Libraries of bisdiazaphospholanes and optimization of rhodium-catalyzed enantioselective hydroformylation

Article abstract of DOI:10.1021/jo400525w

Twelve chiral bis-3,4-diazaphospholane ligands and six alkene substrates (styrene, vinyl acetate, allyloxy-tert-butyldimethylsilane, (E)-1-phenyl-1,3- butadiene, 2,3-dihydrofuran, and 2,5-dihydrofuran) probe the influence of steric bulk on the activity and selectivity of asymmetric hydroformylation (AHF) catalysts. Reaction of an enantiopure bisdiazaphospholane tetraacyl fluoride with primary or secondary amines yields a small library of tetracarboxamides. For all six substrates, manipulation of reaction conditions and bisdiazaphospholane ligands enables state-of-the-art performance (90% or higher ee, good regioselectivity, and high turnover rates). For the nondihydrofuran substrates, the previously reported ligand, (S,S)-2, is generally most effective. However, optimal regio- and enantioselective hydroformylation of 2,3-dihydrofuran (up to 3.8:1 α-isomer/β-isomer ratio and 90% ee for the α-isomer) and 2,5-dihydrofuran (up to <1:30 α-isomer/β- isomer ratio and 95% ee for the β-isomer) arises from bisdiazaphospholanes containing tertiary carboxamides. Hydroformylation of either 2,3- or 2,5-dihydrofuran yields some of the β-formyl product. However, the absolute sense of stereochemistry is inverted. A stereoelectronic map rationalizes the opposing enantiopreferences

Full text of DOI:10.1021/jo400525w

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Featured Article
Libraries of Bisdiazaphospholanes and Optimization of
Rhodium-catalyzed Enantioselective Hydroformylation
Tyler T. Adint, Gene W Wong, and Clark Read Landis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400525w • Publication Date (Web): 12 Apr 2013
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The Journal of Organic Chemistry
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Libraries of Bisdiazaphospholanes and Optimization of Rhodium-
catalyzed Enantioselective Hydroformylation
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Tyler T. Adint, Gene W. Wong, Clark R. Landis*
Department of Chemistry, University of Wisconsin—Madison, 1101 University Avenue, Madison WI 53706
landis@chem.wisc.edu
KEYWORDS: Ligand design, hydroformylation, asymmetric catalysis, rhodium.
ABSTRACT:
Twelve
chiral
bisꢀ3,4ꢀ
diazaphospholane ligands and six alkene
substrates (styrene, vinyl acetate, allyloxyꢀtꢀ
butyldimethylsilane,
(E)ꢀ1ꢀphenylꢀ1,3ꢀ
butadiene, 2,3ꢀdihydrofuran, and 2,5ꢀ
dihydrofuran) probe the influence of steric
bulk on the activity and selectivity of
asymmetric
hydroformylation
(AHF)
catalysts,. Reaction of an enantiopure
bisdiazaphospholane tetraacyl fluoride with primary or secondary amines yields a small library of tetracarboxamides.
For all six substrates manipulation of reaction conditions and bisdiazaphospholane ligands enables stateꢀofꢀtheꢀart
performance (90% or higher ee, good regioselectivity, and high turnover rates). For the nonꢀdihydrofuran substrates
the previously reported ligand, (S,S)ꢀ2, is generally most effective. However, optimal regioꢀ and enantioselective
hydroformylation of 2,3ꢀdihydrofuran (up to 3.8:1 αꢀisomer:βꢀisomer ratio and 90% ee for the αꢀisomer) and 2,5ꢀ
dihydrofuran (up to <1:30 αꢀisomer:βꢀisomer ratio and 95% ee for the βꢀisomer) arises from bisdiazaphospholanes
containing tertiary carboxamides. Hydroformylation of either 2,3ꢀ or 2,5ꢀdihydrofuran yields some of the βꢀformyl
product. However , the absolute sense of stereochemistry is inverted. A stereoelectronic map rationalizes the opposing
enantiopreferences.
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Introduction
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An outstanding challenge in asymmetric hydroformylation (AHF) is the development of robust catalysts that give high
regioꢀ and enantioselectivity, high turnover numbers, and fast rates for a variety of alkenes. Our group and many others
previously have demonstrated effective enantioselective hydroformylation of various alkenes at mild conditions and
with low catalyst loadings.1,2 Although many phosphorusꢀcontaining ligands have been reported for rhodiumꢀcatalyzed
AHF, just a few structure types combine high regioꢀ and enantioselectivity along with high activity. Applications of AHF
that are particularly appealing (and challenging) include diꢀ and triꢀsubstituted alkene substrates. Because increased
substitution of alkenes commonly leads to substantially decreased rates, it makes sense to focus further development of
ligands on frameworks that give high rates and turnover numbers.
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Bisdiazaphospholane ligands enable exceptionally high activity and selectivity for rhodiumꢀcatalyzed AHF under mild
reaction conditions. AHF with bisdiazaphospholanes makes efficient use of expensive rhodium catalysts without the
requirement of high pressure steel reactors (most reactions can be performed in glass pressure bottles).1e Herein, we
report the synthesis of a small library of bisꢀ3,4ꢀdiazaphospholanes and its application to AHF of six different
substrates. Three ligand subsets were synthesized to compare bisdiazaphospholane steric bulk and hydroformylation
selectivity: type I, secondary carboxamides with slight steric modifications from previously reported (S,S)ꢀ2 ligand; type
II, secondary carboxamides with achiral Rꢀgroups of varying steric bulk; and type III, tertiary carboxamides. AHF of
benchmark substrates styrene, vinyl acetate, allyloxyꢀtꢀbutyldimethylsilane and (E)ꢀ1ꢀphenylꢀ1,3ꢀbutadiene provide
baseline comparisons for this ligand library to previously reported ligands. The dihydrofurans, 2,3ꢀ and 2,5ꢀ
dihydrofuran, represent a challenging class of disubstituted alkenes for which there are few high performing catalysts.
Previously we have reported that the related dihydropyrroles, NꢀBocꢀ2,3ꢀ and NꢀBocꢀ2,5ꢀdihydropyrrole, are
hydroformylated with stateꢀofꢀtheꢀart selectivity in the presence of (S,S)ꢀ2 ligand and common rhodium catalyst
precursors.1c
Results and Discussion
We previously have reported the synthesis of C2ꢀsymmetric tetraacid bisꢀ3,4ꢀdiazaphospholane ligand [(rac)ꢀ1] from
1,2ꢀbisphosphinobenzene,
2ꢀcarboxybenzaldehyde azine, and succinyl chloride.1a Resolution of the
bisdiazaphospholane enantiomers was accomplished by coupling of the carboxylic acid groups with enantiopure
methylbenzylamine to yield diastereomeric tetracarboxamide bisdiazaphospholane ligands followed by
chromatography. We find outstanding regioꢀ and enantioselective hydroformylation using the (S,S) phospholane ring
stereochemistry and (S)ꢀmethylbenzylamine [(S,S)ꢀ2] or its diastereomer [(R,R)ꢀ2].2, 3 Based on the crystal structures
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of (S,S)ꢀ2 and (rac)ꢀ1 [see Supporting Information], we hypothesize that steric interaction between the benzamide
substituents and the substrate can be significantly modulated by the bulk of the benzamide. Such steric interactions
could significantly affect rate and selectivity in AHF. To facilitate construction of a library, (rac)ꢀ1 was resolved by
chiral SFC.
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Synthesis of
a
bisdiazaphospholane library.
