An Air- and Water-Stable Hydrogen-Bond-Donor Catalyst for the Enantioselective Generation of Quaternary Carbon Stereocenters by Additions of Substituted Cyanoacetate Esters to Acetylenic Esters

Article abstract of DOI:10.1002/chem.202001639

The chiral enantiopure cobalt(III) complex Δ-[Co((S,S)-dpen)₃]³⁺ 2Cl^?B(C₆F₅)₄^? (Δ-(S,S)-2³⁺ 2Cl^?B(C₆F₅)₄^?; dpen=

Full text of DOI:10.1002/chem.202001639

Accepted Article
Accepted Article
Title: An Air and Water Stable Hydrogen Bond Donor Catalyst
for the Enantioselective Generation of Quarternary Carbon
Stereocenters by Additions of Substituted Cyanoacetate Esters to
Acetylenic Esters
Authors: Quang H Luu and John A. Gladysz
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001639
Link to VoR: https://doi.org/10.1002/chem.202001639
01/2020

10.1002/chem.202001639
Chemistry - A European Journal
An Air and Water Stable Hydrogen Bond Donor Catalyst for the Enantioselective
Generation of Quarternary Carbon Stereocenters by Additions of Substituted
Cyanoacetate Esters to Acetylenic Esters
*[a]
Quang H. Luu and John A. Gladysz
3+
–
–
Abstract: The chiral enantiopure cobalt(III) complex Δ-[Co((S,S)-dpen) ] 2Cl B(C6F5)4 (Δ-
3
3+
–
–
(S,S)-2 2Cl B(C6F5)4 ; dpen = 1,2-diphenylethylenediamine) is an effective catalyst, together
with pyridine (10 mol% each), for enantioselective additions of substituted cyanoacetate esters
NCCH(R)CO R' to acetylenic esters R"C≡CCO R"'. In the resulting adducts NC(R'O C)C-
2
2
2
(R)CR"C=CHCO R"', C=C isomers in which the CO R"' moiety is trans to the new carbon-car-
2
2
bon bond dominate (avg. ratio 98:2). These are obtained in 70-98% ee (avg. 86%; data for opti-
1
3+
–
mum R' and R"'), as determined by H NMR with the chiral solvating agent Λ-(S,S)-2 2I B-
–
(3,5-C H (CF ) ) . NMR experiments show that the cyanoacetate and acetylenic esters and py-
6
3
3 2 4
ridine can hydrogen bond to certain NH groups of the catalyst. Rates are zero order in the cyano-
acetate and acetylenic esters as well as the catalyst, and implications are discussed.
[a]
Mr. Quang H. Luu, Prof. Dr. John. A. Gladysz
Department of Chemistry, Texas A&M University,
P.O. Box 30012,
College Station, Texas 77842-3012 (USA)
E-mail: gladysz@mail.chem.tamu.edu
: Supporting information and the ORCID identification numbers for the authors of this
article can be found under https://doi.org/10.1002/xxxxx.
key words: cobalt, 1,2-diamines, Werner complexes, hydrogen bonding, quaternary carbon
stereocenters, cyanoacetate esters, acetylenic esters, enantioselective catalysis
submitted to Chemistry – A European Journal
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Introduction
The efficient enantioselective synthesis of compounds with quaternary carbon stereocen-
ters has been a subject of immense interest over the last 25 years, as reflected by an extensive re-
[1]
view literature that emphasizes catalytic methods. There has been a particular focus upon conj-
ugate additions. In this context, racemic "active methylene compounds" with a single carbon-hy-
drogen bond and three unlike carbon substituents represent attractive building blocks. One obvi-
ous choice would be substituted cyanoacetate esters NCCH(R)CO R', large numbers of which
2
are commercially available or easily prepared. However, many types of acceptors (e.g., conjugat-
ed cycloalkenones) would yield a second carbon stereocenter, such that diastereoselectivity also
becomes an issue.
Given the new family of catalysts that we were interested in applying to this problem
(vide infra), we sought to evaluate their efficacies one stereocenter at a time. One way to avoid
generating a second stereocenter in additions of substituted cyanoacetate esters would be to em-
ploy an acetylenic acceptor, as generalized in Figure 1 (top). Of course, there would be the possi-
bility of cis/trans or Z/E isomers about the resulting C=C linkage. However, this was seen as a
more tractable complication.
Others have recognized the attractiveness of substituted cyanoacetate esters as building
[2]
blocks. Of particular value is the attendant installation of multiple functional groups that can
[3]
be elaborated under different conditions. However, there have only been scattered reports
dealing with acetylenic acceptors, and the best literature methods are summarized in Figure 1.
[2a]
One of these, developed by Maruoka, used an enantiopure phase transfer catalyst (I).
In this
work, only cyanoacetate esters with aliphatic substituents gave high enantioselectivities. Anoth-
[2b]
er, developed by Ikariya, used an enantiopure ruthenium Lewis acid catalyst.
However, only
cyanoacetate esters with aryl substituents were reported. We saw these divergent strengths and
weaknesses as opportunities that might be addressed with new types of catalysts.
