Zirconium-Catalyzed Hydroalumination of C=O Bonds: Site-Selective De- O-acetylation of Peracetylated Compounds and Mechanistic Insights

Article abstract of DOI:10.1021/acs.joc.1c00060

An unprecedented hydroalumination of C = O bonds catalyzed by zirconocene dichloride is reported herein and applied to the site-selective deprotection of peracetylated functional substrates. A mixed metal hydride, with 1:1 zirconium/aluminum stoichiometry

Full text of DOI:10.1021/acs.joc.1c00060

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Article
Zirconium-Catalyzed Hydroalumination of CO Bonds: Site-
Selective De‑O‑acetylation of Peracetylated Compounds and
Mechanistic Insights
Thibaut Courant, Marine Gavel, Romain M. Q. Renard, Vincent Gandon, Antoine Y. P. Joosten,
and Thomas Lecourt*
Cite This: J. Org. Chem. 2021, 86, 9280−9288
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ABSTRACT: An unprecedented hydroalumination of C  O bonds catalyzed by
zirconocene dichloride is reported herein and applied to the site-selective
deprotection of peracetylated functional substrates. A mixed metal hydride, with
1:1 zirconium/aluminum stoichiometry, is also shown to be the reductive species.
A catalytic cycle is finally proposed for this transformation with no precedent in
the field of zirconium catalysis.
Scheme 1. Zirconium-Mediated Site-Selective Deprotection
of Peracetylated Substrates
INTRODUCTION
■
Zirconium-mediated processes have undergone numerous
developments in organic synthesis for decades.1 Recently, the
chemistry of zirconocenes has been pushed toward an exquisite
level of sophistication with the emergence of dual C−C/C−H
bond activation processes,2 chemoselective transmetallations,3
insertion reactions giving branched products instead of the
usual linear ones,4 formation of frustrated Lewis pairs,5 and
new synthetic approaches toward heterocycles.6 Moreover, the
reduction of carboxylic acid derivatives,7 and more particularly
of amides,8 by zirconium hydrides is a matter of strong interest.
These transformations can indeed be achieved with remarkable
chemoselectivity,9 and involve intermediates having a versatile
reactivity.10,11 However, to the best of our knowledge, the
reduction of CO bonds by zirconium hydrides has never
been achieved with the main group metal hydride used as the
stoichiometric reductant and a catalytic amount of zirconium
complex.12 In this context, we recently reported that a mixture
of Cp2ZrCl2 and DIBAL-H in tetrahydrofuran (THF) induce
the selective de-O-acetylation of the primary position of
peracetylated compounds on a broad scope of polyfunctional
substrates (Scheme 1a).13 Schwartz’s reagent Cp2ZrHCl,
which was initially believed to be formed in situ under our
conditions,14 was eventually discarded as the reductive species.
Our preliminary mechanistic studies rather suggested that
mixed zirconium/aluminum hydrides would be involved in this
site-selective deprotection process.
reactivity studies revealed their critical role in zirconium-
catalyzed hydro- and carboaluminations of alkenes and
Received: January 8, 2021
Published: June 14, 2021
The formation of clusters from mixtures of Cp2ZrCl2 and
organoaluminum compounds in THF has previously been
15
1
monitored by H NMR spectroscopy, but the structure of
these aggregates remains elusive in this polar solvent.16 On the
other hand, several zirconium/aluminum mixed metal hydrides
were fully characterized in apolar solvents, and extensive
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alkynes.17 Herein, we report that a Zr/Al cluster with a 1:1
stoichiometry is the reductive species giving rise to the site-
selective deprotection of peracetylated compounds previously
reported by our group. Furthermore, this mixed metal hydride
has also been shown to promote the catalytic hydro-
alumination of carbon−oxygen double bonds (Scheme 1b).
A putative catalytic cycle is finally proposed for this
transformation with no precedent in the field of zirconium
catalysis.
amount of Cp2ZrCl2 resulted in 91% conversion (entry 2), and
full conversion could even be reached when aluminum hydride
was added dropwise at a 1 mmol/h rate (entry 3). The rate of
the CO bond reduction by DIBAL-H is thus dramatically
increased in the presence of Cp2ZrCl2.
In this context, the use of a substoichiometric amount of
zirconocene dichloride was next considered to develop
reaction conditions catalytic in the zirconium complex.
Addition of DIBAL-H (3 equiv) to a solution of diester 1
and Cp2ZrCl2 (0.3 equiv) resulted in a remarkable 75%
conversion (entry 4). However, compound 2 was obtained in a
modest 43% yield, presumably because of a competitive
reduction of the pivalate when aluminum hydride is added in
one portion. The dropwise addition of DIBAL-H (1 mL/h,
entry 5) markedly improved the conversion of the substrate
but increasing this rate of addition slightly diminished this
conversion (entries 6 and 7). Finally, the use of 20 mol % of
zirconocene dichloride and 3 equiv of DIBAL-H added at 1.8
mmol/h resulted in 68% conversion and gave the desired
product 2 in 53% yield. The dropwise addition of DIBAL-H (3
equiv, 1 mL/h) alone (entry 9) only gave rise to 43%
conversion of the substrate, and 32% of isolated alcohol 2, thus
confirming the catalytic effect of Cp2ZrCl2 for the reduction of
the acetate CO bond.
RESULTS AND DISCUSSION
■
Zirconium-Catalyzed Hydroalumination of CO
Bonds. The ability of mixed Zr/Al hydrides to catalyze
hydroalumination of carbon−carbon multiple bonds17 promp-
ted us to investigate the possibility to achieve the reduction of
CO bonds by DIBAL-H in the presence of a catalytic
amount of Cp2ZrCl2. De-O-acetylation of the model diester 1
with DIBAL-H and various amounts of zirconocene dichloride
was first considered to establish a proof of concept. Addition of
3.0 equiv of aluminum hydride in one portion to a solution of
compound 1 in THF at −20 °C selectively gave the de-O-
acetylation product 2 after 1 h, albeit in only 38% conversion
and 27% yield (Table 1, entry 1). Addition of a stoichiometric
Table 1. Cp2ZrCl2-Catalyzed Reduction of Primary Acetates
by DIBAL-H
We next wondered if the site-selective deprotection of
peracetylated substrates could also be achieved under these
unprecedented catalytic reaction conditions. Our investigations
started with peracetylated methyl-α-D-glucoside 3, whose de-
O-acetylation by DIBAL-H (3 equiv) and a stoichiometric
amount of Cp2ZrCl2 (1 equiv) gave the primary alcohol 4 in
91% isolated yield (Table 2, entry 1).13
When aluminum hydride was added in one portion to a
solution of the substrate (1 equiv) and a catalytic amount of
Cp2ZrCl2 (20 mol %) at −20 °C, random acetate deprotection
took place (entry 2). To our delight, the dropwise addition of
the reducing agent (1.8 mmol/h) nicely restored a fully
selective deprotection process (entry 3). After optimization,
addition of DIBAL-H (5 equiv, 1.8 mmol/h) to a solution of
Cp2ZrCl2 (30 mol %) and 3 in THF at −20 °C, followed by
hydrolysis with 1 M aqueous citric acid and purification over a
small plug of silica, gave the desired primary alcohol 4 in 85%
isolated yield (entry 4).