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Scheme 1. PyBOP coupling of enantioenriched
tetraacid bisdiazaphospholane 1 with various
primary amines
Coupling of the tetraacid bisdiazaphospholane 1 with
various amines yields tetracarboxamides. Most primary
amines underwent quantitative coupling in the presence of
PyBOP/DIEA
to
form
secondary
carboxamide
bisdiazaphospholane ligands (Scheme 1; Type I and II
ligands).
Quantitative transformation of 1 to tertiary carboxamide
bisdiazaphospholane ligands could not be effected with
common coupling reagents such as PyBOP or DCC.
However, successful coupling is achieved by first
transforming
1
into
the
tetraacyl
fluoride
bisdiazaphospholane 9 with DeoxoꢀFluor™.4 Acyl fluorides have been used for coupling of sterically hindered peptide
sequences in typically higher yields than other methods.5 Tetraacyl fluoride precursor 9 can be isolated quantitatively or
generated in situ. Scheme 2 summarizes the
Scheme 2. Deoxo-FluorTM coupling of enantioenriched
tetraacid bisdiazaphospholane 1 with various amines
range of successful couplings that can be
achieved with the 9; dimethylamine, cyclic
amines, or aniline undergo coupling to their
respective carboxamide substituted ligands.
Sterically encumbering secondary amines
(diisopropylamine and dicyclohexylamine) and
less nucleophilic primary amines (2ꢀ
aminopyridine and 2ꢀaminopyrimidine) are
unreactive and result in the reꢀisolation of 9.
Acyl fluorides enable rapid access to a library
of bisdiazaphospholanes that can be used
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without chromatographic purification. The tetraacyl fluoride 9 exhibits low reactivity with water (enabling aqueous
workꢀup procedures) and alcohols.6 From preliminary experiments, higher alcohol concentration and forcing conditions
are required to produce analogous tetraester bisdiazaphospholanes (AHF results of tetraester ligands is enclosed in the
supporting information).
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9
AHF of styrene, vinyl acetate, and allyloxy-tert-butyldimethylsilane. Similar to previously reported studies,
oneꢀpot AHF of styrene, vinyl acetate, and allyloxyꢀtꢀbutyldimethylsilane was used to screen the effects of ligand
structure on activity and selectivity.1a,7 Styrene, vinyl acetate, and allyloxyꢀtꢀbutyldimethylsilane underwent effective
hydroformylation in glass pressure bottles at 150 psig H2/CO (1:1) and 60˚C for all three classes of bisꢀ3,4ꢀ
diazaphospholane ligands (Table 1).
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AHF using tetraacid (R,R)ꢀ1 as the ligand (entry 1) requires atypical conditions (MeOH/Et3N) for ligand solubilization
and yielded modest enantioselectivity (presumably due to baseꢀinduced racemization during the course of the reaction).
Type I ligands include previously reported (S,S)ꢀ2 and its less selective diastereomer (R,R)ꢀ2 (entries 2 and 3,
respectively). Compared to the standard ligand (S,S)ꢀ2, the ligand (S,S)ꢀ3 (for which cyclohexyl replaces phenyl) results
Table 1. Results of one-pot AHF screening of a library of bisdiazaphospholane ligands
Allyloxyꢀtꢀ
butyldimethylsilane
Entry
Type
Ligand
Styrene
b:l ratioa
Vinyl acetate
b:l ratioa % eeb
% eeb
53
b:l ratioa
1.6:1
2.0:1
1.7:1
1.9:1
1.5:1
1.8:1
1.8:1
1.6:1
1.9:1
1.2:1
1.3:1
1.2:1
1.1:1
% eeb
1c
2
(R,R)ꢀ1
(S,S)ꢀ2
10.9:1
18.3:1
9.2:1
7.5:1
6.2:1
9.0:1
8.0:1
6.7:1
3.2:1
4.7:1
12.9:1
6.8:1
8.0:1
15:1
53:1
29:1
53:1
55:1
34:1
33:1
36:1
40:1
44:1
27:1
20:1
25:1
83
98
84
97
95
95
97
90
94
85
92
90
90
75
87
96
3
(R,R)ꢀ2
(S,S)ꢀ3
75
80
91
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4
63
88
87
5
(S,S)ꢀ4
90
94
6
(R,R)ꢀ5
(R,R)ꢀ6
(R,R)ꢀ7
(R,R)ꢀ8
(R,R)ꢀ10
(S,S)ꢀ11
(R,R)ꢀ12
(R,R)ꢀ13
7
89
82
68
26
83
23
84
97
II
8
97
9
95
10
11
12
13
92
90
90
>95
III
Conditions: 4 h, 60°C, 150 psig H2/CO (1:1), 4.3 M total substrate (equal concentrations of each), 1600:1 total substrate:Rh;
complete conversion of alkene is observed in each case expect entry 6: 69%,76%, and 97% conversion of styrene, vinyl acetate,
and allyloxyꢀtꢀbutyldimethylsilane respectively. a Determined by 1H NMR spectroscopy. b Determined by chiral GC analysis. c
1mL MeOH as solvent with 1eq. Et3N to (R,R)ꢀ1 to solubilize ligand.
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in decreased regioꢀ (18.3:1 vs. 7.5:1) and enantioselectivity (87% ee vs. 63% ee) in hydroformylation of styrene, but little
affect on vinyl acetate and allyl silyl ether hydroformylation (entries 2 and 4). In contrast, (S,S)ꢀ4 (entry 5), which bears
tꢀbutyl in place of phenyl, gives decreased regioselectivity but retains high enantioselectivity. Type II ligands, which
contain secondary carboxamides with increasing Rꢀgroup steric bulk (ethyl, benzyl, benzhydryl, and 1ꢀadamantyl),
decrease styrene regioꢀ and enantioselectivity in AHF while leaving selectivities for vinyl acetate and allyl silyl ether
relatively unaffected (entries 6—9). Type III tertiary carboxamide ligands exhibit uniformly lower regioselectivities than
(S,S)ꢀ2 for all three terminal alkenes. Whereas styrene enantioselectivity varied from 23ꢀ86% ee amongst the four type
III ligands, the enantioselectivities for the allyl silyl ether and vinyl acetate were generally similar to (S,S)ꢀ2. Overall,
(S,S)ꢀ2 exhibits optimal regioꢀ and enantioselectivity in the hydroformylation of styrene, vinyl acetate, and allyl silyl
ether.
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AHF of (E)-1-phenyl-1,3-butadiene. We previously
Table 2. AHF of (E)-1-phenyl-1,3-butadiene with
library of bisdiazaphospholanes
reported enantioselective hydroformylation of 1,3ꢀdienes
using bisdiazaphospholanes (S,S)ꢀ2, (R,R)ꢀ2, and (R,R)ꢀ5
leading to β,γꢀunsaturated aldehydes that are useful
%
Entry
Type
I
Ligand
% eeb
conv.a
97
intermediates in the synthesis of complex molecules.1b With
the bisdiazaphospholane library reported here, AHF of (E)ꢀ
1ꢀphenylꢀ1,3ꢀbutadiene produces just one regioisomer,
consistent with our previous studies, but with widely ranging
enantioselectivity (11ꢀ94% ee). Ligands (S,S)ꢀ2 and (S,S)ꢀ3
give the highest enantioselectivity for AHF of (E)ꢀ1ꢀphenylꢀ
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2
3
4
5
6
7
(S,S)ꢀ2
(S,S)ꢀ3
(S,S)ꢀ4
(R,R)ꢀ5
(R,R)ꢀ6
(R,R)ꢀ7
(R,R)ꢀ8
94
93
44
83
78
79
51
95
92
95
92
II
60
90
(R,R)ꢀ
10
8
9
95
95
95
16
11
1,3ꢀbutadiene (entries
1 and 2; 94% and 93% ee,
(S,S)ꢀ11
III
(R,R)ꢀ
12
respectively). In contrast, (S,S)ꢀ3 gives poor
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33
enantioselectivity (64% ee) for styrene. Using type II and III
ligands with increasingly bulky carboxamides results in
decreased enantioselectivity: 51ꢀ83% ee for type II ligands
[83% ee for (R,R)ꢀ5] and 11ꢀ33% ee for type III ligands.
