Asymmetric β-boration of α,β-unsaturated N -acyloxazolidinones by [2.2]paracyclophane-based bifunctional catalyst

Article abstract of DOI:10.1021/ol302839d

An efficient copper-catalyzed asymmetric conjugate boration has been achieved by exploiting a new planar and central chiral bicyclic triazolium ligand. This protocol was highly efficient and gave a variety of chiral secondary alkylboronates in 97-99% ee. A preliminary mechanistic study supports the bifunctional nature of the catalyst.

Full text of DOI:10.1021/ol302839d

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5780–5783
Asymmetric β‑Boration of
r,β-Unsaturated N‑Acyloxazolidinones
by [2.2]Paracyclophane-Based
Bifunctional Catalyst
Lei Zhao, Yudao Ma,* Wenzeng Duan, Fuyan He, Jianqiang Chen, and Chun Song
Department of Chemistry, Shandong University, Shanda South Road No. 27,
Jinan 250100, P. R. China
ydma@sdu.edu.cn
Received October 15, 2012
ABSTRACT
An efficient copper-catalyzed asymmetric conjugate boration has been achieved by exploiting a new planar and central chiral bicyclic triazolium
ligand. This protocol was highly efficient and gave a variety of chiral secondary alkylboronates in 97À99% ee. A preliminary mechanistic study
supports the bifunctional nature of the catalyst.
Optically active R-substituted organoboron derivatives
are not only very important synthetic intermediates which
can be transformed into various functional groups1 but
also useful chiral building blocks for many biologically
active compounds.2 In 1997, the Norman and Marder
groups reported the first racemic work on the diboration
of R,β-unsaturated carbonyl compounds which drives
the development of the catalytic asymmetric variant of
this reaction.3 Recently, asymmetric conjugate addition
of diboron reagents to R,β-unsaturated compounds
through nucleophilic borylcopper species has attracted
considerable interest.4 Yet, although progress on Cu(I)-
catalyzed asymmetric β-boration has been substantial, de-
sign and synthesis of new ligands to broaden the substrate
scope and enhance the selectivity is still a challenge.
(1) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
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H. K.; Aggarwal, V. K. Chem.;Eur. J. 2011, 17, 13124. (e) Sole, C.;
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Figure 1. Design and application of triazolium salts.
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Mazet, C. ChemCatChem 2010, 2, 501. (d) Hartmann, E.; Vyas, D. J.;
Oestreich, M. Chem. Commun. 2011, 47, 7917. For organocatalytic
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Chem., Int. Ed. 2010, 49, 5130. (f) Wu, H.; Radomkit, S.; O’Brien, J. M.;
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r
10.1021/ol302839d
Published on Web 11/06/2012
2012 American Chemical Society