Site-Selective Zirconium-Catalyzed De-O-acetylation
of Polyfunctional Substrates by DIBAL-H. Substrates
previously deprotected successfully by a stoichiometric amount
of Cp2ZrCl2 and DIBAL-H were next subjected to these
catalytic reaction conditions. For each substrate, optimization
a
b
entry
Cp2ZrCl2 (equiv) DIBAL-H (equiv/mmol/h) conversion (%)
c
1
2
3
4
5
6
7
8
9
0.0
1.0
1.0
0.3
0.3
0.3
0.3
0.2
0.0
3.0/one portion
3.0/one portion
3.0/1.0
3.0/one portion
3.0/1.0
3.0/1.5
3.0/1.8
3.0/1.8
3.0/1.8
38
91
100
d
75
89
83
70
e
68
f
41
a
b
Reaction performed on 0.25 mmol of 1. Determined on the crude
c
d
e
f
product by 1H NMR. 27% yield. 43% yield. 53% yield. 32% yield.
Table 2. Cp2ZrCl2-Catalyzed Site-Selective De-O-acetylation of Peracetylated Glucoside 3
a
a
entry
Cp2ZrCl2 (equiv)
DIBAL-H (equiv/mmol/h)
conversion (%)
selectivity (%)
b
c
1
2
3
4
1.0
0.2
0.2
0.3
3.0
3.0
100
96
b
complex mixture
84
100
3.0/1.8
5.0/1.8
96
d
99
a
b
c
d
1
Determined on the crude product by H NMR. Addition in one portion. 91% isolated yield. 85% isolated yield.
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of the conversion and selectivity required some slight
adjustments of the temperature and/or rate of addition of
aluminum hydride. Overall, the formation of the desired
products was achieved by the dropwise addition of DIBAL-H
(3 to 5 equiv, 1.5 or 1.8 mmol/h) to a solution of the substrate
(1 equiv) and zirconocene dichloride (30 mol %) in THF at
−20 or −40 °C (Scheme 2).
mechanism of this unprecedented zirconium-catalyzed reduc-
tion of CO bonds by aluminum hydride.
Identification of the Reductive Species and Proposi-
tion of a Catalytic Cycle for the Zirconium-Catalyzed
Hydroalumination of CO Bonds. Intrigued by the
tolerance of acetamides toward reaction conditions used to
promote this site-selective reduction of acetates, we previously
showed that Schwartz’s reagent was not the reductive
species.13 These preliminary mechanistic studies in THF also
revealed that a mixed metal hydride should be involved.
However, since Zr/Al clusters have not been identified in
THF,15,16 we wanted to transpose the de-O-acetylation
reaction in toluene to identify the active species. Indeed, in
this apolar solvent, extensive structural and reactivity studies
have been performed to rationalize zirconium-catalyzed
hydroalumination of alkenes by mixtures of Cp2ZrCl2 and
aluminum hydrides.17 They revealed that only mixed metal
hydrides 15a/b and 16a/b (Figure 1), with 1:1 or 1:2
Scheme 2. Zirconium-Catalyzed Site-Selective Deprotection
of Peracetylated Substrates
Figure 1. Possible Zr/Al clusters involved in the catalytic hydro-
alumination of CO bonds.
zirconium/aluminum stoichiometries, respectively, and chlor-
ine/hydride bridging ligands, must be considered as possible
reductive species from the complex equilibrium depicted in
Scheme S1.17,18
To identify the reductive and catalytic species involved in
this unprecedented zirconium-catalyzed hydroalumination of
CO bonds, deprotection of peracetylated methyl-α-D-
glucoside 3 in toluene was chosen as a model reaction. Our
rationale was that the primary alcohol 4 would be selectively
obtained in high yield when the proper mixed metal hydride
would be present in the reaction mixture. Otherwise, low
conversion and/or selectivity would be observed.
In our preliminary communication, deprotection of 3 took
place in low conversion and poor selectivity when DIBAL-H (3
equiv) was added to a mixture of the substrate and Cp2ZrCl2
(3.5 equiv) in toluene at −20 °C (Table 3, entry 1).13 In this
apolar solvent, we suspected that strong aggregation of
aluminum hydride might have prevented a fast reduction of
zirconocene dichloride into the active species. The reaction of
the substrate with dimeric and trimeric DIBAL-H would then
lead to random deprotection.
In a new experimental protocol, Cp2ZrCl2 and DIBAL-H
were premixed for 10 min at −20 °C to allow the reduction of
the zirconium complex by aluminum hydride before addition
of 3 to the reaction mixture. Under these slightly modified
reaction conditions, we were pleased to obtain 4 with an 85:15
selectivity (entry 2). When THF was used as an additive (50,
10, or 1.5 equiv, entries 3 to 5, respectively), de-O-acetylation
took place with almost complete regioselectivity. THF is thus
not essential as the solvent and probably plays a key role in the
dissociation of DIBAL-H aggregates. With a single equivalent
of Cp2ZrCl2 and a Zr/Al ratio ranging from 1:2 to 1:4,
selectivity could be increased to 95:5, but the conversion of 3
remained partial (entries 6−8). Finally, 1.5 equiv of
First, site-selective de-O-acetylation of peracetylated methyl
β-gluco- and α-mannopyranosides and of methyl α-ribofurano-
side gave the primary alcohols 5, 6, and 7 in 59 to 82% yields.
Deprotection of glycosyl donors, preactivated as a phenyl
thioglycoside, an anomeric acetate, or a glycal, into compounds
8, 9, and 10 was then successfully achieved under catalytic
reaction conditions. De-O-acetylation of the primary position
of 2-deoxy 2-acetamido and 2-azido sugars also gave 11 and 12
with complete chemoselectivity. Finally, compounds 13 and 14
were obtained from acetylated N-Boc serine tert-butyl ester
and peracetylated betulin without any side-reaction on the
amino acid protecting groups and electron-rich α-olefin. Based
on the low weight of the crude product obtained after the
deprotection of ribofuranoside and 2-deoxy 2-acetamido sugar,
the moderate yields in products 7 and 12 might be due to
competitive de-O-acetylation of secondary positions that
would have given rise to water-soluble side products.
Having shown that the regio- and chemoselective depro-
tection of peracetylated compounds by DIBAL-H could be
achieved with a catalytic amount of Cp2ZrCl2 on a broad scope
of polyfunctional substrates, we next investigated the
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alone (entry 4) or after premixing with DIBAL-H (entry 5),
this zirconium complex gave poor conversion and regiose-
lectivity. However, Cp2ZrH2 in mixture with iBu2AlCl resulted
in 66% conversion of 3, together with the formation of 4 with a
very good site-selectivity (entry 6). Clusters 15a and 16a with
only hydride bridging ligands were thus ruled out from being
involved in the deprotection of 3 by zirconium-catalyzed
hydroalumination of the primary acetate.
