Asymmetric synthesis of 1-(2-pyrrolyl)alkylamines by the addition of organometallic reagents to chiral 2-pyrroleimines

Article abstract of DOI:10.1002/ejoc.200700597

The addition of organometallic (lithium, magnesium, zinc) reagents to 2-pyrroleimines derived from (S)-valinol and (S)-phenylglycinol gave N-substituted-1-(2-pyrrolyl)alkylamines with high yields and diastereoselectivities. The (S,S)-diastereomers were useful intermediates for the preparation of enantiopure 1-[1-(2-pyrrolyl)alkyl]aziridines by routine cyclization of the β-amino alcohol moiety and for the preparation of (S)-N-benzoyl 1-[1-(2-pyrrolyl)alkyl]amines and their N-substituted derivatives by oxidative cleavage of the chiral auxiliary. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700597

FULL PAPER
DOI: 10.1002/ejoc.200700597
Asymmetric Synthesis of 1-(2-Pyrrolyl)alkylamines by the Addition of
Organometallic Reagents to Chiral 2-Pyrroleimines
Giuseppe Alvaro,[a] Romano Di Fabio,[a] Andrea Gualandi,[b] and Diego Savoia*[b]
Keywords: Amines / Asymmetric synthesis / Imines / Organometallic reagents / Pyrrole
The addition of organometallic (lithium, magnesium, zinc)
reagents to 2-pyrroleimines derived from (S)-valinol and (S)-
phenylglycinol gave N-substituted-1-(2-pyrrolyl)alkylamines
with high yields and diastereoselectivities. The (S,S)-dia-
stereomers were useful intermediates for the preparation of
zation of the β-amino alcohol moiety and for the preparation
of (S)-N-benzoyl 1-[1-(2-pyrrolyl)alkyl]amines and their N-
substituted derivatives by oxidative cleavage of the chiral
auxiliary.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
enantiopure 1-[1-(2-pyrrolyl)alkyl]aziridines by routine cycli- Germany, 2007)
Introduction
Lewis acid and an electron-withdrawing N-substituent, or
The chiral 1-(2-pyrrolyl)alkylamino moiety highlighted in an iminium ion, possibly formed in situ (three-component
structure 1 (Scheme 1) bears a stereocenter at the benzylic Mannich reaction).[4] For example, the BF3-mediated ad-
carbon (one configuration is shown) and is a common dition of pyrrole to (S)-N-trifluoromethylidene-1-phenyl-
structural motif in non-cinchona indole alkaloids[1] and ter- ethylamine occurred with good yield but only moderate dia-
pene indole alkaloids,[2] both of which display potent bio- stereoselectivity (dr 78:22), whereas indole reacted (at C-
logical and physiological properties. Mytosene aziridines 3) with complete stereocontrol.[4d] In contrast, an allylic 3-
are also important compounds containing this skeleton methylene-2,3-dihydro-2-indolylindium species generated
fragment.[3]
by a Pd–In bimetallic cascade process from 2-iodo-N-allen-
Given their enormous importance, synthetic methods ylaniline added to enantiopure N-[(R)-tert-butylsulfinyl]
have been developed for these compounds, but efficient glyoxylate imine with complete stereocontrol.[4f]
asymmetric procedures for the construction of the hetero-
The 1,2-(indolyl)alkylamino moiety has been commonly
benzylic stereocenter are still lacking. In principle, this goal prepared by the intramolecular version of this approach,
can be accomplished during the formation of any of the namely, the Pictet–Spengler reaction, which has been a key
four bonds involved. Three of these possibilities concern the step in the synthesis of a large number of alkaloids.[1s,1t,5,6]
formation of bonds a, b, and c as described in Scheme 1. In this reaction, an imine or iminium ion functionality,
For example, the a bond in compounds of type 1 can be which is formed in situ by N-functionalization of trypt-
formed by the inter- or intramolecular attack of the nucleo- amine and its substituted derivatives by reaction with an
philic pyrrole C-2 carbon at the electrophilic carbon of an aldehyde, undergoes intramolecular attack by the indole C-
azomethine compound, which is generally activated by a 2 carbon. Although the reaction often gives mixtures of dia-
Scheme 1.
[a] GlaxoSmithKline, Psychiatry Centre of Excellence for Drug
Discovery,
Via Fleming 4, 37135 Verona, Italy
[b] Dipartimento di Chimica “G. Ciamician”, Università di
Bologna,
stereomers, a number of highly stereoselective reactions
have been reported that rely on the asymmetric induction
of the stereocenter(s) present in the tryptamine aliphatic
chain, the aldehyde, or the amine substituent (chiral auxil-
iary). To the best of our knowledge, the Pictet–Spengler re-
action has rarely been applied to a pyrrole derivative.[1u]
Via Selmi 2, 40126 Bologna, Italy
Fax: +39-051-2099456
E-mail: diego.savoia@unibo.it
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G. Alvaro, R. Di Fabio, A. Gualandi, D. Savoia
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Alternatively, the stereocenter in structure 1 can be con- izine esters gave the corresponding amines by reaction with
structed by formation of bond b from azomethine com- ammonia and alkylamines, but loss of the stereochemical
pounds of type 3.[5t,7] For example, quinolizidine alkaloids integrity of the stereocenter was observed, which points to
have often been prepared by a sequence of steps where a an SN1 mechanism for these reactions.[17]
tetracyclic quaternary 2-indolyliminium ion (R-substituted
Following this extensive literature search, we observed
N-charged cyclic structure 3) was formed by the Bischler– that the asymmetric synthesis of 1-(2-pyrrolyl)alkylamines
Napieralski reaction between indole and lactam rings, then was scarcely explored relative to the analogous indole deriv-
subjected to catalytic hydrogenation or hydride reduction. atives. So, we were prompted to study the auxiliary-induced
More recently, novel polycyclic indolyldiamines have been diastereoselective addition of organometallic reagents to 2-
prepared by completely diastereoselective hydride re- pyrroleimines to fill the gap in our long-term investigation
ductions of chiral, optically pure 2-indolylketimines.[7f]
on the asymmetric synthesis of benzylic and heterobenzylic
The construction of bond c involves the addition of a amines from chiral imines.[18] It should also be noted that
carbon nucleophile or an organometallic reagent to 2-pyr- optimization of this route would open an avenue to op-
rolealdimine 3. However, 2-pyrrole- and 2-indoleimines are tically pure compounds with the pyrrolidine, pyrrolizidine
less electrophilic than other aromatic imines owing to the and indolizidine skeletons,[19] including alkaloids and phar-
electron-donating effect of the pyrrole/indole ring. For ex- macologically interesting molecules, by taking advantage of
ample, 9-benzyl-3,4-dihydro-β-carboline was unreactive the possible hydrogenation of the pyrrole nucleus[20] and the
towards a laterally metalated pyridine, although a success- nucleophilicity of the pyrrole/pyrrolidine nitrogen atom.
ful reaction was observed when the imine was preliminarily
activated by the addition of trimethylsilyl trifluoromethane-
sulfonate.[1d] Similarly, the Lewis acid promoted addition of Results and Discussion
a ketene silyl acetal to a β-carboline hydrochloride derived
Optically pure phenylglycinol and valinol are among the
from -tryptophan[1r] and the addition of allyltrimethylsil-
most used chiral auxiliaries for the diastereoselective ad-
ane to iminium ions derived from -tryptophan[8] have been
described. Benzylic and allylic organometallic reagents re-
dition of organometallic reagents to imines.[21] In particular,
we described that the addition of organolithium reagents to
2-pyridineimines derived from (S)-valinol and (S)-phenyl-
acted smoothly with analogous imines bearing N-aryl or N-
benzenesulfonyl substituents.[9] Recently, the chiral auxil-
glycinol occurred effectively and with very high diastereo-
iary approach was exploited for the asymmetric synthesis
selectivity following the protection of the OH functionality
of 2-(1-aminoalkyl)indoles by the addition of laterally met-
as its trimethylsilyl ether.[18] Hence, we began our investiga-
tion on N,O-disilylated imine 6, which was prepared in two
steps and in almost quantitative yield from 2-pyrrolealde-
hyde and (S)-phenylglycinol through intermediary unpro-
alated 3-cyano-4-methylpyridine to a 1,3-disubstituted 2-in-
doleimine derived from an optically pure sulfinamide and a
de of 82% was obtained under the optimized conditions.[10]
Recently, a ring-substituted 2-pyrroleimine prepared from
(R)-phenylglycinol underwent highly diastereoselective
tected imine 4 (Scheme 2).
addition of isopropylmagnesium chloride (4–5 equiv.),
whereas the addition of allylzinc bromide to an analogous
imine prepared from (R)-phenyl glycineamide was unsatis-
factory.[11] In the addition of an optically pure allylsilane to
an acylhydrazone derived from 2-pyrrolealdehyde, the yield
and ee values were found to be dependent on the pyrrole
N-substitution: a lower yield (49%) but a higher ee value
(92%) was obtained with the N-Boc pyrrole imine with re-
spect to the unprotected imine (ee 48%).[12] Interestingly,
tricyclic pyrrole–pyrazine–oxazole structures were prepared
from 2-formylpyrroles derived from (S)-α-amino esters and
(+)- or (–)-norephedrine. However, the potential of such
compounds as precursors of chiral iminium ions, suitable
substrates for the addition of Grignard reagents, eventually
leading to 2-(1-aminoalkyl)pyrroles, has not yet been con-
sidered.[13]
Another widely exploited method for the asymmetric
synthesis of polycyclic indole alkaloids by construction of
the C–R bond c in structure 1 is the Diels–Alder cycload-
dition of β-carbolines and 2-indoleimine with 1,4-
Scheme 2.
