Synthesis and cross-coupling reactions of substituted 5-triflyloxyindoles

Article abstract of DOI:10.1021/jo050706h

N-Arylsulfonyl quinone monoimines undergo smooth cycloadditions in a [4+2] sense to yield the expected cycloadducts. The crude cycloadducts, when subjected to a short series of simple transformations, produce synthetically useful quantities of 5-triflylox

Full text of DOI:10.1021/jo050706h

SCHEME 1. Plieninger Indole Synthesis
Synthesis and Cross-Coupling Reactions of
Substituted 5-Triflyloxyindoles
Dylan B. England and Michael A. Kerr*
Department of Chemistry, The University of Western
Ontario, London, Ontario, Canada, N6A 5B7
makerr@uwo.ca
SCHEME 2. Strategy for the Formation of
5-Triflyloxyindoles
Received April 8, 2005
N-Arylsulfonyl quinone monoimines undergo smooth cyclo-
additions in a [4+2] sense to yield the expected cycloadducts.
The crude cycloadducts, when subjected to a short series of
simple transformations, produce synthetically useful quanti-
ties of 5-triflyloxyindoles in excellent overall yields. Such
compounds are excellent participants in cross-coupling
chemistry.
of the parent quinone imines could yield 5-hydroxyindoles
or, more importantly, 5-triflyloxyindoles. Such com-
pounds could be important partners in cross-coupling
reactions for the construction of more sophisticated indole
motifs. A survey of the literature reveals only a few
references to the synthesis and reactions of 5-triflyloxy-
indoles (vide infra). Our desire to prepare such com-
pounds is grounded in their potential as starting mate-
rials for a series of benzenoid-substituted indole natural
products. In fact we have recently reported the synthesis
of several such compounds, namely, cis-trikentrin B and
herbindole B.5 In this note we report the efficient
synthesis and cross-coupling reactions of substituted
5-triflyloxyindoles.
The strategy for the formation of 5-triflyloxyindoles via
the Diels-Alder reaction of p-benzoquinone monoimines
is shown in Scheme 2. Issues for consideration are the
regiochemical outcome of the cycloaddition (4 f 5), the
method of aromatization of the initial adduct to a
dihydronaphthalene (5 f 6), regioselective triflylation of
the resulting phenolic group (6 f 8), and subsequent
conversion to the indole (8 f 10 f 12).
The indole moiety remains probably the most studied
of the heteroaromatic compounds. This is due in large
part to the huge number of bioactive natural products
as well as medicinally important unnatural compounds
based on the benzopyrrole skeleton.1 While the 2- and
3-positions of the indole ring system are relatively easy
to functionalize (due to the reactivity of the enamine-
like double bond), the preparation of indoles bearing
complex functionality on the benzenoid portion of the
molecule remains a challenge.
The strategy of converting a 2-aminodihydronaphtha-
lene to a 4-substituted indole (a Plieninger indole syn-
thesis, Scheme 1) has been known for some time2 but has
been scarcely used,3 owing to the lack of a flexible
synthetic approach to the starting material (often by
Birch reduction of a 2-aminonaphthalene). Recently, we
have reported the preparation of highly substituted
5-methoxy- and 5-alkylindoles by oxidative scission of
dihydronaphthalenes, which in turn were prepared by
way of a Diels-Alder reaction of a quinoid imine deriva-
tive.4 It occurred to us that use of the tosyl derivatives
The Diels-Alder reaction of N-arylsulfonyl-p-benzo-
quinone monoimines has been reported6 but scarcely
used. It is known that the tosylimino group dictates the
regiochemistry in the Diels-Alder reaction; that is, it
overrides the carbonyl moiety in terms of stabilization
of the LUMO. Table 1 shows the results of the cyclo-
(1) (a) Gribble, G. W. In Comprehensive Heterocyclic Chemistry, 2nd
ed.; Pergammon Press: New York, 1996; Vol. 2, pp 203-257. (b)
Snieckus V. A. In The Alkaloids; Academic Press: New York, 1968;
Vol. 11, Chapter 1.
