Selective azetidine and tetrahydropyridine formation via Pd-catalyzed cyclizations of allene-substituted amines and amino acids

Article abstract of DOI:10.1021/ol990700c

Formula presented By choosing the right substituents either highly functionalized unusual four-membered ring amino acids or the isomeric pipecolic acid derivatives are obtained in enantiomerically pure form. Starting material is a linear allene-containing amino acid that has been resolved via biocatalysis.

Full text of DOI:10.1021/ol990700c

ORGANIC
LETTERS
1999
Vol. 1, No. 5
717-720
Selective Azetidine and
Tetrahydropyridine Formation via
Pd-Catalyzed Cyclizations of
Allene-Substituted Amines and Amino
Acids
Floris P. J. T. Rutjes,* Kim C. M. F. Tjen, Larissa B. Wolf, Willem F. J. Karstens,
Hans E. Schoemaker,† and Henk Hiemstra*
Institute of Molecular Chemistry, UniVersity of Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands, and DSM Research, Department of Organic
Chemistry and Biotechnology, P.O. Box 18, 6160 MD Geleen, The Netherlands
florisr@org.chem.uVa.nl
Received June 2, 1999
ABSTRACT
By choosing the right substituents either highly functionalized unusual four-membered ring amino acids or the isomeric pipecolic acid derivatives
are obtained in enantiomerically pure form. Starting material is a linear allene-containing amino acid that has been resolved via biocatalysis.
Heteroannulation processes involving unsaturated functional-
ity and Pd catalysis have been extensively studied over the
past decade.1 Beside the use of olefins and acetylenes as the
electrophilic partners, allenes in particular have attracted the
attention of organic chemists in recent years.2,3 In all of these
examples the heteronucleophile attacks one of the sp2-carbon
atoms of the allene.4 Recently, unprecedented alternative
behavior was reported by our group, where a lactam nitrogen
atomswith a two-carbon tether between the allene and the
nitrogen atoms reacted at the sp carbon atom of the allene
to form five-membered ring enamides.5,6 In conjunction with
this work and similar Pd-catalyzed reactions of acetylenic
amino acids in our group,7 we wish to present cyclizations
† DSM Research.
(1) (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York,
1995. (b) For a general review on metal-catalyzed amination, see: Mu¨ller,
T. E.; Beller, M. Chem. ReV. 1998, 98, 675.
(2) For nitrogen nucleophiles, see for example: (a) Larock, R. C.; Tu,
C.; Pace, P. J. Org. Chem. 1998, 63, 6859. (b) Desarbre, E.; Me´rour, J. Y.
Tetrahedron Lett. 1996, 37, 43. (c) Larock, R. C.; He, Y.; Leong, W. W.;
Han, X.; Refvik, M. D.; Zenner, J. M. J. Org. Chem. 1998, 63, 2154. (d)
Larock, R. C.; Zenner, J. M. J. Org. Chem. 1995, 60, 482. (e) Kimura, M.;
Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995, 60, 3764. (f) Davies, I. W.;
Scopes, D. I. C.; Gallagher, T. Synlett 1993, 85. (g) Kimura, M.; Fugami,
K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1992, 60, 6377. (h) Prasad, J.
S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4257. (i) Shimizu, I.; Tsuji,
J. Chem. Lett. 1984, 233.
(4) Reference 1, p 166.
(5) (a) Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron
Lett. 1997, 38, 6275. (b) Karstens, W. F. J.; Stol, M.; Rutjes, F. P. J. T.;
Hiemstra, H. Synlett 1998, 1126.
(6) More recently, similar regiochemistry was observed in lanthanide-
catalyzed cyclizations of aminoallenes: Arredondo, V. M.; McDonald, F.
E.; Marks, T. J. Am. Chem. Soc. 1998, 120, 4871.
(3) For oxygen nucleophiles, see for example: (a) Ma, S.; Shi, Z. J.
Org. Chem. 1998, 63, 6387. (b) Jonasson, C.; Ba¨ckvall, J. E. Tetrahedron
Lett. 1998, 39, 3601. (c) Walkup, R. D.; Guan, L.; Mosher, M. D.; Kim, S.
W.; Kim, Y. S. Synlett 1993, 88. (d) Walkup, R. D.; Guan, L.; Kim, Y. S.;
Kim, S. W. Tetrahedron Lett. 1995, 36, 3805. (e) Besson, L.; Bazin, J.;
Gore´, J.; Cazes, B. Tetrahedron Lett. 1994, 35, 2881.
(7) Wolf, L. B.; Tjen, K. C. M. F.; Rutjes, F. P. J. T.; Hiemstra, H.;
Schoemaker, H. E. Tetrahedron Lett. 1998, 39, 5081.
10.1021/ol990700c CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/30/1999

