Tetrahydropyridinium bromide: Useful synthon to functionalized pyrrolidines

Article abstract of DOI:10.1002/jhet.823

1-benzyl-5-(ethoxycarbonyl)-2,3,4,5-tetrahydropyridinium bromide undergoes ring contraction with a series of nucleophiles, getting 2,2-disubstitued pyrrolidines. Moreover, from some of the new 2,2-disubstitued pyrrolidines were synthesized spiro-pyrrolidines. Copyright

Full text of DOI:10.1002/jhet.823

March 2012
Tetrahydropyridinium Bromide: Useful Synthon to Functionalized
Pyrrolidines
297
Luca Guideri, Rossella Noschese, and Fabio Ponticelli*
`
Dipartimento di Chimica, Universita degli Studi di Siena, Siena 53100, Italy
*E-mail: ponticelli@unisi.it
Received November 5, 2010
DOI 10.1002/jhet.823
Published online 21 November 2011 in Wiley Online Library (wileyonlinelibrary.com).
1-benzyl-5-(ethoxycarbonyl)-2,3,4,5-tetrahydropyridinium bromide undergoes ring contraction with a
series of nucleophiles, getting 2,2-disubstitued pyrrolidines. Moreover, from some of the new 2,2-disub-
stitued pyrrolidines were synthesized spiro-pyrrolidines.
J. Heterocyclic Chem., 49, 297 (2012).
INTRODUCTION
DISCUSSION AND RESULTS
The pyrrolidine ring is a structural fragment present
in many natural alkaloids such as nicotine, cocaine, and
atropine. It is also present in the structure of proline,
a-aminoacid unique in its conformational rigidity due to
a secondary amino group. Moreover, proline and its
derivatives are used as catalysts in asymmetric enantio-
selective synthesis [1], for example, in aldol reactions
and Michael additions [2]. Finally, the pyrrolidine ring
is present in several pharmaceutical compounds [3]: the
most important example is the family of ACE inhibitors,
widely used as antihypertensive. It is clear that the capa-
bility to obtain functionalized pyrrolidine rings is impor-
tant in many aspects of synthetic chemistry.
The nature of the substituent in the nitrogen atom
strongly affects the reaction path. In fact, when an elec-
tron withdrawing group is present, such as an acetyl
group (3) [8,9], the formation of the correspondent tetra-
hydropyridinium bromides is completely prevented.
Moreover, compounds 4 was the unexpected product, as
a mixture of distereoisomers, obtained from the addition
of bromine, in not anhydrous condition. (Scheme 2)
Infrared spectrum showed the presence of a hydroxyl
group and the absolute regioselectivity attack of
water was confirmed by the signal shifts of C2 and C3
in 13C-NMR spectra 80.8 and 74.8, respectively.
On the other hand, compound 1 can be easily
achieved with three simple steps starting from ethyl nic-
otinate through N-alkylation [10], hydrogenation to get
ethyl 1-benzyl-1,4,5,6-tetrahydronicotinate 5 and finally
reactions with bromine, as reported in literature [7b]
(Scheme 3).
In our continuing efforts to develop new and more
general methods for the preparation of heterocycles with
potential biological interest, we considered the synthesis
of 2,2-disubstituted pyrrolidines. For the construction of
this ring, there are several type of reactions, such as
nucleophilic displacement [4] and ring expansion [5]. In
addition, it is known that tetrahydropiridinium bromides
1 give a ring contraction reacting with OHꢀ sources,
such as wet TEA or NaHCO3(aq) to give pyrrolidine
aldehydes 2 (Scheme 1) [6,7]. As a further development,
in this article, we consider the usefulness and the limits
of this synthetic protocol for the preparation of a small
library of proline-like compounds.
It is important to say that, because of its instability
and hygroscopicity, compound 1 must be used fresh-
made. For this reason, ethyl N-benzyl tetrahydronicoti-
nate is the starting material for all the reactions that
involve the use of compound 1. The results of this
investigations are reported in Scheme 4. The first
nucleophile used was EtONa to get acetal 6. On the
other hand, the use of carbanions (methyl lithium or
C
V
2011 HeteroCorporation

298
L. Guideri, R. Noschese, and F. Ponticelli
Vol 49
Scheme 1
Scheme 3
magnesium malonate) resulted in a debromination to the
starting ethyl tetrahydronicotinate (Schemes 4 and 5).
