d-Fructose Based Spiro-Fused PHOX Ligands: Palladium Complexes and Application in Catalysis

Article abstract of DOI:10.1002/ejoc.201900490

Phosphinooxazoline (PHOX) ligands are an important class of ligands in asymmetric catalysis. Recently we reported on the synthesis of d-fructose based spiro-fused PHOX ligands. Here, we now present the application of these ligands in asymmetric alkylation

Full text of DOI:10.1002/ejoc.201900490

A Journal of
Accepted Article
Title: D-fructose based spiro-fused PHOX ligands: Palladium
complexes and application in catalysis
Authors: Michael R Imrich, Cäcilia Maichle-Mössmer, and Thomas
Ziegler
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10.1002/ejoc.201900490
European Journal of Organic Chemistry
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D-fructose based spiro-fused PHOX ligands: Palladium
complexes and application in catalysis
Michael R. Imrich,[a] Cäcilia Maichle-Mössmer [b] and Thomas Ziegler *[a]
Abstract: Phosphinooxazoline (PHOX) ligands are an important
class of ligands in asymmetric catalysis. Recently we reported on the
synthesis of D-fructose based spiro-fused PHOX ligands. Here, we
now present the application of these ligands in asymmetric alkylation.
In addition, we prepared palladium complexes of our previous spiro-
PHOX ligands and characterized them by x-ray crystallography. With
the knowledge of the molecular structure of these spiro-PHOX
palladium complexes we prepared two “improved” D-fructose based
spiro-fused PHOX ligands the application of which in asymmetric
alkylation resulted in high enantioselectivities (er up to 93:7) in a broad
substrate range.
we have extended the concept of spiro-fusion to carbohydrate
based ligands and reported the synthesis of D-fructose derived
spiro-fused pyridyloxazoline-ligands[6] and the respective PHOX-
ligands (Figure 1, 1a-1i).[7] These PHOX ligands were prepared in
four to six steps starting from D-fructose where the key steps had
been first a Ritter reaction of 1,2-isopropylidene protected
fructose derivatives with 2-bromo benzonitrile in order to construct
the oxazoline followed by an Ullmann coupling to introduce the
diphenyl phosphine moiety. Previously, we obtained high
conversion rates (> 99 %) and promising enantiomeric ratios (up
to 84:16) with these PHOX-ligands in a Tsuji-Trost reaction of
diphenylallyl acetate with dimethyl malonate as a model system.[7]
These auspicious results motivated us to further investigate the
application of our spiro-fused PHOX-ligands in asymmetric allylic
alkylation. Here we present the screening of our ligands 1a-1i in
Tsuji-Trost reactions as well as the synthesis and x-ray crystal
structures of palladium complexes of 1a and 1e. Furthermore, we
used these results for mechanistic considerations which led us to
construction and preparation of two improved ligands. In order to
demonstrate the value of such improved ligands we used them in
Pd catalyzed allylic alkylation with various allyl acetates and
different nucleophiles.
Introduction
The efficient synthesis of enantiopure compounds is still a main
challenge in organic chemistry because the majority of
biologically active molecules are chiral compounds and, in most
cases, only one enantiomer has the desired biological effect. The
most important approach to the synthesis of enantiopure
compounds is asymmetric catalysis which is a still a fiercely
embattled field in chemical research. In this context the design of
new effective ligands for metal catalyzed enantioselective
reactions remains a fundamental goal for further progress in this
broad area of research.[1] During the past decades numerous
different ligands have been prepared among which the so-called
privileged ligands are especially notable. One important class of
these privileged ligands in particular are the phosphinooxazoline-
ligands (PHOX-ligands) which were originally developed by
Helmchen, Pfaltz and Williams in 1993.[2] Various different PHOX-
ligands have been synthesized and used in a wide variety of
enantioselective reactions as well as in the total synthesis of
complex natural products.[3] In general, a crucial aspect for the
design of new ligands for metal catalyzed enantioselective
reactions appears to be molecular rigidity of the backbone of the
ligands.[4] Spiro-fusion of bicyclic compounds provides very rigid
molecules in this respect and has already been applied to the
construction of ligands for stereoselective catalysis.[3b, 5] Recently,
Figure 1. Structures of previously reported D-fructose based
spiro-fused PHOX-ligands.
Results and Discussion
We chose to apply PHOX-ligands 1a-1i in a Tsuji-Trost reaction
between diphenylallyl acetate (2) as the electrophile and dimethyl
malonate (3) as the nucleophile. The reaction has already been
studied in detail with other ligands and has often been used as a
benchmark test for new ligands.[3e, 8] The allylic alkylation was
performed according to a standard procedure with [PdCl(C3H5)]2
as palladium source and N,O-bis(trimethylsilyl)acetamide (BSA)
as base (Scheme 1).[9]
[a]
M. R. Imrich, Prof. Dr. T. Ziegler
Institute of Organic Chemistry
University of Tübingen
We screened ligands 1a-1i under different reaction conditions, i.e.
in different solvents and at different temperatures, and evaluated
the respective conversion rate and the enantioselectivity. The
temperature was varied between 0 °C and room temperature and
as solvents CH2Cl2, MeCN, PhMe and Et2O were applied. The
solvents were chosen due to their different properties: a
halogenated solvent, a solvent which is capable of coordinating
metal centers, an aromatic solvent and an ether. All reactions
were run for 24 h in order to achieve comparable results. The
detailed results of the screening of ligands 1a-1i under the
Auf der Morgenstelle 18
72076 Tübingen, Germany
thomas.ziegler@uni-tuebingen.de
http://www.oc2.chemie.uni-tuebingen.de/
Dr. C. Maichle-Mössmer
Institute of Inorganic Chemistry
University of Tübingen
[b]
Auf der Morgenstelle 18
72076 Tübingen, Germany
Supporting information for this article is available on the WWW
under https://doi
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10.1002/ejoc.201900490
European Journal of Organic Chemistry
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mentioned conditions can be found in the supporting information.
(R)-4a was the main enantiomer in all reactions. Regarding the
reaction temperature, it can be concluded that the
enantioselectivity increased slightly (maximum from er 77:23 to
83:17) whereas the conversion decreased heavily (maximum
drop from >99 % to 9 %) when the temperature was lowered from
room temperature to 0 °C. By talking a look at the effect of the
solvent, we found that the er in MeCN and in PhMe was higher
than in CH2Cl2 or Et2O in most cases. At room temperature the
conversion in all solvents was good. Some key results of the
screening of ligands 1a-1i in the Tsuji-Trost reaction are depicted
in Table 1.
The substitution pattern at the fructose moiety of the ligands had
a significant influence on the enantioselectivity of the reaction. An
increase in selectivity was obtained for bulky substituents like the
sterically demanding pivaloyl protective groups in ligand 1e, which
provided an er of 89:11 in PhMe at room temperature (Table 1,
entry 8). 1a with the less sterically demanding acetyl protective
groups provided an er of just 78:22 at the same conditions. The
same trend could be found by comparing ligand 1b with bulky
benzyl protective groups at the carbohydrate moiety with ligand
1d with small methyl groups at the fructose ring. A rigid and
sterically demanding isopropylidene group at position 4 and 5 of
the fructose part even had
a negative effect on the
stereoselectivity of the reaction. Ligands 1f and 1g resulted in low
er values (Table1, entries 12 and 13). In case of ligand 1h which
has a benzyl group at position 3 and methyl groups at positions 4
and 5, the found er value (Table 1, entry 14) was a little higher as
for ligand 1b (Table 1, entry 5) which bears benzyl groups at
position 3, 4 and 5. Ligand 1i carries a small methyl substituent at
position 3 and benzyl substituents at positions 4 and 5. The
stereoselectivity of ligand 1i (Table 1, entry 15) is a little smaller
than the stereoselectivity of the perbenzylated ligand 1b (Table 1,
entries 5). This led us to the assumption that a bulky substituent
at position 3 and small substituents at positions 4 und 5 may have
a positive influence on the stereoselectivity of the D-fructose
based spiro-fused PHOX ligands. In order to confirm this
presumption we decided to prepare palladium complexes of our
ligands and determine their respective x-ray crystal structures,
thus providing more insight into the mechanism of the Tsuji-Trost
reaction with D-fructose based spiro-fused PHOX ligands.
