Sequential one-pot InBr3-catalyzed 1,4-then 1,2-nucleophilic addition to enones

Article abstract of DOI:10.1021/jo0163243

Low sensitivity toward traces of moisture and high tolerance of different functional groups make indium tribromide suitable for carrying out multistep synthetic sequences. In particular, we have realized a 1,4-conjugated addition of indoles/thiols to α,β-

Full text of DOI:10.1021/jo0163243

3700
J . Org. Chem. 2002, 67, 3700-3704
Sequ en tia l On e-P ot In Br 3-Ca ta lyzed 1,4- th en 1,2-Nu cleop h ilic
Ad d ition to En on es
Marco Bandini, Pier Giorgio Cozzi,* Massimo Giacomini, Paolo Melchiorre, Simona Selva, and
Achille Umani-Ronchi*
Dipartimento di Chimica “G. Ciamician”, Universita` degli Studi di Bologna,
via Selmi 2, 40126 Bologna, Italy
pgcozzi@ciam.unibo.it, umani@ciam.unibo.it
Received November 27, 2001
Low sensitivity toward traces of moisture and high tolerance of different functional groups make
indium tribromide suitable for carrying out multistep synthetic sequences. In particular, we have
realized a 1,4-conjugated addition of indoles/thiols to R,â-unsaturated ketones mediated by a catalytic
amount (10 mol %) of InBr3 obtaining the desired â-substituted ketones in good yields. The Lewis
acidity of indium salts was not affected by coordinating and acid nucleophiles; therefore, the
subsequent catalytic 1,2-addition of Me3SiCN to carbonyl compounds can be performed in one pot.
With the optimized atom-efficient protocol, several polyfunctionalized R-silyloxy cyanohydrins were
synthesized in good to excellent yields (up to 97%) and a notable level of simple 1,3-diastereoselection
(up to 84:16) was recorded in the case of 2-cyclohexen-1-one 2c.
Synthetic multistep procedures for the synthesis of two
reaction of ketones bearing strong coordinating groups
using Me3SiCN as the cyano source.10
carbon-carbon bonds catalyzed by single multiacting
Lewis acids are poorly documented,1 and several ma-
nipulations of functional groups (protection, activation,
etc.) are required.2 With the aim of designing a Lewis
acid-mediated one-pot multistep transformation, we have
focused our efforts on the identification of a Lewis acid
capable of catalyzing two subsequent synthetic transfor-
mations without deactivation by the presence of coordi-
nating compounds. Recently, indium salts have emerged
as powerful catalysts in many chemical processes both
in aqueous and organic media.3 For instance, indium
halides are effectively used in promoting the rearrange-
ment of epoxides,4 in the synthesis of R-amino phospho-
nates5 and quinolines,6 in transesterification processes,7
and in the opening reaction of epoxides with nucleo-
philes.8
The conjugate addition of nucleophiles to enones
produces a carbonyl substrate that could react subse-
quently with Me3SiCN (Scheme 1). However, only par-
ticular nucleophiles are suitable for this purpose. In fact,
the nucleophile should contain an acidic proton capable
of protonating the intermediate metallo-enolate of the
Michael addition (Scheme 2a). On the other hand, if the
intermediate enolate is quenched by a scavenger (i.e., a
silylating agent) that traps the carbonyl group, the
successive 1,2-addition reaction cannot take place (Scheme
2b). Indoles and thiols are adapted to this purpose.
Con ju ga te Ad d ition of In d oles to r,â-Un sa tu r a ted
Keton es Ca ta lyzed by In Br 3. In the last few years,
several Lewis acid-mediated Friedel-Crafts-type addi-
tions of electron-rich aromatic compounds (i.e., indoles)
