Cobalt-Catalyzed Stereoselective Synthesis of 2,5- trans-THF Nitrile Derivatives as a Platform for Diversification: Development and Mechanistic Studies

Article abstract of DOI:10.1021/acs.joc.8b00575

A straightforward protocol integrating a sustainable approach for the synthesis of new 2,5-trans-THF nitrile derivatives enabling an easy diversification of its side chain scaffolds is described. The reaction tolerated different aromatic and alkyl substit

Full text of DOI:10.1021/acs.joc.8b00575

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Article
Cobalt-catalysed Stereoselective Synthesis of 2,5-trans-THF Nitrile Derivatives
as a Platform for Diversification: Development and Mechanistic Studies.
Sajjad Ali, Henrique Milanezi, Tânia M. F. Alves, Cláudio
Francisco Tormena, and Marco Antonio Barbosa Ferreira
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00575 • Publication Date (Web): 07 Jun 2018
Downloaded from http://pubs.acs.org on June 7, 2018
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Cobalt-catalysed Stereoselective Synthesis of 2,5-trans-THF Nitrile
Derivatives as a Platform for Diversification: Development and Mechanistic
Studies.
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†
†
†
††
Sajjad Ali, Henrique Milanezi, Tânia M. F. Alves, Cláudio Francisco Tormena, Marco A.
†
B. Ferreira *
†
Centre of Excellence for Research in Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of São Carlos − UFSCar, São Carlos, São Paulo, Brazil,
13565ꢀ905.
†
†
Institute of Chemistry, University of Campinas, Campinas 13083ꢀ970, Brazil.
Corresponding Author *Email: marco.ferreira@ufscar.br (M. A. B. Ferreira) Tel.: +55ꢀ16ꢀ
3518075.
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Graphical Abstract
F C
Ph
3
readily
derivatizable
group
O
O
O
Co
Co(II)L , air
gammaꢀterpinene
OH
CN
2
O
R
O
CN
R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
up to 77%
19 examples
Ph
CF3
Z:E ~ 3:1
dr > 20:1
Abstract
A straightforward protocol integrating a sustainable approach for synthesis of new 2,5ꢀ
transꢀTHF nitrile derivatives enabling an easy diversification of its side chain scaffolds is
described. The reaction tolerated different aromatic and alkyl substituents, affording the
corresponding 2,5ꢀtransꢀTHFs in high diastereoselectivity. A detailed mechanistic study using
DFT calculation reveals details of the ligandꢀexchange step, suggesting an innerꢀsphere syn
attack to form the 2,5ꢀtrans stereochemistry as the most likely pathway, excluding the
previous cation radical intermediate. The formation of a CoꢀC intermediate is suggested based
on the homolytic cleavage to give the previously proposed free carbon radical intermediate.
Keywords:
Mukaiyama oxidative cyclization, cobalt, mechanistic studies, DFT,
tetrahydrofuran.
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Introduction
Tetrahydrofuran (THF) is a wellꢀknown privileged skeleton frequently encountered in
1
many biologically active natural products, widely used as a synthetic building block to
2
3
construct synthetic relevant heterocyclic molecules and as a versatile synthetic precursor. In
view of their distinctive structural features, the stereoselective synthesis of chiral THFs is
often attracting interest from synthetic community, and consequently several synthetic tactics
1
1
1
1
1
1
1
1
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1
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0
4
have been developed. In particular, tremendous efforts have been devoted to the development
of new methodologies employing readily accessible bisꢀhomoallylic alcohols to construct
substituted 2,5ꢀTHF, which are encountered in many biologically active molecules and
2
,3
natural products.
The pioneering work of Mukaiyama disclosed the use of a catalytic amount of Co(II)
complexes for O activation serving as a powerful and selective oxidant for oxidative
2
cyclization of nonꢀactivated bisꢀhomoallylic alcohols, offering a straightforward strategy to
5
obtain 2,5ꢀtransꢀTHF under high levels of diastereoselectivity (Scheme 1a). Some
6
representative synthetic applications are depicted on Scheme 2.
(a) Mukaiyama. (Pioneering work)
OH
O
Co(II)L , O
R
2
2
OH
R
iꢀPrOH
dr > 20:1
(b) Hartung
Unsaturated ester as
single example of
eletrophilic double bond
OH
O
R
Co(II)L , air
2
CO Me
2
R
CO Me
2
gammaꢀterpinene
dr > 20:1
(
c) No solvent, open flask, facile nitrile derivatization. This work
F C
Ph
readily
derivatizable
group
3
O
O
O
Co
CN
Co(II)L , air
2
O
OH
R
gammaꢀterpinene
O
CN
R
up to 77%
Ph
CF3
Z:E ~ 3:1
dr > 20:1
1
9 examples
Scheme 1. Diastereoselective approaches to obtain 2,5ꢀtransꢀTHF from bisꢀhomoallylic
alcohols.
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O
O
OH
O
OH
O
O
OH
O
0
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0
amphidinolide C
(cytotoxic)
Co(II)L , O
2
2
O
O
.
+
O
OH
O
N
NH2
Br
O
Br
OH
R
Aplysiallene
ATPase inhibitor)
CMI-977 (LDP-977)
(antiꢀasthmatic)
F
(
OH
O
1
3
O
OH OH
O
goniotrionin
cytotoxic)
(
Scheme 2. Application of cobaltꢀcatalysed cycloetherification involving nonꢀactivated bisꢀ
homoallylic alcohols under O
2
.
Despite the obvious sustainable advantage of this strategy (including the abundant,
low cost, cobalt metal, use of molecular oxygen as a “green” oxidant, use of “green” solvents,
open reaction conditions and lack of moisture sensitivity), the generated free carbon radical
7
intermediate emerges as a flexible diversityꢀoriented approach to functionalize the side chain
8
alphaꢀcarbon position of THF rings, achieved by slight variations on reaction conditions. In
spite of all these characteristics, there is a lack in the application of this methodology in
7
a,8a
activated electronꢀdeficient olefins. To date, Hartung
partially explored in terms of scope
only single alphaꢀbetaꢀunsaturated ester, which provides excellent 2,5ꢀtrans
a
diastereoselectivities under reductive termination (Scheme 1b). Subsequent application of this
methodology by Wu and Forsyth in the synthesis of C15ꢀC25 fragments of amphidinolide C3
9
showed this to be superior to the oxaꢀMichael strategy. On the basis of these backgrounds,
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herein, we report a protocol to integrate a sustainable approach for synthesis of new 2,5ꢀtransꢀ
THF nitrile derivatives enabling an easy diversification of 2,5ꢀTHF side chain scaffold
(Scheme 1c). The nitrile functional group offers easy access to a vast array of amine,
10
tetrazole, carbonyl, imidate and other motifs.
