Enantioselective copper-catalyzed O-H insertion of α-diazo phosphonates

Article abstract of DOI:10.1055/s-0030-1259710

A copper-catalyzed asymmetric O-H insertion of -di-azo phosphonates with alcohols by using chiral spiro bisoxazoline ligands was developed. The insertion reaction exhibited good yields (up to 89%) with high enantioselectivities (up to 98% ee) and provided

Full text of DOI:10.1055/s-0030-1259710

LETTER
919
Enantioselective Copper-Catalyzed O–H Insertion of a-Diazo Phosphonates
O
–H Insertion
h
of
a
-Diazo
P
o
hosphonate
u
-Fei Zhu, Wang-Qiao Chen, Qian-Qian Zhang, Hong-Xiang Mao, Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
Fax +86(22)23506177; E-mail: qlzhou@nankai.edu.cn
Received 19 November 2010
Dedicated to Professor Xi-Yan Lu and Professor Li-Xin Dai for their life-long contributions to the development of organic chemistry
CuOTf (5 mol%)
(Sa,S,S)-1c (6 mol%)
NaBArF (6 mol%)
Abstract: A copper-catalyzed asymmetric O–H insertion of a-di-
OR2
N2
azo phosphonates with alcohols by using chiral spiro bisoxazoline
ligands was developed. The insertion reaction exhibited good yields
(up to 89%) with high enantioselectivities (up to 98% ee) and pro-
vided an efficient approach for synthesis of enantiomerically en-
riched a-alkoxy and hydroxy phosphonate derivatives starting from
readily available materials.
OMe
OMe
OMe
OMe
R2OH
+
∗
R1
P
R1
P
CH2Cl2, 25 o
C
3
O
O
2
4
O
(Sa,S,S)-1a R = Ph
(Sa,S,S)-1b R = Bn
(Sa,S,S)-1c R = i-Pr
(Sa,S,S)-1d R = t-Bu
R
R
Key words: asymmetric O–H insertion, chiral spiro ligands, copper
catalysts, a-diazo phosphonates, a-alkoxy phosphonates
N
N
O
Enantiomerically enriched a-functionalized phosphonate
derivatives are important building blocks for biologically
active compounds, particular for pharmaceuticals. The
development of efficient and enantioselective methods for
preparation of a-functionalized phosphonates is of high
value and has drawn increasing attention.1 Transition-
metal-catalyzed asymmetric O–H bond insertion reaction
of a-diazo phosphonates provides an convenient approach
to chiral a-alkoxy and hydroxy phosphonate derivatives.2
Although the copper- and iron-catalyzed asymmetric O–
H insertions of a-diazo esters with alcohols, phenols, and
even water have been accomplished with excellent enan-
tioselectivities by Fu’s group3 and our group,4 the enan-
tioselective O–H insertions of a-diazo phosphonates have
not been explored yet,5 partially due to high stability of a-
diazo phosphonates.6 As a part of our continuous efforts
on the transition-metal-catalyzed asymmetric hetero-
atom–hydrogen bond (X–H, X = N, O, S, Si, etc.) inser-
tion reactions,7 we here report a copper-catalyzed
asymmetric O–H insertion of a-diazo phosphonates with
alcohols by using chiral spiro bisoxazoline ligands 1
(Scheme 1). The O–H insertion reaction exhibited good
yields (up to 89%) with high enantioselectivities (up to
98% ee). To the best of our knowledge, this is the first
enantioselective X–H insertion reaction of a-diazo phos-
phonates.
Scheme 1
tion product, dimethyl butoxy(phenyl)methylphospho-
nate (4aa) in 76% yield with 73% ee (Table 1, entry 1).
