Exploiting the gem-Disubstitution Effect in FcPHOX and HetPHOX P,N Ligands: Synthesis and Applications in Pd-Catalyzed Intermolecular Heck Reactions

Article abstract of DOI:10.1021/acs.joc.5b01764

The synthesis of a range of novel gem-disubstituted and electronically varied thiophene-oxazoline (HetPHOX) ligands and ferrocene-oxazoline (FcPHOX) ligands and their application in the Pd-catalyzed intermolecular asymmetric Heck reaction (IAH) is described. These investigations show that gem-disubstitution of i-Pr-PHOX-type ligands can lead to effective and cost-efficient alternatives to the corresponding t-Bu-PHOX systems. The Pd complexes of these ligands were very effective in the IAH, providing phenylated products in up to 100% conversion with up to 97% ee.

Full text of DOI:10.1021/acs.joc.5b01764

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Article
Exploiting the Gem-Disubstitution Effect in FcPHOX
and HetPHOX P,N Ligands - Synthesis and Applications
in Pd-catalyzed Intermolecular Heck Reactions
Dennis Mc Cartney, Chris Nottingham, Helge Müller-Bunz, and Patrick Jerome Guiry
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01764 • Publication Date (Web): 01 Sep 2015
Downloaded from http://pubs.acs.org on September 7, 2015
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Exploiting the Gem-Disubstitution Effect in FcPHOX and
HetPHOX P,N Ligands - Synthesis and Applications in Pd-
catalyzed Intermolecular Heck Reactions
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Dennis Mc Cartney, Chris Nottingham, Helge MüllerꢀBunz and Patrick J.
Guiry*
Centre for Synthesis and Chemical Biology, UCD School of Chemistry and
Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
Email: p.guiry@ucd.ie
Abstract
The synthesis of a range of novel gemꢀdisubstituted and electronically varied
thiopheneꢀoxazoline (HetPHOX) ligands and ferroceneꢀoxazoline (FcPHOX)
ligands and their application in the Pdꢀcatalyzed intermolecular asymmetric
Heck reaction (IAH) is described. These investigations show that gemꢀ
disubstitution of iꢀPrꢀPHOX type ligands can lead to effective and costꢀefficient
alternatives to the corresponding tꢀBuꢀPHOX systems. The Pdꢀcomplexes of
these ligands were very effective in the IAH, providing phenylated products in
up to 100% conversion with up to 97% ee.
Introduction
The design and synthesis of new oxazolineꢀcontaining ligands for asymmetric
1ꢀ3
catalysis is an extensive, thriving field of research.
Metal complexes of
oxazolineꢀbased ligands such as PHOX (Figure 1), bearing a t-Bu group at
C(4) often afford high ee’s for a variety of asymmetric transformations.
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However, the synthesis of these ligands involves starting from the prohibitively
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expensive, nonꢀnatural amino acids (S)ꢀ and (R)ꢀtꢀleucine.
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Figure 1. BOX, PyOX and PHOX analogues with gem-disubstitution at C(5)
In most cases, exchanging the tꢀBu group for an iꢀPr group results in a
significant decrease in enantioselectivity due to conformational control of the
C(4)ꢀstereodirecting group. However, when a gemꢀdimethyl group is located α
to the i-Pr group at C(5) in an oxazoline ring the iꢀPr group is forced to adopt a
conformation analogous to that of a t-Bu group. Some early examples of
oxazolineꢀcontaining ligands featuring gemꢀdisubstitution in order to provide a
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more sterically rigid system include BOX analogues from the group of Corey,
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PyOx analogues from the group of Brunner and PHOX analogues from the
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groups of Pfaltz , Paquin (Figure 1) and most recently, Stoltz . Paquin’s
work, the synthesis and application of 5,5ꢀ(dimethyl)ꢀiꢀPrꢀPHOX as a practical
equivalent of the expensive tꢀBuꢀPHOX, was motivated by a key concept in
modern ligand research, i.e the design and application of more economical
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ligands. Davies was the first to demonstrate the gemꢀdimethyl effect in
asymmetric synthesis when he reported the synthesis and application of a
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cheaper, yet equally efficient, gemꢀdimethyl alternative to Evans’ auxiliary.
Davies also demonstrated that this effect exists both in the solid state and in
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solution through Xꢀray crystallographic and H NMR nOe studies.
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Seebach later reported the synthesis and application of a gemꢀdiphenyl
alternative to Evans’ auxiliary, although this was not investigated in terms of
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providing a tꢀBu mimic. We sought to further examine the effect of gemꢀ
disubstitution on a range of different PHOX systems such as those based on
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thiophene (HetPHOX, ligands 1 ꢀ 6) and ferrocene (FcPHOX, ligand 7) (Figure
2). Both HetPHOX and FcPHOX ligands have previously been applied in a
range of asymmetric transformations by our group and also the groups of
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Richards and Cozzi.
The present study would allow us to probe whether
the gemꢀdimethyl effect is beneficial in these related oxazolineꢀcontaining
ligands while searching for a suitable, cheaper alternative to the “best in
class” tꢀBuꢀPHOX ligand.
Figure 2: Novel, gem-disubstituted HetPHOX and FcPHOX ligands
Results and discussion
Synthesis of HetPHOX ligands
The synthesis of our HetPHOX ligand family began by the reaction of acid
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chloride 8 with gemꢀdisubstituted amino alcohols 9 and 10 under biphasic
reaction conditions to provide amides 11 and 12 in 77% and 83% yields,
respectively (Scheme 1). Heating the resulting gem-disubstituted tertiary
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alcohols in the presence of methanesulfonic acid (MsOH) was enough to
promote dehydration and subsequent cyclization to form oxazolines 13 and 14
in 52% and 98% yields, respectively.
Scheme 1. Synthesis of ligands 1-3
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HetPHOX ligands have previously been synthesized via oxazolineꢀdirected
orthoꢀlithiation with two equivalents of n-BuLi, followed by quenching with the
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desired chlorodiarylphosphine.
This approach produced the HetPHOX
ligands 1ꢀ3 in 30 – 56% yield in the present study (Scheme 1).