1
1
1
1
1
1
1
1
1
1
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2
2
2
3
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5
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0
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9
0
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9
0
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9
0
Results and Discussion
We commenced our investigations with alkenol 1a as the standard substrate by
examining various experimental conditions. On the basis of previous studies on oxidative
2
a,7b,8
cyclization reaction under reductive termination,
in this initial screening we choose 1,4ꢀ
cyclohexadiene (1,4ꢀCHD) as a reducing agent (Table 1). In addition, from these studies it
was wellꢀestablished that the stereochemical information of the olefinic πꢀbond is lost in the
course of reaction due to the assumed radical path, although the 2,5ꢀtrans selectivity is
retained, enabling us to use a mixture of Z:E alkenols (1a). The initial exploration was carried
out by reacting 1a in the presence of 1,4ꢀCHD (20 equiv.), 2a (15 mol%) as cobalt catalyst,
toluene as reaction medium, open flask conditions (atmospheric air), and under reflux (Table
1, entry 1). The oxidative cyclization reaction afforded the 2,5ꢀtransꢀTHF 3a in low yield
(34%) but in high diastereoselectivity (dr > 20:1). Encouraged by this promising result, the
reaction was performed in higher concentration by removing the toluene, and the desired
product 3a was obtained in 60% yield (entry 2). To improve the reaction efficiency further,
different cobalt ligands with diverse electronꢀdemands were subsequently examined (2b-c),
but they all provide disappointing results (entries 3ꢀ4). Therefore, 2a was chosen as the
catalyst for additional optimization of the reaction conditions.
A reducing agent survey revealed that the source of radical hydrogen has a substantial
impact on the conversion efficiency (Table 1, entries 5ꢀ8). While the 1ꢀmethylꢀ1,4ꢀ
cyclohexadiene (1ꢀMeꢀ1,4ꢀCHD), tris(trimethylsilyl)silane (TTMSS), and triethylsilane (TES)
failed in provide the desired compound, the γꢀterpinene provides 3a in 63% of yield.
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Gratifyingly, the use of gammaꢀterpinene as a reductant was more appropriate because it
1
1
provided the benign pꢀcymene as a byproduct. Finally, no substrate consumption occurred in
the absence of O
2
and reductant (entry 9) or the cobalt catalyst 2a (entry 10).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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9
0
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0
a
Table 1. Optimization of the reaction conditions.
d
b
entry
reductant
Co(II)L2
temperature
solvent
yield
1
2
3
4
5
6
7
8
1,4ꢀCHD
1,4ꢀCHD
1,4ꢀCHD
1,4ꢀCHD
1ꢀMeꢀ1,4ꢀCHD
TTMSS
2a
2a
2b
2c
2a
2a
2a
2a
2a
−
reflux
70 ºC
70 ºC
70 ºC
70 ºC
70 ºC
70 ºC
70 ºC
70 ºC
70 ºC
toluene
34%
60%
30%
25%
−
−
−
−
−
−
c
NR
c
NR
c
TES
NR
γꢀterpinene
−
γꢀterpinene
−
toluene
−
63%
e
c
9
NR
c
10
NR
a
The reactions were carried out in toluene (0.09 M) or without additional solvent
(
0.5 M), with 1a (0.1 ꢀ 0.2 mmol) and reductant (20 equiv.) in the presence of 15
b
mol% of catalyst under atmospheric air at the given temperature. Isolated yields
after flash chromatography. No reaction. 1,4ꢀCyclohexadiene (1,4ꢀCHD), 1ꢀ
methylꢀ1,4ꢀcyclohexadiene (1ꢀMeꢀ1,4ꢀCHD), tris(trimethylsilyl)silane (TTMSS),
c
d
e
and triethylsilane (TES). The reaction was carried out under inert atmosphere
(
argon) and toluene (0.5 M).
Having established optimized conditions for the oxidative cyclization of alkenol 1a
(Table 1, entry 8), we evaluated the substrate scope and generality of the transformation using
different substituted alkenols. As illustrated in Table 2, a range of aromatic substituent was
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tolerated. In general, the reaction smoothly afforded the corresponding 2,5ꢀTHFs in moderate
to good yields (52ꢀ77%) with excellent diastereoselectivities (dr > 20:1). The electronic
nature of the aromatic group (ꢀX) only slight affected the yields, with electronꢀneutral (Table
1
, 3b), electronꢀdonating (3c-i) and electronꢀwithdrawing (3j-k) groups giving the
corresponding 2,5ꢀtransꢀTHF in similar yields. Additionally, we found that oꢀMethyl (3d) and
,5ꢀdiꢀtertꢀButyl (3e) substituted derivatives also worked well, despite their steric hindrance.
1
1
1
1
1
1
1
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1
1
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5
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5
5
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0
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9
0
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2
3
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9
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9
0
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2
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7
8
9
0
3
Unfortunately, the use of pꢀNMe (3l), and the tertiary alcohol (3m) derivatives were not
2
compatible with this protocol under the best reaction conditions.
In order to further extend the scope of this protocol, aromatic chain substituents were
replaced by alkyl ones. Applying our optimized reaction conditions, a series of linear alkenols
exhibited comparable reactivity (Table 3, 3n-r) and moderate to good yields (45ꢀ71%),
furnishing the desirable THF in high diastereoselectivity (dr > 20:1). Gratifyingly, the
protocol could be extended to include the formation of sterically hindered derivatives 3s-t in
good yields (Table 3, 69ꢀ74%, dr > 20:1). Other substrates with Oꢀsubstituted derivatives,
including benzyl and phenyl groups, demonstrated good reactivity (Table 3, 3u-v, 59ꢀ64%).
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Table 2: Scope of the aromatic substituents in the cobaltꢀcatalysed oxidative cyclization
reaction.
OH
CN
O
2a (15 mol%)
CN
air, 70 ºC, 12 h
X
X
1
b-m
gammaꢀterpinene (20 equiv)
3b-m
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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0
1
2
3
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9
0
Z :E ~ 3:1
dr > 20:1
O
O
O
CN
CN
CN
Me
3
d: 71% y
3b: 52% y
3c: 77% y
t-Bu
MeO
BnO
O
O
O
CN
CN
CN
CN
t-Bu
3
e: 55% y
3f: 58% y
3g: 69% y
MeO
MeO
F
O
O
O
CN
O
CN
3
h: 68% y
3i: 62% y
3j: 61% y
Cl
O
CN
3
k: 64% y
Failed Reactions
Me N
Me
2
O
O
CN
CN
3
m: 0% y
3
l. 0% y
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Table 3: Scope of the alkyl substituents in the cobaltꢀcatalysed oxidative cyclization reaction.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
4
4
5
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
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8
9
0
1
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0
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To prove the 2,5ꢀrelative configuration of tetrahydrofurans derivatives 3, the previous
6
a
known compound 4 (Scheme 3), obtained by a different synthetic route, was submitted to
1
13
successive derivatizations leading to 3a. The H NMR and C NMR of 3a matched with our
previous data.
OH
CN
2a (15 mol%)
TBDPSO
air, 70 ºC, 12 h
gammaꢀterpinene (20 equiv)
1
a
Z
:
E
~ 3:1
dr > 20:1
63% yield
known relative
stereochemistry
TBDPSO
TBDPSO
TBDPSO
O
O
O
OH
I2, PPh3
imidazole, THF
5 ºC, 7 h
81% yield
I
NaCN
CN
DMSO
4
5
3a
2
60 ºC, 3 h
67% yield
ref 6a
Scheme 3. Proof of stereochemistry for 2,5ꢀtransꢀTHF nitrile derivatives 3.