The addition of organolithium reagents to imine 6 was
dienes.[14,15] Notably, a chiral 2-pyrroleimine failed to react carried out in diethyl ether at –15 or 0 °C, as no reaction
with 1,3-butadiene.[16] For the sake of completeness, the C– was observed at lower temperatures. By using 2–3 equiv. of
N bond can also be formed by nucleophilic substitution of the organometallic reagents, good yields of β-hy-
oxygen-substituted compounds. For example, dihydropyrrol- droxyamines 7 were obtained after protonolysis and de-
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Asymmetric Synthesis of 1-(2-Pyrrolyl)alkylamines
silylation of the organometallic adducts with ammonium tively. This choice required the use of an excess amount of
fluoride in the biphasic system THF/H2O (Table 1). The the organometallic reagent, as the first two equivalents were
(S,S) configuration of the prevalent diastereomer in prod- quenched by the acidic OH and NH functionalities. More-
ucts 7 was assumed on the basis of the sense of asymmetric over, it was expected that the negatively charged pyrrole
induction previously determined in organometallic reac- substituent would decrease the reactivity of the imine func-
tions of analogous aromatic and heteroaromatic imines.[18] tionality. As a matter of fact, the addition of MeLi
Very high diastereoselectivity (dr Ͼ95%) was observed in (4 equiv.) to imine 4 in THF occurred smoothly at –15 to
the formation of amines 7a and 7b with MeLi and nBuLi, 0 °C to give amine 7a in 96% yield with a dr Ͼ95 (Table 2).
respectively, and the main diastereomers (S,S)-7a,b were Similarly, the reaction with nBuLi under the same condi-
isolated in good yields after column chromatography. tions gave amine 7b in high yield and with (almost) com-
Homoallylic amine 7e was then prepared by using either plete diastereoselectivity; only one diastereomer was ob-
1
allylzinc bromide or allylmagnesium chloride in tetra- served by H NMR spectroscopic analysis of the crude re-
hydrofuran, but a better diastereoselectivity was obtained action mixture. Similarly, the addition of iPrMgCl pro-
with the magnesium reagent (dr 90:10 vs. Ͼ96:4). Instead, ceeded smoothly to give 7c in 92% yield and with complete
no reaction was observed with vinylmagnesium bromide.
diastereoselectivity.
In contrast, the addition of tBuLi occurred with quite
poor diastereoselectivity, although the two diastereomers of
7d could be separated by column chromatography. A low
conversion of imine 4 was observed by TLC and GC analy-
ses after the addition of allylzinc bromide; however, the use
of allylmagnesium chloride allowed homoallylic amine 7e
to be obtained in good yield and with high diastereoselec-
tivity (dr Ͼ95:5). The higher yield and complete stereocon-
trol were then obtained by using 4 equiv. of the allyldiethyl-
zincate prepared by the addition of allylmagnesium chloride
to diethylzinc.[21] Aiming to reduce the overall excess of or-
ganometallic reagents, we subsequently developed a more
economic protocol that involved the preliminary addition
of diethylzinc (2 equiv.) to imine 4, followed by the addition
of allylmagnesium chloride (2 equiv.); in this way, homoal-
Table 1. Preparation of amines 7 by the addition of organometallic
reagents to imine 6.[a]
RM (equiv.)
Solvent
dr[b]
(S,S)-7, Yield [%][c]
MeLi (3)
nBuLi (3)
AllylZnBr (2)
AllylMgCl (2)
VinylMgCl (3)
Et2O
Et2O
THF
THF
Et2O
Ͼ95:5
Ͼ95:5
Ͼ90:10
Ͼ96:4
–
7a, 87
7b, 82
7e, 81
7e, 83
no reaction
[a] The organometallic reagent was slowly added to the imine at
–15 °C, and the mixture was then stirred for 3 h allowing the tem-
perature to reach 20 °C. [b] Determined by 1H NMR spectroscopic
analysis. [c] The crude product was treated with NH4F (3 equiv.)
and a catalytic amount of TBAF in THF/H2O (1:1), then subjected
to column chromatography (SiO2).
Subsequently, taking into account a recent report,[11] we lylic amine 7e was obtained in almost identical yield and
wished to check the reactivity of unprotected imines 4 and with complete stereocontrol. Good results were also ob-
5 derived from (S)-phenylglycinol and (S)-valinol, respec- tained by using benzylmagnesium chloride to afford amine
Table 2. Preparation of amines 7 and 8 by the addition of organometallic reagents to imines 4 and 5 in THF.[a]
Imine
Y
RM (equiv.)
dr[b]
(S,S)-7, (S,S)-8, Yield [%][c]
4
4
4
4
4
4
4
4
4
4
4
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
MeLi (4)
nBuLi (4)
Ͼ95:5
Ͼ99:1
Ͼ95:5
55:45
–
Ͼ95:5
Ͼ99:1
Ͼ99:1
Ͼ95:5
–
7a, 96
7b, 91
iPrMgCl (4)
7c, 92
tBuLi (4)[d]
(S,S)-7d, 31; (R,S)-7d, 28
allylZnBr (4)
allylMgCl (4)
allylEt2ZnMgCl (4)
1. Et2Zn (2), 2. allylMgCl (2)
BnMgCl (4)
vinylMgBr (4)
PhMgBr (4)
7e, 10[b,e]
7e, 87
7e, 89
7e, 86
7f, 91
7g, 0
–
7h, 0
PhLi (4)
Ͼ95:5
7h, 95[f]
5
5
5
5
5
5
5
iPr
iPr
iPr
iPr
iPr
iPr
iPr
MeLi (4)
nBuLi (4)
1. Et2Zn (2), 2. allylMgCl (2)
allylMgCl (4)
BnMgCl (4)
1. MeLi (2), 2. vinylLi (2)
PhLi (4)
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ95:5
8a, 91
8b, 87
8e, 89
8e, 78
8f, 90
8g, 92[f]
8h, 91[f]
[a] The organometallic reagent (4 equiv.) was slowly added to the imine at –15 °C, and the mixture was stirred for 3 h allowing the
temperature to reach 20 °C. [b] Determined by 1H NMR spectroscopic analysis. [c] Yield of the pure (S,S)-diastereomer that was isolated
by column chromatography (SiO2). [d] The reaction was performed in Et2O. [e] The product was not isolated. [f] The product decomposed
during chromatography on SiO2.
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G. Alvaro, R. Di Fabio, A. Gualandi, D. Savoia
FULL PAPER
7f in high yield and with dr Ͼ95:5. No reaction was ob-
served with vinylmagnesium bromide or phenylmagnesium
bromide; however, phenyllithium proved to be more reac-
tive and gave desired amine 7h. Unfortunately, crude amine
7h decomposed upon attempted purification by column
chromatography perhaps owing to the acidity of the meth-
ine proton linked to the carbon stereocenter.
We then moved to evaluate the degree of asymmetric in-
duction offered by (S)-valinol-derived 2-pyrroleimine 5 in
the same organometallic reactions carried out on imine 4.