(R,R)ꢀ
13
11
97
30
Following conditions: 4 h, 40°C, 150 psig H2/CO (1:1), 0.55
a
M
1ꢀphenylꢀ1,3ꢀbutadiene, 200:1 substrate:catalyst.
Determined by 1H NMR spectroscopy. Determined by
b
chiral SFC analysis.
AHF of dihydrofurans. Hydroformylation of dihydrofurans leads to enantioenriched carbaldehyde intermediates
useful for organic synthesis.7 A few groups have reported that AHF of dihydrofurans proceeds with modest overall
performance when one takes both rate and selectivity into account.9
The AHF of 2,3ꢀdihydrofuran with bisdiazaphospholanes is modestly regioselective, yielding both αꢀ and βꢀ
carbaldehyde regioisomer products. Initial screening (Table 3) of 2,3ꢀdihydrofuran hydroformylation with a subset of
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the library at 30°C for 18 hours resulted in modest conversions (<50%), 1.7:1—3.9:1 α:β regioselectivity, and
enantioselectivities as high as 89% for both regioisomers. For the initial screening conditions type III ligands exhibited
the highest enantioselectivity (77—90% ee) and conversion.
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2
3
4
5
6
7
8
9
Increasing the reaction temperature for AHF of 2,3ꢀdihydrofuran yields substantially improved conversion with little
change in selectivity (Table 4). At 60°C the αꢀ and βꢀaldehyde regioisomers are produced with high enantioselectivity
(ca. 90% ee) and conversions exceeding 90% (600 turnovers) in 4 hours. Under these conditions the αꢀregioisomer
predominates by an approximately 3:1 ratio. The highest previously reported enantioselectivity for AHF of 2,3ꢀ
dihydrofuran to the αꢀaldehyde was 62% ee with only 8% conversion (16 turnovers) after 22 hours.9a
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Hydroformylation of 2,5ꢀdihydrofuran isomer with all ligands at 40°C for 4 hours proceeds smoothly to the expected βꢀ
regioisomer, with minor formation of the αꢀcarbaldehyde and 2,3ꢀdihydrofuran byproducts (Table 5). Compared to 2,3ꢀ
dihydrofuran, AHF of 2,5ꢀdihydrofuran is faster and more enantioselective. The advantage of the bulky type III ligands
is particularly clear; these ligands give much higher conversions (94%, 630 turnovers, 4 hours) and enantioselectivities
as high as 95 %ee. For comparison, similar conversions with slightly lower selectivities require 10ꢀfold longer reaction
times with phosphineꢀphosphite ligands.9a
Table 3. Initial screening results for AHF of 2,3-dihydrofuran using bisdiazaphospholane ligands
Entry
Type
Ligand
(S,S)ꢀ2
% conv. a
α:β ratioa
2.8:1
1.7:1
1.7:1
3.8:1
3.6:1
3.9:1
3.7:1
a
% ee αb
69 (S)
85 (R)
75 (R)
90 (R)
77 (S)
87 (R)
77 (R)
% ee βb
86 (S)
85 (R)
70 (R)
89 (R)
87 (S)
87 (R)
78 (R)
b
1
2
3
4
5
6
7
11
37
7
I
(R,R)ꢀ2
(R,R)ꢀ8
(R,R)ꢀ10
(S,S)ꢀ11
(R,R)ꢀ12
(R,R)ꢀ13
II
45
16
41
15
III
1
Conditions: 2.6 M 2,3ꢀdihydrofuran, 670:1 substrate:catalyst. Determined by H NMR spectroscopy. Determined by
chiral GC analysis.
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Table 4. Optimization of selected ligands for the AHF of 2,3-dihydrofuran
1
2
3
4
5
6
7
8
α:β ratioa
% ee αb
% ee βb
Entry
Type
Ligand
Temp.
% conv. a
9
1
2
3
4
5
6
7
8
I
(S,S)ꢀ2
(R,R)ꢀ6
(R,R)ꢀ10
(S,S)ꢀ11
(R,R)ꢀ12
(S,S)ꢀ2
40°C
40°C
40°C
40°C
40°C
60°C
60°C
60°C
2.8:1
1.5:1
3.4:1
3.2:1
3.5:1
3.1:1
3.3:1
3.5:1
25
23
30
16
89 (S)
83 (R)
88 (R)
88 (S)
90 (R)
80 (S)
87 (R)
88 (R)
82 (S)
84 (R)
86 (R)
80 (S)
85 (R)
85 (S)
90 (R)
88 (R)
10
11
12
13
14
15
16
17
18
19
II
III
27
94
92
83
I
(R,R)ꢀ10
(R,R)ꢀ12
III
a
1
b
Conditions: 4 h, 150 psig H2/CO (1:1), 2.6 M 2,3ꢀdihydrofuran, 670:1 substrate:catalyst. Determined by H NMR spectroscopy.
Determined by chiral GC analysis.
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Table 5. AHF of 2,5-dihydrofuran using bisdiazaphospholane ligands
% 2,3ꢀ
α:β ratioa
% ee αb
% ee βb
Entry
Type
Ligand
% conv. a
dihydrofurana
1
2
3
4
5
6
7
(S,S)ꢀ2
(R,R)ꢀ2
(R,R)ꢀ8
(R,R)ꢀ10
(S,S)ꢀ11
(R,R)ꢀ12
(R,R)ꢀ13
1:15
1:14
80
61
18
34
4
74 (S)
57 (R)
51 (R)
81 (R)
86 (S)
81 (R)
88 (R)
86 (R)
82 (S)
82 (S)
95 (S)
20 (R)
95 (S)
56 (S)
I
II
<1:30
<1:30
1:28
28
94
97
92
52
4
3
III
<1:30
1:17
5
21
a
Conditions: 40°C, 4 h, 150 psig H2/CO (1:1), 2.6 M 2,5ꢀdihydrofuran, 670:1 substrate:catalyst. Determined by 1H NMR
spectroscopy. b Determined by chiral GC analysis.
Both 2,3ꢀdihydrofuran and 2,5ꢀdihydrofuran yield some amount of the αꢀ and βꢀcarbaldehydes. Although the αꢀ
regioisomers produced from 2,3ꢀ and 2,5ꢀdihydrofuran have the same absolute sense of stereoinduction, the βꢀ
regioisomer produced from 2,3ꢀdihydrofuran (a minor product) has opposite chirality from AHF of 2,5ꢀdihydrofuran.
Similar behavior was first reported by Nozaki et al. for these substrates with BINAPHOS ligand.9e Insertion of 2,5ꢀ
dihydrofuran into the RhꢀH bond leads to four possible products (Scheme 3): (R)ꢀα, (S)ꢀα, (R)ꢀβ, and (S)ꢀβ isomers.
With ligand (R,R)ꢀ10, the main products are (R)ꢀα and (R)ꢀβ. In contrast, direct hydroformylation of 2,5ꢀdihydrofuran
should result in just two aldehydes (Scheme 4): (R)ꢀβ or (S)ꢀβ. However, αꢀproducts may arise via isomerization of the
2,5ꢀdihydrofuran to the thermodynamically preferred 2,3ꢀdihydrofuran followed by AHF. For ligand (R,R)ꢀ10, the αꢀ
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product has primarily the (R) configuration but the βꢀproduct is primarily (S)! These results indicate that (1)
hydroformylation occurs on opposite enantiofaces of the
1
2
3
4
5
two dihydrofuran isomers and (2) the βꢀcarbaldehyde
6
product observed in the hydroformylation of 2,5ꢀ
7
8
dihydrofuran arises from both direct hydroformylation and
9
isomerization/hydroformylation
but
with
opposite
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Scheme 3. Observed
hydroformylation of 2,3-dihydrofuran
products
in
the
Scheme
hydroformylation
4.