Therefore, we investigated the derivatization of compound 3a to demonstrate the
utility of our methodology (Scheme 4a). 3a can be easily converted into amine 6 in 56% yield
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under reduction reaction condition with BH
3 2
.SMe . Furthermore, the tetrazole 7 can be
achieved by using NaN and ZnCl in 61% yield. To demonstrate applicability (Scheme 4b), a
3
2
halfꢀgramꢀscale reaction of 1g was carried out to afford 3g in 53% yield as a single
diastereoisomer (dr > 20:1). The yield remained consistent with the increase of scale.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
synthetic manipulation
TBDPSO
TBDPSO
TBDPSO
BH SMe
ZnCl , NaN
H
3
.
2
2
3
O
O
O
NH2
N
CN
THF
5 ºC, 24 h
6% yield
nꢀBuOH
reflux, 12 h
61% yield
N
N
N
2
6
3a
7
5
scaling effect
OH
CN
BnO
2
a (15 mol%)
O
CN
air, 70 ºC, 12 h
gammaꢀterpinene (20 equiv)
1
g
BnO
Z :E ~ 3:1
dr > 20:1
3g
55 mg (0.19 mmol)
500 mg (1.71 mmol)
69% yield
53% yield
Scheme 4. (a) Synthetic transformations of 3a. (b) Scaling effect of 1g.
Computational Mechanistic Studies
A great progress has been made in understanding the cobaltꢀmediated Mukaiyama
7,12
cyclization by Hartung and coꢀworkers.
In particular, mechanistic interpretations based on
kinetics experiments provide initial thoughts to understand the carbonꢀcentered radical
formation and stereoselectivity. A simple picture for these finding can be seen in Scheme 5.
II
The proposed catalytic cycle starts after O
2
activation of Co forming a superoxoꢀmode
doublet intermediate (I), which trigger an intriguing sequence of single electron transfer
SET) events. First, after ligand exchange, the lowestꢀenergy chairꢀlike olefin conformer in
(
the complex II is converted into radical cation III. This conformation was proposed based on
III
the experimentally observed diastereoselectivities. The electron uptake propensity of Co
complex I in the SET step was associated with the strong oxidative tendency of
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bis(trifluoroacetato)cobalt(III) complexes. Finally, an oxygen attack onto the electrophilic
bond creates the CꢀO bond and set the 2,5ꢀtrans stereochemistry. The reductant chosen on the
present mechanism sequence is of fundamental importance because it not only regenerates the
catalyst but also determines the type of radical termination of intermediate IV in the alkyl
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
chain.
II
L Co + O2
2
O
+
HO
R
R
2,5-trans
III
L Co -- O2
2
I
H O
2
[
H ] / O2
III
L Co -- O2
2
H
O
III
L Co -- O H
2
2
II
L Co -- O2
2
R
O
R
H
O
II
R
IV
III
II
L Co -- O2
2
H
O
O
R
2,5-cis
R
III'
Scheme 5. Proposed mechanism by Hartung et al. for aerobic cobaltꢀcatalyzed
tetrahydrofuran synthesis.
Despite these insights, some detailed reaction steps remain poorly understood,
especially for electrophilic double bonds. In particular, considering the cobaltꢀmediated
oxidation of π system by a SET process, it is reasonable to speculate, based on previous
13,14
reports,
that an intermolecular SET may be appropriate by using a second cobalt complex
(
Scheme 6a). In another hypothesis, we revisited the initial mechanism proposed by
5
Mukaiyama (Scheme 6b), by the reaction of Co complex and O
2
with alkenol, forming a free
radical oxygen which interacts with the coordination sphere of the cobalt complex to drive the
syn radical cyclization attack. We speculate that the abstraction of the radical hydrogen should
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
occur in the complexed alkenol by intraꢀ or intermolecular attack (Scheme 6b). In a new
standpoint, and considering electrophilic olefins, a nucleophilic attack of the hydroxyl group,
through an innerꢀsphere mechanism in a syn fashion on the coordinated alkene, could lead the
15
intermediate V producing the expected radical intermediate IV after homolytic cleavage
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 6c). Considering these entire new hypotheses, the same reaction intermediate will
produce the carbonꢀcentered radical IV. A final aspect refers to the true lowest energy
conformations for cobaltꢀalkenol complexes, which remain unknown. No detailed
II
III
computational study on the mechanism of Co /Co ꢀmediated aerobic oxidative cyclization
was performed up to date. Considering the previous questions and hypothesis, we conducted a
1
6
theoretical investigation using DFT and TDꢀDFT calculation using the Gaussian 09, with
17
18
the BP86 functional and def2ꢀsvp basis set. In all calculations we add the D3 version of
1
9
Grimme’s dispersion with BeckeꢀJohnson damping. We include the effect of toluene on the
calculations by using the IEFꢀPCM implicit model. To refine the electronic energy, singleꢀ
point calculations were performed at BP86ꢀD3BJ/def2ꢀtzvp/IEFꢀPCM level of theory
employing the BP86ꢀD3BJ/def2ꢀsvp/IEFꢀPCM geometries. The Gibbs free energy was
obtained from the sum of Eele at BP86ꢀD3BJ/def2ꢀtzvp/IEFꢀPCM//M062X/def2ꢀsvp/IEFꢀ
PCM and thermal correction at BP86ꢀD3BJ/def2ꢀsvp/IEFꢀPCM. The NBO analyses furnish
2
0
the Wiberg Bond Index (WBI) at BP86ꢀD3BJ/def2ꢀtzvp/IEFꢀPCM. Initially we explore the
conformational behavior of cobaltꢀalkenol complexes. Subsequently, a detailed mechanism
involving the cyclization step was done, including unsaturatedꢀnitrile and terminal double
bond. Among the mechanism evaluated, the syn attack (Scheme 6c) presented the most
feasible Gibbs energy profile and is discussed inꢀdeph in the main text. See SI for further
details of other explored mechanisms.
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a) Formation of cation radical by intermolecular SET
LnCoIII -- O2
HO
CN
LnCoII -- O2
HO
CN
III
II
+
L Co -- O2
L Co -- O2
+
2
2
R
R
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b) Formation of free radical oxygen by intraꢀ or intermolecular attack
III
L Co -- O H
2
2
LnCoIII -- O-O
LnCoIII -- O-OH
H
O
O
R
NC
NC
NC
O
R
CN
intra
R
IV
LnCoIII -- O-O
LnCoIII -- O-O
H
O
O
-- CoIIIL
2
2
O
NC
inter
R
R
c) Syn attack
III
LnCoIII -- O2
LnCo -- O2
O
V
H
R
R
O
CN
CN
Scheme 6. Different hypotheses for the cyclization step in the aerobic cobaltꢀcatalyzed
tetrahydrofuran synthesis.
1
. Conformational search of complex I
We considered the Co(acac) (H O) (acac = acetylacetonate) as the reactive complex in
2
2
order to reduce the computational costs associated with the complicated conformational
behavior of nonꢀsymmetric ligands. It was evaluated only octahedral monomer complexes,
III
despite the possibility of the oxoꢀdimer for Co or more intricate arrangement of atoms as
21
previously disclosed in solid state by Xꢀray structures. We set the doublet spin state as
electronic ground state for Co(acac)
2 2 2 2 2
(H O) and Co(acac) (H O)(O ) according to the
12
previous experimental and theoretical calculation reports.
