Asymmetric diels-alder reactions of vinylindoles using organocatalysis

Article abstract of DOI:10.1055/s-0029-1217046

The different behavior of 3- and 2-vinylindoles in Diels-Alder cycloaddition reactions in the presence of bifunctional hydrogen bond donor organocatalysts is described.

Full text of DOI:10.1055/s-0029-1217046

FEATURE ARTICLE
161
Asymmetric Diels–Alder Reactions of Vinylindoles Using Organocatalysis
Asymmetric
D
iel
l
s–Alde
a
r
Reactions
u
of
V
inylind
d
ole
s
U
sing
O
i
rganoc
o
a
talysis Gioia, Luca Bernardi,* Alfredo Ricci*
Department of Organic Chemistry ‘A. Mangini’, University of Bologna, viale Risorgimento 4, 40136 Bologna, Italy
Fax +39(051)2093654; E-mail: nacca@ms.fci.unibo.it; E-mail: ricci@ms.fci.unibo.it
Received 28 July 2009; revised 8 September 2009
Alder reactions has attracted greater attention, and has
been extensively studied with great success.9 Most of the
reported organocatalysts were ammonium salts of second-
ary amines and the general mode of catalysis was the gen-
eration of iminium cations as active intermediates. In
2003, shortly after the demonstration by Schreiner that
achiral thiourea derivatives can activate a,b-unsaturated
carbonyl compounds in [4+2] cycloadditions,10a,b Rawal
reported that TADDOL catalyses asymmetric hetero-
Diels–Alder reactions.10c,d This achievement marks the
first successful and general application of enantioselec-
tive hydrogen-bonding catalysis to cycloaddition reac-
tions.
Abstract: The different behavior of 3- and 2-vinylindoles in Diels–
Alder cycloaddition reactions in the presence of bifunctional hydro-
gen bond donor organocatalysts is described.
Key words: asymmetric catalysis, Diels–Alder reactions, kinetic
resolution, organocatalysis, vinylindoles
Introduction
The Diels–Alder-type reaction, a powerful and helpful
tool for the formation of C–C bonds in synthetic organic
chemistry, allows facile entry into cyclic and polycyclic
compounds;1 a tremendous effort has been devoted to the
development of catalytic versions of this reaction. Asym-
metric variants of [4+2]-catalyzed cycloadditions have
been reported for various diene–dienophile combinations
leading to important building blocks for the total synthesis
of bioactive natural products.2 Whereas traditionally over
the past decades catalysis has mainly resulted from the ac-
tivity of Lewis acids,3 there is a growing realization that
cycloaddition reactions can be performed under metal-
free catalysis.
Organocatalysts operating through hydrogen bonds, clas-
sified according to Jeffrey into strong, moderate, and
weak,11 may offer interesting perspectives for the devel-
opments of previously unknown cycloaddition reactions,
mimicking enzymatic catalysis. Our interest in applying
organocatalysis in asymmetric synthesis12 and seminal
contributions to asymmetric Diels–Alder reactions of 2-
pyrones and anthrones with bifunctional organic
catalysts13 led us to become interested in whether the clas-
sical Diels–Alder reaction would be promoted by nonco-
valent interactions occurring between a bifunctional
organocatalyst and the reaction partners. Thus, recently,
we embarked on a quest to develop the first direct organo-
catalytic enantioselective Diels–Alder reaction between
3-vinylindoles as versatile heterocyclic diene components
and activated dienophiles.14 To our knowledge only one
report has appeared so far in the literature on asymmetric
Diels–Alder reactions of vinylindoles with chiral auxilia-
ry based carbodienophiles leading to the expected cy-
Over the years, the structures of various secondary metab-
olites have led to an array of provocative proposals that
suggest that Nature might also make use of the Diels–
Alder reaction via enzymatic catalysis. The prospect of
using in catalysis a Diels–Alderase is therefore especially
enticing. Though until recently this discovery remained
quite elusive, catalysis of Diels–Alder cycloaddition reac-
tion by enzymes,4 rybozymes,5 and deoxyribozymes6 has,
indeed, been realized. Hilvert and Schultz were the first to
report the catalysis of the Diels–Alder cycloaddition reac-
tion by an antibody,7 providing an illustrative example of
the key role played by antibodies in mediating a wide va-
riety of transformations including enantioselective pro-
cesses.
cloadducts
in
low
yields
but
excellent
diastereoselectivity.15 Our study was also motivated by
the versatility of the [b]annulation of the indole nucleus
via cycloaddition with vinylindoles for the construction of
azapolyheterocycles.16 The synthesis of various types of
alkaloids has been carried out in the past by this
approach17 as it represents one of the most direct and ver-
satile preparations of the indoline and tetrahydrocarbazole
nuclei, found in numerous naturally occurring alkaloids
and in synthetic analogues of medicinal importance.18
However, in common with metal complexes and en-
zymes, small organic molecules may also promote chem-
ical transformations. Organocatalysis, an increasingly
important segment of organic chemistry, provides a
means of accelerating chemical reactions with a substo-
ichiometric amount of an organic molecule that does not
contain a metal element.8 Recently, the use of organocat-
alysts for enantioselective Diels–Alder and hetero-Diels–
Herein we report the results of a general investigation
aimed at providing a detailed overview of the reaction fea-
tures occurring in the cycloaddition reactions of 3- and 2-
vinylindole with various dienophiles and at highlighting
the differential behavior occurring between 3- and 2-vi-
nylindoles under hydrogen-bond-driven organocatalysis.