Nitrogen-based nucleophiles works, but the yields at this
stage are very poor. However we obtained three new
pyrrolidines as shown in Scheme 4. The use of the very
reactive hydrazine disclosed the possibility to obtain the
interesting spiro-compound 7. X-ray analysis of this
compound confirmed the assigned structure, as shown in
Figure 1. Unfortunately hydroxylamine did not permit
to get the corresponding spiro-compound, but only
oxime 8. 1H NMR spectrum showed the presence of
only one of the two possible stereoisomers, and from
The biological activity of functionalized spiro-com-
pounds, such as buspirone and spiperone, is often linked
to structural and conformational rigidity, which gives
enantiomeric selectivity in the interaction with the
enzymes sites. For this reason and the good result with
compound 7, it was designed to synthesize additional
spiro-compounds from 2,2-disubstituted pyrrolidines so
far obtained. In particular using two equivalents of
a strong base as LDA upon 11, it was possible to get
5,4-spiro-pyrrolidine 16. Starting from 14 with the use
of p-toluensulfonic acid in acetone, we obtained 5,6-
spiro-17. (Scheme 8). At the moment, further insight
into the reactivity of compounds 12 and 15 is under
investigation.
X-ray analysis the
E configuration was assigned.
(Fig. 1) Some attempts to convert 8 into the Z isomer
were made, but without results [11].
The use of ortho-phenylendiamine did not permit to
get the desired product, but the formation of benzimida-
zole and ethyl N-benzylproline was observed. Same
result was obtained starting from aldehyde 2. A possible
reaction mechanism is shown in Scheme 6.
Scheme 4
At this point, considering that bromide 1 gives the
aldehyde 2 in good yield (Scheme 1), we decided to use
this type of compound for the preparation of a family of
pyrrolidines. Following this approach, we improved the
yields for compounds 7 and 8 (Scheme 7). Furthermore,
even protected a-aminoacids can be used, to give for
instance imine 10.
Using a reductive agent, such as sodium cyanoboro-
hydride, together with methylamine or ortho-phenylendi-
amine it was possible to get compounds 11 and 12,
respectively. In addition, compound 2 can be selectively
or totally reduced, using H2/PtO2 or NaBH4 obtaining
13 and 14 respectively in good yields. Oxidation of 2
with I2, in basic condition, offers the possibility to get
15 with quantitative yield.
Scheme 2
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Tetrahydropyridinium Bromide: Useful Synthon to Functionalized Pyrrolidines
299
Scheme 5. Debromination of 1 with carbanions.
Scheme 6. Reaction of ortho-phenylendiamine.
tures in this article have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication n.
CCDC-796487 (4), CCDC-796488 (5). Copies of the data can
be obtained, free of charge via www.ccdc.cam.ac.uk/data_re-
quest/cif or by e-mailing data_request@ccdc.cam.ac.uk or by
contacting The Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223
336033.
CONCLUSIONS
The results presented here suggest that the conversion
of ethyl 1-benzyl-1,4,5,6-tetrahydronicotinate into D1-
piperideinium salts or even into pyrrolidine derivatives
discloses new interesting synthetic pathways to obtain
proline-like derivatives. Moreover, the described strategy
offers an efficient and simple method, often characterized
by good yields, to synthetize compounds of generally
difficult access like spiro-pyrrolidines.
Ethyl 1-acetyl-2-bromo-3-hydroxypiperidine-3-carboxy-
late (4). Ethyl 1-acetyl-1,4,5,6-tetrahydropyridine-3-carboxy-
late 3 [8] (0.58 g, 2.94 mmol) was dissolved in CHCl3 (ethanol
free) (12 mL), then a solution of Br2 (150 lL, 2.94 mmol)
in CHCl3 (ethanol free) (3 mL) was added slowly drop-by-drop.
