Novel and stereoselective methods for the preparation of aromatic lactams via reductive coupling reactions mediated by SmI2

Article abstract of DOI:10.1016/S0040-4039(00)00014-9

Samarium(II) diiodide-mediated reductive cross-coupling of N-alkylated phthalimides with carbonyl compounds is shown to afford hydroxylated α- hydroxylactams. Ketoamides obtained by dehydration of these compounds through keto-enol tautomer isomerization were reduced with NaBH₄ in a completely stereoselective manner in the presence of CeCl₃ to give threo-aromatic lactams as the sole product. Direct reductive deoxygenation of these α- hydroxylactam intermediates with Et₃SiH in the presence of Lewis acid also displayed high stereoselectivity to afford the same threo-lactams exclusively. The mechanistic origins of this stereoselectivity are briefly documented. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00014-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1775–1779
Novel and stereoselective methods for the preparation of aromatic
lactams via reductive coupling reactions mediated by SmI2
Hidemi Yoda,∗ Keigo Matsuda, Hiroaki Nomura and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Hamamatsu 432-8561, Japan
Received 22 November 1999; revised 12 December 1999; accepted 17 December 1999
Abstract
Samarium(II) diiodide-mediated reductive cross-coupling of N-alkylated phthalimides with carbonyl compounds
is shown to afford hydroxylated α-hydroxylactams. Ketoamides obtained by dehydration of these compounds
through keto-enol tautomer isomerization were reduced with NaBH4 in a completely stereoselective manner in
the presence of CeCl3 to give threo-aromatic lactams as the sole product. Direct reductive deoxygenation of these
α-hydroxylactam intermediates with Et3SiH in the presence of Lewis acid also displayed high stereoselectivity to
afford the same threo-lactams exclusively. The mechanistic origins of this stereoselectivity are briefly documented.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cross-coupling reaction; samarium(II) diiodide; cyclic imide; stereoselective reduction; deoxygenation.
Since its introduction by Kagan et al.1 samarium(II) diiodide has been extensively investigated as a
powerful electron donor able to promote a wide range of reduction and coupling reactions.2 Its use in
synthesis has been especially advantageous for ring closure reactions and C–C bond formation such as
hydroxyl-directed addition of carbonyl to C_C double bond and stereocontrolled intramolecular pinacol
reactions.2d,3 The reactions of acid chlorides4 and acid anhydrides5 with this reagent have also been
researched. In addition, intramolecular and intermolecular Barbier-type reactions mediated by SmI2
have recently been reported;4b,6 however, the complete lack of any study concerning the reactivity of
samarium(II) compounds towards cross-coupling of cyclic imides with carbonyl subunits is surprising.
As part of our work designed to explore the use of these imides, we have demonstrated some significant
stereoselective reactions7 and their applications to the total syntheses of biologically active natural
products.8 The purpose of the present communication is to describe the result that N-alkylated phtha-
limides underwent fast reductive cross-coupling reactions with carbonyl compounds mediated by SmI2
to provide pinacol-type α-hydroxylactams with a hydroxyl-containing alkyl side chain, and reduction
of the corresponding ketoamides, derived from dehydration of the coupling products, with NaBH4 in
the presence of CeCl3 occurred with extremely high stereoselectivity, leading to the threo-isomer as
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00014-9
tetl 16294

1776
the sole product. Furthermore, exclusively threo-selective conversion of quaternary α-hydroxylactam
intermediates was also accomplished directly with Et3SiH in the presence of BF3·OEt2 (Scheme 1). The
mechanistic aspects of these reactions were also investigated.
Scheme 1.
Initial experiments have been performed on a reductive cross-coupling reaction mediated by SmI2
between N-benzylsuccinimide and propanal with a variety of additives such as HMPA, CuCl2, FeCl3,
or NiI2.6b The reactions, however, did not proceed under any conditions except for the self-coupling
of propanal. Next, we examined the same type of reactions employing aromatic imides. Whereas the
coupling reactions of N-H- and N-phenylphthalimides with propanal gave inseparable mixtures even in
the absence of an additive, respectively, use of the N-methyl derivative dramatically changed the results
and rapidly brought about the desired coupling products 2 in satisfactory yields (Table 1, entries 1, 2).
Furthermore, it became apparent that this procedure was applicable for the production of a wide range
of reductive cross-coupling compounds employing N-benzyl- and N-naphthylphthalimides and ketones
as well as aldehydes as a carbonyl unit (entries 3–10). Although the reason why such coupling products
were obtained only by the use of aromatic N-alkylimides has not yet been clarified, it could depend on
the capability of these imides to trap the ketyl samarium radical intermediates.
Table 1
Reductive coupling of imides (1) with carbonyl compounds mediated by SmI2
In light of the above outcome, we turned our attention to the utilization of these pinacol-type
compounds. To begin with, treatment of 2 with p-TsOH in benzene at 60°C provided the interesting
ketoamides 3 in high yields in each case (Table 2). These could be derived from keto-enol isomerization