In recent years, chiral bicyclic 1,2,4-triazolium salts have
been developed and successfully applied in asymmetric
organocatalysis.5 Their advantages arise from bicyclic
restriction with the placement of the stereocenter and wide
tunability of the triazolium backbone. Although these salts
have been established, there are still limitations on their
synthesis and application. For example, the chiral center is
only derived from one side of the bicyclic backbone6 and
the bicyclic1,2,4-triazolium salts have not been reported in
transition metal catalysis.7 Based on these facts, we present
two questions: (1) Can we introduce a chirality element
on the triazolium skeleton in the N1 position? (2) Can the
bicyclic 1,2,4-triazolium salts be applied in transition metal
catalysis (Figure 1)?
hydrazine hydrochloride salt 4 can be obtained in pure
form by acid hydrolysis of the optically active 3 which
was synthesized from readily available chiral 4-amine-
[2.2]paracyclophane 111 (Scheme 1). Triazolium salts 6a
and 6b were then generated by treatment of 4 with imidate
5 intwo steps, sothe first triazolium saltsderivedfromPCP
were synthesized. Notably, this procedure also provides
a new way to synthesize other kinds of triazolium salts with
different aromatic groups in the N1 position, especially
some unstable aromatic hydrazine compounds.
Scheme 1. Synthesis of NHC Precursors
As a chiral source, planar chiral [2.2]paracyclophane
(PCP) has inspired great interest from researchers in
asymmetric catalysis.8 Recently our group and co-workers
employed a series of planar chiral NHC precursors based
on PCP and used them in asymmetric transition metal
catalysis.9 Herein, we report the synthesis of bicyclic 1,2,4-
triazolium salts based on PCP and their applications in
asymmetric Cu(I)-catalyzed β-boration of R,β-unsaturated
N-acyloxazolidinones.
Ourstudy beganwiththesynthesisof planar chiralNHC
precursors. On the basis of previous reports on synthesis
of 1,2,4-triazolium salts,10 the hydrazine hydrochloride
salt based on PCP was synthesized first. Unfortunately,
the hydrazine hydrochloride salt was unstable and difficult
to isolate in pure form. Interestingly, the formyl-protected
With novel chiral triazolium salts in hand, we began to
testwhetherourdesignedchiraltriazolium salts6canactas
chiral ligands in Cu(I)-catalyzed asymmetric β-boration.
As a Michael acceptor, R,β-unsaturated N-acyloxazolidinone
has been widely used in asymmetric conjugate addi-
tion reactions. The appeal of such an approach is that
N-acyloxazolidinone can be easily removed and converted
into a variety of carboxylic acids and their derivatives.13
Asa result, the additionofbis(pinacolato)diboron (B2Pin2)
to N-cinnamoyloxazolidin-2-one 7a was chosen as a model
reaction: 5 mol % of Cu(NHC) complex was prepared
from Cu2O (2.5 mol %) and chiral triazolium salt (S,Sp)-6a
(5 mol %) in THF, and then 5 mol % of Cs2CO3, 1.1 equiv
of B2Pin2, 1.0 equiv of 7a, and 2 equiv of MeOH were
added (Table 1, entry 1). To our delight, the reaction was
completed within 10 min at 0 °C, and product 8a was
obtained in good yield and enantioselectivity (93% yield,
94% ee). With this encouraging result, we screened dif-
ferent bases in place of Cs2CO3. Strong bases such as
KOtBu and NaOtBu showed high reactivity, although
the enantioselectivity decreased slightly, while weak bases
CH3COONa and CsF provided poorer reactivity and
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Heidelberg, Germany, 2007. (b) D.-Gonzalez, S.; Marion, N.; Nolan, S. P.
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R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119, 6207. (b) Hermanns, N.;
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S. E.; Knight, J. D. Org. Biomol. Chem. 2003, 1, 1256. (e) Bolm, C.;
Focken, T.; Raabe, G. Tetrahedron: Asymmetry 2003, 14, 1733. (f) Wu,
X.-W.; Zhang, T.-Z.; Hou, X.-L. Tetrahedron: Asymmetry 2004, 15,
2357. (g) Whelligan, D. K.; Bolm, C. J. Org. Chem. 2006, 71, 4609.
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(k) Gleiter, R.; Hopf, H. Modern Cyclophane Chemistry; Wiley-VCH:
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3241. (c) Ma, Q.; Ma, Y.; Liu, X.; Duan, W.; Qu, B.; Song, C.
Tetrahedron: Asymmetry 2010, 21, 292. (d) Hong, B.; Ma, Y.; Zhao,
L.; Duan, W.; He, F.; Song, C. Tetrahedron: Asymmetry 2011, 22, 1055.
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Pizzo, F.; Ruzziconi, R. J. Org. Chem. 1997, 62, 3744. (b) Duan, W.;
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Org. Lett., Vol. 14, No. 22, 2012
5781

