Palladium-catalysed cyclisation of enantiopure allenic lactams prepared from a pyroglutamic acid derived organozinc reagent

Article abstract of DOI:10.1055/s-1998-1859

A route for the synthesis of enantiopure allene-substituted lactams has been developed. The key-step involves the copper(I) mediated S_N2' substitution of propargylic tosylates by a (S)-pyroglutamic acid derived organozinc reagent. Pd-catalysed

Full text of DOI:10.1055/s-1998-1859

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Palladium-Catalysed Cyclisation of Enantiopure Allenic Lactams Prepared from a
Pyroglutamic Acid Derived Organozinc Reagent
*
Willem F. J. Karstens, Marianne Stol, Floris P. J. T. Rutjes and Henk Hiemstra
Laboratory of Organic Chemistry, Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands
Fax +31 20 525 5670; e-mail: henkh@org.chem.uva.nl
Received 25 June 1998
Abstract: A route for the synthesis of enantiopure allene-substituted
lactams has been developed. The key-step involves the copper(I)
mediated S 2’ substitution of propargylic tosylates by
a (S)-
N
pyroglutamic acid derived organozinc reagent. Pd-catalysed reaction of
these allenes with iodobenzene afforded enantiopure bicyclic enamides.
Furthermore the unexpected formation of an interesting diene is
reported.
Equation 3
Our initial attempts to apply the same conditions to the new zinc reagent
5 met with failure (eq 3). The main product appeared to be unsaturated
amide 8, formed as a result of β-elimination. However, if the solvent
used in the formation of the zinc reagent 5 was changed from THF to
Palladium-catalysed reaction of heteroatom nucleophiles with allenes
1-3
provides access to a manifold of interesting compounds.
In most
2
examples the nucleophile attacks one of the sp -carbon atoms of the
14
DMF, which is known to stabilise organozinc reagents, β-elimination
4
allene. Recently, we showed that in the palladium-catalysed reaction
was less than 10%. This side reaction was suppressed completely by
rinsing the activated zinc with DMF and lowering the reaction
between iodobenzene and allenic lactams 1 an unprecedented process
occurs in which the allenic tether is attacked by nitrogen at the central
15
temperature to 0 °C (see experimental procedure).
5,6
sp-carbon atom, leading to cyclic enamides 2 (eq 1).
Having established conditions to generate a sufficiently stable zinc
reagent, reactions of
5 with several propargylic tosylates were
investigated (Table 1). A catalytic quantity of CuBr·SMe was preferred
2
over a stoichiometric amount of CuCN·2LiCl, because of experimental
convenience. Although the yields were moderate, this method allowed
the introduction of oxygen containing substituents and aromatic groups
(entries 6-8).
Equation 1
Herein we report the extension of this methodology to enantiopure
substituted derivatives of 1 and 2, which greatly increases the synthetic
potential of this interesting reaction. Our previous allene synthesis,
7
based on the Crabbé reaction, does not allow the introduction of
substituents at the newly formed allenic double bonds. However, by
using a copper(I)-mediated S 2’ displacement of propargylic tosylates 3
N
with zinc reagents 4 and 5, allenes are accessible with a high degree of
8–11
substitution and functionality (eq 2).
Moreover, the iodides needed
for the synthesis of zinc reagents 4 and 5 are easily synthesised from L-
12,13
14
serine
and (S)-pyroglutamic acid, respectively.
Equation 2
Subjection of the allenic oxazolidinones 6 and allenic lactams 7 to the
15
previously developed cyclisation conditions gave rise to the cyclic
Our work extends the findings of Knochel and coworkers who showed
that the copper(I)-mediated reaction of zinc reagent 4 with propargyl
mesylate in the presence of CuCN·2LiCl in THF leads to enantiopure
allenic oxazolidinone 6a (Table 1) in 29% yield (based on the 5-
16
enamides 9 and 10, presumably via a π-allylpalladium complex (eq 4).
From the Table it is clear that alkyl and phenyl substituents on the
lactam side of the allene (R = Me, Ph entries 2, 4 and 6) led to
1
11
comparable yields in the cyclisation reaction.
