Asymmetric Three-Component Reaction for the Synthesis of Tetrasubstituted Allenoates via Allenoate-Copper Intermediates

Article abstract of DOI:10.1016/j.chempr.2018.04.012

We developed an efficient and direct route for the synthesis of tetrasubstituted allenes via asymmetric multicomponent reaction (AMCR) by utilizing a variety of α-diazoesters, terminal alkynes, and isatins. This method enables Cu(I)-involved AMCRs of α-diazo compounds and also gives solid experimental evidence for the formation of allenoate-Cu(I) intermediates in C–H insertion of α-diazoesters to terminal alkynes. Combined-acid systems of guanidinylated metal complexes lead to higher reactivity and equally effective asymmetric environment. A catalytic asymmetric three-component reaction of α-diazoesters with terminal alkynes and isatins was achieved. This one-pot synthesis gave rise to axially chiral tetrasubstituted allenoates bearing a stereogenic center. The chiral guanidinium salt/CuBr/YBr₃ catalytic system proved efficient and highly diastereo- and enantioselective for a wide range of alkynes, aromatic α-diazoesters, and isatins under mild reaction conditions. This approach enables a Cu(I)-involved asymmetric multicomponent reaction (AMCR) of α-diazo compounds and gives solid experimental evidence for the formation of allenoate-Cu(I) intermediates in C–H insertion of α-diazoesters to terminal alkynes. We also found that additional acids improved the catalyst efficiency of guanidinium salt/CuCl in the direct enantioselective C–H insertion of α-aryl diazoesters. Mechanism studies suggest that the combined-acid systems (Lewis acid combined with assisted Lewis acid or Br?nsted acid combined with assisted Lewis acid) bring out higher reactivity by associative interaction and allow for an equally effective asymmetric environment. Chirality is a universal phenomenon found in nature. Different from the usual central chirality, allenes are a class of compounds bearing three-carbon axially chiral skeletons and have attracted increasing attention for their usefulness as synthetic intermediates. This unique structural feature can provide allenes with specific biological activity and has been found in many drug molecules and natural products; thus, there is increasing demand for new routes toward these pharmaceutically relevant compounds. Nevertheless, the catalytic asymmetric synthesis of axially chiral allenes, especially for tetrasubstituted ones, is still in its infancy. Here, we report the synthesis of tetrasubstituted allenoates via an asymmetric three-component reaction of α-diazoesters with terminal alkynes and isatins. This gives access to the desired central and axial chirality bearing carbinol allenoate by trapping the corresponding allenoate-copper intermediate with isatin.

Full text of DOI:10.1016/j.chempr.2018.04.012

Article
Asymmetric Three-Component Reaction for
theSynthesisof TetrasubstitutedAllenoatesvia
Allenoate-Copper Intermediates
Yu Tang, Jian Xu, Jian Yang, Lili
Lin, Xiaoming Feng, Xiaohua Liu
liuxh@scu.edu.cn
HIGHLIGHTS
Asymmetric three-component
reaction of a-diazoesters, terminal
alkynes, and isatins
Synthesis of tetrasubstituted
allenes bearing axial and central
chirality
Solid evidence of allenoate-
copper intermediates in C–H
insertion
Mechanism study of combined-
acid systems
We developed an efficient and direct route for the synthesis of tetrasubstituted
allenes via asymmetric multicomponent reaction (AMCR) by utilizing a variety of
a-diazoesters, terminal alkynes, and isatins. This method enables Cu(I)-involved
AMCRs of a-diazo compounds and also gives solid experimental evidence for the
formation of allenoate-Cu(I) intermediates in C–H insertion of a-diazoesters to
terminal alkynes. Combined-acid systems of guanidinylated metal complexes lead
to higher reactivity and equally effective asymmetric environment.
Tang et al., Chem 4, 1–15
July 12, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.04.012

Please cite this article in press as: Tang et al., Asymmetric Three-Component Reaction for the Synthesis of Tetrasubstituted Allenoates via Alle-
noate-Copper Intermediates, Chem (2018), https://doi.org/10.1016/j.chempr.2018.04.012
Article
Asymmetric Three-Component Reaction
for theSynthesisof TetrasubstitutedAllenoates
via Allenoate-Copper Intermediates
Yu Tang,1 Jian Xu,1 Jian Yang,1 Lili Lin,1 Xiaoming Feng,1 and Xiaohua Liu1,2,
*
The Bigger Picture
SUMMARY
Chirality is a universal
A catalytic asymmetric three-component reaction of a-diazoesters with terminal
alkynes and isatins was achieved. This one-pot synthesis gave rise to axially chiral
tetrasubstituted allenoates bearing a stereogenic center. The chiral guanidinium
salt/CuBr/YBr3 catalytic system proved efficient and highly diastereo- and enantio-
selective for a wide range of alkynes, aromatic a-diazoesters, and isatins under mild
reaction conditions. This approach enables a Cu(I)-involved asymmetric multicom-
ponent reaction (AMCR) of a-diazo compounds and gives solid experimental
evidence for the formation of allenoate-Cu(I) intermediates in C–H insertion of a-di-
azoesters to terminal alkynes. We also found that additional acids improved the
catalyst efficiency of guanidinium salt/CuCl in the direct enantioselective C–H inser-
tion of a-aryl diazoesters. Mechanism studies suggest that the combined-acid
systems (Lewis acid combined with assisted Lewis acid or Brønsted acid combined
with assisted Lewis acid) bring out higher reactivity by associative interaction and
allow for an equally effective asymmetric environment.
phenomenon found in nature.
