The high selectivity of the Cp2ZrHCl reducing agent for imides: A combined experimental and theoretical study on γ-lactam and isoxazolidinone derivatives

Article abstract of DOI:10.1002/ejoc.201201186

Selective reductions of semicyclic imides either to hemiaminals (endo carbonyl reduction) or to aldehydes and amines (exo carbonyl reduction) in high yields by Schwartz's reagent (Cp₂ZrHCl) are reported. Mechanistic aspects of these reactions have been investigated at the DFT ab initio level with consideration of implicit solvent effects and thermal and pressure corrections to 298 K/1 atm. The reactions proceed from the reagents to very stable final Zr-oxo intermediates through the formation of σ complexes and subsequent four-center transition state structures (1,2-migratory insertion). The energetic barriers for the insertion steps depend strongly on the natures of the ancillary groups at the reducing carbonyl groups. N-Carbamoyl groups are reduced to hemiaminals whereas N-acyl groups react at the exo carbonyl groups. The absence of the second carbonyl group in the simple N-methyl-2-pyrrolidone (less oxidized system) strongly reduces the thermodynamic drive for the formation of the metallocene oxo intermediate and allows an explanation of the remarkable chemoselectivity of the hydrozirconation. The zirconocene-oxo intermediates hydrolyze quickly throughout an ionic mechanism in which water molecules strongly assist the process by stabilizing ion pair separation. The computational results are consistent with a large set of experimental data on reduction of γ-lactam and isoxazolidinone derivatives under mild conditions. They provide a way to explain and predict the relative importance of the two competitive endo/exo reduction channels of semicyclic imides by considering the electronic and steric features of substituents. Semicyclic imides such as γ-lactam and isoxazolidinone derivatives are efficiently and selectivity reduced by the Cp₂ZrHCl agent. The energetic reaction pathways for endo and exo attack, computed at the DFT level including thermal effects, allow an exhaustive interpretation of current and previously reported experimental data. Copyright

Full text of DOI:10.1002/ejoc.201201186

FULL PAPER
DOI: 10.1002/ejoc.201201186
The High Selectivity of the Cp2ZrHCl Reducing Agent for Imides:
A Combined Experimental and Theoretical Study on γ-Lactam and
Isoxazolidinone Derivatives
Giuseppe Lanza,*[a] Maria A. Chiacchio,[a] Salvatore V. Giofrè,[b] Roberto Romeo,[b] and
Pedro Merino[c]
Keywords: Imide reduction / Chemoselectivity / Zirconocene hydride / Lactams / Isoxazolidinones / Density functional
calculations
Selective reductions of semicyclic imides either to hemiamin-
als (endo carbonyl reduction) or to aldehydes and amines
(exo carbonyl reduction) in high yields by Schwartz’s reagent
(Cp2ZrHCl) are reported. Mechanistic aspects of these reac-
tions have been investigated at the DFT ab initio level with
consideration of implicit solvent effects and thermal and
pressure corrections to 298 K/1 atm. The reactions proceed
from the reagents to very stable final Zr-oxo intermediates
through the formation of σ complexes and subsequent four-
center transition state structures (1,2-migratory insertion).
The energetic barriers for the insertion steps depend strongly
on the natures of the ancillary groups at the reducing carb-
onyl groups. N-Carbamoyl groups are reduced to hemiamin-
als whereas N-acyl groups react at the exo carbonyl groups.
The absence of the second carbonyl group in the simple N-
methyl-2-pyrrolidone (less oxidized system) strongly reduces
the thermodynamic drive for the formation of the metallo-
cene oxo intermediate and allows an explanation of the re-
markable chemoselectivity of the hydrozirconation. The zir-
conocene-oxo intermediates hydrolyze quickly throughout
an ionic mechanism in which water molecules strongly assist
the process by stabilizing ion pair separation. The computa-
tional results are consistent with a large set of experimental
data on reduction of γ-lactam and isoxazolidinone derivatives
under mild conditions. They provide a way to explain and
predict the relative importance of the two competitive
endo/exo reduction channels of semicyclic imides by con-
sidering the electronic and steric features of substituents.
On the basis of isotopic experiments, Georg et al. pro-
posed a two-part mechanism (Scheme 1).[1] In the first part,
the Cp2ZrHCl bonds to the carbonyl group of the amide to
form an exceptionally stable metallocene oxo complex and
shields the carbonyl from possible undesirable nucleophilic
attack. The intermediate is then hydrolyzed in an aqueous
or silica gel workup to produce an aldehyde and an amine.
Workup with p-anisidine or aniline instead of water results
in the formation of the corresponding imine.
Introduction
The reduction of amides to aldehydes by Schwartz’s rea-
gent (Cp2ZrHCl) in stoichiometric or excess amounts is a
compelling synthetic tool.[1–4] Generally, these reactions oc-
cur with high yields for tertiary and Weinreb’s amides,
whereas for primary and secondary amides the efficiencies
decrease.[1] The reactions can be performed under very mild
conditions, so there is a great tolerance of many functional
groups, such as esters, aliphatic ketones, alcohols, nitriles,
nitro derivatives, carbamates, alkenes, and internal alk-
ynes.[1–3] This feature makes the reaction appealing in the
development of new synthetic strategies for the preparation
of new[5] and/or well-established pharmaceutical products,
as in the case of the large scale semisynthetic production of
the blockbuster anticancer drug paclitaxel.[2]
[a] Dipartimento di Scienze del Farmaco, Università di Catania,
Viale A. Doria 6, 95125 Catania, Italy
E-mail: glanza@unict.it
Homepage: http://www.dsf.unict.it
[b] Dipartimento di Scienze del Farmaco e dei Prodotti per la
Salute, Università di Messina,
via S. S. Annunziata, 98168 Messina, Italy
[c] Departamento de Química Orgánica, ISQCH, Universidad de
Zaragoza-CSIC,
50009 Zaragoza, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201186.
Scheme 1. Isotopic labeling results for reduction of amides with
Cp2ZrHCl.
