A new synthesis of 3-substituted pyrrolidines using iron catalysed cross-coupling reactions and ring closing metathesis

Article abstract of DOI:10.1055/s-2002-34886

A series of 3-substituted N-Boc protected pyrrolidines have been prepared via iron catalysed cross-coupling between Boc protected N-allyl-N-(2-bromoallyl)amine 3 and organomagnesium compounds followed by ring closing metathesis and subsequent hydrogenatio

Full text of DOI:10.1055/s-2002-34886

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LETTER
1889
A New Synthesis of 3-Substituted Pyrrolidines Using Iron Catalysed
Cross-coupling Reactions and Ring Closing Metathesis
A
New Synthesis
o
i
f
3-Sub
e
stituted Py
l
rrolidin
s
es Østergaard,a,b Brian Thoning Pedersen,a Niels Skjærbæk,b Per Vedsø,a,1 Mikael Begtrup*a
a
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, 2100 Copenhagen, Denmark
Fax +4535306040; E-mail: begtrup@dfh.dk
b
ACADIA Pharmaceuticals A/S, Fabriksparken 58, 2600 Glostrup, Denmark
Received 12 August 2002
We envisaged that the intermediate 3-substituted 3-pyr-
rolines could be prepared from N-protected N-allyl-N-(2-
bromoallyl)amine via two approaches. A: Functionalisa-
tion (cross-coupling) of a 3-bromo pyrroline prepared
via RCM of the N-allyl-N-(2-bromoallyl)amine; B: RCM
of 2-substituted diallylamines prepared via cross-coup-
ling between the N-allyl-N-(2-bromoallyl)amine and an
organometallic reagent (Scheme 1).
Abstract: A series of 3-substituted N-Boc protected pyrrolidines
have been prepared via iron catalysed cross-coupling between Boc
protected N-allyl-N-(2-bromoallyl)amine 3 and organomagnesium
compounds followed by ring closing metathesis and subsequent
hydrogenation of the formed pyrrolines.
Key words: pyrrolidines, ring closing metathesis, Grignard re-
agents, iron catalysed cross-coupling
Pyrrolidine is a frequently found motif in numerous natu-
rally occurring alkaloids and biologically active substan-
ces.2,3 Their synthesis has attracted much attention and a
wide range of different approaches have been reported
which include both inter- and intramolecular reactions.4
N
N
Mes
Mes
Ph
PCy3
Ru
Cl
Cl
Cl
Ru
Cl
Ph
PCy3
PCy3
2
1
As a part of a drug discovery program directed towards
the synthesis of compounds with muscarinic agonist
properties, we became interested in the preparation of 3-
substituted pyrrolidines. Ring closing olefin metathesis
(RCM)5,6 is a powerful tool for the construction of func-
tionalised heterocycles. Recently, RCM has been em-
ployed for the construction of the 3-pyrrolidine ring in the
synthesis of an analogue of swainsonine.7 This result has
prompted us to report our results on the preparation of a
series of 3-alkyl and 3-aryl substituted N-Boc protected
pyrrolidines 8–12 from 3 using a combination of iron
catalysed cross-coupling, RCM and hydrogenation of the
intermediate pyrrolines.
Figure 1
Vinyl bromide 38 did not undergo RCM using Grubb’s
catalysts 1 or the more active ruthenium catalyst 2
(Figure 1). In addition, Lee et al. have reported that Pd
catalysed reactions between 3-trifluorosulfonate-3-
pyrroline and arylboronic acids afford 3-arylpyrroles by a
tandem Suzuki-dehydrogenation reaction.9 We therefore
decided to investigate route B where 3 was functionalised
via a transition metal catalysed C–C bond forming reac-
tion prior to RCM. We noted that treatment of N-protected
N-allyl-N-(2-bromoallyl)amines with either catalytic
amount of palladium or stoichiometric amount of nickel
invariantly gave rise to intramolecular cyclisation.10,11
Moreover, use of the readily removeable Boc protection
group was reported to give complex mixtures, when 3 was
treated with an arylboronic acid and a palladium cata-
lyst.11
Br
route A
c
N
b
R
R
Pg
Br
a
c
Iron catalysed alkenylation of Grignard reagents was first
described by Kochi et al.12 and later optimised by
Cahiez.13 Cheap and stable iron salts have proved efficient
and practicable catalysts for both alkenyl-alkyl cross-
couplings and for the coupling of electron-deficient aryl
chlorides with alkyl Grignard reagents.14
N
b
N
N
Pg
Pg
Pg
R
route B
N
Pg
Scheme 1 Retrosyntetic approaches A and B: a) reduction, b) cross-
Using this approach, treatment of 3 with 1.5 equivalents
of n-BuMgCl in THF–NMP at 0 °C for 30 minutes in the
presence of 2 mol% Fe(acac)3 resulted in full conversion
of 3 and the cross coupled product 4 could be isolated in
64% yield (Table 1). Similarly i-PrMgCl and PhMgCl
could also be coupled with 3, however in the latter case
coupling reaction and c) ring closing metathesis.
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1889,1891,ftx,en;G22602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

