to give the vinyl bromide as a yellow solid (720 mg,
61 %); mp 71e73 ꢀC; nmax (thin film/cmꢁ1) 2933, 2835, 1605, 1575,
1427, 1249, 1175, 773; 1H NMR (CDCl3, 400 MHz) 7.69 (d, J¼8.8 Hz,
2H), 7.38 (d, J¼8.0 Hz, 2H), 7.24 (dd, J¼8.0, 8.0 Hz, 1H), 7.02 (s, 1H),
6.94 (d, J¼8.8, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) 160.5,
135.7, 134.9, 133.4, 131.5, 131.0, 129.3, 127.9, 123.9, 113.7, 55.5; MS
(ESþ) 277, 357, 359, 361; HRMS (ESþ) predicted for
C15H1279Br35Cl35ClO 356.9449, found 356.9455.
4.4. General procedure (C) for the preparation of 1,1-
dibromoalkenes; exemplified by the preparation of 1-bromo-
4-chloro-2-(2,2-dibromovinyl)benzene
Carbon tetrabromide (2.5 g, 7.2 mmol) was added to a solution
of triphenylphosphine (4.0 g, 15.2 mmol) in DCM (30 mL) cooled to
0 ꢀC and the solution was stirred for 40 min. 2-Bromo-5-chloro-
benzaldehyde (1.0 g, 4.6 mmol) was added as a solid and the
resulting suspension stirred at 0 ꢀC for 3 h. Petrol (200 mL) was
added and the suspension filtered through Celite, the Celite was
washed with petrol (3ꢂ50 mL) and the filtrate was reduced to
dryness in vacuo to give a yellow solid. The crude product was
purified via flash chromatography (SiO2, petrol) to give the gem-
dibromide as a colourless solid (977 g, 58%); mp 74e76 ꢀC; nmax
(thin film/cmꢁ1) 3086, 3015, 1889, 1623, 1452, 1387, 1095, 1031; 1H
NMR (400 MHz, CDCl3), 7.59 (d, J¼2.4 Hz,1H), 7.52 (d, J¼8.8 Hz,1H),
7.45 (s, 1H), 7.20 (dd, J¼8.8, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
137.4, 135.4, 133.7, 133.2, 130.2, 129.8, 120.9, 94.3; MS (FIþ) 375, 373,
377, 371; HRMS (FIþ) predicted for C8H479Br79Br79Br35Cl 371.7552,
found 371.7560.
4.5.1. 1-Bromo-2-[(Z)-2-bromo-2-(4-methoxyphenyl)vinyl]-4-chlo-
robenzene (Table 3, entry 2 substrate). Prepared using General
procedure D, employing 1-bromo-4-chloro-2-(2,2-dibromovinyl)
benzene (500 mg, 1.3 mmol), p-methoxyphenylboronic acid
(207 mg, 1.37 mmol), tri(2-furylphosphine) (46 mg, 0.195 mmol),
Pd2(dba)3 (30 mg, 33 mmol) and sodium carbonate (2.6 mL,
2.6 mmol) to give the vinyl bromide (288 mg, 55%); mp 86e87 ꢀC;
nmax (thin film/cmꢁ1) 2957, 2927, 2835, 1603, 1507, 1454, 1178, 1030,
810; 1H NMR (400 MHz, CDCl3) 7.77 (d, J¼2.2 Hz, 1H), 7.65 (d,
J¼9.0 Hz, 2H), 7.55 (d, J¼8.5 Hz, 1H), 7.17 (dd, J¼8.5, 2.2 Hz, 1H), 7.10
(s, 1H), 6.94 (d, J¼9.0 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) 160.5, 138.7, 133.4, 132.9, 132.2, 130.9, 129.3, 129.1, 127.9,
126.6, 122.0, 113.7, 55.4; MS (FIþ) 402, 400, 404; HRMS (FIþ) pre-
dicted for C15H1179Br35Cl35Cl 399.8865, found 399.8868.