We were delighted to observe that even better results were
obtained, as complete stereocontrol was achieved in the
preparation of amines 8a,b,e–h (Table 2). These results are
in line with the previously observed evidence that better
stereocontrol was provided by valinol as the chiral auxiliary
for imines with respect to phenylglycinol.[18] The reaction
with tert-butyllithium was not carried out, as we had no
chance to improve significantly the diastereoselectivity pre-
viously obtained with imine 4. β-Amino alcohols 8g,h were
obtained by using vinyllithium and phenyllithium, respec-
tively. Vinyllithium was prepared by the reaction of tri(n-
butyl)vinyltin and nBuLi; however, we found it more conve-
nient to initially add two equivalents of MeLi to imine 5,
as the first two equivalents of the organometallic reagent
are consumed by the acidic NH and OH groups, followed
by the addition of another two equivalents of vinyllithium.
As previously observed with amine 7h, novel amines 8g,h
underwent decomposition during attempted chromato-
graphic purification. Nevertheless, it is likely that crude
amines 7h and 8g,h, which were obtained with satisfactory
purity, could be used as such in subsequent steps involving
transformation of the alkene functionality.
Scheme 3.
cedure on the valinol derivatives 8; in this case, the crude
compounds were preferably treated with benzoyl chloride
and potassium carbonate in acetone/H2O mixture to easily
obtain the corresponding pure N-benzoyl derivatives
12a,b,e,f in good yields.
At this point we assessed the possibility of using β-amino
alcohol 7 for the construction of new optically active, pyr-
role-containing molecules, such as aziridines by intramolec-
ular cyclization and secondary amines through oxidative
cleavage of the chiral auxiliary (Scheme 3). For the first goal
we followed the same protocol previously applied for the
synthesis of analogous 1-(2-pyridyl)alkylaziridines.[18b,18c]
As a matter of fact, pyrrole–aziridines 9a,b,f were success-
fully obtained in high yields by treatment of β-hy-
droxyamines 7a,b,f with triphenylphosphane and dieth-
ylazodicarboxylate (DEAD) in THF at room temperature.
The hydrogenolysis of 7a with ammonium formate and
Pd/C in ethanol at reflux gave disappointing results, as a
complex mixture of products was obtained. Instead, the
oxidation reaction with the use of periodic acid and methyl-
amine in THF/H2O was successful; however, starting from
β-amino alcohols 7b,c,e, benzaldimines 10b,c,e were iso-
lated, and they were stable towards hydrolysis under the
reaction conditions. In particular, imine 10c was isolated as
a solid and could be purified simply by washing with pen-
tane. Crude imines 10b,c,e were readily reduced to corre-
sponding benzylamines 11b,c,e by sodium borohydride in
methanol (Scheme 3). It is noteworthy that this procedure
is more convenient than the usual stepwise removal of the
chiral auxiliary followed by N-benzylation. The primary
Conclusions
We developed a convenient asymmetric route to 1-[2-
(pyrrolyl)]alkylamines by exploiting the highly diastereo-
selective addition of organometallic reagents to chiral 2-
pyrroleimines derived from (S)-phenylglycinol and (S)-vali-
nol. Although a larger excess of organometallic reagents
was needed, better diastereoselectivities were obtained by
working with the imines with unprotected N–H and O–H
functionalities. Complete or excellent stereocontrol was
achieved, especially with the (S)-valinol-derived imine. Re-
moval of the chiral auxiliaries was achieved by an oxidative
procedure to give the corresponding imines or primary
amines, from which the N-benzyl and N-benzoylamines
could be easily prepared. Pyrrole–aziridines were also pre-
pared by cyclization of the (S)-phenylglycinol derived sec-
ondary amines. Future efforts in our laboratory will be de-
voted to converting unsaturated amines 7h and 8g,h into
bicyclic compounds by linking the pyrrole-NH and alkene
functionalities.
Experimental Section
General: Melting points are uncorrected. Optical rotations were
amines were formed by carrying out the oxidative pro- measured with a digital polarimeter in a 1-dm cell and [α]D values
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Asymmetric Synthesis of 1-(2-Pyrrolyl)alkylamines
1
are given in 10–1 degcm3 g–1. H NMR spectra were recorded with
7.37 (m, 2 H), 7.51 (m, 3 H), 8.26 (s, 1 H) ppm. 13C NMR
Varian Inova and Gemini instruments for samples in CDCl3, which
was stored over Mg: 1H NMR chemical shifts are reported relative
to CHCl3 (δH = 7.27 ppm), and assignments are given as follows:
s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m
= multiplet, br. s = broad singlet, dd = doublet of doublets, and dt
= doublet of triplets. Infrared spectra were recorded with a Nicolet
FT-380 spectrometer. MS spectra were taken at an ionizing voltage
of 70 eV with a Hewlett–Packard 5975 spectrometer with GLC in-
jection. Molecular weight was determined with an Agilent Technol-
ogies MS 1100 instrument. Chromatographic separations were per-
formed on columns of SiO2 (Merck, 230–400 mesh) at medium
pressure. All the organic, inorganic, and organometallic reagents
and reactants and anhydrous solvents were purchased from Ald-
rich.
(75 MHz, CDCl3): δ = –0.5, 1.6, 67.6, 77.3, 100.4, 120.5, 127.1,
127.8, 128.2, 129.5, 141.4, 153.0 ppm. IR (KBr): ν = 3105, 3062,
˜
2962, 2908, 2857, 1640, 1451, 1425, 1247, 1122, 1084, 1051, 916,
902, 842, 739, 700 cm–1. GC–MS: m/z (%) = 255 (100), 73 (34), 183
(22), 150 (19), 343 (15), 358 (12). C19H30N2OSi2 (358.19): calcd. C
63.63, H 8.43, N 7.81; found C 63.48, H 8.45, N 7.79.
Preparation of β-Amino Alcohols 7 and 8. Typical Procedure: Meth-
yllithium (1.6  in diethyl ether, 2.4 mL, 3.8 mmol) was added to a
magnetically stirred solution of imine 4 (0.203 g, 0.95 mmol) in
THF (15 mL) cooled to –15 °C. After 30 min, the reaction mixture
was slowly warmed to room temperature and stirring was contin-
ued for 24 h. The mixture was quenched by the addition of a satu-
rated aqueous solution of NaHCO3 (10 mL) at 0 °C, and the or-
ganic material was then extracted with diethyl ether (3ϫ10 mL).
The collected ethereal layer was dried with Na2SO4 and concen-
trated to leave the crude product. The diastereomeric ratio was de-
termined by 1H NMR spectroscopic analysis. Flash column
chromatography (SiO2; cyclohexane/ethyl acetate, 1:1) gave product
7a. This compound and all β-amino alcohols 7 and 8 prepared,
decomposed on attempted GC–MS and HPLC–MS analyses.
Preparation of Imines 4 and 5: To a solution of (S)-phenylglycinol
(0.823 g, 6 mmol) or (S)-valinol (0.618 g, 6 mmol) in anhydrous
CH2Cl2 (30 mL) was added anhydrous MgSO4 (5 g) and 2-pyr-
rolecarboxaldehyde (0.571 g, 6 mmol), and the mixture was stirred
overnight. The solid was filtered off through a pad of Celite, and
the organic phase was concentrated under reduced pressure. The
residue was crystallized from pentane/CH2Cl2 (5:1) to give the im-
ine, which was used in the following step without purification.
(S)-N-[(S)-1-(2-Pyrrolyl)ethyl]phenylglycinol (7a): Yield: 0.210 g
(96%). White solid. M.p. 86.9–87.4 °C (Et2O). [α]2D0 = +34.5 (c =
0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.39 (d, J = 6.7 Hz,
3 H), 2.66 (br. s, 2 H), 3.57 (dd, J = 8.1 Hz, J = 10.8 Hz, 1 H),
3.74 (dd, J = 4.3 Hz, J = 10.8 Hz, 1 H), 3.80 (q, J = 6.7 Hz, 1 H),
3.96 (dd, J = 4.3 Hz, J = 8.1 Hz, 1 H), 5.97 (m, 1 H), 6.13 (m, 1
H), 6.97 (m, 1 H), 7.34 (m, 5 H), 8.68 (br. s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.0, 47.7, 61.1, 66.8, 104.4, 107.9, 116.7,
(S)-N-(2-Pyrrolmethylidene)phenylglycinol (4): Yield: 1.262 g
(98%). White solid. M.p. 109–109.6 °C. [α]2D0 = +24.3 (c = 1.1,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 4.03 (dd, J = 3.6 Hz, J2
= 12.2 Hz, 1 H), 4.20 (dd, J = 9.9 Hz, J = 12.2 Hz, 1 H), 4.46 (dd,
J = 3.6 Hz, J = 9.9 Hz, 1 H), 6.20 (m, 2 H), 6.99 (m, 1 H), 7.38
(m, 5 H), 7.75 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
67.9, 76.6, 109.6, 117.7, 122.9, 126.9, 127.4, 128.6, 128.9, 140.7,
127.3, 127.7, 128.7, 135.6, 140.4 ppm. IR (nujol): ν = 3295, 2090,
˜
2955, 2928, 2854, 1540, 1459, 1261, 1090, 735 cm–1. C14H18N2O
(230.14): calcd. C 73.01, H 7.88, N 12.16; found C 72.82, H 7.91,
N 12.15.
