Aziridin-2-yl methanols as organocatalysts in Diels-Alder reactions and Friedel-Crafts alkylations of N-methyl-pyrrole and N-methyl-indole

Article abstract of DOI:10.1016/j.tetasy.2006.11.028

A series of enantiomerically pure aziridin-2-yl methanols have been synthesized from aziridine-2-carboxylic esters and have been tested as organocatalysts in Diels-Alder reactions and Friedel-Crafts alkylations of N-methyl-pyrrole and N-methyl-indole usin

Full text of DOI:10.1016/j.tetasy.2006.11.028

Tetrahedron: Asymmetry 17 (2006) 3135–3143
Aziridin-2-yl methanols as organocatalysts in
Diels–Alder reactions and Friedel–Crafts alkylations of
N-methyl-pyrrole and N-methyl-indole
a
a
a
Bianca F. Bonini,a, Elena Capito, Mauro Comes-Franchini, Mariafrancesca Fochi,
*
`
Alfredo Riccia and Binne Zwanenburgb
a
`
Dipartimento di Chimica Organica ‘A. Mangini’, Universita di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
bDepartment of Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Received 9 October 2006; accepted 15 November 2006
Abstract—A series of enantiomerically pure aziridin-2-yl methanols have been synthesized from aziridine-2-carboxylic esters and have
been tested as organocatalysts in Diels–Alder reactions and Friedel–Crafts alkylations of N-methyl-pyrrole and N-methyl-indole using
a,b-unsaturated aldehydes. Moderate to good ee’s have been obtained. The coupling of N-methyl-pyrrole with crotonaldehyde and
cinnamaldehyde using (2S,3S)-3-methylazirin-2-yl(diphenyl)methanol TFA salt as the catalyst gave the best results (ee 75%).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of dialkylzincs to N-(diphenylphosphinoyl) imines.8 Very
recently, the acetate salt of 1 was tested in an intramole-
cular formal aza [3+3] cycloaddition reaction as an organ-
ocatalyst.9 Although the aziridine salt was efficient in
promoting the reaction, a very poor ee was obtained.
Functionalized aziridines are highly valuable three-mem-
bered ring systems in modern synthetic chemistry, because
of their widely recognized versatility as synthetic building
blocks and their use in functional group transformations.1
In synthetic transformations, their utility is mostly associ-
ated with stereo- and regio-controlled ring-opening reac-
tions of the highly strained three-membered ring.2
Moreover, chiral aziridines can serve as a source of chiral-
ity in stereocontrolled reactions and have been employed
both as ligands and chiral auxiliaries in asymmetric synthe-
sis.2d,3 Aziridine-2-carbinols of type 1 have been used in the
preparation of oxazaborolidines, which are mediating
reagents in the enantioselective reduction of ketones.4 It
has been demonstrated that the N-trityl derivative5 and a
number of N-alkylated derivatives6 of 1 are effective
catalysts in the enantioselective addition of diethylzinc to
aromatic and aliphatic aldehydes. N-Trityl-azirin-2-yl-
(diphenyl)methanol 5a turned out to be superior in this
respect.5,7 Aziridine alcohols have also been screened as
chirality transfer reagents in the enantioselective addition
O
R2
R2
OH
N
R1
R2
R1
N
H
N
H
Ph
1
2
In recent years there has been an increasing awareness that
small organic molecules, in addition to metal complexes
and biocatalysts, can serve as highly selective and efficient
catalysts.10 In particular, the use of chiral amines as organo-
catalysts has received considerable attention in enantio-
selective synthesis. Typical reactive intermediates are
iminium ions formed by the reversible reaction of the
amine catalyst with a carbonyl substrate. A pioneering
example of iminium catalysis is MacMillan’s enantioselec-
tive Diels–Alder reactions of a,b-unsaturated aldehydes11
or ketones12 using the chiral imidazolidinone catalyst of
type 2. This type of catalysis has been further extended
to other reactions of a,b-unsaturated aldehydes, such as
*
Corresponding author. Tel.: +39 0512093626; fax: +39 0512093654;
e-mail: bonini@ms.fci.unibo.it
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.028

3136
B. F. Bonini et al. / Tetrahedron: Asymmetry 17 (2006) 3135–3143
[3+2] cycloaddition with nitrones,13 Friedel–Crafts alkyl-
ation with pyrroles,14 indoles15 and benzenes,16 and the
Mukaiyama–Michael reaction17 achieving high yields and
enantioselectivities.
2.2. Enantioselective Diels–Alder reaction
The efficiency of the aziridinyl carbinol catalysts was first
tested in the enantioselective catalytic Diels–Alder reaction
of cyclopentadiene with (E)-cinnamaldehyde 7a and (E)-
crotonaldehyde 7b (Scheme 2).
The efficiency of chiral imidazolidinone as chiral catalysts,
prompted us to investigate the possibility of using the
three-membered ring aziridin-2-yl methanols 1 as organo-
catalysts. An intriguing additional question is whether the
aziridinium ions, which will be the true chirality transfer-
ring species, will be sufficiently stable under these catalytic
processes.
When the cycloaddition reaction was performed in MeOH/
H2O 95:5 (by volume) as the reaction medium, the final
products were mixtures of aldehydes 8 (or 9) and acetals
10 (or 11). The final mixture was completely acetalized
for the determination of the enantiomeric excess (ee) by
1H NMR in the presence of Pirkle’s alcohol. When the sol-
vent was H2O, the final products were the aldehydes 8 (or
9) that were also transformed into the corresponding ace-
tals 10 (or 11) for the ee determination.
2. Results and discussion
2.1. Preparation of aziridine-2-carbinols 1
The aziridine carbinols 1a–f and 4a were used either as pre-
formed HCl salts in 5 mol %, or as in situ prepared HClO4
salts in 10 mol %. It is well known that the highly strained
three-membered ring can undergo a nucleophilic ring-
opening reaction when protonated. Surprisingly, the aziri-
dine salts (HCl and HClO4) were remarkably stable. The
1-HCl salts were generally used in MeOH/H2O while the
1-HClO4 salts were employed in H2O (Table 1).
We prepared a series of compounds 1 with the aim of
exploring their use as organocatalysts. Various ap-
proaches18 for the preparation of optically active aziri-
dine-2-carboxylic esters 3a and 3b, that are the precursors
of the aziridine-2-carbinols 1, have been described. We se-
lected N-tritylmethylesters of L-serine and L-threonine as
starting materials from which the compounds 3a and 3b
could be prepared,4,19 by a convenient multigram ‘one-
pot procedure’ using methansulfonyl chloride and triethyl-
amine. Aziridine esters 3a and 3b were next converted into
the corresponding aziridine carbinols 1a–f by reaction with
a Grignard reagent19 followed by detritylation with sulfuric
acid in MeOH/THF19,20 (Scheme 1). Compounds 4a and
4b were obtained by methylation20 of 5a and 5b with
methyl iodide in the presence of sodium hydride and subse-
quent detritylation.