To understand the role of diastereoselectivity by the cobalt complex, it was obtained
an accurate description of conformational space of complex II varying the conformation of
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8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2 2
alkenol (Scheme 7). In addition, both the cis- and transꢀisomers (relative to the H O and O
position), and both doubleꢀbond faces of complexation generating the complexes II, including
the possibility of hydroxyl proton abstraction from the alkenol (II’) or water (II’’) after ligand
exchange (see in SI all searched conformations for II and II’) were explored. According to
our computational results, in both cases, the cisꢀisomers in chairꢀlike conformations adopted
the lowest energy and the most relevant structures are presented in Scheme 7. The molecular
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
oxygen uptake by the Co(acac) (H O) catalyst decreased the energy gap by ꢀ18.6 kcal.mol ,
2
2
spreading out spin density (SD) ꢀ obtained from the Mulliken population analysis ꢀ from
cobalt (0.96 in Co(acac) (H O)) to complexed O (0.95 in Co(acac) (H O)(O )), as
described previously. The increase in Wiberg bond index (WBI) (from 2.11 to 2.85) also
indicates the superoxoꢀcharacter of Co(acac) (H O)(O ) complex.
2
2
2
2
2
2
1
2
2
2
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II''-a
60.4
II-a
6
0
II-a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
II''-a
.5
1
0
.0
0
Co(acac) (H O)
2
2
II'-b
0.3
ꢀ
1
2
-
-2.1
II'-a
ꢀ
II'-b
ꢀ18
-18.6
Co(acac) (H O)(O )
2
2
2
II'-a
0
.96 SD
2.11 WBI
O2 0.95 SD
Co
Co
O
0.98 SD
2
2.85 WBI
Co 2.83 WBI
H
HO
O
O
OH2
O
H
OH
CN
O
O
O
O
OH
2
CoII
CoIII
O
O
CoIII
O
O
O
O
O
O
ꢀacac
O
O
CN
Co(acac) (H O)
Co(acac) (H O)(O )
2 2 2
2
2
II-a
OH
CN
ꢀ
acac
H
HO
H
HO
O
O
O
O
O
H
H
O
NC
O
O
O
O
CoIII
CoIII
CoIII
O
O
O
O
O
O
CN
CN
II'-b
II'-a
O
0.88 SD
Co 2.87 WBI
II''-a
O
2
0.82 SD
Co 2.99 WBI
2
Scheme 7. Ligand exchange in Co(acac) (H O)(O ), and lowest energy conformation of
2
2
2
intermediates II, II’ and II’’. In blue: SD = spin density. WBI = Wiberg bond index.
From the energetic profile, it is very unlikely to form the cationic complex IIa, due to
ꢀ1
the unfavorable endergonic equilibrium (energy difference of 79.0 kcal.mol ) after ligand
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
exchange involving the alkenol and extrusion of acac
.
The formation of lowest energy chairꢀ
ꢀ1
like complex II’a (ꢀ2.1 kcal.mol ), which leads to the THF 2,5ꢀtrans diastereoisomer,
proceeds by the hydroxyl proton abstraction of alkenol by anionic acac. This endergonic
ꢀ1
process involves 16.5 kcal.mol . A less favorable equilibration involving an intramolecular
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
proton transfer in II’a produces the less stable complex II’’a (0.5 kcal.mol ). The isomeric
boatꢀlike complex II’b, which keeps its doubleꢀbond in axial position, and which is
ꢀ1
responsible for the formation of 2,5ꢀcis diastereoisomer, is 1.8 kcal.mol higher in energy
than II’a. Finally, correlating the ligand exchange and proton abstraction with the SD and
WBI parameters of II-a, II’-a, and II’’-a, any substantial changes were observed.
2
. Studies of single electron transfer (SET) and free radical oxygen pathways for
III
superoxo-Co complexes.
The intramolecular SET mechanism involving the formation of intermediate III
(Scheme 5) was explored for II-a, II’-a, II-a-CF , and II’-a-T using timeꢀdependent density
3
functional theory (TDꢀDFT) calculations as described by Wei, Niu and coworkers (Scheme
14
8
a). The evaluation of transition energies involving the olefin π−orbitals from ground state
ꢀ
to the excited state – HOMOꢀn and SOMO orbitals, respectively ꢀ range from 32ꢀ44 kcal.mol
1
.
These high intramolecular SET energies suggest an unfavorable intramolecular pathway for
both systems – double bond with and without CN group. The proposed intermolecular SET
transition process involving two cobalt complexes, as depicted in the Scheme 8b, involves a
ꢀ1
extremely high Gibbs free energy difference of 72.1 kcal.mol for the cation brokenꢀ
symmetry singlet S -III’-a complex. Finally, the investigation for the cyclization step by
0
hydrogen abstraction and formation of free oxygen radical intermediate were equally
unfavorable (Scheme 8c). By the intramolecular path, the proposed intermediate is not a
minimum structure on the potential energy surface, while the intermolecular attack involves
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an endergonic equilibrium, with energy differences of 16.3 kcal.mol for the triplet complex
T -VI-b.
0
Intramolecular SET
a)
R
R
R
O
O
O
O
O
O
SET
O
H
H
H
Y = O, OH
X = CN, H
R = Me
CoIII
O
R'
Y
CoIII
O
R'
Y
CoIII
O
R'
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Y
H
2
O
X
H O
2
X
H O
2
X
R' = Me, CF3
H
H
Eelec = 32-44 kcal.mol-1
H
H
H
H
II-a, II'-a, II-a-CF , II'-a-T
HOMO-n
SOMO
3
b) Intermolecular SET
SET
LCoIII -- O-O
LCoIII -- O-O
NC
O
NC
O
R
+
Co(acac) (H O)(O )
2 2
Co(acac) (HO)(HO )
2
2
2
R
ΔΔG = 72.1 kcal.mol-1
II'-a
0
S -III'-a
c) Formation of free radical oxygen
hypothetically
intermolecular
abstraction
LCoIII -- O-O
hypothetically
intramolecular
abstraction
NC
O
R
LCoIII -- O-O
LCoIII -- O-O
no reaction
H
H
O
2 2
O L
-- CoIII
T
0
-VI-b
NC
NC
O
ΔΔG =
16.3 kcal.mol-1
+
R
R
-- CoIIIL
HO
2 2
II''-a
II''-a
Scheme 8. (a) Olefin π orbital transition energy for II-a, II’-a, II-a-CF , and II’-a-T. (b)
3
Suggested intermolecular SET. (c) Formation of free radical oxygen by intra or
intermolecular attack.
III
3
. Studies of cyclization pathways for superoxo-Co .