154.6 ppm. IR (KBr): ν = 3331, 3113, 3061, 2921, 2854, 1640, 1425,
˜
1366, 1313, 1073, 1061, 1043, 813, 737, 701 cm–1. GC–MS: m/z (%)
= 183 (100), 156 (12), 214 (7), 80 (7). C13H14N2O (214.11): calcd.
C 72.87, H 6.59, N 13.07; found C 72.57, H 6.62, N 13.10.
(S)-N-[(S)-1-(2-Pyrrolyl)pentyl]phenylglycinol (7b): Yield: 0.235 g
(91%). Yellow oil. [α]2D0 = +48.6 (c = 0.7, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 0.88 (t, J = 7.3 Hz, 3 H), 1.24 (m, 4 H),
1.74 (m, 2 H), 2.51 (br. s, 2 H), 3.59 (dd, J = 7.5 Hz, J = 10.8 Hz,
1 H), 3.72 (dd, J = 4.3 Hz, J = 8.0 Hz, 1 H), 3.77 (dd, J = 4.5 Hz,
J = 10.8 Hz, 1 H), 3.91 (dd, J = 4.4 Hz, J = 7.5 Hz, 1 H), 5.97 (m,
1 H), 6.13 (q, J = 2.8 Hz, 1 H), 6.69 (m, 1 H), 7.23–7.43 (m, 5 H),
8.54 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0, 22.7,
25.6, 27.9, 53.3, 61.2, 66.1, 105.4, 107.8, 116.7, 127.1, 127.5, 128.6,
(S)-N-(2-Pyrrolmethylidene)valinol (5): Yield: 1.051 g (97%). White
solid. M.p. 122.4–123 °C. [α]2D0 = +121.5 (c = 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 0.86 (d, J = 6.9 Hz, 3 H), 0.92 (d, J =
6.9 Hz, 3 H), 1.81 (sept, J = 6.9 Hz, 1 H), 2.92 (dd, J = 3.5 Hz, J
= 8.8 Hz, 1 H), 3.83 (dd, J = 3.5 Hz, J = 11.8 Hz, 1 H), 3.96 (dd,
J = 8.8 Hz, J = 11.8 Hz, 1 H), 6.16 (dd, J = 2.6 Hz, J = 3.6 Hz, 1
H), 6.26 (m, 1 H), 6.89 (m, 1 H), 7.66 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 19.0, 19.6, 30.7, 64.5, 78.3, 109.3, 116.7,
134.0, 140.9 ppm. IR (neat): ν = 3424, 3023, 2856, 2863, 1495,
˜
122.3, 129.0, 153.7 ppm. IR (KBr): ν = 3239, 3114, 3085, 2966,
˜
1391, 1264, 1093, 1021 cm–1. C17H24N2O (272.19): calcd. C 74.96,
H 8.88, N 10.28; found C 74.85, H 8.89, N 10.26.
2924, 2868, 2843, 1633, 1473, 1419, 1373, 1359, 1317, 1217, 1131,
1075, 1053, 1035, 934, 824, 761, 735 cm–1. GC–MS: m/z (%) = 149
(100), 80 (47), 137 (38), 68 (26), 106 (24), 180 (23). C10H16N2O
(180.13): calcd. C 66.63, H 8.95, N 15.54; found C 66.31, H 8.98,
N 15.51.
(S)-N-[(S)-2-Methyl-1-(2-pyrrolyl)propyl]phenylglycinol (7c): Yield:
0.243 g (92%). Yellowish oil. [α]2D0 = +32.4 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 0.93 (d, J = 6.7 Hz, 3 H), 0.97 (d,
J = 6.7 Hz, 3 H), 2.02 (dsept, J = 5.7 Hz, J = 6.7 Hz, 1 H), 2.50
(br. s, 2 H), 3.61 (dd, J = 5.8 Hz, J = 10.2 Hz, 1 H), 3.67 (d, J =
5.7 Hz, 1 H), 3.78 (dd, J = 4.5 Hz, J = 5.7 Hz, 1 H), 3.84 (dd, J =
4.5 Hz, J = 10.2 Hz, 1 H), 5.98 (m, 1 H), 6.15 (q, J = 2.8 Hz, 1 H),
6.65 (m, 1 H), 7.25–7.39 (m, 5 H), 8.39 (br. s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 18.0, 19.7, 32.2, 59.5, 61.2, 63.4, 106.3,
107.6, 114.2, 127.1, 127.2, 127.3, 128.5, 132.2, 141.2 ppm. IR
(S)-N-[(1-Trimethylsilylpyrrol-2-yl)methylidene]phenylglycinol Tri-
methylsilyl Ether (6): Crude imine 4 (1.26 g, 5.9 mmol) was dis-
solved in CH2Cl2 (20 mL), and triethylamine (1.23 g, 12 mmol) and
chlorotrimethylsilane (1.30 g, 12 mmol) were added to the solution
cooled to 0 °C. After 3 h, the solvent was removed under reduced
pressure. A solution of cyclohexane/diethyl ether (1:1, 50 mL) was
added, and the solid precipitate was filtered off through a pad of
Celite. The organic solvent was evaporated under reduced pressure
to leave imine 6, which was used in the following step without puri-
fication. Yield: 2.074 g (98%). White solid. M.p. 94.2–94.9 °C (pen-
tane/Et2O, 5:1). [α]2D0 = –48.1 (c = 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 0.11 (s, 9 H), 0.58 (s, 9 H), 3.93 (d, J =
6.7 Hz, 2 H), 4.37 (t, J = 6.7 Hz, 1 H), 6.36 (dd, J = 2.6 Hz, J =
3.3 Hz, 1 H), 6.78 (dd, J = 1.5 Hz, J = 3.3 Hz, 1 H), 7.05 (m, 1 H),
(neat): ν = 3422, 3024, 2853, 2865, 1492, 1261, 1099, 1021,
˜
742 cm–1. C16H22N2O (258.17): calcd. C 74.38, H 8.58, N 10.84;
found C 74.15, H 8.60, N 10.83.
(S)-N-[(S)-2,2-Dimethyl-1-(2-pyrrolyl)propyl]phenylglycinol [(S,S)-
7d]: Yield: 0.081 g (31%). Yellowish oil. [α]2D0 = +40.7 (c = 1.0,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.98 (s, 9 H), 2.15 (br.
s, 2 H), 3.51 (s, 1 H), 3.59 (dd, J = 5.9 Hz, J = 8.1 Hz, 1 H), 3.63
Eur. J. Org. Chem. 2007, 5573–5582
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5577

G. Alvaro, R. Di Fabio, A. Gualandi, D. Savoia
(dd, J = 8.1 Hz, J = 12.2 Hz, 1 H), 3.83 (dd, J = 5.9 Hz, J = 116.7, 135.7 ppm. IR (neat): ν = 3394, 2961, 2927, 2874, 1465,
FULL PAPER
˜
12.2 Hz, 1 H), 5.92 (m, 1 H), 6.08 (q, J = 2.7 Hz, 1 H), 6.55 (m, 1
1373, 1262, 1104, 1029, 793, 747, 720 cm–1. MS (EI): m/z = 197 [M
H), 7–21–7.32 (m, 5 H), 8.07 (br. s, 1 H) ppm. 13C NMR (75 MHz, + H]+, 94 [M – valinol]+. C11H20N2O (196.16): calcd. C 67.31, H
CDCl3): δ = 27.1, 35.4, 61.5, 64.2, 64.3, 107.0, 107.6, 115.8, 127.1,
10.27, N 14.27; found C 67.02, H 10.30, N 14.23.