Table 3. Cp2ZrCl2-Mediated Site-Selective De-O-acetylation
of 1 in Toluene
To determine if the active cluster was 15b or 16b, with a
chlorine bridging ligand and a 1:1 or 1:2 zirconium/aluminum
stoichiometry, density-functional theory (DFT) calculations
were finally performed. The capacity of Zr/Al clusters to
reduce a model ester was studied using the Gaussian 09
software package. Following a recent report,20 geometry
optimizations were carried out with the B3LYP functional,
the LANL2DZ ECP basis set for Zr and Al, and the 6-31G(d)
basis set for the other elements. Energies were refined by
single-point calculations at the M06 level, using the def2-TZVP
basis set for Zr and Al and the 6-31G(d,p) basis set for the
other elements. Solvation correction for toluene was obtained
with the PCM method. The values presented are ΔG298 (kcal/
mol). Of the many combinations attempted to transfer a
hydride from Zr or Al to the carbonyl functionality, only two
could be modeled.[18] The first one consists of using the 1:1
Zr/Al cluster 15b composed of Cp2ZrHCl and iBu2AlH
(Scheme 3). After the cleavage of the Zr−H−Al bridge, the
formation of I by complexation of the substrate appears to be
slightly endergonic by 0.5 kcal/mol. This activation of carbonyl
by the zirconium fragment is then followed by Al to C hydride
transfer through a six-membered transition state (TSI−II) in
which the Cl atom binds Zr and Al. This step requires only 3.5
kcal/mol of free energy of activation and is strongly exergonic
by 43.0 kcal/mol. It yields ketal II with oxygen engaged in a
four-membered ring with the Zr, Al, and Cl atoms. The low
barrier of the hydride transfer validates the capability of a 1:1
cluster to promote the reduction.
c
c
Cp2ZrCl2
(equiv)
DIBAL-H
(equiv)
conversion
(%)
selectivity
(%)
entry
a
1
3.5
3.5
3.5
3.5
3.5
1
1
1
1.5
3.0
3.0
3.0
3.0
3.0
2.0
3.0
4.0
6.0
17
44
56
83
45
32
47
47
54:46
85:15
97:3
98:2
96:4
87:13
83:17
95:5
b
2
bd
3
be
4
bf
5
b
6
b
7
b
8
b
g
9
94
90:10
a
b
Addition of DIBAL-H to a mixture of 3 and Cp2ZrCl2. Addition of
3 after premixing of DIBAL-H and Cp2ZrCl2 for 10 min. Determined
on the crude product by H NMR. THF (50 equiv) as an additive.
THF (10 equiv) as an additive. THF (1.5 equiv) as an additive.
c
d
1
e
f
g
73% isolated yield.
zirconocene dichloride and 6 equiv of DIBAL-H gave rise to
almost full conversion, and the primary alcohol 4 could be
obtained in 73% isolated yield after purification by silica gel
flash chromatography (entry 9).
Having shown that site-selective de-O-acetylation of 3 could
be achieved in toluene, we next investigated the nature of the
bridging ligand to discriminate clusters 15a and 16a (X = H)
from 15b and 16b (X = Cl). Based on previous works by
Dzhemilev,19 Cp2ZrHCl or Cp2ZrH2 was mixed with either
DIBAL or iBu2AlCl to obtain 1:1 and 1:2 clusters with a
chlorine bridging ligand on one side or with exclusively hydride
bridging ligands on the other side. With Cp2ZrHCl alone, the
starting material was fully recovered (Table 4, entry 1), thus
confirming that Schwartz’s reagent was not the active species.
Addition of DIBAL-H or iBu2AlCl to Cp2ZrHCl resulted in
random deprotection of 3 (entries 2 and 3).
Nevertheless, the 1:2 Zr/Al cluster 16b was also studied
(Scheme 4). In this case, the formation of III by complexation
of the substrate to the open cluster is endergonic by 10.5 kcal/
mol. Reaching the eight-membered reduction transition state
TSIII−IV requires 7.5 kcal/mol. The transformation is also less
exergonic (−22.1 kcal/mol). Thus, the 1:1 cluster is suggested
to be the most efficient species.
Cp2ZrH2, which is more soluble than Schwartz’s reagent in
toluene, was then considered as the zirconium source. Used
Having identified the reductive species, we undertook
additional DFT calculations to identify a chemical pathway,
allowing the product release and regeneration of the Zr/Al
cluster 15b from intermediate II. Based on previous work on
the formation of Zr/Al clusters from Cp2ZrCl2 and DIBAL-
H,17 we identified two possible chemical pathways giving back
15b from II (Scheme 5). In the first one, the release of the
product from II, in the form of acetal V, would give Schwartz’s
reagent 17. In a second step, cluster 15b would be regenerated
by the complexation of DIBAL-H (eq 1). The second possible
pathway would first involve complexation of DIBAL-H to the
bridging chlorine atom of II to give IV. This intermediate
would then spontaneously isomerize into VI, before the release
of V and regeneration of 15b (eq 2). Calculation of the free
energies revealed that the association of DIBAL-H with 17
(ΔG298 = −45.7 kcal/mol) or II (ΔG298 = −26.9 kcal/mol) is
highly exergonic, whereas decomplexation of acetal V from II
(ΔG298 = +39.0 kcal/mol) or VI (ΔG298 = +30.7 kcal/mol) is
strongly endergonic. Because of the large energy cost of both
dissociative steps (from II to 17 in eq 1 and from VI to 15b in
Table 4. Identification of the Bridging Ligand in Zr/Al
Clusters
a
b
b
entry
X = (equiv) Y = (equiv) conversion (%) selectivity (%)
1
2
3
4
5
6
Cl (3.5)
Cl (3.5)
Cl (3.5)
H (3.5)
H (1)
0
96
35
0
29
66
H (3)
Cl (3)
56:44
49:51
H (1)
Cl (1)
69:31
88:12
H (1)
a
Addition of 3 after premixing of DIBAL-Y and Cp2ZrHX for 10 min.
b
1
Determined on the crude product by H NMR.
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Scheme 3. Computed Hydride Transfer with a 1:1 Zr/Al Cluster (kcal/mol)
Scheme 4. Computed Hydride Transfer with a 1:2 Zr/Al Cluster (kcal/mol)
eq 2), these two pathways were ruled out. On the other hand, a
release of V from VI, concomitant with the complexation of
the substrate (eq 3), was found to be a slightly endergonic
process (ΔG298 = +6.0 kcal/mol). This third chemical pathway
giving I from VI was thus chosen to close the catalytic cycle
depicted in Scheme 6.
From the complex equilibrium between the Zr/Al clusters
depicted in Scheme S1, the mixed metal hydride 15b has been
identified as the reductive species. Dissociation of the Zr−H−
Al bridge would first give the Lewis acidic cluster VII.
Complexation of the carbonyl oxygen atom of the substrate
would then give the bipyramidal intermediate I. A 1,6-hydride
transfer from aluminum to the carbonyl carbon atom would
deliver the μ-oxo-μ-chloro Zr/Al cluster II. After the formation
of IV by complexation of DIBAL-H to chlorine and
isomerization into VI, acetal V would be released, concom-
itantly with the association of the substrate, to regenerate I.
The formation of the product would occur during the work-up
by acidic hydrolysis of V.
CONCLUSIONS
■
We report herein that a catalytic amount of Cp2ZrCl2
promotes a fast hydroalumination of CO bonds in THF.
Following this finding, the site-selective de-O-acetylation of
functional peracetylated substrates, previously reported with a
stoichiometric amount of zirconium complex, was developed
under these new catalytic reaction conditions. A mixed metal
hydride with a 1:1 Zr/Al stoichiometry was also identified as
the reductive species based on mechanistic studies performed
in toluene and on DFT calculations. Finally, a putative catalytic
cycle was proposed for this unprecedented zirconium-catalyzed
hydroalumination of CO bonds.