Different from the usual central
chirality, allenes are a class of
compounds bearing three-carbon
axially chiral skeletons and have
attracted increasing attention for
their usefulness as synthetic
intermediates. This unique
structural feature can provide
allenes with specific biological
activity and has been found in
many drug molecules and natural
products; thus, there is increasing
demand for new routes toward
these pharmaceutically relevant
compounds. Nevertheless, the
catalytic asymmetric synthesis of
axially chiral allenes, especially for
tetrasubstituted ones, is still in its
infancy. Here, we report the
synthesis of tetrasubstituted
allenoates via an asymmetric
three-component reaction of
a-diazoesters with terminal
INTRODUCTION
The asymmetric multicomponent reaction (AMCR) has emerged as a powerful tool to
synthesize structural complicate chiral compounds with greater efficiency and atom-
economy.1–9 One way to achieve AMCRs is to trap an active intermediate generated
from two reactants with the third component.10–18 Ylide species formed from hetero
atom-H insertion (such as alcohols,12 amines,13 and mercaptides14) with a-diazo
compounds have been utilized to react with electrophiles to construct polyfunctional
molecules (Scheme 1A). Zwitterionic intermediates generated from the Csp2-H inser-
tion reaction of a-diazocarbonyl compounds to indoles16 (Scheme 1B), or N,N-disubsti-
tuted anilines17 could also participate in AMCRs. These processes have been well
documented by several research groups independently,18 and the use of dirhodium
complexes to generate ylide or zwitterionic intermediates proves to be the general
strategy given the fact that rhodium-carbene enables delayed proton transfer.11–18
Only a few examples show that copper(I) salts allow the MCRs of diazo compounds,
but no asymmetric catalytic version has been realized.15 Moreover, AMCRs via trapping
of intermediates from C–H insertion are less developed than those from O–H and N–H
insertions.11–18 Forexample, catalyticasymmetric Csp-Hinsertionsof diazocompounds
into terminal alkynes to generate axially chiral tri- and disubstituted allenes were
realized recently.19–21 Nevertheless, the reaction process remains disputed and no
experiment has yet been performed to trap the possible intermediates.19–25
alkynes and isatins. This gives
access to the desired central and
axial chirality bearing carbinol
allenoate by trapping the
corresponding allenoate-copper
intermediate with isatin.
Chiral allenes represent a type of three-carbon axially chiral skeleton and have
attracted increasing attention.26–45 Limited examples have been reported in
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1

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noate-Copper Intermediates, Chem (2018), https://doi.org/10.1016/j.chempr.2018.04.012
A
B
Scheme 1. AMCRs via Trapping of Intermediates from X–H or C–H Insertion of Diazocarbonyl
Compounds
Trapping of ylide intermediates (A) and zwitterionic intermediates (B).
asymmetric catalytic synthesis of tetrasubstituted allenes46–49 in comparison with the
achievement of di- and trisubstituted allenes.34–45 Asymmetric nucleophilic addition
with allenic ester or its isomeric compound is useful for the construction of tetrasubsti-
tuted allenic derivatives bearing both axial and central chirality.46–49 Alleno-Mannich-
type reactions via phase-transfer catalysis46 or peptide catalysis47 (Scheme 2, equa-
tion 1), as well as alleno-aldol-type reaction by chiral N,N0-dioxide/Au(III) catalysis48
(Scheme 2, equation 2) gave a- and g-regioselective products, respectively. Alterna-
tively, an enantioselective alkynylogous Mukaiyama aldol reaction worked well for
this purpose (Scheme 2, equation 3).49 However, for these pioneering achievements,
racemic trisubstituted allenoates or ketene acetals should be prepared beforehand.
The substituents of allenoate products are general aliphatic ones, and the relative sta-
bility between alkynoate-allenoate isomeric pairs is affected by the linking groups,46–48
thus affecting the reaction activity and enantioselectivity.
Our group initially developed chiral guanidinium salt and Cu(I) salt-promoted
asymmetric C–H insertion of a-diazoesters to construct tri-substituted allenes.19 We
proposed that the reaction might enantioselectively generate allenoate-Cu(I)
intermediate after proton transfer to give the allenoate product. If this intermediate
could be trapped by an electrophile before H-shift, a direct synthesis of tetrasubsti-
tuted allenic derivatives could be available via a new AMCR (Scheme 2C). Neverthe-
less, such a process is challenging because of possibly competitive pathways, including
alkynylation of the electrophile,50 H-transfer to yield alkyne or trisubstituted alle-
noate,19–21 and trapping of alkynoate-copper intermediate (Scheme 2C) among
others. The control of selectivity is also attractive as both stereogenic center and axial
chirality should be in control simultaneously. The challenge lies in avoiding racemiza-
tion from central chirality to axial chirality via 1,3-copper shift, and discovering more-
organized chiral structures that allow an enantioselective nucleophilic addition to isatin.