(iodomethyl)oxazolidin-2-one). By changing to propargyl tosylate
However, subjection of trisubstituted allene 7c to the cyclisation
conditions, led to a low yield (16%) of the usual cyclic product 10c
(entry 5). This might be explained by steric interactions of the two
methyl groups with the nucleophile, slowing down the attack of
(3a) and using a stoichiometric amount of the electrophile (instead of
0.35 equiv), we raised the yield to 39%. Similarly, zinc reagent 4 reacted
with 3b to give the methyl-substituted allene 6b in a 49% yield (Table
1).

October 1998
SYNLETT
1127
References and Notes
1.
For nitrogen nucleophiles, see e.g.: (a) Desarbre, E.; Mérour, J. Y.
Tetrahedron Lett. 1996, 37, 43; (b) Larock, R. C.; He, Y.; Leong,
W. W.; Han, X.; Refvik, M. D.; Zenner, J. M. J. Org. Chem. 1998,
63, 2154; (c) Larock, R. C.; Zenner, J. M. J. Org. Chem. 1995, 60,
482; (d) Kimura, M.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995,
60, 3764; (e) Davies, I. W.; Scopes, D. I. C.; Gallagher, T. Synlett
1993, 85; (f) Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J.
Org. Chem. 1992, 60, 6377; (g) Prasad, J. S.; Liebeskind, L. S.
Tetrahedron Lett. 1988, 29, 4257; (h) Shimizu, I.; Tsuji, J. Chem.
Lett. 1984, 233.
Equation 4
nitrogen. In this case transfer of the phenyl group to the central allenic
carbon competes with nucleophilic attack, leading to the non-cyclised π-
allylpalladium complex 11 (eq 5). Interestingly, 11 did not cyclise, but
underwent palladium hydride elimination to give the dienes 12 and 13 in
65% combined yield in a ratio of 2:5.
2.
3.
For oxygen nucleophiles, see e.g. : (a) Rutjes, F. P. J. T.; Kooistra,
T. M.; Hiemstra, H.; Schoemaker, H. E. Synlett 1998, 192; (b)
Jonasson, C.; Bäckvall, 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.
4
For carbon nucleophiles, see e.g.: (a) Vicart, N.; Cazes, B.; Goré,
J. Tetrahedron Lett. 1995, 36, 5015 and references cited therein;
(b) Cazes, B. Pure Appl. Chem. 1990, 62, 1867.
4.
5.
6.
Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York,
1995; p 166.
Equation 5
Karstens, W. F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron
Lett. 1997, 38, 6275.
A TBS-protected alcohol adjacent to the allene did not interfere with the
normal reaction pathway as indicated by the cyclisation of 7e to 10e in
an excellent yield of 83% (entry 7). This is in sharp contrast with the
cyclisation of 7f, containing a phenolic group (entry 8). Only 7% of the
anticipated 10f was isolated, along with 50% of the interesting
Lanthanide-catalysed cyclisations of aminoallenes can occur with
the same regiochemistry: Arredondo, V. M.; McDonald, F. E.;
Marks, T. J. Am. Chem. Soc. 1998, 120, 4871.
7.
8.
9.
Searles, S.; Li, Y.; Nassim, B.; Lopes, M. T. R.; Tran, P. T.;
Crabbé, P. J. Chem. Soc., Perkin Trans. 1 1984, 747.
17
enantiopure diene 14 (eq 6).
The mechanism for formation of 14 probably involves the formation of
the usual π-allylpalladium complex (cf. eq 4). Reductive elimination
leads to 10f. However, if the palladium complex undergoes
Ochiai, H.; Tamaru, Y.; Tsubaki, K.; Yoshida, Z. J. Org. Chem.