[1]
In parallel with the review literature cited, there has been extensive recent interest in
[4]
chiral organic hydrogen bond donor catalysts. Some of these are quite effective for the enanti-
-2-
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X
NC
NC
CO2R'
R
Y
+
X
Y
NC
R
CO2R'
Maruoka, 2007: chiral phase transfer catalyst
catalyst I
CO2But
(1 mol%)
Cs2CO3
R
CO2But
R
+
(1.2 equiv)
NC
CO2But
toluene
CO2But
under argon
R = alkyl (11 cases, up to 6.7:1 E/Z and 97% ee)
aryl (1 case, 2.2:1 E/Z and 18% ee)
Ikariya, 2010: chiral transition metal Lewis acid catalyst
R”
NC
CO2But
catalyst II
(1 mol%)
R
CO2Me
R
+
NC
toluene
under argon
CO2Me
CO2Me
R''
R/ R'' = aryl/CO2Me (3 cases, up to 20:1 Z/E and 95% ee
aryl/H (1 case, 22:1 E/Z and 79% ee)
Ar
Ar = 3,5-C6H3[3,5-
C6H3(CF3)2]2
Ru
I
N
O
II
TsN
Ph
NH
Ph
Br–
Ar
Figure 1. Enantioselective catalysts for additions of substituted cyanoacetate esters to acetylenic esters developed to
date.
[1f,5]
oselective construction of quaternary carbon centers from other combinations of reactants.
[6-9]
[10-12]
Our research group,
together with several others,
has been interested in developing
chiral transition metal containing hydrogen bond donors. One impetus has been the application
of an untapped region of the chiral pool, believed to provide binding motifs and modes of action
[13]
that significantly differ from organic counterparts.
Our main catalyst family was inspired by Werner's reports of the first enantiopure chiral
[14,15]
3+
–
3+
–
inorganic compounds over a century ago.
One of these, [Co(en) ] 3Cl (1 3Cl ; en =
3
[14e]
[16]
ethylenediamine),
can be prepared by undergraduate students in an afternoon.
The confi-
[17]
gurations of such "chiral at metal" species are conventionally designated Λ and Δ,
as
depicted in Figure 2 (top). The former exhibits a left handed helical array of chelate rings, and
-3-
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the latter a right handed array. However, tris(1,2-diamine) cobalt(III) complexes are substitution
[18,19]
inert,
which precludes direct activation of substrates by the metal. But tellingly, crystal
[20]
structures reveal extensive NH hydrogen bonding interactions with counter anions.
NH2
H2N
H2
N
H2
N
H2N
NH2
3+
3+
Co
Co
H2N
N
N
NH2
H2
H2
NH2
H2N
3BArf–
3BArf–
Λ-13+ 3BArf–
Δ-13+ 3BArf–
σ
Ar
Ar
S
NH2
S
NH2
H2
H2
H2N
H2N
N
H2N
N
Ar
3+
Co
3+
Co
3 NMe2
S
S
S
N
H2N
N
Ar
H2
H2
S
NH2
NH2
S
–
2X– X'
Ar
3BArf–
Ar
Λ-(S)-43+ 3BArf–
Ar = Ph
Λ-(S,S)-23+ 2Cl– BArf–
Λ-(S,S)-23+ 2BF4– BArf–
Λ-(S,S)-23+ 2Cl– B(C6F5)4
Ar = 2-naphthyl
–
BArf–
B(3,5-C6H3(CF3)2)4
=
–
Λ-(S,S)-33+ 2Cl– BArf–
Figure 2. Catalysts screened in this study.
Accordingly, we prepared various tris(1,2-diamine) cobalt salts with one or more tetra-
–
–
– [6-8,21]
arylborate anions of the formula B(3,5-C H (CF ) ) (BAr ) or B(C F ) .
6 5 4
These an-
6
3
3 2 4
f
[22]
ions are very poor hydrogen bond acceptors
and help to solubilize the trications in standard
organic solvents. In aqueous solution, water would presumably compete for the substrate binding
sites, and many educts would be insoluble. In any case, the complexes in Figure 2 have been ap-
plied to several types of carbon-carbon and carbon-nitrogen bond forming reactions known to be
[6-8]
catalyzed by hydrogen bond donors.
3+
We have found that tris(adducts) of 1,2-diphenyl ethylenediamine (dpen), [Co(dpen) ]
3
–
–
3+
–
–
2X X' (2 2X X' ), are often particularly enantioselective catalysts. The S,S and R,R enantio-
[23]
mers of this ligand are commercially available at surprisingly modest prices.
With the former,
3+
–
–
two sets of diastereomers are possible, the salts Λ-(S,S)-2 2X X' depicted in Figure 2, and the
-4-
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3+
–
–
cobalt epimers Δ-(S,S)-2 2X X' . The enantiomeric catalysts derived from (R,R)-dpen would
be expected to give identical ee values (but opposite product configurations).
Analogous complexes have been prepared with a wide variety of aryl groups in place of
[21]
3+
–
–
the dpen phenyl groups.
Thus, a catalyst with 2-naphthyl substituents, Λ-(S,S)-3 2Cl BAr
f
(Figure 2), has been included in this study. In addition, a bifunctional catalyst with an internal
3+
–
tertiary amine, Λ-(S)-4 3BAr (Figure 2), which obviates the need for an external base and has
f
[8]
given highly enantioselective reactions, has also been examined in screening reactions below.