After 1 h stirring, solvent was removed under reduced pressure
and the residue was purified by chromatography on silica
gel (DCM/MeOH 95:5) getting 4 as a white solid (0.62 g,
EXPERIMENTAL
1
1.74 mmol, 59%). M.p.: 126ꢁC. H-NMR (200 MHz, CDCl3):
3
d 1.31 (t, J ¼ 7.3 Hz, 6H, CH2CH3), 1.78 (m, 4H, H5 þ H50),
General. Melting points were determined with a Kofler hot
stage and are uncorrected. 1H and 13C NMR spectra were
recorded at 27ꢁC (CDCl3), unless otherwise stated, with a
Bruker AC200 MHz instrument operating at 200.13 and 50.33
MHz, respectively, or with a Bruker Advance 400 MHz instru-
ment operating at 400.13 and 100.62 MHz, respectively.
Chemical shifts are reported in ppm from internal TMS. The
1H NMR data are reported as follows: s ¼ singlet, d ¼ dou-
blet, t ¼ triplet, m ¼ multiplet, bs ¼ broad singlet, bt ¼ broad
triplet; coupling constant(s) in Hz. Mass spectra were recorded
in the positive or negative ion mode with a LCQ-DECA
Thermo instrument by using electrospray ionization. GC mass
spectra were recorded with a mass spectrometer Varian Saturn
2000 coupled with a gas chromatograph Varian 3800 equipped
with capillary column Rtx-5MS. All solvents were previously
dried according to standard procedures. Analytical TLC was
performed on silica gel 60 F254 plates. Flash column chroma-
tography was carried out on silica gel (0.040–0.063 mm).
Single crystals of 7 and 8 were submitted to X-ray data collec-
tions by using a Siemens P4 four-circle diffractometer (293K),
equipped with a graphite monochromated Mo-Ka radiation
0
2.10 (s, 3H, COCH3), 2.20 (s, 3H, COCH3 ), 2.38 (m, 4H, H4 þ
3
H40), 2.89 (m, 1H, H6), 3.46 (m, 2H, H6 þ H60), 4.28 (q, J ¼
7.3 Hz, 4H, CH2CH3), 4.38 (m, 1H, H60), 5.75 (s, 1H, H2),
6.40 (s, 1H, H20). 13C-NMR (200 MHz, CDCl3): d 13.8; 20.3;
21.1; 21.4; 21.9; 28.2; 30.7; 34.9; 40.2; 60.9; 62.1; 62.4; 74.8;
80.8; 169.3; 169.7; 170.9; 171.4. MS (ESI): m/z ¼ 294/296
[M þ H]þ, 316/318 [M þ Na]þ. C10H16BrNO4 (294,14): calcd.
C 40.83; H 5.48; Br 27.17; N 4.76; found C 40.87; H 5.52;
Br 27.16; N 4.79.
Ethyl 1-benzyl-2-(diethoxymethyl)pyrrolidine-2-carboxy-
late (6). 1-Benzyl-5-bromo-5-(ethoxycarbonyl)-2,3,4,5-tetrahy-
dropyridinium bromide 1 (2.23 g, 5.5 mmol) was dissolved in
ethanol (20 mL) and it was added EtONa in EtOH (Naꢁ 253
Scheme 7
˚
(k ¼ 0.71073 A). The structures were solved by direct meth-
ods implemented in the SHELXS-97 program [12]. The refine-
ments were carried out by full-matrix anisotropic least-squares
on F2 for all reflections for non-H atoms by means of the
SHELXL-97 program [13]. Crystallographic data for the struc-
Figure 1. X-ray structures of compounds 7 and 8.
Journal of Heterocyclic Chemistry
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L. Guideri, R. Noschese, and F. Ponticelli
Vol 49
Scheme 8
CH2CH3), 1.85 (m, 2H, 4-CH2), 2.29 (m, 2H, 3-CH2), 2.80
(m, 2H, 5-CH2), 3.85 (AB system, 2J ¼ 13.5 Hz, 2H,
7.59 (s, 1H, CHN), 8.30 (bs, 1H, NOH). 13C-NMR (200 MHz,
CDCl3): d 14.3; 22.1; 34.8; 50.9; 54.1; 61.1; 70.9; 126.9;
128.2; 128.4; 139.8; 151.6; 172.3. MS (ESI): m/z ¼ 277 [M þ
H]þ, 299 [M þ Na]þ. C15H20N2O3 (276,33): calcd. C 65.20;
H 7.30; N 10.14; found C 65.19; H 7.32; N 10.17.