Table 1. Screening of ligands 1a-i in allylic alkylation.
entry
1[c]
2[d]
3
1
temperature
solvent
PhMe
PhMe
MeCN
MeCN
PhMe
PhMe
PhMe
PhMe
PhMe
MeCN
MeCN
PhMe
PhMe
PhMe
PhMe
conversion[a]
>99 %
0 %
er (R:S)[b]
78:22
n.d.
1a
1a
1a
1a
1b
1c
1d
1e
1e
1e
1e
1f
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
>99 %
49 %
77:23
75:25
82:18
79:21
76:24
89:11
n.d.
4[d, e]
5
>99 %
>99 %
>99 %
53 %
6[c]
7
8
9[f]
10
11[e, f]
12
13
14
15
0 %
We first attempted to synthesize complexes of our ligands by
>99 %
70 %
82:18
83:17
67:33
73:27
87:13
81:19
using [PdCl(C3H5)]2 as palladium source. The downfield shift in 31
P
NMR and mass spectra (see supporting information for details)
indicated the formation of palladium PHOX complexes of 1a, 1c
and 1e but we were not able to obtain crystals which were suitable
for x-ray crystallography. Next, we used PdCl2(COD) instead of
[PdCl(C3H5)]2 (Scheme 2) and could finally obtain crystals suitable
for x-ray crystallography[11] of the Pd-complexes of 1a and 1e by
covering a saturated solution of the complex in CH2Cl2 with n-
heptane. The complex derived from ligand 1a was of the type
74 %
1g
1h
1i
>99 %
>99 %
>99 %
5
PdCl2(PHOX) and crystallized as monomer 5b exhibiting a C2
[a] Determined by HPLC. [b] er was determined by chiral HPLC,
absolute configuration was assigned by comparison of the optical
rotation values with the literature data.[10] [c] Adapted from
literature data.[7] [d] 5 was used instead of 1a and [PdCl(C3H5)]2.
[e] 20 mol% AgSbF6 were added. [f] 6 was used instead of 1e and
[PdCl(C3H5)]2. n.d: not determined.
2
conformation of the pyranose ring instead of a C5 conformation
as depicted in 5a (Scheme 2, Figure 2). The formation of
complexes of the type PdCl2(PHOX) is common for PHOX ligands
and there are some examples of similar complexes with other
PHOX ligands in the literature.[12] The pivaloyl protected ligand 1e
afforded the complex 6c which crystallized as a dimeric complex
of the type [PdCl2(PHOX)]2 (Scheme 2, Figure 3) with the sugar
2
in a C5 conformation. Similar dimeric Pd-complexes of the type
[PdCl2(PHOX)]2 are reported in the literature for similar P,N-
ligands[13] where the nitrogen does not coordinate the palladium
ion while the phosphorous does and the dimeric form is built up
by bridging via the two chlorines like in our complex 6c. We
suppose that there are equilibria of the monomeric and the
dimeric form for both complexes 5a-d and 6a-d in solution
because mass spectra indicated the existence of a monomer and
Scheme 1. Asymmetric allylic alkylation of diphenylallyl acetate.
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10.1002/ejoc.201900490
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a dimer for both complexes (Scheme 2). Most lilkely, there are
equilibria between different conformations of the pyranose chair
for the monomeric forms, 5a and 5b and 6a and 6b, respectively
as well as for the dimeric forms 5c and 5d, respectively 6c and 6d
(Scheme 2).
To prove that the molecular structures of the isolated complexes
5 and 6 can act as model system for transition state of the allylic
alkylation we decided to use these complexes in the Tsuji-Trost
reaction (Scheme 1) instead of a ligand and [PdCl(C3H5)]2. With
the complexes in PhMe as solvent no conversion was obtained
(Table 1, entries 2 and 9). In situ dehalogenation with AgSbF6 in
MeCN as previously described[8a] provided more reactive
derivatives of 5 and 6 which showed er’s in a comparable range
as for the in situ formed complexes of 1a and 1e with
[PdCl(C3H5)]2 (Table 1, entries 4 and 11).
Figure 2. Molecular structure of complex 5b. Ellipsoids are given at the 50 %
probability level. Grey = carbon, red = oxygen, purple = nitrogen, orange =
phosphorus, blue = palladium, green = chlorine, hydrogens are omitted for
better clarity. 
Scheme 2. Preparation of palladium complexes 5 and 6 of 1a and 1e.
The mechanism of the Tsuji-Trost reaction has been thoroughly
studied in detail with various ligands and reasonable models for
the transition state of this reaction have been proposed.[3a, 5d, 6b, 14]
Taking into account the proposed modes for the transition state of
Tsuji-Trost reactions and our crystal structures we propose the
following transition state for our fructose derived spiro-fused Pd-
PHOX ligands (Scheme 3). Our model implies that after oxidative
addition of the allyl acetate (2) to the palladium PHOX complex
an intermediate allyl palladium species is formed. This
intermediate exists as an equilibrium of two diasteromers 7a and
7b. Diastereomer 7a is most likely the main isomer. Diastereomer
7b should be disfavored due to the steric repulsion between R1
and the phenyl moiety of the allylic system. The nucleophile
preferably attacks the allylic system trans to the phosphorous
atom.[3a, 8f, 15] Intermediate 7a leads to (R)-4 and intermediate 7b
to (S)-4. Under these assumptions the equilibrium should be
forced towards 7a when R1 is bulky and accordingly the
enantiomeric ratio of the products should be increased. This is in
good accordance with our results shown in Table 1. Those ligands
having bulky protective groups at all positions (1b, 1e) or a bulky
Figure 3. Molecular structure of complex 6c. Ellipsoids are given at the 50 %
probability level. Grey = carbon, red = oxygen, purple = nitrogen, orange =
phosphorus, blue = palladium, green = chlorine, hydrogens are omitted for
better clarity. The asymmetric units consist four dimers for better clarity only
one dimer is shown. For full crystallographic data see supporting information.
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protective group at position 3 (1e) gave higher er’s than the
ligands with small substituents (for instance 1d or 1i).
diphenylallyl acetate (2) and dimethyl malonate (3) under
catalysis with ligands 15a and 15b under identical conditions as
depicted in Scheme 1. In almost all tested solvents the er of the
substitution products was higher than 80:20. The highest
enantioselectivities for both ligands 15a and 15b were obtained in
nonpolar aromatic solvents like toluene or benzene (Table 2,
entries 3, 4, 5, 8 and 9) while yields after 24 h were between 19 %
and 36 % due to incomplete turnover. All other solvents resulted
in lower er’s, whereas the yields were much higher in these cases.