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FULL PAPER
In the early synthetic study by Georg et al.[1] the re- onyl group can be involved in reactions similar to those
duction of cyclic amides such as β-lactams and caprolact- discussed above, as was recently reported for the compound
ams at room temperature resulted in the complete loss of with a Cbz substituent [–C(O)OCH2Ph] on the nitrogen
starting material without the formation of aldehyde prod- atom.[5a] To provide a more exhaustive picture of experi-
ucts. Conversely, substituted 2-pyrrolidones treated with mental data, isoxazolidinone derivatives with the same sub-
Cp2ZrHCl at –20 °C underwent reduction at their amide stituents on nitrogen as previously reported for γ-lactams
functionalities to provide Δ1-pyrrolines (Scheme 2).[6]
have now been synthesized and reduced with Schwartz’s
reagent.
The above experimental data, together with data re-
ported by Georg et al.[1] and by Ganem et al.,[2,6] raise intri-
guing questions about the reactivity of Cp2ZrHCl toward
the different cyclic amides. A systematic theoretical investi-
gation based on DFT ab initio computational methods
could provide insights into basic reduction mechanisms and
assist in explaining trends in kinetics and selectivities.
To address the above experimental observations on re-
ductions of cyclic amides with Schwartz’s reagent, the en-
ergy profiles for the formation of the very stable metallo-
cene oxo intermediates and their subsequent hydrolysis
were studied for the γ-lactam and isoxazolidinone deriva-
tives, revealing intriguing and surprising behavior. Elec-
tronic structure analysis has provided insights into the fac-
tors that ultimately control the different reaction pathways.
Scheme 2. Reduction of 2-pyrrolidones to Δ1-pyrrolines with
Cp2ZrHCl.
Recently, Schwartz’s reagent has been used to study re-
duction of N-alkoxycarbonyl-lactams and N-acyl-lactams.
It has been shown that, at room temperature, reductions
with two equivalents of Cp2ZrHCl occur in very short reac-
tion times with good yields and high selectivities
(Scheme 3).[5a,7]
Results and Discussion
Synthesis and Reduction of Isoxazolidin-3-One Derivatives
Isoxazolidin-3-one derivatives 5a–c and 7 (Scheme 4)
were prepared in high yields by treating isoxazolidin-3-one
with appropriate reagents to introduce the desired substitu-
ents on the nitrogen atom (see Exp. Sect.). Reduction of
isoxazolidinone imides with Cp2ZrHCl was carried out un-
der anhydrous conditions with, for compound 5a, variation
of the number of equivalents of Schwartz’s reagent and the
reaction times (Table 1). The reactions were quenched with
silica gel in non-aqueous workups (about 1 min).
Scheme 3. Reductions of γ-lactam derivatives with Cp2ZrHCl at
room temperature.
Because of the presence of two carbonyl groups, there is
competition between reduction of exo and endo carbonyl
groups. It has been observed that reduction of γ-lactam de-
rivatives depends on the nature of their nitrogen substitu-
ents and that, in particular:
i. N-carbamoyl groups are reduced to hemiaminals (aza-
hemiacetal),
ii. N-acyl groups react at the exo carbonyl groups with for-
mation of aldehyde and 2-pyrrolidone, and
iii. N-methyl-2-pyrrolidone and 2-pyrrolidone do not react.
Isoxazolidinone can be regarded as a special case of a
cyclic Weinreb amide, in which the “methoxy” moiety is
Scheme 4. Reductions of isoxazolidinone derivatives with
incorporated into the heterocyclic ring. Therefore, the carb- Cp2ZrHCl at room temperature.
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The High Selectivity of the Cp2ZrHCl Reducing Agent for Imides
Table 1. Reactions between isoxazolidinone imides and Cp2ZrHCl.
Entry
Cp2ZrHCl, time
Imide
Product
Yield [%]
1
2
3
4
5
6
7
8
9
1 equiv., 20 min
1.5 equiv., 66 h
2 equiv., 48 h
3 equiv., 2 h
4 equiv., 5 min
4 equiv., 2 h
4 equiv., 2 h
4 equiv., 2 h
4 equiv., 2 h
5a
5a
5a
5a
5a
5a
5b
5c
7
6a/5a; conversion ratio 1:6
6a/5a; conversion ratio 1:3
6a/5a; conversion ratio 2:3
6a/5a; conversion ratio 3:1
6a/5a; conversion ratio 1:10
6a
14
25
40
75
10
95
95
95
98
6b
6c
isoxazolidinone and benzaldehyde
For carbamates 5a–c the results are similar to those ob-
tained for γ-lactam imides, with selective reduction of their
endo-carbonyl groups, whereas N-benzoyl compound 7 was
reduced at its exo-carbonyl group. These data indicate that
hydrozirconation is a general and efficient way to reduce a
single carbonyl group in an imide under very mild reaction
conditions. The reduction of the endo-carbonyl group is of
great importance because the produced azahemiacetals 6a–
c can be used as precursors for the synthesis of a vast and
variegated class of nucleosides.[5]
The reactions were carried out in THF and toluene as
solvents. In THF the reactions occur quickly (15 min) be-
cause of the greater solubility of Cp2ZrHCl, but we ob-
served the formation of degradation products. Conversely,
in toluene greater amounts of Cp2ZrHCl were required,
with the reactions occurring slowly, but no degradation
products were detected even though the reactions were al-
lowed to proceed for long times. This makes toluene the
more attractive solvent from the preparative point of view.