The investigation of the potential energy surface for the cyclization step was
conducted as depicted on the Scheme 9. The syn attack pathway (hypothesis c on scheme 6)
starting from II’-a provides the lowest activation free energy, and was determined to be only
ꢀ1
1
.8 kcal.mol for TS1. This pathway forms the experimentally trans stereochemistry, and the
ꢀ1
formation of V-a intermediate involves an exergonic process by 9.1 kcal.mol through a nonꢀ
reversible step. The opposite cisꢀstereochemistry would be obtained through TS2, starting
ꢀ1
from II’-b, and was found to be 3.2 kcal.mol , and similarly, lead to the V-b intermediate
ꢀ1
through a nonꢀreversible step and releasing 7.7 kcal.mol of energy. Supposing that II'-a and
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
II'-b can quickly interconvert, the CurtinꢀHammett principle can be assumed, being the
ꢀ1
⧧
energetic difference between TS1 and TS2 (ꢁꢁG = 3.2 kcal.mol ) responsible for the
control of diastereoselectivity, providing a theoretical diastereoisomeric ratio of 99.3:0.7 for
trans stereochemistry at 70 ºC, in excellent agreement with the experimental result (dr >
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20:1). TS1 corresponds to the diastereoselectivityꢀ and rateꢀdetermining cyclization step. The
analysis of the oxidation state of cobalt on TS1 and TS2, by the WBI (2.84 and 2.83 for TS1
III
and TS2, respectively) indicates a Co character for both cases (Scheme 9).
O
2
0.50 SD
Co 0.43 SD
Co 3.07 WBI
O
2
0.90 SD
Co 0.11 SD
Co 2.83 WBI
TS4
1
4
3
TS4
14.3
1
Co-C 0.46 WBI
Co 2.79 WBI
TS2
12
TS3
11
11.2
1
0
V-d
.0
TS2
V-d
6
II''-b
.1
2.9
2
2
O
2
0.54 SD
Co 0.40 SD
Co 3.04 WBI
ꢁꢁG = 3.2
1
0.5
Co-C 0.48 WBI
Co
2.71 WBI
II''-a
II'-b
0
TS1
-0.3
-0.3
ꢀ1
II'-a
2.1
ꢀ
2
V-b
-
ꢀ8
ꢀ9
-8.0
V-b
O
2
0.91 SD
Co 0.11 SD
TS3
Co 2.84 WBI
V-c
11.2
V-a
Co-C 0.46 WBI
Co 2.79 WBI
Co-C 0.52 WBI
Co 3.06 WBI
-
-11.2
TS1
V-c
V-a
O
H
O
H
O
O
H
O
H
HO
OH
HO
O
H
NC
O
O
O
CoIII
O
O
NC
O
CoIII
CoIII
O
CoIII
O
O
O
O
O
O
CN
O
O
CN
II''-a
II''-b
II'-a
II'-b
III
Scheme 9: Cyclization pathways for superoxoꢀCo involving unsaturated nitrile derivatives.
Energy barrier represented in parentesis.
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9
The intermediates II’’-a and II’’-b and their respective transition states – TS3 and
TS4 in Scheme 9 – are responsible for the free radical oxygen attack (hypothesis b on Scheme
6), but they are in much higher energy than the lowest energy transition state TS1, and the
intermediates II'-a and II'-b, indicating that this pathways is not favorable. In particular, we
considered a concerted sequence of events involving radical formation by an intramolecular
process, followed by radical cyclization. However, the mechanism proposed could be safely
ruled out in the light of our theoretical calculations depicted in Scheme 9. Surprisingly, the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
attack of complex O
TS3 and TS4 occurs via a heterolytic cleavage, determined by the Milliken spin density
analysis. The spin densities on TS3 and TS4 remain centered on O ꢀCo atoms (>90%), and
2
to the hydroxyl hydrogen in the intermediates II’’-a and II’’-b through
2
after the proton abstraction occurs, the alkoxy attacks the double bond. Both transition states
are higher in energy than TS1 and TS2. A final analysis of WBI in the Scheme 9 reveals a
covalent bond formation between CoꢀC atoms involving all calculated intermediates Va-d.
After homolytic cleavage and ligand exchange, we must wait for the formation of free
III
2 2
radical carbon IV, together with peroxide L Co (OH )(OOH), as can be seen in Scheme 10.
ꢀ1
This endergonic step requires a significant input of energy (12.5 kcal.mol ), although these
intermediates have similar energy to the starting materials. The formation of the product
3n via radical abstraction of one of the hydrogens of the gammaꢀterpinene passes through
ꢀ1
TS5 involving an energy barrier of 8.7 kcal.mol . Finally, homolytic cleavage of the peroxide
III
III
L
2
Co (OH
2 2 2
)(OOH), provides the cobalt intermediate L Co (OH )(OH) in its most stable
state.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
TS5
1
0
10.0
8
6
4
2
0
CoIII(OH
2 2
IV + L )(O-OH)
1.3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
V-a
TS5
ꢀ
10
12
+
L-H
ꢀ
-11.2
ꢀ14
ꢀ16
ꢀ18
ꢀ50
2 2
n + L )(O-OH)
CoIII(OH
3
-17.3
CoIII(OH
2 2
)(OH)
L
-52.5
H
O
CoIII(OH
)(O-OH)
O
+
L CoIII(OH )(O-OH)
+
2 2
V-a + L-H
+
L
2
2
CN
CN
IV
3
n
O
O
L =
H
CoIII(OH
2 2
L )(OH) + HO +
O
CN
TS5
Scheme 10: (a) Formation of free carbon radical intermediate IV, and final product 3n.
2
2
23
Assuming the energetic span model and rateꢀdetermining state concept, we analyze
the potential energy diagrams (Schemes 7, 9, and 10), and Co(acac) (OH )(OH) can be
2
2
considered as the TOFꢀdetermining intermediate (TDI) and the resting state catalyst. The
transition state TS5 is the TOFꢀdetermining transition state (TDTS). However, these
considerations must be taken with caution, since we do not calculate all the elementary steps
involved in the ligand exchange and catalyst regeneration, being both process not fully
understood.
We extended this mechanistic study including the cyclization step of nonꢀactivated
terminal double bond olefins starting from the lowest energy structures from Scheme 9. Our
intention was to evaluate how much an unactivated olefin could change the energy barriers
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9
via a innerꢀsphere syn attack. We find a remarkable energetic and structural similarity
between the terminal and nitrile substituted olefins. As can be seen in the Scheme 11, the
obtained results point out to a nonꢀradical cyclization step pathway and the experimentally
trans stereochemistry would be obtained through TS1-T starting from II’-a-T exhibiting only
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
2
.8 kcal.mol of free activation energy. The competitive TS2-T provides the cisꢀ
ꢀ1
configuration and is higher in energy (6.8 kcal.mol ) than TS1-T. The energetic difference
ꢀ1
⧧
between TS1-T and TS2-T (ꢁꢁG = 4.0 kcal.mol ) is responsible for the control of
diastereoselectivity, providing a theoretical diastereoisomeric ratio of 99.7:0.3 for trans
stereochemistry at 70 ºC, in perfect agreement with experimental results from the literature.
