Enantioselective syntheses of 2-substituted pyrrolidines from allylamines by domino hydroformylation-condensation: Short syntheses of (S)-nicotine and the alkaloid 225C

Article abstract of DOI:10.1055/s-0029-1217165

Short routes to chiral 2-substituted pyrrolidines based on rhodium-catalyzed hydroformylations of allylamines and their N-alkyl and N-acyl derivatives, which were prepared by asymmetric allylic substitutions, are described. The outcome of the hydroformyla

Full text of DOI:10.1055/s-0029-1217165

LETTER
1413
Enantioselective Syntheses of 2-Substituted Pyrrolidines from Allylamines by
Domino Hydroformylation–Condensation: Short Syntheses of (S)-Nicotine
and the Alkaloid 225C
S
hor
t
Synthese
i
s
of
(
S
e
)-Nicotine
r
A
r
lkaloid
e225C Dübon, Andreas Farwick, Günter Helmchen*
Organisch-Chemisches Institut der Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)544205; E-mail: g.helmchen@oci.uni-heidelberg.de
Received 2 February 2009
phos or Biphephos (Figure 1) as ligands, mixtures of a
Abstract: Short routes to chiral 2-substituted pyrrolidines based on
pyrrolidine of type C and a lactam of type D were formed.
rhodium-catalyzed hydroformylations of allylamines and their N-
This result was an incentive to study the hydroformylation
of allylamine derivatives in detail. As a result, very short
alkyl and N-acyl derivatives, which were prepared by asymmetric
allylic substitutions, are described. The outcome of the hydroformy-
lation reaction was controlled by the substituent at nitrogen, not by and selective syntheses of pyrrolidines of types A, C, and
the substituent at carbon. In the case of N-alkylallylamines in situ
E possessing high enantiomeric purity are now available
reduction to the pyrrolidines occurred, with N-acyl derivatives
hemiaminals and with primary amines cyclic imines were formed.
via hydroformylation.
The rhodium-catalyzed cyclization reactions were probed
with catalysts prepared from Rh(acac)(CO)2 and several
ligands; the best results were obtained with Xantphos and
Biphephos (Figure 1). These ligands have indeed previ-
ously given particularly good results with respect to the
n/iso ratio, which for 1-octene was 52:1 (Xantphos)9 and
40:1 (Biphephos).10 Biphephos has excelled in hydro-
formylations of a large variety of functionalized alkenes.
In our own screening experiments no superior ligand was
found.
Very short syntheses of (S)-nicotine and the alkaloid 225C are pre-
sented.
Key words: domino reactions, hydroformylation, pyrrolidines,
alkaloids, cyclizations
Over the last few years, the iridium-catalyzed allylic sub-
stitution has been developed into a tool for organic syn-
thesis that allows chiral allylamines to be prepared in
great variety with high enantioselectivity (Scheme 1).1
Given these compounds with tailor-made, readily remov-
able N-protection, they were used as starting compounds
of ring-forming reactions.2,3 We have now explored their
use as substrates of the hydroformylation reaction.4 In the
case of secondary amines 3 (cf. Scheme 1), the aldehydes
so produced undergo spontaneous cyclization, elimina-
tion, and sometimes also reduction, namely, a so-called
hydroaminomethylation. This sequence of reactions is
well known for the intermolecular case;5 intramolecular
reactions have been studied in particular with homoal-
lylamine derivatives yielding piperidines.6
R2
R1
R3
H
R2
NHR2R3
[Ir]cat
N
N
deprotection
R1
X
R1
1
3
2
CO, H2
[Rh]
OH
O
R2
R2
N
R2
R2
N
N
N
N
R1
R1
R1
R1
R1
(R2 = H)
A
E
C
D
B
Due to the starting materials, our work was directed at 2-
substituted pyrrolidines,7 particularly pyrrolidine alka-
loids and potential organocatalysts. One point of concern
was racemization, which is not possible for homoal-
lylamines, but could be marked with allylamines if the
hydroformylation reaction was reversible. Therefore,
enantiomeric excesses of starting materials and products
were carefully determined. Furthermore, the outcome of
the seemingly straightforward hydroformylation turned
out to be a function of subtle details of structure, catalyst,
and reaction conditions (cf. Scheme 1).8 For example, an
attempt to prepare nicotine via hydroformylation of the al-
lylamine 3d (R1 = 3-pyridyl, R2 = Me) met with complete
failure, because under standard conditions, using Xant-
Scheme 1 Products potentially formed by hydroformylation of an
allylamine
MeO
t-Bu
OMe
O
O
O
O
t-Bu
O
O
P
P
O
PPh2
PPh2
Xantphos (XP)
Biphephos (BP)
Figure 1 Ligands used for rhodium-catalyzed hydroformylation
reactions
SYNLETT 2009, No. 9, pp 1413–1416
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x.
x
x.