(2) a) Plieninger, H.; Voekl, A. Chem. Ber. 1976, 109, 2121. (b)
Plieninger, H.; Suhr, K.; Werst, G.; Kiefer, B. Chem. Ber. 1956, 89,
270.
(3) (a) Maehr, H.; Smallheer, J. J. Am. Chem. Soc. 1985, 107, 2943.
(b) Kraus, G. A.; Yue, S.; Sy, J. J. Org. Chem. 1985, 50, 283. (c)
Tichenor, M. S.; Kastrinsky, D. B.; Boger, B. L. J. Am. Chem. Soc.
2004, 126, 8396.
(4) (a) Banfield, S. C.; England, D. B.; Kerr, M. A. Org. Lett. 2001,
3, 3325. (b) Zawada, P. V.; Banfield, S. C.; Kerr, M. A. Synlett 2003,
971.
(5) Jackson, S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7,
1215.
(6) (a) Rutolo, D.; Lee, S.; Sheldon, R.; Moore, H. W. J. Org. Chem.
1978, 43, 2304. (b) Adams, R.; Reifschneider, W. Bull. Soc. Chem. Fr.
1958, 23.
10.1021/jo050706h CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/07/2005
J. Org. Chem. 2005, 70, 6519-6522
6519

TABLE 1. Diels-Alder/Aromatization Reactions of 4
CHART 1. Acetylation/Triflylation of
Hydroxydihydronaphthalenes
entry
diene
product (yield)
1
2
3
4
5
6
7
8
R1-R6 ) H
6a (80%)
6b (80%)
6c (86%)
6d (95%)a
6e (85%)
6f (68%)
6g (80%)
6h (66%)b
R1 ) Me, R2-R6 ) H
R3,R4 ) Me, R1,R2,R5,R6 ) H
R1,R3 ) Me, R2,R4,R5,R6 ) H
R1,R5 ) CH2CH2, R1,R2,R5,R6 ) H
R1,R4)Me, R2,R6 ) CH2CH2, R3,R5 ) H
R1 ) Ph, R2-R6 ) H
R4 ) Me, R1,R2,R3,R5,R6 ) H
a Isolated as a 4:1 mixture of regioisomers. Major regioisomer
shown. b Isolated as a 2:1 mixture of regioisomers. Major isomer
shown.
addition of N-p-toluenesulfonyl-p-benzoquinone monoimine
47 with a variety of dienes with subsequent aromatiza-
tion. In practice, the cycloaddition was allowed to proceed
at ambient temperature until TLC indicated the complete
disappearance of starting material. At this time a drop
of DBU was added to the reaction mixture and stirred
for 10 min to effect tautomerization to the dihydronaph-
thalene. Several points from the table are worthy of note.
In all cases the tosylimino group dictated the regiochem-
istry. In the case of 1,2-dimethylbutadiene (entry 4) and
isoprene (entry 8), a mixture of regioisomers was formed
in ratios of 4:1 and 2:1, respectively. The mixture of
isomers for adduct 6d might be expected since the two
methyl groups on the diene have contradicting influences
in regiocontrol. For the isoprene adduct 6h, the lack of
reasonable selectivity is less clear to us. In all other cases
the cycloaddition was very regioselective and follows the
literature precedent of Moore.6a It is also notable that
the aromatization was better effected under basic condi-
tions, which is in contrast to our previous experience with
quinone imine ketals.4a
We attempted to prepare 5-hydroxyindoles by oxidative
cleavage of 6; however, under conditions required for
olefin cleavage, the phenolic compound was oxidized to
the quinoid species, in poor yield. We then protected the
phenolic group as either the acetoxy or triflyloxy deriva-
tives (7 and 8, respectively) under standard conditions.
Chart 1 shows the dihydronaphthalene derivatives 7 and
8, which would serve as substrates for our indole syn-
thesis. In most cases the yields of the desired compounds
were excellent; however N-acylation or sulfonylation was
always a consideration and had to be carefully avoided.