3
NCH2Ph), 4.23 (q, J ¼ 7.1 Hz, CH2CH3), 7.28 (m, 5H, Ph),
Ethyl 1-benzyl-2-((methylimino)methyl)pyrrolidine-2-car-
boxylate (9). 1-Benzyl-5-bromo-5-(ethoxycarbonyl)-2,3,4,5-tet-
rahydropyridinium bromide 1 (1.22 g, 3 mmol) was dissolved
in dry EtOH (15 mL), it was added methylamine in EtOH
33% p/p (1.31 mL, 10.5 mmol), and the reaction was stirred at
r.t. After 12 h solvent was evaporated, the residue was dis-
solved in Et2O (50 mL) and washed with H2O (3 ꢂ 15 mL).
The organic phase was dried over Na2SO4, filtered and evapo-
rated under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether/Et2O 1:1)
obtaining 9 (0.15 g, 0.54 mmol, 18%) as brown–yellow oil.
1H-NMR (200 MHz, CDCl3): d 1.25 (t, 3J ¼ 7 Hz, 3H,
CH2CH3), 1.56 (m, 2H, 4-CH2), 2.08 (m, 2H, 3-CH2), 2.27
(s, 3H, NCH3), 2.75 (m, 2H, 5-CH2), 3.83 (AB system, 2J ¼
12.5 Hz, 2H, NCH2Ph), 4.21 (q, 3J ¼ 7 Hz, 2H, CH2CH3),
7.25 (m, 5H, Ph), 7.85 (s, 1H, CH¼¼N). MS (ESI): m/z ¼ 275
[M þ H]þ. C16H22N2O2 (274,36): calcd. C 70.04; H 8.08; N
10.21; found C 70.07; H 8.10; N 10.18.
mg, 11 mmol, in EtOH 10 mL) and stirred for 2 h at room
temperature. After this time, the solvent was evaporated under
vacuum, and the residue was treated with cyclohexane
(30 mL), filtered and evaporated getting 6 (0.94 g, 2.8 mmol,
51%) as a yellow oil. 1H-NMR (200 MHz, CDCl3): d 1.27
(m, 9H, COOCH2CH3 þ OCH2CH3), 1.78 (m, 2H, 4-CH2),
2.23 (m, 2H, 3-CH2), 2.81 (m, 2H, 5-CH2), 3.69 (q, 3J ¼
7 Hz, 4H, OCH2CH3), 3.83 (AB system, 2J ¼ 13 Hz, 2H,
NCH2Ph), 4.19 (q, 3J ¼ 7 Hz, COOCH2CH3), 4.84 (s, 1H,
CH), 7.22 (s, 5H, Ph). GC-MS (EI): m/z ¼ 336 [M þ H]þ.
C19H29NO4 (335,44): calcd. C 68.03; H 8.71; N 4.18; found
C 68.05; H 8.74; N 4.19.