Accordingly, in this paper we compare the efficacies of the complexes in Figure 2 and
selected diasteromers as catalysts for enantioselective additions of substituted cyanoacetate esters
to acetylenic esters (Figure 1, top). From the standpoints of isolated yields, ee values, and sub-
3+
–
–
strate generality, Λ-(S,S)-2 2Cl B(C F ) clearly emerges as the best of a limited number of
6 5 4
other catalysts (Figure 1) that have previously been reported to effect this transformation.
Results
1. Catalyst Screening. In initial scout experiments, commercial dimethyl acetylenedicar-
boxylate (4a) and ethyl phenylcyanoacetate (5a) were combined in a 1.1:1.0 mol ratio in CH Cl
2
2
at a temperature specified in Table 1. Then the indicated catalyst (10 mol%) and base were add-
ed. The latter was applied in both stoichiometric (100 mol%) and catalytic (10 mol%) quantities.
When TLC indicated that the reaction was complete, the solvent was removed and the residue ta-
1
ken up in CDCl . The Z/E ratio of the crude addition product 6aa was then assayed by H NMR
3
(structure and data: Table 1; Z/E =CH 5.88-5.89/7.07-7.08 ppm, s). Chromatographic workups
1
gave pure 6aa in 99-95% yields. The ee values were determined by H NMR using the chiral
3+
–
– [24]
solvating agent Λ-(S,S)-2 2I BAr .
f
These and all other reactions and workups were carried
out in air.
Table 1 shows that useful levels of enantioselectivities were found only with the catalyst
3+
–
–
Δ-(S,S)-2 2Cl B(C F ) and the base pyridine at –36 °C (entry 12). None of the other cata-
6 5 4
lysts were effective (entries 2-6). Interestingly pyridine was best used in catalytic quantities (ent-
ry 12 vs. 13). Furthermore, these conditions gave close to the highest Z/E product ratio (91:9). As
-5-
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Table 1. Screening of catalysts for the addition of ethyl phenylcyanoacetate (5a) to dimethyl
a
acetylenedicarboxylate (4a).
catalyst
CO2Me
(10 mol%)
Ph
CO2Me
base
NC
CO2Et
MeO2C
CO2Me
+
NC
CH2Cl2, temp.
CO2Et
Ph
4a
5a
6aa
Base
(mol%)
Time Temp. Yield
ee
(%)
c
Entry
Catalyst
Z/E
b
d
(h)
12
0.20
12
12
12
12
12
11
12
24
15
17
17
12
(℃)
(%)
99
99
99
99
99
99
99
99
99
<1
99
95
99
99
Et N
(100)
3
1
2
-
23
78/22
61/39
0/0
0/0
Et N
(100)
3
3+
–
Λ-1 3BAr
23
f
Et N
(100)
3
3+
–
–
3
Λ-(S,S)-2 2BF BAr
23
75/25 10/4
78/22 0/0
4
f
Et N
(100)
3
3+
–
–
–
4
Λ-(S,S)-2 2Cl BAr
23
f
f
Et N
(100)
3
3+
–
5
Λ-(S,S)-3 2Cl BAr
23
83/17 16/0
69/31 18/40
3+
–
-
6
Λ-(S)-4 3BAr
23
f
Et N
(100)
3
3+
–
–
7
Λ-(S,S)-2 2Cl B(C F )
23
79/21
0/0
6 5 4
Et N
(100)
3
3+
–
–
8
Δ-(S,S)-2 2Cl B(C F )
23
85/15 36/2
87/13 30/11
6 5 4
Et N
(10)
3
3+
–
–
–
–
–
–
–
9
Δ-(S,S)-2 2Cl B(C F )
23
6 5 4
3+
–
-
10
11
12
13
14
Δ-(S,S)-2 2Cl B(C F )
23
-
-
6 5 4
Et N
(10)
3
3+
–
Δ-(S,S)-2 2Cl B(C F )
–36
–36
–36
23
88/12 54/13
6 5 4
pyridine
(10)
3+
–
e
Δ-(S,S)-2 2Cl B(C F )
91/9 99 /10
6 5 4
pyridine
(100)
3+
–
Δ-(S,S)-2 2Cl B(C F )
95/5 44/22
95/5 14/13
6 5 4
pyridine
(100)
3+
–
Δ-(S,S)-2 2Cl B(C F )
6 5 4
a
A vial was charged with stir bar, 4a (0.0078 g, 0.055 mmol, 0.0068 mL), 5a (0.0095 g, 0.050 mmol, 0.0087 mL),
and CH Cl (0.50 mL). The sample was bought to the indicated temperature, and a catalyst (0.0050 mmol, 10
mol%) and a base were added with stirring. The reaction was monitored by TLC and was worked up as described in
2
2
b
c
d
1
1
the experimental section. Isolated yields after chromatography. Determined by H NMR. Determined by H
3+
–
– e
NMR using 10 mol% of the CSA Λ-(S,S)-2 2I BAr . Lowering the catalyst loading to 5.0 or 2.0 mol% gave 6aa
f
in 59% or 38% ee.
with the other catalysts, the enantiomeric purity of the minor E isomer was poor (10% ee), but
that of the major Z isomer was excellent (99% ee). However, the ee dropped to 58% when the ca-
-6-
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3+
–
–
talyst loading was decreased to 5%. Although Δ-(S,S)-2 2Cl B(C F ) readily dissolves in
6 5 4
CH Cl solutions of the substrates, per the conditions employed in Table 1, it is only sparingly
2 2
soluble in the absence of substrates. An expanded table with additional screening reactions is gi-
ven in the supporting information (SI).