Data obtained for compound 5a clearly show that the
amount of Cp2ZrHCl and the reaction time are critical
points: 4 equiv. and 2 hours, respectively, are required for
efficient chemical conversion. Conversely, the second part
of the reaction (i.e., the hydrolysis of the stable zirconocene
intermediate) occurs very quickly (1 min), hence indicating
that the formation of the Zr-oxo intermediate is the rate-
determining part of the reaction.
Scheme 5. 1,2-Migratory insertion for the formation of stable zir-
conocene oxo intermediate I.
In this study a methyl group was adopted as R substitu-
ent in all cases (Scheme 6) to improve computational per-
formance, because it has been shown that the progression
of the reaction is independent of the R substituent (R =
tBu, Et, and CH2Ph, Scheme 3 and Scheme 4).
The Reaction Mechanism
Scheme 6. Molecules for which the hydrozirconation reaction path-
An earlier computational DFT study on an acyclic Wein- way was studied.
reb amide, N-methoxy-N-methylnicotinamide, had been re-
ported.[8] The most plausible proposed mechanism for par-
tial reduction of amides, on the basis of the previously re-
Geometrical Structures
ported experimental evidence and computational results, is
shown in Scheme 5. Essentially, it is a 1,2-migratory inser-
For all semicyclic imides and cyclic amides considered
tion: the reaction starts with the coordination of the lone the nitrogen atoms assume almost planar arrangements
pair of the amide carbonyl oxygen to the electrophilic metal with the rings each adopting an envelope conformation
with the formation of a vanishing σ complex (σ) in a pre- with two symmetrical minimum structures separated by a
equilibrium step. The C=O insertion into the Zr–H bond low energy barrier (Scheme 7). In addition, for N-carb-
occurs throughout a four-membered ring transition state amoyl and N-acyl derivatives both of γ-lactams and of isox-
(TS) that is the highest-energy structure and hence deter- azolidinone, the two carbonyl groups can lie either on the
mines the rate-determining step. Finally, there is the forma- same side of the molecule (trans-trans) or distal (cis-trans),
tion of the stable zirconocene oxo intermediate (I).
so four minima are possible.[9] For the isoxazolidinone de-
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G. Lanza, M. A. Chiacchio, S. V. Giofrè, R. Romeo, P. Merino
FULL PAPER
rivatives these structures are almost isoenergetic (Table 2) rier) and so it has not been evaluated presently.[8] Once the
whereas for lactams the cis-trans structures are always more carbonyl group oxygen atom has bonded to the zirconium
stable (by 0.6 and 4.9 kcalmol–1).
along the H–Zr–Cl bond angle bisector, various minimum-
energy structures can be obtained, depending on the relative
orientation of the Cp2ZrHCl molecule fragments, on the
involvement of exo or endo carbonyls, on the relative orien-
tation of the two carbonyls, and also on the disposition of
the ring envelope. Eight minima were thus found for the σ
complexes of each of compounds 2d, 5d, 4a, and 7a,
whereas only two minima were found for the methyl-pyrrol-
idone 1b (Table 2 and Table S1 in the Supporting Infor-
mation). The H–Zr–Cl bond angle undergoes a substantial
enlargement (101° vs. 137°) to allow better for the oxygen
coordination. The isoxazolidinone and lactam rings are
slightly perturbed, whereas the NC(O)CC and C(O)CCX
(X = O and C for isoxazolidinone and lactam rings, respec-
tively) dihedral angles maintain values close to those of the
free species.
For the insertion transition state, the four-membered ring
poses stringent geometrical constraints and a reduced
number of structures are possible. To reduce steric hin-
drance between cyclopentadienyl and pyrrolidone rings,
only one transition state is possible in the endocyclic attacks
of 2d, 4a, and 1b whereas two distinct transition states are
possible for the exocyclic attacks of 2d and 4a. For isoxazol-
idinone derivatives, the reduced size of the –O– group with
respect to the ϾCH2 group allows for the formation of tran-
sition states with both isoxazolidone ring configurations, so
eight transition states were found for each of 5d and 7a
(Table 2, Table S1 in the Supporting Information, and Fig-
ure 1).
Scheme 7. Four minimum-energy structures for the compound 5d.
These conformations are named for the position of the carbonyl
group, relative to the group on the nitrogen. Single prime indicates
inverted ring.
Table 2. Relative Gibbs free energies (ΔG298, kcalmol–1) for various
conformations of reagents, σ complexes, transition states, and in-
termediates.