Ethyl 1-benzyl-2-((2-tert-butoxy-2-oxoethylimino) meth-
yl)pyrrolidine-2-carboxylate (10). Ethyl 1-benzyl-2-formyl-
pyrrolidine-2-carboxylate 2 (0.2 g, 0.77 mmol) was dissolved
in dry CHCl3 (10 mL), then were added tert-butyl glycine
hydrochloride (0.14 g, 0.85 mmol) and DMAP (0.11 g, 0.92
mmol). The mixture was refluxed for 12 h. After this time, the
solvent was evaporated under reduced pressure, and it was
added Et2O (10 mL). The precipitate was filtered off and the
solvent was evaporated, getting 10 (0.26 g, 0.69 mmol, 90%)
1-Benzyl-1,7,8-triazaspiro[4.4]non-8-en-6-one (7). Hydrazine
freshly distilled (170 lL, 5.4 mmol) was dissolved in CHCl3
(5 mL), then a solution of ethyl 1-benzyl-2-formylpyrrolidine-
2-carboxylate 2 (0.4 g, 1.53 mmol) in CHCl3 (15 mL) was
added slowly drop-by-drop. The mixture was refluxed and
stirred for 48 h. After this time, the reaction was diluted in
CHCl3 (30 mL) and washed with H2O (2 ꢂ 15 mL). The
organic phase was dried over Na2SO4, filtrated and evaporated
under vacuum getting a yellow oil. The residue was subli-
mated under vacuum at 100ꢁC getting 7 (0.14 g, 0.61 mmol,
40%) as a white solid; m.p.: 78ꢁC. 1H-NMR (200 MHz,
CDCl3): d 1.96 (m, 2H, 4-CH2), 2.14 (m, 2H, 3-CH2), 3.03
(m, 2H, 5-CH2), 3.65 (s, 2H, NCH2Ph), 7.11 (s, 1H, CH¼¼N),
7.26 (s, 5H, Ph), 8.86 (bs, 1H, NH). 13C-NMR (200 MHz,
CDCl3): d 22.7; 32.6; 51.8; 54.6; 71.9; 127.3; 128.2; 128.7;
1
3
as an orange oil. H-NMR (400 MHz, CDCl3): d 1.27 (t, J ¼
7.2 Hz, 3H, CH2CH3), 1.42 (s, 9H, Boc), 1.84 (m, 2H, 4-CH2),
2.31 (m, 2H, 3-CH2), 2.75 (m, 1H, 5-CH2), 2.90 (m, 1H, 5-
CH2), 3.89 (AB system, 2J ¼ 13.6 Hz, 2H, NCH2Ph), 4.12
2
3
(AB system, J ¼ 15.4 Hz, 2H, NCH2COOtBu), 4.22 (q, J ¼
7.2 Hz, 2H, CH2CH3), 7.17–7.33 (m, 5H, Ph), 7.74 (s, 1H,
CHN). MS (ESI): m/z ¼ 375 [M þ H]þ, 397 [M þ Na]þ.
C21H30N2O4 (374,47): calcd. C 67.35; H 8.07; N 7.48; found
C 67.38; H 8.10; N 7.47.
Ethyl
1-benzyl-2-((methylamino)methyl)-pyrrolidine-2-
carboxylate (11). Ethyl 1-benzyl-2-formylpyrrolidine-2-car-
boxylate 2 (1.04 g, 4 mmol) was dissolved in dry EtOH (2.5
mL), then were added methylamine in EtOH 33% p/p (3 mL,
24 mmol) and NaCNBH3 (0.16 g, 2.4 mmol). The solution
was acidified with HCl 5N in ethanol to pH 5 and stirred at
r.t. for 72 h. After this time, the solvent was evaporated under
reduced pressure, the residue was treated with H2O (50 mL)
and extracted with Et2O (2 ꢂ 20 mL). The aqueous phase was
basified with KOH 4N to pH > 10 and extracted with Et2O (2
ꢂ 20 mL). The organic fractions were reunited and dried over
Na2SO4, filtered and evaporated under vacuum getting 11
138.4; 154.9; 178.1. GC-MS (EI): m/z
C13H15N3O (229,28): calcd. C 68.10; H 6.59; N 18.33; found
C 68.08, H 6.62; N 18.36.
¼
229 [M]þ.
(E)-Ethyl 1-benzyl-2-((hydroxyimino)methyl) pyrrolidine-
2-carboxylate (8). Ethyl 1-benzyl-2-formylpyrrolidine-2-car-
boxylate 2 (0.4 g, 1.53 mmol) was dissolved in dry THF
(10 mL), then were added hydroxylamine hydrochloride
(0.38 g, 5.51 mmol) and TEA freshly distilled (0.77 mL,
5.51 mmol). The mixture was refluxed for 16 h. After this
time, the reaction was filtered, diluted in DCM (40 mL) and
washed with H2O (3 ꢂ 15 mL). The organic phase was dried
over Na2SO4, filtrated and concentrated under vacuum. The
residue was treated with cyclohexane/Et2O 3:1 getting 8
(0.19 g, 0.69mmol, 45%) as a yellow solid; m.p.: 120ꢁC.
