Diastereoselective synthesis of N-secondary alkyl 2- alkoxymethylpyrrolidines via sequential addition reactions of organolithium and -magnesium reagents to N-thioformyl 2-alkoxymethylpyrrolidines

Article abstract of DOI:10.1021/jo8021956

(Chemical Equation Presented) Highly efficient sequential addition reactions of organolithium and -magnesium reagents to N-thioformyl 2-methoxymethylpyrrolidine have been described. Various combinations of these reagents gives successful results. A highly efficient and diastereoselective addition reaction is also described. Use of the opposite combinations of substituents on organolithium and -magnesium reagents leads to the selective formation of the opposite diastereomers. The reaction was extended to N-thioformyl 2-siloxymethypyrrolidine and 2-methoxymethylpiperidine, and these showed similar efficiency and selectivity.

Full text of DOI:10.1021/jo8021956

SCHEME 1. Addition Reactions of Organolithium
and -Magnesium Reagents to Thioformamides
Diastereoselective Synthesis of N-Secondary Alkyl
2-Alkoxymethylpyrrolidines via Sequential
Addition Reactions of Organolithium
and -Magnesium Reagents to N-Thioformyl
2-Alkoxymethylpyrrolidines
TABLE 1. Addition Reaction of Phenyllithium (2a) and
Ethylmagnesium Bromide (3a) to Thioformamide 1aa
Toshiaki Murai* and Fumio Asai
Department of Chemistry, Faculty of Engineering, Gifu
UniVersity, Yanagido, Gifu 501-1193, Japan
yieldb (%)
drc
mtoshi@gifu-u.ac.jp
entry
solvent
3a equiv
conditions
1
2
3
4
5
THF
THF
THF
Et2O
THF
2.0
2.0
2.0
2.0
1.1
rt, 5 h
93
91
17
93
86
88:12
88:12
88:12
88:12
91:9
ReceiVed October 1, 2008
0 °C, 5 h
-20 °C, 5 h
rt, 5 h
rt, 5 h
a A solution of thioformamide 1a (1 mmol, 1.0 M) was treated with
organolithium 2a (1.1 equiv) and -magnesium reagents 3a (1.1 - 2.0
equiv), unless otherwise noted. b Isolated yield. c Ratio was determined
1
by H NMR analysis of crude products.
Highly efficient sequential addition reactions of organo-
lithium and -magnesium reagents to N-thioformyl 2-meth-
oxymethylpyrrolidine have been described. Various combi-
nations of these reagents gives successful results. A highly
efficient and diastereoselective addition reaction is also
described. Use of the opposite combinations of substituents
on organolithium and -magnesium reagents leads to the
selective formation of the opposite diastereomers. The
reaction was extended to N-thioformyl 2-siloxymethypyrro-
lidine and 2-methoxymethylpiperidine, and these showed
similar efficiency and selectivity.
and their ability to act as optically active ligands has been
tested.7 Ring-opening of thiophene 1,1-dioxide with prolinol has
led to N-dieneallyl prolinol.8 Recently, metal-catalyzed three-
component coupling reactions of aldehydes, 2-methoxymeth-
ylpyrrolidine, and terminal alkynes have been intensively
studied.9 In this case, alkynyl groups are introduced to in situ
generated imines to give prolinol derivatives in which the
propargyl groups are on the nitrogen atom. Similarly, the
Mannich-type reaction of prolinol derivatives with organoborane
reagents has been developed.10 Very recently, we have devel-
oped three-component coupling reactions of thioiminium salts
and thioformamides with organolithium and -magnesium re-
agents to give tertiary amines with high efficiency11 (Scheme
1) in studies on the synthesis, properties, and reactivity of
chalcogen isologues of amides.12 In these reactions, even when
excess organolithium reagents were used, the products in which
2 equiv of organolithium reagents were introduced were not
obtained, and two different organometallic reagents were
efficiently incorporated in the products. We report herein
diastereoselective synthesis of N-secondary alkyl prolinol
derivatives via sequential addition reactions of organolithium
and -magnesium reagents to N-thioformyl 2-alkoxymethylpyr-
rolidines.