EXPERIMENTAL SECTION
■
General Information and Method. All reactions were
conducted under an argon atmosphere in distilled THF (sodium/
benzophenone). All reagents were used as received unless otherwise
indicated. Reactions were monitored by thin-layer chromatography
with a silica gel 60 F254 precoated aluminum plate (0.25 mm).
Visualization was performed under UV light and phosphomolybdic
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Scheme 5. Computed Free Energies (kcal/mol) of Possible Intermediates for the Closure of the Catalytic Cycle
acid oxidation. 1H, NMR spectra were recorded at 300 MHz, and 13
C
(75 MHz, CDCl3): δ (ppm) 179.0 (CO), 139.1 (Cquat arom), 128.9
(2 × CHarom), 128.3 (2 × CHarom), 127.5 (CHarom), 65.0 (C2), 63.9
(C3), 47.6 (C1), 40.0 (C(CH3)3), 27.3 (C(CH3)3); FT-IR (film):
2968, 1726, 1480, 1284, 1153, 1032, 758, 699 cm−1 HRMS (ESI+):
m/z calculated for C14H21O3 [M + H]+: 237.1491.1451; found:
237.1501.
NMR spectra at 75 MHz. Abbreviations used for peak multiplicities
are s: singlet, d: doublet, t: triplet, q: quadruplet, and m: multiplet.
Coupling constants J are in Hz and chemical shifts are given in ppm
and calibrated with CDCl3 (residual solvent signals). Carbon
multiplicities were assigned by distortionless enhancement by
1
polarization transfer (DEPT) experiments. The H and 13C signals
Compound 4. To a solution of the corresponding peracetylated
substrate (185 mg, 0.51 mmol) and Cp2ZrCl2 (45 mg, 0.153 mmol)
in dry THF (2.5 mL), DIBAL-H (1 M in THF, 2.5 mL, 2.5 mmol, 1.8
mmol/h) was added dropwise via a syringe pump at −20 °C. After the
end of the addition, the reaction mixture was diluted with DCM (5
mL), quenched with 1 M citric acid solution (4 mL), and stirred for
few seconds until a clear biphasic mixture is obtained. The aqueous
phase was extracted with DCM (3 × 5 mL). The organic phases were
combined, washed with 1 M aq HCl solution (5 mL), dried over
anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by chromatography over silica gel (cyclohexane/
were assigned by COSY and HSQC experiments. Optical rotations
were determined with a water-jacketed 10 cm cell. Specific rotations
are reported in 10−1 deg cm2/g and concentrations in g per 100 mL.
Melting points are uncorrected. Compounds 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, and 14 have been fully characterized in a preliminary
communication.13
Zirconium-Catalyzed Site-Selective De-O-acetylation in
THF. Compound 2. To a solution of 1 (70 mg, 0.25 mmol) and
Cp2ZrCl2 (15 mg, 0.05 mmol) in dry THF (2 mL), DIBAL-H (1 M in
THF, 0.75 mL, 0.75 mmol, 1.8 mmol/h) was added dropwise via a
syringe pump at −20 °C. After the end of the addition, the reaction
mixture was diluted with dichloromethane (DCM) (5 mL), quenched
with 1 M citric acid solution (4 mL), and stirred for few seconds until
a clear biphasic mixture is obtained. The aqueous phase was extracted
with DCM (3 × 5 mL). The organic phases were combined, washed
with 1 M aq HCl solution (5 mL), dried over anhydrous Na2SO4, and
concentrated under vacuum. The crude product was purified by
chromatography over silica gel (cyclohexane/EtOAc 4:1) to give 2
(31 mg, 53%) as a colorless liquid. Rf: 0.24 (silica, cyclohexane/
1
EtOAc 1:2) to give 4 (139 mg, 85%) as a white solid. H NMR
(CDCl3, 300 MHz): δ (ppm) 5.50 (t, J = 9.8 Hz, 1H, H3), 4.98 (t, J =
9.8 Hz, 1H, H4), 4.93 (d, J = 3.6 Hz, 1H, H1), 4.83 (dd, J = 3.6, 9.8
Hz, 1H, H2), 3.56 (m, 1H, H6), 3.75 (ddd, J = 2.2, 3.6, 9.8 Hz, 1H,
H5), 3.68 (ddd, J = 2.2, 6.4, 12.6 Hz, 1H, H6′), 3.38 (s, 3H, OCH3),
2.31 (t, J = 6.4 Hz, 1H, OH), 2.04 (s, 3H, C(O)CH3), 2.02 (s, 3H,
C(O)CH3), 1.98 (s, 3H, C(O)CH3); 13C{1H} NMR (CDCl3, 75
MHz): δ (ppm) 170.6 (C(O)CH3), 170.2 (C(O)CH3), 170.0
(C(O)CH3), 96.8 (C1), 71.0 (C2), 69.8 (C3), 69.3 (C5), 68.9 (C4),
61.0 (C6), 55.4 (OCH3), 20.74 (C(O)CH3), 20.72 (C(O)CH3),
20.68 (C(O)CH3); [α]D20 = +100 (CHCl3, c = 0.1); mp +104−106
°C.
1
EtOAc 4:1); H NMR (300 MHz, CDCl3): δ (ppm) 7.38−7.22 (m,
5Harom), 4.40 (dd, J = 11.2, 6.4 Hz, 1H, H2), 4.33 (dd, J = 11.2, 6.4
Hz, 1H, H2′), 3.83 (d, J = 6.4 Hz, 2H, H3), 3.18 (quint, J = 6.4 Hz,
1H, H1), 1.94 (s, 1H, OH), 1.16 (s, 9H, C(CH3)3); 13C{1H} NMR
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1
EtOAc 1:2) to give 6 (130 mg, 80%) as a white solid. H NMR
(CDCl3, 300 MHz): δ (ppm) 5.37 (dd, J = 3.5, 10.0 Hz, 1H, H3),
5.23 (dd, J = 1.6, 3.5 Hz, 1H, H2), 5.22 (t, J = 10.0 Hz, 1H, H4), 4.70
(d, J = 1.6 Hz, 1H, H1), 3.74 (ddd, J = 2.3, 4.4, 10.0 Hz, 1H, H5), 3.70
(ddd, J = 2.3, 8.5, 12.4 Hz, 1H, H6), 3.61 (ddd, J = 4.4, 5.5, 12.4 Hz,
1H, H6), 3.38 (s, 3H, OCH3), 2.36 (dd, J = 5.5, 8.5 Hz, 1H, OH),
2.13 (s, 3H, C(O)CH3), 2.06 (s, 3H, C(O)CH3), 1.98 (s, 3H,
C(O)CH3); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 170.9
(C(O)CH3), 170.1 (C(O)CH3), 169.9 (C(O)CH3), 98.7 (C1), 70.5
(C5), 69.6 (C2), 68.8 (C3), 66.5 (C4), 61.3 (C6), 55.3 (OCH3), 20.9
Scheme 6. Putative Catalytic Cycle for the Zirconium-
Catalyzed Hydroalumination of CO Bonds
20
(C(O)CH3), 20.8 (C(O)CH3), 20.7 (C(O)CH3); [α]D = +44
(CHCl3, c = 0.13); mp +67−69 °C.