Table 1. Screening of Reaction Conditionsa
Table 2. Substrate Scope of N-Acyloxazolidinones 7a
entry
7, R
t (°C)b
8
yield (%)c ee (%)d
1
7a, Ph
À40
0
8a
8b
8c
8d
8e
8f
95
92
94
93
90
92
91
87
94
96
90
90
91
84
86
93
88
99
99
99
99
98
99
99
99
98
98
98
99
99
98
99
97
99
2
7b, 4-MeC6H4
7c, 2-MeC6H4
7d, 4-ClC6H4
7e, 4-BrC6H4
7f, 4-FC6H4
3
À40
À40
À40
À40
0
entry
ligand
base
solvent
yield (%)b
ee (%)c
4
5
1
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6a
Cs2CO3
KOtBu
NaOtBu
CH3OONa
CsF
THF
93
90
92
48
trace
91
84
74
94
90
88
92
88
92
94
93
88
72
À
6
2
THF
7
7g, 3-ClC6H4
7h, 3-Cl,4-FC6H3
7i, 4-MeOC6H4
7j, 2-MeOC6H4
7k, 3,4-(MeO)2C6H3
7l, 1-naphthyl
7m, 2-naphthyl
7n, 2-furyl
8g
8h
8i
3
THF
8
0
4d
5e
6
THF
9
0
THF
10
11
12
13
14
15
16
17
0
8j
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
dioxane
DME
tBuOH
PhMe
CH2Cl2
PhMe
PhMe
PhMe
PhMe
94
82
90
99
70
70
87
81
97
0
8k
8l
7
0
8f
9
0
8m
8n
8o
8p
8q
0
10
11
12
13
14g
7o, cyclohexyl
7p, Me
À40
À40
À40
7q, n-propyl
a The reaction was carried out with ligand (5 mol %), Cu2O
(2.5 mol %), Cs2CO3 (5 mol %), B2Pin2 (0.11 mmol), 7 (0.1 mmol)
and MeOH (0.2 mmol) in toluene (1 mL). b Reaction for 10 min at 0 °C,
2 h at À40 °C. c Yield of isolated product. d Determined by HPLC
analysis using a chiral stationary phase (Chiralpak IA column).
a The reaction was carried out with ligand (5 mol %), Cu2O(2.5mol%),
base (5 mol %), B2Pin2 (0.11 mmol), 7a (0.1 mmol), and MeOH (0.2 mmol)
in solvent (1 mL) at 0 °C for 10 min. b Yield of isolated product.
c Determined by HPLC analysis using a chiral stationary phase
(Chiralpak IA column). d Reaction for 4 h. e 7a was consumed for 6 h;
no product found. f Without adding MeOH. g The reaction was carried
out with ligand (1 mol %), Cu2O (0.5 mol %), base (1 mol %), B2Pin2
(1.40 g, 5.5 mmol), 7a (1.08 g, 5.0 mmol), and MeOH (10 mmol) in
toluene (20 mL) at 0 °C for 30 min.
R,β-unsaturated N-acyloxazolidinones. As summarized in
Table 2, various β-substituted N-acyloxazolidinones in-
cluding those bearing electron-withdrawing and -donating
substituents at different positions on the aromatic ring,
as well as heterocyclic groups, could be tolerated and
gave the corresponding compounds 8aÀn in good yield
(84À96%) and excellent enantioselectivity (98À99% ee).
To gain excellent enantioselectivity we needed to lower the
temperature to À40 °C for some substrates, because the
enantioselectivity slightly decreased at 0 °C (7c in 98% ee,
7dÀf in 97% ee, not shown in Table 2). The scope was also
extended to β-aliphatic-substituted N-acyloxazolidinones,
which also gave the product in good yield and enantios-
electivity (Table 2, entries 15À17). It is worth pointing out
that the nature of the R substituents had a limited influence
on the reactivity and enantioselectivity. The absolute con-
figuration of the product was determined to be S from
single-crystal X-ray analysis of the bromo-containing pro-
duct 8e. The configurations of other products were as-
signedtoS by comparisonwiththe CDspectraof 8aand 8e
(see Supporting Information).
enantioselectivity (Table 1, entries 2À5). Among the sol-
vents screened(Table 1, entries6À10), toluene gave the best
yield (94% yield) and excellent enantioselectivity (99% ee)
so it was chosen as the optimal solvent (Table 1, entry 9).
Then, we testedchira triazolium salt (S,Rp)-6bas the ligand.
The enantioselectivity dropped severely under the opti-
mized conditions, but the absolute configuration was not
changed (Table 1, entry 11). The results indicated that the
diastereomers (S,Rp)-6b showed mismatched planar and
central chirality while (S,Sp)-6a was matched. In addition,
the absolute configuration was determined by the central
chirality of the triazolium salts 6. Interestingly, the chiral
triazolium salt (S,Sp)-6c without hydroxyl afforded de-
creased enantioselectivity (Table 1, entry 12) which re-
vealed that the hydroxyl group plays an important role
in the catalytic process. The chiral triazolium salt (S)-6d,
bearing only the element of central chirality, gave rise to the
product in moderate enantioselectivity (Table 1, entry 13).
Notably, asymmetric boration was conducted on a gram
scale at a low catalyst loading (1 mol %), and the reaction
completed within 30 min and gave the corresponding
product in 92% yield and 97% ee (Table 1, entry 14).
Having identified the optimal set of reaction condi-
tions, we then investigated the reactions with a variety of
As we mentioned above, the boration products are
versatile intermediates in organic synthesis and can be
transformed into a number of valuable compounds. For
example, treatment of 8a with LiOH/H2O2 gave (S)-3-
hydroxy-3-phenylpropanoic acid in one step without loss
of enantiopurity (Scheme 2). The result is notable because
chiral β-hydroxy carboxylic acids are important building
blocks for pharmaceuticals and natural products.12
5782
Org. Lett., Vol. 14, No. 22, 2012