2. Reaction scope. The conditions in entry 12 of Table 1 were then applied to a variety of
substrates as illustrated in Figure 3. When ethyl phenylacetate was replaced by ethyl benzylcya-
noacetate (5b), the Z/E ratio of the product remained high (6ab; 99:1) but the enantiomeric purity
fell to 44% ee. However, t-butyl benzylcyanoacetate (5c), which features a bulkier ester alkyl
group, gave the corresponding adduct 6ac as a >99:<1 Z/E mixture in 88% ee. Thus, t-butyl est-
ers were used for the remaining reactions.
Next, the benzyl group in the preceding reaction was replaced by allyl, homoallyl, and
related alkyl substituents. As shown for the adducts 6ad-g in Figure 3, only Z isomers were ob-
tained (88->99% yields), and with ee values of 70-98%. A series of four substrates with CH aryl
2
substituents gave similar results (6ah-k, 70-99% yields, 85-91% ee). When diethyl acetylenedi-
carboxylate (4b) and 5c were similarly reacted, the enantiomeric purity of the product 6bc was
close to that obtained with 4a (83% vs, 88% ee).
Other alkyne substrates were briefly investigated. When unsymmetrically substituted t-
butyl propiolate (4c) and 5c were analogously combined, a slower reaction took place. After 72 h
at 23 °C, the addition product 6cc (Figure 3) was isolated in 53% yield as a <1:>99 Z/E mixture
with an enantiomeric purity of 94% ee. Note that despite the inverted Z/E ratio, the quarternary
carbon atom remains trans to the carboalkoxy C=C substituent, exactly as in the other products.
When di(t-butyl) acetylenedicarboxylate (4d) and 5c were similarly combined, no reaction oc-
curred, even after 72 h at 23 °C, presumably for steric reasons.
In view of evidence for catalyst/pyridine binding presented below, the reaction of 4a and
5c was also investigated with the more hindered Brønsted bases 2,6-dimethylpyridine (2,6-luti-
dine) and 2,6-di(t-butyl) pyridine (10 mol%). After 19 h, workups gave 6ac in 99% and 22%
yields, respectively. Much starting material remained in the second reaction. However, the enant-
-7-
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ioselectivities were essentially unaffected (89% and 86% ee), so these more costly bases offer no
advantages.
–
Δ-(S,S)-23+ 2Cl–B(C6F5)4
R
''
(10 mol%)
R
CO2R'''
pyridine (10 mol%)
NC
CO2R
'
R
''
CO2R'''
+
NC
6
CO2R
Ph
EtOOC
'
CH2Cl2, –36 °C
COOMe
R
5a-k
4a, R'' = CO2Me, R''' = Me
4b, R'' = CO2Et, R''' = Et
4c, R'' = H, R''' = tBu
COOMe
COOMe
Ph
COOMe
EtOOC
t
4d, R'' = CO2 Bu, R''' = tBu
CN
CN
6ab: >99%, 19 h
Z/E = 99/1a (99/1)b
ee (%)b = 44/-
6aa: 95%, 17 h
Z/E = 91/9a (91/9)b
ee (%)b = 99 (R)/10
COOMe
COOMe
COOMe
Ph
tBuOOC
COOMe
COOMe
7
COOMe
COOMe
COOMe
tBuOOC
tBuOOC
tBuOOC
CN
CN
CN
CN
6af: 96%, 22 h
Z/E = 99/1a (98/2)b
ee (%)b = 70/-
6ae: >99%, 17 h
Z/E = 99/1a (99/1)b
ee (%)b = 98/-
6ac: >99%, 19 h
Z/E = 99/1a (99/1)b
ee (%)b = 88/-
6ad: >99%, 17 h
Z/E = 99/1a (99/1)b
ee (%)b = 80/-
Br
COOMe
12
O
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
tBuOOC
tBuOOC
tBuOOC
CN
CN
CN
tBuOOC
6ag: 88%, 24 h
Z/E = 99/1a (98/2)b
ee (%)b = 80/-
6ah: 99%, 18 h
Z/E = 99/1a (>99/<1)b
ee (%)b = 88/-
CN
6aj: 70%, 13 h
6ai: 82%, 18 h
Z/E = 99/1a (>99/<1)b
ee (%)b = 88/-
Z/E = 97.5/2.5a,c (96/4)b,c
ee (%)b = 85c/-
Ph
COOtBu
COOtBu
Ph
Ph
tBuOOC
COOEt
COOEt
COOtBu
COOMe
tBuOOC
tBuOOC
CN
COOMe
CN
CN
tBuOOC
6dc: 0%, 72 h at 23 °C
6ak: 90%, 17 h
Z/E = 99/1a (98/2)b
ee (%)b = 91/-
6cc: 53%, 72 h at 23 °C
Z/E = <1/>99a (<1/>99)b
ee (%)b = -/94
6bc: >99%, 17 h
CN
Z/E = 98/2a (99/1)b
ee (%)b = 83/-
a
1
b
Figure 3. Substrate scope of the title reaction. Determined by a H NMR spectrum of the crude mixture. Deter-
1
c
mined by H NMR analysis of the purified product. Average of six runs.