Reagents
σ Complex Transition state Intermediate
1b
1bЈ
0.0 11.1
–0.4
1.3
11.4
0.4 16.4
15.9
0.0 16.7
16.8
25.5
27.7
2d-endo-trans-trans
2dЈ-endo-trans-trans
2d-endo-cis-trans
2dЈ-endo-cis-trans
2d-exo-trans-trans
2dЈ-exo-trans-trans
2d-exo-cis-trans
2dЈ-exo-cis-trans
5d-endo-trans-trans
5dЈ-endo-trans-trans
5d-endo-cis-trans
5dЈ-endo-cis-trans
5d-exo-trans-trans
5dЈ-exo-trans-trans
5d-exo-cis-trans
5dЈ-exo-cis-trans
4a-endo-trans-trans
4aЈ-endo-trans-trans
4a-endo-cis-trans
4aЈ-endo-cis-trans
4a-exo-trans-trans
4aЈ-exo-trans-trans
4a-exo-cis-trans
4aЈ-exo-cis-trans
7a-endo-trans-trans
7aЈ-endo-trans-trans
7a-endo-cis-trans
7aЈ-endo-cis-trans
7a-exo-trans-trans
7aЈ-exo-trans-trans
7a-exo-cis-trans
7aЈ-exo-cis-trans
–10.3
–9.5
–9.5
–8.9
–0.8
1.1
28.1
33.7
34.2
34.7
34.7
28.2
28.8
29.1
29.8
34.1
33.9
32.8
33.1
20.0
19.5
21.5
20.8
–4.5
–3.3
–12.3
–13.2
–10.2
–12.2
–4.2
–3.3
–4.8
–3.5
–7.9
–6.0
–5.6
–7.4
–7.4
–6.9
–10.6
–11.0
–13.7
–13.8
–9.2
–9.9
–11.2
–12.4
–13.9
–13.9
0.0 17.9
17.6
0.3 18.6
18.9
The geometrical structures of the four-membered rings
are similar for all the transition states. The Zr–H and
O=CϽ bonds lie essentially in the same plane, with ring
puckering of a few degrees. The Zr–H and O=CϽ bonds
lengthen and reach values of ca. 1.91 and ca. 1.27 Å, respec-
tively, whereas the newly formed H–C and Zr–O bonds are
ca. 1.8 and ca. 2.3 Å. The reactions are essentially con-
certed, but the Zr–O bonds forms slightly before the C–H
bonds, being already formed in the σ complexes.
20.4
20.6
19.5
19.4
4.9 19.2
20.2
0.0 17.4
16.8
31.2
30.1
31.6
32.5
28.3
28.7
27.5
28.0
29.8
30.0
28.3
28.0
26.9
27.7
20.5
19.2
17.3
16.6
The zirconocene oxo intermediate I can assume several
conformations upon rotation around the Zr–O, O–C, and
other σ bonds, as well as through the pyrrolidine and isox-
azolidine ring conformations. Significant dihedral angles of
some of these structures are reported in Table S2 in the
Supporting Information. In all intermediates the Zr–O–C
bond angle is almost linear (167°), indicative of a partial π
bond involving the oxygen lone pair and the Zr4d orbitals
of the electron-deficient metal.[10]
0.6 16.9
17.3
0.0 18.6
18.9
17.7
17.8
17.0
16.7
–
+
Zr–OR ↔ Zr=OR
The compounds under analysis are prochiral molecules,
so intermediates and transition states formed in the re-
In the most stable conformations, the isoxazolidine and
duction process can adopt both S and R configurations, pyrrolidine rings point away from the cyclopentadienyl
thus doubling the number of possible structures. Here, in- rings in order to minimize repulsive steric interactions, with
termediates and transition states of single enantiomers are the rings lying in front of the Cl–Zr–O bond angle (i.e., the
reported. To coordinate the carbonyl oxygen atom to the less hindered region of the molecules, Figure 1). Although
zirconium an energy barrier must be overcome, but this is in many cases the nitrogen lies in front of the metal, there
small in relation to the rate-limiting step (the insertion bar- is no significant interaction between Zr···N as suggested by
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The High Selectivity of the Cp2ZrHCl Reducing Agent for Imides
Figure 1. Molecular structures of σ complexes, transition states, and stable intermediates for the two competitive endo and exo carbonyl
reductions of compound 5d in the trans-trans conformation.
Georg et al.;[1] rather, the great stabilities of the intermedi- Energetics
ates are due to the strong Zr–O bonds (the disruption en-
thalpies of Zr–O measured for various zirconocenes are
greater than 100 kcalmol–1).[10a] Because the Zr···N interac-
tions have been postulated as a major factor in stabilizing
intermediates such as I, computational efforts were under-
taken with the goal of verifying the existences and the sta-
bilities of these 18-electron structures. Actually, though, for
intermediates related to semicyclic imides it was not pos-
sible to locate any stable conformation with significant Zr–
N interaction, whereas for N-methyl-2-pyrrolidone (1b),
two structures were found (Figure 2 and Table S2 in the
Supporting Information). In the case of intermediates re-
lated to imides, the nitrogen lone pairs are delocalized over
the remaining carbonyl groups, so they have only modest
tendencies to be involved in interaction with the metal.
Conversely, for intermediate I-1b the nitrogen lone pair is
available and can efficiently coordinate the metal (Figure 2).