While these yields were in line with those previously obtained for HetPHOX
16
ligands synthesized using an orthoꢀlithiation strategy, it was felt that there
was scope for optimisation. Preliminary results (vide infra) indicated that
ligand 3 showed the most interesting catalytic activity and was chosen as the
target for route optimization to allow synthesis of a ligand library. A second
route to the desired ligands employed lithiumꢀbromide exchange. Therefore,
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the bromoꢀsubstituted acid chloride 15 was synthesized in high yield via
reaction of the corresponding carboxylic acid with oxalyl chloride. Subsequent
reaction with gemꢀdisubstituted amino alcohol 10 provided amide 16 in 92%
yield. An acidꢀmediated cyclization of 16 then provided oxazoline 17 in 78%
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yield (Scheme 2).
Scheme 2. Synthesis of Ligands 3-6
With bromoꢀsubstituted thiophene 17 in hand, lithiumꢀhalogen exchange with
1.1 eq. of n-BuLi and subsequent quench with the appropriate
chlorophosphine afforded ligands 3-6 in 28 – 62% yield. Even with the
addition of an extra step (synthesis of acid chloride 15), the overall yield of
ligand 3 increased from 28% to 39% using the optimised route.
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Synthesis of gem-disubstituted FcPHOX ligand
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Ferrocene carboxylic acid was converted into the corresponding acid
chloride 18 in 94% yield before reaction with gemꢀdisubstituted amino alcohol
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9 in the presence of Et N to provide the ferrocenyl amide 19 in 70% yield
(Scheme 3). Subsequent cyclization with MsOH provided the ferrocene
oxazoline 20 in 82% yield.
Scheme 3. Synthesis of Ferrocene Oxazoline Ligand 7
Subsequently, a diastereoselective lithiation procedure, closely following
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conditions developed by Sammakia, proved successful for the preparation
of FcPHOX ligand 7. Treatment of the oxazoline 20 with sꢀBuLi in the
presence of TMEDA, followed by quenching with chlorodiphenylphosphine
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gave ligand 7 in 59% yield as a single diastereomer by H NMR spectroscopy.
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Application of Ligands in the Intermolecular Asymmetric Heck (IAH)
reaction
With our novel ligands in hand we turned our attention to the asymmetric
phenylation of 2,3ꢀdihydrofuran 21 as a test reaction to evaluate our ligand
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25ꢀ27
class.
In the IAH reaction [P,N] ligands such as PHOX generally provide
much higher enantioselectivities and regioselectivities compared to [P,P]
ligands such as BINAP, however, one of the major drawbacks with [P,N]
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ligands is the long reaction times required to ensure full conversion.
In
order to decrease reaction time, microwaveꢀassisted asymmetric Heck
reactions have been developed by the groups of Larhed, Andersson, Diéguez
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and Pámies and most recently Paquin.
Although a small decrease in
levels of enantioselectivity is generally observed, the benefit is a greatly
reduced reaction time. Paquin’s microwave conditions (100 °C, 150 W for 18
h) represent a significant reduction over the 7 days usually taken using PHOX
and HetPHOX ligands, and the even more prolonged 14 days required for
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some FcPHOX ligands. Preliminary reactions employing our novel ligand
class were carried out in combination with known ligands 25 and 26 as
controls (Scheme 4). The results of the initial ligand screen are reported in
Table 1.
Scheme 4. Asymmetric phenylation of 2,3-dihydrofuran with MW
irradiation
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Table 1: Asymmetric phenylation of 2,3ꢀdihydrofuran with MW irradiation
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Entry
Ligand
Conversion (%) 23:24
ee 23 (%) (R) ee 24 (%) (R)
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a,b,c
Conversions were determined using triꢀn-decane as an internal standard.
Regioisomeric ratios, conversions and enantiomeric excesses were determined by
chiral GC, see Experimental Section.
The results obtained with ligand 25 (Entry 1) (84% conversion and 90% ee)
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closely agree with the reported results (73% yield and 91% ee). Pleasingly,
all of the novel ligands evaluated successfully catalyzed the phenylation of
2,3ꢀdihydrofuran and provided (R)ꢀ23 as the major product, with the highest
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observed ee (96%) induced by the palladium complex of gemꢀdiphenyl
substituted ligand 3.
Ligand 26 was reported by Pfaltz but has not previously been evaluated in the
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IAH reaction. Pd complexes of o-tolyl substituted ligand 26 facilitated
formation of (R)ꢀ23 in high yield, but with lower levels of enantioselectivity and
regioselectivity compared to its diꢀphenylphosphineꢀsubstituted analogue 25
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(Entries 1 and 2). This trend was replicated with the two gemꢀdimethyl
HetPHOX ligands 1 and 2 (Entries 3 and 4). The reaction using
diphenylphosphineꢀsubstituted ligand 1 provided better results in conversion
(100% vs. 92%), regioisomeric ratio (97:3 vs. 93:7) and enantiomeric excess
(93% vs. 91%) than its di(oꢀtolyl)phosphineꢀsubstituted analogue 2. The gemꢀ
diphenyl substituted HetPHOX ligand 3 provided complete conversion and
facilitated the formation of (R)ꢀ23 in an excellent ee of 96%, gratifyingly
matching the levels of enantioselectivity reported by Paquin with t-Buꢀ
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PHOX. Unfortunately, an appreciable amount of the minor regioisomer was
produced using ligand 3 (regioisomeric ratio 81:19). Finally, excellent results
were obtained in the reactions catalyzed by Pd complexes of FcPHOX ligand
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(Entry 6). The kinetic product (R)ꢀ23 was formed in an excellent 95% ee
and, in contrast to 3, afforded much lower levels of the thermodynamic
product 24 (97:3). Where observed, the ees of the minor isomeric product 24
were generally high to very high (81 – 92%) and were almost identical to the
ee of the major product in many instances (entries 1ꢀ4, table 1) with the
largest ee difference being 14% (entry 6). We propose that, as with previous
examples employing Pd complexes of P,N ligands, kinetic resolution, as
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observed by Hayashi with BINAP, is not occurring to a large extent. The
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reaction employing ligand 3 was also monitored over time and the ratio of
23:24 remained reasonably constant as expected.