When using the preformed HCl salt of 1a in the reaction
with (E)-cinnamaldehyde 7a, the Diels–Alder adducts were
obtained in rather low yield (with the exo-isomer predom-
inanting) and in modest enantiomeric excess (entry 1). A
somewhat better result was obtained at lower temperature,
but an attempted reaction at 0 ꢁC did not produce any
adduct. An increase in the amount of catalyst to 20%
decreased both the yield and the ee. The use of a different
R2
R2
OH
1a: R1 = H, R2 = Ph
b)
b)
a)
R1
R1
CO2Me
1a-f
N
Tr
1b: R1 = Me, R2 = Ph
N
Tr
1c: R1 = H, R2 = p-CF3-C6H4
1d: R1 = H, R2 = i-Pr
5a-f
3a: R1 = H
1e: R1 = H, R2 = Me
3b: R1 = Me
c)
1f: R1 = H, R2 = β-Napht
R2
R2
OMe
4a: R1 = H, R2 = Ph
4b: R1 = Me, R2 = Ph
R1
4a-b
N
Tr
6a,b
Scheme 1. Reagents and conditions: (a) R2MgBr, THF, 3 h, reflux; (b) H2SO4, THF, MeOH, 18 h, rt; (c) NaH, MeI, DMF, 48 h, rt.
CHO
R
CHO
+
R
R
endo
endo
exo
exo
8 R = Ph
9 R = Me
and/or
Cat
+
R
O
Solvent
CH(OMe)2
7a: R = Ph
7b: R = Me
R
+
CH(OMe)2
10 R = Ph
11 R = Me
Scheme 2. Organocatalyzed Diels–Alder reaction.

B. F. Bonini et al. / Tetrahedron: Asymmetry 17 (2006) 3135–3143
Table 1. Organocatalyzed Diels–Alder reaction
3137
Entry
Aldehyde
Catalyst
Time (h)
T (ꢁC)
Yielda (%)
endo:exob
exo eec (%)
endo eec (%)
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7b
7b
7b
7b
1a-HCld
1a-HClO4
1b-HCld
1b-HCld
1c-HCld
1a-HCld
1a-HClO4
1b-HCld
1b-HCld
48
48
48
48
48
24
24
24
18
18
18
18
30
18
18
18
18
30
33
74
16
35
35
85
88
83
88
1.8:1
1.7:1
1.4:1
1.4:1
1.5:1
1:1
1:1.4
1:1.6
1:1
36
66
43
51
28
24
10
37
45
37
57
38
48
24
22
11
25
35
e
e
a Calculated after chromatography.
b Determined by 1H NMR on the crude reaction mixture.
c Determined by 1H NMR on the dimethylacetal in the presence of Pirkle’s alcohol.
d As a preformed salt, using MeOH/H2O 95:5 (by volume) as the reaction medium.
e Prepared in situ, using H2O as solvent.
solvent (CH2Cl2/i-PrOH 85:15) in the absence of any
water, had only a marginal effect.
cycloadducts in comparable yields after 72 h but with prac-
tically no asymmetric induction. Aziridine 1b furnished the
better ee (entry 8) that can be improved upon by conduct-
ing the reaction at 30 ꢁC (entry 9).
Better results with (E)-cinnamaldehyde 7a were obtained in
terms of the yield of adducts and ee using the HClO4 salt of
1a, prepared in situ (entry 2). Under these conditions, the
highest level of enantiofacial discrimination was achieved,
with 66% ee for the exo adduct and 57% for the endo
adduct.
2.3. Enantioselective Friedel–Crafts alkylation to N-methyl-
pyrrole and N-methyl-indole
The efficiency of the aziridine carbinol catalysts was then
tested in the enantioselective catalytic Friedel–Crafts alkyl-
ation reaction of N-methyl-pyrrole and N-methyl-indole
with (E)-crotonaldehyde 7b and (E)-cinnamaldehyde 7a
in CH2Cl2/i-PrOH 85:15 (by volume) as the solvent
(Schemes 3 and 4). Aziridine carbinols 1 were used as pre-
formed TFA (trifluoroacetic acid) salts in 10 mol %. Only
decomposition was observed when in situ prepared cata-
lysts were used.
Next, our attention was focused on the influence of a struc-
tural variation of the catalyst on the outcome of the asym-
metric induction; thus the series of catalysts 1b–f and 4a
was tested as a preformed HCl salt with (E)-cinnamalde-
hyde 7a. The presence of a methyl group at the 3-position
of the aziridine ring 1b led to a very low yield of adduct,
but to a slightly better ee (compare entries 1 and 3). Both
the yield and the ee values were improved by performing
the reaction at higher temperature (30 ꢁC) (entry 4). The
presence of an electron withdrawing substituent at the para
position of the phenyl ring 1c (entry 5), did not lead to bet-
ter results when compared with 1a. Both the yields and the
enantioselectivities realized with catalysts 1d and 1e with
R2 = alkyls, with catalyst 1f having the hindered b-naph-
thyl group and with catalyst 4a, in which the hydroxy
group of 1a was replaced with a methoxy group, were very
low. In this case, the use of HCl or HClO4 as the acid com-
ponent did not make much difference.
As shown in Table 2, the alkylation of N-methyl-pyrrole
with (E)-crotonaldehyde 7b in the presence of aziridine car-
binol catalyst 1a (entry 1) afforded the desired conjugate
addition adduct 12 with moderate enantioselectivity after
18 h at 18 ꢁC. The presence of a methyl group at the
Cat
+
R
H
O
N
CH3
N
CH3
CH2Cl2/i-PrOH
R
O
85:15
7b: R = Me
7a: R = Ph
12 R = Me
13 R = Ph
It is important to note that a reaction performed with (E)-
cinnamaldehyde 7a in the absence of the aziridine carbi-
nols, but in the presence of 10 mol % of HClO4 in H2O
or of 5 mol % of HCl in MeOH/H2O 95:5 for 48 h afforded
aldehydes 8 or acetals 10 in about 10% yield. This back-
ground reaction, probably due to the long reaction time,
might contribute, with a detrimental effect, to the generally
low ee’s.
Scheme 3. Organocatalyzed Friedel–Crafts alkylation of N-methyl
pyrrole.
O
R
Cat
+
R
O
N
CH3
Variation in the steric effect of the olefin substrate was also
examined. The reaction of (E)-crotonaldehyde 7b and
cyclopentadiene afforded the corresponding cycloadducts
in better yields and in a shorter reaction time, when com-
pared to (E)-cinnamaldehyde but with lower ee’s (entries
6 and 7). The reaction proceeds also at 0 ꢁC affording the
CH2Cl2/i-PrOH
N
85:15
CH3
14 R = Me
15 R = Ph
7b: R = Me
7a: R = Ph
Scheme 4. Organocatalyzed Friedel–Crafts alkylation of N-methyl indole.