127.3, 128.4, 132.0, 142.1 ppm. IR (neat): ν = 3425, 2953, 2868,
˜
(S)-N-[(S)-1-(2-Pyrrolyl)pentyl]valinol (8b): Yield: 0.207 g, 0.173 g
(87%, from 1 mmol of 5). Yellow oil. [α]2D0 = –4.6 (c = 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 5.2 Hz, 3 H), 0.89
(d, J = 6.7 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 1.25 (m, 4 H), 1.62
(m, 2 H), 1.74 (m, 1 H), 1.98 (br. s, 2 H), 2.36 (ddd, J = 4.3 Hz, J
= 5.3 Hz, J = 8.0 Hz, 1 H), 3.41 (dd, J = 5.6 Hz, J = 10.8 Hz, 1
H), 3.64 (dd, J = 4.1 Hz, J = 10.8 Hz, 1 H), 3.77 (dd, J = 5.9 Hz,
J = 8.0 Hz, 1 H), 5.99 (m, 1 H), 6.13 (q, J = 2.9 Hz, 1 H), 6.72 (m,
1 H), 8.42 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.8,
18.5, 19.2, 22.5, 26.4, 29.2, 36.3, 54.2, 60.3, 61.1, 105.5, 107.4,
2867, 1478, 1391, 1362, 1260, 1095 cm–1. C17H24N2O (272.19):
calcd. C 74.96, H 8.88, N 10.28; found C 74.98, H 8.91, N 10.26.
(S)-N-[(R)-2,2-Dimethyl-1-(2-pyrrolyl)propyl]phenylglycinol [(S,R)-
7d]: Yield: 0.072 g (28%). Yellowish oil. [α]2D0 = +109.6 (c = 1.9,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.39 (s, 9 H), 2.33 (br.
s, 2 H), 3.26 (s, 1 H), 3.55 (dd, J = 4.6 Hz, J = 8.1 Hz, 1 H), 3.61
(dd, J = 8.1 Hz, J = 10.0 Hz, 1 H), 3.68 (dd, J = 4.6 Hz, J =
10.0 Hz, 1 H), 5.97 (m, 1 H), 6.19 (m, 1 H), 6.77 (m, 1 H), 7.22 (2
H), 7.31–7.40 (m, 3 H), 8.44 (br. s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 27.0, 34.8, 61.7, 63.1, 66.7, 107.6, 108.3, 116.5, 127.4,
116.6, 134.0 ppm. IR (neat): ν = 3362, 3301, 3101, 2957, 2929,
˜
2860, 1567, 1464, 1026, 925, 792, 717 cm–1. MS (EI): m/z = 136.1
[M – nBu]+. C14H26N2O (238.20): calcd. C 70.54, H 10.99, N 11.75;
found C 70.59, H 10.97, N 11.71.
127.7, 128.6, 130.4, 140.1 ppm. IR (neat): ν = 3425, 3029, 2853,
˜
2868, 1492, 1392, 1363, 1260, 1096, 1028 cm–1. C17H24N2O
(272.19): calcd. C 74.96, H 8.88, N 10.28; found C 74.82, H 8.89,
N 10.26.
(S)-N-[(S)-1-(2-Pyrrolyl)-3-buten-1-yl]valinol (8e): Yield: 0.173 g
(78%, from 1 mmol of 5). Yellow oil. [α]2D0 = –12.4 (c = 1.1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.87 (d, J = 6.8 Hz, 3 H), 0.93
(d, J = 6.8 Hz, 3 H), 1.74 (sept, J = 6.8 Hz, 1 H), 1.96 (br. s, 2 H),
2.37 (dd, J = 4.1 Hz, J = 5.3 Hz, 1 H), 2.46 (dd, J = 6.7 Hz, J =
6.9 Hz, 2 H), 3.43 (dd, J = 5.3 Hz, J = 10.8 Hz, 1 H), 3.68 (dd, J
= 4.1 Hz, J = 10.8 Hz, 1 H), 3.90 (t, J = 6.7 Hz, 1 H), 5.08–5.17
(m, 2 H), 5.76 (m, 1 H), 6.01 (m, 1 H), 6.14 (q, J = 2.7 Hz, 1 H),
6.72 (m, 1 H), 8.52 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 18.7, 19.3, 29.2, 41.3, 53.3, 60.4, 61.2, 105.3, 107.8, 116.6, 117.4,
(S)-N-[(S)-1-(2-Pyrrolyl)-3-buten-1-yl]phenylglycinol (7e): Yield:
0.217 g (89%). Yellow oil. [α]2D0 = +16.5 (c = 0.4, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 2.40 (br. s, 2 H), 2.79 (m, 2 H), 3.84 (dd,
J = 7.6 Hz, J = 10.8 Hz, 1 H), 4.01 (dd, J = 4.5 Hz, J = 10.8 Hz,
1 H), 4.09 (t, J = 5.9 Hz, 1 H), 4.19 (dd, J = 4.5 Hz, J = 7.6 Hz, 1
H), 5.36 (dd, J = 10.8 Hz, J = 17.2 Hz, 2 H), 6.01 (m, 1 H), 6.23
(m, 1 H), 6.38 (d, J = 2.7 Hz, 1 H), 6.91 (dd, J = 1.5 Hz, J =
2.7 Hz, 1 H), 7.52–7.61 (m, 5 H), 8.73 (br. s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 38.9, 52.5, 61.3, 66.4, 105.3, 108.0, 116.7,
117.9, 127.3, 127.7, 128.7, 133.6, 134.7, 140.3 ppm. IR (neat): ν =
˜
133.9, 135.1 ppm. IR (neat): ν = 3296, 3090, 3062, 2956, 2928,
˜
2858, 1582, 1454, 1379, 1264, 1093, 1027, 934 cm–1. MS (EI): m/z
= 120 [M – valinol]+. C13H22N2O (222.17): calcd. C 70.23, H 9.97,
N 12.60; found C 69.96, H 9.99, N 12.58.
3364, 3102, 3076, 2958, 2930, 2873, 1466, 1437, 1093, 1044, 2026,
914, 796, 717 cm–1. C16H20N2O (256.16): calcd. C 74.97, H 7.86, N
10.93; found C 75.02, H 7.87, N 10.89.
(S)-N-[(S)-2-Phenyl-1-(2-pyrrolyl)ethyl]phenylglycinol (7f): Yield:
0.265 g (91%). White solid. M.p. 115.2–116.2 °C (pentane/Et2O,
1:1). [α]2D0 = +82.5 (c = 1.1, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.94 (br. s, 2 H), 3.08 (d, J = 6.6 Hz, 2 H), 3.55 (dd, J = 7.4 Hz,
J = 10.8 Hz, 1 H), 3.71 (dd, J = 4.3 Hz, J = 10.8 Hz, 1 H), 3.86
(dd, J = 4.3 Hz, J = 7.4 Hz, 1 H), 3.08 (t, J = 6.6 Hz, 1 H), 5.98
(m, 1 H), 6.12 (q, J = 6.7 Hz, 1 H), 6.63 (m, 1 H), 7.09 (m, 2 H),
7.24–7.38 (m, 8 H), 8.19 (br. s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 42.3, 54.9, 61.6, 66.1, 105.3, 108.0, 116.6, 126.4, 127.2,
(S)-N-[(S)-2-Phenyl-1-(2-pyrrolyl)ethyl]valinol (8f): Yield: 0.245 g
(90%, from 1 mmol of 5). White solid. M.p. 109.5–110.8 °C (pen-
tane/Et2O, 1:1). [α]2D0 = –9.8 (c = 0.8, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.84 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H),
1.58 (br. s, 2 H), 1.69 (sept, J = 6.8 Hz, 1 H), 2.29 (dd, J = 4.1 Hz,
J = 4.9 Hz, 1 H), 2.91 (dd, J = 7.6 Hz, J = 13.6 Hz, 1 H), 3.00 (dd,
J = 6.0 Hz, J = 13.6 Hz, 1 H), 3.34 (dd, J = 4.9 Hz, J = 11.2 Hz,
1 H), 3.53 (dd, J = 4.1 Hz, J = 11.2 Hz, 1 H), 2.29 (dd, J = 6.0 Hz,
J = 7.6 Hz, 1 H), 5.59 (m, 1 H), 6.14 (q, J = 2.7 Hz, 1 H), 6.69 (m,
1 H), 7.10–7.16 (m, 2 H), 7.20–7.32 (m, 3 H), 8.33 (br. s, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 19.0, 19.5, 29.4, 44.4, 55.4, 60.4,
61.5, 105.3, 108.1, 116.4, 126.5, 128.4, 129.2, 134.1, 138.8 ppm. IR
127.6, 128.2, 128.6, 129.3, 133.7, 138.5, 140.8 ppm. IR (nujol): ν =
˜
3353, 3028, 2926, 2856, 1539, 1453, 1261, 1094, 1027, 749 cm–1.