Increasing attention has been paid to N-secondary chiral alkyl
prolinol derivatives because of their importance as synthetic
intermediates1 and optically active ligands,2 as well as their
biological activity.3 The first synthesis was achieved via [2,3]
sigmatropic rearrangement of chiral ammonium salts derived
from prolinol.4 Later, N-cyanoalkyl prolinol derivatives have
been used as starting materials,5 although KCN or HCN was
necessary for their synthesis. Alternatively, N-alkylation of
prolinol derivatives with secondary alkyl halides, R,ꢀ-unsatur-
ated esters, and nitroalkenes gives the corresponding products.6
Ti-mediated regioselective ring-opening of oxiranes with 2-meth-
oxymethylpyrrolidine leads to N-chiral secondary derivatives,
Initially, (S)-2-methoxymethyl-1-thioformylpyrrolidine (1a)13
was sequentially reacted with phenyllithium (2a) and ethyl-
magnesium bromide (3a) (Table 1). As a result, two different
organometallic reagents were selectively introduced to the
thioformyl carbon atom, and the corresponding amine 4a was
obtained as a diastereomeric mixture in a ratio of 88:12 (entry
(1) (a) Kametani, T.; Kawamura, K.; Tsubuki, M.; Honda, T. Chem. Pharm.
Bull. 1985, 33, 4821. (b) Pohl, M.; Thieme, M.; Jones, P. G.; Liebscher, J. Liebigs
Ann. 1995, 1539. (c) Ahlbrecht, H.; Kramer, A. Chem. Ber. 1996, 129, 1161.
(d) Boswell, G. E.; Musso, D. L.; Davis, A. O.; Kelly, J. L.; Soroko, F. E.;
Cooper, B. R. J. Heterocycl. Chem. 1997, 34, 1813. (e) Lo, V. K.-Y.; Wong,
M.-K.; Che, C.-M. Org. Lett. 2008, 10, 517. (f) Nakamura, H.; Ishikura, M.;
Sugiishi, T.; Kamakura, T.; Biellmann, J.-F. Org. Biomol. Chem. 2008, 6, 1471.
(2) (a) Jimeno, C.; Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron Lett. 1999, 40, 777. (b) Almansa, R.; Guijarro, D.; Yus, M.
Tetrahedron: Asymmetry 2007, 18, 2828. (c) Almansa, R.; Guijarro, D.; Yus,
M. Tetrahedron: Asymmetry 2008, 19, 1376.
(5) (a) Enders, D.; Lotter, H. Tetrahedron Lett. 1982, 23, 639. (b) Maigrot,
N.; Mazaleyrat, J. P.; Welvart, Z. J. Chem. Soc., Chem. Commun. 1984, 40. (c)
Enders, D.; Lotter, H.; Maigrot, N.; Mazaleyrat, J. P.; Welvart, Z. NouV. J. Chim.
1984, 8, 747. (d) Ahlbrecht, H.; Dollinger, H. Synthesis 1985, 743. (e) Ahlbrecht,
H.; Sommer, H. Chem. Ber. 1990, 123, 829. (f) Trost, B. M.; Spagnol, M. D.
J. Chem. Soc., Perkin Trans. 1 1995, 2083. (g) Myers, A. G.; Kung, D. W.;
Zhong, B.; Movassaghi, M.; Kwon, S. J. Am. Chem. Soc. 1999, 121, 8401.
(3) Ducray, P.; Cavaliero, T.; Lohrmann, M.; Bouvier, J. PCT WO
2008062006, 2008.
(4) Hiroi, K.; Nakazawa, K. Chem. Lett. 1980, 1077.
9518 J. Org. Chem. 2008, 73, 9518–9521
10.1021/jo8021956 CCC: $40.75 2008 American Chemical Society
Published on Web 11/13/2008

TABLE 2. Addition Reaction of Organolithium 2 and -Magnesium Reagents 3 to Thioformamide 1aa
a For details, see Supporting Information. b Isolated yield. c Ratio was determined by 1H NMR or GC analyses of crude products. d The
stereochemistry of the products was determined by comparing their NMR data with those in the literature (ref 9a).