Herein, we discover that in the presence of a catalytic amount of chiral guanidinium
salt, CuBr, and YBr3 catalysts, AMCRs among aromatic a-diazoesters, aryl- or alkyl-
substituted terminal alkynes, and isatin derivatives perform well under mild reaction
conditions. The desired carbinol allenoates are afforded in good to excellent yields,
diastereoselectivities, and enantioselectivities for a wide range of substrates. Aryl
groups were readily introduced into the substituents of alkynoates, which is a useful
complementation to previous strategies.46–49 Furthermore, this AMCR provides
solid experimental evidence for the formation of allenoate-Cu(I) intermediate via
1,3-copper shift from alkynylcopper intermediate in the C–H insertion of terminal
alkynes with a-diazoesters. With regard to the chiral catalyst system, this reveals
1Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of
Chemistry, Sichuan University, Chengdu 610064,
P.R. China
2Lead Contact
*Correspondence: liuxh@scu.edu.cn
https://doi.org/10.1016/j.chempr.2018.04.012
2
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Scheme 2. Asymmetric Catalytic Synthesis of Tetrasubstituted Allenoates
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Table 1. Optimization of the Reaction Conditions
Entrya
Guanidinium
L1-HCl
L2-HCl
L3-HCl
L4-HCl
L5-HCl
L6-HCl
L5-HI
CuX
Yield (%)b
drc
erd
1
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
41
19
27
7
63:37
45:55
61:39
49:51
78:22
84:16
80:20
80:20
80:20
80:20
80:20
85:15/63:37
67:33/56:44
88:12/70:30
68:32/58:42
97:3/71:29
96:4/87:13
94:6/76:24
98:2/75:25
98:2/75:25
98:2/74:26
98:2/74:26
2
3
4
5
24
14
31
76
42
71
94
6
7
8
L5-HBr
L5-HBr
L5-HBr
L5-HBr
CuBr
CuBr
CuBr
CuBr
9e
10e,f
11e,f,g
aUnless otherwise noted, all reactions were carried out with CuX (100 mol %), guanidinium salt (10 mol %), 1a (0.10 mmol), 2a (1.2 equiv), and 3a (1.0 equiv) in CHCl3
(0.6 mL) at 30ꢀC for 3 hr (see Tables S1–S6 for details). The absolute configuration of 4aa was determined by comparison with the CD spectra of 4hc (see also
Figures S5, S6, and S8).
bIsolated yield.
cDetermined by 1H NMR.
dDetermined by high-performance liquid chromatography (HPLC).
eCuBr (15 mol %), 8 hr.
fYBr3 (5 mol %).
g2a (1.5 equiv) in CHCl3 (0.2 mL).
that Brønsted acid as hydrogen halide (BLA) or Lewis acid as YBr3 (LLA) increases the
reactivity of the chiral guanidine-Cu(I) complex. The BLA or LLA combined-acid
system51–53addresses the issue that an excessive amount of copper salt was used
in previous C–H insertion of a-diazoesters to terminal alkynes.19
RESULTS AND DISCUSSION
We initially examined conditions on the basis of those we reported for the C–H inser-
tion of a-diazoester with terminal alkyne,19 employing isatin as the electrophile to
trap the possible intermediates, because isatin is an active electrophile and oxindole
derivatives present a type of unique biologically active structures.54 Table 1 outlines
optimization studies for a model AMCR among alkyne 1a, a-naphthyl substituted
4
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a-diazoester 2a, and N-Bn protected isatin 3a (see Tables S1–S9 for details). Chiral
guanidinium salt (10 mol %) and 1.0 equiv of CuCl were used as the catalyst, and the
desired three-component reaction product 4aa via trapping of allenoate-Cu(I) inter-
mediate could be detected, albeit the reactivity and selectivity was poor. A screen of
a series of hydrochloride salts of guanidine-amides L1–L4 revealed that L-proline-
and L-ramipril-derived guanidine L1 and L3 could provide somewhat better yield
and selectivities (Table 1, entries 1–4). Considering the participation of isatin 3a,
which will raise issues including activity of nucleophilic addition and formation of a
stereogenic center, we introduced guanidine L5 and L6 bearing sulfonamide substit-
uent (Table 1, entries 5 and 6),50,55,56 allowing us to activate and fix isatin with an
intermolecular H-bonding (see Figure S4 for details). To our delight, experimentally
significant diastereo- and enantioselectivity with a maximum enantiomeric ratio (er)
of 97:3 and 24% yield was obtained with 2,4,6-triisopropylbenzenesulfonamide-
substituted guanidinium salt L5-HCl (Table 1, entry 5). We changed the salt of
guanidine and copper into L5-HBr and CuBr, resulting in a yield of 76%, 80:20
diastereomeric ratio (dr), and 98:2 er for the major diastereomer (Table 1, entries
5, 7, and 8; see Table S2 for details). An attempt to decrease the amount of CuBr
to 15 mol % led to a dropped yield of 42% (Table 1, entry 9). We initially wondered
whether additional Lewis acid could suppress the interaction between CuBr and the
carbonyl groups of isatin and a-diazoester, thus reducing the amount of CuBr.