With dihydronaphthalenes 7 and 8 in hand, attention
was turned to formation of the indoles. Treatment of 7
and 8 with catalytic osmium tetroxide in the presence of
NMO yielded a diol, which was isolated in crude form
and treated with NaIO4 supported on silica gel.8 The
crude dicarbonyl compounds (9 and 10) were then treated
with several drops of concentrated H2SO4 in tetrahydro-
furan to effect ring closure to the requisite indoles 11 and
12 in generally excellent overall yields (Chart 2). Inter-
estingly, in some cases the intermediate hydroxyindoline
was observed but was converted to the indole upon
prolonged stirring with acid.
To illustrate the utility of the 5-triflyloxyindoles pre-
pared by this method, we selected a typical example (12a)
and subjected it to a series of cross-coupling experiments.
The cross-coupling of 5-triflyloxyindoles has been re-
ported on only several occasions.9 Furthermore, these
types of reactions are typically performed on indoles
unsubstituted on the benzenoid portion of the molecule.
Scheme 3 shows a variety of coupling reactions performed
on an indole derived from 12a. In these cases typical
experimental procedures from the literature were em-
ployed without optimization, with the yields ranging from
good to excellent. In all cases the presence of the aldehyde
in 12a was problematic and appeared to be participating
in the reaction in a manner that remains unknown to
(9) Homogeneous hydrogenation: (a) Engler, T. A.; Wanner, J. J.
Org. Chem. 2000, 65, 2444. (b) Engler, T. A.; Chai, W.; LaTessa, K. O.
J. Org. Chem. 1996, 61, 9297. (c) Yokoyama, Y.; Sagisaka, T.; Mizuno,
Y.; Yokoyama, Y. Chem Lett. 1996, 587. Heck coupling: (d) Barf, T.
A.; Boer, P. de; Wikstroem, H.; Peroutka, S. J.; Svensson, K. A.; Ennis,
M. D.; Ghazal, N. B.; McGuire, J. C.; Smith, M. W. J. Med. Chem.
1996, 39, 4717. (e) Arcadi, A.; Cacchi, S.; Marinelli, F.; Morera, E.;
Ortar, G.; Tetrahedron 1990, 46, 7151. Negishi coupling: (f) Arcadi,
A.; Burini, A.; Cacchi, S.; Delmastro, M.; Marinelli, F.; Pietroni, B.
Synlett 1990, 1, 47. Carbonylation: (g) Frenette, R.; Hutchinson, J.
H.; Leger, S.; Therien, M.; Brideau, C.; Chan, C. C.; Charleson, S.;
Ethier, D.; Guay, J.; Jones, T. R.; McAuliffe, M.; Piechuta, H.;
Riendeau, D.; Tagari, P.; Girard, Y. Bioorg. Med. Chem. Lett. 1999,
2391, 1. Suzuki coupling: (h) Meng, C. Q.; Rakhit, S.; Lee, D. K. H.;
Kamboj. R.; McCallum, K. L.; Mazzocco, L.; Dyne, K.; Slassi, A. Bioorg.
Med. Chem. Lett. 2000, 903.
(7) Dienophile 4 was best prepared by oxidation of N-p-toluene-
sulfonyl-p-hydroxyaniline with NaIO4 supported on silica gel. See
Supporting Information for details.
(8) Zhong, Y. L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
6520 J. Org. Chem., Vol. 70, No. 16, 2005

CHART 2. Preparation of 5-Hydroxyindole
Derivatives
SCHEME 3. Cross-Coupling of a
5-Triflyloxyindolea
a Reaction conditions: (a) NaBH4, MeOH, THF; (b) AcCl, Et3N,
THF (98% overall); (c) NH4CO2H, LiCl, Pd(PPh3)2Cl2, DMF (88%);
(d) MVK, Pd(PPh3)4, Et3N, DMF (65%); (e) CH2dCHSnBu3, LiCl,
Pd(PPh3)2Cl2, DMF (80%); (f) phenylacetylene, Et3N, CuI, LiCl,
Pd(PPh3)2Cl2, DMF (95%); (g) PhB(OH)2, LiCl, Na2CO3, Pd-
(PPh3)2Cl2, DMF (88%).