Compound 7. To a solution of the corresponding peracetylated
substrate (165 mg, 0.569 mmol) and Cp2ZrCl2 (67 mg, 0.228 mmol)
in dry THF (3 mL), DIBAL-H (1 M in THF, 2.9 mL, 2.9 mmol, 1.5
mL/h) was added dropwise via a syringe pump at −20 °C. After the
end of the addition, the reaction mixture was diluted with DCM (6
mL), quenched with 1 M citric acid solution (5 mL), and stirred for
few seconds until a clear biphasic mixture is obtained. The aqueous
phase was extracted with DCM (3 × 6 mL). The organic phases were
combined, washed with 1 M aq HCl solution (5 mL), dried over
anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by chromatography over silica gel (cyclohexane/
1
EtOAc 1:2) to give 7 (84 mg, 59%) as a colorless oil. H NMR
(CDCl3, 300 MHz): δ (ppm) 5.35 (t, J = 5.7 Hz, 1H, H3), 5.22 (d, J =
5.7 Hz, 1H, H2), 4.90 (br s, 1H, H1), 4.21 (td, J = 4.1, 5.7 Hz, 1H,
H4), 3.79 (td, J = 4.1, 11.3 Hz, 1H, H5), 3.64 (ddd, J = 4.1, 8.2, 11.3
Hz, 1H, H5), 3.41 (s, 3H, OCH3), 2.21 (dd, J = 4.1, 8.2 Hz, 1H, OH),
2.10 (s, 3H, C(O)CH3), 2.04 (s, 3H, C(O)CH3); 13C{1H} NMR
(CDCl3, 75 MHz): δ (ppm) 170.1 (C(O)CH3), 169.7 (C(O)CH3),
106.5 (C1), 82.4 (C3), 75.2 (C2), 71.2 (C4), 62.9 (C5), 55.8 (OCH3),
20
20.6 (2 × C(O)CH3); [α]D = −2 (CHCl3, c = 1.4).
Compound 8. To a solution of the corresponding peracetylated
substrate (231 mg, 0.525 mmol) and Cp2ZrCl2 (61 mg, 0.21 mmol)
in dry THF (1 mL) and dry DCM (2 mL), DIBAL-H (1 M in THF,
1.7 mL, 1.7 mmol, 1.5 mL/h) was added dropwise via a syringe pump
at −40 °C. After the end of the addition, the reaction mixture was
diluted with DCM (5 mL), quenched with 1 M citric acid solution (4
mL), and stirred for few seconds until a clear biphasic mixture is
obtained. The aqueous phase was extracted with DCM (3 × 5 mL).
The organic phases were combined, washed with 1 M aq HCl solution
(5 mL), dried over anhydrous Na2SO4, and concentrated under
vacuum. The crude product was purified by chromatography over
silica gel (cyclohexane/EtOAc 2:1) to give 8 (142 mg, 68%) as a
Compound 5. To a solution of the corresponding peracetylated
substrate (1.464 g, 4.044 mmol) and Cp2ZrCl2 (355 mg, 1.213 mmol)
in dry THF (20 mL), DIBAL-H (1 M in THF, 16 mL, 16 mmol, 12
mL/h) was added dropwise via a syringe pump at −20 °C. After the
end of the addition, the reaction mixture was diluted with DCM (50
mL), quenched with 1 M citric acid solution (30 mL), and stirred for
few seconds until a clear biphasic mixture is obtained. The aqueous
phase was extracted with DCM (3 × 30 mL). The organic phases
were combined, washed with 1 M aq HCl solution (30 mL), dried
over anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by chromatography over silica gel (cyclohexane/
1
colorless oil. H NMR (CDCl3, 300 MHz): δ (ppm) 7.45 (m, 2H,
HAr), 7.28 (m, 3H, HAr), 5.49 (m, 2H, H1, H2), 5.35 (dd, J = 3.0, 10.1
Hz, 1H, H3), 5.29 (t, J = 10.1 Hz, 1H, H4), 4.26 (td, J = 3.2, 10.1 Hz,
1H, H5), 3.64 (m, 2H, H6, H6), 2.26 (t, J = 6.4 Hz, 1H, OH), 2.12 (s,
3H, C(O)CH3), 2.08 (s, 3H, C(O)CH3), 2.00 (s, 3H, C(O)CH3);
13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 170.8 (C(O)CH3), 170.0
(C(O)CH3), 169.8 (C(O)CH3), 132.7 (CQuat Arom.), 132.1 (2 ×
CHArom.), 129.3 (2 × CHArom.), 128.1 (CHArom.), 85.8 (C1), 71.8 (C5),
71.0 (C2), 69.2 (C3), 66.5 (C4), 61.2 (C6), 20.9 (C(O)CH3), 20.8
1
EtOAc 1:2) to give 5 (1.062 g, 82%) as a white solid. H NMR
(CDCl3, 300 MHz): δ (ppm) 5.23 (t, J = 9.6 Hz, 1H, H3), 5.01 (t, J =
9.6 Hz, 1H, H4), 4.94 (dd, J = 8.1, 9.6 Hz, 1H, H2), 4.43 (d, J = 8.1
Hz, 1H, H1), 3.74 (ddd, J = 2.2, 8.4, 12.5 Hz, 1H, H6), 3.59 (td, J =
5.2, 12.5 Hz, 1H, H6), 3.47−3.51 (m, 1H, H5), 3.49 (s, 3H, OCH3),
2.21 (dd, J = 5.2, 8.4 Hz, 1H, OH), 2.03 (s, 6H, 2 × C(O)CH3), 1.99
(s, 3H, C(O)CH3); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm)
170.3 (C(O)CH3), 170.2 (C(O)CH3), 169.5 (C(O)CH3), 101.6
(C1), 74.0 (C5), 72.7 (C3), 71.4 (C2), 68.7 (C4), 61.3 (C6), 57.1
(OCH3), 20.73 (C(O)CH3), 20.68 (C(O)CH3), 20.66 (C(O)CH3);
20
(C(O)CH3), 20.7 (C(O)CH3); [α]D = +74 (CHCl3, c = 0.5).
Compound 9. To a solution of the corresponding peracetylated
substrate (198 mg, 0.508 mmol) and Cp2ZrCl2 (59 mg, 0.203 mmol)
in dry THF (2.5 mL), DIBAL-H (1 M in THF, 2.0 mL, 2.0 mmol, 1.5
mL/h) was added dropwise via a syringe pump at −40 °C. After the
end of the addition, the reaction mixture was diluted with DCM (5
mL), quenched with 1 M citric acid solution (4 mL), and stirred for
few seconds until a clear biphasic mixture is obtained. The aqueous
phase was extracted with DCM (3 × 5 mL). The organic phases were
combined, washed with 1 M aq HCl solution (5 mL), dried over
anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by chromatography over silica gel (cyclohexane/
EtOAc 1:2) to give 9 (153 mg, 87%). 1H NMR (CDCl3, 300 MHz): δ
(ppm) 6.20 (d, J = 3.8 Hz, 0.95H, H1A), 5.61 (d, J = 7.6 Hz, 0.05H,
H1B), 5.35 (t, J = 10.4 Hz, 0.95H, H3A), 5.15 (d, J = 9.3 Hz, 0.05H,
H3B), 5.02 (t, J = 10.4 Hz, 0.95H, H4A), 5.01 (m, 0.10H, H2B, H4B),
4.97 (dd, J = 3.8, 10.4 Hz, 0.95H, H2A), 4.19 (m, 1H, 0.05H, H6B),
20
[α]D = −48 (CHCl3, c = 0.1); mp +136−137 °C.