The change of ligand (Sa,S,S)-1a to (Ra,S,S)-1a slowed the
reaction down and markedly decreased the yield and
enantioselectivity (entry 2), indicating that the ligand
(Sa,S,S)-1a has matched chiralities, which is consistent
with our previous findings in the O–H and N–H insertion
reactions of a-diazo esters. The further studies on the sub-
stituent effects of oxazoline rings of ligand 1 revealed that
the alkyl substituents, such as benzyl and isopropyl, were
beneficial for gaining high enantioselectivity (Table 1,
entries 3 and 4). The ligand (Sa,S,S)-1c with isopropyl
groups exhibited best chiral induction (Table 1, entry 4).
Increasing the steric hindrance of the substituent on ox-
azoline rings of ligand to tert-butyl (1d) had a negative
effect on the reactivity as well as enantioselectivity
(Table 1, entry 5). The solvent impacted on the reactivity
and enantioselectivity of reaction. Similar with other cop-
per-catalyzed carbene transfer reactions, the O–H inser-
tion of a-diazo phosphonates performed well in
chlorinated solvents, giving good yields and high ee val-
ues (Table 1, entries 4, 6, and 7). The less polar solvent
toluene slowed down the reaction significantly and af-
forded only moderate enantioselectivity (Table 1, entry
8). The reaction was fully prohibited when performed in
THF, a strong coordinating solvent (Table 1, entry 9). All
the tested copper salts including Cu(I) and Cu(II) were
suitable catalyst precursors for the insertion reaction.
However, Cu(I) precursors such as CuCl, CuPF6, and
CuOTf afforded higher yields and enantioselectivities
comparing to Cu(II) precursor CuCl2 (Table 1, entries 4,
10–12). Among the copper precursors studied, CuOTf
showed the best reactivity and enantioselectivity (Table 1,
entry 11). The additive NaBArF played an important role
In the initial study, the insertion reaction of dimethyl di-
azo(phenyl)methylphosphonate (2a) with n-butanol (3a)
was performed in dichloromethane at 25 °C in the pres-
ence of 5 mol% catalyst generated in situ from CuCl,
8
(Sa,S,S)-1a, and NaBArF (Table 1). To our delight, the
reaction ran smoothly and afforded the desired O–H inser-
SYNLETT 2011, No. 7, pp 0919–0922
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259710; Art ID: W32310ST
© Georg Thieme Verlag Stuttgart · New York

920
S.-F. Zhu et al.
LETTER
enantioselectivity of the catalysts. Although the iron was
found to be superior catalyst for O–H insertion of a-diazo
esters,4c it was proven to be less efficient for the present
insertion reaction (Table 1, entry 17).
Table 1 Copper-Catalyzed Asymmetric Insertion of Dimethyl Di-
azo(phenyl)methylphosphonate (2a) into O–H Bonds of n-Butanol:
Optimization of Reaction Conditionsa
[Cu] (5 mol%)
ligand (6 mol%)
NaBArF (6 mol%)
N2
On-Bu
OMe
OMe
OMe
Under the optimal reaction conditions, the insertion reac-
tions between dimethyl diazo(phenyl)methylphosphonate
(2a) with various alcohols were carried out. As shown in
Table 2, all the tested saturated primary alcohols accom-
plished the insertion reaction within one hour, yielding the
corresponding products 2-alkoxy phosphonates in good
yields (74–89%) with high enantioselectivities (84–92%
ee) (Table 2, entries 1–8). In contrast, the secondary alco-
hol, isopropanol afforded insertion product in only 19%
yield, but with 89% ee (Table 2, entry 9). Besides, the
prop-2-en-1-ol (3j) can also complete the transformation
albeit a longer reaction time was required for full conver-
sion and only moderate enantioselectivity (38% ee) was
obtained (Table 2, entry 10). Interestingly, introducing a
2-methyl group to the allylic alcohol, the reaction became
faster and the enantioselectivity was significantly in-
creased to 85% ee (Table 2, entry 11). The benzyl alcohol
(3l) was also suitable substrate for O–H insertion with 2a,
giving acceptable yield (69%) and good enantioselectivity
(87% ee) under the standard reaction conditions (Table 2,
entry 12).