Comparison between ligand 3 and t-Bu-PHOX 27 under conventional
heating
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Due to the increased reaction temperatures involved under microwave
irradiation, levels of enantiomeric excess are generally found to be marginally
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lower than under conventional heating. To investigate the performance of
the ligands under thermal heating, sideꢀbyꢀside reactions with palladium
complexes of t-BuꢀPHOX 27 and the novel gemꢀdiphenylꢀsubstituted ligand 3
were carried out (Scheme 5).
Scheme 5. Asymmetric phenylation of 2,3-dihydrofuran under conventional heating
Pd (dba) (3 mol% Pd)
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3
Ligand (6 mol%)
OTf
i-Pr NH (3 eq.)
2
+
+
THF, 70 °C, 40 h
O
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O
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Ph
PPh N
N
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3% conversion
75% conversion
86:14 (23:24), 97% ee (23)
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3:17 (23:24), 97% ee (23)
The reactions provided identical and excellent levels of enantioselectivity with
ligands 3 and 27 (97% ee of (R)ꢀ23). A significantly higher level of conversion
was obtained with ligand 3 over tꢀBuꢀPHOX 27 (75% vs. 53%). Formation of
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similar levels of the minor thermodynamic product 24 was observed with both
ligands.
Screening of reaction conditions
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The solvent, base and Pd source used in the IAH reactions thus far were
those reported by Paquin. It was felt that investigating variations of these
conditions could prove beneficial in the present study. In particular, the choice
of base for the reaction was investigated as, in previous work using HetPHOX
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ligands, high levels of enantioselectivity were obtained with iꢀPr NEt and 1,8ꢀ
®
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bis(dimethylamino)naphthalene (Proton Sponge , PS). The gemꢀdimethyl
ligand 1 was chosen for the screen and the conditions were evaluated in
terms of the level of conversion and the ee of the kinetic product 23 (Scheme
6, Table 2).
Scheme 6. Screening of reaction conditions for IAH reaction
Table 2: Screening of reaction conditions for IAH reaction.
Entry Ligand Base Pd Source Solvent Conversion (%)
a
c
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Conversions were determined using triꢀn-decane as an internal standard.
Regioisomeric ratios, conversions and enantiomeric excesses were determined by
chiral GC, see Experimental Section.
It was found that ligand 1 provided generally high levels of ee – up to 96%
with DMF as the solvent (Entry 4). These results represented an increase on
the 93% ee obtained under microwave irradiation (Table 1), similar to the
increases in enantioselectivity obtained with t-BuꢀPHOX 27 and gem-diphenyl
ligand 3 under conventional heating (Scheme 5). There was a larger degree
of variability in the levels of conversion obtained. The highest conversion
2
observed was 92% with iꢀPr NEt as the base (Entry 2). PS has previously
been successful in the IAH reaction with HetPHOX ligands, but in this case
facilitated only low levels of conversion (35%) and the lowest observed level
1
6
2
of ee (90%, Entry 6). Changing the Pd source to Pd(OAc) proved slightly
deleterious – reducing ee by 2% and conversion by 29% (Entry 3 vs 2). With
regards to choice of solvent, the best combination of conversion and
enantioselectivity was observed when reactions were carried out in THF
(
Entry 3, 92% conversion, 95% ee). Based on the above observations, it was
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2 2 3
decided to evaluate the complete ligand series using i-Pr NEt, Pd (dba) and
THF as optimized reaction conditions.
Application of full ligand range to the phenylation of 2,3-dihydrofuran
under optimised conditions and microwave irradiation
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With optimised reaction conditions the full series of novel ligands was applied
to the IAH reaction between phenyl trifluoromethanesulfonate 22 and 2,3ꢀ
2
dihydrofuran 21 (Scheme 7, Table 3). Changing the base from i-Pr NH to i-
Pr NEt had a positive impact on the levels of conversion observed with
2
essentially complete conversions obtained in all instances. The gemꢀdimethyl
substituted HetPHOX ligands 1 and 2 both provided (R)ꢀ23 in 91% ee (Entries
2
and 3), while the FcPHOX 7 ligand promoted its formation in 94% ee (Entry
8). The series of gemꢀdiphenyl ligands was expanded by both increasing and
decreasing the electron density on the biarylphosphine (ligands 4 and 5,
respectively). In these cases, electronic variation of the phosphine had little or
no impact on the levels of enantioselectivity or conversion obtained (Entries 5
and 6). A poor regioisomeric ratio was obtained using gemꢀdiphenyl HetPHOX
ligands 3 and 4 (78:22 and 87:13 of 23:24, respectively, Entries 4 and 5),
although reactions with the analogous diꢀpꢀfluorophenylphosphineꢀcontaining
ligand 5 produced a much lower amount of regioisomer 24 (96:4, Entry 6).
Scheme 7. Application of ligands 1-7 in asymmetric phenylation of 2,3-dihydrofuran
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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
Pd (dba) (3 mol% Pd)
Ligand (6 mol%)
2
3
OTf
i-Pr NEt (3 eq.)
2
+
+
THF, 100 °C
MW 150 W, 18 h
O
O
O
21
22
23
24
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
Me
Me
S
S
O
O
O
Me
Me
O
Ph
Ph
N
PPh2
PPh N
2
N
N
Ar P
2
R P
2
Fe
2
7
1 Ar = Ph
Ar = oꢀTolyl
3 R = Ph
4 R = oꢀTolyl
R = pꢀFC H
7
2
5
6
6 4
R = Cyclohexyl
Table 3: Application of ligands 1-7 in asymmetric phenylation of 2,3-dihydrofuran
b
c
d
Entry
Ligand
Conversion (%)
23:24
ee 23(%) (R)
1
2
3
4
5
6
7
8
27
1
97
80:20
n.d.
95
91
91
95
95
95
95
94
a
75
2
100
98
92:8
78:22
87:13
96:4
n.d.