to enones, in the presence of a catalytic or stoichiometric
amount of Lewis acids, have been published.11,12
This class of aromatic substitution reactions plays a
relevant role in organic synthesis. In fact, the â-indolyl-
ketones obtained are highly interesting building blocks
for the synthesis of biologically active compounds and
natural products. We found that indoles smoothly reacted
with enones at room temperature in the presence of a
catalytic amount of InBr3 (10 mol %) affording the desired
adduct in high yields (Scheme 3).13
In this context, it is worthy to note that, due to the
remarkable tolerance of indium salts toward coordinating
functional groups, even strong coordinating amines can
be used in the presence of indium trichloride.9 We have
taken advantage of this compatibility in developing a
practical and simple methodology for the cyanation
(1) For catalytic tandem processes, see: (a) Ghosh, A. K.; Kawahama,
R. Tetrahedron Lett. 1999, 40, 1083. (b) J eong, N.; Seo, S. D.; Shin, J .
Y. J . Am. Chem. Soc. 2000, 122, 10220. (c) Yamasaki, S.; Kanai, M.;
Shibasaki, M. J . Am. Chem. Soc. 2001, 123, 1256. (d) Bielawski, C.
W.; Louie, J .; Grubbs, R. H. J . Am. Chem. Soc. 2000, 122, 12872. (e)
Louie, J .; Bielawski, C. W.; Grubbs, R. H. J . Am. Chem. Soc. 2001,
123, 11312. (f) Giusepponi, N.; Collin, J . Tetrahedron 2001, 57, 8989.
(2) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S.
Angew. Chem., Int. Ed. 2000, 39, 44.
Substituted and unsubstituted indoles can be utilized
in the optimized procedure (Table 1). 2-Methyl-indole 2c
furnished higher conversions in comparison to other
(3) (a) Ranu, B. C. Eur. J . Org. Chem. 2000, 2347. (b) Chauhan, K.
K.; Frost, C. G. J . Chem. Soc., Perkin Trans. 1 2000, 3015.
(4) Ranu, B. C.; J ana, U. J . Org. Chem. 1998, 63, 8212.
(5) Ranu, B. C.; Hajra, A.; J ana, U. Org. Lett. 1999, 1, 1141.
(6) Ranu, B. C.; Hajra, A.; J ana, U. Tetrahedron Lett. 2000, 41, 531.
(7) Ranu, B. C.; Dutta, P.; Sarkar, A. J . Org. Chem. 1998, 63, 6027.
(8) (a) Amantini, D.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J . Org.
Chem. 2001, 66, 6734. (b) Fringuelli, F.; Pizzo, F.; Vaccaro, L. J . Org.
Chem. 2001, 66, 3554.
(10) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A.
Tetrahedron Lett. 2001, 42, 3041.
(11) (a) Clay catalyst: Iqbal, Z.; J ackson, A. H.; Rao, K. R. N.
Tetrahedron Lett. 1988, 29, 2577. (b) BF3‚OEt2: Dujardin, G.; Poirier,
J .-M. Bull. Soc. Chim. Fr. 1994, 131, 900. (c) Yb(OTf)3: Harrington, P.
E.; Kerr, M. A. Synlett 1996, 1047. (d) Sc(DS)3: Manabe, K.; Aoyama,
N.; Kobayashi, S. Adv. Synth. Catal. 2001, 343, 174.
(12) For a comprehensive review focused on the asymmetric catalytic
arylation reaction, see: Bolm, C.; Hildebrand, J . P.; Mun˜iz, K.;
Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284.
(9) Reddy, L. R.; Reddy, M. A.; Bhanumathi, N.; Rao, K. R. New J .
Chem. 2001, 25, 221.
10.1021/jo0163243 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/04/2002

InBr3-Catalyzed 1,4- then 1,2-Nucleophilic Addition to Enones
J . Org. Chem., Vol. 67, No. 11, 2002 3701
Ta ble 1. Mich a el Ad d ition of In d oles to En on es
Sch em e 1
a
Ca ta lyzed by In Br 3
Sch em e 2
Sch em e 3
indoles 2a and 2b (entries 1 and 3, Table 1). The catalytic
action of the indium tribromide is evident by comparing
the procedure for the 2-cyclohexen-1-one (InBr3 10 mol
%, 2-Me-indole 1.5 equiv, yield ) 95%) with the same
reaction in the absence of catalyst. In this case, the
reaction did not occur at all after 3 days (entry 4). The
reaction seems to occur via a classic Friedel-Crafts
alkylation pathway.12 The NH proton of the indole does
not play a significant role in the turnover of the catalytic
cycle (entries 2 and 9, Table 1). The reaction can be also
performed using reagent-grade CH2Cl2 and does not
require strictly anhydrous conditions (entries 3, 4, 6, and
8, Table 1).