Indeed, the addition of 5 mol % of YBr3 resulted in formation of the desired product
4aa in 71% yield with maintained diastereo- and enantioselectivity in the presence of
10 mol % L5-HBr and 15 mol % CuBr (Table 1, entry 10). Increasing the amount of
a-diazoester to 1.5 equiv and reducing the amount of solvent CHCl3 provided a
higher yield of 94% (Table 1, entry 11). Under these optimized conditions, AMCR
product 4aa was obtained in 94% yield, 98:2 er, and 80:20 dr. Trace amount of
C–H insertion product19 was detected in this route, and no alkynylation50 or propar-
gylation of isatin were observed (Scheme 2).
The applicability of this process to a broad range of aromatic a-diazoesters with
cyclohexyl acetylene 1a and isatin 3a is shown in Table 2 (see Table S11, Schemes
S11–S31, and Figures S6–S41 for details). For phenyl-substituted a-diazoesters,
steric hindered tert-butyl ester showed higher reactivity and selectivity than ethyl
ester (Table 2, entry 1 versus 2). The aryl moiety tolerated significant electronic
perturbation: both electron-donating and -withdrawing substituents yielded the
corresponding AMCR products in good yields and good diastereo- and enantiose-
lectivities (Table 2, 84%–98% yield, 78:22 to 90:10 dr, and 94:6 to 98:2 er; entries
2–10). Ortho-halo-substituted tert-butyl a-diazo-phenylacetates gave better
diastereoselectivities and yields than the others. The piperonyl-substituted a-diazo-
ester 2k had a deleterious effect on the reactivity, and 71% yield with 96:4 er and
83:17 dr was obtained (Table 2, entry 11) with a higher amount of CuBr. Furthermore,
1- or 2-naphthyl- or 2-thienyl-substituted a-diazoesters were tolerated such that the
reaction proceeded smoothly in 88%–96% yield with comparably excellent enantio-
selectivity and diastereoselectivity (Table 2, entries 12–14). It is noteworthy that
when ethyl 2-diazopropanoate 2s was used in the AMCR with cyclohexyl acetylene
1a and isatin 3a, racemic carbinol pent-3-ynoate product 6sa via trapping of
alkynoate-copper intermediate was detected rather than carbinol allenoate product
(Figure 1, equation 1; see Scheme S3 for details). Interestingly, the reaction among
ethyl 2-diazopropanoate 2s, ethynylbenzene 1g, and isatin 3a enable the formation
of carbinol allenoate 4sg with good yield and enantioselectivity, albeit the diaster-
eoselection was poor (Figure 1, equation 2; see Scheme S3 for details). This indicates
the formation of alkyl-substituted alknynoate-copper species, which might be more
stable than the corresponding allenoate-copper species.
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Table 2. Substrate Scope for a-Diazoesters
Entrya
1b,d
2c,d
3
2: Ar
Yield (%)
27 (4b0a)
90 (4ba)
90 (4ca)
81 (4da)
91 (4ea)
92 (4fa)
83 (4ga)
98 (4ha)
91 (4ia)
84 (4ja)
71 (4ka)
96 (4la)
89 (4ma)
88 (4na)
er
dr
2b0: C6H5
95:5
97:3
96:4
96:4
95:5
97:3
97:3
98:2
97:3
94:6
96:4
96:4
96:4
95:5
80:20
80:20
78:22
83:17
82:18
90:10
83:17
90:10
88:12
79:21
83:17
80:20
82:18
81:19
2b: C6H5
2c: 2-MeC6H4
2d: 3-MeC6H4
2e: 4-MeC6H4
2f: 2-FC6H4
2g: 4-FC6H4
2h: 2-ClC6H4
2i: 2-BrC6H4
2j: 4-tBuC6H4
2k: piperonyl
2l: 1-naphthyl
2m: 2-naphthyl
2n: 2-thienyl
4c,e
5
6
7
8
9
10
11c,e
12
13c,d
14
aUnless otherwise noted, the reactions were carried out on 0.1 mmol scale under the reaction condition of entry 11 in Table 1 for 3 hr.
bCuBr (60 mol %).
cCuBr (30 mol %).
dReacting for 8 hr.
eReacting for 5 hr.