1987, 52, 4418.
a
Gooding, O. W.; Beard, C. C.; Jackson, D. Y.; Wren, D. L.;
deoxypalladation reaction, it will lead to 14. The difference with 7e
Cooper, G. F. J. Org. Chem. 1991, 56, 1083.
might be ascribed to the better leaving group ability of the phenoxide
anion compared to TBSO . At present we are investigating the synthetic
utility of enantiopure dienes of type 14. Moreover, the subtle
mechanistic details of the palladium-catalysed cyclisation reaction will
be probed by utilising intrinsically chiral allenes.
10. (a) Dunn, M. J.; Jackson, R. F. W.; Pietruszka, J.; Wishart, N.;
Ellis, D.; Wythes, M. J. Synlett 1993, 499; (b) Dunn, M. J.;
Jackson, R. F. W.; Pietruszka, J.; Turner, D. J. Org. Chem. 1995,
60, 2210.
–
11. Duddu, J.; Eckhardt, M.; Furlong, H.; Knoess; H. P.; Berger, S.;
Knochel, P. Tetrahedron 1994, 50, 2415.
12. (a) Sibi, M. B.; Renhowe, P. A. Tetrahedron Lett. 1990, 31, 7407;
(b) Sibi, M. B.; Christensen, J. W.; Li, B.; Renhowe, P. A. J. Org.
Chem. 1992, 57, 4329.
13. (a) Provot, O.; Célérier, J. P.; Petit, H.; Lhommet, G. J. Org.
Chem. 1992, 57, 2163; (b) Holmes, A. B.; Smith, A. L.; Williams,
S. F. J. Org. Chem. 1991, 57, 1393.
Equation 6
14. Dexter, C. S.; Jackson, R. F. W. J. Chem. Soc., Chem. Commun.
1998, 75.
In conclusion, we have shown that organozinc reagent 5 is a useful
reagent for the preparation of enantiopure lactams. These lactams as
well as their oxazolidinone analogues undergo the expected cyclisation-
coupling reaction to give bicyclic enamides in good yields, provided
they are not too sterically hindered. If a relatively good leaving group is
present allylic to the allene a cyclisation-elimination process may occur
to give a bicyclic diene.
15. Typical experimental procedures were as follows:
Formation of organozinc reagent 5: Under an atmosphere of
nitrogen, 1,2-dibromoethane (85 µL, 1.0 mmol) was added to a
suspension of zinc powder (654 mg, 10.0 mmol) in dry DMF (2
ml), after which it was stirred at 60 °C for 10 min. The reaction
mixture was cooled, followed by the addition of TMSCl (100 µL,
0.80 mmol) and sonication at room temperature for 30 min. The
zinc was allowed to settle and the supernatant was removed by
syringe. DMF (2 mL) was added and the suspension was cooled to
0 °C, followed by the addition of (S)-5-(iodomethyl)pyrrolidin-2-
one (1.13 g, 5.0 mmol) in DMF (2 mL) and the mixture was
stirred at 0 °C for 4-6 h until no starting material remained (TLC).
Acknowledgement: These investigations were supported (in part) by
the Netherlands Foundation for Chemical Research (SON) with
financial aid from the Netherlands Organization for Scientific Research
(NWO).

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SYNLETT
At this point the excess of zinc was allowed to settle.