1H-NMR (200 MHz, CDCl3): d 1.30 (t, 3J ¼ 7.1 Hz, 3H,
1
(0.66 g, 2.4 mmol, 60%) as a yellow oil. H-NMR (200 MHz,
CDCl3): d 1.31 (t, 3J ¼ 7 Hz, 3H, CH2CH3), 1.63 (bs, 1H,
NH), 1.81 (m, 2H, 4-CH2), 2.15 (m, 2H, 3-CH2), 2.43 (s, 3H,
NHCH3), 2.70 (m, 2H, 5-CH2), 2.82 (AB system, 2J ¼ 11.9
Hz, 2H, CH2NHCH3), 3.66 (AB system, 2J ¼ 13.7 Hz, 2H,
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Tetrahydropyridinium Bromide: Useful Synthon to Functionalized Pyrrolidines
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NCH2Ph), 4.21 (q, 3J ¼ 7 Hz, 2H, CH2CH3), 7.25 (m, 5H,
Ph). 13C-NMR (200 MHz, CDCl3): d 14.5; 22.5; 33.7; 37.0;
52.3; 53.6; 55.0; 60.2; 70.6; 126.8; 128.2; 129.0; 140.3; 174.7.
MS (ESI): m/z ¼ 277 [M þ H]þ. C16H24N2O2 (276,37): calcd.
C 69.53; H 8.75; N 10.14; found C 69.54; H 8.72; N 10.16.
Ethyl 2-((2-aminophenylamino)methyl)-1-benzyl pyrroli-
dine-2-carboxylate (12). Ethyl 1-benzyl-2-formylpyrrolidine-
2-carboxylate 2 (0.5 g, 1.92 mmol), ortho phenylendiamine
(0.23 g, 2.11mmol) and sodium cyanoborohydride (0.13 g,
2.11 mmol) were dissolved in dry THF (12 mL) and stirred at
r.t. for 16 h. It was added HCl 2N (1 mL) and stirred for 1h at
r.t. After this time, the mixture was diluted with Et2O (40 mL)
and washed with H2O (3 ꢂ 20 mL). The organic phase was
dried over Na2SO4, filtered and evaporated under reduced pres-
sure. The residue was purified by chromatography on silica gel
(petroleum ether/ Et2O 1:1) getting 12 (0.28 g, 0.79 mmol,
41%) as a brown yellow oil. 1H-NMR (200 MHz, CDCl3):
Diethyl 1-benzylpyrrolidine-2,2-dicarboxylate (15). Ethyl
1-benzyl-2-formylpyrrolidine-2-carboxylate 2 (0.28 g, 1.07 mmol)
was dissolved in dry EtOH (5 mL). At 0ꢁC, it was added KOH
1N in EtOH (3 mL) and I2 (0.34 g, 1.34 mmol) dissolved in
EtOH (2 mL). The reaction was stirred at r.t. for 60 h. After this
time, it was added sodium thiosulfate (1 mL) and stirred for 5
minutes. The solvent was removed under reduced pressure and
the residue was suspended in H2O (30 mL) and extracted with
CHCl3 (3 ꢂ 10 mL). The organic fractions were reunited and
dried over Na2SO4, filtered and evaporated under vacuum getting
15 (0.32 g, 1.05 mmol, 98%) as a brown–yellow oil. 1H-NMR
3
(200 MHz, CDCl3): d 1.27 (t, J ¼ 7.3 Hz, 6H, CH2CH3), 1.84
3
(m, 2H, 4-CH2), 2.38 (m, 2H, 3-CH2), 2.77 (t, J ¼ 6.8 Hz, 2H,
5-CH2), 3.87 (s, 2H, NCH2Ph), 4.23 (q, 3J ¼ 7.3 Hz, 4H,
CH2CH3), 7.29 (m, 5H, Ph). MS (ESI): m/z ¼ 306 [M þ H]þ.
C17H23NO4 (305,37): calcd. C 66.86; H 7.59; N 4.59; found
C 66.87; H 7.60; N 4.62.
