Hydrozirconation of four-, five-, six- and seven-membered N-alkoxycarbonyl lactams to lactamols

Article abstract of DOI:10.1016/j.tetlet.2011.10.006

A general, practical, and efficient reduction of four-, five-, six- and, seven-membered N-alkoxycarbonyl lactams to the aldehyde oxidation state is reported. The reduction methodology involves the hydrozirconation reaction by Cp₂Zr(H)Cl under m

Full text of DOI:10.1016/j.tetlet.2011.10.006

Tetrahedron Letters 52 (2011) 6880–6882
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Hydrozirconation of four-, five-, six- and seven-membered
N-alkoxycarbonyl lactams to lactamols
⇑
Anna Piperno , Caterina Carnovale, Salvatore V. Giofrè, Daniela Iannazzo
Dipartimento Farmaco-Chimico, University of Messina, Via SS. Annunziata, 98168 Messina, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A general, practical, and efficient reduction of four-, five-, six- and, seven-membered N-alkoxycarbonyl
lactams to the aldehyde oxidation state is reported. The reduction methodology involves the hydrozirc-
onation reaction by Cp2Zr(H)Cl under mild conditions and proceeds with very short reaction times and in
excellent to good yields. The hydrozirconation of N-alkoxycarbonyl lactams with the Schwartz reagent
demonstrated to be the mildest and most general method for the formation of lactamols with a high func-
tional group tolerance.
Received 26 July 2011
Revised 1 October 2011
Accepted 3 October 2011
Available online 8 October 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Bis(cyclopentadienyl)zirconium chloride
hydride
Lactamols
Lactam carbamates
a-Hydroxycarbamates
Hemiaminals
The amide group is an important moiety in the areas of poly-
(2.4 equiv) at ꢀ20 °C was applied, following a nonaqueous workup.
Generally, the controlled reduction of lactam type 1 leads to
lactamols 2 which may evolve into the enamine derivatives 3 by
dehydration or afford the tautomeric aldehydes 4 by ring opening
mers, natural products, and pharmaceuticals and is fairly inert to
many reductive conditions.1 The simple reduction of amides to
the corresponding alcohol or amine, by metal hydride reagents,
has been realized under different experimental conditions, several
of which proceed in high yields.2 The reduction of an amide to the
aldehyde oxidation state has proven to be more difficult and has
been performed with several reducing agents.3 To address these is-
sues, direct reduction methods have been described to yield the
corresponding aldehyde or imine. Among these, the use of Weinreb
amides4 or morpholine-derived amides5 in combination with DI-
BAL is known to control the outcome of the reduction to aldehydes.
Also, Buchwald reported a more general and chemoselective
(Fig. 1). Literature data report that N-acyl
c-, d-, and e-lactams can
be converted into the corresponding hemiaminals (also termed lac-
tamols or
a
-hydroxycarbamates) employing DIBAL-H,9 LiEt3BH,10
or NaBH4,11 while no procedure is known for the controlled
reduction of b-lactams to b-lactamols.
Hemiaminals are important intermediates in the preparation of
azanucleosides with antiviral, antiprotozoan, and anticancer prop-
erties.12 Furthermore, the dehydration reaction of
a-hydroxycarba-
mates leads to enecarbamates which are useful building blocks for
the synthesis of nitrogen-containing heterocycles with biological
significance.13 In this Letter we exploited the use of Cp2Zr(H)Cl in
the reduction of four-, five, six-, and seven-membered N-alkoxy-
carbonyl lactams to lactamols in the presence of different protect-
ing groups on the nitrogen atom.
In order to determine the feasibility of the reduction of lactams
to the corresponding lactamols, we have investigated the reaction
of the chosen model c-lactams 5a–f, bearing different substituents
on the nitrogen atom, with Cp2Zr(H)Cl (Fig. 2). The reaction was car-
ried out in THF, under nitrogen, at room temperature by varying the
equivalents of Cp2ZrHCl and the reaction times (Table 1). The non-
aqueous workup was performed by loading the reaction mixture
into a short plug of silica gel (ꢁ1 g) and eluting with ethyl acetate.