were washed with water (20 mL) and brine (20 mL), dried
Reaction of organozinc reagent 5 with propargylic tosylates:
Propargylic tosylate 3b (1.23 g, 5.5 mmol) was dissolved in DMF
(Na SO ) and concentrated. Flash chromatography (silica gel,
2 4
EtOAc/hexanes 1:2) afforded 10b as a colorless solid: yield 80 mg
(70%); mp = 86-89 °C (CH Cl /pentane); [α] = -15.2 (c = 1.2 in
(10 mL), and CuBr·SMe (51 mg, 0.25 mmol) was added. The
2
2
2
D
-1
1
mixture was cooled to -20 °C using an ice-salt bath, and the
previously formed DMF solution of 5 was slowly added by
cannula, rinsing the residual excess of zinc with DMF (1 mL). The
reaction mixture was allowed to warm to room temperature
overnight. The mixture was quenched with a saturated ammonium
chloride solution (25 mL) and extracted with ethyl acetate (4 × 50
ml). The combined extracts were washed with brine (2 × 20 mL),
dried (Na SO ) and concentrated. Flash chromatography (silica
CHCl ); IR (neat) ν
1698, 1403, 1371, 1070 cm ; H NMR
max
3
(400 MHz, CDCl ) δ 7.24-7.31 (m, 4H), 7.15-7.19 (m, 1H), 4.21-
3
4.30 (m, 2H), 3.65 (AB, J = 14.8 Hz, 1H), 2.60-2.69 (m, 1H),
2.34-2.47 (m, 3H), 2.21-2.27 (m, 1H), 1.76-1.86 (m, 1H), 1.77 (s,
13
3H); C NMR (100 MHz, CDCl ) δ 171.2, 139.1, 134.0, 128.5,
3
128.2, 126.0, 120.5, 62.1, 40.4, 36.9, 30.2, 28.7, 12.8; MS (EI, 70
+
eV) m/z (relative intensity) 357 (M , 36), 300 (30), 226 (100), 91
(12). Anal. Calcd for C
H NO: C, 79.26; H, 7.54; N, 6.16.
2
4
15 17
gel, MeOH/CH Cl 5:95) afforded 10b as a pale yellow oil: yield
Found: C, 78.95; H, 7.44; N 5.92.
2
2
443 mg (59%); [α] = +73.3 (c = 2.7 in CHCl ); IR (neat) 3227,
D
3
16. In principle, the π-allylpalladium complex can lead to two
different regioisomers. However, in the cases reported in Table 1
only one isomer was isolated. For examples giving both possible
products see ref. 5.
-1
1
1960, 1692, 1423, 1284 cm ; H NMR δ 6.77 (br. s, 1H), 4.57-
4.64 (m, 2H), 3.75 (quint., J = 6.6 Hz, 1H), 2.15-2.31 (m, 3H),
2.02-2.07 (m, 2H), 1.64-1.72 (m, 1H), 1.62 (t, J = 3.1 Hz, 3H);
13
C NMR δ 206.1, 178.0, 95.2, 75.1, 52.6, 40.5, 29.9, 26.9, 19.0;
+
17. Spectral data of diene 14: [α] = +63.8 (c = 1.0 in CHCl ); IR
MS (EI, 70 eV) m/z (relative intensity) 151 (M , 7), 84 (100),41
(44), 29 (65), 15 (76); HRMS calcd for C H NO (M ) 151.0997,
D
3
-1
1
+
(neat) ν
2974, 2930, 1698, 1397, 1313 cm ; H NMR (400
max
9
13
MHz, CDCl ) δ 5.44 (dd, J = 3.4, 1.3 Hz, 1H), 5.43 (s, 1H), 5.02
m/z found 151.0999
3
(dd, J = 3.0, 1.2 Hz, 1H), 4.95 (s, 1H), 4.07-4.15 (m, 1H), 2.69-
Palladium catalysed cyclisations of the allenes:
2.76 (m, 2H), 2.50 (ddd, J = 16.8, 8.8, 0.9 Hz, 1H), 2.27-2.33 (m,
Under an argon atmosphere, a mixture of 7b (76 mg, 0.50 mmol),
K CO (276 mg, 2.0 mmol), PhI (408 mg, 2.0 mmol), Bu NCl
13
2H), 1.72-1.78 (m, 1H); C NMR (100 MHz, CDCl ) δ 171.8,
3
2
3
4
145.3, 139.6, 107.5, 89.8, 60.7, 38.1, 36.0, 28.4; MS (EI, 70 eV)
(208 mg, 0.75 mmol) and Pd(PPh ) (57 mg, 0.05 mmol) in
3 4
+
m/z (relative intensity) 149 (M , 25), 94 (37), 31 (100), 29 (45), 17
MeCN (10 mL) was refluxed for 2-3 h (TLC showed complete
conversion). The mixture was cooled, diluted with water (10 mL)
and extracted with ether (3 × 15 mL). The combined ether extracts
+
(39). HRMS calcd for C H NO (M ) 149.0841, m/z found
9
11
149.0842.