of the linear â-aminoallenes 4 (R ) H, CO2Me; P )
protecting group), where the allene and the amine are also
separated by a two-carbon tether (Scheme 1).
amine.11 The enantiomerically pure allene-containing amino
acid 8 was prepared via an enzymatic resolution of the
corresponding racemic amide 7 (Scheme 2).12
Scheme 1
Scheme 2
In this case, four- and six-membered ring amines and
amino acids are obtained with high selectivity.8 Interestingly,
attempts of the group of Yamamoto to cyclize such an
unsubstituted â-aminoallene (viz., 4, R ) H, P ) Ts) failed,
resulting in the isomerized diene product.9 Very recently,
the group of Kang presented a single example of the
cyclization of this unsubstituted aminoallene, where in a
moderate yield both the four- and six-membered heterocycle
were obtained in a 2:1 ratio. The latter example, however,
is rather limited in terms of selectivity, substitution pattern,
and yield.10 Our method, on the other hand, holdssin
addition to the selective formation of four- and six-membered
ringssa promising potential for introduction of various R1
substituents and thus arrive at unique enantiopure amino acid
derivatives.
The latter compound was synthesized via (i) alkylation of
the glycine-derived ketimine 513 with 4-bromo-1,2-butadiene
(prepared from 2,3-butadienol14 with Br2PPh3 and imidazole),
(ii) acid hydrolysis of the ketimine to give 6, and (iii) reaction
with aqueous ammonia affording the amino acid amide 7.15
Subjection to the enzymatic resolution conditions (aminopep-
tidase produced by Pseudomonas putida ATCC 12633,16 pH
8.5, 37 °C, 60 h)17 and separation of the resulting acid and
amide15 provided the (S)-acid 8 in 44% yield and 82% ee
after purification by ion exchange chromatography.18 The
(R)-amide 7 was hydrolyzed by subjection to a nonspecific
amidase produced by Rhodococcus erythropolis NCIB
1154019 to afford (R)-8 in 35% yield (two steps) and >98%
The starting aminoallenes were synthesized as follows. The
unsubstituted â-aminoallene 4 (R ) P ) H) was obtained
via a literature procedure, involving a Crabbe´ reaction of
3-butyn-1-ol and conversion of the resulting alcohol into the
20
ee.
Functionalization to the cyclization precursors proceeded
by using standard methodology leading to the desired
precursors 9-10 and 21-24 in good yields and without
detectable racemization. The cyclization results for the
unsubstituted aminoallenes 9 and 10 are shown in Table 1.
Application of the cyclization conditions (10 mol % Pd-
(PPh3)4, 5 equiv of K2CO3, and 5 equiv of R1X, DMF, 80
°C)2f onto allene 9 (entry 1) led in 30 min to complete
conversion, affording a 67:33 ratio of the four- and six-
membered rings 16a and b, respectively, which is in line
with the result of Kang.10 Upon prolonged reaction times,
this ratio changed in favor of the six-membered ring (entry
2).21 Use of the pyridine-derived iodide 13 gave a similar
(8) Similar three- vs five-membered ring formation of R-amino allenes
was reported recently: Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Osawa,
E.; Yamaoka, Y.; Fuji, N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992.
(9) Meguro, M.; Yamamoto, Y. J. Org. Chem. 1998, 39, 5421.
(10) Kang, S.-K.; Baik, T.-G.; Kulak, A. N. Synlett 1999, 324.
(11) (a) Li, D.; Zhou, H.-Q.; Dakoji, S.; Shin, I.; Oh, E.; Liu, H.-W. J.
Am. Chem. Soc. 1998, 120, 2008. (b) Hanack, M.; Haeffner, J. Chem. Ber.
1966, 99, 1077.
(12) 2-Amino-4,5-hexadienoic acid (homo-allenylglycine) is a naturally
occurring amino acid of which several syntheses have been published.
Isolation: Chilton, W. S.; Tsou, G.; Kirk, L.; Benedict, R. G. Tetrahedron
Lett. 1968, 6283. Racemic synthesis: (b) Cazes, B.; Djahanbini, D.; Gore´,
J.; Geneˆt, J.-P.; Gaudin, J.-M. Synthesis 1988, 983. (c) Black, D. K.; Landor,
S. R. J. Chem. Soc. (C) 1968, 281. (d) Black, D. K.; Landor, S. R. J. Chem.
Soc. (C) 1968, 283. (S)-Enantiomer: (e) Baldwin, J. E.; Adlington, R. M.;
Basak, A. J. Chem. Soc., Chem Commun. 1984, 1284. (S)-Enantiomer
(benzyl ester): (f) Dunn, M. J.; Jackson, R. F. W.; Pietruszka, J.; Turner,
D. J. Org. Chem. 1995, 60, 2210.
(13) (a) O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663. (b)
O’Donnell, M. J.; Wojciechowski, K.; Ghosez, L.; Navarro, M.; Sainte, F.;
Antoine, J.-P. Synthesis 1984, 313.
(18) The ee was determined using chiral HPLC (Crownpak CR(+))
following a known protocol: Miyazawa, T.; Iwanaga, H.; Yamada, T.;
Kuwata, S. Chem. Express 1991, 6, 887.
(19) Boesten, W. H. J.; Cals, M. J. H. U.S. Patent 4 705 752, 1987;
Chem. Abstr. 1987, 105, 170617k.
(20) By using an aminopeptidase produced by a genetically modified
Escherichia coli strain both enantiomers were produced in a single run in
>98% ee. This experiment, however, has not yet been carried out on a
preparative scale. Sonke, T.; Boesten, W. H. J.; Broxterman, Q. B.;
Kamphuis, J.; Formaggio, F.; Toniolo, C.; Rutjes, F. P. J. T.; Schoemaker,
H. E. In StereoselectiVe Biocatalysis Handbook; Patel, R. N., Ed.; Marcel
Dekker, in press.
(14) Bailey, W. J.; Pfeifer, C. R. J. Org. Chem. 1955, 20, 1337.
(15) The amide was separated from residual acid via formation of the
Schiff base (PhCHO, H2O, pH ∼9), extraction from the water layer, and
precipitation upon hydrolysis in acetone using 1 equiv of HCl.
(16) The aminopeptidase was generously provided by DSM Research.
(17) For related examples, see: (a) Schoemaker, H. E.; Boesten, W. H.
J.; Broxterman, Q. B.; Roos, E. C.; Kaptein, B.; van den Tweel, W. J. J.;
Kamphuis, J.; Rutjes, F. P. J. T. Chimia 1997, 51, 308-311. (b) Schoemaker,
H. E.; Boesten, W. H. J.; Kaptein, B.; Roos, E. C.; Broxterman, Q. B.; van
den Tweel, W. J. J.; Kamphuis, J. Acta Chem. Scand. 1996, 50, 225-233.
718
Org. Lett., Vol. 1, No. 5, 1999