Of all the products in Figure 3, only 6aa has been previously reported in the literature.
1
13
1
The others were characterized by NMR ( H, C{ H}) and C/H/N microanalyses, as summarized
1
in the SI. For adducts with =CHCO R"' moieties, the H NMR signal for the E C=C isomer was
2
always downfield of the Z. Otherwise, all NMR features were routine. Four of the t-butyl cyano-
acetate substrates were also new compounds (5f,g,h,k), and were prepared by standard proced-
ures (usually alkylation) as described in the SI.
-8-
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3. Probes of mechanism. One fundamental question concerns the interaction of the reac-
3+
–
–
tion components with the catalyst Δ-(S,S)-2 2Cl B(C F ) . The chiral cobalt trication has id-
6 5 4
ealized D symmetry, which means a principal C axis that defines two "C faces" and three C
3
3
3
2
[7a]
axes in a perpendicular plane that define three "C faces". These are illustrated in Figure 4,
2
although it merits note that the idealized symmetry is never found crystallographically. For each
NH group, one proton is associated with a C face, and the other (diastereotopic) with a C face.
2
3
2
3+
Figure 4. Representations of the trication Δ-(S,S)-2 ; left, view down the idealized C axis; right, view down one
3
of three idealized C axes.
2
–
3+
–
–
Previous studies, especially with the diastereomeric BAr salt Λ-(S,S)-2 2Cl BAr ,
f
f
have established significant hydrogen bonding between the two chloride anions and the two C
3
[7a,21]
faces.
Each face offers three roughly synperiplanar NH protons, which are depicted in
1
green in Figure 4. Hence, the H NMR chemical shifts of these six NH protons are significantly
downfield of the other six. Each C face features two roughly synperiplanar NH protons, which
2
are depicted in magenta.
Thus, 10.0 equiv of dimethyl acetylenedicarboxylate (4a), ethyl phenylcyanoacetate (5a),
3+
–
and pyridine were separately titrated into a sample of CD Cl and the catalyst Δ-(S,S)-2 2Cl
2
2
–
B(C F ) . The amounts of the catalyst and solvent were identical to those used in Table 1, and
6 5 4
therefore the catalyst was only partially soluble until ca. 4 equiv of the additive was present. This
renders the spectra with 1.0-3.0 equiv of additive less rigorously comparable to the others. In any
case, the initial chemical shift difference between the diastereotopic protons associated with the
-9-
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3+
–
Figure 5. NMR titration of Δ-(S,S)-2 2Cl B(C F ) – in CD Cl with (a) 4a, (b) 5a, and (c) pyridine.
6
5 4
2
2
-10-
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C and C faces is ca. 2.1 ppm (the former signal is obscured by the phenyl protons of the cata-
3
2
lyst).
As shown in Figure 5a (top), the successive addition of 4a led to a slight downfield shift
of the C NH signal (δ 5.12 to 5.27 ppm; Δδ 0.15 ppm). Any shift of the obscured C NH signal
2
3
could be bounded as less than Δδ 0.01 ppm (upfield). For reference, the signal of the aliphatic
CH groups, which always neighbor a NH group, shifted less than the C NH signal (δ 4.21 to
2
2
4.26 ppm; Δδ 0.05 ppm).
As shown in Figure 5b (middle), the successive addition of 5a led to a more pronounced
downfield shift of the C NH signal (δ 5.12 to 5.42 ppm; Δδ 0.30 ppm). The C NH signal was
2
3
obscured by the phenyl protons of the catalyst and 5a, and the aliphatic CH signal was obscured
by the methylene protons of 5a.
As shown in Figure 5c (bottom), the successive addition of pyridine led to a pronounced
downfield shift of the C NH signal (δ 5.12 to 6.12 ppm; Δδ 1.00 ppm). The C NH signal was
2
3
obscured by the aromatic protons of the catalyst and pyridine. The aliphatic CH signal shifted
much less than the C NH signal (δ 4.21 to 4.42 ppm; Δδ 0.21 ppm).
2
In a quest for further insight, reaction orders were sought. For this purpose, the recently
[25]
popularized reaction progress kinetic analysis method was applied.
Accordingly, 4a, 5a, pyri-
3+
–
–
dine, Δ-(S,S)-2 2Cl B(C F ) , and CD Cl were combined in a NMR tube in a manner simi-
6 5 4
2
2
lar to that in Table 1. but in the presence of the internal standard Ph SiMe . The reaction was
2
2
1
monitored by H NMR at –36 °C. The concentration of 5a and the rate (Δ([5a])/Δt) were then
plotted against the reaction time as shown in Figure 6 for three experiments with 2.0, 5.0, and 10
mol% catalyst loadings.
Concentration and rate data for 4a were similarly treated (Figure s18, SI). Analyses est-
ablished positive orders for 4a and 5a during the first hour after mixing. These then transitioned
to zero order, which was maintained until the reaction was complete. The same data set was used
[26]
for probing the order in catalyst. In an application of the time normalization method,
the con-
centration of 5a was plotted against the normalized time (see experimental section) at different
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10.1002/chem.202001639
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orders n as shown in Figure s19 (SI). The best fit was obtained for n = 0, indicating a rate zero
3+
–
–
order in Δ-(S,S)-2 2Cl B(C F ) . These data are further interpreted in the discussion section.