3138
B. F. Bonini et al. / Tetrahedron: Asymmetry 17 (2006) 3135–3143
Table 2. Organocatalyzed Friedel–Crafts alkylation of N-methyl pyrrole
with (E)-crotonaldehyde 7b
entry 3). Variation of the temperature did not improve
the performance of the catalyst.
Entry
Catalyst
T (ꢁC)
Time
(h)
Yielda
(%)
eeb
(%)
Abs.
Config.c
Aziridine carbinol catalysts 1 were next employed in the
Friedel–Crafts alkylation reaction of N-methyl-indole with
a,b-unsaturated aldehydes. It has since long been estab-
lished21 that the pyrrole p-system is significantly more
active toward electrophilic substitution than indole, despite
the structural similarities.
1
2
3
4
5
6
7
1a-TFA
1b-TFA
1a-TFA
1a-TFA
1b-TFA
1b-TFA
1b-TFA
18
18
18
18
60
18
18
1
50
60
42
58
51
60
60
30
69
26
32
75
60
36
(S)
(S)
(S)
(S)
(S)
(S)
(S)
À20
40
40
70d
MWe
0.25
The reactions were performed in CH2Cl2/i-PrOH 85:15 as
the solvent and 10 mol % of catalyst as preformed TFA salt
was used. As shown in Table 4, the reaction was successful
with both aziridine carbinol catalysts 1a and 1b giving the
desired conjugate addition products 14 and 15 with moder-
ate enantioselectivity. In an attempt to improve the asym-
metric induction, the temperature was varied: lowering of
the temperature led to an improvement of the ee, with an
increase from 20% to 58% at À10 ꢁC (entries 3–5) when
(E)-crotonaldehyde 7b was employed and from 40% to
50% at À10 ꢁC for (E)-cinnamaldehyde 7a as the reactant
(entries 7 and 8). The results show that asymmetric cataly-
sis is less effective for indole than for pyrrole, as expected.
a The reactions were performed with an excess of N-methyl pyrrole in
order to avoid the bis-alkylation of the heteroaromatic ring; yield cal-
culated after chromatography.
b The ee was determined by chiral GLC (see Section 4).
c The absolute configuration was determined by chemical correlation.14
d 1,2-Dichloroethane as the solvent.
e Under microwave irradiation.
3-position of the aziridine ring 1b gave a great increase in
the ee (entry 2), whereas the presence of an electron with-
drawing substituent at the para-position of the phenyl ring,
as in 1c and the replacement of the hydroxy group by a
methoxy 4a or 4b had a detrimental effect on the asymmet-
ric induction. With these preliminary results in hand we
tried to optimize the reaction conditions by varying the
amount of catalysts and the temperature. The use of 5 or
20 mol % of catalyst led to the desired product with a dif-
ferent rate but with no effect on the ee. Variation of the
temperature only slightly affected the ee when catalyst 1a-
TFA was used (compare entries 1, 3, and 4). Conducting
the reaction with 1b-TFA at a higher temperature had a
beneficial effect, with an ee of 75% for compound 12 (entry
5). A further increase of temperature to 70 ꢁC using
1,2-dichloroethane instead of dichloromethane as the sol-
vent (entry 6) as well as the application of microwave irra-
diation (entry 7) led to a lowering of the asymmetric
induction.
Table 4. Organocatalyzed Friedel–Crafts alkylation of N-methyl indole
with (E)-crotonaldehyde 7b or (E)-cinnamaldehyde 7a
Entry Product
T
Time Catalyst Yielda eeb Abs.
(ꢁC) (h)
(%)
(%) Config.c
1
2
3
4
5
6
7
8
14
14
14
14
14
15
15
15
40 18
1a-TFA 66
6
0
20
40
58
0
—
—
0
18
18 18
30
1a-TFA 70
1b-TFA 78
1b-TFA 85
1b-TFA 30
1a-TFA 11
1b-TFA 42
1b-TFA 40
(S)
(S)
(S)
—
(S)
(S)
0
À10 48
18 48
18 48
À10 72
40
50
a Calculated after chromatography.
b Determined by HPLC analysis (Chiracel AD-H) of the alcohol obtained
by NaBH4 reduction of the aldehyde.
c The absolute configuration was determined by chemical correlation or by
comparison of the HPLC retention times with those reported in the
literature.
The scope of the organocatalytic Friedel–Crafts alkylation
was extended to the (E)-cinnamaldehyde 7a. The condi-
tions for the reaction with N-methyl-pyrrole are listed in
Table 3. The ee values were in all cases higher compared
to the corresponding reaction with the (E)-crotonaldehyde.
Also in this case, catalyst 1b with a methyl group on the
aziridine ring gave the best ee value, viz. 75% (Table 3,
3. Conclusion
A series of aziridine carbinol catalysts 1 was prepared with
the aim of investigating their capacity to asymmetrically
catalyze Diels–Alder reactions and Friedel–Crafts alkyl-
ations of N-methyl-pyrrole and N-methyl-indole using
a,b-unsaturated aldehydes. The Diels–Alder reaction took
place with moderate ee’s ranging from 10% to 66% with
catalyst 1a-HClO4 giving the best results. The asymmetric
alkylation of N-methyl-pyrrole with (E)-crotonaldehyde
7b as well as with (E)-cinnamaldehyde 7a, occurred with
ee values ranging from 26 to 75% with catalyst 1b-TFA.
The alkylation of N-methyl-indole with crotonaldehyde
or cinnamaldehyde took place with moderate enantioselec-
tivities (ee’s ranging from 6% to 58%). A Friedel–Crafts
alkylation performed with aziridinium TFA (1b-TFA)
salts, derived from threonine, gave the best results. All
Table 3. Organocatalyzed Friedel–Crafts alkylation of N-methyl pyrrole
with (E)-cinnamaldehyde 7a
Entry Catalyst Time T (ꢁC) Yielda (%) eeb (%) Abs.
(h)
Config.c
1
2
3
4
1a-TFA 18
1a-TFA 18
1b-TFA 18
1b-TFA 18
18
40
18
40
60
62
58
55
48
50
75
74
(S)
(S)
(S)
(S)
a The reactions were performed with an excess of N-methyl pyrrole in
order to avoid the bis-alkylation of the heteroaromatic ring; yield cal-
culated after chromatography.
b The ee was determined by chiral GLC (see Section 4).
c The absolute configuration was determined by chemical correlation.14

B. F. Bonini et al. / Tetrahedron: Asymmetry 17 (2006) 3135–3143
3139
the prepared aziridinium salts 1-HX are remarkably stable.