SYNTHESIS 2010, No. 1, pp 0161–0170
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Advanced online publication: 19.10.2009
DOI: 10.1055/s-0029-1217046; Art ID: E25009SS
© Georg Thieme Verlag Stuttgart · New York

162
C. Gioia et al.
FEATURE ARTICLE
visioned
a
scenario where the catalyst might
Results and Discussion
simultaneously raise the energy of the HOMO of the diene
At the outset of our investigations on the development of and lower the energy of the LUMO of the dienophile
a catalytic enantioselective Diels–Alder reaction of 3- and while orienting the two reactants to exert stereochemistry
2-vinylindoles, we turned our attention to bifunctional control. Guided by this hypothesis we considered a series
catalysts bearing hydrogen bond donor frameworks and of bifunctional organic catalysts (Figure 1) for the devel-
acceptor motifs.19 These organic molecules have proven, opment of an asymmetric Diels–Alder cycloaddition reac-
in the past, to be exceptionally effective in activating and tion of vinylindoles. The mild acidic nature of the
organizing the nucleophiles and the electrophiles, respec- screened catalysts, based on the (thio)urea or amide mo-
tively, leading to a stabilized, well-organized transition tifs, was dictated by the rather acid-sensitive nature of the
state giving the products with high selectivity in a variety vinylindoles.
of organic reactions. In particular, to find a suitable cata-
lytic system for the [4+2]-cycloaddition reaction, we en-
The asymmetric Diels–Alder reaction of 3-vinyl-1H-in-
dole (1a) with N-phenylmaleimide (2a) was investigated
Biographical Sketches
Claudio Gioia studied in- nal project dealing with or- suing his Ph.D. studies at
dustrial chemistry at the ganocatalytic
enantio- the same university, work-
University of Bologna (I), selective Diels–Alder cy- ing on the development of
where he received his B.Sc. cloadditions of 3-vinylin- new organocatalytic asym-
in 2006, and his M.Sc. in doles (supervisor Prof. A. metric transformations.
2008 (cum laude), with a fi- Ricci). He is currently pur-
Luca Bernardi studied in- chemistry working in the returned to Bologna, work-
dustrial chemistry at the group of Prof. A. Ricci at ing on the development of
University of Bologna (I) the University of Bologna new organocatalytic trans-
and at the University of and Prof. K. A. Jørgensen, formations. He was the re-
Kent (UK), receiving his at the University of Aarhus cipient of the C.I.N.M.P.I.S.
B.Sc. (Distinction) and (DK), which were complet- award in 2004, and of the
M.Sc. (cum laude) in 1998 ed in 2004. After a post-doc- Thieme Journal Prize in
and 2000, respectively. He toral stay in Aarhus as 2009.
then carried out his Ph.D. fellow of the Danish Nation-
studies in synthetic organic al Research Foundation he
Alfredo Ricci studied University of Bologna Marseille, and Barcelona
Chemistry at the University where he is Head of the De- and in several Japanese Uni-
of Bologna and after gradu- partment of Organic Chem- versities as Fellow of the
ation in 1964 he worked for istry and Vice-Dean of the Japan Society for the Pro-
one year as a NATO Fellow Faculty. His research inter- motion of Science. He has
at UCL London under the ests span target-oriented or- co-authored over 280 papers
guidance of Prof. J. H. Ridd. ganic
synthesis, and several patents and is
In 1975 he was appointed organometallic chemistry, the Editor of two Wiley-
full Professor in Organic development of unconven- VCH books: Modern Ami-
Chemistry at the University tional synthetic methodolo- nation Methods (2000) and
of Florence, where subse- gies, and metal-mediated The Amino Group Chemis-
quently he spent part of his catalysis. More recently or- try: from Synthesis to the
career covering for many ganocatalysis and the as- Life Sciences (2008). In
years the roles of Head of sembly and the applications 2000 he was the recipient of
Department and Director of of nanobioreactors entered the ‘French-Italian Prize for
a National Research Coun- into his research activities. Organic Synthesis’, in 2005
cil (CNR) Center. Since As a Visiting Professor he of the ‘Angelo Mangini
1990 he has held an appoint- has spent several periods at Gold Medal’ and in 2006
ment at the Faculty of In- the Universities of Paris, and 2007 of the Merck-
dustrial Chemistry of the Bordeaux,
Toulouse, IRBM ADP Grant.
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Diels–Alder Reactions of Vinylindoles Using Organocatalysis
163
CF3
CF3
H
S
S
S
S
H
N
H
N
H
F3C
N
H
N
H
N
N
H
F3C
N
H
N
H
OH
OH
OH
OH
H
IV
I
II
III
N
N
N
CF3
CF3
OMe
OMe
OMe
S
O
N
OH
N
N
N
N
N
N
CF3
CF3
H
H
H
H
H
H
H
V
VI
VII
N
N
N
CF3
OMe
OMe
CF3
OMe
O
S
S
H
N
N
N
N
H
N
N
N
CF3
CF3
N
H
H
H
H
H
H
VIII
IX
X
Figure 1 Bifunctional organic catalysts tested in the asymmetric Diels–Alder cycloadditions of 3- and 2-vinylindoles 1 and 4
first (Table 1). Preliminary experiments indicated the ne- alysts (entries 1–5, 10–12), dichloromethane was identi-
cessity of operating at low temperatures, in order to over- fied as the solvent of choice for this transformation, and
come a significant background reaction occurring at room excellent selectivity (98% ee) was finally reached by per-
temperature. Furthermore, although under the mild reac- forming the reaction at –55 °C using catalyst VIII derived
tion conditions employed the cycloaddition reaction fur- from hydroquinine (entry 17). A decrease in the catalyst
nished smoothly the product bearing the double bond at loading to 10 mol% was found to be detrimental to the
the 3,4-position, stabilized by conjugation with the aro- enantioselectivity of the product 3a (entry 18). Back-
matic nucleus, this compound proved to be rather difficult ground reactivity can be considered responsible for this
to isolate in a pure form by chromatography on silica gel, decrease, as a control experiment in dichloromethane
presumably for its tendency to undergo a formal 1,3-hy- without catalyst showed a significant noncatalyzed cy-
drogen shift to the rearomatized compound under acidic cloaddition reaction between 1a and 2a even at –55 °C
conditions. As this shift proceeds through protonation of (33% conversion after 48 h).
the double bond,20 we reasoned that decreasing its elec-
tron density could prevent the rearomatization process. In-
deed, it was found that derivatization with trifluoroacetic
anhydride of the indoline nitrogen atom after completion
of the reaction rendered the 3,4-unsaturated cycloadduct
3a sufficiently stable to be isolated by chromatography
and subsequent chiral stationary phase HPLC analysis.