4.5.2. 1-Bromo-2-[(Z)-2-bromo-2-(4-methoxyphenyl)vinyl]-5-chlo-
robenzene (Table 3, entry 3 substrate). Prepared using General
procedure D, employing 1-bromo-5-chloro-2-(2,2-dibromovinyl)
benzene (214 mg, 0.65 mmol), tri(2-furyl)phosphine (23 mg,
4.4.1. 1-Bromo-5-chloro-2-(2,2-dibromovinyl)benzene. Prepared
using General procedure C, employing 2-bromo-4-chloro-
benzaldehyde (0.5 g, 2.3 mmol), carbon tetrabromide (1.26 g,
3.8 mmol) and triphenylphosphine (2 g, 7.50 mmol) to give the
gem-dibromide as a white solid (705 g, 83%); mp 70e71 ꢀC; nmax
(thin film/cmꢁ1) 3018, 3066, 1733, 1593, 1578, 1550, 1464, 1374,
1139,1040; 1H NMR (400 MHz, CDCl3) 7.61 (d, J¼2.0 Hz,1H), 7.55 (d,
J¼8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (dd, J¼8.4, 2.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3), 135.6, 134.9. 134.5, 132.3, 131.0, 127.5, 123.4, 93.6;
m/z (FIþ) 375, 373, 377, 371; HRMS (FIþ) predicted for
C8H479Br79Br79Br35Cl 371.7552, found 371.7545.
0.1 mmol), Pd2dba3 (15 mg, 16.2 mmol) and p-methoxyphenylbor-
onic acid (103 mg, 0.68 mmol) to give the vinyl bromide (142 mg,
55%); mp 76e77 ꢀC, nmax(thin film/cmꢁ1) 2931, 2835, 1602, 1506,
1458, 1251, 1173, 1026, 820; 1H NMR (CDCl3, 400 MHz) 7.72 (d,
J¼8.4 Hz, 1H), 7.66e7.63 (m, 3H), 7.35 (dd, J¼8.4, 2.4 Hz, 1H), 7.11 (s,
1H), 6.94 (d, J¼8.4 Hz, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3,)
160.5, 135.7, 134.0, 132.3, 132.0, 131.7, 129.2, 127.4, 127.2, 126.7,
124.5, 113.7, 55.4; MS (FIþ) 402, 404, 400; HRMS (FIþ) predicted for
C15H1179Br79Br35ClO 399.8865, found 399.8869.
4.4.2. 1-Bromo-6-chloro-2-(2,2-dibromovinyl)benzene. Prepared
using General procedure C, employing 2-bromo-3-chlor-
obenzaldehyde (0.50 g, 2.3 mmol), carbon tetrabromide (1.25 g,
3.77 mmol) and triphenylphosphine (1.97 g, 7.52 mmol) to give the
gem-dibromide as a white solid (0.74 mg, 86%); mp 71e73 ꢀC; nmax
(thin film/cmꢁ1) 3019, 1589, 1445, 197, 1150, 824; 1H NMR
(400 MHz, CDCl3) 7.50 (s, 1H), 7.45 (m, 2H), 7.29 (app. t, J¼8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) 138.6, 136.8, 135.3, 130.0, 128.5,
127.9, 123.1, 93.9; MS (EIþ) 375; HRMS (EIþ) predicted for
C8H479Br79Br79Br35Cl 371.7552, found 371.7562.
4.5.3. 1-Bromo-2-[(Z)-2-bromo-2-(4-methoxyphenyl)vinyl]-6-chlo-
robenzene (Table 3, entry 4 substrate). Prepared using General
procedure D, employing 1-bromo-6-chloro-2-(2,2-dibromovinyl)
benzene (200 mg, 0.533 mmol), p-methoxyphenylboronic acid
(89 mg, 0.587 mmol), sodium carbonate (1 M, 1.07 mL, 1.07 mmol),
tri(2-furyl) phosphine (18.6 mg, 80
mmol) and Pd2(dba)3 (12 mg,
13.3 mol) to give the vinyl bromide a white solid (111 mg, 52%);
m
mp; 92e93 ꢀC; nmax (thin film/cmꢁ1) 2993, 2932, 2834, 1508, 1284,
1172, 1030, 819; 1H NMR (400 MHz, CDCl3) 7.66 (d, J¼8.0 Hz, 2H),
7.61 (dd, J¼8.0, 1.0 Hz, 1H), 7.44 (dd, J¼8.0, 1.0 Hz, 1H), 7.31 (app. t,
J¼8.0 Hz, 1H), 7.17 (s, 1H), 6.94 (d, J¼8.0, 2H), 3.87 (s, 3H); 13C NMR
(100 MHz, CDCl3) 160.5, 147.5, 140.0, 135.0, 132.2, 129.4, 129.3,
129.2, 128.0, 127.6, 127.5, 113.8, 55.5; MS (CIþ) 322; HRMS predicted
for C15H1179Br79Br35ClO 399.8865, found 399.8856.