In the first experiment (Table 1, entry 1) the protocol developed for
the reduction of secondary amides and lactams to imines was
reduction of
a-enolizable amides to aldehydes in the presence of
Ti(Oi-Pr)4 and Ph2SiH2.6 Alternatively, the use of stoichiometric
or excess amounts of Schwartz’s reagent (Cp2ZrHCl) can lead to
the formation of a variety of aldehydes7 or imines8 with a great
functional group tolerance. However, till now the utility of
Cp2ZrHCl has not been shown in the reduction of lactams. In the
investigated cases, b-lactams and caprolactams, a complete loss
of starting material without the formation of aldehydic products
was observed7a; only the reduction of 2-azacyclotridecanone to
1-azacyclotridecene was effectively achieved in 25% yield.8b In
the latter case the procedure for the reduction of secondary
carboxamides to imines with potassium hydride and Cp2ZrHCl
⇑
Corresponding author.
E-mail address: apiperno@unime.it (A. Piperno).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.006

A. Piperno et al. / Tetrahedron Letters 52 (2011) 6880–6882
6881
Figure 3. Reduction of c-lactam 7 with Cp2Zr(H)Cl.
sive reduction of the exo carbonyl group in 5e, as confirmed by tlc
and 1H NMR benzaldehyde detection.
The reduction of methyl (4R)-trans-N-Boc-4-tert-butyldimeth-
ylsilyloxy pyroglutamate 7 to hemiaminals 8a,b (a 4:1 mixture of
anomers, 80% yield) with LiBEt3H in dry THF at ꢀ78 °C, is the key
step in the preparation of anti-HCV 30-deoxy-40-azaribonucleo-
Figure 1. General reduction pathways of c-lactams.
sides.13a Having optimized the reduction condition of
c-lactams,
we have investigated the ability of Cp2Zr(H)Cl to reduce 7 (Table
1, Fig. 3, entry 9). Notably, an almost complete conversion was ob-
served in 1 h, using 1.5 equiv of reducing agent and a 1:1 mixture
of hemiaminals 8a,b was recovered in 95% yield.
The conversion of amides into aldehydes via Cp2Zr(H)Cl was
experimentally studied in depth, but the reaction mechanism has
not yet been completely elucidated.7a,14 The reaction of secondary
amides with 2 equiv of Cp2ZrHCl involves the formation of enolate
zirconium(IV) salt and its subsequent reduction to imine derivative
(Eq. 1, Fig. 4). The reduction of tertiary amides into the correspond-
ing aldehydes requires 1 equiv of the reducing agent and the resid-
ual amine component, probably bounded to the zirconium
byproduct, was unrecoverable. Additionally, the reaction shows a
minimal substrate dependence and the tertiary amide is selectively
reduced in the presence of an ester group. On the basis of the
experimental evidence7a which considers that the hydrogen atom
of the aldehyde group comes from Cp2Zr(H)Cl and that the car-
bonyl oxygen comes from water, the more plausible reaction path-
way is reported in Figure 4, Eq. 2.
Figure 2. Reduction of c-lactams with Cp2Zr(H)Cl.
applied. However, the addition of 2 or more equiv of Cp2Zr(H)Cl to
the unsubstituted lactam 5a was not able to elicit product forma-
tion after 12 h of reaction. The MPLC purification of the crude reac-
tion mixture afforded the unreacted lactam 5a in 73% yield and no
discernable amount of reduced products was observed. Lactam car-
bamates 5b–d were efficiently reduced to the corresponding lac-
tamols 6b–d in high yields (90–95%, Table 1, entries 4–6) by
using 2 equiv of Cp2Zr(H)Cl for 1 h. The amount of Schwartz reagent
appeared essential for the reduction; increasing the equivalents
from 1.5 to 2 or 2.5, an improvement of the conversion, from 75
to 95%, respectively, was detected; prolonged reaction times did
not affect the conversion rate (Table 1, entries 2–3).