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0
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Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217165; Art ID: G02709ST
© Georg Thieme Verlag Stuttgart · New York

1414
P. Dübon et al.
LETTER
First, the N-benzyl- and N-(p-methoxyphenyl)methylal- These were prepared using salt-free conditions of the
lylamines 3a–c, prepared by standard Ir-catalyzed allylic Ir-catalyzed allylic substitution and partial N-deprotec-
amination,11 were probed using conditions published by tion.11c,17–19 The course of the hydroformylation of these
Eilbracht et al. (Scheme 2).12 The aforementioned in- compounds, using slightly modified conditions A (cf.
tramolecular hydroaminomethylation gave the 2-substi- Scheme 2), was different from that with N-alkyl-allyl-
tuted pyrrolidines 4a–c in 57–72% yield. Careful amines (Scheme 5). Hemiaminals 9 were produced after
determination of the enantiomeric excess of the starting cyclization of the intermediary aldehydes.20 The isolated
materials and the products showed that racemization had yields of the hemiaminals 9 were good to excellent. Race-
not occurred.13
mization did not occur. The hemiaminals were reduced
with TFA and HSiEt3 to give 2-substituted pyrrolidines 4
in yields of 51–87% (over two steps, Scheme 5).
Conditions A:
H2/CO 1:1 (60 bar)
Rh(acac)(CO)2 (0.9 mol%)
Xantphos (1.8 mol%)
R2
Remarkably, hydroformylations of N-acyl-homoallyl-
amines in aprotic solvents, using Biphephos as ligand,
yield aldehydes or N-acyl-dehydropiperidines (i.e., enam-
ines), according to Ojima et al.6c,d These authors also re-
ported that elimination of water from corresponding
hemiaminals under acidic conditions is facile. Under the
same conditions, the hemiaminals 9 did not react. Thus,
the rate of elimination of water likely is the cause of the
differing reaction modes of N-alkyl- and N-acyl-allyl-
amines.
NHR2
N
R1
R1
CH2Cl2, 80 °C, 18 h
3
4
R
R
R
R
1 = Ph
R2 = Bn
a
b
c
d
72% (96% ee)
64% (98% ee)
57% (98% ee)
4d (23%) + 8d (44%)
1 = Ph
R
R
R
2 = CH2(4-MeOC6H4)
2 = CH2(4-MeOC6H4)
2 = Me
1 = 3-Py
1 = 3-Py
Scheme 2 Domino hydroformylation–reductive amination
The substrate 3d, as was mentioned above, proved prob-
lematic. With Xantphos as ligand in a variety of experi-
ments the major product was the lactam cotinine (8d), also
a tobacco alkaloid (Scheme 3). This compound is presum-
ably formed via the rhodium complex 6 by b-H elimina-
tion. Lactams as hydroformylation products have
previously been observed.5b,6b
OCO2Me
OMe
N
S
O
O
aS
P
N
MeNH2 (1.3 equiv)
[Ir(cod)Cl]2 (2 mol%)
L* (4 mol%)
TBD (8 mol%)
THF, r.t.
S
OMe
L*
H[Rh]
NH
[Rh]H
OH
R2
R1
O
R2
R1
NHR2
H2/CO
[Rh]cat
N
Me
R1
Conditions B:
H2/CO 5:1 (30 bar)
Me
NH
6
N
3
5
Rh(acac)(CO)2 (0.9 mol%)
Biphephos (1.8 mol%)
CHCl3, 50 °C, 24 h
N
3d
O
N
R2
4d
R2
R2
H
b/l = >99:1, 99% ee (74%)
N
(S)-nicotine (61%)
N
N
CHO
4
R1
Scheme 4 Enantioselective synthesis of (S)-nicotine (preparation of
L* according to Alexakis et al.).21 The designations b and l refer to the
branched (3d) and linear product, respectively, of the allylic aminati-
on.