4.5. General procedure (D) for the preparation of aryl-
substituted substrates using Suzuki chemistry; exemplified by
the preparation of 2-[(Z)-2-bromo-2-(4-methoxyphenyl)
vinyl]-1,3-dichlorobenzene (Table 3, entry 1 substrate)
4.5.4. 3-[(Z)-1-Bromo-2-(2,6-dichlorophenyl)vinyl]furan (Table 3,
entry 5 substrate). Prepared using General procedure D, employing
1,3-dichloro-2-(2,2-dibromovinyl)benzene (0.5 g, 1.5 mmol), tri(2-
furyl) phosphine (123 mg, 53 mmol), furan-3-boronic acid (176 mg,
DME (15 mL) was added to a flask containing Pd2(dba)3 (68 mg,
75 mmol), tri(2-furyl)phosphine (105 mg, 0.45 mmol), p-methoxy-
phenylboronic acid (502 mg, 3.33 mmol) and 1,3-dichloro-2-(2,
2-dibromovinyl)benzene (1.0 g, 3.0 mmol). The suspension was
stirred for 10 min at room temperature then aqueous sodium car-
bonate (1 M, 6.0 mL, 6.0 mmol) was added and the solution heated
to 70 ꢀC for 4 h. The solution was then cooled to room temperature
and water (50 mL) was added, and the aqueous phase then
extracted with ether (3ꢂ20 mL). The combined organic phases
1.59 mmol), Pd2(dba)3 (35 mg, 38 mmol) and sodium carbonate
(1 M, 3.0 mL) to give the furan as a yellow oil (326 mg, 68%); nmax
(thin film/cmꢁ1) 2925, 1557, 1387, 1164, 790, 774; 1H NMR
(400 MHz, CDCl3) 7.76 (m, 1H), 7.50 (m, 1H), 7.38 (d, J¼8.4 Hz, 2H),
7.24 (dd, J¼8.4 Hz, 1H), 7.05 (s, 1H), 6.73 (dd, J¼2.0, 0.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) 144.1, 143.5, 135.0, 129.4, 127.9, 127.5, 126.2,

L.C. Henderson et al. / Tetrahedron 66 (2010) 6632e6638
6637
122.9, 120.6, 108.1; MS (ESIꢁ) 316, 318, (ESIþ) 235; HRMS (CIþ)
predicted for C12H8O79Br35Cl35Cl 316.9136, found 316.9133.
0.62 mmol), tert-butyl carbamate (29 mg, 0.25 mmol) in DME
(0.5 mL) gave the crude product as a black oil. Purification via flash
chromatography (SiO2, 5% Et2O/petrol) gave the indole as a white
solid (72 mg, 81%); mp 122e123 ꢀC; nmax (thin film/cmꢁ1) 2979,
2932, 2836, 1731, 1503, 1323, 1247, 1158; 1H NMR (400 MHz, CDCl3)
8.26 (d, J¼2.0 Hz, 1H), 7.44 (d, J¼8.4 Hz, 1H), 7.35 (d, J¼8.8 Hz, 2H),
7.23 (dd, J¼8.4, 2.0 Hz, 1H), 6.96 (d, J¼8.8 Hz, 2H), 6.48 (s, 1H), 3.87
(s, 3H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) 159.4, 149.9, 141.0,
137.6, 129.9, 127.7, 126.9, 123.4, 120.9, 155.5, 113.3, 109.0, 83.8, 55.3,
27.6 (one quaternary carbon not observed); MS (FI) 380; HRMS (FI)
predicted for C20H2035ClNaNO3 380.1025, found 380.1024.
4.5.5. Ethyl (Z)-2-bromo-3-(2-bromo-6-chlorophenyl)acrylate (Table
3, entry 6 substrate). Potassium tert-butoxide (336 mg, 3.0 mmol)
was added to a solution of ethyl bromo(diethoxyphosphoryl)ace-
tate (906 mg, 3.0 mmol) in THF (10 mL) at 0 ꢀC and stirred at this
temperature for 1 h. 2-Bromo-4-chlorobenzaldehyde (500 mg,
2.85 mmol) was added to the solution, the solution heated to 50 ꢀC
for 16 h. Water (50 mL) was added and the aqueous phase extracted
with ether (3ꢂ30 mL), the combined organic phases washed with
brine (3ꢂ20 mL), dried (MgSO4) and the solvent removed in vacuo
to give a yellow oil. Purification by flash chromatography (SiO2, 2.5
to 5% ether/petrol) gave the styrene as a white solid (153 mg, 15%);
mp 58e59 ꢀC; nmax (thin film/cmꢁ1) 2982, 2928, 1731, 1430, 1268,
1201, 1152, 779, 758; 1H NMR (400 MHz, CDCl3) 8.07 (s, 1H), 7.55 (d,
J¼8.0 Hz, 1H), 7.41 (d, J¼8.0 Hz,1H), 7.19 (dd, J¼8.0, 8.0 Hz,1H), 4.39
(q, J¼8.0 Hz, 2H), 1.41 (t, J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
161.9, 139.7, 135.2, 133.5, 131.0, 130.4, 128.6, 122.8, 121.5, 63.1, 14.1;
MS (FIþ) 367.8, 369.8; HRMS predicted for C11H9O279Br79Br35Cl
365.8658, found 365.8658.