Compound 6. To a solution of the corresponding peracetylated
substrate (179 mg, 0.495 mmol) and Cp2ZrCl2 (58 mg, 0.198 mmol)
in dry THF (2.5 mL), DIBAL-H (1 M in THF, 2.5 mL, 2.5 mmol, 1.5
mL/h) was added dropwise via a syringe pump at −20 °C. After the
end of the addition, the reaction mixture was diluted with DCM (5
mL), quenched with 1 M citric acid solution (4 mL), and stirred for
few seconds until a clear biphasic mixture is obtained. The aqueous
phase was extracted with DCM (3 × 5 mL). The organic phases were
combined, washed with 1 M aq HCl solution (5 mL), dried over
anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by chromatography over silica gel (cyclohexane/
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4.16 (dd, J = 4.1, 12.8 Hz, 0.95H, H6A), 4.01 (ddd, J = 2.3, 4.1, 10.4
Hz, 0.95H, H5A), 3.98 (m, 0.05H, H6B), 3.97 (dd, J = 2.3, 12.8 Hz,
0.95H, H6A), 3.75 (ddd, J = 2.1, 4.4, 10.1 Hz, 0.05H, H5B), 2.06−1.91
(m, 13H, C(O)CH3, OH); 13C{1H} NMR (CDCl3, 75 MHz): δ
(ppm) 170.5 (C(O)CH3B), 170.1 (C(O)CH3A), 169.9 (C(O)CH3A),
169.5 (C(O)CH3A), 169.3 (C(O)CH3B), 169.1 (C(O)CH3A), 168.8
(C(O)CH3B), 168.6 (C(O)CH3B), 91.6 (C1B), 88.9 (C1A), 72.63
(C3B), 72.56 (C5B), 70.1 (C2B), 69.7 (C3A, C5A), 69.1 (C2A, C6B), 67.8
(C4A), 67.6 (C4B), 61.4 (C6B), 20.8−20.3 (C(O)CH3).
dried over anhydrous Na2SO4, and concentrated under vacuum. The
crude product was purified by chromatography over silica gel
(EtOAc/MeOH, 95:5) to give 12 (78 mg, 47%) as a colorless oil.
1H NMR (CDCl3, 300 MHz): δ (ppm) 5.77 (d, J = 8.9 Hz, 1H, H1),
5.30 (dd, J = 10.6, 9.5 Hz, 1H, H3), 5.03 (t, J = 9.5 Hz, 1H, H4), 4.59
(d, J = 9.5 Hz, 1H, H2), 3.90 (m, 1H, H5), 3.75 (dd, J = 12.5, 3.5 Hz,
1H, H6), 3.65−3.47 (m, 6H, OCH3, H6, NH, OH), 2.05 (s, 3H,
CH3CO), 2.04 (s, 3H, CH3CO), 1.95 (s, 3H, CH3C(O)NH);
13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 171.1 (NHC(O)CH3),
170.5 (C(O)CH3), 170.2 (C(O)CH3), 101.7 (C1), 74.0 (C2), 72.3,
(C5) 68.9 (C4), 61.3 (C3), 56.8 (C6), 54.5 (OCH3), 23.3 (C(O)
CH3), 20.8 (C(O)CH3), 20.7 (C(O)CH3).
Compounds 10/10′. To a solution of the corresponding
peracetylated substrate (143 mg, 0.526 mmol) and Cp2ZrCl2 (46
mg, 0.158 mmol) in dry THF (2.5 mL), DIBAL-H (1 M in THF, 2.1
mL, 2.1 mmol, 1.5 mL/h) was added dropwise via a syringe pump at
−40 °C. After the end of the addition, the reaction mixture was
diluted with DCM (5 mL), quenched with 1 M citric acid solution (4
mL), and stirred for few seconds until a clear biphasic mixture is
obtained. The aqueous phase was extracted with DCM (3 × 5 mL).
The organic phases were combined, washed with 1 M aq HCl solution
(5 mL), dried over anhydrous Na2SO4, and concentrated under
vacuum. The crude product was purified by chromatography over
silica gel (cyclohexane/EtOAc 1:1) to give 10/10′ (83 mg, 69%) as
Compound 13. To a solution of the corresponding peracetylated
substrate (164 mg, 0.541 mmol) and Cp2ZrCl2 (48 mg, 0.162 mmol)
in dry THF (2.5 mL), DIBAL-H (1 M in THF, 1.6 mL, 1.6 mmol, 1.5
mL/h) was added dropwise via a syringe pump at −20 °C. After the
end of the addition, the reaction mixture was diluted with DCM (5
mL), quenched with 1 M citric acid solution (4 mL), and stirred for
few seconds until a clear biphasic mixture is obtained. The aqueous
phase was extracted with DCM (3 × 5 mL). The organic phases were
combined, washed with 1 M aq HCl solution (5 mL), dried over
anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by chromatography over silica gel (petroleum
1
an inseparable mixture. H NMR (CDCl3, 300 MHz): δ (ppm) 6.45
(dd, J = 1.3, 6.0 Hz, 0.92H, H1A), 6.37 (dd, J = 0.9, 6.1 Hz, 0.08H,
H1B), 5.41 (ddd, J = 1.3, 2.4, 6.2 Hz, 0.92H, H3A), 5.18 (dd, J = 6.2,
8.9 Hz, 0.92H, H4A), 4.95 (dd, J = 5.8, 8.8 Hz, 0.08H, H4B), 4.83 (dd,
J = 2.8, 6.1 Hz, 0.08H, H2B), 4.77 (dd, J = 2.4, 6.0 Hz, 0.92H, H2A),
4.38 (dd, J = 5.4, 12.2 Hz, 0.08H, H6B), 4.28 (ddd, J = 0.9, 2.8, 5.8 Hz,
0.08H, H3B), 4.21 (dd, J = 2.5, 12.2 Hz, 0.08H, H6B), 4.10 (ddd, J =
2.5, 5.4, 8.8 Hz, 0.08H, H5B), 3.99 (ddd, J = 3.0, 4.6, 8.9 Hz, 0.92H,
H5A), 3.76 (dd, J = 3.0, 12.8 Hz, 0.92H, H6A), 3.69 (dd, J = 4.6, 12.8
Hz, 0.92H, H6A), 2.59 (br s, 0.08H, OHB), 2.38 (br s, 0.92H, OHA),
2.11 (s, 0.24H, C(O)CH3B), 2.09 (s, 2.76H, C(O)CH3A), 2.07 (s,
0.24H, C(O)CH3B), 2.03 (s, 2.76H, C(O)CH3A); 13C{1H} NMR
(CDCl3, 75 MHz): δ (ppm) 171.0 (2 × C(O)CH3B), 170.6 (2 ×
C(O)CH3A), 145.8 (C1A), 144.0 (C1B), 102.9 (C2B), 99.1 (C2A), 76.6
(C5A), 74.0 (C5B), 71.6 (C4B), 68.4 (C3A), 67.8 (C4A), 67.1 (C3B),
61.9 (C6B), 60.6 (C6B), 21.1 (C(O)CH3A), 21.0 (C(O)CH3A), 20.9
(C(O)CH3A), 20.8 (C(O)CH3B).