R1
R1
8
7
8d R1 = 3-Py, R2 = Me
cotinine
Scheme 3 Intermediates of the domino-hydroformylation–reduc-
tive amination
H2/CO 1:1 (60 bar)
Rh(acac)(CO)2 (1.0 mol%)
Xantphos (5.0 mol%)
Et3N (1.0 equiv)
OH
R2
NHR2
N
In order to accelerate the hydrogenation step, the partial
pressure of hydrogen was increased (H2/CO = 5:1). Fur-
thermore, the phosphite Biphephos was used as ligand,
which induces higher activity than Xantphos. This al-
lowed decrease of the reaction pressure (30 bar) and tem-
perature (50 °C). Under optimized conditions (B,
Scheme 4)14 (S)-nicotine (6d) was obtained in 61% yield,
not contaminated by cotinine, with 99% ee, that is, with-
out racemization. This route constitutes a very short syn-
thesis of (S)-nicotine.15,16
TFA (0.9 equiv)
HSiEt3 (3.0 equiv)
CH2Cl2, r.t.
R1
toluene, 80 °C, 18–25 h
R1
3
9
R2
N
4
R1
1 = Ph
R
R
R
R
R
2 = SO2t-Bu 64% (2 steps) (91% ee)
e
f
g
h
i
R
R
R
R
R
1 = Ph
2 = Ts
87% (2 steps) (98% ee)
83% (2 steps) (98% ee)
51% (2 steps) (96% ee)
77% of 9i (92% ee)
1 = Ph
1 = n-Pr
1 = (CH2)2OTr
2 = Boc
2 = Boc
2 = Boc
As second class of substrates N-sulfonyl- (3e,f) and N-
acyl-allylamines (3g–i) were investigated (Scheme 5). Scheme 5 Hydroformylation of N-sulfonyl- and N-acyl-allylamines
Synlett 2009, No. 9, 1413–1416 © Thieme Stuttgart · New York

LETTER
Short Syntheses of (S)-Nicotine and the Alkaloid 225C
1415
Finally, N-unprotected primary allylamines were subject- cyclic imines were formed. The insight gained allowed
ed to the hydroformylation reaction (Scheme 6). Under very short syntheses of (S)-nicotine and the alkaloid 225C
standard hydroformylation conditions [Xantphos, 60 bar, to be carried out.
H2/CO (1:1), CH2Cl2 or toluene, 80 °C, 24 h] conversion
was low. Under the conditions B optimized for nicotine
[Biphephos, 30 bar, H2/CO (5:1), CHCl3] the imines 10a
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 623) and the Fonds der Chemischen Industrie. We thank Prof.
Eilbracht, Dortmund, for useful hints concerning hydroformylation
procedures. Continued supply of chiral amines by Prof. Ditrich,
BASF SE, Ludwigshafen, is gratefully acknowledged.
and 10b were formed in good yield; reductive amination
did not occur (GC-MS).22
H2/CO 5:1 (30 bar)
Rh(acac)(CO)2 (0.9 mol%)
Biphephos (1.8 mol%)
NH2
N
HN
H2, Rh/C
R
CHCl3, 50 °C, 18–24 h
MeOH, r.t.
18–20 h
R
R
References and Notes
3
10
11
(1) (a) Helmchen, G. In Iridium Complexes in Organic
Synthesis; Oro, L. A.; Claver, C., Eds.; Wiley-VCH:
Weinheim, 2009, 211. (b)Helmchen, G.; Dahnz, A.; Dübon,
P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007,
675. (c) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349.
(d) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641.
(2) (a) Streiff, S.; Welter, C.; Schelwies, M.; Lipowsky, G.;
Miller, N.; Helmchen, G. Chem. Commun. 2005, 2957.
(b) Welter, C.; Moreno, R. M.; Streiff, S.; Helmchen, G.
Org. Biomol. Chem. 2005, 3, 3266. (c) Böhrsch, V.;
Blechert, S. Chem. Commun. 2006, 1968.
3k, 10a, 11a
3l, 10b, 11b
R = Ph
R = n-Hept 69%
57% (98% ee)
73% (96% ee)
89%
Scheme 6 Hydroformylation–cyclization of primary allylamines
Hydrogenation of the imines 10 was carried out with
Rh/C as catalyst (methanol, r.t., 1 atm of H2). The enantio-
meric excess decreased slightly, from 98% (10a) to 96%
(11a, Scheme 6). In contrast, with Pd/C as catalyst under
otherwise identical conditions the ee decreased to 90%.