III
The oxidation state of cobalt and WBI also indicate a Co character for all intermediates and
transition states. A covalent bond character between CoꢀC atoms was also observed by the
WBI analysis. These results, along with the studies of single electron transfer (SET) that
contemplated unsubstituted olefins, give evidence that in these systems a syn addition
mechanism could also be acting in the cyclization step.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
2
0.93 SD
Co 0.10 SD
Co 2.82 WBI
O
2
0.91 SD
Co 0.01 SD
Co 2.88 WBI
TS2-T
TS2-T
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
.8 (2.6)
O
2
0.92 SD
Co 0.11 SD
Co 2.83 WBI
6
5
II'-b-T
4
3
2
1
0
4.2
II'-b-T
TS1-T
2.8
TS1-T
II'-a-T
0.0
ꢀ
1
2
ꢀ
V-b-T
ꢀ3
-
2.1
O
2
0.96 SD
Co 0.05 SD
Co 2.88 WBI
O
2
0.93 SD
Co
0.09 SD
II'-a-T
ꢀ
4
V-a-T
4.5
V-b-T
Co 2.77 WBI
Co-C 0.60 WBI
-
O
2
0.93 SD
Co 0.10 SD
Co 2.79 WBI
Co-C 0.59 WBI
V-a-T
III
Scheme 11: Cyclization pathways for superoxoꢀCo involving nonꢀactivated terminal
olefins.
According to the theoretical calculations, and precedent reports, a modified reaction
mechanism is proposed in Scheme 12 for Mukaiyama radical cyclization of nitrile derivatives.
The major modification of the previous mechanism involves the formation of intermediate II’
after ligandꢀexchange, followed by an innerꢀsphere syn attack of oxygen, forming the transꢀ
stereochemistry. Despite some evidence found during this work, it is not clear whether this
conclusion is really general for other Mukaiyama radical cyclization variations.
From our calculations, we could hypothesize that the probable resting state catalyst
III
2
L Co OH and the transition state involved in the radical termination and formation of the
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product are the turnover determiningꢀstates. The energy differences between the transition
states forming 2,5ꢀantiꢀV and 2,5ꢀsynꢀV drive the stereochemical preference. Finally, the
5,15
intermediate V is suggested to participate in the catalytic cycle,
which after a homolytic
cleavage forms the free carbon radical intermediate IV, and follow the previously proposed
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
radical termination step and cobalt regeneration.
HO
R
II
L Co + O
catalyst
2
2
regeneration
CN
LH
H O
2
III
L Co -- O2
2
[
H ] / O2
I
III
O -- Co L
III
2
O
L Co -- OH
R
2
CN
CN
O
radical
termination
2,5-trans
[
H ]
R
II'
III
L Co -- O H
2
2
inner-sphere
syn attack
+
III
O -- Co L
2
O
R
O
CN
R
CN
IV
V
LH
homolytic
cleavage
Scheme 12. Proposed modified mechanism for aerobic cobaltꢀcatalyzed tetrahydrofuran
synthesis of nitrile derivatives.
Conclusions
In summary, we report a protocol integrating a sustainable approach for synthesis of
new 2,5ꢀtransꢀTHF nitrile derivatives enabling an easy diversification of 2,5ꢀTHF side chain
scaffolds. The reaction tolerated different aromatic and alkyl substituents, affording the
corresponding 2,5ꢀtransꢀTHFs in high selectivity. A detailed mechanistic study using DFT
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1
1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
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5
5
5
5
5
5
5
5
5
6
calculation investigates the conformational behavior of reactive intermediates, and afforded
insights into cyclization step, including the unsaturatedꢀnitrile and terminal double bond. The
major highlights include details of ligandꢀexchange step, and an innerꢀsphere syn attack to
form the 2,5ꢀtrans stereochemistry, excluding the previously cation radical intermediate. It
was suggested that the formation of CoꢀC intermediate V which can be easily decomposed by
a homolytic cleavage forms the previously proposed free carbon radical intermediate IV.
More detailed studies to support our theoretical conclusions are in progress and will be
disclosed in due course.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
Commercial grade reagents and solvents were purchased and used without further
2
4
purification; when necessary, they were purified as recommended. Tetrahydrofuran (THF)
and diethyl ether (Et O) were distilled from sodium/benzophenone. Dichloromethane
(CH Cl ) was distilled from CaH . Flash column chromatography was carried out using silica
2
2
2
2
gel 60 (230ꢀ400 mesh). Analytical thin layer chromatography (TLC) was performed using
silica gel aluminum sheets. The TLC plates were visualized with UV light, and stained with
1
13
phosphomolybdic acid, vanillin, or KMnO solution, followed by heating. The H and
C
4
1
13
NMR spectra were recorded at 400MHz for H and at 100 MHz for C, respectively. The
1
13
chemical shifts (δ) for H and C are reported in ppm using tetramethylsilane (TMS) as an
1
internal standard for H NMR spectra, and using the solvent peak as an internal standard
1
3
(CDCl at 77.0 ppm) for C NMR spectra. Coupling constants (J) are given in hertz. The
3
following abbreviations are used to indicate the multiplicity: s = singlet; d = doublet; t =
triplet; q = quartet; m = multiplet; b = broad; quint = quintet; sext = sextet; dd = doublet of
doublets; dt = doublet of triplets; dq = doublet of quartets; tt = triplet of triplets; ddt = doublet
of doublet of triplets; ddq = doublet of doublet of quartets; dddd = doublet of doublet of
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doublet of doublets. The signals from the minor isomers, when not superimposed with the
major isomer, are listed in brackets. For the infrared spectra, wavelengths of maximum
−
1
absorbance (max) are quoted in wavenumbers (cm ). Highꢀresolution mass spectra (HRMS)
were recorded using electrospray ionization (ESI) (Hybrid linear ion trap–orbitrap FTꢀMS and
QqTOF/MS – Microtof – QII models). For details of theoretical calculations and citation of
the programs, please see the SI.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
5
2
c
26
Preparation of catalysts 2a-c: The catalysts 2a, 2b, and 2c were prepared according to
the literature.
General procedure for preparation of alkenols 8a-v: The alkenols 8a-v were prepared
following the Method A or B, starting from an aldehyde or epoxide, respectively.
Method A: Freshly prepared 3ꢀbutenylmagnesium bromide solution (2 equiv, 0.5 M in THF)
was added to a flameꢀdried flask under an Ar atmosphere at 0 °C, and a solution of aldehyde
(
15 mmol) in anhydrous THF (20 mL) was added dropwise while stirring the reaction
vigorously. After 10 min at −20 °C and 1 h at r.t., a saturated aqueous solution of ammonium
chloride (10 mL) and H O (5 mL) were added. The suspension was warmed to r.t., and the
2
reaction mixture was extracted with EtOAc (2 × 10 mL). The combined organic phases were
dried (Na SO ) and filtered, and the solvent was removed in vacuum. Purification by flash
2
4
column chromatography using EtOAc/hexane (2:8) as the eluent gave the secondary alcohol
8
.
2
Method B: Freshly prepared allyl magnesium bromide solution (3 equiv, 0.5 M in Et O) was
added to a flameꢀdried flask under an Ar atmosphere at 0 °C, and a solution of epoxide (15
mmol) in anhydrous THF (20 mL) was added dropwise while stirring the reaction vigorously.
After 10 min at −20 °C and 1 h at r.t., a saturated aqueous solution of ammonium chloride (10
mL) and H
2
O (5 mL) were added. The suspension was warmed to r.t., and the reaction
mixture was extracted with EtOAc (2 × 10 mL). The combined organic phases were dried
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8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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5
5
5
5
5
6
(
Na
2
SO
4
) and filtered, and the solvent was removed in vacuum. Purification by flash column
chromatography using EtOAc/hexane (2:8) as eluent gave the secondary alcohol 8.