3
4
100
100
5
a
6
65
7
98
98:2
a
b,c,d
n.d. = not determined Based on yield
Conversions were determined using
triꢀn-decane as an internal standard. Regioisomeric ratios, conversions and
enantiomeric excesses were determined by chiral GC, see Experimental
Section.
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9
Although levels of conversion and enantioselectivity observed using Pd
complexes of t-BuꢀPHOX 27 were excellent, the regioisomeric ratio was
36
poorer than the literature value (99:1 23:24 with 86% ee). This may be
attributed to the specific reaction conditions used in this study, which differ to
10
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16
17
18
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20
21
22
23
24
25
26
27
28
29
30
31
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
6,37
those under which optimal results for ligand 27 were obtained.
It has been
reported that, in the phenylation of 2,3ꢀdihydrofuran under microwave
irradiation at high temperatures using 27, high levels of the minor regioisomer
30
24 can form (17:83 of 23:24 at 160 °C).
Overall, the best combination of conversion, product ratio and
enantioselectivity was facilitated using FcPHOX 7 (Entry 8), which provided
(
R)ꢀ23 in 94% ee and almost complete conversion, and with by far the best
isomeric ratio (98:2). The results obtained for the phenylation of 2,3ꢀ
dihydrofuran 21 for our novel series of ligands compare very favorably with
the literature – only a handful of ligand classes have exceeded the levels of
2
5
conversion or enantioselectivity provided by tꢀBuꢀPHOX. It has been
demonstrated in this work that under conventional heating, Pd complexes of
ligand 3 provide superior rates of conversion and match the levels of
enantioselectivity provided by Pd complexes of tꢀBuꢀPHOX 27. It therefore
appears that significant progress towards the objective of creating an effective
mimic of 27 has been achieved.
Asymmetric 2-(2-naphthyl)ation of 2,3-dihydrofuran
To further evaluate our novel ligands we sought to apply them in the IAH
reaction
between
2,3ꢀdihydrofuran
21
and
2ꢀnaphthyl
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2
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2
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2
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4
4
4
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4
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5
5
5
5
5
5
5
5
5
5
6
trifluoromethanesulfonate 28 (Scheme 8). This transformation has not been
as widely studied as the phenylation process, yet a range of ligands have
16,38,39
been reported for the 2ꢀ(2ꢀnaphthyl)ation of 2,3ꢀdihydrofuran.
Reactions
were carried out using the conditions previously described for the phenylation
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
of 2,3ꢀdihydrofuran (Table 4).
Scheme 8. Asymmetric 2-(2-naphthyl)ation of 2,3-dihydrofuran
Pd (dba) (3 mol% Pd)
2
3
Ligand (6 mol%)
OTf
i-Pr NEt (3 eq.)
2
+
+
O
O
O
THF, 100 °C
MW 150 W, 18 h
21
28
29
30
Me
Me
S
S
O
O
O
Me
Me
O
Ph
Ph
N
PPh2
PPh N
2
N
N
Ar P
2
R P
2
Fe
27
1 Ar = Ph
Ar = oꢀTolyl
3 R = Ph
4 R = oꢀTolyl
7
2
5
R = pꢀFC H
6 4
6
R = Cyclohexyl
Table 4: Asymmetric 2ꢀ(2ꢀnaphthyl)ation of 2,3ꢀdihydrofuran
a
c
c
Yield
ee 29 (%)
ee 30 (%)
b
Entry
Ligand
29:30
(
%)
(R)
85
84
86
87
87
90
86
88
(R)
85
80
60
86
74
81
70
n.d.
1
2
3
4
5
6
7
8
27
1
97
92
73
47
62
45
24
57
97:3
80:20
80:20
76:24
72:28
91:9
2
3
4
5
6
71:29
n.d.
7
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a
Yields reported are of a regioisomeric mixture of 29 and 30 after purification by
b,c
column chromatography. n.d. : not determined Regioisomeric ratios and
enantiomeric excess ware determined by chiral HPLC, see Experimental Section.
10
11
12
13
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15
16
17
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19
20
21
22
23
24
25
26
27
28
29
30
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43
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47
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49
50
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52
53
54
55
56
57
58
59
60
All ligands successfully catalyzed the 2ꢀ(2ꢀnaphthyl)ation of 2,3ꢀdihydrofuran
21, with (R)ꢀ29 being the predominant product in all cases. Yields from the
reactions catalyzed by gemꢀdiphenyl substituted ligands ranged from
moderate to poor (24 – 62%, entries 4ꢀ7) while the gemꢀdimethyl substituted
ligands provided higher yields, with the best result provided by ligand 1, which
provided regioisomeric products 29 and 30 in an overall 92% yield (Entry 2).
The ee’s obtained were lower than in the phenylation (Table 3) but were
generally good to very good (84 – 90%) with the diꢀpꢀfluorophenylphosphine
ligand 5 facilitating the highest levels of ee (90%) and regioselectivity (91:9 of
29:30), albeit in a modest 45% yield (Entry 6). Where determined, significant
amounts of the minor regioisomer 30 were obtained with all other novel
ligands (80:20 – 71:29). The t-BuꢀPHOX ligand 27 was used as a control for
the experiments, and it provided a much higher regioisomeric ratio of products
(97:3, Entry 1). The ees of the minor regioisomer were also moderate to good
(60% to an optimal 86% ee obtained with 3). In contrast to the phenylation of
21, none of our novel ligands afforded a superior combination of yield,
regioisomeric ratio and enantiomeric excess to t-BuꢀPHOX 27. However, the
levels of ee observed with novel ligands 5 and 7 (Entries 6 and 8,
respectively) are superior to those previously obtained with i-Prꢀsubstituted
HetPHOX ligands and demonstrate the generality of the beneficial effect of
16
gemꢀdisubstitution on enantioselectivity. As with the phenylation of 2,3ꢀ
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1
1
1
1
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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
dihydrofuran, the results obtained with our novel ligand series compare
favourably to the ligands reported to date in the literature. For the 2ꢀ(2ꢀ
naphthyl)ation of 2,3ꢀdihydofuran 21, even under microwave accelerated
conditions, levels of enantioselectivity close to those obtained with tꢀBu
HetPHOX derivatives have been achieved (up to 94% ee of 29 under
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
6
conventional heating).