The two N-1b structures are very similar and differ mainly
in the conformation of the pyrrolidine ring. In each case
the Zr–N distance is 2.52 Å and the Zr–O–C bond angle
assumes a value close to standard sp3-hybridization (108°),
whereas the Cl–Zr–C angle opens (133°) to allow for the
nitrogen coordination. These structures lie at high energy
(ΔG298 = 14 kcalmol–1) with respect to those without Zr–
N interaction – I – and they do not therefore play any sig-
nificant role in the progress of the reactions.[11]
Computed free Gibbs energy profiles along the carbonyl
activation/insertion pathways at the zirconocene hydro-
chloride are given in Table 2 and Figure 3. σ complexation
is an endoergonic process for all systems, mainly because of
the reduction in entropy contents due to the degrees of free-
dom lost in the carbonyl incorporation (–TΔS
≈
12 kcalmol–1). The ΔG298 values for the imides are similar,
indicating that the O=CϽ groups bind to the metal centers
with similar strengths, and hence involve similar electronic
and steric interactions. These data are consistent with the
comparable Zr···OCϽ bond length (Table S1 in the Sup-
porting Information). The less endoergonic value obtained
for the 1b system agrees well with the shorter (0.1 Å)
Zr···OCϽ distance, which indicates stronger bonding.
Mainly this is due to the greater electronic assistance of the
nitrogen lone pair to the nucleophilic carbonyl oxygen in
an amide rather than in an imide (in an amide the lone pair
is delocalized over only one carbonyl group).
For the carbamate series (compounds 2d and 5d), σ com-
plexation, transition state, and final intermediate formation
energies show a clear preference for the coordination/inser-
tion of the endo carbonyl groups (2d-endo and 5d-endo) over
their exo counterparts independently of conformations. For
the N-acyl series (compounds 4a and 7a) the relative sta-
bilities of various endo and exo σ complexes and transition
states depend significantly on the conformations of groups
not directly involved in the insertion and in particular on
the trans-trans or cis-trans orientations of the carbonyls. In
all cases, the lowest-energy transition states correspond to
exo carbonyl insertion with the cis-trans orientation of the
two carbonyls (7a-exo-cis-trans, 4a-exo-cis-trans, and 4aЈ-
exo-cis-trans). For compound 4a the exocyclic pathway is
favored by about 2 kcalmol–1 whereas for 7a it is preferred
by 0.6 kcalmol–1.
For compounds 2d, 5d, 4a, and 7a, the formation of in-
termediates such as I is a highly exoergonic process (ΔG298
Figure 2. Molecular structures of the intermediate 18-electron com-
plexes related to N-methyl-2-pyrrolidone 1b.
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Figure 3. Energy profile (ΔG298, kcalmol–1) for carbonyl activation/insertion at the Cp2ZrHCl along the two competitive endo and exo
pathways for compound 5d in the trans-trans conformation.
≈ –11 kcalmol–1) and hence irreversible. Once the zir- vides an explanation for the different behavior observed for
conocene-oxo complexes are formed, they cannot convert 2-pyrrolidones at –20 °C and at room temperature (see
back into the reactants and it will be hydrolyzed in the sub- Schemes 2 and 3).
sequent workup. Therefore, the selectivity of the overall re-
actions depend on the stabilities and the rates of formation
of intermediates of type I. All these data are in good agree-
ment with experimental evidence on the selectivity of re-
Electronic Structures
duction of imides by Cp2ZrHCl (see Schemes 3 and 4 and
Table 1).
Like all migratory insertion processes,[12] the reactions
start with the nucleophilic attack (oxygen of a carbonyl
A different energetic situation applies for compound 1b. group) on the metal with a small electronic density transfer
Both σ complexation and transition state energies suggest to the metal (≈ 0.1 e.u.). The nitrogen lone pairs play
high reactivity towards Schwartz’s reagent. However, the in- pivotal roles in the reaction progress because they assist the
termediate I-1b has a stability comparable to those of the formation of the σ complexes and transition states, increas-
reagents (i.e., the reaction is thermally neutral). The absence ing the nucleophilicities of the oxygen atoms of the carbonyl
of any significant thermodynamic drive prevents the reac- groups directly involved in the reactions.[1] Because of the
tion, in qualitative agreement (within the experimental error presence of a single carbonyl group in 1b, the formation of
of the computational method) with experimental data the σ complex and transition state are favored kinetically
(Scheme 3).
(Table 2). However, for the same reason, this reaction is
As already mentioned, the thermodynamic driving force thermodynamically disfavored and actually it does not oc-
for these reaction is the formation of stronger bonds (ΔHr cur. Conversely, the presence of two carbonyl groups in the
Ͻ 0), whereas entropy decreases (ΔSr Ͻ 0) due to the re- imides kinetically disfavors the reactions but imparts high
duction of the total particles in solution. The –TΔS term thermodynamic stability to the final intermediates. In other
thus disfavors the reactions, and actually for compound 1b words, imides are more oxidized than the cyclic amide, and
the reaction does not occur. With a reduction in tempera- so they can be more easily reduced by a mild reducing agent
ture the unfavorable entropic contribution to free Gibbs en- such as Cp2ZrHCl.
ergy is decreased and at –20 °C the entire energy profile for
In agreement with this view, the LUMOs of the com-
the reduction of 1b has been shifted downward by about pounds under analysis, mainly representing the antibonding
–1.5 kcalmol–1, so the formation of the intermediate I-1b π*C=O molecular orbitals (Figure S1 in the Supporting In-
becomes spontaneous (ΔG298 = –1.8 kcalmol–1). This pro- formation), show greater stability for imides (negative en-
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The High Selectivity of the Cp2ZrHCl Reducing Agent for Imides
ergy) than for N-methyl-2-pyrrolidone (positive energy), phenomena hard to treat by quantum chemical procedures.