The actual intermediates in all these reactions must be the
iminium salt 16 derived from aziridine carbinol catalysts. It
is surprising that these species are sufficiently stable to
serve as reasonably effective chirality transferring interme-
diates in asymmetric carbon–carbon bond forming
reactions.
of the title compound as a white solid. Mp 158–159 ꢁC;
[a]D = À76.1 (c 0.72, CHCl3); MS (ESI) m/z: 626
(M+Na)+; 604 (M+1)+; Anal. Calcd for C36H27F6NO:
C, 71.63; H, 4.51; N, 2.32. Found; C, 71.69; H, 4.60, N,
2.29; IR (CCl4): 1070, 1133, 1169, 1325 and 3376 cmÀ1
;
1H NMR (600 MHz, CDCl3)
d
(ppm): 1.31 (d,
J = 6.3 Hz, 1H, Ha–CH2), 2.05 (d, J = 3.2 Hz, 1H, Hb–
CH2), 2.44 (dd, J = 6.3, 3.2 Hz, 1H, CH), 4.57 (s, 1H),
7.14–7.20 (m, 9H, ArCH), 7.27–7.31 (m, 6H, ArCH),
7.41–7.57 (3 d, J = 8.1 Hz, 8H, 2C6H4); 13C NMR
(150 MHz, CDCl3) d (ppm): 23.9 (CH2), 40.4 (CH), 73.8,
74.0 (C), 123.99 (q, 1J(CF) = 272 Hz, CF3), 124.06 (q,
R2
R2
H
OH
R2
R2
OH
R1
H
R1
N
N
X
X
1-HX
16
3
1J(CF) = 272 Hz, CF3), 125.0 (q, J(CF) = 3.8 Hz), 125.2
R
R1 = H, Me
(q, 3J(CF) = 3.8 Hz), 126.1, 126.5 127.05, 127.5, 129.2
(ArCH), 129.3 (q, 2J(CF) = 32.2 Hz, ArC), 129.4 (q,
2J(CF) = 32.7 Hz, ArC), 143.2, 148.4, 150.4 (ArC); 19F
NMR (376 MHz, CDCl3) d: À63.03, À63.05 (CF3). Proton
and carbon assignments were made by gCOSY and
gHSQC.
R2 = Ph, p-CF3-C6H4
-
-
X- = Cl-, ClO4 , CF3CO2
R = Me, Ph
4. Experimental
4.1. General methods
4.3. ((S)-Aziridin-2-yl)bis(4-[trifluoromethyl]phenyl)metha-
nol 1c
Unless stated otherwise, all reagents were obtained from
commercial suppliers and used without further purifica-
tion. Column chromatography was carried out with 70–
230 mesh silica gel. Light petroleum ether refers to the frac-
tion with a boiling range of 40–60 ꢁC. Melting points are
To a solution of 5c (3.7 g, 6.1 mmol) in a 1:1 mixture of
THF and MeOH (10 mL) cooled at 0 ꢁC, H2SO4 6 M
(22 mL), was added dropwise. The resulting mixture was
stirred at room temperature overnight. The white precipi-
tate was removed by Et2O extraction. NaOH 20% was
slowly added to the aqueous layer (pH = 12) until precipi-
tation of a white solid. The precipitate was then extracted
with CHCl3. The organic layer was dried over Na2SO4
and concentrated to dryness affording 1.55 g (4.3 mmol,
70% yield) of the title compound as a white solid.
Mp 151–153 ꢁC; [a]D = À14.7 (c 1.0, CHCl3); MS (ESI)
m/z: 384 (M+Na)+; 362 (M+1)+; Anal. Calcd for
C17H13F6NO: C, 56.52; H, 3.63; N, 3.88. Found; C,
56.58; H, 3.69, N, 3.82; IR (CCl4): 1068, 1130, 1160,
1
uncorrected. H and 13C NMR spectra were recorded at
400 and 100 MHz, respectively, in CDCl3 as solvent.
Chemical shifts are reported on the d scale and measured
in parts per million relative to residual CHCl3
(d = 7.26 ppm) for 1H NMR and to the central line of
CDCl3 (d = 77.0 ppm) for 13C NMR spectra. J values are
given in Hertz. 13C NMR spectra assignments were based
on the results of DEPT experiments. The manufacturer’s
software was used for DEPT, gradient-enhanced COSY,
as well as for the inversed-detected gradient selected hetero-
nuclear correlations gHMBC and gHSQC data analysis.
All the ESIMS spectra were performed using MeOH as
the solvent. [a]D values are given in 10À1 deg cm2 gÀ1. Ele-
mental analyses were performed using Flash EA1112 Auto-
matic Elemental Analyzer CE instruments. The originality
of all compounds was checked by a CAS on-line structure
search.
1
1321, 3341, and 3414 cmÀ1; H NMR (600 MHz, CDCl3)
d (ppm): 0.81 (br s, 1H), 1.73 (d, J = 3.5 Hz, 1H, Ha–
CH2), 1.96 (d, J = 6.0 Hz, 1H, Hb–CH2), 2.99 (m, 1H,
CH), 3.99 (br s, 1H), 7.54–7.58 (d, J = 8.2 Hz, 4H, ArCH),
7.59–7.62 (d, J = 8.2 Hz, 4H, ArCH); 13C NMR
(150 MHz, CDCl3) d (ppm): 21.9 (CH2), 36.3 (CH), 73.8
(C), 124.04 (q, 1J(CF) = 272 Hz, CF3), 124.06 (q,
1J(CF) = 272 Hz, CF3), 125.26 (q, 3J(CF) = 3.9 Hz),
Compounds 3a and 3b,19 5a and 5b19 and 1a and 1b19,20
were prepared following literature procedure.
3
125.34 (q, J(CF) = 3.9 Hz), 126.6, 126.8 (ArCH), 129.68
2
2
(q, J(CF) = 32.4 Hz, ArC), 129.70 (q, J(CF) = 32.2 Hz,
ArC), 148.3, 150.6 (ArC); 19F NMR (376 MHz, CDCl3)
d: À63.0 (CF3). Protons and carbons assignments were
made by gCOSY and gHSQC.
4.2. (2S)-1-Tritylaziridin-2-yl bis[4-(trifluoromethyl)-
phenyl]methanol 5c
To a stirred suspension of magnesium turnings (0.81 g,
33.3 mmol) in THF (5 mL) was gradually added 1-bromo-
4-(trifluoromethyl)benzene (5.0 g, 22.2 mmol) in THF
(20 mL). After heating the Grignard reagent for 1.5 h, com-
pound 3a (2.5 g, 7.3 mmol) in THF (25 mL) was added
dropwise over a period of 20 min. The reaction was moni-
tored with TLC and quenched after 1.5 h with saturated
aqueous (NH4)2SO4. The organic layer was extracted with
diethyl ether (3 · 50 mL), dried over Na2SO4, and concen-
trated. The crude product was purified by chromatography
(hexane/Et2O 10:1) affording 3.78 g (6.3 mmol, 86% yield)
4.4. Preparation of the HCl salts
The aziridine carbinol 1 (0.5 mmol) was dissolved in 4 mL
of Et2O and a solution of HCl 4 M in dioxane was added
(pH = 2). The precipitated white solid was washed twice
with diethyl ether, dried in vacuo, and used as catalyst
without any further purification.