P
*
P
+
n-BuOH
3a
OMe
O
O
2a
4aa
Entry [Cu]
Ligand
Solvent Time Yield ee
(h) (%)b (%)c
1
2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
(Sa,S,S)-1a CH2Cl2
(Ra,S,S)-1a CH2Cl2
(Sa,S,S)-1b CH2Cl2
(Sa,S,S)-1c CH2Cl2
1.5 76 73
4
1
3
31
9
3
77 87
88 90
4
5
(Sa,S,S)-1d CH2Cl2 12 70 19
6
(Sa,S,S)-1c CHCl3
(Sa,S,S)-1c DCE
3
6
84 90
85 83
7
8
(Sa,S,S)-1c toluene 12 65 40
9
(Sa,S,S)-1c THF
n.r.d
3
–
–
10
11
12
CuPF6(MeCN)4
(Sa,S,S)-1c CH2Cl2
86 91
89 91
79 74
77 48
63 87
88 10
We then explored the scope of 2-diazo phosphonate sub-
strates 2 in the O–H insertion with n-butanol (Table 3).
The impact of substituent groups on phenyl of dimethyl
(CuOTf)2·toluene (Sa,S,S)-1c CH2Cl2
CuCl2 (Sa,S,S)-1c CH2Cl2
1
3
13e (CuOTf)2·toluene (Sa,S,S)-1c CH2Cl2
5
Table 2 Copper-Catalyzed Asymmetric Insertion of Dimethyl Di-
azo(phenyl)methylphosphonate (2a) into the O–H Bond of Alcoholsa
14f
15
16
17
(CuOTf)2·toluene (Sa,S,S)-1c CH2Cl2
(CuOTf)2·toluene (S,S)-Box CH2Cl2
1
(CuOTf)2⋅toluene (5 mol%)
OR2
N2
1
(Sa,S,S)-1c (6 mol%)
OMe
OMe
OMe
OMe
NaBArF (6 mol%)
*
P
P
+
(CuOTf)2·toluene (S,S)-Pybox CH2Cl2
FeCl2·4H2O
3
n.p.g
–
R2OH
CH2Cl2, 25 °C
3
O
O
(Sa,S,S)-1c CH2Cl2 48 57 rac
2a
4
a Reaction conditions: [Cu]/ligand/NaBArF/2a/
3a = 0.02:0.024:0.024:0.4:2.0 (mmol), in 4 mL solvent at 25 °C.
b Isolated yield.
Entry R2
Product
4aa
4ab
4ac
Time (h) Yield (%)ee (%)
1
2
n-Bu
Me
Et
1
1
89
87
82
82
84
87
74
83
19
81
70
69
91
84
91
87
88
90
92
92
89
38
85
87
c Determined by HPLC using a Chiralcel OJ-H column.
d No reaction.
e Without NaBArF.
f Using 2 equiv of n-BuOH.
3
1
g No desired product.
4
n-C8H17
4ad
4ae
1
for the insertion reaction, because the absence of additive
lowered the yield as well as enantioselectivity (Table 1,
entry 13). The sufficient excess of n-butanol was neces-
sary for obtaining high yield. Decreasing the amount of n-
butanol to two equivalents compromised the reactivity of
reaction (Table 1, entry 14). Under the standard reaction
conditions, chiral bisoxazoline ligand (S,S)-Box9 only af-
forded the O–H insertion product in 10% ee albeit with
good yield (Table 1, entry 15). Although the copper com-
plex of (S,S)-Pybox10 promoted the decomposition of di-
azo compound 2a easily, no desired O–H insertion
product was determined (Table 1, entry 16). These results
clearly demonstrated that the spirobiindane backbone of
the ligands 1 plays a key role in tuning both reactivity and
5
n-C10H21
1
6
TMSCH2CH2
i-Bu
4af
1
7
4ag
4ah
4ai
1
8
i-Arm
1
9
i-Pr
1
10
11
12
CH=CHCH2
4aj
12
3
CH=C(CH3)CH2 4ak
Bn 4al
3
a The reaction conditions were the same as those in Table 1, entry 11.