(3) Schelwies, M.; Dempwolff, A.; Rominger, F.; Helmchen, G.
Angew. Chem. Int. Ed. 2007, 46, 5598; Angew. Chem. 2007,
119, 5694.
The cyclic imines 10 are of interest for syntheses of bio-
logically active compounds. We have used ent-10b for a
short synthesis of the alkaloid 225C [(+)-12], a constituent
of the venom of the fire-ant Solenopsis fugax.23 Introduc-
tion of the n-Bu group by addition of n-BuLi was an obvi-
ous route (Scheme 7). The addition of a nucleophile to an
imine generally requires the presence of an electron-with-
drawing N-substituent24 or addition of a Lewis acid.25 Fol-
lowing a procedure by Nakagawa et al.,25b a solution of
ent-10b in toluene was cooled to –78 °C, treated with
BF3×OEt2 (1.6 equiv) and then with n-BuLi (2 equiv, 1.6
M in n-hexane). The addition proceeded with a low dr of
66:34 (trans/cis). However, with diethyl ether as solvent
at –100 °C using n-BuLi, which was precooled26 to the
same temperature, an excellent dr of 95:5 resulted.
(4) (a) Allylamines prepared by Ir-catalyzed asymmetric allylic
substitution have been used in hydroformylation–
indolization sequences: Bondzić, B. P.; Farwick, A.;
Liebich, J.; Eilbracht, P. Org. Biomol. Chem. 2008, 3723.
(b) For preparation of an indolizine via hydroformylation of
an N-allyl-pyrrole, see: Guazzelli, G.; Lazzaroni, R.;
Settambolo, R. Beilstein J. Org. Chem. 2008, 4, 2.
(5) For a review, see: (a) Eilbracht, P.; Schmidt, A. M. Top.
Organomet. Chem. 2006, 18, 65. (b) Eilbracht, P.;
Bärfacker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon,
B. E.; Kranemann, C. L.; Roggenbruck, R.; Schmidt, A.
Chem. Rev. 1999, 99, 3329. (c) Ahmed, M.; Seayad, A. M.;
Jackstell, R.; Beller, M. J. Am. Chem. Soc. 2003, 125,
10311. (d) Ahmed, M.; Buch, C.; Routaboul, L.; Jackstell,
R.; Klein, H.; Spannenberg, A.; Beller, M. Chem. Eur. J.
2007, 13, 1594; and previous work cited there.
(6) (a) Vieira, T. O.; Alper, H. Chem. Commun. 2007, 2710.
(b) Wittmann, K.; Wisniewski, W.; Mynott, R.; Leitner, W.;
Kranemann, C. L.; Rische, T.; Eilbracht, P.; Sander, S.;
Ernsting, J. M. Chem. Eur. J. 2001, 7, 4584. (c)Eguchi, M.;
Tzamarioudaki, M.; Ojima, I. J. Org. Chem. 1995, 60, 7078.
(d) Vidal, E. S.; Ojima, I. J. Org. Chem. 1998, 63, 7999.
(e) Spangenberg, T.; Airiau, E.; Bui The Thuong, M.;
Donnard, M.; Billet, M.; Mann, A. Synlett 2008, 2859.
(f) Airiau, E.; Spangenberg, T.; Girard, N.; Schoenfelder, A.;
Salvadori, J.; Taddei, M.; Mann, A. Chem. Eur. J. 2008, 14,
10938. (g) Spangenberg, T.; Breit, B.; Mann, A. Org. Lett.
2009, 11, 261.
(7) For leading references to asymmetric syntheses of
pyrrolidines, including alkaloid 225C, see: Davis, F. A.; Xu,
H.; Wu, Y.; Zhang, J. Org. Lett. 2006, 8, 2273.
(8) Rhodium-Catalyzed Hydroformylation; van Leeuwen, P. W.
N. M.; Claver, C., Eds.; Kluwer Academic: Dordrecht, 2000.
(9) Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H.
Acc. Chem. Res. 2001, 34, 895.
n-BuLi (2.0 equiv)
BF3⋅OEt2 (1.6 equiv)
S
S
n-Hept
n-Bu
OEt2, –100 °C (2 h) to r.t.