4.4.1. ((S)-Aziridin-2-yl)diphenylmethanol-HCl salt 1a-HCl.
[a]D = +44.9 (c 1.00, MeOH); MS (ESI positive ions) m/z:
226 (M)+; MS (ESI negative ions) m/z: 262 (M37ClÀ1)À,

3140
B. F. Bonini et al. / Tetrahedron: Asymmetry 17 (2006) 3135–3143
260 (M35ClÀ1)À. IR (KBr): 1177, 1448, 1492, 1509, 2915,
sitive ions) m/z: 240 (M)+; MS (ESI negative ions) m/z: 113
2982, 3047, 3108, and 3272 cmÀ1
;
1H NMR (400
(CF3CO2)À. IR (KBr): 1208, 1450, 1550, 1661, 1689, 3033,
1
MHz, DMSO-d6) d (ppm): 2.68 (dd, J = 1.5, 7.0 Hz, 1H,
Ha–CH2), 2.83 (dd, J = 1.5, 5.9 Hz, 1H, Hb–CH2), 3.95
(dd, J1 = J2 = 6.5 Hz, 1H, CH), 6.42 (br s, 1H, OH),
7.23–7.58 (m, 10H, ArCH), 8.40 (br s, 2H, NH2). 13C
NMR (100 MHz, DMSO-d6) d (ppm): 24.5 (CH2), 42.0
(CH), 74.1 (C), 127.1, 127.2, 128.4, 128.5, 129.1, 129.2
(ArCH), 145.3, 145.9 (ArC).
3068, 3173, and 3291 cmÀ1; H NMR (400 MHz, DMSO-
d6) d (ppm): 1.48 (d, J = 6.3 Hz, 3H, CH3), 3.21 (m, 1H,
CH), 3.85 (d, J = 7.8 Hz, 1H, CH), 6.93 (br s, 1H, OH),
7.28–7.58 (m, 10H, ArCH), 8.67 (br s, 2H, NH2). 13C
NMR (100 MHz, DMSO-d6) d (ppm): 10.5 (CH3), 37.5,
46.6 (CH), 75.0 (C), 127.2, 127.3, 128.6, 129.2 (ArCH),
144.6, 147.2 (ArC).
4.4.2. (2S,3S)-3-Methylaziridin-2-yl(diphenyl)methanol HCl
salt 1b-HCl. [a]D = +43.2 (c 0.47, MeOH); MS (ESI posi-
tive ions) m/z: 240 (M)+; MS (ESI negative ions) m/z: 262
(M37ClÀ1)À, 260 (M35ClÀ1)À. IR (KBr): 1178, 1408, 1449,
4.6. Diels–Alder reaction
4.6.1. General procedure using the preformed salt 1-HCl.
To a solution of 1-HCl (0.05 mmol), in 1 mL of MeOH/
H2O (95:5 by volume) was added the a,b-unsaturated
aldehydes (1 mmol). The solution was stirred for 10 min
before the addition of cyclopentadiene (2 mmol). The
reaction was stirred for the given time and at the tempera-
ture reported in Table 1 and then diluted with Et2O and
washed with water. The organic layer was dried over
Na2SO4, filtered, and concentrated. endo/exo Ratios were
1536, 1611, 2890, 3040, 3260, 3387, and 3467 cmÀ1 1H
;
NMR (400 MHz, DMSO-d6)
d
(ppm): 1.49 (d,
J = 6.4 Hz, 3H, CH3), 3.12–3.16 (m, 1H, CH), 3.79 (d,
J = 7.9 Hz, 1H, CH), 6.82 (br s, 1H, OH), 7.35–7.52 (m,
10H, ArCH), 8.96 (br s, 2H, NH2). 13C NMR (100 MHz,
DMSO-d6) d (ppm): 10.4 (CH3), 37.2, 46.4 (CH), 75.1
(C), 127.17, 127.23, 128.56, 128.58, 129.18, 129.20 (ArCH),
144.6, 147.2 (ArC).
1
determined by H NMR on the crude reaction mixtures.
Chromatography (hexane/Et2O 10:1 as eluent) of the crude
afforded a mixture of aldehydes and dimethylacetals. The
mixture was completely acetalized with MeOH and cata-
lytic amounts of p-toluensulfonic acid for the ee
determination.
4.4.3. ((S)-Aziridin-2-yl)bis(4-(trifluoromethyl)phenyl)meth-
anol-HCl salt 1c-HCl. [a]D = +44.5 (c 0.47, MeOH); MS
(ESI positive ions) m/z: 362 (M)+; MS (ESI negative
ions) m/z: 398 (M37ClÀ1)À, 396 (M35ClÀ1)À. IR (KBr):
1071, 1118, 1170, 1331, 1619, 3200, and 3343 cmÀ1 1H
;
NMR (600 MHz, CD3OD) d (ppm): 3.05 (dd, J = 2.4,
7.4 Hz, 1H, Ha–CH2), 3.10 (dd, J = 2.4, 6.3 Hz, 1H, Hb–
CH2), 4.16 (dd, J1 = J2 = 7.0 Hz, 1H, CH), 7.65 (br d,
J = 8.5 Hz, 2H), 7.73 (m, 6H). 13C NMR (150 MHz,
CD3OD) d (ppm): 25.05 (CH2), 41.9 (CH), 72.9 (C),
4.6.2. General procedure using the in situ formed salt 1-
HClO4. To a suspension of 1 (0.1 mmol) in H2O
(0.2 mL), was added the a,b-unsaturated aldehydes
(1 mmol) and then 70% HClO4 (0.1 mmol). The solution
was stirred for 10 min before the addition of cyclopentadi-
ene (2 mmol). The reaction was stirred for the given time
and at the temperature reported in Table 1, and then
diluted with Et2O and washed with water. The organic
layer was dried over Na2SO4, filtered, and concentrated.
endo/exo Ratios were determined by 1H NMR on the crude
reaction mixtures. Chromatography (hexane/Et2O 10:1 as
eluent) of the crude afforded the aldehydes that were acetal-
ized for the determination of ee.