We, thus, screened catalysts and reaction conditions
It is worthy of note that a single diastereoisomer was
formed in all cases, derived from an endo approach as de-
termined by 1H NMR NOE experiments on the 1-tosyl de-
rivative 3l (Figure 2), obtained simply quenching the
reaction mixture with 4-toluenesulfonic anhydride instead
of trifluoroacetic anhydride. The use of the tosyl deriva-
tive was found to be necessary as in the 1H NMR spectrum
of the trifluoroacetate 3a some of the protons showed
multiple resonances, due to the presence of slowly inter-
(Table 1). Performing the reaction at –25 °C gave 3a with
significant, though still unsatisfactory, enantioselectivity
converting rotamers.
with catalyst I, which had shown good performance in the
Friedel–Crafts alkylation of indole,12a and with slightly
H
O
modified catalysts II and III (entries 1–7). Replacement
of the structurally rigid aminoindanol motif in IV with
NOE
H
N
other amino alcohol moieties or the use of the natural Cin-
chona alkaloid quinine V resulted in no enantioselection
(entries 8, 9). The use of catalysts VI–VIII, obtained by
combining the (thio)urea and quinine moieties,21 proved
to be of critical importance for the catalytic efficiency in
the asymmetric Diels–Alder reaction (entries 10–18). In
contrast, the corresponding amide X gave very low enan-
tioselectivity, even at –55 °C (entry 16). After briefly
screening the reaction medium with the most efficient cat-
Ph
N
H
O NOE
Ts
3l
Figure 2 Observed NOE effects on compound 3l
This exceptional endo diastereoselectivity is however not
attributable to catalyst activity, as it is a common feature
of all the reported Diels–Alder cycloadditions of 3-vi-
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York

164
C. Gioia et al.
FEATURE ARTICLE
only serious decrease in enantioselectivity (52% ee) was
noticed in the case of the N-unprotected maleimide 2e.
Compound 1a reacted stereoselectively also with 1,4-ben-
zoquinone (2f) and 1,4-napthoquinone (2g), another use-
ful class of dienophiles for Diels–Alder cycloadditions, to
furnish 3j,k, respectively, in very good yields and excel-
lent enantioselectivities. Using the pseudoenantiomeric
catalyst IX derived from dihydroquinidine (Figure 1) led
to the expected cycloadducts ent-3a,d,j in comparable
yields, but with a slight decrease in enantioselectivity
(Scheme 1).
Table 1 Catalyst and Solvent Screening and Temperature Effect on
the Cycloaddition Reaction of 3-Vinyl-1H-indole (1a) with N-Phe-
nylmaleimide (2a)a
H
i) cat. (20 mol%)
solvent (0.1 M)
T, 18–48 h
O
O
Ph
+
N
N
ii) TFAA
Ph
N
N
H
O
H
H
endo/exo >95:5
75–90% conv.
O
O
3a
1a
2a
F3C
Entry
1
Catalyst
I
Solvent
CH2Cl2
toluene
n-hexane
MTBE
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Temp (°C) eeb (%)
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
–25
–55
–25
–25
–55
–55
–55
63
66
17
10
5
The stereospecific Diels–Alder reactions leading to prod-
ucts 3a–k are indicative of a concerted mechanism and a
stepwise tandem Michael–aldol-type reaction can be
ruled out. A zwitterionic intermediate with a long lifetime
that could neither be detected nor captured in these reac-
tions can be discounted since such an intermediate would
lead to a stereomeric mixture of products. Furthermore
looking at the reactivity of 3-vinylindole 1e with a methyl
group on the exocyclic double bond, although this diene
was employed as an E/Z mixture (1:1), the E-isomer ex-
clusively underwent the cycloaddition reaction, giving the
expected product 3e as a single diastereoisomer
(Scheme 2). This reaction outcome closely echoes the
preferential reactivity of (E)-2¢-methoxy-substituted 3-vi-
nylindole over its (Z)-counterpart previously described by
Pindur et al.22 in the uncatalyzed cycloaddition of some
carbo- and azadienophiles, which has been rationalized by
the greater stability of the s-cis-E-endo-transition state to-
wards the s-cis-Z-endo analogue due to the presence in the
former of more favorable stereoelectronic (n/s*) interac-
tions and of lower steric requirements. The preferential re-
activity of (E)-1e towards (Z)-1e can be justified along the
same lines and strongly points in favor of an easier acces-
sibility to the s-cis-conformation, which is, on the other
hand, the key structural feature for the cycloaddition to
occur (Scheme 2).
2
I
3
I
4
I
5
I
6
II
52
22
0
7
III
IV
V
8
9
0
10
11
12
13
14
15
16
17
18
VI
VI
VI
VI
VII
VIII
X
91
88
87
96
91
93
10
98
93c
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
VIII
VIII
Replacement of 1-H in the indole with methyl, tosyl, or
Boc moieties in 1f–h was detrimental in the reaction with
2a (Scheme 3). Whereas the use of 1-methyl-3-vinyl-1H-
indole (1f) resulted in extensive decomposition at differ-
ent temperatures, probably due to its increased acid sensi-
tivity, 1-tosyl and 1-Boc derivatives 1g and 1h smoothly
afforded the expected products 3l,n as single diastereoiso-
mers, at –4 °C and –25 °C, respectively, though in racemic
form in both cases (Scheme 3).
a Conditions: (i) 2a (0.10 mmol), catalyst (0.02 mmol), 1a (0.12
mmol), solvent (1.0 mL), 18–48 h, (ii) TFAA (0.50 mmol). Conver-
sion 75–90% (1H NMR). A single endo-diastereoisomer (1H NMR)
was observed in all cases.
b Determined by chiral HPLC analysis.
c With 0.01 mmol catalyst (10.0 mol%).
nylindoles,16 and is normally ascribed to secondary orbital
interactions. The absolute configuration of the cycload-
duct 3a was instead determined by chemical correlation.14
These latter results support the crucial role played by the
indole N–H as a suitable moiety for recognition of the in-
dole nucleus by the Brønsted basic site of the organocata-
lytic species, giving a highly organized hydrogen bond
network, as envisioned in a number of highly enantiose-
lective indole alkylation reactions performed by using ni-
troalkenes,12a,23 a-keto esters,24 and imines.25 Furthermore
a reasonable assumption for the rather low enantioselec-
tivity observed when using 2e as the dienophile
(Scheme 1), could be accounted by the possibility that the
imide hydrogen might interfere with the organization of
this hydrogen bond system.