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1890
N. Østergaard et al.
LETTER
large amounts of the homocoupling product (biphenyl) In summary, a new simple, practical and convenient ap-
was observed. Addition of large excess of PhMgCl (3 proach for the synthesis of 3-substituted pyrrolidines
equiv) increased the yield of 6 from 37% to 61%. Sterical- starting from 3 has been developed using iron catalysed
ly congested t-BuMgCl gave no reaction even if used in cross-coupling, ruthenium catalysed ring closing metathe-
large excess (Table 1). As the crude products were gener- sis and palladium catalysed hydrogenation. We are cur-
ally fairly pure they were used directly in the following rently investigating the application of this methodology in
step in order to circumvent chromatographic purification. combination with asymmetric hydrogenation and dihy-
Thus, the crude pyrrolines were ring closed using 10 droxylation for preparation of chiral functionalised pyr-
mol% of 1 or 5 mol% of 2.
rolidines.
Table 1 Iron Catalysed Cross-coupling of 3 with Grignard Reagents
Acknowledgement
Br
R
2 mol% Fe(acac)3
THF-NMP
This work was supported by ACADIA Pharmaceuticals A/S and
The Danish Academy of Technical Sciences. The GC-MS was a gift
from the Velux Foundation of 1981 and the Ib Henriksen Foundati-
on. The 300 MHz NMR instrument was provided by The Danish
National Science Research Council. We are also grateful to Ms.
Malene Mohr, LEO Pharma, Denmark, for providing the HRMS
data.
RMgCl
+
N
N
0 °C, 30 min
Boc
Boc
4-7
3
R
Product
Yield (%)
n-Bu
i-Pr
Ph
4
5
6
7
64
References
59a
(1) Current address: Novo Nordisk A/S, Medicinal Chemistry
Research, 2760 Måløv, Denmark.
(2) Derwick, P. M. Medicinal Natural Products, Chap. 6; J.
Wiley and Sons: Chichester, 1997, 270.
37a (61)b
0
t-Bu
(3) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.;
Nash, R. J. Phytochemistry 2001, 56, 265.
(4) For general information see: Mitchinson, A.; Nadin, A. J.
Chem. Soc., Perkin Trans. 1 2000, 2862; (contemporary
review) and former reviews cited therein.
(5) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(6) Fürstner A.; Angew. Chem. Int. Ed.; 2000, 39: 3012.
(7) Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2002, 731; for
the application of RCM reaction to the synthesis of
pyrrolines see references cited therein.
a 2 Equiv of Grignard reagent was used.
b 3 Equiv of PhMgCl was used.
This furnished the 3-substituted 3-pyrrolines, which in or-
der to avoid oxidation to the corresponding pyrroles upon
exposure to air were reduced to the stable and desired 3-
substituted pyrrolidines using hydrogen (3 bar) and Pd/C.
Following the procedure described in the reference15
a
(8) Compound 3 was synthesized in ~20 g scale from allylamine
and 2,3-dibromopropene followed by Boc protection using
the procedure described by: Shi, L.; Narula, C. K.; Mak, K.
T.; Kao, L.; Xu, Y.; Heck, R. F. J. Org. Chem. 1983, 48,
3894.
(9) Lee, C.-W.; Chung, Y. J. Tetrahedron Lett. 2000, 41, 3423.
(10) Cancho, Y.; Martin, J. M.; Martinez, M.; Llebaria, A.;
Moreto, J. M.; Delgado, A. Tetrahedron 1998, 54, 1221.
(11) Lee, C.; Oh, K. S.; Kim, K. S.; Ahn, K. H. Org. Lett. 2000,
2, 1213.
range of 3-substituted pyrrolidines were synthesised in
38–55% overall yield in 3 steps from 3 involving only a
single and final chromatographic purification (Table 2).
Table 2 Synthesis of Pyrrolidines 8–12 from 3
R
R
R
a
b
c
3
N
N
N
(12) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487.
(13) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199.
(14) Fürstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2002, 41,
609.
Boc
Boc
Boc
8-12
Entry
R
Product
Yieldd
(15) Typical Procedure: To a stirred solution of allyl-(2-
bromoallyl)-carbamic acid tert-butyl ester (3) (1.49 g, 5.4
mmol) and Fe(acac)3 (38 mg, 2 mol%) in THF (7.5 mL) and
NMP (5.4 mL) at 0 °C was added a THF solution of i-
PrMgCl (6.0 mL, 1.8 M, 10.8 mmol) drop wise over a period
of 30 min. After stirring for 1 h the reaction mixture was
quenched with sat. NH4Cl (20 mL) followed by extraction
with CH2Cl2 (3 20 mL). Drying of the organic layers
(Na2SO4) and removal of the solvents in vacuo gave crude 5.
An analytically sample was purified on silica gel (heptane/
EtOAc 20:1). Data for 5: 1H NMR: = 5.84–5.68 (m, 1 H),
5.16–5.03 (m, 2 H), 4.86 (br s, 1 H), 4.73 (br s, 1 H), 3.88–
3.68 (m, 4 H), 2.26–2.14 (m, 1 H), 1.46 (s, 9 H), 1.06 (d,
J = 7 Hz, 6 H). 13C NMR: = 151.0 (s), 144.4 (s), 133.9 (d),
116.5 and 116.2 (t), 108.0 and 107.5 (t), 49.4 and 48.3 (t),
1
2
3
4
5
n-Bu
8
9
51%
55%
53%
52%
38%e
n-Pentyl
n-Hexyl
i-Pr
10
11
12
Ph
a 2 Equiv RMgCl, 1 mol% Fe(acac)3, THF–NMP, 0 °C, 1 h.
b 10 mol% of 1 for 36 h or 5 mol% of 2 for 24 h in CH2Cl2 at r.t.
c 10 mol% Pd/C, 3 atm H2, MeOH, 24 h.
d Yields are isolated overall yields from 3.
e 3 Equivalents of PhMgCl was used.
Synlett 2002, No. 11, 1889–1891 ISSN 0936-5214 © Thieme Stuttgart · New York