The organic layer was separated and the aqueous portion
extracted several times with EtOAc. The combined organic
layers were washed with 5% HCl, followed by H2O and brine.
The organic solution was then dried over anhydrous MgSO4,
filtered, and concentrated. The crude solid was purified by
trituration with Et2O to yield 7.57 g (80%) of 6a as a yellow
us. To this end 12a was reduced and protected as an
acetate to furnish a suitable substrate. The addition of
lithium chloride to the reaction mixture was crucial to
the success of the cross-coupling reactions10 with the
exception of the Heck reaction.
In summary we have reported the Diels-Alder reac-
tions of a quinone monoimine with a variety of 1,3-
butadienes to provide, in excellent yields, the expected
cycloadducts. The adducts were aromatized and subjected
to a series of transformations leading to 5-triflyloxy-
indoles. The utility of these compounds was illustrated
by their participation in cross-coupling chemistry. The
use of this chemistry for the synthesis of complex indole-
containing natural products will be the subject of forth-
coming reports from our laboratory.
1
solid: mp 165 °C (dec). H NMR (400 MHz, DMSO-d6): δ 9.43
(s, 1H), 9.10 (s, 1H), 7.52 (d, 2H, J ) 8.2 Hz), 7.33 (d, 2H, J )
8.0 Hz), 6.47 (AB quartet, 2H), 5.79-5.69 (m, 2H), 3.07 (broad
s, 4H), 2.36 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 153.4,
142.7, 138, 133, 129.4, 126.7, 125.7, 125, 123.6, 123.4, 121.5,
111.6, 25.5, 24.2, 21. IR (thin film): νmax 3428, 3271, 2874, 1595,
1468, 1305, 1155. HRMS: calcd for C17H17NO3S 315.0929, found
315.0934.
Typical Procedure for the Triflylation of the Diels-
Alder Adducts. Synthesis of 8a. A suspension of sodium
hydride (1.14 g, 28.5 mmol) in THF (70 mL) was purged with
argon and cooled in a flask to 0 °C. The Diels-Alder adduct 6a
(6.00 g, 19 mmol) dissolved in THF (70 mL) was added to this
suspension via cannula and allowed to stir for 30 min. N-
Phenyltriflimide (8.15 g, 22.8 mmol) in THF (70 mL) was then
added via cannula, and the reaction mixture was stirred for 30
min at 0 °C, followed by another hour at room temperature. The
reaction was partitioned between EtOAc and H2O. The aqueous
layer was extracted several times with EtOAc. The combined
organic layers were washed twice with water and once with
brine. The organic solution was dried over anhydrous MgSO4,
filtered, and concentrated. The mixture was purified by flash
column chromatography on silica (30% EtOAc/hexanes) to yield
Experimental Section
General Procedure for the Diels-Alder Reaction: Prepa-
ration of 6a. The N-p-toluenesulfonyl-p-benzoquinone monoimine
4 (7.84 g, 30 mmol) was added to a sealable tube and dissolved
in CH2Cl2 (30 mL). 1,3-Butadiene (5.68 g, 105 mmol) was
condensed into the tube and the reaction purged with argon.
The tube was sealed and the reaction stirred at room temper-
ature for 2 days, after which time the reaction mixture was
diluted with CH2Cl2 and DBU (8 drops) was added. After 10 min,
the reaction mixture was partitioned between EtOAc and H2O.
1
8a (7.9 g, 93%) as an off-white solid, mp 138-139 °C. H NMR
(400 MHz, CDCl3): δ 7.67 (d, 2H, J ) 8.2 Hz), 7.27 (d, 2H, J )
7.9 Hz), 7.25 (d, 1H, J ) 9.1 Hz), 7.08 (d, 1H, J ) 9.1 Hz), 6.66
(s, 1H), 5.85-5.82 (m, 1H), 5.79-5.75 (m, 1H), 3.37-3.34 (m,
2H), 3.10-3.07 (m, 2H), 2.41 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 145.2, 144.4, 136.3, 133.9, 130.2, 129.9, 128.8, 127.1,
122.5, 122.2, 121.9, 119.2, 25.6, 24.6, 21.6 (CF3 quartet not
observed). 19F NMR (376 MHz, CDCl3): δ -74.2. IR (thin film):
(10) The use of lithium chloride to facilitate palladium-catalyzed
cross-coupling reactions is well documented. See: Farina, V.; Krishnan,
B.; Marshall, D. R.; Roth, G. P. J. Org. Chem. 1993, 58, 5434.