The scope of the reaction was investigated by using cata-
lyst VIII and it was found to tolerate a significant degree
of alterations in both diene and dienophile partners
(Scheme 1). Both electron-withdrawing or -donating
groups at the 5-position of the indole nucleus were toler-
ated as well as a methyl substituent at the exocyclic dou-
ble bond (cycloadducts 3a–e). Using the unsubstituted 3-
vinylindole 1a variation in the dienophile counterpart was
also examined. Maleimides 2a–e, differently substituted
at nitrogen, afforded the cycloadducts 3f–i in generally
very good yields and excellent enantioselectivities; the
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Diels–Alder Reactions of Vinylindoles Using Organocatalysis
165
O
O
R3
O
2a: R3 = Ph
2b: R3 = Me
2c: R3 = Bn
2d: R3 = t-Bu
2e: R3 = H
R2
N
R2
H
O
R1
i) cat. VIII or IX (20 mol%)
CH2Cl2, –55 °C, 48 h
ii) TFAA
R1
X
N
+
H H
O
endo/exo > 95:5
N
H
O
F3C
1a: R1 = H, R2 = H
3a–k (cat. VIII)
ent-3a,d,j (cat. IX)
1b: R1 = Br, R2 = H
1c: R1 = MeO, R2 = H
1d: R1 = H, R2 = 1'-Me
O
2f: H,H
2g: Ph
1e: R1 = H, R2 = 2'-Me (E/Z = 1:1)
H
O
H
H
O
H
O
O
R1
N
N
N
N
Ph
R3
Ph
Ph
N
N
H H
H H
O
N
N
H H
O
H H
O
O
O
O
O
O
F3C
F3C
F3C
F3C
3a: R1 = H; 91% yield, 98% ee
3b: R1 = Br; 86% yield, 90% ee
3c: R1 = MeO; 77% yield, 96% ee
3e: 58% yield, 92% ee
3d: 79% yield, 96% ee
3f: R3 = Me; 89% yield, 98% ee
3g: R3 = Bn; 89% yield, 96% ee
3h: R3 = t-Bu; 81% yield, 88% ee
3i: R3 = H; 72% yield, 52% ee
O
H
O
H
H
H
O
O
N
N
Ph
Ph
N
N
H H
N
H H
O
N
H H
O
H H
O
O
O
O
O
O
F3C
F3C
F3C
F3C
ent-3j: 71% yield, 98% ee
ent-3d: 89% yield, 86% ee
3j: H,H; 83% yield, >99% ee
3k: Ph; 77% yield, 96% ee
ent-3a: 86% yield, 95% ee
Scheme 1 Generality of the catalytic asymmetric Diels–Alder reaction of 3-vinylindoles 1. Reagents and conditions: (i) 2 (0.15 mmol), ca-
talyst VIII for 3a–k, or catalyst IX for ent-3a,d,j (0.030 mmol), 1a,d (0.18 mmol) or 1b,c,e (0.30 mmol), solvent (1.5 mL), –55 °C, 48 h, (ii)
TFAA (0.75 mmol), (iii) chromatography (silica gel).
With these encouraging results for the cycloaddition of 3-
vinylindoles 1 in hand, we turned our attention to the cor-
responding reaction employing the isomeric 2-vinyl-1H-
indole (4). The olefin moiety of this diene is considerably
less electron rich with respect to the 3-vinylindole 1, ren-
dering this compound more stable towards acidic condi-
tions.
H
N
H
N
H
N
H
N
H
s-trans
s-trans
s-cis
s-cis
(Z)-1e
(E)-1e
[4+2]
Considering the lower reactivity of 2-vinylindole 4 as a
diene, we examined the cycloaddition reaction of 4 at
room temperature using N-methylmaleimide (2b)
(Table 2) and employing some of the catalysts (Figure 1)
that had given the most promising results with the 3-vi-
nylindoles 1 and in Friedel–Crafts alkylations of in-
doles.12a,23–25 As the double bond in the [4+2] cycloadduct
5 derived from the cycloaddition reaction is not stabilized
by conjugation as it was in the cycloadducts 3 from 3-vi-
nylindoles 1, a fast formal 1,3-hydrogen shift occurred in
cycloadduct 5 providing the tetrahydrocarbazole 6b. This
aromatic compound was sufficiently stable to be isolated
by chromatography on silica gel and analyzed by chiral
stationary phase HPLC without requiring trifluoroacetic
anhydride derivatization. To our disappointment, howev-
er, all catalysts tested in dichloromethane as a solvent
gave very low enantiomeric excesses in this reaction, ac-
companied by an incomplete conversion of starting mate-
rials 4 and 2b (entries 1–6). Also changing the reaction
medium did not seem to give any improvement (entries 7,
NOE
O
H
H
H3C
H
N
Ph
N
H
O
O
CF3
3e
Scheme 2 The s-cis and s-trans conformations in compounds (E)-
1e and (Z)-1e and resulting Diels–Alder adduct 3e
H
O
O
VIII (20 mol%)
CH2Cl2
Ph
N
48 h
N
+
Ph
N
H
H
N
O
O
R
R
1f: R = Me
1g: R = Ts
1h: R = Boc
2a
3m: R = Me, <10% yield
3l: R = Ts, 65% yield, 0% ee
3n: R = Boc, 55% yield, 0% ee
Scheme 3 Diels–Alder cycloadditions of 3-vinylindoles 1f–h
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York