124.22 (q, 1J(CF) = 272 Hz, CF3), 124.28
(q,
1J(CF) = 271 Hz, CF3), 125.5 (q, 3J(CF) = 3.7 Hz, ArCH),
125.6 (q, 3J(CF) = 4.0 Hz, ArCH), 127.06, 127.70 (ArCH),
130.05 (q, 2J(CF) = 37.7 Hz, ArC), 130.07 (q,
2J(CF) = 37.1 Hz, ArC), 147.21, 148.06 (ArC); 19F NMR
(376 MHz, CD3OD) d: À64.7, À64.6 (CF3).
4.5. Preparation of the TFA salts
The aziridine carbinol 1 (0.5 mmol) was dissolved in 4 mL
of Et2O and trifluoroacetic acid (0.6 mmol) was added. The
precipitated white solid was washed twice with diethyl
ether, dried in vacuo, and used as catalyst without any
further purification.
4.6.3. endo-3-Phenylbicyclo[2.2.1]hept-5-ene-2-carboxalde-
hyde 8.22 1H NMR (400 MHz, CDCl3) d (ppm): 1.59–
1.65 (m, 1H), 1.79–1.84 (m, 1H), 2.98 (ddd, J = 2.3, 3.5,
4.9 Hz, 1H), 3.09 (dd, J = 1.6, 4.9 Hz, 1H), 3.14 (br s,
1H), 3.34 (br s, 1H), 6.17 (dd, J = 2.8, 5.8 Hz, 1H), 6.42
(dd, J = 3.3, 5.8 Hz, 1H), 7.13–7.34 (m, 5H), 9.60 (d,
J = 2.3 Hz, 1H).
4.5.1. ((S)-Aziridin-2-yl)diphenylmethanol-TFA salt 1a-TFA.
[a]D = +31.3 (c 0.67, MeOH); MS (ESI positive ions) m/z:
226 (M)+; MS (ESI negative ions) m/z: 113 (CF3CO2)À.
IR (KBr): 1206, 1393, 1447, 1493, 1587, 1651, 3065, 3136,
4.6.4. exo-3-Phenylbicyclo[2.2.1]hept-5-ene-2-carboxalde-
hyde 8. 1H NMR (400 MHz, CDCl3) d (ppm): 1.53–1.59
(m, 2H), 2,60 (ddd, J = 2.3, 3.5, 4.9 Hz, 1H), 3.22 (m,
2H), 3.72 (dd, J = 3.4, 4.9 Hz, 1H), 6.07 (dd, J = 3.2,
5.8 Hz, 1H), 6.34 (dd, J = 3.5, 5.8 Hz, 1H), 7.13–7.34 (m,
5H), 9.92 (d, J = 2.1 Hz, 1H). The endo/exo ratio was
1
3217, and 3380 cmÀ1; H NMR (400 MHz, DMSO-d6) d
(ppm): 2.54 (dd, J = 1.6, 7.0 Hz, 1H, Ha–CH2), 2.98 (dd,
J = 6.0, 1.6 Hz, 1H, Hb–CH2), 3.70 (dd, J = 6.0, 7.0 Hz,
1H, CH), 7.21–7.46 (m, 10H, ArCH). 13C NMR
(100 MHz, DMSO-d6) d (ppm): 24.3 (CH2), 41.6 (CH),
77.45 (C), 126.0, 126.5, 128.2, 128.8, 129.05 (ArCH),
143.3, 145.7 (ArC).
1
determined by H NMR analysis (400 MHz): d 9.60 (d,
J = 2.3 Hz, 1H, CHO endo), 9.93 (d, J = 2.3 Hz, 1H,
CHO exo).
4.5.2. (2S,3S)-3-Methylaziridin-2-yl(diphenyl)methanol TFA
salt 1b-TFA. [a]D = +35.2 (c 0.885, MeOH); MS (ESI po-
4.6.5.
endo-5-(Dimethoxymethyl)-6-phenylbicyclo[2.2.1]-
1
hept-2-ene 10. MS (ESI) m/z: 267 (M+Na)+. H NMR

B. F. Bonini et al. / Tetrahedron: Asymmetry 17 (2006) 3135–3143
3141
(400 MHz, CDCl3) d (ppm): 1.52–1.57 (2br dd, 1H, Ha–
CH2), 1.77 (d, J = 8.7 Hz, 1H, Hb–CH2), 2.40 (dd,
J = 1.5, 4.8 Hz, 1H, CH), 2.51–2.56 (m, 1H, CH), 2.87
(br s, 1H, CH), 2.96 (br s, 1H, CH), 3.13 (s, 3H, OCH3),
3.33 (s, 3H, OCH3), 3.94 (d, J = 9.0 Hz, 1H, CH(OCH3)2),
6.16 (dd, J = 2.8, 5.7 Hz, 1H, CH@), 6.36 (td, J = 2.8,
5.7 Hz, 1H, CH@), 7.12–7.37 (m, 5H, ArCH).
1.44–1.48 (2br dd, 1H, Ha–CH2), 1.82–1.86 (m, 1H), 2.63
(br s, 1H, CH), 2.66 (br s, 1H, CH), 3.30 (s, 3H, OCH3),
3.31 (s, 3H, OCH3), 4.18 (d, J = 8.6 Hz, 1H, CH(OCH3)2),
6.06 (dd, J = 2.9, 5.7 Hz, 1H, CH@), 6.22 (dd, J = 2.9,
5.8 Hz, 1H, CH@). 13C NMR (100 MHz, CDCl3) d
(ppm): 19.1 (CH3), 37.4, 44.9 (CH), 47.1 (CH2), 47.9,
49.6 (CH), 52.4, 53.8 (OCH3), 108.6 (CH), 134.9, 137.5
(CH@). Protons and carbons assignments were made by
gCOSY and gHSQC.
4.6.6. exo-5-(Dimethoxymethyl)-6-phenylbicyclo[2.2.1]hept-
2-ene 10. MS (ESI) m/z: 267 (M+Na)+. 1H NMR
(400 MHz, CDCl3) d (ppm): 1.46–1.52 (m, 1H, Ha–CH2),
1.68 (d, 1H, J = 8.6 Hz, Hb–CH2), 2.03 (ddd, J = 1.6, 5.1,
8.2 Hz, 1H, CH), 2.90 (d, J = 1.4, 4.9 Hz, 1H, CH), 3.00
(br s, 1H, CH), 3.07 (s, 3H, OCH3), 3.12 (dd, J = 3.4,
5.1 Hz, 1H), 3.38 (s, 3H, OCH3), 4.37 (d, J = 8.3 Hz, 1H,
CH(OCH3)2), 5.94 (dd, J = 2.9, 5.6 Hz, 1H, CH@), 6.36
(td, J = 2.8, 5.7 Hz, 1H, CH@), 7.12–7.37 (m, 5H, ArCH).
Protons and carbon assignments were made by gCOSY
and gHSQC.