Observed
of
products
in
the
2,5-dihydrofuran
Figure 1. Empirical energetic map to rationalize
regioꢀ and enantioselectivity of 2,3ꢀdihydrofuran and
2,5ꢀdihydrofuran
hydroformylation
using
Rhꢀ
stereochemical preferences. The counteracting selectivity
preferences of direct and isomerization/hydroformylation
pathways indicate that the direct pathway must have higher
bisdiazaphospholane catalysts. Blue boxes indicate
varying levels of steric bulk (dark blue = large
repulsion, light blue = small repulsion), red dots
indicate electronically unfavorable orientations of
inductively electron withdrawing substituents. Boxes
labeled as product carbaldehydes.
Absolute
intrinsic
enantioselectivity.
Previously we have developed an energetic quadrant map
enantioselection
than
the
observed
stereochemistry based on (S,S)ꢀbisdiazaphospholanes.
that graphically summarizes hypothetical steric and electronic contributions to the transition state energies for alkene
insertion in the RhꢀH bond (Figure 1).1a, 10 We presume equatorialꢀaxial coordination of all bisdiazaphospholane ligands
in trigonal bipyramidal rhodiumꢀalkene intermediates. The perspective shown places the axial RhꢀH and RhꢀP bonds in
the plane of the paper, the coordinated alkene lies in front of that plane and the remaining RhꢀP and RhꢀCO vectors
behind. Regions colored in blue indicate varying levels of steric bulk and red dots indicate less favorable orientations of
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inductively electron withdrawing alkene substituents. Application of this map to 2,3ꢀdihydrofuran suggests a preference
for Reꢀface coordination with the ether oxygen lying in the bottom right quadrant. This model predicts formation of the
(S)ꢀα stereoisomer [based on (S,S)ꢀbisdiazaphospholane ligands] as is observed. For the hydroformylation of 2,5ꢀ
1
2
3
4
5
6
7
8
dihydrofuran, the energetic map correctly predicts formation of the (R)ꢀβ product. Furthermore, the stereoelectronic
map of Figure 1 reveals that Eꢀ1,2ꢀdisubstituted alkenes should hydroformylate more slowly than the Zꢀstereoisomers
because one of the substitutents of the Eꢀisomer necessarily lies in a sterically crowded quadrant. The map also predicts
lower enantioselectivity for the Eꢀisomer, as seen for βꢀmethylstyrene and 1ꢀacetamidoꢀ1ꢀpropene.1c, d Remarkably, the
energetic quadrant map developed for terminal alkenes robustly rationalizes the absolute configuration of dihydrofuran
AHF products, the selection of different enantiofaces for 2,3ꢀ and 2,5ꢀdihydrofurans, and rates and selectivities for E-
vs. Zꢀ1,2ꢀdisubstituted alkenes.
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Conclusions
This work addresses the challenge of AHF of dihydrofurans with useful selectivities and activities by exploiting the
synthetic extensibility of bisdiazaphospholane ligands. The creation of small ligand libraries is made possible by
formation of enantiopure tetraacyl fluoride 9 which can be rapidly transformed to a variety of bulky secondary and
tertiary tetracarboxamides. Application of this library to rhodiumꢀcatalyzed AHF of styrene, vinyl acetate, alloxyꢀtꢀ
butyldimethylsilane, and 1ꢀphenylꢀ1,3ꢀbutadiene appears to follow the “principle of initial optimization” 11 in which one
of the earliest ligands, (S,S)ꢀ2, uncovered in the discovery process exhibits the best overall selectivity trends. For the
substrate styrene, highly varied enantioꢀ and regioselectivity results with different library members, in keeping with
previous observations10 of a delicate balance among competing pathways for aryl alkene hydroformylation. For the
substrate 1ꢀphenylꢀ1,3ꢀbutadiene an inverse correlation of steric bulk with enantioselectivity (increasing steric bulk
leads to decreasing enantioselectivity) is observed. The value of a library approach is seen in the hydroformylation of
2,3ꢀ and 2,5ꢀdihydrofurans. The tertiary carboxamide, type III ligands (R,R)ꢀ10 and (R,R)ꢀ12 give unprecedented
combination of high activity with high regioꢀ and enantioselectivity for the AHF of 2,3ꢀ and 2,5ꢀdihydrofuran.
Stereoelectronic maps predict the qualitative activity and selectivity trends for a wide variety of monoꢀ and
disubstituted alkenes. These results provide encouragement as applications of catalytic AHF move to bulky diꢀ and triꢀ
substituted alkenes and other challenging substrates.
Experimental
Materials and Methods
All phosphines were prepared under N2 using standard Schlenk line techniques. Work up and flash column
chromatography were performed open to air. Ligands (rac)ꢀ1, (S,S)ꢀ2, (R,R)ꢀ2 were prepared according to literature
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procedure1a and (rac)ꢀ1 was resolved by chiral supercritical fluid chromatography. Unless mentioned below all
chemicals were purchased and used without further purification. Rh(acac)(CO)2 was recrystallized from
Page 10 of 18
1
2
3
4
5
6
toluene/hexanes (green needles) prior to use. THF and toluene were distilled over Na/benzophenone under a nitrogen
atmosphere was further deoxygenated by at least three freezeꢀthaw cycles prior to use. Dichloromethane was distilled
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8
1
under nitrogen over P2O5. The percent conversion and regioisomer ratios were determined by H NMR analysis of the
9
crude reaction mixture. Gas chromatography (GC) was performed using a βꢀDEX 225 column (30m x 0.25mm ID).
Super Critical Fluid Chromatography (SFC) was performed using a Chiracel OJꢀH column. Silica gel, 230ꢀ400 mesh
(40ꢀ63ꢁm) was used for column chromatography. Vinyl acetate, styrene, TBSO allyl ether, phenylꢀ1,3ꢀbutadiene, 2,5ꢀ
dihydrofuran, and 2,3ꢀdihydrofuran were all sparged w/ N2 before use. Phenylꢀ1,3ꢀ(E)ꢀbutadiene1b and 7ꢀ
azanoraborane12 was synthesized according to literature procedure. (R) and (S)ꢀMethylprolinate were synthesized from
(R) and (S)ꢀproline respectively, and recrystallized. Synthesis of bisdiazaphospholanes using PyBOP often contains low
amounts of the tris(pyrollidinophosphine) oxide byproduct (31P δ: 16 (s)), even after column chromatography, which has
not been observed or is expected to affect AHF. Proton (1H) and carbon (13C) NMR spectra were referenced to TMS
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1
(0.00 ppm) and CDCl3 (77.0 ppm) respectively. The fluorine (19F) spectra were referenced to TMS in the H spectra,
using the Unified Scale. Phosphorus (31P) chemical shifts were referenced to an external 85% phosphoric acid (H3PO4)
1
sample. H NMR splitting patterns were designated as singlet (s), doublet (d), triplet (t), quartet (q). Firstꢀorder
splitting patterns were assigned on the basis of the multiplet. Splitting patterns that could not be interpreted are
designated as multiplet (m) or broad (br). Mass spectra were collected using an instrument with electrospray ionization
and a TOF analyzer. Ligands 7 and 8 were prepared from a sample of tetraacid bisdiazaphospholane (1) that was
partially oxidized at one phosphine, <5% by 31P NMR (δ: 42.7 (d, J = 238 Hz), 0.3 (d, J = 238 Hz)).