X-ray crystallographic investigations
In order to gain an insight into the full structural effect gem-disubstitution had
2
on the novel ligand classes evaluated, PdCl complexes of the representative
class members were prepared by mixing the free ligand with PdCl (Scheme
2
9) and their resulting crystal structures were determined by Xꢀray diffraction
(Figure 3).
2
Scheme 9 Synthesis of PdCl complexes of ligands 1, 3 and 7
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3
1
32
2
PdCl Complex of HetPHOX 3
PdCl
2
Complex of HetPHOX 1
33
PdCl Complex of FcPHOX 7
2
Figure 3 PdCl
2
complexes of HETPHOX ligands 1 and 3 and FcPHOX ligand 7.
By utilising structural data obtained by Paquin for PdCl complexes of both tꢀ
2
BuꢀPHOX 27 and its gemꢀdimethyl substituted analogue it was possible to
make a detailed comparison between these structures and our structures
33
(Table 5).
For HetPHOX complexes 31 and 32, the distances from Pd to the two methyl
groups of the iꢀPr functionality (4.35 and 4.49 Å to CH (C5), 3.63 and 3.52 Å
3
to CH
PdCl
3.61 and 3.30 Å to CH
3
(C6)) correspond closely to the same intramolecular distances for the
2
complexes of known ligands 25 and 27 (4.38 and 4.36 Å to CH (C5),
3
3
(C6)). This indicates that a similar steric environment
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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
exists around the Pd centre, hence, rationalising the high levels of
enantiomeric excess obtained with HetPHOX ligands 1 and 3 in the IAH. For
FcPHOX complex 33, while the intramolecular distances to the two methyl
groups of the iꢀPr group are similar in magnitude, the order is inverted. The
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
CH group furthest from the Pd centre in 31 and 32 is the closest to Pd in 33.
3
Table 5 Comparison of some key structural values obtained by Xꢀray
crystallography
a
b
2
PdCl [Ligand] PdꢀC5 (Å) PdꢀC6 (Å) NꢀC3ꢀC4ꢀC5 Cl1ꢀPdꢀNꢀC3
3
1
4.35
4.49
3.38
4.38
4.36
3.63
3.52
4.95
3.61
3.30
49.4°
56.8°
ꢀ38.0°
50.6°
58.3°
32.6°
32.2°
25.2°
38.7°
47.3°
32
3
3
5
7
2
2
a
Dihedral angle formed by NꢀC3ꢀC4ꢀC5
Dihedral angle formed by Cl1ꢀPdꢀNꢀC3
b
The magnitude of this difference can be quantified by examining the internal
dihedral angle formed between N–C3–C4–C5. For FcPHOX complex 33 the
angle of this dihedral is ꢀ38.0°, a 96.3° difference from the same dihedral
angle in tꢀBuꢀPHOX 27. This is most likely a result of steric repulsion between
the lower cyclopentadieneyl ring of the ferrocene and the iꢀPr group, which
can be seen in Figure 4. The distance between H2 of the isopropyl methyl
group and H3 of the ferrocenyl cyclopentadienyl ring is 2.63Å, indicating these
atoms are very close in space. This H2ꢀH3 interaction is likely preventing the
iꢀPr group from rotating in towards the metal centre any further and is thus
reducing the conformational bias provided by the gem-dimethyl substituents.
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4 View looking at the lower cyclopentadienyl ring of the FcPHOX complex 33.
Spacefill representation (left) and ball and stick model from the same perspective (right).
For HetPHOX complexes 31 and 32, a much closer correlation is found
between the same dihedral angles. 31 forms a 49.4° dihedral N–C3–C4–C5,
which is similar to the 58.3° observed in the PdCl
The same dihedral for gemꢀdiphenyl ligand 32 forms an angle of 56.8°, very
closely correlating to the PdCl complex of tꢀBuꢀPHOX 27. This indicates that
2
complex of tꢀBuꢀPHOX 27.
2
gemꢀdiphenyl substitution is more effective in biasing the orientation of the iꢀ
Pr group so as to mimic a tꢀBu group. Gemꢀdisubstitution also has an effect
on the conformation of the oxazoline ring itself. The orientation of the
oxazoline ring is distorted compared to tꢀBuꢀPHOX 27. The Cl1ꢀPdꢀNꢀC3
dihedral angle, which is 47.3° for ligand 27, is altered in all three of our novel
ligands. The largest divergence is found for FcPHOX complex 33 (difference
of 22.1°) and the lowest variance is a still significant (14.7°) for gem-dimethyl
complex 31.
Mechanistic Considerations
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1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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3
4
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4
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4
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5
5
5
5
5
5
5
5
5
5
6
For the arylation of 2,3ꢀdihydrofuran 21, the possible intermediates prior to
migratory insertion utilising palladium complexes of [P,N] ligands 1 ꢀ 7 are
shown in Figure 5. The alkene can be bound to palladium by either of its faces
and can bind in a transꢀfashion to either the nitrogen atom or the phosphorus
atom. We would expect the more labile alkene to bind trans- to the soft
0
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7
8
9
0
1
2
3
4
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8
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3
4
5
6
7
8
9
0
40
phosphorus, with the harder nitrogen trans- to the aryl group. Similar
intermediates have been proposed by Hallberg and Ripa for the tꢀBuꢀPHOX
41
ligand 27 in an intramolecular Heck reaction.
Alkene approaches trans to phosphorous
Me
Me
O
Me
H
H
Me
*
R
*
R
O
P
P
(S)
R
N
R
N
(
R)
Pd
Pd
O
O
A
B
Alkene approaches trans to nitrogen (Disfavoured)
Me
Me
O
Me
H
H
Me
R
*
R
*
O
P
P
R
N
R
N
(S)
Pd
Pd
(R)
O
O
C
D
*
= Thiophene or Ferrocene
backbone
Figure
5 Possible diastereotopic ligandꢀPdꢀsubstrate complexes formed with gemꢀ
disubstituted ligands 1 – 7 prior to migratory insertion.