When R,â-unsaturated carbonyl compounds are used,
the procedure appeared to be effective for both cyclic and
acyclic substrates, and no significant effects of bulky
aromatic substituents toward the carbonyl moiety were
observed (entries 11 and 12). Of special interest is the
result obtained with the symmetric enone dibenzyli-
denacetone (entry 13, Table 1). In this case, the presence
of 10 mol % InBr3 guarantees the double-conjugate 1,4-
addition forming two C-C bonds in one pot in excellent
isolated yield (95%). Finally, when the procedure did not
a
All reactions were carried out in anhydrous CH2Cl2 at room
b
temperature, employing 10 mol % InBr3. Chemical yields are
given on the isolated product after chromatographic purification.
c Reaction was run in the absence of catalyst. Dry PrOH was
added (3 equiv with respect to the enone). e Undried CH2Cl2 was
utilized as the solvent.
d
i
afford acceptable conversions (entries 1, 2, 4, and 8), for
instance, when the less electron-rich indole 2a was
utilized as the nucleophile, the presence of an external
proton source (3 equiv of PrOH) was beneficial for
improving the chemical yields (entries 1 and 2).
(13) During the preparation of this paper, J . S. Yadav et al.
independently described the catalytic addition of pirroles and indoles
to electron-deficient olefins in the presence of InCl3: Yadav, J . S.;
Abraham, S.; Reddy, B. V. S.; Sabitha, G. Tetrahedron Lett. 2001, 42,
8063. Yadav, J . S.; Abraham, S.; Reddy, B. V. S.; Sabitha, G. Synthesis
2001, 2165.
i

3702 J . Org. Chem., Vol. 67, No. 11, 2002
Bandini et al.
Sch em e 4
thiols (4a -c) and with numerous cyclic and acyclic
ketones. Products 5 were isolated in good yields (65-90%
after flash chromatography) and fully characterized.
Even in the case of thiols, the reaction outcome is strictly
correlated to the presence of InBr3. In fact, the uncata-
lyzed procedure (1a , PhSH 1.5 equiv) gave after 2 days
only 6% of the desired ketone (entry 1, Table 2). Finally,
it is interesting to note that the indium-catalyzed pro-
cedure allowed also the addition of substituted aryl thiols
such as the commercially available thiolsalicylic 4c acid
to 1c affording the desired product in excellent yield after
crystallization (entry 8, Table 2).
Ta ble 2. Mich a el Ad d ition of Ar yl Th iols to En on es
a
Ca ta lyzed by In Br 3
Th e On e-P ot 1,2-1,4-Ad d ition of In d oles/Th iols
a n d TMSCN to r,â-Un sa tu r a ted Keton es. The excel-
lent results obtained by InBr3 in promoting both the
cyanation process and the 1,4-addition prompted us to
design and optimize synthetic strategies for one-pot atom-
efficient catalyzed processes. The optimized reaction
conditions involve the initial catalytic 1,4-Michael addi-
tion of the appropriate nucleophile to the enone (checked
by TLC and GC, 16-24 h) and the subsequent 1,2-
addition of TMSCN. The one-pot addition of Me3SiCN to
the resulting â-substituted ketone took place smoothly
as shown by the data in Table 3.
Noteworthy is the simple stereoselectivity obtained
using 2-methyl-indole 2c. In fact, while with unsubsti-
tuted indole 2a and acyclic enones a 1:1 mixture of
diastereoisomers was generally obtained (entries 1, 2, 5,
and 6, Table 3), with 2-methyl indole 2c, the R-silyloxy-
γ-indolyl nitriles 8 and 9 were isolated with good dia-
stereoselection (74:26 and 84:16 cis-1,3-OTMSTInd as
the major diastereoisomer) for 2-cyclopenten-1-one and
2-cyclohexen-1-one, respectively (entries 3 and 4, Table
3). The relative configuration of the prevalent 1,3-cis
diastereoisomer 9 was assigned by X-ray analysis (see
Supporting Information).