SCHEME 2. Addition Reactions of Organolithium and
-Magnesium Reagents to Thioformamide 1a
and phenyl metallic reagents (entries 3 and 4), but also for two
different alkyl metallic reagents (entries 5 and 6), although the
relative stereochemistry of the products has not yet been
determined. The combination of aryllithium and -magnesium
reagents also shows high stereoselectivity (entries 7-9). In
particular, diarylmethylamines such as 4e and 4f are not readily
accessible, and the development of their synthetic methods via
(6) (a) Brand, M.; Drewes, S. E.; Emslie, N. D.; Khan, A. A. Synth. Commun.
1991, 21, 727. (b) Morris, M. L.; Sturgess, M. A. Tetrahedron Lett. 1993, 34,
43. (c) Uenish, J.; Hamada, M. Tetrahedron: Asymmetry 2001, 12, 2999. (d)
Uenishi, J.; Hamada, M.; Aburatani, S.; Matsui, K.; Yonemitsu, O.; Tsukube,
H. J. Org. Chem. 2004, 69, 6781.
(7) Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem.
1997, 62, 4970.
1). The reaction temperature did not influence the ratio of
diastereomers (entries 2 and 3), but the reaction at lower
temperature was very slow (entry 3). The use of Et2O as a
solvent showed an efficiency and stereoselectivity equal to those
in the reaction with THF (entry 4). The reaction with 1.1 equiv
of EtMgBr gave 4a with a slightly higher selectivity but in lower
yield (entry 5).
(8) Tsirk, A.; Gronowitz, S.; Hornfeldt, A.-B. Acta Chem. Scand. 1998, 52,
533.
(9) (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763. (b) Xu, Q.; Rozners, E. Org. Lett. 2005, 7,
2821. (c) Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8,
1529. (d) Gommermann, N.; Knochel, P. Chem.sEur. J. 2006, 12, 4380. (e)
Zhang, X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47, 4358.
(10) (a) Suginome, M.; Uehlin, L.; Murakami, M. J. Am. Chem. Soc. 2004,
126, 13196. (b) Nanda, K. K.; Wesley, T. B. Tetrahedron Lett. 2005, 46, 2025.
(c) Tanaka, Y.; Hasui, T.; Suginome, M. Synlett 2008, 1239.
(11) (a) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc.
2004, 126, 5968. (b) Murai, T.; Toshio, R.; Mutoh, Y. Tetrahedron 2006, 62,
6312. (c) Murai, T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780.
(12) For recent examples, see: (a) Mutoh, Y.; Murai, T.; Mutoh, Y. J.
Organomet. Chem. 2007, 692, 129. (b) Shibahara, F.; Suenami, A.; Yoshida, A.
Chem. Commun. 2007, 2354. (c) Murai, T.; Nogawa, S.; Mutoh, Y. Bull. Soc.
Chem. Jpn. 2007, 80, 2220. (d) Murai, T.; Fukushima, K.; Mutoh, Y. Org. Lett.
2007, 9, 5295. (e) Shibahara, F.; Yoshida, A.; Murai, T. Chem. Lett. 2008, 37,
646.
Various combinations of organolithium and -magnesium
reagents were applied to the addition reaction to 1a. The results
are listed in Scheme 2 and Table 2.
In all cases, the reaction was highly stereoselective. For
example, the addition of PhLi (2a) to 1a followed by the
addition of MeMgBr (3b) gave the amine 4b exclusively as a
single diastereomer, whereas the sequential addition reaction
of MeLi (2b) and PhMgBr (3c) to 1a led to the opposite
diastereomer 4b′ as a major product (entries 1 and 2). The
stereochemistries of 4b and 4b′ were determined by comparing
their NMR spectroscopic data with those in the literature.5b
A
similar trend in stereoselectivity was observed not only for butyl
J. Org. Chem. Vol. 73, No. 23, 2008 9519

SCHEME 3. Plausible Reaction Pathway
SCHEME 4. Reaction of Thioformamide 1b and 7
asymmetric addition of organometallic reagents to imines is one
of the great topics.15 Finally, the combination of alkynyl and
aryl or alkyl metallic reagents was tested. The use of alkynyl-
magnesium reagents in the second step gave the products with
high diastereoselectivity (entries 10 and 12). In contrast, the
initial addition of lithium acetylide 2e to 1a decreased the
selectivity to some extent, although the desired products 4g′
and 4h′ were obtained in good yields (entries 11 and 13).16 This
may be because alkynyl groups are the least sterically hindered
substituents. Therefore, the stereochemistry of the products is
not determined thermodynamically but rather is kinetically
controlled.