and hence a greater tendency to be involved in the re- Nevertheless, application of the solvent reaction field model
duction processes. For imides, the LUMOs have very similar for implicit solvent effects and introduction of a limited
compositions in terms of atomic orbitals. Figure S1 in the number of explicit water molecules might provide a reliable
Supporting Information clearly shows an equal mixture of qualitative understanding.[13]
the two carbonyl groups’ π*C=O orbitals, cannot easily ac-
The electronic energy curve for the heterolytic cleavage of
count for the preferential site for reduction, and suggests the Cp2ClZrO–CHC2H4ON(COOCH3) bond in the stable
that the difference in transition state stabilities between intermediate I-5d-endo-trans-trans was determined in an an-
endo and exo attack is often low. The high preference for hydrous environment (i.e., considering THF solvent effects
endocyclic attack in carbamates 2d and 5d is due to the only implicitly) and under aqueous conditions (i.e., with the
–OR groups, which significantly reduce the nucleophilicities presence of a water molecule taken into account). The ener-
of the oxygen atoms in the exo positions. For compounds gies were evaluated for selected ZrO–CH bond lengths with
4a and 7a the differences in stability between endo and exo optimization of all other geometrical parameters without
transition states are small and often depend on the confor- constraints (Figure 4).
mations of the two carbonyl groups (trans-trans or cis-trans)
and also on the pyrrolidine and isoxazolidine ring confor-
mations (i.e., they are influenced by steric effects). The exo
carbonyl groups lie in less hindered regions of the mole-
cules, and so can more efficiently attack the electron-de-
ficient zirconium.
These conclusions are in good agreement with the large
spread of data on semicyclic imides reported for oxazolid-
inone derivatives (Scheme 8).[1] Because of the bonded elec-
tron-withdrawing oxygen atoms and the ring steric hin-
drance, the nucleophilicities of the endo carbonyl groups are
greatly reduced and the exo attack is the predominant path-
way.
Figure 4. Electronic energy profiles for heterolytic bond cleavage in
Cp2ClZrO–CHC2H4ON(COOCH3) (intermediate I-5d-endo-trans-
trans) calculated in anhydrous THF solvent (solid line) and with
explicit consideration of one water molecule in THF solvent (hy-
drous environment, dotted line).
In the anhydrous environment, the electronic energy in-
creases substantially when the two fragments are displaced
from their equilibrium positions, and Mulliken charges
show substantial electron density transfer, with the two
fragments acquiring increasing ionic character. The carbon
atom involved in the cleavage progressively changes its hy-
Scheme 8. Reduction of N-acyl oxazolidinones. The * indicates
bonded atom.
The Final Products Formation
The previously discussed experimental results suggest bridization to sp2 and a partial C=N double bond (i.e., the
that the rate-limiting steps of the overall reactions are in iminium cation) is formed. For a high value of the reaction
the first parts of the reactions. Consistently with this, com- coordinate, the isoxazolidine ring moves and a hydrogen
putational data have been successful used to interpret the atom of the adjacent ϾCH2 group approaches the
large number of currently available experimental results on Cp2ClZrO– anionic oxygen: the H-abstraction occurs with
reduction of cyclic amides and semicyclic imides. Never- formation of enamine. This reaction channel is energetically
theless, hydrolysis is a significant part of these reactions, expensive (ΔE‡ = 46.8 and ΔG‡ = 41.7 kcalmol–1) for this
and so it is instructive to clarify the second part for at least isoxazolidinone and has not actually been experimentally
one case: the hydrolysis of I-5d-endo-trans-trans [Cp2ClZrO- observed. For δ-lactams such reactions occur significantly
CHC2H4ON(COOCH3)].
and a mixture of enamine and hemiaminal has previously
From a computational point of view the simulation of a been observed.[7] The reduction of the 2-pyrrolidones to Δ1-
chemical reaction in an aqueous environment is a challeng- pyrrolines (Scheme 3) occurs with a similar mechanism. In
ing task because of the high polarity of water molecules that case, however, the H-abstraction involves the H–NϽ
and their ability to form very strong H-bonds. Reactions do group, which is well known to have a greater acidity than
not strictly involve two species; rather they are collective aliphatic hydrogen atoms.
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101

G. Lanza, M. A. Chiacchio, S. V. Giofrè, R. Romeo, P. Merino
FULL PAPER
Because of the formation of ionic species in ZrO–CN cules surround charged atoms through ion–dipole interac-
heterolytic separation, the high polarity and strongly coor- tions and form strong H-bonds with the anion and water
dinating water molecules have a profound effect on the molecules themselves, thus allowing efficient charge disper-
energetics. The water molecule can bond the I-5d-endo- sion. For the anion, six water molecules form a true first
trans-trans stable intermediate in several ways; some struc- solvation shell around the oxygen, whereas for the iminium
tures are reported in Figure S2 in the Supporting Infor- cation it is possible to obtain solvated species up to the
mation, together with their stabilities relative to the isolated coordination of three water molecules. As a fourth water
species. The water molecule can coordinate a single hetero- molecule is added, hydrolysis occurs without any energetic
atom or it can function as a bridge between two of them, barrier with the formation of hemiaminal final product and
both situations having comparable stabilities. Many other the H3O+·(H2O)2 hydrated proton. Even though a pro-
structures can be obtained once the relative orientation of portion of the solvation energies for ions reported in Fig-
the Cp2ZrClO–CHC2H4ON(COOCH3) fragments is ure 5 are due to H-bonding between the water molecules
changed upon rotation around the Zr–O and/or O–C bonds themselves, it should be clear that ion–dipole and H-bond-
and on increasing the number of coordinating water mole- ing interactions between water molecules and ions are very
cules. We decided to study the heterolytic separation, start- strong, making their separation, and hence the pathway
ing from the structure in which the water molecule simulta- that leads the I-5d-endo-trans-trans intermediate to the final
neously coordinates chlorine and oxygen atoms directly products, facile. The ionic nature of the fundamental pro-
bonded to the metal (Figure 4). On increasing the ZrO–C cesses involved in the hydrolysis derived from the above
separation we found a transition state in which the water computations are consistent with the experimentally ob-
molecule forms a bridge between the Cp2ZrClO– anion and served vigorous reaction when water or silica gel are added
the iminium cation, giving the greatest assistance to the to the reaction mixture.