3
d 1.39 (t, J ¼ 7 Hz, 3H, CH2CH3), 1.90 (m, 2H, 4-CH2), 2.19
5-Benzyl-2-methyl-2,5-diazaspiro[3.4]octan-1-one (16). Ethyl
1-benzyl-2-((methylamino)methyl)pyrrolidine-2-carboxylate 11
(0.30 g, 1.08 mmol) was dissolved in dry THF (2 mL) and
added in a round bottom flask containing LDA 1.8 M (1.2 mL,
2.16 mmol) at ꢀ20ꢁC. The mixture was stirred at ꢀ20ꢁC for
1 h, and then at room temperature for 12 h. After this time,
it was added H2O (10 mL) and extracted with DCM (4 ꢂ
5 mL). The organic fractions were reunited and dried over
Na2SO4, filtered and evaporated under vacuum. The residue
was purified by chromatography on silica gel (eluent ¼ Et2O)
(m, 1H, 3-CH2), 2.35 (m, 1H, 3-CH2), 2.86 (m, 1H, 5-CH2),
3.06 (m, 1H, 5-CH2), 3.43 (AB system, 2J ¼ 11.9 Hz, 2H,
2
CH2NH), 3.70 (AB system, J ¼ 13.1 Hz, 2H, NCH2Ph), 4.30
(q, 3J ¼ 7 Hz, 2H, CH2CH3), 6.78 (m, 4H, NHAr), 7.30 (m,
5H, Ph). 13C-NMR (200 MHz, CDCl3) d 14.4; 22.4; 33.7;
45.1; 51.8; 52.9; 60.4; 70.0; 111.6; 116.0; 118.2; 120.3; 126.8;
128.2; 128.3; 134.5; 137.8; 139.4; 174.3. MS (ESI): m/z ¼ 354
[M þ H]þ, 376 [M þ Na]þ. C21H27N3O2 (353,46): calcd.
C 71.36; H 7.70; N 11.89; found C 71.38; H 71.73; N 11.88.
Ethyl 1-benzyl-2-(hydroxymethyl)pyrrolidine-2-carboxy-
late (13). PtO2 (70 mg) was suspended in dry EtOH (10 mL)
and activated under hydrogen pressure (50 p.s.i.) at r.t. for 10
minutes. After this time, ethyl 1-benzyl-2-formylpyrrolidine-2-
carboxylate 2 (0.28 g, 1.07 mmol) in dry EtOH (10 mL) was
added, and hydrogenated (50 p.s.i.) for 16 h. At the end of the
reaction, the catalyst was removed by filtration and the solvent
was evaporated under reduced pressure. The residue was puri-
fied by chromatography on silica gel (1ꢁ eluent ¼ petroleum
ether/Et2O 2:1, 2ꢁ eluent ¼ Et2O/MeOH 1:1) getting 13
(0.11 g, 0.42 mmol, 39%) as a yellow oil. 1H-NMR (200
MHz, CDCl3): d 1.31 (t, 3J ¼ 7 Hz, CH2CH3), 1.81 (m, 2H,
4-CH2), 2.14 (m, 2H, 3-CH2), 2.82 (m, 2H, 5-CH2), 3.65 (AB
system, 2J ¼ 13.2 Hz, 2H, CH2OH), 3.71 (s, 2H, NCH2Ph),
4.22 (q, 3J ¼ 7 Hz, CH2CH3), 7.28 (m, 5H, Ph). MS (ESI):
m/z ¼ 264 [M þ H]þ. C15H21NO3 (263,33): calcd. C 68.42;
H 8.04; N 5.32; found C 68.43; H 8.06; N 5.31.
1
getting 16 (0.14 g, 0.59 mmol, 56%) as a yellow oil. H-NMR
(200 MHz, CDCl3): d 1.82 (m, 2H, 4-CH2), 2.13 (m, 2H, 3-
CH2), 2.28 (m, 2H, 5-CH2), 2.76 (s, 3H, NCH3), 3.20 (AB sys-
tem, 2J ¼ 5.7 Hz, 2H, CH2NCH3), 3.76 (AB system, 2J ¼
13.3 Hz, 2H, NCH2Ph), 7.27 (m, 5H, Ph). 13C-NMR (200
MHz, CDCl3): d 22.2; 28.0; 31.8; 52.7; 53.8; 53.9; 79.6;
126.9; 128.1; 128.5; 139.2; 172.4. MS (ESI): m/z ¼ 231 [M þ
H]þ 253 [M þ Na]þ. C14H18N2O (230,31): calcd. C 73.01;
H 7.88; N 12.16; found C 72.98; H 7.91; N 12.19.