Once again, by lowering the reaction temperature the
enatioselectivity increased slightly but the yield decreased rapidly
(Table 2, entries 1, 6, 7, 10). Best results (96 % yield, er 93:7)
were obtained with 15a in toluene at room temperature after 72 h
(Table 2, entry 5). In summary, the er’s of the products of the
allylic Tsuji-Trost alkylation was significantly higher under
catalysis with our improved ligands 15a and 15b than with ligands
1a-1i.
Scheme 3. Plausible transition state for the Tsuji-Trost reaction with D-fructose
based spiro-fused PHOX ligands.
Considering the aforementioned proposed stereo-directing effect
of a substituent at position 3 of the spiro-PHOX ligands we
prepared some ligands with bulkier substituents at position 3.
Although ligand 1e which bears bulky pivaloy groups gave the
highest er in our screening (Table 1, entry 8) we chose ether
substituents instead because for acyl protecting groups at the
carbohydrate moiety the overall yields in the synthesis of the
ligands were significantly lower.[7] Thus, we prepared
benzylbromides 9a and 9b in one step from known 8[16] (Scheme
4). Compound 9b is also commercially available. Next, bromides
9a and 9b were reacted with diisopropyl-fructose[16] 10 to afford
fructose derivatives 11a and 11b in 88% and 84% yield,
respectively (Scheme 5). Selective hydrolysis of the 4,5-di-O-
siopeopylidene group in the latter with diluted hydrochloric acid
gave 12a and 12b in high yields which were finally methylated to
afford fructosides 13a and 13b in almost quantitative yields.
Finally, we also reacted a variety of different allylic substrates with
dimethyl or diethyl or dibenzyl malonate, malonyldinitrile and 1,3-
dimethyl barbituric acid using the optimized reaction conditions
with ligand 15a (Table 3). In all cases yields were high and er
ranged from 85:15 to 93:7 with (R) configuration for the main
enantiomer. A noteworthy influence of substituents at the
aromatic rings of the allylic acetates on the enantioselectivity of
the Tsuji-Trost reaction is not observed. Likewise, we did not find
any significant dependence of the enatatioselectivity on the
nucleophile.
Table 2. Ligands 15a and 15b in allylic alkylation.
entry
ligand
temp.
solvent
time
Yield
[a]
er
(R:S)[b]
1
2
15a
15a
15a
15a
15a
15a
15b
15b
15b
15b
rt
rt
CH2Cl2
MeCN
PhMe
PhH
24 h
24 h
24 h
24 h
72 h
24 h
24 h
24 h
24 h
24 h
95 %
99 %
36 %
19 %
96 %
67 %
97 %
33 %
22 %
75 %
82:18
82:18
93:7
3
rt
4
rt
93:7
5
rt
PhMe
CH2Cl2
CH2Cl2
PhMe
PhH
93:7
Scheme 4. Synthesis of benzyl bromide 9a and structure of 9b.
6
0 °C
rt
85:15
85:15
91:9
For the construction of the oxazoline moiety we used the
previously reported Ritter reaction of the 1,2-isopropylidene
protected pyranoses 13a and 13b with 2-bromobenzonitrile and
7
[7]
8
rt
BF3·OEt2. In the final steps we applied Stoltz’ protocol for the
copper catalyzed coupling of an arylbromide with
diphenylphosphine to give PHOX ligands 15a and 15b in 86 %
and 88 % yield, respectively.
9
rt
92:8
10
0 °C
CH2Cl2
89:11
[a] Isolated yield. [b] er was determined by chiral HPLC, absolute configuration
was assigned by comparison of the optical rotation values with the literature
data.[10]
Table 2 summarizes some results (for screening of more solvents
see supporting information) of the Tsuji-Trost reaction between
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Scheme 5. Synthesis of improved PHOX ligands 15a and 15b.
Table 3. Scope of the allylic alkylation using 15a as ligand.
[a] Isolated yield, reaction was performed on a 100 mg scale, [b] Determined by chiral HPLC, [c] Determined by NMR with Eu(hfc)3 a chiral shift reagent.
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was obtained as orange solid. Crystals for x-ray crystallography were
prepared by covering a saturated solution of 5 in CH2Cl2 with n-heptane.
Rf = 0.11 (EtOAc + 2 % Et3N); [α]20D + 241° (c = 0.1, CH2Cl2); mp = >
207 °C (decomposition, CH2Cl2/n-heptane); 31P NMR (162 MHz, CDCl3) δ
= 28.48, 22.36 ppm; MS (ESI): m/z 716.0 [M-Cl]+, 1468.9 [2M-Cl]+; HRMS
(ESI-TOF) m/z [M-Cl]+: calcd for C31H30NClO8PPd: 716.04269, found:
716.04220; Anal calcd for C31H30NCl2O8PPd: C 49.46, H 4.02, N 1.86,
found: C 49.34, H 4.31, N 1.85.
Conclusions
We studied previously reported D-fructose based spiro-fused
PHOX ligands as catalysts in asymmetric allylic alkylations (Tsuji-
Trost reactions) in different solvents and at different temperatures.
Furthermore, we could obtain x-ray structures of two palladium-
PHOX complexes which allowed a better understanding of the
reaction mechanism and the factors influencing the
enantioselectivity of this reaction. Based on these studies we
developed a second generation of two D-fructose based spiro-
fused PHOX ligands having bulky benzyl groups at position 3 of
the fructose moiety. This second generation of spiro-fused PHOX
ligands allowed to prepare a series of diarylallyl malonates with
high enantiomeric ratios (er’s up to 93:7). Further improvement
(for instance by modification of the electronically environment at
the phosphorous) may lead to D-fructose based spiro-fused
PHOX ligands with an enantioselectivity comparable to classical
PHOX ligands.[2]
Dichloro[(5R,8R,9R,10S)-2-(2-(diphenylphosphaneyl)phenyl)-3,6-dioxa-
1-azaspiro[4.5]dec-1-ene-8,9,10-triyl-tris(2,2-dimethylpropanoate)] palla-
dium(II) (6): To a solution of 1e (23 mg, 0.033 mmol) in 1.5 ml dry CH2Cl2
PdCl2COD (9.4 mg, 0.033 mmol) was added and the reaction mixture was
stirred at room temperature for 30 min. The solvent was evaporated in
vacuo and the residue was recrystallized from CH2Cl2 and n-hexanes. 6
(25 mg, 86 %) was obtained as orange solid. Crystals for x-ray
crystallography were prepared by covering a saturated solution of 6 in
CH2Cl2 with n-heptane. Rf = 0.75 (EtOAc/2-propanol 1/1 + 2 % Et3N); [α]20
D
-260 ° (c = 0.1, CH2Cl2); mp = > 230 °C (decomposition, CH2Cl2/n-
heptane); 31P NMR (162 MHz, CDCl3) δ = 26.62, 23.76 ppm; HRMS (ESI-
TOF) m/z [M-Cl]+: calcd for C40H48NClO8PPd: 842.18354, found:
842.1895, m/z [2M-Cl]+: calcd for C80H96N2Cl2O16P2Pd2: 1719.34405,
found: 1719.33649; Anal calcd for C40H48NCl2O8PPd: C 54.65, H 5.50, N
1.59, found: C 54.40, H 5.74, N 1.40.