The ee was determined in the presence of (S)-(+)-1-(9-an-
thryl)-2,2,2-trifluoroethanol as the chiral solvating agent
in CD2Cl2. The singlets of the methoxy group of the endo
and exo acetals 11 were split into two: 3.27, 3.29 (s, 3H,
OCH3 endo-isomer); 3.30, 3.31 (s, 3H, OCH3 exo-isomer).
4.7. Alkylation of N-methyl-pyrrole. General procedure
A 10 mL vial equipped with a magnetic stir bar was
charged with the appropriate aziridine-salt (0.10 equiv),
2 mL of CH2Cl2/i-PrOH (85:15 by volume), then cooled
at the desired temperature. The solution was stirred for
5 min before the N-methyl-pyrrole (5 equiv) was added.
After stirring for 5 min, the a,b-unsaturated aldehyde
(1 equiv) was added in one portion. The resulting suspen-
sion was stirred at constant temperature until complete
consumption of the aldehyde as determined by TLC. The
reaction mixture was then passed through a silica gel plug
using Et2O as eluent and then concentrated. The resulting
residue was purified by silica gel chromatography (hex-
ane/EtOAc 5:1) to afford the title compound. The ee was
determined by GLC analysis of the aldehyde.
The ee was determined in the presence of (S)-(+)-1-(9-an-
thryl)-2,2,2-trifluoroethanol as the chiral solvating agent
in CDCl3. The singlets of the methoxy group of the exo
and endo acetals 10 were split into two: 3.30, 3.31 (s, 3H,
OCH3 endo-isomer); 3.34, 3.35 (s, 3H, OCH3 exo-isomer).
4.6.7. endo-3-Methylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde
9.22 1H NMR (400 MHz, CDCl3) d (ppm): 1.17 (d,
J = 6.9 Hz, 3H), 1.44–1.51 (m, 1H), 1.55–1.60 (m, 1H),
1.77–1.87 (m, 1H), 2.34 (dd, J = 3.2, 4.3 Hz, 1H), 2.56
(br s, 1H), 3.13 (br s, 1H), 6.05 (dd, J = 2.8, 5.6 Hz,
1H), 6.29 (dd, J = 3.0, 5.8 Hz, 1H), 9.37 (d, J = 3.2 Hz,
1H).
4.6.8. exo-3-Methylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde
9.11 1H NMR (400 MHz, CDCl3) d (ppm): 0.90 (d,
J = 6.9 Hz, 3H), 1.44–1.48 (m, 2H), 1.70–1.73 (m, 1H),
2.37–2.45 (m, 1H), 2.79 (br s, 1H), 3.02 (br s, 1H), 6.16
(dd, J = 5.7, 3.0 Hz, 1H), 6.24 (dd, J = 5.7, 3.1 Hz, 1H)
9.78 (d, J = 2.8 Hz, 1H). The endo/exo ratio was deter-
mined by 1H NMR analysis (400 MHz): d 9.37 (d,
J = 3.2 Hz, 1H, CHO endo), 9.78 (d, J = 2.8 Hz, 1H,
CHO exo).
4.7.1. (R)-3-(1-Methyl-1H-pyrrol-2-yl)-butanal 12.14 1H
NMR (400 MHz, DMSO-d6) d (ppm): 1.15 (d, J =
6.8 Hz, 3H, CH3), 2.56 (ddd, J = 2.0, 7.6, 17.2 Hz, 1H,
CH2), 2.72 (ddd, J = 2.0, 6.8, 17.2 Hz, 1H, CH2), 3.32–
3.42 (m, 1H, CH), 3.53 (s, 3H, N–CH3), 5.75 (dd,
J = 1.6, 3.2 Hz, 1H, ArCH), 5.85 (t, J = 3.2 Hz, 1H,
ArCH), 6.56 (t, J = 2.2 Hz, 1H, ArCH), 9.61 (t, J =
1.8 Hz, 1H, CHO). The ee was determined by GLC analy-
sis of the aldehyde (RT-BetaDEX-sm 50 ꢁC, 5 ꢁC/min; (S)-
isomer rt = 26.8 min and (R)-isomer rt = 26.5 min). Abso-
lute configuration was determined via reduction to the cor-
responding alcohols and comparison of specific rotation.
4.6.9.
endo-5-(Dimethoxymethyl)-6-methylbicyclo[2.2.1]-
hept-2-ene 11. MS (ESI) m/z: 159 (M+Na)+. H NMR
(400 MHz, CD2Cl2) d (ppm): 1.11 (d, J = 6.3 Hz, 3H,
CH3), 1.16 (m, 1H, CH), 1.34–136 (2br dd, 1H, Ha–
CH2), 1.47–1.50 (2br dd, 1H, Ha–CH2), 1.76–1.82 (m,
1H, CH), 2.38 (br s, 1H, CH), 2.76 (br s, 1H, CH), 3.27
(s, 3H, OCH3), 3.29 (s, 3H, OCH3), 3.72 (d, J = 9.2 Hz,
1H, CH(OCH3)2), 5.98 (dd, J = 2.9, 5.8 Hz, 1H, CH@),
6.22 (dd, J = 2.9, 5.8 Hz, 1H, CH@). 13C NMR
(100 MHz, CDCl3) d (ppm): 21.1 (CH3), 36.8, 44.7 (CH),
45.9 (CH2), 49.1, 50.5 (CH), 52.0, 53.6 (OCH3), 108.6
(CH), 133.5, 138.3 (CH@). Protons and carbons assign-
ments were made by gCOSY and gHSQC.
1
4.7.2.
(S)-3-Phenyl-3-(1-methyl-1H-pyrrol-2-yl)-propanal
13.14 1H NMR (400 MHz, DMSO-d6) d (ppm): 2.89
(ddd, J = 1.6, 6.8, 16.8 Hz, 1H, CH2), 3.09 (ddd, J = 2.0,
8.4, 16.8 Hz, 1H, CH2), 3.30 (s, 3H, N–CH3), 4.63 (t,
J = 7.6 Hz, 1H, CH), 5.92 (t, J = 3.0 Hz, 1H, ArCH),
5.99–5.98 (m, 1H, ArCH), 6.59 (t, J = 2.0 Hz, 1H, ArCH),
7.15–7.29 (m, 5H, ArCH), 9.61 (t, J = 1.6 Hz, 1H, CHO).
The ee was determined by GLC analysis of the alde-
hyde (RT-BetaDEXsm isotherm 160 ꢁC; (S)-isomer
rt = 35.1 min and (R)-isomer rt = 34.1 min). Absolute con-
figuration was determined via reduction to the correspond-
ing alcohols and comparison of optical rotation power.