The scope of this reaction with respect to isatin component is summarized in Table 3
(see Table S12, Schemes S32–S44, and Figures S42–S67 for details). Variation of
isatins was studied with 2-chlorophenyl a-diazoester 2h and alkyne 1a as the
substrates. Generally, isatins 3 bearing both electron-donating and -withdrawing
groups provided the corresponding products 4hb to 4hk in excellent yields
(88%–97%) and enantioselectivities (98:2 to 91:9 er; Table 3, entries 1–11). Excellent
diastereoselectivity (95:5 dr) was obtained when 4-fluoro-, 4-chloro-, and 4-bromo-
substituted isatins were inducted into the reaction (Table 3, entries 1–4). Changing
the N-protecting group of isatin from Bn to other electron-donating groups (Me,
PMB, and BnCH2) had no significant influence on the results, but NH-free and
N-Ts protected isatins were inert in the reactions (Table 3, entries 12–15). It is inter-
esting to note that a gram-scale enantioselective synthesis of 4hc could also be
accommodated under the standard reaction condition (Table 3, entry 3; see Scheme
S9 for details). The absolute configuration of the corresponding thiophene-
2-carboxylate derivative 7hc was established to be (S, Sa) by X-ray diffraction analysis
(Figure S5 and Scheme S74)57; thus the major enantiomer of the product 4hc was
assigned to be (S, Sa). According to a comparison with the CD spectra of 4hc, the ab-
solute configurations of 4hb and 4hd were also determined as (S, Sa) (see Figures
S153–S156 for details). In addition, terminal alkyne 1t decorated with an aldehyde
group could perform the C–H insertion and nucleophilic addition reaction, yielding
6
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Figure 1. Reaction with a-Methyl-a-diazoesters
the desired cyclic allenoate 4t, albeit the yield and stereoselectivity were not satis-
fied (Figure 2; see Table S15, Scheme S65, and Figures S108–S109 for details). Other
nucleophiles, such as 1H-indene-1,2,3-trione and ethyl 3,3,3-trifluoro-2-oxopropa-
noate, underwent the AMCRs with cyclohexyl acetylene 1a and phenyl a-diazoester
2h to give the corresponding carbinol allenoate products in moderate to good yields
but without stereocontrol (see Schemes S2 and S62–S64 and Figures S102–S107 for
details). Nevertheless, the reaction of ethyl 2-oxoacetate yielded the carbinol pent-
3-ynoate product via trapping of alkynoate-copper intermediate (Scheme S2).
We next conducted an exploration of the scope of terminal alkynes in AMCRs under
optimized reaction conditions. Table 4 shows the results of alkyl- and aryl-
substituted alkynes (see Table S13, Schemes S1 and S45–S61, and Figures S68–
S101 for details). A range of alkyl acetylenes including cyclic and acyclic groups
were tolerated and, generally, high levels of reaction efficiency and good enantiose-
lectivities were observed (Table 4, entries 1–4; 90%–98% yield, 88:12 to 95:5 er).
A similar result could be obtained from the reaction of propargyl (S)-citronellyl ether
1f (Table 4, entry 5). The alkyne 1g bearing methylcarbamate substituent underwent
the reaction in good yield and moderate stereoselectivity, possibly because of the
inherent H-bonding interaction with the guanidinium ligand (Table 4, entry 6). For
the terminal alkyne 1h with an acetal group complete reactions occurred, giving a
mixture of the desired product 4h in good diastereo- and enantioselectivity (49%
yield, 96:4 er, and 80:20 dr) and the corresponding H-trapping allenoate 5hh
(Table 4, entry 7; 38% yield, racemate). The alkenyl group was perfectly tolerated
to give the desired AMCR product 4i in 90% yield, 97:3 er, and 80:20 dr, and a cyclo-
propanation by-product was not observed (Table 4, entry 8). Pleasingly, aryl acety-
lenes also performed well, giving the desired diaryl-substituted allenoates 4j–4q in
87%–97% yield, 93:7 to 97:3 er, and 76:24 to 88:12 dr (Table 4, entries 9–16). There-
fore, this AMCR is a good complement to the alleno-addition process46–48 and
alkynylogous Mukaiyama aldol strategy.49
How did the MCR reaction perform in this catalytic system? Our mechanistic hy-
pothesis (Scheme 2C) was supported by control experiments (see Schemes 3 and
S4 for details). Indeed, trisubstituted allenoate 5ha was obtained in 98% yield
and 68:32 er under the standard catalytic condition in the absence of isatin.
When 5ha was subjected to reaction with isatin 3a assisted by various catalyst com-
ponents, even in the presence of guanidine L5/CuBr/YBr3 for 12 hr, no targeted
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Table 3. Substrate Scope for Isatins
Entrya
1
X
R
Yield (%)
94 (4hb)
95 (4hc)
91 (4hc)
96 (4hd)
97 (4he)
96 (4hf)
96 (4hg)
96 (4hh)
96 (4hi)
88 (4hj)
97 (4hk)
98 (4hl)
98 (4hm)
98 (4hn)
ND
er
dr
4-F
Bn
96:4 (S,Sa)
96:4 (S,Sa)
96:4 (S,Sa)
96:4 (S,Sa)
92:8
95:5
2
4-Cl
4-Cl
4-Br
5-Br
6-Br
7-Br
5-Me
5-MeO
6-MeO
5,7-Me2
H
Bn
95:5
3b
4
Bn
95:5
Bn
95:5
5
Bn
85:15
80:20
64:36
88:12
86:14
90:10
84:16
82:18
89:11
85:15
–
6
Bn
94:6
7
Bn
91:9
8
Bn
98:2
9
Bn
97:3
10
11
12
13
14
15
Bn
98:2
Bn
98:2
Me
PMB
Ph(CH2)2
H or Ts
93:7
H
98:2
H
98:2
H
–
ND, not determined.
aUnless otherwise noted, the reactions were carried out on 0.10 mmol scale under the reaction condition of entry 11 in Table 1 for 3 hr.
bThe reaction was carried out on 2.0 mmol scale.