Experimental Section
General
All reactions were carried out under an atmosphere of nitrogen. Dry
toluene and THF were distilled from sodium, dry CH2Cl2, C2H4Cl2, MeCN
and DMF were distilled from P4O10. Chlorobenzene, nitrobenzene and
benzonitrile were dried with a column of basic aluminium oxide. Dry
solvents were stored over molecular sieves under an atmosphere of
nitrogen. For reaction monitoring TLC plates from Macherey–Nagel
“Polygram Sil G/U254” were used. Preparative column chromatography
was performed with silica gel “60 M” which was purchased from
Macherey–Nagel. Solvents used as eluents were technical grade and
distilled prior to their use. Petroleum ether (PE) refers to the fraction boiling
at 60 – 90 °C. NMR spectra were recorded on a Bruker “Avance III HD 400”
5-(Bromomethyl)-1,3-di-tert-butyl-2-methoxybenzene (9a): A mixture of
8[16] (5.30 g, 22.6 mmol), N-bromosuccinimide (4.03 g, 22.6 mmol) and
benzoyl peroxide (219 mg, 0.68 mmol; 75 %, remainder water) in dry
C2H4Cl2 was heated at reflux (oil bath: 90 °C) for 90 min, after 60 min again
benzoyl peroxide (219 mg, 0.68 mmol; 75 %, remainder water) was added.
The reaction mixture was cooled to room temperature, filtered and the
solvent evaporated in vacuo. Column chromatography (PE) provided 9a
(4.23 g, 60 %) as a colorless solid. Rf = 0.25 (PE); mp = 58 °C (CH2Cl2);
1H NMR (400 MHz, CDCl3) δ = 7.28 (s, 2 H, H-Ar), 4.50 (s, 2 H, CH2Br),
3.70 (s, 3 H, OCH3), 1.44 (s, 18 H, C(CH3)3) ppm; 13C NMR (101 MHz,
CDCl3) δ = 159.7 (COCH3), 144.1 (CCH2Br), 131.6 (CC(CH3)3), 127.7 (CH),
64.3 (OCH3), 35.8 (C(CH3)3), 34.82 (CH2Br), 32.0 (C(CH3)3) ppm; HRMS
(EI) m/z [M]+ calcd for C16H25BrO: 312.10833, found: 312.11107; Anal
calcd for C16H25BrO: C 61.34, H 8.04, found: C 61.55, H 8.10.
spectrometer and calibrated to the solvent signal (CDCl3: 1H 7.27 ppm, 13
C
77.0 ppm; CD3OD: 1H 3.31 ppm, 13C 49.2 ppm) or to the internal standard
TMS (1H 0.00 ppm, 13C 0.0 ppm). For peak assignment additional NMR
spectra (DEPT-135, 1H,1H-COSY, 1H,13C -HMBC, 1H,13C-HSQC) were
used and atoms were numbered according to the carbohydrate
nomenclature. High resolution mass spectra were measured on a Bruker
“maXis 4G” with electrospray ionization and a time of flight detector or on
3-O-(3,5-Di-tert-butyl-4-methoxy)benzyl-1,2:4,5-O-diisopropylidene-β-D-
fructopyranose (11a): To a solution of 10[17] (3.22 g, 12.4 mmol) 35 ml dry
DMF NaH (904 mg, 22.6 mmol; 60 % dispersion in mineral oil) was added.
The solution was cooled to 0 °C and a solution of 9a (3.63 g, 11.6 mmol)
in 20 ml dry DMF was added over a period of 10 min. The cooling was
removed, the reaction mixture was stirred at room temperature for 2 h,
quenched with MeOH and concentrated in vacuo. The residue was re-
dissolved in EtOAc (150 ml) and washed with water (1 × 75 ml). After
drying over Na2SO4 the solvent was evaporated in vacuo. Column
chromatography (PE/EtOAc, 10/1) provided 11a (5.04 g, 88 %) as a
colorless syrup. Rf = 0.42 (PE/EtOAc, 8/1); [α]20D - 61.5° (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ = 7.24 (s, 2 H, H-Ar), 4.92 (d, J=11.9 Hz, 1
H, CH2Ar), 4.61 (d, J=11.9 Hz, 1 H, CH2Ar), 4.36 – 4.42 (m, 1 H, H-4), 4.21
– 4.25 (m, 1 H, H-5), 4.10 – 4.19 (m, 2 H, H-1a, H-6a), 4.02 (d, J=13.3 Hz,
1 H, H-6b), 3.90 (d, J=8.4 Hz, 1 H, H-1b), 3.68 (s, 3 H, OCH3), 3.51 (d,
J=7.3 Hz, 1 H, H-3), 1.56 (s, 3 H, C(CH3)2), 1.51 (s, 3 H, C(CH3)2), 1.45 (s,
3 H, C(CH3)2), 1.43 (s, 18 H, C(CH3)3), 1.40 (s, 3 H, C(CH3)2) ppm; 13C
NMR (101 MHz, CDCl3) δ = 158.9, 143.4, 132.1, 125.8 (C-Ar), 112.1,
108.9 (C(CH3)2), 104.5 (C-2), 77.9 (C-5), 76.1 (C-3), 73.9 (C-4), 73.5
(CH2Ar), 71.9 (C-1), 64.2 (OCH3), 60.1 (C-6), 35.7 (C(CH3)3), 32.1
(C(CH3)3), 28.3, 26.8, 26.3, 26.1 (C(CH3)2) ppm; HRMS (ESI-TOF) m/z
[M+Na]+: calcd for C28H44O7Na: 515.29792, found: 515.29813; Anal calcd
for C28H44O7: C 68.26, H 9.00, found: C 68.14, H 9.07.
a
Finnigan “MAT95” with electronic ionization. Mass spectra were
recorded on a “Bruker Esquire 3000 Plus”. Optical rotations were
measured with a Perkin-Elmer “Polarimeter 341”. Melting points were
determined with a Büchi “Melting Point M-560” apparatus. Elemental
analysis was performed on a HEKAtech “Euro 3000 CHN”. X-ray data were
collected on
a Bruker “SMART APEX II DUO” diffractometer.
Crystallographic data have been deposited to the Cambridge
Crystallographic Data Centre, CCDC (1906320 for 5b; 1906321 for 6c).
Enantiomeric ratio was determined by HLPC, using a Sykam “S 1121”
chromatograph equipped with a Dr Maisch “Reprosil Chiral-NR, 8 μm, 150
× 4.6 mm” column or a Dr Maisch “Reprosil Chiral-AM, 5 μm, 125 × 4.6
mm” column. Conversions were measured by HPLC using a Sykam “S
1121” chromatograph equipped with a Grom “Saphir 65 Si, 5 μm, 250 ×
4.6 mm” column.