4.6.10.
exo-5-(Dimethoxymethyl)-6-methylbicyclo[2.2.1]-
1
hept-2-ene 11. MS (ESI) m/z: 159 (M+Na)+. H NMR
(400 MHz, CD2Cl2) d (ppm): 0.85 (d, J = 6.7 Hz, 3H,
CH3), 1.12 (m, 1H), 1.34–136 (2br dd, 1H, Ha–CH2),

3142
B. F. Bonini et al. / Tetrahedron: Asymmetry 17 (2006) 3135–3143
4.8. Alkylation of N-methyl-indole. General procedure
Acknowledgments
A 10 mL vial equipped with a magnetic stir bar was
charged with the aziridine-salt (0.10 equiv), 2 mL of
CH2Cl2/iPrOH (85:15), and then cooled to the desired tem-
perature. The solution was stirred for 5 min before the a,b-
unsaturated aldehyde (2.5 equiv) was added. After stirring
for 5 min, the N-methyl indole (1 equiv) was added in one
portion. The resulting suspension was stirred at constant
temperature until complete consumption of the N-methyl-
indole as determined by TLC. The reaction mixture was
then passed through a silica gel plug using diethyl ether
as eluent and then concentrated. The resulting residue
was purified by silica gel chromatography (hexane/EtOAc
10:1) to afford the title compound. The ee was determined
by HPLC analysis of the alcohol obtained by NaBH4
reduction of the aldehyde.
We acknowledge financial support by the University of
Bologna (ex 60% mpi) and by the National Project ‘Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni’
2005.
References
1. (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A.
K., Ed.; Wiley-VCH: Weinheim, Germany, 2006; (b) Hou, X.
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Vol. 1A, p 1.
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Int. Ed. Engl. 1994, 33, 599–619.
4.8.1. 3-(1-Methyl-1H-indol-3-yl)-butanal 14.15 1H NMR
(400 MHz, CDCl3) d (ppm): 1.44 (d, J = 7.2 Hz, 3H,
CH3), 2.71 (ddd, J = 2.7, 6.9, 16.2 Hz, 1H, CH2), 2.88
(ddd, J = 2.7, 6.9, 16.2 Hz, 1H, CH2), 3.68 (dt, J = 6.9,
13.8 Hz, 1H, CH), 3.75 (s, 3H, N–CH3), 6.84 (s, 1H,
ArCH), 7.12 (ddd, J = 1.5, 7.4, 8.1 Hz, 1H, ArCH), 7.21–
7.32 (m, 2H, ArCH), 7.63 (d, J = 7.8 Hz, 1H, ArCH),
9.75 (dd, J = 2.1, 2.1 Hz, 1H, CHO).
4. Willems, J. G. H.; Dommerholt, F. J.; Hammink, J. B.;
Vaarhorst, A. M.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1995, 36, 603–606.
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Synlett 1999, 1571–1572.
6. Tanner, D.; Korno, H. T.; Guijarro, D.; Andersson, P. G.
Tetrahedron 1998, 54, 14213–14232.
7. Rasmussen, T.; Norrby, P.-O. J. Am. Chem. Soc. 2003, 125,
5130–5138.
4.8.2.
3-(1-Methyl-1H-indol-3-yl)-butanol. 1H
NMR
(400 MHz, CDCl3) d (ppm): 1.44 (d, J = 6.9 Hz, 3H,
CH3), 1.90–2.12 (m, 2H, CH2), 3.20–3.30 (m, 1H, CH),
3.66–3.72 (m, 2H, CH2), 3.76 (s, 3H, N–CH3), 6.88 (s,
1H, ArCH), 7.16 (d, J = 7.5 Hz, 1H, ArCH), 7.25–7.35
(m, 2H, ArCH), 7.71 (d, J = 7.8 Hz, 1H, ArCH). The ee
was determined by HPLC using a Chiralcel AD-H (95:5
hexane/iPrOH 0.75 mL/min), (S)-isomer rt = 19.68 min
and (R)-isomer rt = 21.07 min.
8. (a) Andersson, P. G.; Guijarro, D.; Tanner, D. Synlett 1996,
727–728; (b) Andersson, P. G.; Guijarro, D.; Tanner, D. J.
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9. Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. J.
Org. Chem. 2005, 70, 4248–4256.
4.8.3. 3-(1-Methyl-1H-indol-3-yl)-3-phenyl-propanal 15.15
1H NMR (400 MHz, CDCl3) d (ppm): 3.10 (4d, J = 2.7,
8.4, 16.5 Hz, 1H, Ha–CH2), 3.22 (4d J = 2.7, 8.4, 16.5 Hz,
1H, Hb–CH2), 3.76 (s, 3H, NCH3), 4.88 (dd,
J1 = J2 = 7.5 Hz, 1H, Ph–CH), 6.88 (s, 1H, NCH), 7.04
(ddd, J = 1.2, 6.9, 8.1 Hz, 1H, ArH), 7.19–7.26 (m, 2H,
ArH), 7.28–7.36 (m, 5H, ArH), 7.43 (dt, J = 0.9, 8.0 Hz,
1H, ArH), 9.76 (dd, J = 2.8, 1.8 Hz, 1H, CHO).
10. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40,
3726–3748; (b) Asymmetric Organocatalysis: From Biomi-
metic Concepts to Applications in Asymmetric Synthesis;
Berkessel, A., Gro¨ger, H., Eds.; Wiley-VCH: Weinheim,
2005; (c) Special issue: Asymmetric Organocatalysis, Acc.
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Catalysis Issue, Adv. Synth. Catal. 2004, 346, 1005–1250; (e)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138–5175; (f) Special issue: Organocatalysis in Organic
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Chem. Soc. 2000, 122, 4243–4244.
12. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. 2002,
124, 2458–2460.
13. (a) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2000, 122, 9874–9875; (b) Karlsson, S.;
Ho¨gberg, H.-E. Tetrahedron: Asymmetry 2002, 13, 923–
926.
14. Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 4370–4371.
4.8.4. 3-(1-Methyl-1H-indol-3-yl)-3-phenyl-propanol. 1H
NMR (400 MHz, CDCl3) d (ppm): 2.28 (m, 1H, Ha–
CH2), 2.46 (m, 1H, Hb–CH2), 3.68 (m, 2H, CH2), 3.75 (s,
3H, NCH3), 4.39 (dd, J1 = J2 = 7.8 Hz, 1H, Ph–CH), 6.90
(s, 1H, NCH), 7.01 (ddd, J = 1.1, 6.9, 8.0 Hz, 1H, ArH),
7.14–7.20 (m, 1H, ArH), 7.24–7.30 (m, 2H, ArH) 7.31–
7.35 (m, 4H, ArH), 7.46 (dt, J = 0.9, 8.0 Hz, 1H, ArH).
The ee was determined by HPLC analysis of the alcohol,
obtained by NaBH4 reduction of the aldehyde, using a Chi-
ralcel AD-H (90:10 hexane/iPrOH 1.0 mL/min), (S)-isomer
rt = 43.5 min and (R)-isomer rt = 35.6 min.
15. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 1172–1173.

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