heterolytic ZrO–C bond cleavage. This transition state lies
rather high in energy (ΔE‡
= =
37.9 and ΔG‡
Conclusions
35.4 kcalmol–1) but it is significantly lower than that re-
quired for the enamine formation. Of course, we assume
that many more water molecules are involved in assisting
the heterolytic ZrO–C separation, lowering the hydrolysis
energetic barrier. For ZrO–C cleavage in the intermediate
related to the N-methoxy-N-methylnicotinamide with the
explicit coordination of two water molecules, for example,
the energetic barrier is reduced to ΔE‡ = 19.8 kcalmol–1,
still highlighting the importance of the number of water
molecules in assisting ion pairs separation.
Hydrozirconation of isoxazolidinone imides and the pre-
viously reported lactam imides by the mild Cp2ZrHCl agent
is a general, practical, and efficient method for selective re-
duction of a single carbonyl group. Intermediates and tran-
sition states for the two competitive exo/endo reduction
channels of semicyclic imides have been computationally
analyzed to provide insights into the reaction mechanism
and the electronic factors that determine the experimentally
observed high chemoselectivities. The formation (kinetic
control) and the stability (thermodynamic control) of zir-
conocene oxo intermediate I are both key elements for the
occurrence of the reaction and for the final product forma-
tion. The intermediates of type I are greatly stabilized by
their strong Zr–O bonds, which assume partial double char-
acter. Conversely, the nitrogen lone pairs play a very impor-
tant role in increasing oxygen nucleophilicity and stabilizing
the σ complexes and the transition states. The selectivity for
reduction of exo/endo carbonyl groups in semicyclic imides
is driven by electronic and steric effects of the nitrogen sub-
stituents.
To provide an idea of the bonding strengths between ions
generated by heterolytic ZrO–C cleavage and water mole-
cules, a series of calculations on the Cp2ClZrO–·(H2O)n and
CHC2H4ON(COOCH3)+·(H2O)n systems were carried out
(Figure 5). The optimized structures show that water mole-
For the less highly oxidized N-methyl-2-pyrrolidone, the
Cp2ZrHCl is thermodynamically unable to reduce cyclic
amide at room temperature, conversely to what occurs for
the more highly oxidized imides.
These results might be expected to guide and to facilitate
the further evaluation of important parameters relevant to
the mechanism of the hydrozirconation of imide/amide
functionalities and for its application in rational designs of
new synthetic procedures.
Figure 5. Molecular structures and hydration energies of
Cp2ClZrO–·(H2O)n and CHC2H4ON(COOCH3)+·(H2O)n ions. The
interaction energies were computed with respect to isolated ions
and the number n of isolated water molecules.
Experimental Section
Calculation Methods: Computations were performed at the density
functional level with employment of the hybrid B3LYP functional
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The High Selectivity of the Cp2ZrHCl Reducing Agent for Imides
and the 6-31G** basis set. Solvent effects were modeled by use of
the polarized continuum method (PCM) with adoption of a 7.4257
dielectric constant for THF as implemented in the G09 program.[14]
The geometries were optimized by standard gradient techniques
including solvent effects (B3LYP/6-31G**/PCM=THF) and char-
acterized by evaluation of the Hessian matrix and the associated
harmonic vibrational frequencies. The computed electronic ener-
gies were corrected for zero-point vibrational and thermal energies
and entropies to obtain free energy changes at 298 K (ΔG298).
General Methods: 1H NMR spectra were recorded with Varian
500 MHz spectrometers. Chemical shifts are reported in ppm from
TMS with the solvent resonance as internal standard (deuterio-
chloroform: δ = 7.26 ppm). 13C NMR spectra were recorded with
Varian 500 (125 MHz) spectrometers and with complete proton de-
coupling. Chemical shifts are reported in ppm from TMS with the
34.5, 67.0, 128.0, 129.6, 131.9, 132.9, 168.1 ppm. C10H9NO3
(191.19): calcd. C 62.82, H 4.74, N 7.33; found C 62.83, H 4.73, N
7.32.
NMR Spectroscopic Data for tert-Butyl 3-Hydroxyisoxazolidine-2-
carboxylate (6b): Colorless oil, 95 % yield. 1H NMR (500 MHz,
CDCl3): δ = 1.49 (s, 9 H), 2.23–2.29 (m, 1 H, 4-H) 2.42–2.48 (m, 1
H, 4-H), 3.51–3.57 (m, 1 H, 5-H), 3.71–3.78 (m, 1 H, 5-H), 5.48
(dd, J = 2.5, 6.5 Hz, 1 H, 3-H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 28.2, 36.0, 68.2, 81.8, 82.7, 154.5 ppm. C8H15NO4 (189.21):
calcd. C 50.78, H 7.99, N 7.40; found C 50.79, H 7.98, N 7.41.