Dichloro[(5R,8R,9R,10S)-2-(2-(diphenylphosphaneyl)phenyl)-3,6-dioxa-
1-azaspiro[4.5]dec-1-ene-8,9,10-triyl-triacetate]palladium(II) (5): To
a
solution of 1a (102 mg, 0.177 mmol) in 5 ml dry CH2Cl2 was PdCl2COD
(50.5 mg, 0.177 mmol) added and the reaction mixture was stirred at room
temperature for 90 min. The solvent was evaporated in vacuo and the
residue was recrystallized from CH2Cl2 and n-hexanes. 5 (130 mg, 98 %)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900490
European Journal of Organic Chemistry
FULL PAPER
3-O-(3,5-Dimethyl)benzyl-1,2:4,5-O-diisopropylidene-β-D-fructopyranose
(11b): To a solution of 10[17] (3.22g, 12.4 mmol) 40 ml in dry NaH (904 mg,
22.6 mmol; 60 % dispersion in mineral oil) DMF was added. The solution
was cooled to 0 °C and a solution of 9b (2.24 g, 11.3 mmol) in 20 ml dry
DMF was added over a period of 10 min. The cooling was removed, the
reaction mixture was stirred at room temperature for 2 h and poured into
50 ml of ice-water. The resulting solution was extracted with EtOAc (3 ×
100 ml), dried over Na2SO4 and the solvent evaporated in vacuo. Column
chromatography (PE/EtOAc, 8/1) provided 11b (3.94 g, 84 %) as a
colorless oil. Rf = 0.33 (PE/EtOAc, 8/1); [α]20D - 73.3° (c = 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) δ = 6.99 (s, 2 H, H-Ar), 6.92 (s, 1 H, H-Ar), 4.91
(d, J = 11.9 Hz, 1 H, CH2Ar), 4.60 (d, J = 11.9 Hz, 1 H, CH2Ar), 4.39 (dd, J
= 7.1, 5.9 Hz, 1 H, H-4), , 4.23 (dd, J = 5.9, 2.2 Hz, 1 H, H-5), 4.15 (dd, J
= 13.3, 2.2 Hz, 1 H, H-6a), 4.09 (d, J = 8.4 Hz, 1 H, H-1a), 3.00 (d, J =13.3
Hz, 1 H, H-6b), 3.88 (d, J = 8.4 Hz, 1 H, H-1b), 3.49 (d, J = 7.1 Hz, 1 H, H-
3), 2.31 (s, 6 H, CH3Ar), 1.55 (s, 3 H, CH3), 1.51 (s, 3 H, CH3), 1.44 (s, 3
H, CH3), 1.40 (s, 3 H, CH3) ppm; 13C NMR (101 MHz, CDCl3) δ = 138.0,
137.7, 129.1, 125.7 (C-Ar), 112.1, 109.0 (C(CH3)2), 104.4 (C-2), 77.8 (C-
4), 75.6 (C-3), 73.8 (C-5), 73.0 (CH2Ar), 71.8 (C-1), 60.1 (C-6), 28.1, 26.9,
26.2, 26.0 (C(CH3)2), 21.2 (CH3Ar) ppm; HRMS (ESI-TOF) m/z [M+Na]+:
calcd for C21H30O6Na: 401.19346, found: 401.19356; Anal calcd for
C21H30O6: C 66.65, H 7.99, found: C 66.87, H 8.06.
was added over a period of 20 min. After complete addition the reaction
mixture was cooled to 0 °C and MeI (1.6 ml, 26 mmol) was added over a
period of 10 min. The reaction was allowed to reach room temperature and
it was stirred at this temperature for 4 h. The reaction mixture was
quenched with MeOH and concentrated in vacuo. The residue was
dissolved in EtOAc (100 ml), washed with water (2 × 50 ml), dried over
Na2SO4 and the solvent was evaporated in vacuo. Column
chromatography (PE/EtOAc, 5/1) provided 13a (2.09 g, 95 %) as a
colorless oil. Rf = 0.30 (PE/EtOAc, 4/1); [α]20D - 76.8 ° (c = 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3) δ = 7.23 (s, 2 H, H-Ar), 4.90 (d, J = 11.2 Hz, 1 H,
CH2Ar), 4.53 (d, J = 11.2 Hz, 1 H, CH2Ar), 3.96 (d, J = 8.4 Hz, 1 H, H-1a),
3.93 – 3.86 (m, 2 H, H-1b, H-6a), 3.80 – 3.63 (m, 7 H, H-3, H-4, H-5, H-6b,
OCH3), 3.52 (s, 3 H, OCH3), 3.49 (s, 3 H, OCH3), 1.48 (s, 3 H, C(CH3)2),
1.43 (s, 3 H, C(CH3)2), 1.42 (s, 18 H, C(CH3)3) ppm; 13C NMR (101 MHz,
CDCl3) δ = 159.0, 143.4, 132.3, 126.3 (C-Ar), 111.8 (C(CH3)2), 105.7 (C-
2), 81.4 (C-5), 75.9 (CH2Ar), 75.6 (C-4), 74.9 (C-3), 71.8 (C-1), 64.2
(OCH3), 59.9 (C-6), 57.5 (OCH3), 57.2 (OCH3), 35.6 (C(CH3)3), 31.9
(C(CH3)3), 27.0 (C(CH3)2), 26.2 (C(CH3)2) ppm; HRMS (ESI-TOF) m/z
[M+Na]+: calcd for C27H44O7Na: 503.29792, found: 503.29768 ; Anal calcd
for C20H30O6: C 67.47, H 9.23, found: C 67.47, H 9.33.
3-O-(3,5-Dimethyl)benzyl-1,2-O-isopropylidene-4,5-di-O-methyl-β-D-
fructopyranose (13b): To a solution of 12b (2.04 g, 6.03 mmol) in 50 ml dry
DMF NaH (964 mg, 24.1 mmol; 60 % dispersion in mineral oil) was added
and the reaction mixture was stirred for 60 min at room temperature. MeI
(1.5 ml, 24 mmol) was added and the resulting solution was stirred at room
temperature for 4 h. The reaction was quenched with MeOH and
concentrated in vacuo. The residue was dissolved in EtOAc (100 ml),
washed with water (2 × 50 ml), dried over Na2SO4 and the solvent was
evaporated in vacuo. Column chromatography (PE/EtOAc, 3/1) provided
3-O-(3,5-Di-tert-butyl-4-methoxy)benzyl-1,2-O-isopropylidene-β-D-fructo-
pyranose (12a): 11a (4.10 g, 8.32 mmol) was dissolved in 250 ml THF,
200 ml hydrochloric acid (0.1 % in water) were added and the mixture was
stirred at room temperature for 13 d. The reaction mixture was neutralized
with Na2CO3 and the THF was evaporated in vacuo. The resulting aqueous
suspension was extracted with EtOAc (3 × 250 ml), dried over Na2SO4 and
concentrated in vacuo. Column chromatography of the residue (PE/EtOAc,
1/1) provided 12a (3.54 g, 94 %) as a colorless solid. Rf = 0.36 (PE/EtOAc,
1/1); mp = 62 °C (CH2Cl2); [α]20D – 79.4° (c = 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ = 7.24 (s, 2 H, H-Ar), 4.70 (s, 2 H, CH2Ar), 4.06 (d, J = 8.7
Hz, 1 H, H-1a), 4.03 – 3.98 (m, 2 H, H-1b, H-4), 3.97 – 3.91 (m, 2 H, H-5,
H-6a), 3.77 (dd, J = 2.0, 13.0 Hz, 1 H, H-6b), 3.70 – 3.65 (m, 4 H, H-3,
OCH3), 2.50 (bs, 2 H, 2×OH), 1.50 (s, 3 H, C(CH3)2), 1.45 (s, 3 H, C(CH3)2),
1.42 (s, 18 H, C(CH3)3) ppm; 13C NMR (101 MHz, CDCl3) δ = 159.4, 144.0,
131.7, 126.5 (C-Ar), 111.8 (C(CH3)2), 105.6 (C-2), 76.3 (C-3), 75.9
(CH2Ph), 71.7 (C-1), 71.2 (C-4), 69.6 (C-5), 64.2 (OCH3), 63.5 (C-6), 35.7
(C(CH3)3), 32.0 (C(CH3)3), 26.8, 26.2 (C(CH3)2) ppm; HRMS (ESI-TOF)
m/z [M+Na]+: calcd for C25H40O7Na: 475.26662, found: 475.26672; Anal
calcd for C25H40O7: C 66.35, H 8.91, found: C 66.35, H 9.07.