J. Org. Chem, Vol. 70, No. 16, 2005 6521

νmax 3301, 1597, 1475, 1416, 1331, 1210, 1142. HRMS: calcd for
1.6, 1.6 Hz), 8.0 (d, 1H, J ) 9.2 Hz), 7.79 (d, 2H, J ) 8.6 Hz),
7.71 (d, 1H, J ) 3.7 Hz), 7.28 (d, 1H, J ) 9.2 Hz), 7.28 (d, 2H,
J ) 8.0 Hz), 6.62 (d, 1H, J ) 3.7 Hz), 3.99 (d, 2H, J ) 1.6 Hz),
2.38 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 196.1, 145.8, 143.6,
134.8, 133.3, 132.1, 130.2, 128.8, 127, 118.1, 118, 114.1, 106.8,
42.2, 21.6 (CF3 quartet not observed). 19F NMR (376 MHz,
CDCl3): δ -73.9. IR (thin film): νmax 3147, 2927, 1728, 1596,
1476, 1424, 1380, 1214, 1137. HRMS: calcd for C18H14F3NO6S2
461.0215, found 461.0215.
C
18H16F3NO5S2 447.0422, found 447.0418.
Typical Procedure for Indole Formation. Synthesis of
12a. The dihydronaphthalene 8a (3.94 g, 8.8 mmol) was sus-
pended in a 2:1 mixture of THF and H2O (105 mL). A crystal of
osmium tetroxide (<1 mg) was added, and the mixture stirred
for 5 min, giving a black solution, after which NMO (1.24 g, 10.56
mmol) was added portionwise. The solution was stirred until
starting material was consumed by TLC, at which point Na2-
SO3 (about 12 equiv) was added. The mixture was then stirred
for a further 10 min and extracted with EtOAc (3 times). The
combined organic layers were then washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated to yield the crude
diol. The diol was used without further purification and dissolved
in CH2Cl2. NaIO4 supported on SiO2 gel (20.7 g, 14.08 mmol)4
was added to this mixture and stirred vigorously until the
starting material was consumed, as indicated by TLC. The
mixture was filtered, rinsed with CH2Cl2, and concentrated to
yield the crude dialdehyde. The dialdehyde was taken up in dry
THF, treated with concentrated sulfuric acid (15 drops), and
stirred under argon until consumption of the dialdehyde was
indicated by TLC. Solid NaHCO3 was then added, and the
mixture was stirred for 10 min. Anhydrous MgSO4 was added,
and the mixture was stirred for another 10 min. Filtration and
concentration yielded the crude indole, which was purified by
column chromatography on silica gel using 20% EtOAc/hexanes.
The solid was isolated as an off-white solid (3.74 g, 92% overall),
mp 83-85 °C. 1H NMR (400 MHz, CDCl3): δ 9.71 (t, 1H, J )
Acknowledgment. We thank the Natural Sciences
and Engineering Research Council of Canada, Medmira
Laboratories Inc., the Ontario Ministry of Science and
Technology, and GlaxoSmithKline for funding. Acknowl-
edgment is made to the Donors of the American Chemi-
cal Society Petroleum Research Fund, for partial sup-
port of this research. We are grateful to Mr. Doug
Hairsine for performing MS analyses. D.B.E. is a
recipient of an OGSST and an NSERC (PGSB) scholar-
ship.
Supporting Information Available: Complete experi-
mental procedures as well as 1H NMR, 13C NMR, IR, and MS
analysis data for compounds 4, 6-8, and 11-18. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO050706H
6522 J. Org. Chem., Vol. 70, No. 16, 2005