166
C. Gioia et al.
FEATURE ARTICLE
8). Furthermore, a control experiment in the absence of of these reaction mixtures revealed the presence of the
catalyst (entry 9) indicated the absence of a significant ac- diastereomerically pure tandem Diels–Alder–Michael ad-
celeration of the Diels–Alder cycloaddition by the cata- duct 7 as the major component (entries 10–12), and as the
lysts employed. In a last attempt several reactions were only observable product when quinine V was employed
carried out at 0 °C, under more concentrated conditions in (entry 13). This product derives from the reaction of the
order to reach a reasonable conversion, using the ‘best’ intermediate [4+2] cycloadduct 5 with a second molecule
catalysts quinine V and amide X found in the first set of of N-methylmaleimide (2b) through an ene-type reaction,
experiments (entries 10–13). To our surprise, the cycload- before rearomatization occurred. This tandem process, fa-
duct 6b obtained with catalyst X using these conditions vored by the enamine functionality, has been already re-
showed a great enhancement in its enantiomeric excess ported for thermal cycloadditions of 2-vinylindoles.26 In
(entries 10–12, up to 74% ee), compared to the same reac- our reactions carried out at room temperature in dichlo-
tions carried out at room temperature. A closer inspection romethane under more diluted conditions (entries 1–6), in
Table 2 Screening of Catalysts and Reaction Conditions in the Diels–Alder Reaction between 2-Vinyl-1H-indole (4) and N-Methylmaleimide
(2b)a
Me
O
N
O
H
Me
H
1,3-H shift
O
N
O
H
H
Me
O
cat. (20 mol%)
solvent
N
H
N
H
Me
6b
+
O
N
H
O
N
N
O
H
H
2b
4
2b
5
H
N
H
O
7
N
O
Me
Entry
1
Catalyst
Solvent (M)
Temp (°C)
Time (h)
48
Conv.b (%)
eec (%) of 6b Ratiob 6b/7
I
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
CH2Cl2 (0.2)
toluene (0.25)
CH2Cl2–TBME (7:3) (0.25)
CH2Cl2 (0.2)
CH2Cl2 (1.0)
CH2Cl2 (1.5)
CH2Cl2 (2.0)
CH2Cl2 (1.0)
CH2Cl2 (1.0)
25
25
25
25
25
25
25
25
25
0
35
29
46
40
45
21
69
78
19
39
39
47
55
30
3
2
>95:5
>95:5
52:48
90:10
58:42
71:29
58:42
63:37
>95:5
22:78
23:77
19:81
<5:95
90:10
2
II
V
VI
VII
X
X
X
–
47
3
120
120
120
47
23
3
4
5
4
6
15d
15
14
–
7
72
8
72
9
47
10
11
12
13
14
X
X
X
V
–
65
67
67
74e
0
47
0
47
f
0
60
–
0
48
–
a Conditions: 2b (0.05 mmol), catalyst (0.01 mmol), 4 (0.056 mmol), solvent.
b Determined by 1H NMR spectroscopy.
c Determined by chiral stationary phase HPLC.
d 7: 5% ee.
e 7: 5% ee.
f 7: 1% ee.
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Diels–Alder Reactions of Vinylindoles Using Organocatalysis
167
all cases the 1,3-hydrogen shift predominated over the Our current interpretation, which accounts for the ob-
tandem product 7.
served results, considers that the enantioselectivity of 6b
originates mainly from a kinetic resolution of the transient
intermediate 5 (Scheme 4). Our hypothesis involves the
formation of the intermediate 5 in low enantiomeric ex-
cess, promoted only marginally by the catalyst. This inter-
mediate can then undergo a presumably noncatalyzed 1,3-
hydrogen shift (i.e., k1 = k2), giving the tetrahydrocarba-
zole 6b. Under more diluted conditions (0.2 M, entries 1–
6), this hydrogen shift is considerably faster than the
Michael addition involving also a second molecule of ma-
leimide 2b and the catalyst, and the tetrahydrocarbazole
6b is obtained as the major product with understandably
low enantioselectivity. However, if the concentration of
catalyst and maleimide 2b is sufficiently high, the trimo-
lecular Michael addition can compete with the mono- or
bimolecular 1,3-hydrogen shift. If the catalyst is able to
discriminate between the two enantiomers of 5 (i.e., k3 ≠
k4), giving possibly some enantioenrichment in the re-
maining unreacted 5, the 1,3-hydrogen shift then affords
the tetrahydrocarbazole 6b with appreciable enantiomeric
excess. This scheme does not fall into the general catego-
ries of kinetic resolution processes,27 as we consider the
catalyst influencing only marginally, if at all, the 1,3-hy-
drogen shift, in contrast with what would be a parallel ki-
netic resolution. It is instead a kinetic resolution involving
a transient intermediate, wherein the resolution step needs
A second control experiment carried out at 0 °C (entry 14)
further confirmed the inability of the catalysts employed
to catalyze the Diels–Alder cycloaddition. From these
data, it, thus, seems clear that the enantioselectivity ob-
served in the cycloadduct 6b does not originate from the
organocatalyzed Diels–Alder cycloaddition reaction of 4
with 2b. On the other hand, the participation of the cata-
lyst in the following Michael reaction was proven by the
almost complete absence of 7 when the reactions were
carried out without catalyst (entries 9, 14). In particular,
the basic moiety of the catalysts employed seems to play
a crucial role in the formation of 7, as witnessed by the ap-
parent correlation between the amount of 7 and the basic-
ity of the catalyst in the reactions carried out at room
temperature, wherein catalysts V–VII and X bearing a ba-
sic tertiary amino moiety furnished substantially higher
amounts of 7 compared to I and II. The role of the catalyst
in the process leading to enantioenriched 6b seems, thus,
rather connected with the second Michael addition step
leading to 7, presumably with a hydrogen bond interaction
between the basic moiety of the catalysts and the N–H of
the enamine, which results thus activated for the Michael
addition. However, the tandem adduct 7 was obtained
with low enantioselectivity, even when the cycloadduct
6b showed an appreciable enantioenrichment (entries 6,
12).
Me
O
N
O
H
H
1,3-H shift
k1
N
Me
H
Me
6b
O
N
O
N
O
H
O
H
H
H
H
2b, cat.
k3
N
N
H
H
O
7
N
O
Me
O
Me
N
[4+2]
Me
+
O
N
H
O
N
O
H
4
2b
H
Me
1,3-H shift
k2
O
N
N
O
H
H
Me
H
6b
H
O
N
O
H
H
N
2b, cat.