In order to investigate the dependence of the substituent on the
nitrogen atom on the efficiency of the lactam reduction, 1-benzoyl-
pyrrolidin-2-one 5e and 1-methylpyrrolidin-2-one 5f were treated
with bis(cyclopentadienyl)zirconium chloride hydride under the
experimental reaction conditions applied for 5b–d (Table 1, entries
7–8). The attempted hydrozirconation of 5f did not result in the
product formation and the substrate was recovered in 95% yield.
The reduction of the bis-amide 5e led to removal of the N-protect-
ing group affording 5a in 80% yield. This is likely due to the exclu-
Comparing the literature data on the reduction of tertiary
amides into the corresponding aldehydes with our results on the
reduction of the c-lactam systems, some experimental differences
came out: (1) the lactams reduction depends on the nature of the
nitrogen substituent: lactam carbamates were reduced to hemia-
minals while N-methyl lactam did not react and N-benzoyl lactam
reacted on the exo carbonyl group; (2) the residual amine compo-
nents were always recovered from the reaction mixture and (3) the
reduction required 1.5–2 equiv of reagent. According to the litera-
ture data none of the over- reduction product was detected even in
the presence of an excess of Cp2Zr(H)Cl. Thus, the experimental re-
sults suggest the presence of a seemingly stable zirconacycle inter-
mediate in the reaction pathway; while there is no evidence of
iminium ions formation involved in the reaction mechanism of lac-
tam carbamate.
The experimental protocol (2 equiv of Cp2Zr(H)Cl, THF, 1 h, rt)
was applied successfully to four-, six-, and seven-membered N-alk-
oxycarbonyl lactams (Fig. 5).
Table 1
Reaction of
c-lactams 5a–f and 7 with Cp2Zr(H)Cl
Entry
Lactam
Conditions
Product
Yield%
a
1
2
3
4
5
6
7
8
9
5a
5b
5b
5b
5c
5d
5e
5f
Cp2Zr(H)Cl (2.5 equiv), 12 h
Cp2Zr(H)Cl (2.5 equiv), 12 h
Cp2Zr(H)Cl (1.5 equiv), 12 h
Cp2Zr(H)Cl (2 equiv), 1 h
Cp2Zr(H)Cl (2 equiv), 1 h
Cp2Zr(H)Cl (2 equiv), 1 h
Cp2Zr(H)Cl (2 equiv), 1 h
Cp2Zr(H)Cl (2 equiv), 1 h
Cp2Zr(H)Cl (1.5 equiv), 1 h
—
6b
6b
6b
—
95
75b
95
90
92
80
6c
6d
5ad
c
—
—
7
8a,b (1:1 ratio)
95
a
The unreacted lactam 5a (73%) was recovered after MPLC.
The unreacted lactam 5b (15%) was recovered after MPLC.
The unreacted lactam 5f (95%) was recovered after MPLC.
tlc and 1H NMR revealed the benzaldehyde formation.
b
c
d
Figure 4. Mechanism of converting amides to aldehydes using Cp2Zr(H)Cl.

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A. Piperno et al. / Tetrahedron Letters 52 (2011) 6880–6882
Figure 5. Reduction of b-, d-, and
e
-lactams with Cp2Zr(H)Cl.
Biochemistry and Materials Science In Greenberg, A., Breneman, C. M.,
Liebman, J. F., Eds.; John Wiley& Sons Inc.: New York, 2000.
2. (a) Smith, M. B. Organic Synthesis; McGraw-Hill: New York, 1994. pp 347–490;
(b) Addis, D.; Das, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 6004–
6011.
3. (a) Laval, S.; Dayoub, W.; FavreReguillon, A.; Demonchaux, P.; Mignani, G.;
Lemaire, M. Tetrahedron Lett. 2010, 51, 2092–2094; (b) Pelletier, G.; Bechara, W.
S.; Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817–12819.
4. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
5. Douat, C.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2000, 41, 37–
40.