tetrasubstituted allenoate 4ha was detected. These results indicate that the
process in this case is different from the previous reactions using trisubstituted al-
lenoates as the reactants.46–48 Moreover, in view of the observation of pentynoate
product 6sa (Figure 1, equation 1) and the desired carbinol allenoates 4, the forma-
tion of alkynoate-copper species from the C–H insertion and 1,3-copper shift into
allenoate-Cu(I) intermediate are possible. The low er value of 5ha implies that the
enantio- and diastereoselectivities in AMCRs are influenced by the interaction of
isatin with the guanidine. The guanidinylated amides L5 might act as multifunc-
tional ligands: the CN3 unit of L5 interacts with copper salt to enable the formation
of allenoate-copper intermediate, and sulfonamide unit bonds the isatin via intra-
molecular H-bond (see Figure S4 and Scheme S6 for details). The diastereo- and
enantioselective addition reaction results in the formation of the desired product
with axial chirality and tertiary alcoholic center. The latter nucleophilic addition
Figure 2. Reaction of Aldehyde in an Intramolecular Manner
8
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Table 4. Substrate Scope for Terminal Alkynes
Entrya
R
Yield (%)b
90 (4b)
98 (4c)
98 (4d)
98 (4e)
82 (4f)
erc
drd
1
2
3
4
5
cyclopentyl (1b)
Bn (1c)
95:5
90:10
88:12
90:10
91:9
84:16
67:33
67:33
69:31
70:30
BnCH2 (1d)
n-C10H21 (1e)
(1f)
6
81 (4g)
49 (4h)
84:16
96:4
64:36
80:20
(1g)
7e
(1h)
8
1-cyclohexenyl (1i)
C6H5(1j)
90 (4i)
94 (4j)
88 (4k)
87 (4l)
92 (4m)
90 (4n)
96 (4o)
94(4p)
97 (4q)
97:3
97:3
93:7
94:6
97:3
96:4
96:4
97:3
97:3
80:20
84:16
76:24
78:22
87:13
85:15
88:12
84:16
85:15
9
10
11
12
13
14
15
16
2-FC6H4 (1k)
3-FC6H4 (1l)
3-MeC6H4 (1m)
2-MeOC6H4 (1n)
3-MeOC6H4 (1o)
4-MeOC6H4 (1p)
4-EtC6H4 (1q)
aUnless otherwise noted, all reactions were carried out with L5-HBr (10 mol %), CuBr (15 mol %), YBr3 (5 mol %), 1 (0.10 mmol), 2h (0.15 mmol), and 3a (0.10 mmol) in
CH3Cl (0.2 mL) at 30ꢀC for 3 hr.
bIsolated yield.
cDetermined by chiral HPLC.
dDetermined by NMR.
eTri-substituted allene by-product 5hh via H-trapping pathway was obtained in 38% yield and 50:50 er.
step is the enantioselection-determining step, and the C–H insertion is the diaster-
eoselection-determining step, but the two stereocontrol factors will influence one
another.
The fact that combination of L5/CuBr/YBr3 is highly reactive for the generation of
allenoate 5ha from alkyne 1a and a-diazoester 2h (Scheme 3) also reveals that
Y(III) salt benefits the C–H insertion step rather than the electrophilic addition of
isatin through a Lewis acid activation manner, given the fact that C–H insertion of
aromatic a-diazoester to terminal alkynes required CuCl as high as 90 mol % in
our previous study.19 Thus, the assistance of another acid might address the draw-
back of a large amount of copper salt used in the asymmetric C–H insertion step.
Pleasingly, it was true that the loading of CuCl could be greatly reduced in the
C–H insertion by adding 5 mol % of YCl3 instead (see Tables S5–S7 for details).
Chem 4, 1–15, July 12, 2018
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Scheme 3. Control Experiments
The enantioselectivity of the C–H insertion of a-diazoester to alkyne 1r was not
affected and the reaction efficiency improved (Table 5, entry 2 versus entry 1). We
also noticed that long-time stored YCl3 was superior to newly purchased YCl3, indi-
cating that moisture might cause the hydrolysis of YCl3, generating a trace amount of
HCl to assist the reaction (Table 5, entry 2 versus entry 3). Considering the perfor-
mance of guanidinium halo salt in comparison with the corresponding guanidine,
we wondered whether a catalytic amount of hydrogen halide could work. Thus,
various additives were tested as shown in Table 5. When the YCl3/HCl combination
was introduced into the catalytic system, the yield increased and the reaction time
shortened (Table 5, entry 4). Furthermore, it was extremely interesting that using
HCl as the sole additive could also improve the efficiency of the reaction (Table 5, en-
tries 5 and 6). When the amount of HCl increased, a similar result with regard to the
HCl/YCl3 system was obtained. In the presence of L4-HCl/CuCl/HCl (1:2:1, 5 mol %),
the asymmetric C–H insertion reaction occurred rapidly, and the targeted allenoate
5br was given in 90% yield and 96:4 er (Table 5, entry 6). We also confirmed the crit-
ical role of guanidine L4 in that only a trace amount of the C–H insertion product was
detected without it, revealing an obvious ligand-accelerating effect58 (Table 5, en-
try 7). Other control experiments using N-Boc-protected amino amide L10
and amino amide L11 instead of L4 resulted in poor yield and enantioselectivity
(Table 5, entries 8 and 9), indicating the unique characteristic of the guanidine unit.