When the alkene approaches trans- to the nitrogen there is little discrimination
between the two faces of the alkene. Thus, if migratory insertion were to occur
from the complexes C and D a low ee would be observed. However, when the
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alkene approaches trans- to the phosphorus, intermediate A suffers from a
high degree of steric repulsion between the iꢀPr group of the oxazoline ring
and the alkene. Conversely, intermediate B is unhindered, meaning that
migratory insertion via this route would result in a high ee of (R) 23/29, which
correlates with the results we have obtained herein. These proposed
transitions states may explain why the bulkier tꢀBu oxazoline ligands generally
outperform their iꢀPr substituted counterparts in this reaction and thus, why
gemꢀdisubstituted iꢀPr oxazolines also provide high ees (Figure 6). However,
these transition states do not help to rationalize the regioselectivity of kinetic
vs. thermodynamic products for 23/24 or 29/30.
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17
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21
22
23
24
25
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27
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29
30
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6 Comparison of tꢀBu and gemꢀdisubstituted iꢀPr oxazoline ligands (left) with iꢀPr
oxazoline ligands (right) to rationalise why gemꢀdisubstitution of iꢀPr oxazoline ligands results
in higher ee’s for the IAH.
Conclusions
Seven novel gemꢀdisubstituted ligands (1 - 7) have successfully been
synthesized and applied to the asymmetric intermolecular Heck reaction,
where the phenylation and 2ꢀ(2ꢀnaphthyl)ation of 2,3–dihydrofuran were
investigated. Under microwave irradiation, enantiomeric excesses of up to
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96% were achieved using ligand 3, increasing to 97% under conventional
heating, matching the levels of enantioselectivity observed when using “best
in class” tꢀBuꢀPHOX ligand 27. An Xꢀray crystallographic investigation of
2
PdCl complexes of 1, 3 and 7 detailed the full structural effect of gem-
0
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disubstitution. Consideration of these crystal structures allowed us to propose
transition states which account for the higher ee’s obtained using tꢀBu or gemꢀ
disubstituted iꢀPr oxazoline ligands when compared with their iꢀPr oxazoline
counterparts. These results represent only the second example of a gemꢀ
disubstituted i-Pr oxazoline ligand successfully replicating the stereoinduction
10
provided by Pd complexes of tꢀBuꢀPHOX 27. We hope that the high
enantioselectivities provided by ligand 3, coupled with its cheap, modular
synthesis will promote its use in asymmetric catalysis.
Experimental Section
General Information. Unless otherwise noted, all commercial reagents were
used as received without further purification. Anhydrous diethyl ether (Et
tetrahydrofuran (THF) and dichloromethane (CH Cl ) were obtained from a
dry solvents dispenser. Diisopropylethylamine (iꢀPr NEt) was distilled from
2
O),
2
2
2
ninhydrin and KOH and stored over 3Å molecular sieves. All microwave
reactions were conducted in a CEM Discover Sꢀclass microwave reactor,
which utilizes an external infrared temperature sensor.
(S)-N-(2-Hydroxy-2,4-dimethylpentan-3-yl)thiophene-2-carboxamide (11).
To a solution of (S)ꢀ2ꢀaminoꢀ1,1,3ꢀtrimethylbutanol 9 (262 mg, 2.0 mmol, 1
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2 2 2 3
eq.) in CH Cl (7 mL) was added a solution of Na CO (636 mg, 6.0 mmol, 3
eq.) in deionised water (7 mL). The mixture was stirred vigorously and 2ꢀ
thiophenecarbonyl chloride 8 (0.30 mL, 504 mg, 2.30 mmol, 1.15 eq.) was
added dropwise. The reaction mixture was allowed to stir at room temperature
over 16 h. The phases were then separated and the aqueous phase was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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48
49
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59
60
2 2
extracted with CH Cl (2 x 7 mL). To the combined organic phases was added
methanolic 1M KOH (1.5 mL) and the reaction was stirred for 15 min then
neutralised with 10% v/v aq. HCl (10 mL). The phases were separated and
2 2
the aqueous phase extracted with CH Cl (2 x 10 mL). The combined
organics were dried over MgSO , filtered and concentrated in vacuo. The
4
crude residue was purified by column chromatography (20% v/v acetone in
cyclohexane on SiO
2
) to give the title compound as a fluffy white solid (372
) δ 7.55 (dd, J = 3.7, 1.1 Hz, 1H),
1
mg, 77 % yield). H NMR (500 MHz, CDCl
3
7.47 (dd, J = 5.0, 1.1 Hz, 1H), 7.08 (dd, J = 5.0, 3.7 Hz, 1H), 6.43 (d, J = 9.5
Hz, 1H), 3.94 (dd, J = 10.0, 2.7 Hz, 1H), 2.28 – 2.18 (m, 1H), 2.05 (br s, 1H),
13
1
1
.35 (s, 3H), 1.26 (s, 3H), 1.00 (app. t, J = 7.1 Hz, 6H). C{ H} NMR (126
MHz, CDCl ) δ 162.4, 139.2, 129.8, 127.9, 127.6, 73.7, 60.3, 29.5, 28.5, 27.4,
2.4, 17.0; IR νmax (Nujol, cm ) 3419, 1632, 1531; HRMS (ESIꢀTOF) m/z
3
ꢀ
1
2
20
264.1021 [M+Na] C12
1.9 ° (c = 1.05, CHCl3).