6 5 4
[25]
Figure 6. Application of the reaction progress kinetic analysis method
(further details: see text). Top: plot of the concentration of 5a versus time. Bottom: plot of Δ([5a])/Δt versus time.
to a reaction similar to entry 12 of Table 1
-12-
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Discussion
3+
–
–
As summarized in Figure 3, the cobalt complex Δ-(S,S)-2 2Cl B(C F ) and the base
6 5 4
pyridine represent the best available catalyst system for enantioselective additions of substituted
cyanoacetate esters to acetylenic esters, a powerful route to quaternary carbon stereocenters. The
[3]
products are amenable to a number of subsequent functionalization protocols, rendering them
versatile synthetic building blocks. Furthermore, the reactions may be conducted in air, and the
[27]
cobalt catalyst is commercially available.
The objective of Figure 3 is to present the substrate scope in its entirety, with full repre-
sentation of strengths and weaknesses. In some of the products with lower ee values, it is a sim-
ple matter of introducing a bulkier ester alkyl group on the cyanoacetate to obtain much higher
ee values (e.g., ethyl vs. t-butyl as in 6ab and 6ac). However, replacing the methyl or ethyl
groups of the acetylene dicarboxylate diester with t-butyl groups kills all reactivity (e.g., 6ac or
6bc vs. 6dc). In any case, considering only the optimum ester alkyl groups (R', R"'), the ee val-
ues range from 70 to 98% with an average of 86%.
It would be premature to read too much significance into the poorer performing catalysts
in Table 1. For example, bifunctional organocatalysts often give superior enantioselectiv-
[4d,e]
3+
–
ities.
Indeed, Λ-(S)-4 3BAr , which features a tertiary amine tethered by a (CH ) spac-
f 2 3
er, has proven to be a highly enantioselective catalyst for certain addition reactions that require a
[8]
Brønsted base, and was therefore available in quantity for this study. However, catalysts with
other tether lengths have also been prepared (e.g., (CH ) with n = 1-4), as have the correspond-
2 n
ing Δ diastereomers, and these remain to be screened. In the same vein, the naphthyl substituted
3+
–
–
–
catalyst Λ-(S,S)-3 2Cl BAr is not yet available as the Δ diasteromer or analogous 2Cl B(C -
f
6
–
F ) salt, two attributes of the best catalyst in Table 1.
5 4
3+
–
Our data also illustrate the versatility of the chiral solvating agent (CSA) Λ-(S,S)-2 2I
–
BAr , which is easily prepared in one step from a commercial precursor, for determining the en-
f
[24]
antiomeric purities of analytes with Lewis basic functional groups.
For most of the products
in Figure 3, only 10 mol% is required. It is not surprising that a class of complexes capable of
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highly sensitive chiral recognition also can effect highly enantioselective catalysis.
Finally, to round out the picture with respect to other chiral hydrogen bond donor catal-
ysts, three protocols that give other types of addition products with quaternary carbon stereocen-
[5,10e]
ters are illustrated in Figure 8.
All of these deliver excellent enantioselectivities. One,
developed by Meggers, features an iridium containing catalyst with NH donor groups that effects
[10e]
additions of indoles to trisubstituted nitroalkenes.
t
CO2 Bu
O
R
tBuO2C
R
catalyst III
(20 mol%)
4 Å MS
O
N
+
Boc
CCl4, N2 atm
–25 °C
N
Boc
t
tBuO2C
CO2 Bu
up to 88/12 Z/E
up to 96% ee
2
R2
R
R1
catalyst IV
(0.1-2.0 mol%)
NO2
NO2
R2
+
toluene
20 °C
N
H
N
up to 98% ee
H
TMS catalyst V
(10 mol%)
Me
Ar
up to 98% ee
TMS
+
AcO
Me
Ar
Et2O
TMS
–78 °C
Ar
HN
O
V
III
O
O
tBu
HN
N
Ar
N
H
N
H
N
MeO
Ph
R'
O
Ph
R
CF3
O
S
R''
HN
N
Ir
HN
N
N
HN
O
N
HN
R
R''
S
CF3
IV
R'
Figure 8. Enantioselective syntheses of compounds with quaternary sterecenters using other chiral hydrdogen bond
donor catalysts.
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Some headway has been made in computationally determining the mechanisms of enant-
[9c]
ioselective addition reactions catalyzed by metal containing hydrogen bond donors.
However,
these have involved ruthenium catalysts where the NH groups are remote from the metal and on-
ly three can simultaneously participate in the transition state. The situations with cobalt(III) cata-
lysts of the types in Figure 2 are potentially much more complex. For example, it is clear from
Figure 4 that 4-5 NH groups could potentially participate in a transition state assembly.