13b (2.09 g, 95 %) as a colorless oil. Rf = 0.32 (PE/EtOAc, 3/1); [α]20
–
D
106.4° (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 6.99 (s, 2 H, H-Ar),
6.91 (s, 1 H, H-Ar), 4.93 (d, J = 11.5 Hz, 1 H, CH2Ar), 4.54 (d, J = 11.5 Hz,
1 H, CH2Ar), 4.01 – 3.85 (m, 3 H, H-1a, H-1b, H-6a), 3.82 – 3.63 (m, 4 H,
H-3, H-4, H-5, H-6b), 3.52 (s, 3 H, OCH3), 3.49 (s, 3 H, OCH3), 2.30 (s, 6
H, CH3Ar), 1.49 (s, 3 H, C(CH3)2), 1.44 (s, 3 H, C(CH3)2) ppm; 13C NMR
(101 MHz, CDCl3) δ = 138.4, 137.7, 129.0, 125.5 (C-Ar), 111.8 (C(CH3)2),
105.7 (C-2), 81.4 (C-4 or C-5), 75.7 (C-4 or C-5), 75.4 (CH2Ar), 74.9 (C-3),
71.8 (C-1), 59.8 (C-6), 57.4 (OCH3), 57.3 (OCH3), 27.1 (C(CH3)2), 26.1
(C(CH3)2), 21.2 (CH3Ar) ppm; HRMS (ESI-TOF) m/z [M+Na]+: calcd for
C20H30O6Na: 389.19346, found: 389.19344 ; Anal calcd for C20H30O6: C
65.55, H 8.25, found: C 65.17, H 8.22.
3-O-(3,5-Dimethyl)benzyl-1,2-O-isopropylidene-β-D-fructopyranose (12b):
11b (3.75 g, 9.9 mmol) was dissolved in 250 ml THF and 150 ml
hydrochloric acid (0.1 % in water) were added and the mixture was stirred
at room temperature for 4 d. The reaction mixture was neutralized with
Na2CO3 and the solvents were evaporated in vacuo. Column
chromatography (PE/EtOAc, 1/2) provided 12b (3.03 g, 90 %) as a
(5R,8R,9R,10S)-2-(2-Bromophenyl)-10-((3,5-di-tert-butyl-4-methoxy-
benzyl)oxy)-8,9-dimethoxy-3,6-dioxa-1-azaspiro[4.5]dec-1-ene (14a): 13a
(900 mg, 1.87 mmol) and 2-bromobenzonitrile (5.11 g, 28.1 mmol) were
dissolved in 5 ml dry CH2Cl2 and BF3·OEt2 (0.50 ml, 1.9 mmol; 48 % in
Et2O) was added. After stirring at room temperature for 90 min the reaction
was quenched with Et3N (3 ml) und the solvent was evaporated in vacuo.
Column chromatography of the residue (PE + 2 % Et3N  PE/EtOAc, 5/1
+ 2% Et3N) provided 14a (825 mg, 73 %) as colorless oil. Rf = 0.40
(PE/EtOAc, 3/1 + 2 % Et3N); [α]20D - 110.0° (c = 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ = 7.75 – 7.70 (m, 1 H, H-Ar), 7.66 – 7.60 (m, 1 H, H-Ar),
7.35 – 7.24 (m, 2 H, H-Ar), 7.18 (s, 2 H, H-Ar), 4.94 (d, J = 11.6 Hz, 1 H,
CH2Ar), 4.62 (d, J = 11.6 Hz, 1 H, CH2Ar), 4.25 – 4.08 (m, 3 H, H-1a, H-
1b, H-6a), 4.04 – 3.94 (m, 2 H, H-4, H-6b), 3.87 (d, J = 9.7 Hz, 1 H, H-3),
3.80 – 3.75 (m, 1 H, H-5), 3.65 (s, 3 H, OCH3), 3.56 (s, 3 H, OCH3), 3.54
(s, 3 H, OCH3), 1.38 (s, 18 H, C(CH3)3) ppm; 13C NMR (101 MHz, CDCl3)
δ = 165.8 (OCN), 158.9, 143.4, 133.9, 132.5, 131.8, 131.7, 129.4, 126.9,
126.2, 122.1 (C-Ar), 103.2 (C-2), 81.8 (C-4), 77.1 (C-3), 76.2 (C-5), 75.4
(CH2Ar), 74.6 (C-1), 64.2 (OCH3), 61.6 (C-6), 57.7 (OCH3), 57.3 (OCH3),
35.6 (C(CH3)3), 32.0 (C(CH3)3) ppm; HRMS (ESI-TOF) m/z [M+H]+: calcd
colorless solid. Rf = 0.39 (PE/EtOAc, 1/2); mp = 103 °C (CH2Cl2); [α]20
-
D
124.5° (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 6.98 (s, 2 H, H-Ar),
6.95 (s, 1 H, H-Ar), 4.69 (s, 2 H, CH2Ar), 4.06 (d, J = 8.7 Hz; 1 H, H-1a),
3.90 – 4.03 (m, 4 H, H-1b, H-4, H-5, H-6a), 3.75 (dd, J = 2.0, 13.0 Hz, 1 H,
H-6b), 3.67 (d, J = 9.5 Hz, 1 H, H-3), 2.54 (bs, 2 H, 2×OH), 2.31 (s, 6 H,
CH3Ar), 1.50 (s, 3 H, C(CH3)2), 1.45 (s, 3 H, C(CH3)2) ppm; 13C NMR (101
MHz, CDCl3) δ = 138.2, 137.7, 129.7, 125.7 (C-Ar), 111.9 (C(CH3)2), 105.6
(C-2), 76.4 (C-3), 75.4 (CH2Ar), 71.7 (C-1), 71.1 (C-4), 69.6 (C-5), 63.5 (C-
6), 26.8, 26.1 (C(CH3)2), 21.2 (CH3Ar) ppm; HRMS (ESI-TOF) m/z
[M+Na]+: calcd for C18H26O6Na: 361.16212, found: 361.16225; Anal calcd
for C18H26O6: C 63.89, H 7.74, found: C 63.84, H 7.82.
3-O-(3,5-Di-tert-butyl-4-methoxy)benzyl-1,2-O-isopropylidene-4,5-di-O-
methyl-β-D-fructopyranose (13a): To a solution of 12a (2.96 g, 6.55 mmol)
in 40 ml dry DMF NaH (1.05 g, 26.2 mmol, 60 % dispersion in mineral oil)
for C31H43NBrO6: 604.22683,
found: 604.22647; Anal calcd for
C31H42NBrO6: C 61.59, H 7.00, N: 2.32 found: C 61.87, H 7.15, N 2.19.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900490
European Journal of Organic Chemistry
FULL PAPER
(5R,8R,9R,10S)-2-(2-Bromophenyl)-10-((3,5-dimethylbenzyl)oxy)-8,9-
dimethoxy-3,6-dioxa-1-azaspiro[4.5]dec-1-ene (14b): 13b (902 mg, 2.46
mmol) and 2-bromobenzonitrile (6.72 g, 36.9 mmol) were dissolved in 5 ml
dry CH2Cl2 and BF3·OEt2 (0.65 ml, 2.5 mmol; 48 % in Et2O) was added.