S)-N-(1-Hydroxy-3-methyl-1,1-diphenylbutan-2-yl)thiophene-2-
carboxamide (12). To a solution of (S)ꢀ2ꢀaminoꢀ3ꢀmethylꢀ1,1ꢀdiphenylbutanꢀ
1ꢀol 10 (2.54 g, 10 mmol, 1 eq.) in CH Cl (50 mL) was added a solution of
Na CO (3.18 g, 30 mmol, 3 eq.) in deionised water (25 mL). The mixture was
2 D
H19NNaO S requires 264.1034; MP 79ꢀ81 °C; [α] = ꢀ
4
(
2
2
2
3
stirred vigorously and 2ꢀthiophenecarbonyl chloride 8 (1.23 mL, 11.5 mmol,
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1.15 eq.) was added dropwise. The reaction mixture was allowed to stir at
room temperature over 16 h. The phases were then separated, and the
2 2
aqueous phase was extracted with CH Cl (2 x 30mL). To the combined
organic phases was added methanolic 1M KOH (15 mL) and the reaction was
stirred for 15 min then neutralised with 10% v/v aq. HCl. The phases were
0
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2
3
4
5
6
7
8
9
0
1
2
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8
9
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2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 2
separated and the aqueous phase extracted with CH Cl (2 x 300 mL). The
combined organics were dried over MgSO , filtered and concentrated in
4
vacuo to give a crude product which was recrystallized from aqueous EtOH to
1
give the title compound as white needles (3.04 g, 83 % yield). H NMR (400
MHz, CDCl ) δ 7.53 – 7.45 (m, 4H), 7.40 (dd, J = 5.0, 1.0 Hz, 1H), 7.37 – 7.30
3
(m, 3H), 7.28 – 7.20 (m, 3H), 7.13 (app t, J = 7.3 Hz, 1H), 7.02 – 6.97 (m, 1H),
6.49 (d, J = 9.8 Hz, 1H), 5.12 (app. d, J = 9.8 Hz, 1H), 2.70 (s, 1H), 1.96 –
13
1
1
3
.84 (m, 1H), 0.95 (app. t, J = 6.1 Hz, 6H); C{ H} NMR (101 MHz, CDCl ) δ
161.9, 145.9, 145.4, 139.0, 129.6, 128.6, 128.5, 127.8, 127.5, 127.1, 127.0,
ꢀ
1
1
1
3
25.4, 125.3, 82.4, 58.0, 29.3, 22.9, 17.6; IR νmax (Nujol, cm ) 3120, 1629,
534; HRMS (ESIꢀTOF) m/z 388.1363 [M+Na] C22 NaS requires
H
23NO
2
20
88.1347; MP 212ꢀ213 °C; [α]
D 3
= ꢀ119.7 ° (c = 0.75, CHCl ).
(
S)-4-Isopropyl-5,5-dimethyl-2-(thiophen-2-yl)-4,5-dihydrooxazole (13). A
solution of (S)ꢀNꢀ(2ꢀhydroxyꢀ2,4ꢀdimethylpentanꢀ3ꢀyl)thiopheneꢀ2ꢀ
carboxamide 11 (290 mg, 1.2 mmol, 1 eq.) in CH Cl (50 mL) was cooled to 5
2
2
°
C in an ice bath. Methanesulfonic acid (0.39 mL, 0.56 g, 6.0 mmol, 5 eq.)
was added dropwise over 10 min. The reaction was transferred to a 40 °C oil
bath and heated until starting material was consumed by TLC (21 h). The
reaction was quenched with saturated aq. NaHCO
3
(10 mL), and the phases
were separated. The aqueous phase was extracted with CH Cl (2 x 20mL),
2
2
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dried over MgSO
4
, filtered and concentrated in vacuo to give a crude yellow
oil, which was purified by column chromatography (10% v/v Et
2
O in
) to give the title compound as a clear oil (140 mg, 52 %
) δ 7.56 (dd, J = 3.7, 1.1 Hz, 1H), 7.40 (dd, J
cyclohexane on SiO
2
1
yield). H NMR (500 MHz, CDCl
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
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= 5.0, 1.1 Hz, 1H), 7.05 (dd, J = 5.0, 3.7 Hz, 1H), 1.92 – 1.82 (m, 1H), 1.51 (s,
1
3
1
3
H), 1.38 (s, 3H), 1.12 (d, J = 6.5 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H); C{ H}
NMR (126 MHz, CDCl ) δ 140.6, 137.1, 129.7, 129.2, 127.4, 115.3, 80.5,
9.2, 29.1, 21.3, 21.0, 20.5; IR νmax (Nujol, cm ) 3076, 1531, 1061; HRMS
3
ꢀ1
2
2
0
(
ESIꢀTOF) m/z 224.1115 [M+H] C12
° (c = 1.29, CHCl3).
S)-4-Isopropyl-5,5-diphenyl-2-(thiophen-2-yl)-4,5-dihydrooxazole (14). A
solution of (S)ꢀNꢀ(1ꢀhydroxyꢀ3ꢀmethylꢀ1,1ꢀdiphenylbutanꢀ2ꢀyl)thiopheneꢀ2ꢀ
carboxamide 12 (2.66 g, 7.28 mmol, 1 eq.) in CH Cl (200 mL) was cooled to
D
H18NOS requires 224.1109; [α] = ꢀ48.9
(
2
2
5 °C in an ice bath. Methanesulfonic acid (2.36 mL, 3.50 g, 36.39 mmol, 5
eq.) was added dropwise over 10 min. The reaction was transferred to a 40
°
C oil bath and heated until starting material was consumed by TLC (21 h).
The reaction was quenched with saturated aq. NaHCO (100 mL), and the
phases were separated. The aqueous phase was extracted with CH Cl (2 x
200 mL), dried over MgSO , filtered and concentrated in vacuo to give a
3
2
2
4
yellow oil, which was triturated in pentane and concentrated in vacuo to give
1
the title compound as an oily semiꢀsolid (2.48 g, 98 % yield). H NMR (500
3
MHz, CDCl ) δ 7.76 (dd, J = 3.7, 1.1 Hz, 1H), 7.57 – 7.53 (m, 2H), 7.47 (dd, J
= 5.0, 1.1 Hz, 1H), 7.37 – 7.22 (m, 8H), 7.11 (dd, J = 5.0, 3.7 Hz, 1H), 4.77 (d,
J = 4.6 Hz, 1H), 1.85 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H), 0.63 (d, J = 6.7 Hz,
13
1
3
H); C{ H} NMR (126 MHz, CDCl ) δ 157.3, 145.3, 140.6, 130.8, 130.2,
3
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129.7, 128.3 (2C), 127.8, 127.7 (2C), 127.6, 127.2, 126.9 (2C), 126.2 (2C),
ꢀ
1
9
3.0, 80.0, 30.4, 21.9, 17.0; IR νmax (Nujol, cm ) 3059, 1655, 1529; HRMS
20
(
D
ESIꢀTOF) m/z 348.1420 [M+H] C22H22NOS requires 348.1411; [α] = ꢀ354
°
3
(c = 0.55, CHCl ).