treated under similar conditions as 9 for 4 h (entry 1),
resulting selectively in the pipecolic acid derivative 25b in
78% yield. Closer examination of the conditions revealed
that with shorter reaction times a considerable amount of
the four-membered ring 25a was formed as a single cis-
isomer.
Table 1
The best example is shown in entry 3: the reaction was
finished in 10 min, with 25a being the major product.
Surprisingly, the reaction also proceeded at room tempera-
ture, but did not show any selectivity (entry 2). To improve
the ratio in favor of the four-membered ring, different
parameters (temperature, solvent, and reaction time) were
varied, resulting in a maximum selectivity of 88:12 (THF,
60 °C), albeit the yield was moderate (entry 4). Again,
interesting results were obtained by using the vinyl triflates
14 and 15. This led to fast reactions (finished in 10 min)
and excellent yields of the four-membered amino acids 26a
and 27a, with only a small degree of formation of the six-
membered rings (entries 5 and 6). The benzylated precursor
22 led in a clean reaction to the pipecolic ester 28b (entry
7). This result is in accord with previous reports on
cyclizations of amines onto π-allylpalladium intermediates,
where also complete conversion into the thermodynamic
product was encountered.22 Introduction of a methyl car-
bamate (entry 8) or an amide function (entry 9) did not lead
to satisfactory results: the low yields did not encourage
further investigations into optimization of the product ratio.
Interestingly, the carbamate-functionalized azetidine ester 29a
was the only product that gave crystals that could be
subjected to an X-ray structure determination. Thus, the
structure and absolute orientation of the substituents in the
azetidine were unambiguously established (Figure 1).23
result, with the six-membered ring being the major isomer
(entry 3). In contrast, reactions with the vinyl triflates 14
and 15 led to pleasing results. The azetidine 18a was formed
selectively by using triflate 14 (entry 4), while reaction with
triflate 15 gave a selectivity of 95:5 in favor of the four-
membered ring 19a (entry 5). On the other hand, subjection
of aminoallene 10sprotected with the more easily removable
p-nitrobenzenesulfonyl (Ns) groupsto these reaction condi-
tions provided the tetrahydropyridine 20b selectively in 55%
yield (entry 6).
To study the influence of the ester substituent, the
enantiopure amino acid derivatives 21-24 were subjected
to identical cyclization conditions (Table 2). Initially, 21 was
Table 2
Figure 1. Crystal structure of 29a.
An explanation for these results can be found by consider-
ing the different pathways that play a role (Scheme 3).
Initially, reaction of the allene with the in situ formed
(21) A similar ring expansion (from three- to five-membered rings) has
been reported previously: Fugami, K.; Morizawa, Y.; Oshima, K.; Nozaki,
H. Tetrahedron Lett. 1985, 26, 857.
(22) Review: Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173.
(23) X-ray data for 29a: C15H17NO; Mr ) 227.3; monoclinic; Cc; a )
12.994(2), b ) 9.907(1), c ) 10.371(2) Å; â ) 111.36(1)°; V ) 1243.4(3)
Å3; Z ) 4, Dx ) 1.21 g cm-3; λ(Cu KR) ) 1.5418 Å, µ(Cu KR) ) 5.57
cm-1; F(000) ) 488, -25 °C. Final R ) 0.040 for 1064 observed reflections.
Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC-114107.
Org. Lett., Vol. 1, No. 5, 1999
719