The simple diastereoselection observed is notable
because, although the asymmetric induction of stereo-
genic centers near to the carbonyl moieties are well
studied, 1-3 inductions are less investigated. The ster-
eochemical trend observed, however, appeared to be
strictly affected by the nature of the ketone as well. In
fact, with the more flexible 2-cyclopenten-1-one, the
diastereoselection obtained after the cyanation process
was lower (entry 3, Table 3).
In general, the products were isolated as silylated
cyanohydrins after flash chromatography in good yields.
The power of the process is summarized by the one-pot
procedure carried out with 2-cyclohexen-1-one. In this
case, the desired indolyl-cyano derivative 9 was isolated
in 87% yield using only 1 mol % InBr3 (entry 4, Table 3).
Moreover, the ability of InBr3 in promoting double-
conjugate addition and cyanation sequential on the
dibenzylidenacetone allows the one-pot formation of three
carbon-carbon bonds with an almost quantitative yield
(97%, entry 6, Table 3).
a
All reactions were carried out in anhydrous CH2Cl2 at room
b
temperature, employing 10 mol % InBr3. Chemical yields are
given on the isolated product after chromatographic purification.
c Reaction was run in the absence of catalyst.
Con ju ga te Ad d ition of Th iols to r,â-Un sa tu r a ted
Keton es Ca ta lyzed by In Br 3. 1,4-Selective addition of
thiols is a very important reaction for the synthesis of
biologically active products such as the calcium antago-
nist diltiazem.14 In the literature, a large number of
conjugate additions based on the activation of thiols by
bases have been reported.15 In contrast, only a few re-
ports on the addition of thiols by activation of acceptors
with Lewis acids are known.16 Addition of sulfur nucleo-
philes to enones has been carried out in a similar way
by the use of InBr3 (Scheme 4). In Table 2 we report a
list of representative results obtained with aromatic
This InBr3-promoted one-pot multistep process can be
carried out for 1,4-Michael addition of thiols to an enone
and subsequent 1,2-cyanation reaction of the carbonyl
moiety. In Table 3 (entries 6-8), we collected some
representative results obtained for the case of R,â-
unsaturated cyclic and acyclic enones 11-13. Noteworthy
is the reaction of 2-cyclohexen-1-one 1b and p-Me-
thiophenol in the presence of 10 mol % catalyst that gave
the desired R-silyloxy-γ-thiophenol nitriles 13 with mod-
erate 1,3-diastereoselectivity (75:25, yield ) 69%).
(14) Sheldon, R. A. Chirotechnologies, Industrial Synthesis of Opti-
cally Active Compounds; Dekker Publishing: New York, 1993.
(15) Chiral bases such as amino alcohols, lithium thiolate complexes
of amino bis-ether, and lanthanoid (binaphthoxide) were also exten-
sively utilized in promoting the 1,4-addition. See: Hiemstra, H.;
Wiberg, H. J . Am. Chem. Soc. 1981, 103, 417. Suzuki, K.; Ikekawa,
A.; Mukaiyama, T. Bull. Soc. Chem. J pn. 1982, 55, 3277. Yamashita,
H.; Mukaiyama, T. Chem. Lett. 1985, 363. Nishimura, K.; Ono, M.;
Nagaoka, Y.; Tomioka, K. J . Am. Chem. Soc. 1997, 119, 12974. Emori,
E.; Arai, T.; Sasai, H.; Shibasaki, M. J . Am. Chem. Soc. 1998, 120,
4043.
(16) Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J . Am. Chem. Soc.
1999, 121, 8675 and refs cited therein.

InBr3-Catalyzed 1,4- then 1,2-Nucleophilic Addition to Enones
J . Org. Chem., Vol. 67, No. 11, 2002 3703
Ta ble 3. On e-P ot 1,2-1,4-Ad d ition to En on es Ca ta lyzed
as the internal standard (deuteriochloroform δ ) 77.0 ppm;
deuteriodimethyl sulfoxide δ ) 39.0 ppm). GC-MS spectra were
recorded with GC injection and EI ionization at 70 eV. They
are reported as m/z (relative intensity). Flash column chro-
matographies were run over 270-400 mesh silica gel. Anhy-
drous CH2Cl2 was purchased and used as received. All the
commercially available ketones were freshly distilled or crys-
tallized before use. The R,â-usaturated ketones 1d ,17 1e,18 1f,17
and 1g17 were synthesized following the literature. X-ray
analysis was performed on a diffractomer equipped with a
CCD detector and graphite monochromated Mo ΚR radiation
(λ ) 0.71073 Å). The data handling was performed using the
SMART software package. IR spectra of neat compounds are
expressed as wavenumbers (cm-1).