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(S)-2-(3-(Diphenylphosphanyl)thiophen-2-yl)-4-isopropyl-5,5-dimethyl-
,5-dihydrooxazole (1). solution of (S)ꢀ4ꢀisopropylꢀ5,5ꢀdimethylꢀ2ꢀ
thiophenꢀ2ꢀyl)ꢀ4,5ꢀdihydrooxazole 13 (590 mg, 2.64 mmol, 1 eq.) in Et O (6
mL) was cooled to ꢀ78 °C in an acetone/liq. N bath. nꢀBuLi (1.18 mL, 2.33M
4
A
(
2
2
in hexane, 2.76 mmol, 1.05 eq.) was added dropwise and stirring continued at
ꢀ78 °C for 30 min. The reaction vessel was transferred to an ice bath and
2
stirred at 0 °C for 30 min, and then returned to the acetone/liq. N bath and reꢀ
cooled to ꢀ78 °C. Chlorodiphenylphosphine (0.53 mL, 2.89 mmol, 1.1 eq) was
added dropwise, and the reaction was then stirred to room temperature over
16 h. The reaction mixture was diluted with water (15 mL), and then extracted
with Et O (3 x 40 mL). The organic layers were combined and dried over
2
4
MgSO , filtered and concentrated in vacuo to give a crude residue which was
purified by column chromatography (5:1 pentane:CH
2
Cl
2
2
on SiO ) to yield the
1
product as a white crystalline solid (600 mg, 56 % yield). H NMR (400 MHz,
CDCl
3
) δ 7.36 – 7.27 (m, 9H), 7.26 (m, 2H), 6.31 (dd, J = 5.1, 1.0 Hz, 1H),
3.28 (d, J = 8.2 Hz, 1H), 1.65 – 1.58 (m, 1H), 1.31 (s, 3H), 1.11 (s, 3H), 0.86
13
1
(
app. d, J = 6.5, 6H); C{ H} NMR (101 MHz, CDCl
40.8 (d, J = 27.1 Hz), 138.4 (d, J = 11.5 Hz), 137.8 (d, J = 10.5 Hz), 133.7 (d,
2C, J = 21.0 Hz), 133.5 (d, 2C, J = 20.7 Hz), 133.3, 132.7, 132.5, 128.5 (d,
3
) δ 157.1 (d, J = 3.6 Hz),
1
2C, J = 11.2 Hz), 128.4 – 128.2 (m, 3C), 127.3 (d, J = 2.3 Hz), 87.6, 80.6,
31
2
9.0, 28.8, 20.9, 20.8, 20.3; P NMR (162 MHz, CDCl ) δ ꢀ13.76 (s); IR ν
3
max
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ꢀ
1
(Nujol, cm ) 1638, 1061, 744; HRMS (ESIꢀTOF) m/z 408.1559 [M+H]
20
C
24
H
27NOPS requires 408.1551; MP 140ꢀ142 °C; [α]
CHCl ).
S)-2-(3-(Di-o-tolylphosphanyl)thiophen-2-yl)-4-isopropyl-5,5-dimethyl-
4,5-dihydrooxazole (2). solution of (S)ꢀ4ꢀisopropylꢀ5,5ꢀdimethylꢀ2ꢀ
thiophenꢀ2ꢀyl)ꢀ4,5ꢀdihydrooxazole 13 (590 mg, 2.64 mmol, 1 eq.) in Et
10mL) was cooled to ꢀ78 °C in an acetone/liq. N bath. nꢀBuLi (1.18 mL,
.33M in hexane, 2.76 mmol, 1.05 eq.) was added dropwise and stirring
D
= ꢀ176.3 ° (c = 0.4,
3
(
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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59
60
A
(
(
2
O
2
2
continued at ꢀ78 °C for 30 min. The reaction vessel was transferred to an ice
bath and stirred at 0 °C for 30 min, and then returned to the acetone/liq. N2
bath and reꢀcooled to ꢀ78 °C. Chlorodiꢀ(oꢀtolyl)phosphine (1.00 g, 4 mmol, 1.5
eq.) was added in one portion, and the reaction was then stirred to room
temperature over 16 h. The reaction mixture was diluted with water (15 mL),
and then extracted with Et
2
O (3 x 40 mL). The organic layers were combined
and dried over MgSO , filtered and concentrated in vacuo to a crude residue
4
which was purified by column chromatography (5:1 pentane:CH
2
Cl
2
2
on SiO )
1
to yield the product as a white crystalline solid (341 mg, 30 % yield). H NMR
(
400 MHz, CDCl
3
) δ 7.28 – 7.26 (m, 1H), 7.25 – 7.15 (m, 4H), 7.04 (app t, J =
7.2 Hz, 2H), 6.82 – 6.77 (m, 2H), 6.31 (dd, J = 5.0, 0.7 Hz, 1H), 3.30 (d, J =
8
.1 Hz, 1H), 2.44 (dd, J = 10.5, 1.6 Hz, 6H), 1.63 – 1.56 (m, 1H), 1.31 (s, 3H),
13
1
1
3
.09 (s, 3H), 0.83 (dd, J = 15.8, 6.5 Hz, 6H); C{ H} NMR (101 MHz, CDCl )
δ 157.2 (d, J = 3.6 Hz), 142.4 (d, J = 14.8 Hz), 142.2 (d, J = 15.1 Hz), 139.9,
139.7, 136.6 (d, J = 13.4 Hz), 136.0 (d, J = 11.7 Hz), 133.4, 132.9, 132.9,
1
32.7, 132.6, 129.9 – 129.7 (m, 2C), 128.5 (d, J = 7.4 Hz), 127.4 (d, J = 1.9
Hz), 125.9 (d, J = 13.2 Hz), 87.3, 80.5, 29.0, 28.8, 21.3 (d, J = 8.0 Hz), 21.1
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