6
a
8
a: Synthesized according to the literature.
27
8
b: Synthesized according to Method A furnishing the known compound in 63% (12.3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
mmol, 1.99 g) isolated yield as light yellow oil; R
NMR (400 MHz, CDCl
H), 5.03 (dq, J = 17.1, 1.7 Hz, 1H), 5.00ꢀ4.95 (m, 1H), 4.70 (dd, J = 7.9, 5.5 Hz, 1H), 2.15
(m, 2H), 1.97ꢀ1.75 (m, 3H).
f
0.71 (20% ethyl acetate in hexane). H
3
) δ 7.37ꢀ7.32 (m, 3H), 7.28 (m, 2H), 5.83 (ddt, J = 17.1, 10.2, 6.6 Hz,
1
2
8
8
c: Synthesized according to Method A furnishing the known compound in 77% (6.29
1
mmol, 1.50 g) isolated yield as a white solid; R
400 MHz, CDCl
Hz, 1H), 5.04 (dq, J = 1.6, 10.4 Hz, 1H), 5.00ꢀ4.96 (m, 1H), 4.69 (dd, J = 5.3, 7.6 Hz, 1H),
f
0.60 (20% ethyl acetate in hexane). H NMR
(
3
) δ 7.59ꢀ7.52 (m, 4H), 7.44ꢀ7.29 (m, 5H), 5.94ꢀ5.84 (ddt, J = 17.1, 10.4, 6.7
13
2
.23ꢀ2.05 (m, 3H), 1.96ꢀ1.76 (m, 2H). C NMR (101 MHz, CDCl
3
) δ 143.6, 140.7, 140.4,
138.1, 128.7, 127.2, 127.1, 127.0, 126.3, 115.0, 73.7, 38.0, 30.0.
2
9
8d: Synthesized according to Method A furnishing the known compound in 74% (8.85
1
mmol, 1.56 g) isolated yield as a pale yellow oil; R
f
0.42 (20% ethyl acetate in hexane). H
NMR (400 MHz, CDCl ) 7.43 (d, J = 8.0 Hz, 1H), 7.23ꢀ7.07 (m, 3H), 5.83 (ddt, J = 17.4,
3
1
3
0.4, 6.7 Hz, 1H); 5.08ꢀ5.00 (m, 1H), 5.00ꢀ4.95 (m, 1H), 4.9 (dd, J = 7.5, 4.7 Hz, 1H), 2.29 (s,
H), 2.27ꢀ2.08 (m, 2H), 2.03 (bs, 1H), 1.86ꢀ1.69 (m, 2H).
8e: Synthesized according to Method A furnishing the new compound in 69% (4.12 mmol,
1
1.13 g) isolated yield as a white solid; R 0.59 (20% ethyl acetate in hexane). H NMR (400
f
MHz, CDCl ) δ 7.34 (t, J = 1.8 Hz, 1H). 7.19 (d, J = 1.8 Hz, 2H), 5.87 (ddt, J = 17.2, 10.3,
3
6
.5 Hz, 1H), 5.05 (dq, J = 17.2, 1.5 Hz, 1H), 5.01ꢀ4.96 (m, 1H), 4.68 (dd, J = 7.9, 5.3 Hz,
13
1
H), 2.29ꢀ2.08 (m, 2H), 1.97ꢀ1.85 (m, 2H), 1.84ꢀ1.73 (m, 1H), 1.33 (s, 18H); C NMR (101
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MHz, CDCl
3
) δ 150.9, 143.9, 138.4, 121.6, 120.0, 114.8, 74.7, 38.1, 34.9, 31.5, 30.3. HRMS:
+
calculated for C H NaO (M+Na) 297.2189; found 297.2189.
19
30
30
8
f: Synthesized according to Method A furnishing the known compound in 70% (6.97
1
mmol, 1.34 g) isolated yield as a yellow oil; R
f
0.59 (20% ethyl acetate in hexane). H NMR
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(400 MHz, CDCl
3
) δ 7.26 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.83 (ddt, J = 17.0,
1
2
0.2, 6.5 Hz, 1H), 5.05ꢀ4.99 (m, 1H), 4.99ꢀ4.94 (m, 1H), 4.66ꢀ4.60 (m, 1H), 3.78 (s, 3H),
1
3
.25ꢀ2.01 (m, 3H), 1.96ꢀ1.71 (m, 2H); C NMR (101 MHz, CDCl ) δ 30.0, 37.9, 55.5, 73.5,
3
113.7, 114.7, 127.1, 136.8, 138.2, 158.9.
8g: Synthesized according to Method A furnishing the new compound in 53% (5.29 mmol,
1
1.42 g) isolated yield as a white solid; R
f
0.61 (20% ethyl acetate in hexane). H NMR (400
MHz, CDCl
3
) δ 7.45ꢀ7.28 (m, 5H), 7.25 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 5.82
(ddt, J = 17.2, 10.2, 6.5 Hz, 1H), 5.05 (s, 2H), 5.03 (dq, J = 17.2, 1.7 Hz, 1H), 4.99ꢀ4.95 (m,
1H), 4.62 (dd, J = 7.2, 6.1 Hz, 1H), 2.19ꢀ2.00 (m, 2H), 1.93ꢀ1.83 (m, 2H), 1.81ꢀ1.71 (m, 1H);
1
3
C NMR (101 MHz, CDCl
3
) δ 158.2, 138.2, 137.0, 136.9, 128.6, 127.9, 127.4, 127.1, 114.9,
+
114.7, 73.6, 70.0, 37.9, 30.1. HRMS: calculated for C18
H20NaO
2
(M+Na) 291.1356; found
2
8
1
91.1356.
h: Synthesized according to Method A furnishing the new compound in 51% (4.59 mmol,
1
.02 g) isolated yield as a yellow oil; R
f
0.54 (20% ethyl acetate in hexane). H NMR (400
3
MHz, CDCl ) δ 6.87 (d, J = 1.7 Hz, 1H), 6.82 (dd, J = 8.3, 1.7 Hz, 1H), 6.80 (d, J = 8.3 Hz,
1H), 5.82 (ddt, J = 17.2, 10.3, 6.7 Hz, 1H), 5.02 (dq, J = 17.2, 1.6 Hz, 1H), 4.99ꢀ4.94 (m, 1H),
4.59 (dd, J = 7.5, 5.8 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 2.45 (bs, 1H), 2.19ꢀ2.01 (m, 2H),
1
3
1
1
.93ꢀ1.81 (m, 1H), 1.80ꢀ1.69 (m, 1H); C NMR (101 MHz, CDCl ) δ 148.8, 148.1, 138.1,
3
37.2, 118.0, 114.7, 110.7, 108.8, 73.6, 55.7, 55.6, 37.8, 30.0. HRMS: calculated for
+
C
13
H18NaO
3
(M+Na) 245.1148; found 245.1148.