4.6.3. 2-Bromo-1-chloro-3-[(4-methoxyphenyl)ethynyl]benzene
(Table 3, entry 4). Prepared using General procedure E, employing
1-bromo-2-[(Z)-2-bromo-2-(4-methoxyphenyl)vinyl]-6-chloro-
benzene (85 mg, 0.21 mmol), Pd2(dba)3 (4.8 mg, 5.2
mmol), ligand
12 (7.5 mg, 16 mol), Cs2CO3 (172 mg, 0.53 mmol) and tert-butyl
m
carbamate (26 mg, 0.22 mmol) to give the alkyne as a yellow solid
(58 mg, 78%); mp 53e54 ꢀC; nmax (thin film/cmꢁ1) 2972, 2936,
2839, 2222, 2193, 1603, 1572, 1508, 1399, 1245, 1023, 831; 1H NMR
(400 MHz, CDCl3) 7.53 (d, J¼8.8 Hz, 2H), 7.44 (dd, J¼7.8, 1.6 Hz, 1H),
7.22 (dd, J¼7.8, 7.8 Hz, 1H); 7.39 (dd, J¼7.8, 1.2 Hz, 1H), 6.91 (d,
J¼8.8 Hz, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) 160.1, 135.2,
133.2, 130.9, 129.4, 128.1, 127.7, 125.5, 114.6, 114.1, 94.8, 86.9, 55.3;
MS (EIþ) 322; HRMS (EIþ) predicted for C15H1079Br35ClO 319.9604,
found 319.9604.
4.6. General procedure (E) for the preparation of alkenyl-
substituted indoles; exemplified by the preparation of tert-
butyl 4-chloro-2-(4-methoxyphenyl)-1H-indole-1-carboxylate
(Table 3, entry 1)
DME (0.44 mL) was added to a flask charged with Pd2(dba)3
(5.1 mg, 5.6 mmol), ligand 12 (8 mg, 16.7 mmol), Cs2CO3 (181 mg,
4.6.4. tert-Butyl 4-chloro-2-(3-furyl)-1H-indole-1-carboxylate (Table
3, entry 5). Prepared using General procedure E, employing 3-[(Z)-
1-bromo-2-(2,6-dichlorophenyl)vinyl]furan (100 mg, 0.31 mmol),
0.56 mmol), tert-butyl carbamate (27 mg, 0.23 mmol), 2-[(Z)-2-
bromo-2-(4-methoxyphenyl)vinyl]-1,3-dichlorobenzene (80 mg,
0.22 mmol) and the solution heated at 90 ꢀC for 16 h. The crude
product was filtered through Celite, the Celite washed with DCM
(50 mL), and the crude filtrate was reduced to dryness in vacuo to
give a brown gum. Purification via flash chromatography (SiO2, 10%
ether/petrol) gave the indole as a yellow oil (56 mg, 71%); nmax (thin
film/cmꢁ1) 2979, 1736, 1607, 1506, 1249, 1153; 1H NMR (400 MHz,
CDCl3) 8.10 (dd, J¼6.6, 2.8 Hz, 1H), 7.37 (d, J¼8.6 Hz, 2H), 7.27e7.10
(m, 2H), 6.96 (d, J¼8.6 Hz, 2H), 6.65 (s, 1H), 3.87 (s, 3H), 1.36 (s, 9H);
13C NMR (100 MHz, CDCl3) 159.5, 149.9, 141.0, 137.9, 129.9, 128.0,
126.8, 125.4, 124.5, 122.5, 113.6, 113.3, 107.3, 83.8, 55.3, 27.6; MS
(FIþ) 380, 382; HRMS (FIþ) for C20H2035ClNaNO3 predicted
380.1029, found 380.1024.