Caution: Syngas (1:1 H2:CO) is flammable! Carbon monoxide is toxic! All hydroformylation reactions
should be carried out in a well ventilated fume hood.
General Method A An ovenꢀdried 50mL Schlenk flask was loaded with 0.2g (0.22mmol) enantiopure tetraacid
bisdiazaphospholane (R,R)ꢀ1 and 5 eq. of PyBOP and pumped/purged three times with N2. The solid was suspended in
20ꢀ30mL of dichloromethane and stirred at room temperature. DIEA (5eq.) was added to the stirred suspension
(0.2mL, 1.15mmol) at which point the solution becomes homogenous. Primary amine (5 eq.) was added by syringe or
cannula and the solution was stirred overnight. The reaction mixture was washed with sat. NaHCO3 solution, 1M HCl,
and brine. The organic layer was dried with Na2SO4 followed by removal of volatiles on a rotary evaporator to give
crude material which is purified by flash column chromatography.
General Method B An ovenꢀdried 50mL Schlenk flask was loaded with 0.2g (0.22mmol) enantiopure tetraacyl
fluoride bisdiazaphospholane (R,R)ꢀ9 and pumped/purged three times with N2. The solid was dissolved in 20ꢀ30mL of
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dichloromethane and stirred at room temperature. DIEA (5 eq) was added to the stirred solution (0.2mL, 1.15mmol).
Secondary amine (5 eq.) was added by syringe to the stirred solution (solid amines dissolved in DCM) and stirred
overnight. The reaction mixture was washed with sat. NaHCO3 solution, 1M HCl, and brine. The organic layer was
dried with Na2SO4 followed by rotary evaporation to give the corresponding tetraamide bisdiazaphospholane.
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2,2’,2’’,2’’’-(1,2-phenylenebis((1S,3S)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-a)pyridazine-
2,1,3(3H)-triyl))tetrakis(N-((1S)-1-(1-cyclohexyl)ethylbenzamide)) (S,S)-3. Following general method A
using 0.2g (0.22mmol) enantiopure tetraacid bisdiazaphospholane (S,Sꢀ1) and 5 eq. of (S)ꢀcyclohexylethylamine
(0.17mL, 1.1mmol). (S,S)ꢀ3 was isolated from silica gel chromatography using 2:1 ethyl acetate and dichloromethane
(Rf = 0.43). Isolated 0.21g, 69% yield, quantitatively pure by 31P NMR. 1H NMR (300 MHz, CDCl3) δ: 0.72 ppm (d, J =
6.6 Hz), 0.81 – 0.93 (m), 1.03 – 1.22 (m), 1.46 – 1.82 (m), 2.41 – 2.71 (m), 3.53 – 3.60 (m), 3.99 – 4.09 (m), 6.14 – 6.16
(m), 6.64 – 6.69 (m), 6.90 – 6.94 (m), 7.03 – 7.11 (m), 7.23 – 7.26 (m, overlap with CHCl3 residual solvent peak), 7.33 –
7.40 (m), 7.45 – 7.50 (m), 7.54 – 7.56 (m), 7.62 – 7.68 (m), 7.75 – 7.78 (m), 8.06 – 8.08 (m). 13C NMR (75 MHz, CDCl3)
δ: 17.3, 17.8, 26.4, 26.6, 26.7, 29.0, 29.2, 29.5, 29.8, 304, 42.6, 42.9, 50.5, 51.3, 55.6, 57.6, 125.3, 125.9, 126.4, 127.1,
127.9, 128.3, 128.7, 128.8, 129.9, 130.5, 130.6, 131.5, 133.6, 134.3, 137.1, 138.6, 165.7, 167.3 , 168.3, 168.6. 31P{1H} NMR
(120 MHz, CDCl3) δ: 5.6 (broad s). HRMSꢀESI (m/z): [M + Na]+ calcd for C78H96N8NaO8P2, 1357.6719; found, 1357.6763
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(Δ = 3.2 ppm).
2,2’,2’’,2’’’-(1,2-phenylenebis((1S,3S)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-a)pyridazine-
2,1,3(3H)-triyl))tetrakis(N-((1S)-1-(1,2,2-trimethyl)propylbenzamide)) (S,S)-4. Following general method A
using 0.2g (0.22mmol) enantiopure tetraacid bisdiazaphospholane (S,Sꢀ1) and 5 eq. of (S)ꢀ3,3ꢀdimethylꢀ2ꢀ
butylamine(0.15mL, 1.1mmol). (S,S)ꢀ4 was isolated from silica gel chromatography using 4:1 ethyl acetate and
dichloromethane solvent mixture. Isolated 0.14g, 51% yield, quantitatively pure by 31P NMR. 1H NMR (300 MHz,
CDCl3) δ: 0.81 ppm (d, J = 6.6 Hz), 0.90 (s), 1.00 (s), 1.20 (d, J = 6.9), 2.38 – 2.69 (m), 3.49 – 3.54 (m), 4.12 – 4.17 (m),
6.20 (d, J = 8.1 Hz), 6.35 (br s), 6.66 – 6.80 (m), 6.98 (br d, J = 9.0 Hz), 7.16 (br s), 7.30 – 7.40 (m), 7.45 – 7.52 (m),
7.66 – 7.69 (m), 7.76 – 7.79 (m), 7.90 (br d, J = 9.3 Hz). 13C NMR (75 MHz, CDCl3) δ: 15.8, 16.1, 26.7, 26.9, 29.2, 29.4,
34.3, 34.6, 54.1, 54.7, 55.3, 57.2, 117.5, 125.0, 126.4, 127.6, 128.5, 128.9, 129.1, 130.8, 132.9, 134.1, 135.9, 137.7, 165.7,
166.7, 168.7, 169.4. 31P{1H} NMR (120 MHz, CDCl3) δ: 10.4 (broad s). HRMSꢀESI (m/z): [M + Na]+ calcd for
C70H88N8NaO8P2, 1253.6093; found, 1253.6074 (Δ = 1.5 ppm).
2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis(N-ethylbenzamide) (R,R)-5. Following general method A using 0.25g
(0.28mmol) enantiopure tetraacid bisdiazaphospholane (R,Rꢀ1) and 5 eq. of ethylamine 2M in THF(0.7mL, 1.4mmol).
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(R,R)ꢀ5 can be recrystallized from 8:1 hexane:ethyl acetate solution obtaining a white solid. Isolated 0.09g, 30% yield,
1
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1
95% pure by 31P NMR. H NMR (300 MHz, CDCl3) δ: 1.04 (t, J = 7.3 Hz), 1.24 (t, J = 7.3 Hz), 2.40 – 2.85 (m, 8 H), 3.12
3
4
5
6
7
– 3.30 (m, 3H), 3.45 – 3.75 (m, 5H), 6.17 (d, J = 7.5 Hz, 2H), 6.33 (s, 2H), 6.67 (m, 2H), 6.85 – 7.00 (m, 4 H) 7.05 –
7.30 (m, overlap with CHCl3 residual solvent peak), 7.40 – 7.68 (m, 9H), 8.61 (broad t, J = 5.2 Hz, 2H). 13C NMR (75
MHz, CDCl3) δ: 14.8, 15.0, 29.1, 29.4, 34.6, 35.0, 55.1, 57.5, 125.6, 127.1, 127.6, 128.3, 128.7, 129.1, 129.7, 130.2, 130.6,
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9
130.7, 134.0, 134.4, 134.6, 137.3, 138.6, 165.7, 167.3, 168.1, 169.0. 31P{1H} NMR (120 MHz, CDCl3) δ: 9.2 (s). HRMSꢀESI
(m/z): [M + NH4]+ calcd for C54H60N9O8P2, 1024.4035; found, 1024.4059 (Δ = 2.3 ppm).