For analyses of products, see Supporting Information.
Synlett 2011, No. 7, 919–922 © Thieme Stuttgart · New York

LETTER
O–H Insertion of a-Diazo Phosphonates
921
a-Alkoxy phosphonates have potential utilities in pharma-
ceutical chemistry. For instance, a-alkoxynaphthylmeth-
ylphosphonic acid has been developed as a highly active
purple acid phosphatases (PAPs) inhibitor.11 Moreover, a-
alkoxy phosphonates can be easily transformed to a-hy-
droxy phosphonates or a-hydroxy phosphonic acids,
which are also biologically important compounds.1c As an
example, the compound (R)-4af was converted into a-hy-
droxy phosphonate (R)-5 in the presence of trifluoro-
borane in high yield and with conservation of the
enantiomeric excess (Scheme 2).
Table 3 Copper-Catalyzed Asymmetric Insertion of Diazo Phos-
phonate into O–H Bonds of n-Butanola
(CuOTf)2⋅toluene (5 mol%)
(Sa,S,S)-1c (6 mol%)
N2
On-Bu
NaBArF (6 mol%)
OMe
OMe
OMe
OMe
+
n-BuOH
3a
R1
P
∗
R1
P
CH2Cl2, 25 °C
O
O
2
4
Entry R1
Product
4aa
4ba
4ca
Time (h) Yield (%) ee (%)
1
2
3
4
5
6
7
8
9
Ph
2-FC6H4
1
1
1
1
1
1
1
1
8
89
82
91
90
98
87
88
84
92
88
n.d.
The studies on the mechanism of the O–H insertion of a-
diazo phosphonates are in progress in this laboratory. At
this stage, we performed a kinetic isotopic experiment. As
shown in Scheme 3, the O–H insertion of a-diazo phos-
phonate 2a with methanol had a secondary kinetic isoto-
pic effect (kH/kD = 1.5). This quotient is significantly
lower than those of copper-catalyzed O–H insertion reac-
tion of a-diazo esters (kH/kD = 2.6)3 and implies that the
metal carbene formation, rather than the proton migration,
is most likely the rate-determining step.12
2-MeOC6H4
3-ClC6H4
3-MeOC6H4
4-ClC6H4
4-MeC6H4
2-naphthyl
Me
45
4da
4ea
86
80
4fa
83
4ga
4ha
4ia
70
80
In summary, asymmetric copper-catalyzed O–H insertion
reaction of a-diazo phosphonates with alcohols was de-
veloped. The copper complexes of chiral spiro bisoxazo-
line ligands were proven to be efficient catalysts,
producing a-alkoxy and hydroxy phosphonates in good
yields and high enantioselectivities.
<10%
a The reaction conditions were the same as those of Table 1, entry 11.
For analyses of products, see Supporting Information.
diazo(aryl)methylphosphonates was evaluated. All the
tested diazo phosphonates with different substituents on
the phenyl group afforded high level of enantioselectivity
(84–98% ee, Table 3, entries 2–7). The substrates with an
electron-donating group, such as methyl or methoxy
group, at 2- or 4-position showed higher enantioselectivi-
ty, with the diazo compound 2c with a 2-methoxy group
being the highest enantioselective (98% ee) (Table 3, en-
try 3). Besides phenyl group, 2-naphthyl-substituted diazo
phosphonates 2h also exhibited high yield with good
enantioselectivity (Table 3, entry 8). The substrate 2i,
containing an alkyl group at a-position of diazo phospho-
nate, was also examined in the O–H insertion reaction,
however, the desired insertion product was isolated in
very low yield (Table 3, entry 9).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the National Natural Science Foundation of China, the
National Basic Research Program of China (973 Program,
No.2010CB833300, 2011CB808600), the Ministry of Health
(2009ZX09501-017) and the ‘111’ project (B06005) of the Ministry
of Education of China for financial support.