by In Br 3
Typ ica l Exp er im en ta l P r oced u r e for th e Ca ta lytic
Ad d ition of Th iop h en ols a n d In d oles to r,â-Un sa tu r ed
Keton es Med ia ted by An h yd r ou s In Br 3. A flamed two-
necked flask was charged, under a nitrogen atmosphere, with
2 mL of anhydrous CH2Cl2, InBr3 (11 mg, 0.03 mmol), and 0.3
mmol of carbonyl compound. The mixture was stirred until
the indium tribromide was completely dissolved. Finally, the
desired nucleophile (0.45 mmol) was added.19 This clear
solution was then stirred at room temperature until the
disappearance of the ketone (16-24 h, checked by TLC). Then,
the reaction was quenched with
a saturated solution of
NaHCO3 (3 mL) and extracted with Et2O (3 × 3 mL). The
organic phases were combined, dried over Na2SO4, and con-
centrated under reduced pressure, and the crude mixture was
purified by flash chromatography.
3-(3-In d olyl)-cyclop en ta n -1-on e (3a a ): yield 85% (with
3 equiv of iPrOH); 6:4 cHex/Et2O; 1H NMR (200 MHz, CDCl3)
δ 2.14-2.33 (m, 2 H), 2.37-2.52 (m, 3 H), 2.72-2.85 (m, 1 H),
3.63-3.3.82 (m, 1 H), 7.00 (d, J ) 2.2 Hz, 1 H), 7.16-7.26 (m,
2 H), 7.38-7.42 (m, 1 H), 7.63 (dd, J ) 1.1 Hz, J ) 7.6 Hz, 1
H), 8.06 (br, 1 H); 13C NMR (50 MHz, CDCl3) δ 29.74, 33.56,
38.07, 45.21, 111.27, 118.06, 118.82, 119.12, 119.90, 121.99,
126.36, 136.50, 219.67; GC-MS m/z (rel intensity) 63 (8), 89
(10), 115 (25), 143 (100), 156 (22), 170 (36), 199 (69); IR (neat)
3409, 2957, 2924, 1733, 1457, 1400, 1229, 742 cm-1; Anal.
Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03. Found: C,
78.21; H, 6.52, N, 7.01.
Typ ica l Exp er im en ta l P r oced u r e for th e Ca ta lytic
On e-P ot Ad d ition of Th iop h en ols/In d oles a n d TMSCN
to r,â-Un sa tu r ed Keton es Med ia ted by In Br 3. A flamed
two-necked flask was charged, under a nitrogen atmosphere,
with 2 mL of anhydrous CH2Cl2, InBr3 [0.03 mmol (1 mol %)
or 0.3 mmol (10 mol %)], and 3 mmol of carbonyl compound.
The mixture was stirred until the indium tribromide was
completely dissolved, and then the desired nucleophile [thiol
or indole (4.5 mmol)] was added. This clear solution was then
stirred at room-temperature overnight (about 18 h) until the
disappearance of the starting R,â-unsatured ketone (checked
by TLC and GC-MS). The chromatographic analysis detected
the formation of the 1-4 conjugate addition adduct. TMSCN
(9 mmol) was added by syringe, and the mixture was stirred
at room temperature for 3 h. Finally, the reaction was
quenched with a saturated solution of NaHCO3 (3 mL) and
extracted with Et2O (3 × 3 mL). The organic phases were
combined, dried over Na2SO4, and concentrated under reduced
pressure, and the crude mixture was purified by flash chro-
matography.
a
All reactions were carried out in anhydrous CH2Cl2 at room
b
temperature, employing 10 mol % InBr3. Chemical yields are
given on the isolated product after chromatographic purification.
c Relative configuration was assigned on the basis of GC retention
times and 1H and 13C NMR signals in comparison to the cis/trans
d
diastereoisomers 9. Reaction was carried out in dry toluene.
e Reaction was run in the presence of 1 mol % InBr3. f Relative
configuration was not assigned.