1-Benzyl-8,8-dimethyl-7,9-dioxa-1-azaspiro[4.5]
decane
(17). In a test tube (1-benzylpyrrolidine-2,2-diyl)dimethanol 14
(0.15 g, 0.68 mmol) was dissolved in dry acetone (10 mL), it
was added p-toluensulfonic acid (40 mg, 0.23 mmol) and
˚
some 4A activated MS. The tube was sealed and refluxed for
96 h. After this time, the reaction was filtered, concentrated
under vacuum, and neutralized with NaHCO3 sat. sol. It was
added H2O (10 mL) and extracted with CHCl3 (3 ꢂ 5 mL).
The organic fractions were reunited and dried over Na2SO4,
filtered and evaporated under vacuum. The residue was puri-
fied by chromatography on silica gel (eluent ¼ Et2O) getting
17 (91 mg, 0.34 mmol, 51%) as a yellow oil. 1H-NMR (200
MHz, CDCl3): d 1.40 (s, 6H, CH3), 1.70 (m, 2H, 4-CH2), 1.84
(m, 2H, 3-CH2), 2.64 (t, 3J ¼ 6.6 Hz, 2H, 5-CH2), 3.78 (AB
(1-Benzylpyrrolidine-2,2-diyl)dimethanol (14). Ethyl 1-
2
benzyl-2-formylpyrrolidine-2-carboxylate
(0.28 g, 1.07
mmol) and sodium cyanoborohydride (0.67 g, 10.7 mmol)
were dissolved in dry EtOH (8 mL) and refluxed for 3 h. After
this time, the solvent was evaporated under reduced pressure
and the residue was suspended in H2O (30 mL) and extracted
with DCM (4 ꢂ 10 mL). The organic fractions were reunited
and dried over Na2SO4, filtered and evaporated under vacuum.
The residue was purified by chromatography on silica gel (1ꢁ
eluent ¼ petroleum ether/Et2O 2:1, 2ꢁ eluent ¼ Et2O/MeOH
1:1) getting 14 (0.19 g, 0.85 mmol, 79%) as a brown–yellow
2
system, J ¼ 11.7 Hz, 4H, OCH2), 3.97 (s, 2H, NCH2Ph), 7.31
(m, 5H, Ph). MS (ESI): m/z ¼ 262 [Mþ H]þ. C16H23NO2
(261,36): calcd. C 73.53; H 8.87; N 5.36; found C 73.50; H
8.89; N 5.37.
1
oil. H-NMR (200 MHz, CDCl3): d 1.69 (m, 2H, 4-CH2), 1.93
(m, 2H, 3-CH2), 2.74 (t, 3J ¼ 6.5 Hz, 2H, 5-CH2), 3.03 (bs,
2H, OH), 3.57 (m, 4H, CH2OH), 3.76 (s, 2H, NCH2Ph), 7.28
(s, 5H, Ph). 13C-NMR (200 MHz, CDCl3): d 21.5; 31.4; 52.2;
52.3; 63.6; 68.6; 126.8; 128.2; 128.3; 128.4; 139.8. MS (ESI):
m/z ¼ 222 [M þ H]þ. C13H19NO2 (221,30): calcd. C 70.56;
H 8.65; N 6.33; found C 70.54; H 8.66; N 6.35.
Acknowledgments. This work was financially supported by
the University of Siena as a PAR Project (quota servizi) 2008.
The authors wish to thank the ‘‘Centro di Analisi e Determi-
nazioni Strutturali’’ of the University of Siena for MS spectra
and X-ray data collection and Dr. Sara Draghi for helpful
collaborations.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

302
L. Guideri, R. Noschese, and F. Ponticelli
Vol 49
[8] Lei, A.; Chen, M.; He, M.; Zhang, X. Eur J Org Chem
2006, 4343.
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