Pd2(dba)3 (7.2 mg, 8 mmol, 2.5 mol %), ligand 12 (11.2 mg, 24 mmol),
Cs2CO3 (252 mg, 0.78 mmol) and tert-butyl carbamate (41 mg,
0.35 mmol) in toluene (0.62 mL) to give the indole as a yellow oil
after purification via flash chromatography (SiO2, Et2O/petrol),
(61 mg, 61%); nmax (thin film/cmꢁ1); 1H NMR (400 MHz, CDCl3,)
8.06 (dd, J¼6.0, 0.8 Hz, 1H), 7.65 (m, 1H), 7.49 (m, 1H), 7.20e7.33 (m,
2H), 6.70 (br s, 1H), 6.56 (m, 1H), 1.54 (s, 9H); 13C NMR (100 MHz,
CDCl3) 149.8, 142.3, 140.6, 137.8, 132.9, 127.8, 125.4, 124.7, 122.5,
118.9, 113.9, 112.7, 108.0, 84.4, 27.8; MS (ESþ) 340; HRMS (ESþ)
predicted for C17H1635ClNNaO3 340.0712, found 340.0711.
4.6.5. 1-tert-Butyl 2-ethyl 4-chloro-1H-indole-1,2-dicarboxylate
(Table 3, entry 6). Prepared using General procedure E, employing
ethyl (Z)-2-bromo-3-(2-bromo-6-chlorophenyl)acrylate (100 mg,
4.6.1. tert-Butyl 5-chloro-2-(4-methoxyphenyl)-1H-indole-1-carboxy-
late (Table 3, entry 2). Prepared using General procedure E,
employing 1-bromo-2-[(Z)-2-bromo-2-(4-methoxyphenyl)vinyl]-
0.27 mmol), ligand 12 (9.7 mg, 20.4
0.68 mmol), tert-butyl carbamate (35 mg, 0.3 mmol) and Pd2(dba)3
(6.2 mg, 6.8 mol). Purification by flash chromatography (SiO2, 5%
mmol), Cs2CO3 (220 mg,
m
4-chlorobenzene (78 mg, 0.2 mmol), Pd2(dba)3 (4.5 mg, 5
m
mol),
ether/petrol) gave the indole as a yellow oil (53 mg, 61%); nmax (thin
film/cmꢁ1) 2982, 1734, 1325, 1278, 1212, 1155; 1H NMR (400 MHz,
CDCl3), 7.99 (d, J¼8.4 Hz, 1H), 7.33 (dd, J¼8.4 Hz, 1H), 7.27 (d,
J¼8.4 Hz, 1H), 7.21 (s, 1H), 4.40 (q, J¼7.2 Hz, 2H), 1.64 (s, 9H), 1.42 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 161.5, 148.9, 138.2, 131.2,
127.8, 127.3, 126.5, 123.0, 113.4, 112.4, 85.1, 61.6, 27.8, 14.3; MS (ESþ)
346; HRMS (ESþ) predicted for C16H1835ClO4Na 346.0811, found
346.0817.
ligand 12 (7.2 mg, 15 mol), tert-butyl carbamate (44 mg,
m
0.26 mmol), Cs2CO3 (163 mg, 0.26 mmol) in DME (0.4 mL) gave
a crude black oil. Purification via flash chromatography (SiO2, 5%
Et2O/petrol) gave the indole as a white powder (54 mg, 75%); mp
134e135 ꢀC; nmax (thin film/cmꢁ1) 2953, 2907, 2836, 1726, 1502,
1448, 1245; 1H NMR (400 MHz, CDCl3) 8.12 (d, J¼8.6 Hz, 1H), 7.51
(d, J¼2.0 Hz, 1H), 7.34 (d, J¼8.6 Hz, 2H), 7.27 (dd, J¼8.6, 2.0 Hz, 1H),
6.95 (d, J¼8.6 Hz, 2H), 6.45 (s, 1H), 3.87 (s, 3H),1.36 (s, 9H); 13C NMR
(CDCl3, 100 MHz) 159.4, 150.0, 141.7, 135.6,130.4, 129.9, 128.3, 126.8,
124.0, 119.7, 116.2, 113.3, 108.6, 83.7, 55.3, 27.6; MS (FIþ) 380, 382;
HRMS (FIþ) predicted for C20H2035ClNaNO3 380.1024, found
380.1024.
Acknowledgements
This work was supported by the EPSRC and GlaxoSmithKline.
References and notes
4.6.2. tert-Butyl
6-chloro-2-(4-methoxyphenyl)-1H-indole-1-car-
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5-chlorobenzene (100 mg, 0.25 mmol), Pd2(dba)3 (5.7 mg,
6.2 mmol), ligand 12 (118 mg, 18.6 mmol), Cs2CO3 (201 mg,

6638
L.C. Henderson et al. / Tetrahedron 66 (2010) 6632e6638
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