After stirring at room temperature for 120 min the reaction was quenched
with Et3N (3 ml) und the solvent was evaporated in vacuo. Column
chromatography of the residue (PE + 2 % Et3N  PE/EtOAc, 3/1 + 2%
Et3N) provided 14b (898 mg, 75 %) as colorless oil. Rf = 0.29 (PE/EtOAc,
3/1 + 2 % Et3N); [α]20D - 148.1° (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ = 7.73 (dd, J = 1.8, 7.6 Hz, 1 H, H-Ar), 7.64 (dd, J = 1.2, 7.8 Hz, 1 H, H-
Ar), 7.38 – 7.26 (m, 2 H, H-Ar), 6.95 (s, 2 H, H-Ar), 6.89 (s, 1 H, H-Ar), 4.98
(d, J = 11.9 Hz, 1 H, CH2Ar), 4.62 (d, J = 11.9 Hz, 1 H, CH2Ar), 4.22 – 4.14
(m, 3 H, H-1a. H-1b, H-6a), 4.03 – 3.94 (m, 2 H, H-4, H-6b), 3.87 (d, J =
9.7 Hz, 1 H, H-3), 3.80 – 3.75 (m, 1 H, H-5), 3.54 (s, 3 H, OCH3), 3.54 (s,
3 H, OCH3), 2.27 (s, 6 H, CH3Ar) ppm; 13C NMR (101 MHz, CDCl3) δ =
166.0, 138.6, 137.7, 133.8, 131.8, 131.6, 129.7, 129.0, 126.9, 125.3, 122.0
(C-Ar), 103.1 (C-2), 81.7 (C-4), 77.2 (C-3), 76.2 (C-5), 74.9 (CH2Ar), 74.8
(C-1), 61.5 (C-6), 57.7 (OCH3), 57.4 (OCH3), 21.2 (CH3Ar) ppm; HRMS
(ESI-TOF) m/z [M+H]+: calcd for C24H29NBrO5: 490.12236, found:
490.12222; Anal calcd for C24H28NBrO5: C 58.78, H 5.76, N: 2.86 found: C
58.77, H 5.89, N 2.68.
3 H, H-3, H-6a, H-6b), 3.37 (s, 3 H, OCH3), 3.35 – 3.32 (m, 1 H, H-5), 3.23
(s, 3 H, OCH3), 3.15 (dd, J = 3.3, 9.7 Hz, 1 H, H-4), 2.17 (s, 6 H, CH3Ar)
ppm; 13C NMR (101 MHz, CDCl3) δ = 164.4 (d, J = 2.2 Hz, OCN), 139.4
(d, J = 13.2 Hz) 139.2 (d, J = 6.6 Hz), 139.1 (d, J = 9.5 Hz), 137.5, 134.1
(d, J = 20.5 Hz), 133.5 (d, J = 19.0 Hz), 131.9 (d, J = 21.3 Hz), 130.9, 129.6,
128.7, 128.3, 128.3, 128.2, 128.1, 125.0 (C-Ar), 103.6 (C-2), 81.0 (C-4),
77.1 (C-3), 76.5 (C-5), 74.2 (C-1), 73.7 (CH2Ar), 61.7 (C-6), 57.6 (OCH3),
57.3 (OCH3), 21.2 (CH3Ar) ppm; 31P NMR (126 MHz, CDCl3) δ = -5.77
ppm; HRMS (ESI-TOF) m/z [M+H]+: calcd for C36H39NPO5: 596.25604,
found: 596.25662; Anal calcd for C36H38NPO5: C 72.59, H 6.43, N: 2.35
found: C 72.29, H 6.55, N 2.32.
General procedure for the small scale allylic alkylation: A mixture of
[PdCl(C3H5)]2 (0.5 ml, 29 μmol; 5.7 mM in dry CH2Cl) and ligand (0.5 ml,
66 μmol; 13.2 mM in dry CH2Cl) was stirred at room temperature for 30 min
and the solvent was evaporated in vacuo. A solution of dimethyl malonate
(3) (20 μl, 174 μmol), rac-diphenylallyl acetate (2) (14.6 mg, 58 μmol),
KOAc (0.3 mg, 3 μmol) and N,O-bis(trimethylsilyl)acetamide (43 μl, 174
μmol) in 1 ml dry solvent was added to the residue. After stirring at room
temperature or 0 °C for 24 h the reaction was quenched with saturated
NH4Cl solution (2 ml). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (reactions performed in CH2Cl2) or EtOAc
(reactions performed in other solvents). The combined organic layers were
dried over Na2SO4 and the solvent was evaporated in vacuo. Conversion
was determined by HPLC (n-hexane/2-propanol, 9/1; 1.6 ml/min) tR(2) =
2.0 min ; tR(4a) = 2.4 min. Enantiomeric ratio was determined by chiral
HPLC (n-hexanes/2-propanol, 9/1; 1.6 ml/min) tR((R)-4a) = 5.2 min, tR((S)-
4a) = 6.8 min.
(5R,8R,9R,10S)-10-((3,5-di-tert-butyl-4-methoxybenzyl)oxy)-2-(2-(di-
phenylphosphaneyl)phenyl)-8,9-dimethoxy-3,6-dioxa-1-azaspiro[4.5]dec-
1-ene (15a):
A
solution of CuI (16.5 mg, 87μmol), N,N’-
dimethylethylenediamine (65 μl, 0.61 mmol) and diphenylphosphine (230
μl, 1.31 mmol) in 3 ml dry toluene was stirred at room temperature for 20
min. Cs2CO3 (849 mg, 2.61 mmol) and 14a (420 mg, 0.70 mmol; 0.1 M in
dry toluene) were added and the mixture was heated to 110 °C for 17 h.
The reaction mixture was cooled to room temperature, filtered and
concentrated. Column chromatography of the residue (n-hexanes/EtOAc,
5/1 + 2% Et3N) provided 15a (434 mg, 86 %) as colorless solid. Rf = 0.45
(n-hexanes/EtOAc, 3/1 + 2% Et3N); mp = 86 °C (CH2Cl2); [α]20D - 162.7° (c
= 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.02 – 7.96 (m, 1 H, H-Ar),
7.44 – 7.37 (m, 1 H, H-Ar), 7.36 – 7.18 (m, 11 H, H-Ar), 7.14 (s, 2 H, H-Ar),
6.92 – 6.86 (m, 1 H, H-Ar), 4.84 (d, J = 12.0 Hz, 1 H, CH2Ar), 4.51 (d, J =
12.0 Hz, 1 H, CH2Ar), 4.17 (d, J = 9.5 Hz, 1 H, H-1a), 4.08 (d, J = 9.5 Hz,
1 H, H-1b), 3.74 – 3.65 (m, 5 H, H-3, H-6a, OCH3), 3.60 – 3.51 (m, 1 H, H-
6b), 3.46 (s, 3 H, OCH3), 3.44 – 3.41 (m, 1 H, H-5), 3.36 (s, 3 H, OCH3),
3.29 (dd, J = 3.4, 9.7 Hz, 1 H), 1.38 (s, 18 H, C(CH3)3) ppm; 13C NMR (101
MHz, CDCl3) δ = 164.3 (d, J = 2.2 Hz, OCN), 158.5, 143.2, 139.6 (d, J =
12.5 Hz), 139.3 (d, J = 6.6 Hz), 139.0 (d, J = 10.3 Hz), 134.4 (d, J = 64.6
Hz), 133.8 (d, J = 8.8 Hz), 133.3 (d, J = 65.3 Hz), 131.8, 131.6, 130.9,
129.7, 128.3, 128.2, 128.1, 128.0, 125.4 (C-Ar), 103.8 (C-2), 81.3 (C-4),
77.2 (C-3) 76.6 (C-5), 74.1 (CH2Ar), 74.1 (C-1), 64.2 (OCH3), 61.8 (C-6),
57.6 (OCH3), 57.4 (OCH3), 35.7 (C(CH3)3), 32.0 (C(CH3)3) ppm; 31P NMR
(126 MHz, CDCl3) δ = -5.56 ppm; HRMS (ESI-TOF) m/z [M+H]+: calcd for
C43H53NPO6: 710.36050, found: 710.35992; Anal calcd for C43H52NPO6:
C 72.76, H 7.38, N: 1.97 found: C 72.67, H 7.60, N 1.96.