C20H22N2O (306.17): calcd. C 78.40, H 7.24, N 9.14; found C
78.50, H 7.27, N 9.11.
(KBr): ν = 3295, 3021, 2948, 2818, 1711, 1492, 1457, 1361, 1334,
˜
1095, 1040, 989, 798, 753, 729, 728, 714, 700 cm–1. MS (EI): m/z =
170 [M – valinol]+. C17H24N2O (272.19): calcd. C 74.96, H 8.88, N
10.28; found C 74.62, H 8.91, N 10.25.
(S)-N-[(S)-1-Phenyl-1-(2-pyrrolyl)methyl]phenylglycinol (7h): The
crude compound (0.263 g, 95%) was not purified owing to decom-
position during column chromatography. Relevant absorptions for
1
structural identification were drawn from H NMR spectroscopic
(S)-N-[(S)-1-(2-Pyrrolyl)-2-propen-1-yl]valinol (8): The crude com-
pound (0.191 g, 92%) could not be purified owing to decomposi-
tion during column chromatography. The structure was confirmed
1
analysis. H NMR (300 MHz, CDCl3): δ = 3.22 (br. s, 2 H), 3.62–
6.70 (m, 3 H), 4.73 (s, 1 H), 5.84 (m, 1 H), 6.13 (q, J = 3.1 Hz, 1
H), 6.71 (m, 1 H), 7.26–7.49 (m, 10 H), 8.54 (br. s, 1 H) ppm. The
compound was not eluted by GC–MS analysis.
1
1
by H NMR spectroscopic analysis. H NMR (300 MHz, CDCl3):
δ = 0.91 (d, J = 6.9 Hz, 3 H), 0.97 (d, J = 6.9 Hz, 3 H), 1.87 (m, 1
(S)-N-[(S)-1-(2-Pyrrolyl)ethyl]valinol (8a): Yield: 0.179 g (91%, H), 2.58 (dd, J = 4.1 Hz, J = 7.2 Hz, 1 H), 3.39 (dd, J = 7.2 Hz, J
from 1 mmol of 5). Yellow oil. [α]2D0 = –7.7 (c = 0.9, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 0.89 (d, J = 6.8 Hz, 3 H), 0.95 (d,
J = 6.8 Hz, 3 H), 1.39 (d, J = 6.5 Hz, 3 H), 1.77 (sept, J = 6.8 Hz,
1 H), 2.2 (br. s, 2 H), 2.45 (dd, J = 4.1 Hz, J = 6.2 Hz, 1 H), 3.64
= 10.7 Hz, 1 H), 3.66 (dd, J = 4.1 Hz, J = 10.7 Hz, 1 H), 4.43 (d,
J = 7.6 Hz, 1 H), 5.18 (dd, J = 1.4 Hz, J = 10.0 Hz, 1 H), 5.25 (dd,
J = 1.4 Hz, J = 17.4 Hz, 1 H), 5.90 (ddd, J = 7.6 Hz, J = 10.0 Hz,
J3 = 17.4 Hz, 1 H), 6.07 (m, 1 H), 6.17 (t, J = 3.1 Hz, 1 H), 6.75
(dd, J = 6.2 Hz, J = 10.8 Hz, 1 H), 3.39 (dd, J = 4.1 Hz, J = (dd, J = 1.4 Hz, J = 2.7 Hz, 1 H), 8.78 (br. s, 1 H) ppm. 13C NMR
10.8 Hz, 1 H), 4.01 (q, J = 6.5 Hz, 1 H), 6.02 (m, 1 H), 6.15 (m, 1
H), 6.72 (m, 1 H), 8.55 (br. s, 1 H) ppm. 13C NMR (75 MHz, 108.1, 116.0, 117.1, 132.8, 139.5 ppm. The compound was not
CDCl3): δ = 18.4, 19.3, 22.3, 29.2, 48.9, 60.0, 61.1, 104.4, 107.8, eluted by GC–MS analysis.
(75 MHz, CDCl3): δ = 17.9, 19.3, 28.8, 57.3, 60.6, 61.1, 105.3,
5578
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5573–5582

Asymmetric Synthesis of 1-(2-Pyrrolyl)alkylamines
(S)-N-[(S)-1-Phenyl-1-(2-pyrrolyl)methyl]valinol (8h): The crude
compound (0.235 g, 91%) could not be purified owing to decompo-
sition during column chromatography. The structure was con-
firmed by 1H NMR spectroscopic analysis. 1H NMR (300 MHz,
CDCl3): δ = 0.95 (d, J = 6.9 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3 H),
1.95 (m, 1 H), 2.07 (br. s, 2 H), 2.45 (dd, J = 4.1 Hz, J = 6.8 Hz,
1 H), 3.40 (dd, J = 6.8 Hz, J = 10.8 Hz, 1 H), 3.58 (dd, J = 4.1 Hz,
solvent was evaporated under reduced pressure, and the organic
materials were extracted with Et2O (3ϫ20 mL). The collected ethe-
real layer was dried with Na2SO4 and concentrated to leave inter-
mediate imine 10b. This was dissolved in MeOH and NaBH4
(0.75 mmol, 0.028 g) was added at 0 °C. After 1 h, the mixture was
quenched with H2O (5 mL), and the mixture was then concentrated
to remove most of the MeOH. The organic materials were extracted
J = 10.8 Hz, 1 H), 5.05 (s, 1 H), 6.01 (m, 1 H), 6.14 (q, J = 3.1 Hz, with Et2O (3ϫ20 mL). and the collected ethereal layer was dried
1 H), 6.71 (m, 1 H), 7.29–7.45 (m, 5 H), 8.32 (br. s, 1 H) ppm. The
compound was not eluted by GC–MS analysis.
with Na2SO4 and concentrated to leave a yellow oil that was sub-
jected to flash chromatography (SiO2; cyclohexane/ethyl acetate,
8:2) to give compound 11b (0.39 mmol) as a yellow oil.
Preparation of Aziridines 9. Typical Procedure: To a solution of β-
amino alcohol 7a (0.299 g, 1.3 mmol) in THF (20 mL) was added
PPh3 (0.511 g, 1.95 mmol) and then DEAD (0.340 g, 1.95 mmol)
(S)-N-[1-(2-Pyrrolyl)butyl]benzaldimine (10b): Yield: 0.117 g (93%),
1
Ͼ90% pure. Brown oil. H NMR (300 MHz, CDCl3): δ = 0.98 (t,
was added dropwise. After stirring for 4 h, the mixture was concen- J = 6.4 Hz, 3 H), 1.32 (m, 4 H), 1.94 (m, 2 H), 4.44 (t, J = 6.6 Hz,
trated under reduce pressure, and the residue was subjected to flash
chromatography (SiO2; cyclohexane/ethyl acetate, 9:1) to give com-
pound 9a as yellow oil.
1 H), 6.09 (m, 1 H), 6.18 (q, J = 2.9 Hz, 1 H), 6.74 (m, 1 H), 7.45
(m, 3 H), 7.79 (m, 2 H), 8.32 (s, 1 H), 8.57 (br. s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 160.6, 136.0, 134.0, 130.7, 128.5,
128.2, 116.6, 108.0, 104.3, 68.7, 32.3, 28.5, 22.5, 14.0 ppm. GC–
MS: m/z (%) = 106 (100), 80 (60), 136 (56), 183 (56), 93 (16), 240
(7).
(S)-2-Phenyl-1-[(S)-1-(2-pyrrolyl)ethyl]aziridine (9a): Yield: 0.240 g
(87%). Yellow oil. [α]2D0 = +85.4 (c = 0.8, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.54 (d, J = 6.6 Hz, 3 H), 1.89 (d, J =
3.5 Hz, 1 H), 2.10 (d, J = 6.7 Hz, 1 H), 2.55 (dd, J = 3.5 Hz, J =
6.6 Hz, 1 H), 2.93 (q, J = 6.6 Hz, 1 H), 6.02 (m, 1 H), 6.16 (q, J =
2.8 Hz, 1 H), 6.66 (m, 1 H), 7.21–7.35 (m, 5 H), 8.44 (br. s, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 22.0, 36.8, 41.1, 63.2, 104.4,
(S)-N-[2-Methyl-1-(2-pyrrolyl)propyl]benzaldimine (10c): Yield:
0.096 g (85%). White solid. M.p. 135.2–135.8 °C (pentane). [α]2D0
–31.2 (c = 0.7, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.92 (d,
J = 6.7 Hz, 3 H), 0.96 (d, J = 6.7 Hz, 3 H), 2.12 (dsept, J = 6.6 Hz,
J = 6.7 Hz, 1 H), 4.14 (d, J = 6.6 Hz, 1 H), 6.06 (m, 1 H), 6.19 (q,
=
1
107.9, 116.6, 126.3, 127.0, 128.4, 134.4, 139.8 ppm. IR (neat): ν =
˜
3214, 3103, 2922, 2856, 1460, 1383, 805, 748, 712 cm–1. GC–MS: J = 2.9 Hz, 1 H), 6.74 (q, J = 2.6 Hz, 1 H), 7.44 (m, 3 H), 7.79 (m,
m/z (%) = 118 (100), 93 (91), 94 (50) (54) 92, 156 (12), 197 (9), 212
(5). C14H16N2 (212.13): calcd. C 79.21, H 7.60, N 13.20; found C
79.02, H 7.63, N 13.18.