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LETTER
A New Synthesis of 3-Substituted Pyrrolidines
1891
31.2 (d), 28.4 (q), 21.7 (q). HRMS calcd for C14H25NO2:
239.1886. Found: 239.1877. The crude residue was
dissolved in degassed CH2Cl2 (270 mL) and 2 (229 mg, 5
mol%) were added. After stirring for 24 h at r.t. under
nitrogen the solvent was removed in vacuo. The mixture was
redissolved in MeOH (20 mL) and 10 wt% Pd/C (400 mg)
was added. The mixture was stirred in a hydrogen
and gently concentrated in vacuo. Purification on silica gel
(heptane/EtOAc 20:1) provided 630 mg (52%) of 11 as a
clear oil. Data for 11: 1H NMR: = 3.59–3.44 (m, 2 H),
3.26–3.15 (m, 1 H), 2.91–2.82 (m, 1 H), 2.03–1.92 (m, 1 H),
1.87–1.71 (m, 1 H), 1.54–1.35 (m, 11 H), 0.96–0.89 (m, 6
H). 13C NMR: = 154.7, 78.7, 50.1, 46.1, 45.9, 31.8, 29.9,
28.3, 21.2, 20.9. HRMS calcd for C12H23NO2: 213.1729.
Found: 213.1724.
atmosphere (3 bar) for 24 h and then filtered through celite
Synlett 2002, No. 11, 1889–1891 ISSN 0936-5214 © Thieme Stuttgart · New York