H
k4
N
H
5
O
7
N
O
Me
Scheme 4 Current working hypothesis justifying the enantioselectivity observed in 6b
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York

168
C. Gioia et al.
FEATURE ARTICLE
to compete with the transformation of this transient inter- obtained in low yields, though with substantial enantiose-
mediate to be proficient.
lectivity together with variable amounts of tandem Micha-
el-type adducts, derived from attack of the enamine of the
intermediate cycloadduct to the dienophile. Evidence in
favor of the intervention of the catalyst mainly in the
Michael step of the reaction suggest an unusual resolu-
tion-type process accounting for the observed enantiose-
lectivity.
The collected data indicate that in our case the catalysts
are operating with low efficiency, as 7 was obtained with
low enantiomeric excess in all cases (entries 6, 12, 13).
However, in a classical kinetic resolution even with a low
selective catalyst the starting material can be recovered
with significant enantioenrichment when the conversion
is high. According to our scheme it should be possible to
raise the enantioselectivity of the tetrahydrocarbazole 6b,
at the expense of its yield, increasing the ratio between the
rate of formation of the tandem product and the 1,3-hydro-
gen shift. Indeed, we observed, in our case, considerable
enantioselectivity in the cycloadduct 6b only when most
of the intermediate 5 to be resolved is consumed to give
the tandem adduct 7 (Table 2, entries 10–12).
1H, 13C, and 19F NMR spectra were recorded on a Varian AS 400 or
600 spectrometer relative to residual solvent signals for 1H and 13
C
NMR [1H NMR: d = 7.26 (CDCl3), d = 2.50 (DMSO-d6), d = 3.34
(CD3OD); 13C NMR: d = 77.0 (CDCl3), d = 39.5 (DMSO-d6), d =
49.0 (CD3OD)], or to an external reference for 19F NMR [d = –163.0
(C6F6)]. 13C NMR spectra were acquired with 1H broad band decou-
pled mode. Mass spectra were recorded on a micromass LCT spec-
trometer using electrospray (ES+) ionization techniques. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter. The
enantiomeric excess of the products was determined by chiral sta-
tionary phase HPLC (Daicel Chiralpak AD-H or Daicel Chiralcel
OD columns), using a UV detector operating at 254 nm. Analytical
grade solvents and commercially available reagents were used as re-
ceived, unless otherwise stated. CH2Cl2 was passed through basic
alumina before use. Chromatographic purifications were performed
using 70–230 mesh silica. Catalysts I,12a VII–IX,21a and X,29 3-vi-
nylindole 1a,30 and 2-vinylindole 431 were prepared according to the
literature.
Although as mentioned the selectivity of the catalyst X in
this particular resolution process is rather low, it should be
considered that the tetrahydrocarbazole 6b is very easily
separated by column chromatography both from starting
materials and from the tandem adduct 7 [CH2Cl2–Et2O,
97:3; Rf (4,2b) >0.8; Rf (6b) = 0.30, Rf (7) <0.1]. Hence,
this protocol, despite its inherent limitation in terms of
yield, gives an unprecedented entry to the cycloadducts
deriving from 2-vinylindole 4 with reasonable enantiose-
lectivity. The possibility of using different maleimides
was then tested (Scheme 5), showing that despite the ex-
pected low yields, the corresponding Diels–Alder cy-
cloadducts 6a–d could be isolated with moderate
enantioselectivity; this has promise for further develop-
ments.
Further experimental and characterization data for compounds
1b–e and 3a–j can be found in ref. 14.
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-hydroxy-2,3-
dihydro-1H-inden-1-yl]thiourea (II)
To a stirred soln of 3,5-bis(trifluoromethyl)phenyl isothiocyanate
(271 mg, 182 mL, 1.0 mmol) in CH2Cl2 (1.0 mL) was added in 1 por-
tion (1S,2S)-trans-1-aminoindan-2-ol (120 mg, 0.80 mmol). The
mixture was stirred at r.t. for 18 h, then the solvent was removed in
vacuo. Catalyst II was obtained after precipitation (n-hexane–ace-
tone) as a white solid in quantitative yield.
R
O
N
O
H
X (20 mol%)
CH2Cl2 (2.0 M)
0 °C, 84 h
R
[a]D25 –128 (c 0.50, CHCl3).
H
O
N
1H NMR (400 MHz, DMSO-d6): d = 10.04 (br s, 1 H), 8.65 (br s,
J = 8.2 Hz, 1 H), 8.27 (br s, 2 H), 7.73 (br s, 1 H), 7.31–7.13 (m, 4
H), 5.71 (br t, J = 6.7 Hz, 1 H), 5.37 (br d, J = 4.7 Hz, 1 H), 4.37
(quint, J = 6.9 Hz, 1 H), 3.14 (dd, J1 = 15.7 Hz, J2 = 7.2 Hz, 1 H),
2.74 (dd, J1 = 15.7 Hz, J2 = 7.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 182.0, 142.6, 141.8, 140.6,
131.0 (q, J = 32 Hz), 128.6, 127.3, 125.5, 125.1, 123.0 (q, J = 273
Hz), 122.9, 116.9, 78.0, 66.5, 39.4.
+
O
N
H
N
H
4
2a–d
6a: R = Ph, 10% yield, 58% ee
6b: R = Me, 12% yield, 72% ee
6c: R = Bn, 15% yield, 72% ee
6d: R = t-Bu, 14% yield, 68% ee
Scheme 5 Enantioenriched tetrahydrocarbazoles 6a–d
19F NMR (376 MHz, DMSO-d6): d = –62.1.
MS (ESI+): m/z = 421 [M + H+].
Conclusion
We have described the first application of asymmetric or-
ganocatalysis to the [4+2]-cycloaddition reaction of vi-
nylindoles 1 and 4.28 With 3-vinylindoles 1 the reactions
proceed under mild operational conditions to give a wide
range of optically active tetrahydrocarbazoles 3 in syn-
thetically useful yields and excellent enantioselectivities.