Although details of the reaction mechanism can not yet be
discussed, the presumed reaction pathway is shown in Scheme 3.
Organolithium reagents 2 may attack the thiocarbonyl carbon atom
of the major conformer of 1a from the side opposite the meth-
oxymethyl group in the pyrrolidinyl group to form lithium thiolates
5. An SN2 substitution reaction may then occur at the carbon atom
adjacent to the nitrogen atom in 5 with elimination of a LiS group.
The results in Table 2 show that diastereoselectivity is controlled
not solely by the organolithium reagents, but also by the organo-
magnesium reagents. Therefore, the step from 5 to 4 may partly
involve an SN1 mechanism. Prior to the attack of organomagnesium
reagents, a LiS group is eliminated from 5 to exclusively form
E-iminium salts 6. Then, 3 adds to the iminium carbon atom from
the side opposite the methoxymethyl group to lead to the major
isomers 4 (path a), whereas the addition of 3 to 6 from the same
side of the methoxymethyl group gives the minor isomers 4′ (path
b). In fact, the generation of 6 has been postulated in the reaction
of N-1-cyanophenylmethyl 2-methoxymethylpyrrolidine with
MeMgBr.5b In this case, the product 4b is obtained with a
diastereoselectivity of 90:10.
showed efficiency and diastereoselectivity similar to those
observed in Table 1 and entry 11 in Table 2.
In summary, sequential addition reactions of widely used
organolithium and -magnesium reagents17 to N-thioformyl
2-alkoxymethylpyrrolidine have been demonstrated. Various
combinations of these two different types of organometallic
reagents have been shown to be useful. The reaction shows high
efficiency and diastereoselectivity. The synthesis of diastereo-
mers with opposite stereochemistries can be achieved by simply
reversing the order of introduction of the substituents on
organolithium and -magnesium reagents. Further studies on the
sequential addition of organometallic reagents to thioamides and
on the application of the products obtained as optically active
ligands are in progress.
Experimental Section
Typical Experimental Procedure for the Sequential Addi-
tion Reaction of Organolithium and -Magnesium Reagents to
Thioformamides 1. To a solution of (S)-2-methoxymethyl-1-
thioformylpyrrolidine (1a; 0.16 g, 1.0 mmol) in THF (1.0 mL) was
slowly added 1.00 M solution of phenyllithium in cyclohexane-
Et2O (1.1 mL, 1.1 mmol) at -78 °C. After the addition was
complete, the mixture was stirred for 0.5 h at room temperature.