27
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The Journal of Organic Chemistry
Page 28 of 56
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
1
8
i: Synthesized according to Method A furnishing the known compound in 61% (9.13
1
mmol, 1.39 g) isolated yield as a yellow oil; R 0.71 (20% ethyl acetate in hexane). H NMR
f
(
400 MHz, CDCl
3
) δ 7.38ꢀ7.34 (m, 1H), 7.32 (dd, J = 3.2, 1.9 Hz, 1H), 6.23 (d, J = 3.2 Hz,
1
4
H), 5.83 (ddt, J = 17.1, 10.3, 6.6 Hz, 1H), 5.05 (dq, J = 10.1, 1.6 Hz, 1H), 5.01ꢀ4.96 (m, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
.69 (t, J = 6.8 Hz, 1H), 2.24ꢀ1.98 (m, 3H), 1.94 (q, J = 7.1 Hz, 2H); C NMR (101 MHz,
CDCl
3
) δ 156.6, 141.9, 137.8, 115.1, 110.1, 105.9, 67.2, 34.5, 29.7.
2
8
8
j: Synthesized according to Method A furnishing the known compound in 71% (7.10
1
mmol, 1.28 g) isolated yield as yellow oil; R
400 MHz, CDCl
f
0.69 (20% ethyl acetate in hexane). H NMR
(
3
) δ 7.32–7.26 (m, 2H), 7.04–6.99 (m, 2H), 5.82 (ddt, J = 17.1, 10.2, 6.5 Hz,
H), 5.03 (dq, J = 17.2, 1.6 Hz, 1H), 5.00–4.96 (m, 1H), 4.70ꢀ4.64 (m, 1H), 2.17–1.98 (m,
H), 1.93–1.70 (m, 2H).
1
3
8
3
2
k: Synthesized according to Method A furnishing the known compound in 71% (7.06
1
mmol, 1.39 g) isolated yield as a pale yellow oil; R
NMR (400 MHz, CDCl
4.62 (m, 1H), 2.21ꢀ2.03 (m, 2H), 2.02ꢀ1.68 (m, 3H).
f
0.62 (20% ethyl acetate in hexane). H
3
) δ 7.34ꢀ7.22 (m, 4H), 5.90ꢀ5.74 (m, 1H), 5.09ꢀ4.94 (m, 2H), 4.72ꢀ
3
3
8
l: Synthesized according to Method A furnishing the known compound in 50% (4.31
1
mmol, 885 mg) isolated yield as a green oil; R 0.76 (20% ethyl acetate in hexane). H NMR
f
(
400 MHz, CDCl
3
) δ 7.19 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 8.9 Hz, 2H), 5.82 (ddt, J = 17.1,
1
0.3, 6.4 Hz, 1H), 5.01 (dq, J = 17.1, 1.8 Hz, 1H) 4.97ꢀ4.92 (m, 1H), 4.57ꢀ4.52 (m, 1H), 2.91
1
3
(s, 6H), 2.18ꢀ1.93 (m, 3H), 1.94ꢀ1.83 (m, 1H), 1.80ꢀ1.69 (m, 1H); C NMR (101 MHz,
CDCl ) δ 150.1, 138.4, 132.5, 126.9, 114.6, 112.5, 73.7, 40.6, 37.6, 30.2.
3
3
2
8
m: Synthesized according to Method A furnishing the known compound in 57% (6.81
1
mmol, 1.20 g) isolated yield as a colorless oil; R
NMR (400 MHz, CDCl
.72 (m, 1H), 4.98ꢀ4.92 (m, 1H), 4.92ꢀ4.88 (m, 1H), 2.09ꢀ1.97 (m, 2H), 1.96ꢀ1.84 (m, 3H),
f
0.52 (20% ethyl acetate in hexane). H
3
) δ 7.44ꢀ7.39 (m, 2H), 7.36ꢀ7.29 (m, 2H), 7.25ꢀ7.19 (m, 1H), 8.83ꢀ
5
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
3
1
.55 (s, 3H); C NMR (101 MHz, CDCl
3
) δ 147.6, 138.7, 128.1, 126.5, 124.7, 114.5, 74.6,
43.0, 30.2, 28.4.
3
4
8
n: Synthesized according to Method B furnishing the known compound in 59% (4.71
1
mmol, 472 mg) isolated yield as a colorless oil; R
NMR (400 MHz, CDCl
f
0.57 (20% ethyl acetate in hexane). H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
) δ 5.83 (ddq, J = 17.1, 10.2, 6.3 Hz, 1H), 5.04 (dq, J = 17.1, 1.7 Hz,
H), 4.99ꢀ4.95 (m, 1H), 3.82 (sext, J = 6.2 Hz, 1H), 2.24ꢀ2.07 (m, 2H), 1.71 (bs, 1H), 1.62ꢀ
1
1
13
.49 (m, 2H), 1.20 (d, J = 6.4 Hz, 3H); C NMR (101 MHz, CDCl ) δ 138.5, 114.7, 67.6,
3
38.2, 30.1, 23.4.
3
2
8
o: Synthesized according to Method A furnishing the known compound in 67% (8.04
1
mmol, 1.37 g) isolated yield as a colorless oil; R
f
0.67 (20% ethyl acetate in hexane). H
NMR (400 MHz, CDCl
3
) δ 5.91ꢀ5.77 (m, 1H), 5.08ꢀ5.00 (m, 1H), 4.99ꢀ4.91 (m, 1H), 3.65ꢀ
3
.54 (m, 1H), 2.27ꢀ2.05 (m, 2H), 1.76ꢀ1.20 (m, 12H), 0.89 (t, J = 6.9 Hz, 3H).
3
5
8
p: Synthesized according to Method A furnishing the known compound in 73% (13.8
1
mmol, 2.94 g) isolated yield as a yellow oil; R
f
0.64 (20% ethyl acetate in hexane). H NMR
(400 MHz, CDCl
3
) δ 5.84 (ddt, J = 17.1, 10.3, 6.9 HZ, 1H), 5.05 (dq, J = 17.1, 1.7 Hz, 1H),
4
5
1
8
.96 (ddt, J = 10.3, 1.7, 1.2 Hz, 1H), 3.65ꢀ3.57 (m, 1H), 2.25ꢀ2.07 (m, 2H), 1.64ꢀ1.36 (m,
13
H), 1.36ꢀ1.18 (m, 13H), 0.88 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl ) δ 138.6,
3
14.7, 71.5, 37.5, 36.5, 31.9, 30.1, 29.66, 29.60, 29.55, 29.3, 25.6, 22.7, 14.1.
3
6
q: Synthesized according to Method A furnishing the known compound in 64% (8.00
1
mmol, 1.41 g) isolated yield; R
f
0.59 (20% ethyl acetate in hexane). H NMR (400 MHz,
CDCl ) δ 7.32ꢀ7.26 (m, 2H), 7.24ꢀ7.17 (m, 3H), 5.82 (ddt, J = 17.1, 10.2, 6.7 Hz, 1H), 5.07ꢀ
3
5
1
.00 (m, 1H), 4.99ꢀ4.94 (m, 1H), 3.80 (tt, J = 8.1, 4.6 Hz, 1H), 2.80 (dd, J = 13.6, 4.6 Hz,
13
H), 2.64 (dd, J = 13.6, 8.1 Hz, 1H), 2.30ꢀ2.09 (m, 2H), 1.70 (bs, 1H), 1.66ꢀ1.61 (m, 2H); C
3
NMR (101 MHz, CDCl ) δ 138.5, 138.4, 129.5, 128.5, 126.4, 114.8, 77.0, 44.0, 35.8, 30.0.
29
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