The operational mode of the catalysis can be established
according to a HOMO and LUMO activation respectively
by the Brønsted basic and acidic sites of the organocata-
lytic species. As compared to the 3-vinylindoles 1, its 2-
vinyl counterpart 4 under similar reaction conditions ex-
hibits poor reactivity and the expected cycloadducts are
1-[(1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl]-3-
[(1S,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]thiourea
(III)
Following the procedure used for II using (R)-bornyl
isothiocyanate32 (195 mg, 1.0 mmol) and (1R,2S)-cis-1-aminoin-
dan-2-ol (120 mg, 0.80 mmol) and after chromatography (silica gel,
EtOAc) gave catalyst III as a pale yellow solid in 65% yield.
[a]D25 +48 (c 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.40 (m, 2 H), 7.28–7.25 (m, 4 H),
6.35 (d, J = 6.9 Hz, 1 H), 6.20 (br s, 1 H), 5.87 (br s, 1 H), 4.76 (m,
1 H), 3.22 (dd, J1 = 16.6 Hz, J2 = 5.7 Hz, 1 H), 2.95 (dd, J1 = 16.5
Hz, J2 = 2.6 Hz, 1 H), 2.37 (m, 1 H), 1.77 (m, 1 H), 1.69 (dd, J1 = 4.7
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Diels–Alder Reactions of Vinylindoles Using Organocatalysis
169
Hz, J2 = 4.7 Hz, 1 H), 1.47–1.38 (m, 1 H), 0.99 (m, 2 H), 0.90 (s, 3
H), 0.89 (s, 3 H), 0.87 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 179.0, 177.3, 135.5, 134.2, 126.7,
122.0, 120.2, 119.7, 110.5, 103.6, 40.1, 39.5, 24.7, 21.3, 19.8.
13C NMR (100 MHz, CDCl3): d = 180.2, 140.4, 140.1, 128.6, 127.4,
125.6, 74.0, 63.2, 59.1, 50.0, 48.4, 44.9, 39.7, 37.6, 28.3, 19.9, 18.9,
14.5.
MS (ESI+): m/z = 277 [M + Na+]
(3aR*,10cR*)-2-Benzyl-4,5,6,10c-tetrahydropyrrolo[3,4-c]car-
bazole-1,3(2H,3aH)-dione (6c)
Pale-yellow solid; yield: 15%; 72% ee [chiral HPLC (Daicel Chiral-
pak AD-H, n-hexane–i-PrOH, 80:20, flow rate 0.75 mL/min):
tR = 17.1 (minor), 21.0 min (major)].
MS (ESI+): m/z = 345 [M + H+].
1-(2-Hydroxyphenyl)-3-[(1S,2S,4R)-1,7,7-trimethylbicyc-
lo[2.2.1]heptan-2-yl]thiourea (IV)
To a stirred soln of (R)-bornyl isothiocyanate32 (195 mg, 1.0 mmol)
in THF (4.0 mL) was added in 1 portion 2-aminophenol (90 mg,
0.80 mmol). The mixture was refluxed for 6 h with stirring, then the
solvent was removed in vacuo followed by chromatography (silica
gel, n-hexane–EtOAc, 1:1) to give catalyst IV as a white solid in
80% yield.
[a]D30 +142 (c 0.45, CDCl3).
1H NMR (400 MHz, DMSO-d6): d = 10.97 (s, 1 H), 7.72 (d, J = 8.2
Hz, 1 H), 7.27–7.16 (m, 4 H), 7.12–7.07 (m, 2 H), 7.06–6.94 (m, 2
H), 4.51 (d, J = 15.4 Hz, 1 H), 4.48 (d, J = 15.4 Hz, 1 H), 4.31 (d,
J = 7.7 Hz, 1 H), 3.54 (dt, Jd = 7.8 Hz, Jt = 4.9 Hz, 1 H), 2.73 (dt,
Jd = 16.3 Hz, Jt = 4.5 Hz, 1 H), 2.55–2.54 (m, 1 H), 2.32–2.22 (m,
1 H), 1.94–1.83 (m, 1 H).
[a]D25 +9 (c 0.5, MeOH).
1H NMR (400 MHz, CD3OD): d = 7.04–6.99 (m, 1 H), 6.37–6.27
(m, 3 H), 4.98 (br s, 3 H), 4.08–4.02 (m, 1 H), 2.50–2.40 (m, 2 H),
1.97–1.80 (m, 3 H), 1.62–1.51 (m, 1 H), 1.44–1.33 (m, 2 H), 1.03
(s, 1 H), 1.02 (s, 3 H), 0.97 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 181.0, 129.7, 127.1, 121.6,
118.5, 60.2, 44.9, 37.6, 28.7, 28.3, 19.8, 18.9, 14.1.
13C NMR (100 MHz, DMSO-d6): d = 179.6, 177.7, 136.9, 136.3,
135.8, 129.1, 128.0, 127.8, 127.3, 121.5, 119.9, 119.4, 111.5, 103.1,
55.6, 41.8, 22.4, 20.3.
MS (ESI+): m/z = 353 [M + Na+].
(3aR*,10cR*)-2-tert-Butyl-4,5,6,10c-tetrahydropyrrolo[3,4-
c]carbazole-1,3(2H,3aH)-dione (6d)
Pale-yellow solid; yield: 14%; 68% ee [chiral HPLC (Daicel Chiral-
pak AD-H, n-hexane–i-PrOH, 80:20, flow rate 0.75 mL/min):
tR = 7.6 (major), 9.0 min (minor)].
MS (ESI+): m/z = 305 [M + H+].
Catalytic Reactions between 2-Vinylindole 4 and Maleimides
2a–d; General Procedure
In a test tube the maleimide 2a–d (0.20 mmol) and catalyst X (17.2
mg, 0.04 mmol) were dissolved in CH2Cl2 (0.10 mL). The mixture
was cooled to 0 °C and 2-vinylindole 4 (34.3 mg, 0.24 mmol) was
added. The reaction was left at this temperature for 84 h then direct-
ly purified by chromatography (silica gel, CH2Cl2, then CH2Cl2–
Et2O, 97:3).