In summary, the unique properties of indium tribro-
mide allowed us to introduce new concepts of one-pot
multistep organic synthesis mediated by Lewis acids and
suggest indium salts as a possible answer for the
increasing demand of clean and atom-efficient carbon-
carbon bond-forming processes. In fact, such a class of
weak Lewis acids could be the right choice for performing
subsequent organic transformations with high overall
yields. Further studies addressing the extension of these
concepts to different organic reactions and to an enan-
tioselective version of chiral Lewis acid-catalyzed trans-
formations will be explored in our laboratory.
1-Cya n o-1-tr im eth ylsilyloxy-3-(2-m eth yl-3-in d olyl)-cy-
cloh exa n e (9): yield 87%; 85:15 cHex/Et2O; diastereomeric
1
mixture ) 84:16; H NMR (200 MHz, CDCl3) δ 0.25 (s, 9 H),
1.65-1.98 (m, 4 H), 2.18-2.35 (m, 2 H), 2.42 (s, 3 H), 2.38-
2.44 (m, 2 H), 3.07-3.18 (m, 1 H), 7.05-7.15 (m, 2 H), 7.27-
7.30 (m, 1 H), 7.59-7.64 (m, 1 H), 7.74 (br, 1 H); 13C NMR (75
MHz, CDCl3) δ (major diasteroeisomer) 1.51, 11.97, 23.46,
26.87, 30.90, 39.39, 45.39, 71.98, 100.12, 110.47, 113.49,
Exp er im en ta l Section
1
Gen er a l. Chemical shifts of H NMR spectra are given in
parts per million with respect to TMS, and coupling constants
J
are measured in hertz. Data are reported as follows:
(17) Pitts, M. R.; Harrison, J . R.; Moody, C. J . J . Chem. Soc., Perkin
Trans. 1 2001, 955.
(18) Kohler, B. J . Am. Chem. Soc. 1933, 55, 6920.
(19) For the procedure employing iPrOH, the secondary alcohol was
added after the nucleophiles.
chemical shifts, multiplicity (s ) singlet, d ) douplet, t )
triplet, q ) quartet, br ) broad, m ) multiplet). 13C NMR
spectra were with complete proton decoupling. Chemical shifts
are reported in parts per million from TMS with the solvent

3704 J . Org. Chem., Vol. 67, No. 11, 2002
Bandini et al.
118.74, 120.58, 121.74, 130.29, 135.19; (minor diastereoisomer)
δ 1.22, 12.05, 20.75, 29.29, 99.89, 110.17, 114.07, 122.68,
130.09; GC-MS m/z (rel intensity) 59 (2), 73 (15), 115 (12), 130
(20), 144 (100), 157 (41), 170 (41), 184 (31), 221 (16), 258 (30),
283 (39), 311 (9), 326 (72); IR (neat) 3410, 3049, 2942, 2864,
2250, 1692, 1613, 1461, 1253, 1124, 848, 735 cm-1; Anal. Calcd
for C19H26N2OSi: C, 69.89; H, 8.03; N, 8.58. Found: C, 69.77;
H, 7.97; N, 8.57.
to Mr. Andrea Garelli (University of Bologna) for some
experimental suggestions.
Su p p or tin g In for m a tion Ava ila ble: Physical properties
and spectroscopic data for the compounds 3a b, 3a c, 3bc, 3ca ,
3cc, 3d a , 3d c, 3d d , 3ec, 3fc, 3h c, 3gc, 5a a , 5a b, 5ba , 5ca ,
5cb, 5eb, 5h b, 5cc, 6-8, and 10-13; tables of crystal data
for the compound 9 (bond lengths and angles, atomic coordi-
nates, and anisotropic thermal parameters); and the relative
configuration of the prevalent 1,3-cis diastereoisomer 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This work was financially sup-
ported by MURST - Rome - (Progetto Nazionale
Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni), COST 12 and by Bologna University
(Funds for selected research Topics). We are grateful
J O0163243