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2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis(N-benzylbenzamide) (R,R)-6. Following general method A using 0.3g
(0.33mmol) enantiopure tetraacid bisdiazaphospholane (R,Rꢀ1) and 5 eq. of benzylamine (0.18mL, 1.7mmol). (R,R)ꢀ6
was purified by flash column chromatography using ethyl acetate as eluent (Rf = 0.05). Isolated 95mg, 32% yield, 95%
pure by 31P NMR. 1H NMR (300 MHz, CDCl3) δ: 2.30 – 2.63 (m, 8 H), 3.64 (dd, J = 15.6, 5.1 Hz, 2H), 4.26 (dd, J =
15.1, 6.4 Hz, 2H), 4.29 – 4.71 (m, 4H), 6.16 (d, J = 7.8 Hz, 2H), 6.22 (s, 2H), 6.61 – 6.67 (m, 2H), 6.78 – 6.86 (m, 4H),
7.03 – 7.12 (m, 9 H), 7.18 – 7.40 (m, overlap with CHCl3 residual solvent peak), 7.49 – 7.52 (m, 2H), 7.60 – 7.80 (m,
2H), 8.68 (broad s, 1H). 13C NMR (75 MHz, CDCl3) δ: 29.0, 29.4, 43.3, 44.4, 55.7, 57.7, 125.6, 127.1, 127.6, 128.3, 128.8,
129.1, 129.7, 130.2, 130.6, 130.7, 134.0, 134.4, 134.6, 137.4, 138.6, 165.5, 167.3, 168.6, 169.6. 31P{1H} NMR (120 MHz,
CDCl3)δ: 7.3 (s). HRMSꢀESI (m/z): [M + NH4]+ calcd for C74H68N9O8P2, 1272.4661; found, 1272.4634 (Δ = 2.1 ppm).
2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis(N-benzhydrylbenzamide) (R,R)-7. Following general method A using
0.20g (0.22mmol) enantiopure tetraacid bisdiazaphospholane (R,Rꢀ1) and 5 eq. of benzhydrylamine (0.19mL,
1.1mmol). Ligand (R,R)ꢀ7 was isolated by way of flash column chromatography using 2:1 ethyl acetate and
1
dichloromethane (Rf = 0.30) solvent mixture. Isolated 215mg, 64% yield, 79% pure by 31P NMR. H NMR (300 MHz,
CDCl3) δ: 2.30 – 2.63 (m, 8 H), 4.29 – 4.71 (m, 4H), 6.16 (d, J = 7.8 Hz, 2H), 6.22 (s, 2H), 6.61 – 6.67 (m, 2H), 6.78 –
6.86 (m, 4H), 7.03 – 7.12 (m, 9 H), 7.18 – 7.40 (m, overlap with CHCl3 residual solvent peak), 7.49 – 7.52 (m, 2H), 7.60
– 7.80 (m, 2H), 8.68 (broad s, 1H). 13C NMR (75 MHz, CDCl3) δ: 28.9, 29.1, 57.7, 57.9, 125.3, 125.9, 127.6, 127.9, 128.3,
128.7, 129.1, 129.3, 129.9, 130.3, 130.8, 133.4, 134.0, 134.3, 136.3, 137.4, 166.1, 167.0, 168.4, 168.6. 31P{1H} NMR (120
MHz, CDCl3) δ: 9.8 (broad s). HRMSꢀESI (m/z): [M + Na]+ calcd for C98H80N8NaO8P2, 1581.5467; found, 1581.5500 (Δ
= 2.1 ppm).
2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis(N-(1-adamantyl)benzamide) (R,R)-8. Following general method A
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using 0.20g (0.22mmol) enantiopure tetraacid bisdiazaphospholane (R,Rꢀ1) and 5 eq. 1ꢀadamantylamine (0.17g,
1.1mmol) dissolved in dichloromethane solution and cannula transferred to the (R,Rꢀ1), PyBOP, and DIEA mixture.
After 4 hours stirring, a white solid precipitated out of solution; this material was separated from the supernatant. The
filtrate was washed with sat. NaHCO3 solution, 1M HCl, and brine. The organic layer was dried with Na2SO4 followed by
rotary evaporation to give crude material which is purified by flash column chromatography. The solvent from the
filtrate was removed and (R,R)ꢀ8 was purified by way of silica gel chromatography utilizing ethyl acetate (Rf = 0.05) as
an eluent, resulting in a white solid. Isolated 130mg, 41% yield, 85% pure by 31P NMR. 1H NMR (500 MHz, CD2Cl2) δ:
1.54 (apparent Abs, JAB = 61.6 Hz, J = 11.8 Hz, 14 H), 1.74 (m, 13H), 1.89 (m, 16H), 2.14 (m, 17H) 2.25 – 2.55 (m, 8H),
6.23 (broad s, 2H), 6.45 – 6.70 (m), 6.78 (broad s), 6.92 (m), 7.18 – 7.40 (m), 7.40 – 7.50 (m), 7.60 – 7.85 (m). 13C NMR
(75 MHz, CDCl3) δ: 14.3, 21.1, 29.4, 29.6, 36.3, 36.6, 41.4, 41.9, 53.1, 53.4, 60.5, 111.4, 117.3, 125.0, 126.2, 126.4, 127.4,
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127.7, 128.7, 130.8, 132.2, 136.5, 137.9, 166.1, 166.9, 168.5, 171.3. 31P{1H} NMR (120 MHz, CDCl3) δ: 10.9 (broad s).
HRMSꢀESI (m/z): [M + Na]+ calcd for C86H96N8NaO8P2, 1453.6719; found, 1453.6727 (Δ < 1 ppm).
2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakiscarbonyl fluoride (R,R)-9. An ovenꢀdried 50mL Schlenk flask was
loaded with 0.2g (0.22mmol) enantiopure tetraacid bisdiazaphospholane (R,Rꢀ1) and pumped/purged three times with
N2. Solid was suspended in 20ꢀ30mL of dichloromethane and stirred at 24°C. Addition of 5 eq. of DIEA (0.2mL,
1.15mmol) resulted in a homogenous yellow solution. Addition of 5 eq. of DeoxoꢀFluor™(0.21mL, 1.15mmol)
immediately resulted in an orange homogenous solution. The reaction was stirred for 2 hours then washed with sat.
NaHCO3 solution, 1M HCl, and brine. The organic layer was dried with Na2SO4 followed by rotary evaporation.
Isolated yellow/orange powder, 0.2g, quantitative yield. 1H NMR: (300.1 MHz, CDCl3) δ 8.07 (dd, J = 7.9, 1.1 Hz, 2H),
7.70 (td, J = 8.4, 1.2 Hz, 2H), 7.51 (t, J = 7.9 Hz, 2H), 7.36 (dd, J = 7.9, 1.5 Hz, 2H), 7.28 (m, 2H), 7.20 (m, overlap with
residual CHCl3), 7.13 (d, J = 7.8 Hz, 2H), 7.08 (td, J = 7.7, 1.5 Hz, 2H), 7.00 (dd, J = 7.8, 0.9 Hz, 2H), 6.94 (t, J = 8.2 Hz,
2H), 6.83 (s, 2H), 6.54 (d, J = 8.1 Hz, 2H), 2.75ꢀ2.27 (AA’BB’, 8H). 13C NMR: (75.4 MHz, CDCl3) δ 166.3, 164.0, 139.9,
135.0, 133.0, 131.6, 131.5, 130.2, 127.9, 126.7, 125.7, 125.2, 57.1, 53.9, 28.5, 19.8. 19F {1H} NMR: (282 MHz, CDCl3) δ
30.12 (s), 28.12 (s). 31P {1H} NMR: (120 MHz, CDCl3) δ 3.936 (s). HRMSꢀESI (m/z): [M+Na]+ calcd for
C46H32F4N4NaO8P2, 929.1524; found, 929.1519 (Δ < 1 ppm).