results in attack of the nitrogen on the central sp allene carbon
atom under similar reaction conditions, providing the cor-
responding five-membered ring 32.5b
Scheme 3
Scheme 4
In conclusion, we have shown that Pd-catalyzed cycliza-
tions of â-aminoallenes can selectively lead to four- or six-
membered nitrogen heterocycles without loss of optical
activity in high yields. In particular vinyl triflates show a
promising selectivity in the cyclization processes leading to
the four-membered rings. In addition, we have shown that
via conversion into the more restricted oxazolidinone ana-
logues, the corresponding five-membered rings are also
accessible in both the (R)- and (S)-conformation. The
mechanistic basis of this remarkable behavior is currently
under further investigation.
organopalladium(II) species will give rise to the more stable
syn-π-allylpalladium complex 3,24 which via π-σ-π isomer-
ization can be converted to the more hindered anti-isomer.25
The syn-isomer can only cyclize in a 4-exo-trig-fashion
to give the kinetic product 1. The four-membered ring,
however, can under the influence of Pd(PPh3)4 undergo ring
opening to regenerate the π-allylpalladium complex, which
eventually via the equilibrium with the anti-complex under
the reaction conditions can isomerize to the thermodynami-
cally more stable six-membered ring 2.26 The rate of
isomerization will depend on the substituents P and R1. For
example, for R1 ) alkenyl, it is more difficult to form the
intermediate complex so that isomerization does not rapidly
occur and a relatively large amount of the four-membered
ring is formed. On the other hand, improving the leaving
group ability of the nitrogen (by going from Ts to Ns)
enhances the isomerization process in such a way that the
four-membered ring is no longer observed.
Acknowledgment. DSM Research is gratefully acknowl-
edged for providing research grants to K.C.M.F.T. and
L.B.W. This research has been financially supported by the
Council for Chemical Sciences of The Netherlands Organi-
zation for Scientific Research (CW-NWO). J. Fraanje and
K. Goubitz (Laboratory of Crystallography, University of
Amsterdam) are acknowledged for the X-ray structure
determination.
Supporting Information Available: A general procedure
for the cyclization reactions and full characterization for
compounds 7, 8, 18a, 20b, 25a,b, 26a, and 27a. This material
is available free of charge via the Internet at http://pubs.acs.org.
Thus, by changing different parameters either four- or six-
membered ring formation is observed resulting from attack
of the nitrogen onto one of the sp2-allene carbon atoms.
Remarkably, a slight substrate modificationsester reduction
followed by oxazolidinone formation (viz., 31, Scheme 4)s
OL990700C
(25) For a similar discussion, see: Ahmar, M.; Cazes, B.; Gore´, J.
Tetrahedron Lett. 1985, 26, 3795.
(26) The four- to six-membered ring isomerization was proven in a
separate experiment via subjection of 25a to the cyclization conditions,
resulting in complete conversion into the tetrahydropyridine 25b.
(24) An alternative cyclization mechanism-activation of the allene by
the organopalladium(II) species as the π-complex followed by nucleophilic
attack of the nitrogen, which has been proposed by Walkup (ref 3c,d) and
Gallagher (ref 2f), cannot be ruled out.
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Org. Lett., Vol. 1, No. 5, 1999