Compound 11. To a solution of the corresponding peracetylated
substrate (176 mg, 0.510 mmol) and Cp2ZrCl2 (45 mg, 0.153 mmol)
in dry THF (2.5 mL), DIBAL-H (1 M in THF, 1.75 mL, 1.75 mmol,
1.5 mL/h) was added dropwise via a syringe pump at −20 °C. After
the end of the addition, the reaction mixture was diluted with DCM
(5 mL), quenched with 1 M citric acid solution (4 mL), and stirred
for few seconds until a clear biphasic mixture is obtained. The
aqueous phase was extracted with DCM (3 × 5 mL). The organic
phases were combined, washed with 1 M aq HCl solution (5 mL),
dried over anhydrous Na2SO4, and concentrated under vacuum. The
crude product was purified by chromatography over silica gel
(cyclohexane/EtOAc 1:1) to give 11 (122 mg, 79%). 1H NMR
(CDCl3, 400 MHz): δ (ppm) 5.46 (dd, J = 9.4, 8.9 Hz, 0.66H, H3A),
4.85−4.78 (m, 1H, H3B, H1A), 4.49−4.43 (m, 1H, H1B, H4A), 4.38−
4.25 (m, 1.30H, H6A, H5B, H4B), 3.83 (ddd, J = 9.6, 4.7, 2.0 Hz, 0.66H,
H5A), 3.58 (s, 1H, OMeB), 3.56−3.45 (m, 1H,, H2A, H6B), 3.44 (s, 2H,
OMeA), 3.43−3.28 (m, 1.3H, H6B, H2B, H6A), 3.09 (d, J =3.4 Hz,
0.66H, OHA), 3.00 (d, J =5.3 Hz, 0.34H, OHB), 2.08−1.93 (m, 6H,
C(O)CH3); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 170.7
(C(O)CH3), 170.4 (C(O)CH3), 170.3 (C(O)CH3), 170.0 (C(O)
CH3), 102.8 (C1), 98.8 (C1), 73.9 (C2), 72.3 (C5), 70.1 (C2), 69.5
(C5), 68.9 (C4), 68.6 (C4), 63.8 (C3), 61.1 (C3), 61.0 (C6), 60.8 (C6),
57.4 (OCH3), 55.5 (OCH3), 20.7 + 20.6 + 20.6 (4 × C(O)CH3).
Compound 12. To a solution of the corresponding peracetylated
substrate (187 mg, 0.518 mmol) and Cp2ZrCl2 (45 mg, 0.155 mmol)
in dry THF (2.5 mL), DIBAL-H (1 M in THF, 1.55 mL, 1.55 mmol,
1.5 mL/h) was added dropwise via a syringe pump at −20 °C. After
the end of the addition, the reaction mixture was diluted with DCM
(5 mL), quenched with 1 M citric acid solution (4 mL), and stirred
for few seconds until a clear biphasic mixture is obtained. The
aqueous phase was extracted with DCM (3 × 5 mL). The organic
phases were combined, washed with 1 M aq HCl solution (5 mL),
1
ether/EtOAc 4:1) to give 13 (124 mg, 88%) as a colorless oil. H
NMR (CDCl3, 300 MHz): δ (ppm) 5.47 (bs, 1H), 4.24 (bs, 1H),
3.89 (dd, J = 4.0 Hz, J = 6.1 Hz, 2H), 2.73 (d, J = 4.8 Hz, 1H), 1.48
(s, 9H), 1.45 (s, 9H); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm)
169.8, 155.8, 82.5, 80.1, 63.9, 56.3, 28.3, 27.9; [α]D20 = −23 (CHCl3,
c = 0.5).
Compound 14. To a solution of the corresponding peracetylated
substrate (198 mg, 0.376 mmol) and Cp2ZrCl2 (33 mg, 0.112 mmol)
in dry THF (2 mL), DIBAL-H (1 M in THF, 1.1 mL, 1.1 mmol, 1.5
mL/h) was added dropwise via a syringe pump at −20 °C. After the
end of the addition, the reaction mixture was diluted with DCM (5
mL), quenched with 1 M citric acid solution (4 mL), and stirred for
few seconds until a clear biphasic mixture is obtained. The aqueous
phase was extracted with DCM (3 × 5 mL). The organic phases were
combined, washed with 1 M aq HCl solution (5 mL), dried over
anhydrous Na2SO4, and concentrated under vacuum. The crude
product was purified by chromatography over silica gel (petroleum
1
ether/EtOAc 95:5) to give 14 (130 mg, 71%) as a colorless oil. H
NMR (CDCl3, 300 MHz): δ (ppm) 4.60 (s, 1H), 4.51 (s, 1H), 4.40
(dd, J = 9.6, 6.6 Hz, 1H), 3.72 (d, J = 10.9 Hz, 1H), 3.25 (d, J = 10.9
Hz, 1H), 2.39.2.25 (m, 1H), 1.97 (s, 3H), 1.93−1.72 (m, 3H), 1.65−
0.86 (m, 32H), 0.80−0.73 (m, 9H); 13C{1H} NMR (CDCl3, 75
MHz): δ (ppm) 171.2, 150.6, 109.9, 81.1, 60.7, 55.5, 50.5, 48.9, 47.95,
47.93, 42.9, 41.1, 38.5, 37.9, 37.4, 37.2, 34.3, 34.1, 29.9, 29.3, 28.1,
27.2, 25.3, 23.8, 21.5, 21.0, 19.2, 18.3, 16.6, 16.3, 16.1, 14.9.
Site-Selective De-O-acetylation of 3 in Toluene. A mixture of
Cp2ZrCl2 (163 mg, 0.56 mmol) and of a 1.5 M solution of DIBAL-H
in toluene (1.5 mL, 2.24 mmol) in dry toluene (2 mL) was stirred at
−20 °C for 10 min. After addition of a solution of 3 (185 mg, 0.51
mmol) in dry toluene (1 mL), the reaction mixture was stirred for 30
min at this temperature. CH2Cl2 (5 mL) and a 1 M citric acid solution
(4 mL) were then added. After vigorous stirring for a few minutes, a
clear biphasic mixture was obtained. The aqueous phase was extracted
with CH2Cl2 (3 × 5 mL). The organic phases were combined, washed
with 1 M aq HCl solution (5 mL), dried over anhydrous Na2SO4, and
concentrated under vacuum. The crude product was purified by
chromatography over silica gel (cyclohexane/EtOAc 1:2) to give 4
(87 mg, 73%) as a white solid.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00060.
1
Detailed DFT calculations and H and 13C{1H} NMR
spectra of compounds 2 and 4−14 (PDF)
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(7) (a) Laycock, D. E.; Alper, H. Hydrozirconation of thioketones. A
simple, convenient entry into a variety of organosulfur compounds.
An interesting ether synthesis. J. Org. Chem. 1981, 46, 289−293.
(b) Gambarotta, S.; Strologo, S.; Floriani, C.; Chiesi-Villa, A.;
Guastini, C. Stepwise reduction of carbon dioxide to formaldehyde
and methanol: reactions of CO2 and CO2-like molecules with
hydridochlorobis(cyclopentadienyl)zirconium(IV). J. Am. Chem. Soc.
1985, 107, 6278−6282. (c) Cénac, N.; Zablocka, M.; Igau, A.;
Majoral, J.-P.; Showronska, A. Reduction of secondary carboxamides
to imines. J. Org. Chem. 1996, 61, 796−798. (d) Pinheiro, D. L. J.;
Avila, E. P.; Batista, G. M. F.; Amarante, G. W. Chemoselective
reduction of azlactones using Schwartz’s reagent. J. Org. Chem. 2017,
82, 5981−5985.