2 H), 8.31 (s, 1 H), 8.60 (br. s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.6, 136.2, 133.1, 130.6, 128.5, 128.2, 116.3, 107.8,
104.8, 75.2, 35.2, 19.4, 19.2 ppm. IR (neat): ν = 3457, 3249, 2964,
˜
2868, 2825, 1634, 1447, 1383, 1096, 1012, 725, 696 cm–1. GC–MS:
m/z (%) = 183 (100), 104 (51), 121 (36), 80 (32), 156 (6), 226 (3).
C15H18N2 (226.15): calcd. C 79.61, H 8.02, N 12.38; found C 79.31,
H 8.05, N 12.35.
(S)-2-Phenyl-1-[(S)-1-(2-pyrrolyl)pentyl]aziridine (9b): Yield: 0.304 g
(92%). White solid. M.p. 78.3–79.6 °C. [α]2D0 = +74.8 (c = 0.7,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.94 (t, J = 6.7 Hz, 3
H), 1.36–1.38 (m, 6 H), 1.92 (d, J = 3.4 Hz, 1 H), 2.14 (d, J =
6.6 Hz, 1 H), 2.55 (dd, J = 3.4 Hz, J = 6.6 Hz, 1 H), 2.76 (dd, J =
5.2 Hz, J = 7.8 Hz, 1 H), 6.01 (m, 1 H), 6.15 (q, J = 2.7 Hz, 1 H),
6.67 (dd, J = 1.7 Hz, J = 2.7 Hz, 1 H), 7.16–7.22 (m, 2 H), 7.24–
7.34 (m, 3 H), 8.44 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.0, 22.8, 28.2, 36.4, 37.9, 40.1, 68.3, 105.4, 107.5, 116.6, 126.3,
(S)-N-[1-(2-Pyrrolyl)-3-buten-1-yl]benzaldimine (10e): Isolated im-
pure as a brown oil (0.096 g, 86%). Relevant absorptions for struc-
tural identification of the main compound were drawn from 1H
NMR spectroscopic analysis. 1H NMR (300 MHz, CDCl3): δ =
2.68 (m, 2 H), 4.51 (dd, J = 6.3 Hz, J = 7.6 Hz, 1 H), 5.11 (m, 2
H), 5.80 (m, 1 H), 6.06 (m, 1 H), 6.17 (q, J = 3.2 Hz, 1 H), 6.75
126.8, 128.3, 133.1, 140.0 ppm. IR (KBr): ν = 3218, 3100, 3055,
˜
2924, 2852, 1461, 1388, 1135, 1096, 1029, 807, 744, 718, 699 cm–1. (m, 1 H), 7.42 (m, 3 H), 7.77 (m, 2 H), 8.30 (s, 1 H), 8.61 (br. s, 1
GC–MS: m/z (%) = 106 (100), 118 (74), 1636 (62), 80 (51), 91 (34),
197 (16), 254 (10). C17H22N2 (254.18): calcd. C 80.27, H 8.72, N
11.01; found C 80.35, H 8.75, N 11.00.
H) ppm.
(S)-Benzyl-1-(2-pyrrolyl)pentylamine (11b): Yield: 0.094 g (78%).
Yellow oil. [α]2D0 = –26.5 (c = 0.6, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.91 (t, J = 6.8 Hz, 3 H), 1.32 (m, 4 H), 1.73 (m, 2
H), 2.11 (br. s, 1 H), 3.65 (d, J = 13.4 Hz, 1 H), 3.74 (d, J = 13.4 Hz,
1 H), 3.80 (t, J = 7.0 Hz, 1 H), 6.09 (m, 1 H), 6.20 (q, J = 2.7 Hz,
1 H), 6.79 (m, 1 H), 7.31–7.39 (m, 5 H), 8.69 (br. s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.0, 22.6, 28.3, 36.4, 51.4, 55.9,
(S)-2-Phenyl-1-[(S)-2-phenyl-1-(2-pyrrolyl)ethyl]aziridine (9f): Yield:
0.341 g (91%). White solid. M.p. 80.9–81.3 °C (pentane). [α]2D0
=
+94.4 (c = 0.3, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.72 (d,
J = 6.6 Hz, 1 H), 2.05 (d, J = 3.5 Hz, 1 H), 2.48 (dd, J = 3.5 Hz,
J = 6.6 Hz, 1 H), 3.80 (t, J = 6.5 Hz, 1 H), 3.14 (dd, J = 6.5 Hz, J
= 13.1 Hz, 1 H), 3.22 (dd, J = 6.5 Hz, J = 13.1 Hz, 1 H), 5.89 (m, 106.1, 107.7, 116.6, 126.9, 128.1, 128.4, 133.7, 140.4 ppm. IR
1 H), 6.11 (q, J = 2.7 Hz, 1 H), 6.62 (dd, J = 1.6 Hz, J = 2.7 Hz, (neat): ν = 3432, 3376, 3297, 3062, 3027, 2955, 2928, 2857, 1494,
˜
1 H), 7.15–7.22 (m, 5 H), 7.26–7.35 (m, 5 H), 8.28 (br. s, 1 H) ppm. 1453, 1092, 1026, 792, 717 cm–1. C16H22N2 (242.18): calcd. C 79.29,
13C NMR (75 MHz, CDCl3): δ = 26.9, 38.5, 40.1, 43.9, 69.9, 105.5,
H 9.15, N 11.56; found C 79.06, H 9.16, N 11.53. The compound
107.6, 126.2, 126.9, 128.1, 128.3, 129.7, 132.4, 138.6, 139.9 ppm.
was not eluted by GC–MS analysis.
IR (KBr): ν = 3426, 3175, 3107, 3059, 3026, 2976, 2917, 2832, 1494,
˜
(S)-Benzyl[2-methyl-1-(2-pyrrolyl)propyl]amine (11c): Yield: 0.087 g
(76%). Yellow oil. [α]2D0 = –37.6 (c = 0.8, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 0.83 (d, J = 6.7 Hz, 3 H), 0.95 (d, J =
6.7 Hz, 3 H), 1.87 (sept, J = 6.7 Hz, 1 H), 3.52 (d, J = 5.8 Hz, 1
H), 3.58 (d, J = 13.1 Hz, 1 H), 3.71 (d, J = 13.1 Hz, 1 H), 6.04 (m,
1 H), 6.15 (m, 1 H), 6.76 (m, 1 H), 7.25–7.38 (m, 5 H), 8.58 (br. s,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.8, 19.7, 33.9, 52.0,
62.1, 106.9, 107.7, 116.2, 126.9, 128.1, 128.4, 131.1, 140.6,
1454, 1396, 1125, 1100, 1030, 1014, 744, 725 699 cm–1. GC–MS:
m/z = 168 (100), 169 (94), 197 (66), 118 (60). C20H20N2 (288.16):
calcd. C 83.30, H 6.99, N 9.71; found C 83.42, H 7.01, N 9.68.
Preparation of Amines 11b,c,e through Imines 10b,c,e. Typical Pro-
cedure: Phenylglycinol derivative 7b (0.136 g, 0.5 mmol) and
MeNH2 (40% in H2O, 0.6 mL) were dissolved in THF (5 mL).
Then, a solution of H5IO6 (0.400 g) in H2O (5 mL) was added
dropwise. After stirring for 1 h at room temperature, most of the
150.9 ppm. IR (nujol): ν = 3430, 3371, 3062, 3024, 2953, 2922,
˜
Eur. J. Org. Chem. 2007, 5573–5582
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5579

G. Alvaro, R. Di Fabio, A. Gualandi, D. Savoia
FULL PAPER
2853, 1491, 1022, 794 cm–1. C15H20N2 (228.16): calcd. C 78.90, H 3081, 3001, 2922, 2853, 1626, 1577, 1529, 1489, 1292, 720,
8.83, N 12.27; found C 79.10, H 8.85, N 12.26. The compound was
not eluted by GC–MS analysis.