We tried to determine the X-ray crystal structure of the catalyst but without a pos-
itive result. However, it was found that the addition of L4, L4-HCl, or L11 could
accelerate the dissolution of CuCl in tetrahydrofuran with obvious color change,
whereas N-Boc-protected L10 did not work (see Figure S1 for details). The NMR
study of L4-HCl combined with CuCl showed obvious changes in chemical shift
in comparison with the sole L4-HCl (see Scheme S7 and Figures S128–S140 for de-
tails). This implied the coordination of guanidinium salt with the copper salt,59 and
the developed compounds represent a type of guanidinylated ligand for asym-
metric catalysis. Furthermore, the role of HX or YX3 (X = Br, Cl) is proposed to
interact with the basic nitrogens of the guanidine unit of the ligand, which belongs
to the concept of combined acids.51–53 The performance of L4-HCl/CuCl/HCl or
L4-HCl/CuCl/YCl3 is similar to cationic oxazaborolidine catalyst (Corey’s BLAs)52
and Corey-Bakshi-Shibata catalyst (known as CBS catalyst, a type of LLAs),53
respectively. This hypothesis was supported by the NMR study of L4-HCl/CuCl,
L4-HCl/CuCl/HCl, and L4-HCl/CuCl/YCl3 catalytic systems. A slight chemical shift
is detected in 1H NMR and 13C NMR spectra along with the addition of HCl and
YCl3 (see Scheme S7 for details). Although the actual coordination mode of the
10
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Table 5. Optimization of the Reaction Conditions of C–H Insertion Reactions
Entrya
1
L
Additive (mol %)
Conversion of 2 (%)b
Yield (%)b
erc
L4-HCl
L4-HCl
L4-HCl
L4-HCl
–
35
100
47
31
85
42
99
97:3
97:3
96:4
96:4
2d
YCl3 (5)
YCl3 (5)
3e
4e,f
YCl3 (5)
100
HCl (2.5)
5e
L4-HCl
L4-HCl
–
HCl (2.5)
HCl (5)
68
100
84
59
90
4
96:4
96:4
–
6e,f
7e
YCl3 (5)
HCl (2.5)
8
9
L10
L11
HCl (5)
82
6
50:50
55:45
HCl (10)
100
26
aAll reactions were carried out with L4-HCl (5 mol %), CuCl (10 mol %), and YCl3 (0–5 mol %), HCl (2.5–10 mol %), 1r (0.10 mmol), and 2b (0.12 mmol) in CH2Cl2
(0.5 mL) at 30ꢀC for 2.5 hr. HCl (2.5 mol %: aq. 0.5 M, 5 mL); (5 mol %: aq. 1.0 M, 5 mL); (10 mol %: aq. 1.0 M, 10 mL).
bDetermined by NMR using CH2Br2 as an internal standard.
cDetermined by chiral HPLC.
dLong-time stored YCl3 was used.
eNewly purchased YCl3 was used.
fThe reaction finished in 1 hr.
guanidinylated ligands remained unclear, the study is ongoing (see Figures S2 and
S3 for proposed catalyst structures).
On the basis of this observation, we updated the asymmetric catalytic C–H inser-
tion reaction of a-diazoesters. The substrate scope of various a-aryl a-diazoesters
with the optimal L4-HCl/CuCl/HCl catalytic system is listed in Table 6 (see Table
S14, Schemes S66–S72, and Figures S110–S123 for details). The desired allenoates
5 were given in good yields (86%–94%) and enantioselectivities (94:6 to 97:3 er),
albeit the amount of HCl varied depending on the electronic nature of the substit-
uents. Taking advantage of combined acids, the efficiency of guanidinylated
copper complex was greatly improved with excellent maintained asymmetric
environment.
We next extended the combined acids to the AMCRs to improve the reaction
efficiency of some inert a-diazoesters (see Tables 7, S10, and S11 for details). It
is no surprise to question whether hygroscopic property of YBr3 will affect the
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Table 6. Asymmetric C–H Insertion Reactions by the Combined-Acid System
Entrya
2: Ar
aq. HCl
1.0 M
3.0 M
1.0 M
1.0 M
3.0 M
3.0 M
4.0 M
Yield (%)b
88 (5br)
87 (5cr)
86 (5dr)
84 (5er)
90 (5fr)
erc
1
2b: C6H5
96:4
94:6
95:5
95:5
97:3
95:5
94:6
2
2c: 2-MeC6H4
2d: 3-MeC6H4
2e: 4-MeC6H4
2f: 2-FC6H4
2o: 4-ClC6H4
2p: 4-BrC6H4
3
4d
5
6
94 (5or)
99 (5pr)
7
aL4-HCl (5 mol %), CuCl (10 mol %), and aq. HCl (x M, 5 mL), 1r (0.10 mmol), and 2 (0.12 mmol) in CH2Cl2 (0.5 mL) at 30ꢀC for 1 hr.
bIsolated yield.
cDetermined by chiral HPLC.
dCuCl (5 mol %) was used.