General procedure for the allylic alkylation with isolated yields: A
mixture of [PdCl(C3H5)]2 (5 mol% relating to the allyl acetate) and ligand
(11 mol % relating to the allyl acetate) in 3 ml dry solvent was stirred at
room temperature for 30 min. N,O-bis(trimethylsilyl)acetamide (3 equiv.),
nucleophile (3 equiv.), KOAc (5 mol% relating to the allyl acetate) and allyl
acetate (100 mg, 1 equiv.; solution in 4 ml solvent) were added and the
reaction mixture was stirred at the temperature indicated in Table 2 for the
time noted in Table 2. The reaction was quenched with saturated NH4Cl
solution (5 ml). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (reactions performed in CH2Cl2) or EtOAc
(reactions performed in other solvents). The combined organic layers were
dried over Na2SO4 and the solvent was evaporated in vacuo. The products
were isolated after column chromatography using mixtures of PE/EtOAc.
The analytical data for 4a - 4j, 4l and 4m are in accordance with the
literature. Absolute configurations were assigned by comparison of optical
rotations with literature values.[5e, 6b, 8a, 9-10, 14d, 18] For the determination of
er’s see supporting information.
(E)-2-(1,3-Di-p-tolylallyl)malononitrile (4k): light yellow oil, Rf = 0.36
(PE/EtOAc, 6/1); 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.06 (m, 8 H, H-Ar),
6.57 (d, J = 15.8 Hz, 1 H, H-olefin), 6.32 (dd, J = 7.9, 15.7 Hz, 1 H, H-
Olefin), 4.02 – 3.86 (m, 2 H, 2 × CH), 2.28 (s, 3 H, CH3), 2.26 (s, 3 H, CH3)
ppm; 13C NMR (101 MHz, CDCl3) δ = 138.8, 138.5, 135.4, 133.6, 132.7,
130.0, 129.4, 127.5, 126.7, 123.0 (C-Ar, C-olefin), 111.8, 111.7 (CN), 49.5
(CH), 30.3(C(CN)2), 21.2, 21.1(CH3) ppm; HRMS (ESI-TOF) m/z [M+Na]+:
calcd for C20H18N2Na: 309.13622, found: 309.13622; Anal calcd for
C20H18N2: C 83.88, H 6.34, N 9.78, found: C 83.43, H 6.53, N: 9.56.
(5R,8R,9R,10S)-10-((3,5-Dimethylbenzyl)oxy)-2-(2-(diphenyl-
phosphaneyl)phenyl)-8,9-dimethoxy-3,6-dioxa-1-azaspiro[4.5]dec-1-ene
(15b): A solution of CuI (14.5 mg, 77μmol), N,N’-dimethylethylenediamine
(57 μl, 0.54 mmol) and diphenylphosphine (200 μl, 1.15 mmol) in 3 ml dry
toluene was stirred at room temperature for 20 min. Cs2CO3 (748 mg, 2.30
mmol) and 14b (300 mg, 0.61 mmol; 0.1 M in dry toluene) were added and
the mixture was heated to 110 °C for 20 h. The reaction mixture was cooled
to room temperature, filtered and concentrated. Column chromatography
of the residue (PE/EtOAc, 3/1 + 2% Et3N) provided 15b (321 mg, 88 %) as
colorless solid. Rf = 0.39 (PE/EtOAc, 4/1 2% Et3N); mp = 62 °C (CH2Cl2);
[α]20D - 126.7° (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.94 – 7.88
(m, 1 H, H-Ar), 7.31 – 7.11 (m, 12 H, H-Ar), 6.83 – 6.75 (m, 4 H, H-Ar),
4.72 (d, J = 12.1 Hz, 1 H, CH2Ar), 4.40 (d, J = 12.1 Hz, 1 H, CH2Ar), 4.08
(d, J = 9.4 Hz, 1 H, H-1a), 3.99 (d, J = 9.4 Hz, 1 H, H-1b), 3.70 – 3.53 (m,
(E)-5-(1,3-Di-p-tolylallyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
(4n): white solid, Rf = 0.20 (PE/EtOAc, 6/1); mp = 133 °C (CH2Cl2); 1H
NMR (400 MHz, CDCl3) δ = 7.29 (d, J = 8.1 Hz, 2 H, H-Ar), 7.15 – 7.04 (m,
4 H, H-Ar), 7.02 – 6.93 (m, 2 H, H-Ar), 6.75 (dd, J = 8.8, 15.8 Hz, 1 H, H-
olefin), 6.54 (d, J = 15.8 Hz, 1 H, H-olefin), 4.36 (dd, J = 3.7, 8.7 Hz, 1 H,
CH), 3.84 (d, J = 3.8 Hz, 1 H, CH(CO)2), 3.15 – 3.06 (2 s, 6 H, NCH3), 2.31
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10.1002/ejoc.201900490
European Journal of Organic Chemistry
FULL PAPER
(2 s, 6 H, Ar-CH3) ppm; 13C NMR (101 MHz, CDCl3) δ = 168.0, 167.2, 151.0
(CO), 137.8, 137.6, 134.9, 133.9, 132.5, 129.3, 129.2, 127.4, 126.6, 126.4
(C-Ar, C-olefin), 56.3 (CH(CO)2), 52.9 (CH), 28.2, 28.1 (NCH3), 21.2, 21.1
(Ar-CH3) ppm; HRMS (ESI-TOF) m/z [M+Na]+: calcd for C23H24N2O3Na:
399.16.91, found: 399.16813; Anal calcd for C23H24N2O3: C 73.38, H 6.43,
N: 7.44 found: C 73.38, H 6.45, N 7.49.
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(E)-5-(1,3-Bis(4-chlorophenyl)allyl)-1,3-dimethylpyrimidine-2,4,6(1H, 3H,
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NMR (101 MHz, CDCl3) δ = 167.4, 166.8, 150.8 (CO), 136.5, 134.9, 134.1,
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depositions
1906320,
1906321
contain
all
supplementary
Acknowledgements
crystallographic data for this paper. These data can be obtained free of
charge from The Cambrige Crystallographic Data Centre via
www.ccdc.cam.ac.uk.
We would like to thank Dr. Jochen Kraft for the various
discussions about spiro-PHOX ligands, Dr. Gregor Lemanski and
Anna Stroppel for lecturing the manuscript, Petra Krüger for the
elemental analysis measurements, Dr. Jochen Neumaier for the
help with the HPLC measurements, Dr. Dorothee Wistuba and her
team for recording the mass spectra and Dr. Markus Kramer and
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Entry for the Table of Contents
FULL PAPER
PHOX-ligands
Michael R. Imrich, Cäcilia Maichle-
Mössmer, Thomas Ziegler*
Page No. – Page No.
D-fructose based spiro-fused PHOX
ligands: Palladium complexes and
application in catalysis
The x-ray crystal structure of Pd-complexes of D-fructose based spiro-fused PHOX
is described. Furthermore, the synthesis of two new, improved ligands is reported.
These ligands were applied in asymmetric allylic alkylation with various substrates.
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