In any case, NMR data (Figure 5) establish that the C site is capable of binding both
2
types of substrates as well as the base pyridine. The greater downfield shifts observed with pyri-
dine suggest a stronger binding constant. This could be a factor in the lower enantioselectivities
when pyridine is used in a ten fold molar excess of the catalyst as opposed to a 1:1 ratio (Table 1,
entries 13 vs. 12). Similar NMR evidence has been obtained with related catalysts, such as the
3+
–
–
[7a,24]
diastereomeric salt Λ-(S,S)-2 2Cl BAr , for substrate binding to the C site.
f
2
However, there is also evidence that some level of access to the C site can be required.
3
Specifically, rates of additions of malonate esters to nitroalkenes become faster when the chlor-
3+
–
–
ide ions of Λ-(S,S)-2 2Cl BAr are replaced by more weakly hydrogen bonding anions such
f
–
– [7a]
as BF and PF .
4
Our own view is that a multitude of mechanistic pathways is available to
6
this family of cobalt(III) complexes for catalyzing various addition reactions. For example, with
3+
–
–
[7a,7c]
some reactions Λ diastereomers of (S,S)-2 2X X' provide higher enantioselectivities,
[7b]
and with other reactions Δ diastereomers are more effective.
The reaction orders supplied by the data in Figures 6, s18, and s19 generate more ques-
tions than answers. The zero order dependence upon the concentrations of the alkyne, cyanoacet-
ate ester, and catalyst suggest a rest state and transition state of the same atomic compensation. A
3+
–
low energy ternary adduct is consistent with the enhanced solubility of Δ-(S,S)-2 2Cl B(C -
6
–
F ) in CD Cl in the presence of the alkyne and cyanoacetate substrates. However, efforts to
5 4
2
2
further define the mechanism have been hampered by problems with parallel experiments involv-
ing pyridine. For some reason, the data do not give interpretable plots. Despite the incomplete
picture, it was felt best to share all data at this time.
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In terms of reactions that can be effected with organocatalysts, zero order behavior with
[25,28]
respect to one or both substrates is not unusual.
Initial regimes with positive order, as ob-
served in Figures 6 and s18, have been attributed to the interval required for accumulating both
[25,28b,c]
substrates on the catalyst to form the intermediate.
Also, reactions of metal containing
[29]
catalysts that are zero order in catalyst have ample precedent.
In summary, this study has significantly expanded the scope of enantioselective reactions
that can be catalyzed with chiral tris(1,2-diamine) cobalt(III) hydrogen bond donor catalysts of
the types in Figure 2. Furthermore, it is the first that can be advertised as significantly improving
upon existing literature catalysts, as opposed to being comparably effective. The synthesis and
evaluation of new types of enantiopure cobalt(III) catalysts in additional organic reactions will
be described in future reports.
Experimental Section
3+
– [6]
3+
–
– [21]
3+
General. The complexes Λ-1 3BAr , Λ-(S,S)-2 2Cl BAr ,
f
Λ-(S,S)-2 2B-
f
–
– [21]
3+
–
– [21]
3+
–
– [21]
3+
–
F BAr ,
4
Λ-(S,S)-2 2Cl B(C F ) ,
6 5 4
Δ-(S,S)-2 2Cl B(C F ) ,
6 5 4
Λ-(S,S)-3 2Cl
f
– [21]
3+
– [8]
3+
–
– [24]
BAr ,
f
Λ-(S)-4 3BAr , and Λ-(S,S)-2 2I BAr ,
f
most of which are shown in Fig-
f
ure 2, were synthesized as reported earlier. Data on the starting materials, solvents, and instru-
mentation are provided in the supporting information (SI). All reactions and workups were
conducted in air.
Catalyst screening (Tables 1 and s1). A vial was charged with a stir bar, 4a (0.0078 g,
0.055 mmol, 0.0068 mL), 5a (0.0095 g, 0.0050 mmol, 0.0087 mL), and CH Cl (0.50 mL). The
2
2
sample was bought to the indicated temperature, and the catalyst (0.0050 mmol, 10 mol%) and
base were added with stirring (100 mol% base: neat Et N (0.0051 g, 0.050 mmol, 0.0070 mL) or
3
pyridine (0.0040 g, 0.050 mmol, 0.0040 mL); 10 mol% base: 0.20 mL of a 0.025 M CH Cl so-
2
2
lution). The reaction was monitored by TLC (silica gel, 9:1 v/v hexanes/ethyl acetate). After the
time indicated in Table 1, the vial was opened to air and (for low temperature runs) allowed to
warm to room temperature. The solvent was removed by rotary evaporation, and CDCl (0.70
3
1
mL) was added. The Z/E C=C ratio was assayed by H NMR (Z/E =CH: 5.88-5.89/7.07-7.08
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ppm, s/s). The sample was chromatographed (silica gel, 1 × 20 cm column, packed in and eluted
with 9:1 v/v hexanes/ethyl acetate). The product containing fractions were combined and the sol-
vents were removed by rotary evaporation to give 6aa. See the SI for further data.
Additions of cyanoacetate esters 5 to acetylenic esters 4 (Figure 3). A vial was charg-
ed with a stir bar, an alkyne 4 (0.055 mmol), a cyanoacetate 5 (0.050 mmol), and CH Cl (0.50
2
2
mL). Except for the last two systems in Figure 3, the sample was placed in a –36 ℃ freezer and
3+
–
–
stirred. After 10 min, Δ-(S,S)-2 2Cl B(C F ) ·3H O (0.010 g, 0.0050 mmol, 10 mol%) and a
6 5 4
2
CH Cl solution of pyridine (0.025 M, 0.20 mL, 0.0050 mmol) were added. The reaction was
2
2
monitored by TLC (silica gel, 9:1 v/v hexanes/ethyl acetate). After the specified time, the samples
of 6 were transferred to a hood, opened to air, and worked up analogously to those in Table 1.