AUTHOR INFORMATION
Corresponding Author
Thomas Lecourt − Normandie Univ, INSA Rouen,
UNIROUEN, CNRS, COBRA UMR 6014, 76000 Rouen,
France; orcid.org/0000-0002-2532-3012; Phone: (+33)
2 35 52 24 31; Email: thomas.lecourt@insa-rouen.fr
■
Authors
Thibaut Courant − Normandie Univ, INSA Rouen,
UNIROUEN, CNRS, COBRA UMR 6014, 76000 Rouen,
France
Marine Gavel − Normandie Univ, INSA Rouen,
UNIROUEN, CNRS, COBRA UMR 6014, 76000 Rouen,
France
Romain M. Q. Renard − Normandie Univ, INSA Rouen,
UNIROUEN, CNRS, COBRA UMR 6014, 76000 Rouen,
France
Vincent Gandon − Institut de Chimie Moléculaire et des
Matériaux d’Orsay (ICMMO), CNRS UMR 8182,
Université Paris-Saclay, 91405 Orsay, France; Laboratoire de
Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole
Polytechnique, Institut Polytechnique de Paris, 91128
Palaiseau, France; orcid.org/0000-0003-1108-9410
Antoine Y. P. Joosten − Normandie Univ, INSA Rouen,
UNIROUEN, CNRS, COBRA UMR 6014, 76000 Rouen,
France
(8) (a) Schedler, D. J. A.; Li, J.; Ganem, B. A new method for the in
situ generation of Cp2Zr(H)Cl. Tetrahedron Lett. 1990, 31, 7257−
7260. (b) Zhao, Y.; Snieckus, V. A Practical in situ Generation of the
Schwartz reagent. Reduction of tertiary amides to aldehydes and
hydrozirconation. Org. Lett. 2014, 16, 390−393.
(9) (a) White, J. P.; White, J. M.; Georg, G. I. A novel and
expeditious reduction of tertiary amides to aldehydes using Cp2Zr-
(H)Cl. J. Am. Chem. Soc. 2000, 122, 11995−11996. (b) Spletstoser, J.
T.; White, J. M.; Tunoori, A. R.; Georg, G. I. Mild and selective
hydrozirconation of amides to aldehydes using Cp2Zr(H)Cl: scope
and mechanistic insight. J. Am. Chem. Soc. 2007, 129, 3408−3419.
(10) For a review, see Wieclaw, M. M.; Stecko, S. Hydrozirconation
of C=X with Schwartzʼs reagent. Eur. J. Org. Chem. 2018, 6601−6623.
(11) For a recent application in the field of glycochemistry, see
Foucart, Q.; Shimadate, Y.; Marrot, J.; Kato, A.; Désiré, J.; Blériot, Y.
Synthesis and glycosidase inhibition of conformationally locked DNJ
and DMJ derivatives exploiting a 2-oxo-C-allyl iminosugar. Org.
Biomol. Chem. 2019, 17, 7204−7241.
(12) For an attempt of amide reduction by aluminium hydrides and
a catalytic amount of zirconocene dichloride, seeW., Schulz Ph.D.
Thesis, Queen’s University: Kingston, Canada, 2010.
(13) Gavel, M.; Courant, T.; Joosten, A. Y. P.; Lecourt, T. Regio-
and chemoselective deprotection of primary acetates by zirconium
hydrides. Org. Lett. 2019, 21, 1948−1962.
(14) Huang, Z.; Negishi, E.-I. A convenient and genuine equivalent
to HZrCp2Cl generated in situ from ZrCp2Cl2-DIBAL-H. Org. Lett.
2006, 8, 3675−3678.
(15) Weliange, N. M.; McGuiness, D. S.; Gardiner, M. G.; Patel, J.
Insertion, elimination and isomerisation of olefins at alkylaluminium
hydride: an experimental and theoretical study. Dalton Trans. 2015,
44, 15286−15296.
(16) Weliange, N. M.; McGuiness, D. S.; Gardiner, M. G.; Patel, J.
Insertion and isomerisation of internal olefins at alkylaluminium
hydride: catalysis with zirconocene dichloride. Dalton Trans. 2015, 44,
20098−20107.
(17) Parfenova, L. V.; Khalikov, L. M.; Dzhemilev, U. Mechanisms
of reactions of organoaluminium compounds with alkenes and alkynes
catalyzed by Zr complexes. Russ. Chem. Rev. 2012, 81, 524−548.
(18) See the Supporting Information for more details.
(19) Parfenova, L. V.; Pechatkina, S. V.; Khalikov, L. M.; Dzhemilev,
U. Mechanisms of Cp2ZrCl2-catalyzed olefin hydroalumination by
alkylalanes. Russ. Chem. Bull. 2005, 54, 316−327.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00060
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors would like to thank LABEX SynOrg (ANR-11-
LABX-0029) and ANR (JCJC-2013-QuatGlcNAc) for their
financial support.
REFERENCES
■
(1) Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.;
Wiley-VCH: Weinheim, 2002; pp 1−498.
(2) Masarwa, A.; Didier, D.; Zabrodski, T.; Schinkel, M.;
Ackermann, L.; Marek, I. Merging allylic carbon−hydrogen and
selective carbon−carbon bond activation. Nature 2014, 505, 199−
203.
(3) Castelló-Micó, A.; Herbert, S. A.; Leon, T.; Bein, T.; Knochel, P.
Functionalizations of mixtures of regioisomeric aryllithium com-
pounds by selective trapping with dichlorozirconocene. Angew. Chem.,
Int. Ed. 2016, 55, 401−404.
(4) Haehnel, M.; Yim, J. C.-H.; Schafer, L. L.; Rosenthal, U. Facile
access to tunable Schwartz’s reagents: oxidative addition products
from the reaction of amide N-H bonds with reduced zirconocene
complexes. Angew. Chem., Int. Ed. 2013, 52, 11415−11419.
(5) (a) Jian, Z.; Kehr, G.; Daniliuc, C. G.; Wibbeling, B.; Wiegand,
T.; Siedow, M.; Eckert, H.; Bursch, M.; Grimme, S.; Erker, G. CO-
reduction chemistry: reaction of a CO-derived formylhydridoborate
with carbon monoxide, with carbon dioxide, and with dihydrogen. J.
Am. Chem. Soc. 2017, 139, 6474−6483. (b) Podiyanachari, S. K.;
(20) Theurkauff, G.; Bondon, A.; Dorcet, V.; Carpentier, J.-F.;
Kirillov, E. Heterobi- and -trimetallic ion pairs of zirconocene-based
isoselective olefin polymerization catalysts with AlMe3. Angew. Chem.,
Int. Ed. 2015, 54, 6343−6346.
Fröhlich, R.; Daniliuc, C. G.; Petersen, J. L.; Muck-Lichtenfeld, C.;
̈
Kehr, G.; Erker, G. Hydrogen activation by an intramolecular boron
Lewis acid/zirconocene pair. Angew. Chem., Int. Ed. 2012, 51, 8830−
8833.
(6) Yu, S.; Xiong, M.; Xie, X.; Liu, Y. Insertion of nitriles into
zirconocene 1-aza-1,3-diene complexes: chemoselective synthesis of
N−H and N-substituted pyrroles. Angew. Chem., Int. Ed. 2014, 53,
11596−11599.
9288
https://doi.org/10.1021/acs.joc.1c00060
J. Org. Chem. 2021, 86, 9280−9288