N
N
n-Hept
H
(+)-12
dr = 95:5, 97% ee (72%)
ent-10b
Scheme 7 Application of a cyclic imine in the synthesis of an alka-
loid
In summary, we present short routes to chiral 2-substitut-
ed pyrrolidines27 based on rhodium-catalyzed hydro-
formylations of allylamines, which were derived from
asymmetric allylic substitutions. The outcome of the
hydroformylation reaction was found to be controlled by
the nature of the substituent at nitrogen, fortunately not by
the substituent at carbon. In the case of N-alkylallyl-
amines in situ reduction to the pyrrolidines occurred, with
N-acyl derivatives hemiaminals and with primary amines
(10) Cuny, G. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115,
2066.
Synlett 2009, No. 9, 1413–1416 © Thieme Stuttgart · New York

1416
P. Dübon et al.
LETTER
(19) (a) Spiess, S.; Berthold, C.; Weihofen, R.; Helmchen, G.
(11) (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
15164. (b) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.;
Dübon, P.; Helmchen, G. Org. Lett. 2005, 7, 1239.
(c) Gnamm, C.; Franck, G.; Miller, N.; Stork, T.; Brödner,
K.; Helmchen, G. Synthesis 2008, 3331.
Org. Biol. Chem. 2007, 5, 2357. (b) Pouy, M. J.; Leitner, A.;
Weix, D. J.; Ueno, S.; Hartwig, J. F. Org. Lett. 2007, 9,
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(12) Keränen, M. D.; Eilbracht, P. Org. Biomol. Chem. 2004, 2,
(20) This has only been observed previously with derivatives of
the parent allylamine using Ph3P as ligand, see: Dong, Y.;
Busacca, C. A. Tetrahedron Lett. 1996, 37, 3947.
(21) (a) Tissot-Croset, K.; Polet, D.; Gille, S.; Hawner, C.;
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A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem.
Eur. J. 2006, 12, 3596.
(22) We have found only one report on such a reaction, the
hydroformylation of the parent allylamine, see: Lin, J. J.;
Larkin, J. M.; Knifton, J. F. In Catalysis of Organic
Reactions; Augustine, R. L., Ed.; Dekker: New York, 1988,
29.
(23) For previous syntheses, see: (a) Pedder, D. J.; Fales, H. M.;
Jaouni, T.; Blum, M.; MacConnell, J.; Crewe, R. M.
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(26) We used apparatus described in: Bartels, B.; Garcia-Yebra,
C.; Helmchen, G. Eur. J. Org. Chem. 2003, 1097.
(27) Our procedure complements Buchwald’s similarly short
asymmetric hydrogenation route: Willoughby, C. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8952.
1688.
(13) All new compounds described were fully characterized by
elemental analysis and spectroscopic data. Yields always
refer to isolated products.
(14) General Procedure for the Rh-Catalyzed
Hydroformylation–Reduction (cf. Conditions B,
Scheme 4)
A cylindrical glass vessel (2.5 × 7 cm) with a perforated snap
on lid was charged with Rh(acac)(CO)2 (2.3 mg, 9.0 mmol),
Biphephos (18 mmol), and a soln of the allylic amine (1.0
mmol) in CHCl3 (10 mL/mmol). The vessel was placed in an
autoclave, which was pressurized (30 bar) with H2/CO (5:1);
oxygen was removed by flushing twice with the gas mixture.
The autoclave was then heated for 18–24 h at 50 °C. The
resulting brown mixture was analyzed by GC-MS. The
solvent was removed in vacuo and the residue subjected to
flash chromatography on SiO2.
(15) For a review, see: (a) Felpin, F.-X.; Lebreton, A. Eur. J.
Org. Chem. 2003, 3693. (b) Wagner, F. F.; Comins, D. L.
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2002, 143. (e) Welter, C.; Moreno, R. M.; Streiff, S.;
Helmchen, G. Org. Biomol. Chem. 2005, 3, 3266.
(16) Very recently, a short synthesis of (S)-nicotine via
hydroformylation of a homoallylazide has been reported,
cf. ref. 6g.
(17) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem.
Int. Ed. 2006, 45, 5546; Angew. Chem. 2006, 118, 5673.
(18) Weihofen, R.; Dahnz, A.; Tverskoy, O.; Helmchen, G.
Chem. Commun. 2005, 3541.
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