1777
after dehydration. Since the stereodefined construction of threo- or erythro-heterocyclic moieties with a
hydroxyl-containing side chain attracts considerable attention due to their presence in the framework of
natural products,9 we examined stereoselective reduction of 3. As shown in Table 2, reduction of the N-
methyl derivative 3a with NaBH4 only in MeOH gave the corresponding alcohols, threo-4a and erythro-
5a, as a non-stereoselective mixture10 (55:45) in a quantitative yield (entry 1). Even in the presence of
8a
metal halides such as MgBr2 and CeCl3 remarkable enhancement of the selectivity was not observed
(entries 2 and 3). Replacement of the N-methyl group by the larger benzyl function also had no effect as
shown in entries 4 and 5. On the contrary, the use of CeCl3 in the reduction of the N-benzyl compound
3b surprisingly and dramatically changed the selectivity to yield threo-4b as the sole product (entry
7). The beneficial effect of CeCl3 on this reduction was again established in reactions employing other
ketoamides (entries 8 and 9).
Table 2
Dehydration of (2) and stereoselective reduction of ketoamides (3) in the presence of metal halides
Next, we examined the direct conversion of quaternary α-hydroxylactams 2 to deoxygenated aromatic
lactams. After unsuccessful attempts to obtain the hydrogenated products 4 or 5 under several conditions
such as treatment with H2 on Pd/C11 or NaBH3CN in acidic medium,12 we found that the use of N-
8c
methyl derivative with Et3SiH in the presence of BF3·OEt2 underwent fast reaction to afford the
corresponding deoxygenated products threo-4 and erythro-5 (Table 3, entry 1) with moderately diastereo-
facial differentiation (79:21). After investigation of a variety of conditions, a surprising enhancement in
stereoselectivity was finally observed upon employing the largest N-naphthylethyl group, leading to the
threo-isomers 4 as the sole product (entries 3–5).
The same observed stereochemical outcome of these two reactions can be explained as follows,
respectively: In the former, the reaction progressed through attack of NaBH4 on the carbonyl group from
the top face of the cis-fused metal–chelate in the reactions with CeCl3 due to shielding of the bottom
face by the large benzyl group, leading to exclusive formation of the corresponding threo-isomers (Fig.
1, Model A). On the other hand, in the Lewis acid-mediated deoxygenation the fact that increasing the

1778
Table 3
Stereoselective hydrogenation of α-hydroxyaromatic lactams (2)
steric bulkiness of the nitrogen-protecting group clearly leads to an increase in threo-selectivity can
be ascribed to the attack of Et3SiH on the iminium ion intermediate from the bottom face of the non-
chelation structure. This occurs due to the shielding effect of the three faces by the alkyl function and the
two large groups of the alkoxyborane complex and N-substituent, which occupy positions furthest away
from each other (Model B).
Fig. 1. Mechanistic origins of the stereoselective reduction of (3) and direct deoxygenation of (2)
In summary, we have disclosed herein the first example of samarium(II) diiodide-mediated coupling
reaction of N-alkylphthalimides with carbonyl compounds. The use of CeCl3 in the NaBH4-reduction
enabled complete threo-selective reduction of the ketoamides derived from dehydration of these adducts.
Furthermore, direct hydrogenation of quaternary α-hydroxyl compounds also led to the threo-lactams
with extremely high selectivity. This procedure will find application in the synthesis of some natural
products.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research from Japan Society for the
Promotion of Science.
References
1. (a) Girard, P.; Kagan, H. B.; Namy, J.-L. J. Am. Chem. Soc. 1980, 102, 2693. (b) Namy, J.-L.; Girard, P.; Kagan, H. B. Nouv.
J. Chim. 1977, 1, 5. (c) Kagan, H. B. New. J. Chem. 1990, 14, 453.