[a]D30 +177 (c 0.35, CDCl3).
1H NMR (400 MHz, CDCl3): d = 7.96–7.91 (m, 2 H), 7.30–7.25 (m,
1 H), 7.18–7.13 (m, 2 H), 4.14 (d, J = 8.2 Hz, 1 H), 3.21 (dt, Jd = 8.2
Hz, Jt = 4.9 Hz, 1 H), 2.69 (dd, J1 = 7.2 Hz, J2 = 4.4 Hz, 1 H), 2.50–
2.41 (m, 1 H), 1.99–1.89 (m, 2 H), 1.51 (s, 9 H).
13C NMR (400 MHz, CDCl3): d = 180.3, 178.5, 135.8, 134.5, 127.3,
122.1, 120.4, 120.1, 110.7, 104.3, 58.5, 40.3, 40.2, 28.6, 22.1, 20.1.
(3aR*,10cR*)-2-Phenyl-4,5,6,10c-tetrahydropyrrolo[3,4-c]car-
bazole-1,3(2H,3aH)-dione (6a)
MS (ESI+): m/z = 219 [M + Na+]
Pale-yellow solid; yield: 10%; 58% ee [chiral HPLC (Daicel Chiral-
pak AD-H, n-hexane–i-PrOH, 80:20, flow rate 0.75 mL/min):
tR = 24.3 (major), 28.1 min (minor)].
[a]D30 +129 (c 0.25, CDCl3).
1H NMR (400 MHz, DMSO-d6): d = 11.01 (s, 1 H), 7.73 (d, J = 7.8
Hz, 1 H), 7.42–7.38 (m, 2 H), 7.35–7.32 (m, 1 H), 7.27 (d, J = 7.5
Hz, 1 H), 7.18–7.15 (m, 2 H), 7.02 (t, J = 6.9 Hz, 1 H), 6.97 (t,
J = 6.9 Hz, 1 H), 4.39 (d, J = 7.9 Hz, 1 H), 3.65 (dt, Jd = 8.3 Hz,
Jt = 4.8 Hz, 1 H), 2.76 (dt, Jd = 15.9 Hz, Jt = 4.9 Hz, 1 H), 2.64 (ddd,
J1 = 16.3 Hz, J2 = 11.0 Hz, J3 = 5.3 Hz, 1 H), 2.41–2.35 (m, 1 H),
1.96–1.89 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 178.8, 176.9, 136.4, 136.1,
133.1, 129.5, 128.8, 127.5, 127.3, 121.5, 119.9, 119.4, 111.5, 102.9,
60.4, 55.5, 21.4, 20.2.
(3aR*,10cR*)-2-Methyl-5-(1-methyl-2,5-dioxopyrrolidin-3-yl)-
4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H,3aH)-di-
one (7)
White solid; 15% ee [chiral HPLC (Daicel Chiralpak AD-H, n-hex-
ane–i-PrOH, 80:20, flow rate 0.75 mL/min): tR = 21.3 (minor), 53.4
min (major)].
1H NMR (400 MHz, DMSO-d6): d = 11.03 (s, 1 H), 7.75 (d, J = 8.0
Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.06 (t, J = 7.6 Hz, 1 H), 7.00 (t,
J = 6.8 Hz, 1 H), 4.22 (dd, J1 = 7.9 Hz, J2 = 1.6 Hz, 1 H), 3.78
(quint, J = 4.3 Hz, 1 H), 3.57–3.49 (m, 1 H), 3.35–3.25 (m, 1 H),
2.89 (s, 3 H), 2.73 (s, 3 H), 2.66 (dd, J1 = 18.1 Hz, J2 = 9.3 Hz, 1 H),
2.18 (dd, J1 = 18.2 Hz, J2 = 4.4 Hz, 1 H), 2.08 (dddd, J1 = 13.2 Hz,
J2 = 7.6 Hz, J3 = 4.7 Hz, J4 = 2.8 Hz, 1 H), 1.53 (dt, Jt = 12.6 Hz,
Jd = 5.5 Hz, 1 H).
MS (ESI+): m/z = 339 [M + Na+].
13C NMR (100 MHz, DMSO-d6): d = 179.3, 178.8, 177.7, 177.0,
136.7, 135.3, 127.0, 122.0, 120.3, 119.6, 111.7, 105.6, 55.6, 41.6,
30.9, 30.7, 25.2, 25.0, 21.7.
(3aR*,10cR*)-2-Methyl-4,5,6,10c-tetrahydropyrrolo[3,4-c]car-
bazole-1,3(2H,3aH)-dione (6b)
Pale-yellow solid; yield: 12%; 72% ee [chiral HPLC (Daicel Chiral-
cel OD, n-hexane–i-PrOH, 80:20, flow rate 1.0 mL/min): tR = 14.8
(minor), 21.1 min (major)].
MS (ESI+): m/z = 388 [M + Na+]
Acknowledgment
[a]D30 +146 (c 0.25, CDCl3).
We acknowledge financial support from ‘Stereoselezione in Sintesi
Organica Metodologie e Applicazioni’ 2007. We are grateful to
Berardino Giannichi for the preparation of catalysts II–IV, and to
Agnès Hauville for preliminary experiments.
1H NMR (600 MHz, CDCl3): d = 8.00–7.93 (m, 2 H), 7.26–7.22 (m,
1 H), 7.17–7.13 (m, 2 H), 4.28 (d, J = 7.9 Hz, 1 H), 3.38–3.34 (m, 1
H), 2.91 (s, 3 H), 2.72–2.61 (m, 2 H), 2.60–2.54 (m, 1 H), 1.99–1.92
(m, 1 H).
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York

170
C. Gioia et al.
FEATURE ARTICLE
(15) Pindur, U.; Lutz, G.; Fischer, G.; Schollmeyer, D.; Massa,
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(32) Obtained from (R)-bornylamine and 1,1¢-thiocarbonyl-
diimidazole in THF, followed by chromatographic
purification.
Synthesis 2010, No. 1, 161–170 © Thieme Stuttgart · New York