Additional data are supplied in the SI.
[24]
Determination of ee values.
An NMR tube was charged with CDCl (0.30 mL), a
3
product 6 (0.010 mmol), and a 0.0050 M CDCl solution of the chiral solvating agent Λ-(S,S)-
3
3+
–
–
2
2I BAr ·0.5H O (0.20 mL, (0.0010 mmol, 10 mol%) for 6aa-6ae, 6ah, 6ai, 6ak, 6bc, and
f 2
6cc; 0.40 mL (0.0020 mmol, 20 mol%) for 6af and 6ag; 0.80 mL (0.0045 mmol, 45 mol%) for
[24]
1
6aj).
grated (see Figures s5-s17).
NMR titration experiments (Figure 5). An NMR tube was charged with Δ-(S,S)-2
A H NMR spectrum was acquired and selected signals of the enantiomers were inte-
3+
–
–
2Cl B(C F ) ·3H O (0.010 g, 0.0050 mmol) and CD Cl (0.70 mL). The catalyst was only
6 5 4
2
2
2
1
partially soluble. A H NMR spectrum was recorded. A 1.0 M CD Cl solution of pyridine was
2
2
1
added in 0.0050 mL increments (0.0050 mmol). A H NMR spectrum was recorded after each
addition. The experiment was repeated with solutions of 4a and 5a.
Rate Experiments (Figure 6). A (determination of the order in 4a and 5a). An NMR
tube was charged with a stir bar, 4a (0.0078 g, 0.055 mmol, 0.0068 mL), 5a (0.0095 g, 0.0050
mmol, 0.0087 mL), the internal standard Ph SiMe (0.0021 g, 0.010 mmol, 0.0022 mL), and
2
2
CD Cl (0.50 mL). The sample was vigorously stirred. The resulting solution was cooled to –36
2
2
1
℃, the stir bar removed, and a H NMR spectrum recorded. The stir bar was reintroduced, the
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3+
–
–
solution cooled to –36 °C, and Δ-(S,S)-2 2Cl B(C F ) ·3H O (0.010 g, 0.0050 mmol, 10
6 5 4
2
mol%), and a CD Cl solution of pyridine (0.025 M, 0.20 mL, 0.0050 mmol) were added with
2
2
1
stirring. H NMR spectra were recorded at t (min) = 5, 15, 30, 60, 90, 120, 180, 240, 300, 360,
420, 480, 540 (always temporarily removing the stir bar). The experiment was repeated with 5.0
[25]
and 2.0 mol% catalyst loadings. The reaction progress kinetic analysis method
was applied.
The concentration of 5a at each time point t was calculated from the relative integration of the
standard and plotted versus t (Figure 6). The instantaneous rate (Δ([5a])/Δt) was similarly plotted
and the same analysis was performed for 4a (Figure s18). B (determination of the order in cata-
[26]
lyst). The time normalization method
was used. The concentration of 5a from A was plotted
against the normalized time t' for each catalyst loading. The order in catalyst n was varied until
[26]
the data points for all catalyst loadings overlaid (Figure s19).
3+
–
– n
t' = t × [Δ-(S,S)-2 2Cl B(C F ) ]
6 5 4
3+
–
–
where [Δ-(S,S)-2 2Cl B(C F ) ] represents total concentration of the catalyst in the reaction
6 5 4
(M) and n is the order in catalyst.
Acknowledgements
The authors thank the Welch Foundation (Grant A-1656) for support.
Conflict of interest
The authors have a financial interest in the cobalt(III) catalysts and chiral solvating agents de-
scribed in this work, some of which are commercially available or easily accessed from commer-
[27]
cial precursors.
˜
ORCID
Quang H. Luu: 0000-0003-0772-4004
John A. Gladysz: 0000-0002-7012-4872
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10.1002/chem.202001639
Chemistry - A European Journal
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-22-
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Chemistry - A European Journal
TEXT for TABLE OF CONTENTS GRAPHIC
Thirteen examples of the title reaction are effected with a catalyst derived from the D
3+
3
symmetric chiral trication Δ-[Co((S,S)-dpen) ] (dpen = 1,2-diphenylethylenediamine), which
3
contains both cobalt and carbon stereocenters. The mechanism involves hydrogen bonding be-
tween the NH groups and the substrates.
up to 99:1 Z/E and 98% ee
with R/R'' = alkyl / CO2R'''
total 13
cases
up to 91:9 Z/E and 99% ee
with R/R'' = aryl / CO2R'''
up to >99:<1 Z/E and 94% ee
with R/R'' = alkyl / H
NC
CO2R
'
Ph
Ph
NH
H2N
CN
R
H2
N
R
CO2R
'
Ph
Ph
air
water
stable
3+
Co
+
stable
N
NH2
Ph
H2
R''
H2N
CO2R'''
Ph
R
''
CO2R'''
-23-
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