691 cm–1. GC–MS: m/z (%) = 105 (100), 77 (51), 199 (46), 118 (42),
240 (6). C15H16N2O (240.13): calcd. C 74.97, H 6.71, N 11.66;
found C 75.16, H 6.70, N 11.68.
(S)-Benzyl-[1-(2-pyrrolyl)-3-buten-1-yl]amine (11e): Yield: 0.081 g
(72%). Yellowish oil. [α]2D0 = –13.9 (c = 1.2, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 2.04 (br. s, 1 H), 2.53 (m, 2 H), 3.66 (d, J
= 13.2 Hz, 1 H), 3.77 (d, J = 13.2 Hz, 1 H), 3.90 (t, J = 5.5 Hz, 1
H), 5.16 (m, 2 H), 5.82 (m, 1 H), 6.12 (m, 1 H), 6.22 (dq, J =
2.7 Hz, J = 5.5 Hz, 1 H), 6.79 (m, 1 H), 7.30–7.41 (m, 5 H), 8.72
(br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.2, 51.1, 54.7,
105.6, 107.9, 116.6, 117.8, 126.9, 128.0, 128.4, 133.5, 135.1,
(S)-N-[2-Phenyl-1-(2-pyrrolyl)ethyl)]benzamide (12f): Yield: 0.278 g
(87%). White solid. M.p. 115.5–116.4 °C (cyclohexane/CH2Cl2,
1
9:1). [α]2D0 = –61.8 (c = 0.8, CHCl3). H NMR (300 MHz, CDCl3):
δ = 3.26 (dd, J = 9.8 Hz, J = 14.2 Hz, 1 H), 3.48 (dd, J = 5.7 Hz,
J = 14.2 Hz, 1 H), 3.96 (ddd, J = 4.3 Hz, J = 8.3 Hz, J = 9.8 Hz,
1 H), 6.10 (q, J = 2.7 Hz, 1 H), 6.14 (m, 1 H), 6.27 (d, J = 8.3 Hz,
1 H), 6.72 (m, 1 H), 7.17–7.38 (m, 3 H), 7.69–7.50 (m 3 H), 7.51–
7.64 (m, 4 H), 9.35 (br. s, 1 H) ppm. 13C NMR (75 MHz, Cl3): δ
= 38.8, 48.8, 104.6, 107.5, 118.0, 126.8, 128.5, 128.6, 128.7, 129.0,
140.3 ppm. IR (nujol): ν = 3430, 3373, 3292, 3065, 2957, 2922,
˜
2853, 1499, 1454, 797 cm–1. C15H18N2 (226.15): calcd. C 79.61, H
8.02, N 12.38; found C 79.91, H 8.05, N 12.36. The compound was
not eluted by GC–MS analysis.
130.2, 131.7, 133.7, 168.5 ppm. IR (KBr): ν = 3056, 2925, 2676,
˜
1690, 1622, 1532, 1423, 1291, 1174, 1042, 1017, 935, 804, 778,
707 cm–1. GC–MS: m/z (%) = 105 (100), 168 (56), 199 (55), 169
(52), 77 (48), 121 (15). C19H18N2O (290.14): calcd. C 78.59, H 6.25,
N 9.65; found C 78.14, H 6.27, N 9.62.
Preparation of α-Substituted Benzamides 12a,b,e,f. Typical Pro-
cedure: Valinol derivative 8b (0.238 g, 1.1 mmol) and MeNH2 (40%
in H2O, 1.3 mL, 17 mmol) were dissolved in THF (5 mL) and a
solution of H5IO6 (0.907 g, 4.0 mmol) in H2O (5 mL) was added
dropwise. The mixture was stirred for 2 h at room temperature. The
organic materials were extracted with Et2O (3ϫ20 mL), and the
collected ethereal layer was then washed with brine, dried with
Na2SO4, and concentrated to leave the primary amine as a yellow
oil. This was dissolved in acetone (5 mL), and then H2O (5 mL),
K2CO3 (0.304 g, 2.2 mmol), and benzoyl chloride (191 µL,
1.7 mmol) was added while magnetically stirring. After 12 h, most
of the solvent was evaporated under reduced pressure, and the or-
ganic materials were extracted with Et2O (3ϫ20 mL). The col-
lected ethereal layer was dried with Na2SO4 and concentrated to
leave a white solid, which was crystallized from acetone to give
pure 12b.
Acknowledgments
This work was carried out in the field of the Prin Project: “Sintesi
e stereocontrollo di molecole organiche per lo sviluppo di metodol-
ogie innovative”. A. G. held a scholarship from GlaxoSmithKline
(Verona). We also thank the University of Bologna for financial
support.
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(S)-N-[1-(2-Pyrrolyl)ethyl]benzamide (12a): Yield: 0.203 g (86%).
White solid. M.p. 167.9–168.5 °C. [α]2D0 = –74.1 (c = 0.8, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.69 (d, J = 7.0 Hz, 3 H), 5.34
(qd, J = 7.0 Hz, J = 7.2 Hz, 1 H), 6.12 (m, 2 H), 6.33 (d, J =
7.2 Hz, 1 H), 6.75 (m, 1 H), 7.72–7.78 (m, 5 H), 9.36 (br. s, 1 H)
ppm. 13C NMR (75 MHz, Cl3): δ = 18.3, 43.0, 104.1, 107.3, 117.9,
126.9, 128.6, 131.7, 134.0, 134.3, 168.0 ppm. IR (KBr): ν = 3396,
˜
3312, 2925, 1853, 1625, 1578, 1524, 1331, 1083, 1031, 736, 717,
655 cm–1. GC–MS: m/z (%) = 105 (100), 77 (74), 93 (55), 214 (46),
121 (24), 199 (18). C13H14N2O (214.11): calcd. C 72.87, H 6.59, N
13.07; found C 73.03, H 6.58, N 13.05.
(S)-N-[1-(2-Pyrrolyl)pentyl]benzamide (12b): Yield: 0.247 g (88%).
White solid. M.p. 137.5–138.2 °C. [α]2D0 = –90.7 (c = 0.8, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.95 (t, J = 5.2 Hz, 3 H), 1.47
(m, 4 H), 1.96 (m, 1 H), 2.15 (m, 1 H), 5.17 (dt, J = 6.1 Hz, J =
8.3 Hz, 1 H), 6.08 (m, 1 H), 6.12 (q, J = 2.9 Hz, 1 H), 6.26 (d, J =
8.3 Hz, 1 H), 6.73 (m, 1 H), 7.39–7.55 (m, 5 H), 9.18 (br. s, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9, 22.4, 28.7, 32.4, 47.5,
104.1, 107.4, 117.6, 126.9, 128.5, 131.6, 133.6, 134.1, 168.1 ppm.
IR (KBr): ν = 3336, 2957, 2927, 2856, 1625, 1533, 1337, 12643,
˜
1091, 1029, 801, 722 cm–1. GC–MS: m/z (%) = 105 (100), 106 (97),
77 (61), 199 (42), 135 (36), 121 (27), 256 (11). C16H20N2O (256.16):
calcd. C 74.97, H 7.86, N 10.93; found C 74.76, H 7.89, N 10.89.
(S)-N-[1-(2-Pyrrolyl)-3-buten-1-yl)]benzamide (12e): Yield: 0.217 g
(82%). White solid. M.p. 122.3–122.8 °C (Et2O). [α]2D0 = –53.7 (c =
1
2.1, CHCl3). H NMR (300 MHz, CDCl3): δ = 2.83 (m 2 H), 5.22
(m, 2 H), 5.25 (m, 1 H), 5.95 (m, 1 H), 6.10 (m, 1 H), 6.14 (q, J =
2.9 Hz, 1 H), 6.52 (d, J = 6.9 Hz, 1 H), 6.74 (m, 1 H), 7.37–7.46
(m, 3 H), 7.47–7.54 (m, 2 H), 9.39 (br. s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 36.9, 46.6, 104.5, 107.4, 117.8, 118.4, 126.9,
128.5, 131.6, 132.7, 134.0, 134.4, 168.1 ppm. IR (nujol): ν = 3320,
˜
5580
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5573–5582

Asymmetric Synthesis of 1-(2-Pyrrolyl)alkylamines
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FULL PAPER
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Received: June 27, 2007
Published Online: September 25, 2007
5582
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5573–5582