References and Notes
(1) For reviews, see: (a) Wiemer, D. F. Tetrahedron 1997, 53,
16609. (b) Gröger, H.; Hammer, B. Chem. Eur. J. 2000, 6,
943. (c) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 2005,
16, 3295; and references therein. (d) Merino, P.; Marqués-
López, E.; Herrera, R. P. Adv. Synth. Catal. 2008, 350, 1195.
(2) For reviews on O–H insertion reactions, see: (a) Doyle, M.
P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; Wiley: New
York, 1998, Chap. 8. (b) Miller, D. J.; Moody, C. J.
TMS
OH
O
OMe
OMe
OMe
OMe
BF3⋅OEt2
P
P
O
O
CH2Cl2, r.t.
(R)-4af
89.7% ee
(R)-5
93% yield
89.2% ee
Scheme 2 Deprotection of (R)-4af
60% H
(CuOTf)2⋅toluene (5 mol%)
N2
OMe
OMe
(D)H
(Sa,S,S)-1c (6 mol%)
MeOH
OMe
OMe
(2.5 equiv)
NaBArF (6 mol%)
P
O
P
+
OMe
MeOD
(2.5 equiv)
CH2Cl2, 25 °C
80%
O
2a
4ab
kH/kD = 1.5
Scheme 3 Kinetic isotopic experiment
Synlett 2011, No. 7, 919–922 © Thieme Stuttgart · New York

922
S.-F. Zhu et al.
LETTER
Tetrahedron 1995, 51, 10811. (c) Zhang, Z.-H.; Wang, J.-B.
Tetrahedron 2008, 64, 6577.
Asymmetry 2001, 12, 1657.
(6) (a) Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R. H. B.;
Kluagowski, J. J. Tetrahedron 1994, 50, 3195. (b) Moody,
C. J.; Miller, D. J. Tetrahedron 1998, 54, 2257.
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ref. 4.
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(4) (a) Chen, C.; Zhu, S.-F.; Liu, B.; Wang, L.-X.; Zhou, Q.-L.
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Li, Y.; Cai, Y.; Zhou, Q.-L. J. Am. Chem. Soc. 2010, 132,
16374.
(5) For non-asymmetric rhodium-catalyzed O–H insertion
reactions of a-diazo phosphonates, see: (a) Paquet, F.;
Sinaÿ, P. J. Am. Chem. Soc. 1984, 106, 8313. (b) Davies,
M. J.; Moody, C. J.; Taylor, R. J. J. Chem. Soc., Perkin
Trans. 1 1991, 1. (c) Kim, S.; Fuchs, P. L. Tetrahedron Lett.
1994, 35, 7163. (d) Xu, C.-F.; Zhang, Y.-H.; Yuan, C.-Y.
Eur. J. Org. Chem. 2004, 2253. (e) Candeias, N. R.; Gois,
P. M. P.; Afonso, C. A. M. J. Org. Chem. 2006, 71, 5489.
For a rhodium-catalyzed diastereoselective O–H insertion of
chiral a-diazo phosphonic acid derivatives, see: (f) Moody,
C. J.; Morfitt, C. N.; Slawin, A. M. Z. Tetrahedron:
(8) NaBArF = sodium tetrakis[3,5-bis(trifluoromethyl)-
phenyl]borate.
(9) Box = 2,2¢-(1-methylethyliene)bis(4,5-dihydro-4-tert-
butyloxazole).
(10) Pybox = 2,6-bis(4,5-dihydro-4-isopropyloxazole)pyridine.
(11) McGeary, R. P.; Vella, P.; Mak, J. Y. W.; Guddat, L. W.;
Schenk, G. Bioorg. Med. Chem. Lett. 2009, 19, 163.
(12) (a) Helson, H. E.; Jorgensen, W. L. J. Org. Chem. 1994, 59,
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Soc. 2009, 131, 17783.
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