reaction in view of the positive influence of HCl in a two-component reaction
(Table 5). Results in entries 2 and 3 showed that both anhydrous and long-time
stored YBr3 greatly accelerated the reaction, as did HBr as the additive (Table 7,
entries 4–5). Nevertheless, YBr3 was more efficient than HBr in AMCR. Superacid51
combination of YBr3/HBr could further increase the reaction activity without loss of
the stereoselectivity. For the reaction of ethyl 2-diazo-2-phenylacetate 2b0, signifi-
cant improvement of yield was observed, whereas the amount of CuBr and reaction
time was halved (Table 7, entry 6; versus Table 2, entry 1). The rise in the reactivity
via additives was also useful for the reactions of a-diazoester 2d and 2m (Table 7,
entries 7 and 8; versus Table 2, entries 4 and 13). The NMR study also suggested
the interaction of the additives with L5-HBr/CuBr (see Scheme S8 and Figures
S141–S152 for details). The counterions of the acids might have an influence on
the acidity of the catalyst. In this sense, the involvement of Lewis acid (YBr3)- or
Brønsted acid (HBr)-assisted Lewis acid system (L5-HBr/CuBr) might be speculated
for this AMCR although the main role of the copper center is to generate copper-
carbene intermediate instead of a Lewis acid (see Figure S4 for the proposed
mechanism).
In summary, the catalytic asymmetric and direct synthesis of tetrasubstituted
allenoates through AMCRs of a-diazoesters with terminal alkynes and isatins was
realized. A wide range of tetrasubstituted allenoates can be obtained in one pot
with good to excellent yields and good chemo-, enantio-, and diastereoselectiv-
ities. The results confirmed the existence of allenoate-Cu(I) intermediates in C–H
insertion of a-diazoesters. The use of a multifunctional chiral guanidinium salt
ligand led to the success of Cu(I)-involved asymmetric MCRs of diazo compounds.
Additionally, the reactivity of both C–H insertion of alkynes and MCRs has
benefited greatly from the combined-acid strategy. The unique multi-nitrogen
structure of guanidine provides variable opportunity to form designer acid cata-
lysts. Further efforts are under way to illuminate the role of catalytic components
in this route and optimize the reaction conditions for the enantioselective trap of
the alkynoate intermediates.
12
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Table 7. Asymmetric Multicomponent Reactions by the Combined-Acid System
Entrya
2: Ar/R
Additives (mol %)
–
Yield (%)b
53 (4aa)
94 (4aa)
94 (4aa)
60 (4aa)
84 (4aa)
73 (4b0a)
erc
drd
1
2a: 1-naphthyl/Et
2a: 1-naphthyl/Et
2a: 1-naphthyl/Et
2a: 1-naphthyl/Et
2a: 1-naphthyl/Et
2b0: C6H4/Et
98:2
98:2
98:2
98:2
98:2
95:5
80:20
80:20
80:20
80:20
80:20
80:20
2
YBr3 (5)
3b
4
YBr3 (5)
HBr (12.5)
HBr (25)
5
6c
YBr3 (10)
HBr (37.5)
7d
8d
2d: 3-MeC6H4/tBu
2m: 2-naphthyl/tBu
YBr3 (5)
HBr (12.5)
90 (4da)
89 (4ma)
95:5
94:6
83:17
83:17
YBr3 (5)
HBr (12.5)
aUnless otherwise noted, L5-HBr (10 mol %), CuBr (15 mol %), YBr3 (0–5 mol %), HBr (12.5–37.5 mol %; 2.5–7.5 M, 5 mL), 1a (0.10 mmol), 2 (0.15 mmol), and 3a
(0.10 mmol) in CH3Cl (0.2 mL) at 30ꢀC for 8 hr. Isolated yield. er determined by HPLC; dr determined by 1H NMR.
bNewly purchased YBr3 was used instead and the reaction was carried out in a glovebox.
cCuBr (30 mol %) for 4 hr.
dReacting for 0.5 hr.
EXPERIMENTAL PROCEDURES
Detailed experimental procedures are provided in the Supplemental Information.
DATA AND SOFTWARE AVAILABILITY
Crystallographic data have been deposited in the Cambridge Crystallographic Data
Center under accession number CCDC: 1582751.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 156 fig-
ures, 15 tables, 74 schemes, and 1 data file and can be found with this article online
at https://doi.org/10.1016/j.chempr.2018.04.012.
ACKNOWLEDGMENTS
We appreciate the National Natural Science Foundation of China (nos. 21625205
and 21332003) and the National Program for Support of Top-Notch Young Profes-
sionals for financial support.
AUTHOR CONTRIBUTIONS
Methodology, Y.T. and X.L.; Investigation, Y.T., J.X., and J.Y.; Writing – Original
Draft, Y.T.; Writing – Review & Editing, X.L., L.L., and X.F.; Supervision, X.L.
DECLARATION OF INTERESTS
There are no competing interests.
Chem 4, 1–15, July 12, 2018
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Please cite this article in press as: Tang et al., Asymmetric Three-Component Reaction for the Synthesis of Tetrasubstituted Allenoates via Alle-
noate-Copper Intermediates, Chem (2018), https://doi.org/10.1016/j.chempr.2018.04.012
Received: November 6, 2017
Revised: January 28, 2018
Accepted: April 23, 2018
Published: May 17, 2018
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