In the reduction of
c
-lactams 5b–d only the corresponding lac-
tamols 6b–d have been detected in the reaction with Cp2Zr(H)Cl,
while the reduction of d-lactam 12 afforded a 4:1 mixture of the
hemiaminal 13 and enecarbamate 14 in 98% global yield. The con-
strained b-lactam carbamate 9 was efficiently reduced to the alde-
hyde oxidation state and
a 1:1 inseparable mixture of the
corresponding hemiaminal/aldehyde 10/11 was recovered after
workup; to our knowledge, this reaction represents the first exam-
ple of reduction of a constrained b-lactam carbamate to hemiami-
nal. Compound 10 was detected in the 1H NMR spectrum but it is
not isolable from 11 to which in a short time, it is converted; thus,
the column silica gel purification affords only compound 11, as a
colorless oil in 95% yield. The tert-butyl-oxoazepane-1-carboxylate
15 reacted in the same way affording a 1:1 mixture of hemiaminal/
aldehyde 16/17 in 90% global yield.
In summary, we reported here a mild procedure for the reduc-
tion of N-alkoxycarbonyl lactams to the aldehyde oxidation state in
high yields, by using bis(cyclopentadienyl)zirconium chloride hy-
dride. This reaction proceeds with very short reaction times, and
constitutes an alternative to existing methods which use metal hy-
drides at ꢀ78 °C and works on a four-, five-, six-, and seven-mem-
bered N-alkoxycarbonyl lactams.
6. Bower, S.; Kreutzer, K. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 1996, 35, 1515–
1516.
7. (a) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc.
2007, 129, 3408–3419; (b) Spletstoser, J. T.; White, J. M.; Georg, G. I.
Tetrahedron Lett. 2004, 45, 2787–2789; (c) White, J. M.; Tunoori, A. R.; Georg,
G. I. J. Am. Chem. Soc. 2000, 122, 11995–11996; (d) Wang, J.; Xu, H.; Gao, H.; Su,
C.-Y.; Phillips, D. L. Organometallics 2010, 29, 42–51; (e) Gondi, V. B.; Hagihara,
K.; Rawal, V. H. Chem. Commun. 2010, 46, 904–906.
8. (a) Schedler, D. J. A.; Godfrey, A. G.; Ganem, B. Tetrahedron Lett. 1993, 34, 5035–
5038; (b) Schedler, D. J. A.; Li, J.; Ganem, B. J. Org. Chem. 1996, 61, 4115–4119;
(c) Xia, Q.; Ganem, B. Tetrahedron Lett. 2002, 43, 1597–1598; (d) Xia, Q.; Ganem,
B. Org. Lett. 2001, 3, 485–487; (e) Ganem, B.; Franke, R. R. J. Org. Chem. 2007, 72,
3981–3987.
9. Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J. Org. Chem. 1999, 64, 6646–
6652.
10. Yu, J.; Truc, V.; Riebel, P.; Hierl, E.; Mudrykauph, B. Tetrahedron Lett. 2005, 46,
4011–4013.
11. Ramegowda, N. S.; Modi, M. N.; Koul, A. K.; Bora, J. M.; Narang, C. K.; Mathur, N.
K. Tetrahedron 1973, 29, 3985–3986.
12. (a) Chiacchio, U.; Borrello, L.; Crispino, L.; Rescifina, A.; Merino, P.; Macchi, B.;
Balestrieri, E.; Mastino, A.; Piperno, A.; Romeo, G. J. Med. Chem. 2009, 52, 4054–
4057; (b) Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia, C. R. D. Org.
Lett. 2003, 5, 305–308.
13. (a) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9, 367–370; (b) Wu,
P.; Lin, D.; Lu, X.; Zhou, L.; Sun, J. Tetrahedron Lett. 2009, 50, 7249–7251; (c) Lu,
M.; Lu, Y.; Zhu, D.; Zeng, X.; Zhong, G. Angew. Chem., Int. Ed. 2010, 49, 8588–
8592.
Supplementary data
Supplementary data (experimental procedures and character-
ization data for each reaction) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.10.006.
14. Wang, J.; Xu, H.; Gao, H.; Su, C.-Y.; Chao, C.; Phillips, D. L. Organometallics 2010,
29, 42–51.
References and notes
1. (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243–2266; (b)
Brown, R. S. The Amide Linkage: Structural Significance in Chemistry