Scheme 2. Synthesis of Chiral 3-Hydroxy-3-Phenylpropanoic
Acid
Scheme 3. Asymmetric β-Boration of R,β-Unsaturated Amide
Figure 3. Proposed transition state model.
ThebigPCP group shields the Refaceofthesubstrate; thus
the Cu-Bpin could only attack from the Si face of the
substrate, accounting for the absolute configuration of the
final products. However, it is difficult to explain whether
it is the boron that activates the carbonyl group or the
H-bonding effect.15 We think this is a new bifunctional
catalyst in the asymmetric boration reaction, and such a
powerful precatalyst might find utility in other metal-
catalyzed asymmetric processes.
In conclusion, we have developed a series of new planar
and central chiral bicyclic triazolium salts based on
[2.2]paracyclophane and demonstrated their utilization
in the Cu(I)-catalyzed asymmetric β-boration of R,β-un-
saturated N-acyloxazolidinone. The procedure tolerates
a relatively wide range of substrates and shows excellent
selectivity (up to 99% ee) and high reactivity (up to 96%
yield). Further investigations into other reaction variants
in both organocatalysis and organometallic catalysis are
currently underway in our laboratory.
Figure 2. Relationship between the enantiomeric excess of ligand
6a and that of the product 8a.
For an in-depth understanding of the reaction mechan-
ism, the relationship between the ligand 6a and the pro-
duct 8a in enantioselectivity was examined. As shown in
Figure 2, a clear linear effect was observed on this reaction.
We therefore assumed that a single catalyst was involved in
the activation of the R,β-unsaturated N-acyloxazolidinone.14
To gain further insight into the correlation between 6a
and the substrate 7, an R,β-unsaturated amide was also
investigated in the β-boration reaction, and the boration
product was only in 67% ee under the optimized condi-
tions (Scheme 3). The poor enantiomeric excess indicates
the possible coordination between the catalyst and 7.
On the basis of these observations, two possible transi-
tion states are proposed in Figure 3. It is possible that
the transition state is a bridged complex with two active
centers in which the conformation of the substrate is fixed.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant No. 20671059).
Supporting Information Available. Full experimental
details and compound characterization data. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(14) (a) Satyanarayana, T.; Abraham, S.; Kagan, H. B. Angew.
Chem., Int. Ed. 2009, 48, 456. (b) Zhang, Z.; Wang, Z.; Zhang, R.; Ding,
K. Angew. Chem., Int. Ed. 2010, 49, 6746.
(15) For examples on boron activation or H-bonding effects, see: (a)
Zhang, Z.; Jain, P.; Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 10961.
(b) Sun, L. H.; Shen, L. T.; Ye, S. Chem. Commun. 2011, 47, 10136.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5783