2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis(N-pyrrolidinyl-benzamide) (R,R)-9. Following general method B
using 0.13g (0.14mmol) enantiopure tetraacyl fluoride bisdiazaphospholane (R,Rꢀ9) 5 eq. of pyrrolidine (0.06mL,
0.7mmol) Isolated 0.14g, 88% yield, quantitatively pure by 31P NMR. 1H NMR: (299.9 MHz, CDCl3) δ 7.70 (t, J = 5.7
Hz), 7.64 (dd, J = 7.7, 1.2 Hz), 7.52 (m), 7.34 (m), 7.24 (m), 6.99 (m), 6.81 (m), 6.59 (d, J = 6.8 Hz), 6.48 (m), 6.15 (s),
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5.88 (t, J = 10.1 Hz), 3.7ꢀ3.1 (m), 2.7ꢀ2.4 (m), 1.9ꢀ1.7 (m), 1.51 (d, J = 6.7 Hz), 1.42 (d, J = 6.8 Hz); 13C NMR: (75.4 MHz,
CDCl3) δ 169.0, 167.9, 167.2, 165.9, 137.1, 134.6, 133.5, 133.1, 129.3, 128.8, 128.1, 127.4, 127.2, 126.4, 126.0, 125.7, 58.9,
58.4, 53.5, 49.6, 48.6, 46.1, 45.9, 45.5, 29.9, 29.6, 26.1, 24.7, 24.6, 24.4; 31P {1H} NMR: (120 MHz, CDCl3) δ 9.2. HRMSꢀ
ESI (m/z): [M+NH4]+ calcd for C62H68N9O8P2 1128.4661; found, 1128.4612 (Δ = 4.3 ppm).
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2,2’,2’’,2’’’-(1,2-phenylenebis((1S,3S)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-a)pyridazine-
2,1,3(3H)-triyl))tetrakis(N-(7-azabicyclo[2.2.1]heptane) benzamide) (S,S)-11. Following general method B
using 0.10g (0.11mmol) enantiopure tetraacyl fluoride bisdiazaphospholane (S,Sꢀ9) and 5eq. 7ꢀazanorbornane•HCl
(7.5mg, 0.55mmol) dissolved in DCM and mixed with Et3N (8µL, 0.55mmol). Isolated 0.11g, 80% yield, quantitatively
pure by 31P NMR. 1H NMR: (299.9 MHz, CDCl3) δ 7.83 (d, J = 8.1 Hz, 2H), 7.54 (m, 2H), 7.380 (m, 4H), 7.11 (m, 2H),
6.93 (t, J = 6.91 Hz, 4H), 6.85 (m, 4H), 6.74 (m, 4H), 6.12 (bs, 2H), 5.98 (t, J = 10.2 Hz, 2H), 4.71 (bs, 2H), 4.06 (bs,
4H), 3.67 (bs, 2H), 2.78 (m, 4H), 2.57 (m, 4H), 2.43 (m, 2H), 1.80 (m, 12H), 1.36 (m, 16H); 13C NMR: (125.7 MHz,
CDCl3) δ 167.2, 166.7, 165.5, 135.3, 132.7, 129.4, 129.0, 128.8, 128.5, 127.7, 127.5, 126.9, 126.6, 125.7, 58.7, 58.3, 58.2,
53.6, 53.4, 53.1, 30.5, 30.3, 30.3, 30.2, 30.1, 29.9, 29.6, 29.3, 29.1, 28.8, 28.4, 14.1; 31P {1H} NMR: (120 MHz, CDCl3) δ
12.4 (s).HRMSꢀESI (m/z): [M+Na]+ calcd for C70H72N8NaO8P2, 1237.4841; found, 1237.4899 (Δ = 4.7 ppm).
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2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis((S)-N-2-(methoxycarbonyl)pyrrolidinyl-benzamide)
(R,R)-12.
Following general method B using 0.10g (0.11mmol) enantiopure tetraacyl fluoride bisdiazaphospholane (R,Rꢀ9) and 5
eq. of (S)ꢀmethylprolinate (90mg, 0.7mmol) in 10mL DCM. Silica gel column chromatography can be performed using
5% MeOH in DCM but was found to be unnecessary. Isolated 0.15g, quantitative yield, quantitatively pure by 31P NMR.
1H NMR: (299.9 MHz, CDCl3) δ 7.55 (t, J = 6.3 Hz), 7.49 (d, J = 7.0 Hz), 7.45 (t, J = 3.1 Hz), 7.42 (br), 7.40 (d, J = 2.6
Hz), 7.36 (br), 7.25 (m), 7.2ꢀ6.8 (br), 6.82 (d, J = 8.4 Hz), 6.77 (d, J = 7.9 Hz), 6.71 (t, J = 7.3 Hz), 6.51 (m), 6.26 (s),
6.22 (d, J = 7.9 Hz), 5.91 (t, J = 9.6 Hz), 4.77 (m), 4.53 (m), 4.19 (t, J = 7.3 Hz), 3.79 (s), 3.70 (s), 3.54 (m), 2.6ꢀ2.2 (br);
13C NMR: (125.7 MHz, CDCl3) δ 173.2, 172.9, 168.9, 168.3, 167.2, 165.8, 139.4, 136.2, 135.1, 134.8, 133.0, 131.4, 130.1,
129.8, 128.2, 127.7, 127.5, 126.9, 126.7, 58.5, 58.2, 53.5, 52.2, 52.1, 52.0, 51.8, 50.4, 49.4, 29.9, 29.8, 29.7, 29.6, 25.2,
25.1; 31P {1H} NMR: (120 MHz, CDCl3) δ 7.479 (s).HRMSꢀESI (m/z): [M+NH4]+ calcd for C70H76N9O16P2, 1360.4880;
found, 1360.4912 (Δ = 2.4 ppm).
2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis((R)-N-2-(methoxycarbonyl)pyrrolidinyl-benzamide)
(R,R)-13.
Following general method B using 0.10g (0.11mmol) enantiopure tetraacyl fluoride bisdiazaphospholane (R,Rꢀ9) and 5
eq. of (R)ꢀmethylprolinate (90mg, 0.7mmol) in 10mL DCM. Silica gel column chromatography can be performed using
5% MeOH in DCM but was found to be unnecessary. Isolated 0.15g, quantitative yield, quantitatively pure by 31P NMR.
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1H NMR: (400.2 MHz, CDCl3) δ 8.45 (d, J = 9.0 Hz), 8.27 (d, J = 7.9 Hz), 8.12 (m), 8.07 (d, J = 9.0 Hz), 7.98 (m), 7.90
(d, J = 7.89 Hz), 7.78 (d, J = 9.0 Hz), 7.71 (t, J = 7.9 Hz), 7.64 (m), 7.57ꢀ7.49 (m), 7.46 (m), 7.39ꢀ7.26 (m), 7.13ꢀ6.93 (m),
6.83 (s), 6.75ꢀ6.68 (m), 6.54 (d, J = 6.8 Hz) 4.77 (m), 4.53 (m), 4.19 (t, J = 7.3 Hz), 3.79 (s), 3.70 (s), 3.54 (m), 2.6ꢀ2.2
(br); 31P {1H} NMR: (120 MHz, CDCl3) δ 2.93 (s).HRMSꢀESI (m/z): [M+NH4]+ calcd for C70H76N9O16P2, 1360.4880;
found, 1360.4843 (Δ = 2.7 ppm). Material synthesized on small scale, not enough material for 13C NMR.