To this was added a 1.0 M solution of ethylmagnesium bromide in
THF (2.0 mL, 2.0 mmol) at room temperature, and this mixture
was stirred at this temperature for 5 h. The resulting mixture was
poured into a saturated aqueous solution of NH4Cl and extracted
with Et2O. The organic layer was dried over MgSO4 and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy (SiO2, hexane/EtOAc/Et3N ) 5:1:0.01) to give (2S)-2-
(methoxymethyl)-1-(1-phenylpropyl)pyrrolidine (4a) (0.170 g, 73%
as a major isomer; 0.021 g, 9% as a mixture of isomers; 0.025 g,
11% as a minor isomer) as a yellow oil; dr ) 88:12. Major isomer:
Finally, thioformamides 1b and 7 were used as starting
materials (Scheme 4). The combinations of phenyllithium (2a)
and ethylmagnesium bromide (3a) and of lithium acetylide (2e)
and phenylmagnesium bromide (3c) were used. The reaction
20
[R]D ) -34.0 (c ) 0.73, CHCl3); IR (neat) 2963, 2931, 2873,
1
2823, 1492, 1452, 1197, 1116, 762, 704 cm-1; H NMR (CDCl3)
δ 0.68 (t, J ) 7.6 Hz, 3H), 1.45-1.71 (m, 5H), 1.85-1.92 (m,
1H), 2.18-2.24 (m, 1H), 2.68-2.81 (m, 2H), 3.16 (dd, J ) 9.4,
7.6 Hz, 1H), 3.31 (s, 3H), 3.38 (dd, J ) 9.4, 4.4 Hz, 1H), 3.49 (dd,
J ) 9.6, 5.6 Hz, 1H), 7.14-7.25 (m, 5H); 13C NMR (CDCl3) δ
11.3, 23.0, 27.8, 28.6, 49.8, 58.8, 59.1, 67.9, 76.9, 126.7, 127.8,
128.9, 140.6; MS (EI) m/z 232 (M+ - H): HRMS (EI) Calcd for
C15H22NO (M+ - H): 232.1701. Found: 232.1719. Minor isomer:
(13) Pyrrolidine 1a was prepared by thionation of N-formyl 2-methoxymethyl
pyrrolidine14 with Lawesson reagent.
(14) Enders, D.; Fey, P.; Kipphardt, H. Organic Syntheses; Wiley and Sons:
New York, 1993; Collect. Vol. No. 8, p 26.
(15) For recent examples, see: (a) Le Fur, N.; Mojovic, L.; Ple, N.; Turck,
A.; Reboul, V.; Metzner, P. J. Org. Chem. 2006, 71, 2609. (b) Jagt, R. B. C.;
Toullec, P. Y.; Geerdink, D.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J.
Angew. Chem., Int. Ed. 2006, 45, 2789. (c) Duan, H.-F.; Jia, Y.-X.; Wang, L.-
X.; Zhou, Q.-L. Org. Lett. 2006, 8, 2567. (d) Berthon-Gelloz, G.; Hayashi, T. J.
Org. Chem. 2006, 71, 8957. (e) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-
Q. J. Am. Chem. Soc. 2007, 129, 5336. (f) Marelli, C.; Monti, C.; Gennari, C.;
Piarulli, U. Synlett 2007, 2213. (g) Nakagawa, H.; Rech, J. C.; Sindelar, R. W.;
Ellman, J. A. Org. Lett. 2007, 9, 5155.
IR (neat) 2963, 2931, 2873, 2807, 1453, 1196, 1114, 768 cm-1
;
1H NMR (CDCl3) δ 0.58 (t, J ) 7.2 Hz, 3H), 1.63-1.74 (m, 5H),
(17) For reviews, see: (a) Main Group Metals in Organic Synthesis;
Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1. (b)
Handbook of Functionalized Organometallics; Knochel, P., Ed.; Wiley-VCH:
Weinheim, 2005; Vol. 1.
(16) In contrast to these successful results, the combination of lithium
acetylides and alkynylmagnesium reagents gave the corresponding products in
only low yields along with the formation of unidentified byproducts.
9520 J. Org. Chem. Vol. 73, No. 23, 2008

1.88-1.94 (m, 1H), 2.41-2.47 (m, 1H), 2.72-2.81 (m), 2.87-2.90
(m, 1H), 2.98-3.03 (m, 1H), 3.01 (s, 3H), 3.28 (dd, J ) 10.8, 4.0
Hz, 1H), 7.14-7.25 (m, 5H); 13C NMR (CDCl3) δ 11.1, 23.7, 26.3,
28.6, 52.4, 58.6, 60.4, 71.0, 76.1, 127.0, 128.0, 128.8, 142.8; MS
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Experimental proce-
dures and characterization of new compounds 1, 4, 7, and 8.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(EI) m/z 232 (M+ - H); HRMS (EI) Calcd for C15H22NO (M+
-
H): 232.1701. Found: 232.1698.
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research on Priority Area (No. 19020020,
“Advanced Molecular Transformations of Carbon Resources”)
JO8021956
J. Org. Chem. Vol. 73, No. 23, 2008 9521