NMR Spectroscopic Data for Ethyl 3-Hydroxyisoxazolidine-2-carb-
oxylate (6c): (Colorless oil, 95 % yield). 1H NMR (500 MHz,
CDCl3): δ = 1.32 (t, J = 7.5 Hz, 3 H) 2.95 (ddd, J = 2.2, 7.0,
13.5 Hz, 1 H, 4-H), 2.46–2.51 (m, 1 H, 4-H), 4.0 (dd, J = 8.0,
13.5 Hz, 1 H, 5-H), 4.20–4.23 (m, 1 H, 5-H), 4.25 (q, J = 7.5 Hz, 2
H), 5.78 (dd, J = 2.2, 6.4 Hz, 1 H, 3-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 14.5, 36.6, 62.7, 68.6, 81.9, 147.0 ppm. C6H11NO4
(161.16): calcd. C 44.72, H 6.88, N 8.69; found C 44.71, H 6.86, N
8.71.
solvent as the internal standard (deuteriochloroform:
δ =
77.0 ppm). All reactions were carried out in flame or oven-dried
glassware under nitrogen with use of standard gastight syringes,
cannulas, and septa unless otherwise noted. THF and toluene were
purified by distillation over sodium and benzophenone. Cp2ZrHCl
and other reagents were purchased and used without further purifi-
cation. Thin-layer chromatographic separations were performed on
silica gel 60-F254 precoated aluminum plates. Preparative separa-
tions were carried out by medium pressure liquid chromatography
(MPLC) on silica gel (0.035–0.070 mm).
Reactions of the Isoxazolidinone Derivatives with Cp2ZrHCl: An
isoxazolidinone derivative (1 mmol) dissolved in toluene or THF
was added under nitrogen to a solution of Cp2ZrHCl in dry toluene
or THF (5 mL) and the mixture was stirred at room temperature.
It was then loaded directly into a short plug of silica gel (ca. 1 g)
and eluted with ethyl acetate, and the eluted solvent was concen-
trated in vacuo. The residue was purified by MPLC.
Synthesis of Compounds
tert-Butyl 3-Oxoisoxazolidine-2-carboxylate (5b): Di-tert-butyl di-
carbonate (2.55 g, 17.23 mmol) was added to a solution of isoxazol-
idin-3-one (1 g, 11.49 mmol) in anhydrous dichloromethane
(15 mL) and triethylamine (2.40 mL, 17.23 mmol). The resulting
mixture was stirred at room temperature for 24 h. The mixture was
concentrated under vacuum and extracted with ethyl acetate (10ϫ
3 mL). Purification by MPLC (cyclohexane/ethyl acetate 7:3) af-
forded the title compound (2.11 g, 98 % yield) as a colorless oil. 1H
NMR (500 MHz, CDCl3): δ = 1.54 (s, 9 H), 2.91 (t, J = 7.5 Hz, 2
H, 4-H) 4.40 (t, J = 7.5 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 28.0, 34.4, 68.8, 85.0, 146.3, 167.1 ppm. C8H13NO4
(187.20): calcd. C 51.33, H 7.00, N 7.48; found C 51.34, H 7.00, N
7.49.
Supporting Information (see footnote on the first page of this arti-
cle): Additional NMR figures, characterization of compounds 6b
and 6c, LUMO electron densities of compounds 1b, 2d, 4a, 5d, and
7a and structures for hydrated I-5d-endo-trans-trans intermediate.
Computed geometrical parameters and Cartesian coordinates of
intermediates, transition states, and final products.
Acknowledgments
We thank the Ministero dell’Università e della Ricerca (MIUR),
Messina and Catania Universities and Consorzio Interuniversitario
Nazionale Metodologie e Processi Innovativi di Sintesi (CINMPIS)
for partial financial support and the CINECA Supercomputing
Center for a grant of computer time.
Ethyl 3-Oxoisoxazolidine-2-carboxylate (5c): Ethyl chloroformate
(1.64 mL, 17.23 mmol) was added to a solution of isoxazolidin-3-
one (1 g, 11.49 mmol) in anhydrous dichloromethane (15 mL) and
triethylamine (2.40 mL, 17.23 mmol). The resulting mixture was
stirred at room temperature for 24 h. The mixture was concentrated
under vacuum and extracted with ethyl acetate (10ϫ 3 mL). Purifi-
cation by MPLC (cyclohexane/ethyl acetate 5:5) afforded the title
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triethylamine (2.40 mL, 17.23 mmol). The resulting mixture was
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under vacuum and extracted with ethyl acetate (10ϫ 3 mL). Purifi-
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compound (1.75 g, 80 % yield) as a white solid, m.p. 100–106 °C.
1H NMR (500 MHz, CDCl3): δ = 3.0 (t, J = 8 Hz, 2 H, 4-H), 4.55
(t, J = 8 Hz, 2 H, 5-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
Eur. J. Org. Chem. 2013, 95–104
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103

G. Lanza, M. A. Chiacchio, S. V. Giofrè, R. Romeo, P. Merino
FULL PAPER
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Received: September 4, 2012
Published Online: November 21, 2012
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