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2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis(methylbenzoate) (R,R)-MeO-BDP. Following general method B using
0.07g (0.08mmol) enantiopure tetraacyl fluoride bisdiazaphospholane (R,Rꢀ9) and 50 eq. methanol. Isolated .06g,
78% yield, 72% pure by 31P NMR. 1H NMR: (400.2 MHz, CDCl3) δ 8.37 (J = 10.3 Hz), 8.12 (J = 7.4 Hz), 8.08 (J = 8.8
Hz), 8.00 (J = 7.4 Hz), 7.89 (m), 7.52 (t, J = 8.8 Hz), 7.41ꢀ6.7 (m), 6.38 (d, J = 7.6 Hz), 6.20 (d, J = 8.7 Hz), 5.92 (s),
3.91 (s), 3.33 (s), 2.71ꢀ2.15 (m);31P {1H} NMR: (120 MHz, CDCl3) δ 2.81 (s).HRMSꢀESI (m/z): [M+H]+ calcd for
C50H45N4O12P2, 955.2504; found, 955.2543 (Δ = 4 ppm). Material synthesized on small scale, not enough material for
13C NMR.
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2,2’,2’’,2’’’-(1,2-phenylenebis((1R,3R)-tetrahydro-5,8-dioxo-1H-(1,2,4)diazaphospholo(1,2-
a)pyridazine-2,1,3(3H)-triyl))tetrakis(phenylbenzoate) (R,R)-PhO-BDP. Following general method B using
0.07g (0.08mmol) enantiopure tetraacyl fluoride bisdiazaphospholane (R,Rꢀ9) and 5 eq. phenol. Isolated .07g, 73%
yield, 90% pure by 31P NMR. 1H NMR: (400.2 MHz, CDCl3) δ 7.98 (d, J = 7.97 Hz), 7.66 (t, J = 8.2 Hz), 7.37 (m), 7.31
(s), 7.29 (s), 7.22 (m), 7.12 (m), 7.01 (m), 6.89 (m), 6.52 (t, J = 6.49 Hz), 6.27 (d, J = 7.9 Hz), 2.66ꢀ2.17 (m); 13C NMR:
(100.6 MHz, CDCl3) δ 167.3, 164.2, 163.7, 163.7, 149.9, 149.4, 138.3, 137.7, 137.6, 132.7, 131.1, 130.9, 130.5, 129.8, 128.6,
128.3, 128.2, 128.1, 127.2, 126.5, 126.0, 125.0, 124.3, 124.2, 121.0, 120.8, 58.5, 58.3, 53.4, 53.0, 52.5, 28.7, 28.4, 28.2,
17.4, 17.4, 16.2, 11.0; 31P {1H} NMR: (120 MHz, CDCl3) δ ꢀ1.74 (s).HRMSꢀESI (m/z): [M+NH4]+ calcd for C70H56N5O12P2,
1220.3396; found, 1220.3397 (Δ < 1 ppm).
General asymmetric hydroformylation procedure
An oven dried 15mL Ace glass pressure bottle with magnetic stir bar is charged with a Rh(acac)(CO)2 toluene solution,
bisdiazaphospholane THF solution, and neat substrate using 1000ꢂL and 200ꢂL Eppendoft® pipettes in a dinitrogen
filled glove box. Pressure bottle is attached to pressure reactor and removed from the glove box, placed in a fume hood,
purged three times with 150psi of synthesis gas to remove dinitrogen and filled to the appropriate synthesis gas
pressure. The pressure bottle is placed in an oil bath and stirred at a high speed to ensure gas mixing. Upon
completion of the reaction, the reaction tube is removed from the oil bath, allowed to cool to room temperature, and
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vented inside the fume hood. An aliquot of the reaction mixture is dissolved in d8ꢀtoluene for H NMR for percent
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conversion and determining regioselectivity. Enantiomeric excess of the branched hydroformylation product is
determined by chiral GC/SFC.
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Hydroformylation Product Analysis. Vinyl acetate. (GC) Supelco’s Beta Dex 225, 100°C for 5 min, then
4°C/min to 160°C, tR(S) = 6.7 and tR(R) = 8.5 min.7a Styrene (GC) Supelco’s Beta Dex 225, 100°C hold 5 min, then
160°C (4°C /min), tR(S) = 9.0 min, tR(R) = 9.2 min, , β isomer tR = 12.4 min.1d Allyloxy-t-butyldimethylsilane (GC)
Supelco’s Beta Dex 225, 65 °C, isothermal); tR(R) = 60.8 min, tR(S) = 62.4.1c 1-Phenylbutadiene Crude aldehyde
products reduced using NaBH4 followed by SFC analysis: Chiracel OJꢀH column, (50°C oven temp, 3% MeOH, pressure
= 100 bar, 3ml/min flow rate); tR(R) = 6.8 min, tR(S) = 7.5 min.1b 2,3-Dihydrofuran/2,5-dihydrofuran (GC)
Supelco BETA–DEX 225, initial temperature 50 °C, hold for 0.10 min.; ramp 1, 15 °C/min. to 150 °C, hold 0.2 min.;
ramp 2, 100 °C/min. to 215 °C. αꢀCarbaldehyde tR (R)= 4.8 min., tR (S)= 5.0 min. βꢀCarbaldehyde; tR (S) = 5.3 min., tR
(R) = 5.6 min. Absolute configuration for the βꢀcarbaldehyde has been previously reported.9a
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Determination of absolute configuration of tetrahydrofuran-2-carboxaldehyde
Reduction of (S)ꢀ(ꢀ)ꢀtetrahydrofuranꢀ2ꢀcarboxylic acid (TCI 97% pure) with LiAlH4 to tetrahydrofurfuryl alcohol was
compared with the reduction of the crude hydroformylation product of 2,3ꢀdihydrofuran with NaBH4. Resolution of the
resulting alcohols using GC, Supelco’s BETA–DEX 225, method: initial temperature 50 °C, hold for 5 min.; ramp 1, 5
°C/min. to 70 °C, hold 55 min.; ramp 2, 20 °C/min. to 180 °C. Tetrahydrofurfuryl alcohol; tR (R)= 55.9 min., tR (S)=
57.2 min.
ASSOCIATED CONTENT
Supporting Information. Representative GC trace for 2,3ꢀdihydrofuran, NMR/MS spectra for ligands 3-12, preliminary
results of tetraester bisdiazaphospholane AHF, and Xꢀray structure of (rac)ꢀ1. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
landis@chem.wisc.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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We thank The Dow Chemical Company for their generous donation of Rh(acac)(CO)2, Merck & Co. (Dr. Neil Strotman) for
resolution of ligand 1, Prof. Tehshik Yoon and coꢀworkers (UWꢀMadison) for access to chiral SFC instrumentation, and Dr. Ilia
Guzei (UWꢀMadison) for the Xꢀray structure of (rac)ꢀ1. The National Science Foundation (CHEꢀ0715491, CHEꢀ1152989, and a
graduate fellowship to G.W.W.) supported this work. We also acknowledge the NSF (CHEꢀ9208463 and CHEꢀ0342998) for
funding the NMR facilities.
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(11) Peters, J. C.; Mehn, M. P. in Activation of Small Molecules: Organometallic and Bioinorganic Perspectives, Tolman, W. C.,
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