1779
2. For recent reviews, see: (a) Kagan, H. B.; Namy, J.-L. Tetrahedron 1986, 42, 6573. (b) Kagan, H. B.; Sasaki, M.; Collin, J.
Pure Appl. Chem. 1988, 60, 1725. (c) Molander, G. A. Chem. Rev. 1992, 92, 29. (d) Matsuda, F. J. Synth. Org. Chem. Japan
1995, 53, 65. (e) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. (f) Molander, G. A.; Harris, C. R. Tetrahedron
1998, 54, 3321. (g) Molander, G. A. Sono, M. Tetrahedron 1998, 54, 9289. (h) Mochrouhi, F.; Namy, J.-L. Tetrahedron
1998, 54, 11 111.
3. (a) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 5763. (b) Fukuzawa, S.; Nakanishi, A.; Fujinami, T.;
Sakai, S. J. Chem. Soc., Chem. Commun. 1986, 624.
4. (a) Souppe, J.; Namy, J.-L.; Kagan, H. B. Tetrahedron Lett. 1984, 25, 2869. (b) Mochrouhi, F.; Namy, J.-L.; Kagan, H. B.
Tetrahedron Lett. 1997, 38, 7183.
5. Mochrouhi, F.; Pârlea, E.; Namy, J.-L. Eur. J. Org. Chem. 1998, 2431.
6. (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1993, 58, 7216. (b) Mochrouhi, F.; Namy, J.-L.; Kagan, H. B. Synlett 1996,
633.
7. (a) Yoda, H.; Shirakawa, K.; Takabe, K. Tetrahedron Lett. 1991, 32, 3401. (b) Yoda, H.; Kitayama, H.; Yamada, W.; Katagiri,
T.; Takabe, K. Tetrahedron: Asymmetry 1993, 4, 1451. (c) Yoda, H.; Kitayama, H.; Takabe, K.; Kakehi, A. Tetrahedron:
Asymmetry 1993, 4, 1759.
8. (a) Yoda, H.; Nakajima, T.; Takabe, K. Tetrahedron Lett. 1996, 37, 5531. (b) Yoda, H.; Nakajima, T.; Takabe, K. Synlett
1997, 911. (c) Yoda, H.; Shimojo, T.; Takabe, K. Tetrahedron Lett. 1999, 40, 1335.
9. For examples, see: (a) Rieser, M. J.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L. Tetrahedron Lett. 1991, 32, 1137. (b)
Baussanne, I.; Schwardt, O.; Royer, J.; Pichon, M.; Figadère, B.; Cavé, A. Tetrahedron Lett. 1997, 38, 2259. (c) Capon, R.
J.; Barrow, R. A.; Rochfort, S.; Jobling, M.; Skene, C.; Lacey, E.; Gill, J. H.; Friedel, T.; Wadsworth, D. Tetrahedron 1998,
54, 2227.
10. Relative threo/erythro stereochemistry of 4a and 5a was easily assigned based on the observed vicinal coupling constants as
shown below according to the following references in addition to Ref. 9b: (a) Baussanne, I.; Royer, J. Tetrahedron Lett. 1996,
37, 1213. (b) Pichon, M.; Jullian, J.-C.; Figadère, B.; Cavé, A. Tetrahedron Lett. 1998, 39, 1755. (c) Uno, H.; Nishihara, Y.;
Mizobe, N.; Ono, N. Bull. Chem. Soc. Jpn. 1999, 72, 1533.
11. Ohta, T.; Shiokawa, S.; Sakamoto, R.; Nozoe, S. Tetrahedron Lett. 1990, 31, 7329.
12. Drage, J. S.; Earl, R. A.; Vollhardt, K. P. C. J. Heterocyclic Chem. 1982, 19, 701.