Synthesis of α-Quaternary Formimides and Aldehydes through Umpolung Asymmetric Copper Catalysis with Isocyanides

Article abstract of DOI:10.1021/jacs.6b12881

A highly regio- and enantioselective copper-catalyzed three-component coupling of isocyanides, hydrosilanes, and γ,γ-disubstituted allylic phosphates/chlorides to afford chiral α-quaternary formimides was enabled by the combined use of our original chiral

Full text of DOI:10.1021/jacs.6b12881

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Communication
Synthesis of #-Quaternary Formimides and Aldehydes through
Umpolung Asymmetric Copper Catalysis with Isocyanides
Kentaro Hojoh, Hirohisa Ohmiya, and Masaya Sawamura
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b12881 • Publication Date (Web): 26 Jan 2017
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Synthesis of α-Quaternary Formimides and Aldehydes through Um-
polung Asymmetric Copper Catalysis with Isocyanides
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Kentaro Hojoh, Hirohisa Ohmiya,* and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
Supporting Information Placeholder
phosphates (chlorides) yielding chiral α-quaternary formimides,
which were readily converted to the corresponding α-quaternary
aldehydes (Figure 1b).5–7 Due to the importance of acyl anion
equivalents as umpolung reagents in organic synthesis,8 numer-
ous efforts have been made in developing metal-catalyzed
enantioselective allylic alkylation reactions using this type of
nucleophile.9 However, the reported protocols constructed only
tertiary carbon stereogenic centers. The enantioselective con-
struction of all-carbon quaternary stereogenic centers remains
highly challenging.10–12
ABSTRACT: A highly regio- and enantioselective copper-
catalyzed three-component coupling of isocyanides, hy-
drosilanes,
and
γ,γ-disubstituted
allylic
phos-
phates/chlorides to afford chiral α-quaternary formimides
was enabled by a combined use of our original chiral naph-
thol-carbene ligand as a functional Cu-supporting ligand
and LiOtBu as a stoichiometric Lewis base for Si. The
formimides were readily converted to the corresponding α-
quaternary aldehydes.
a) Cu-catalyzed1,1-hydrosilylation reported by Saegusa and Ito (1967, ref 2)
CyN
H
CyN
H
cat. Cu(acac)2
via
HSiMe3
+
CyNC
SiMe3
Cu
Isocyanides have been employed as one-carbon reagents
through their 1,1-insertion reactions into metal–element (M–E)
bonds to form imidoylmetal species [M-C(=NR)-E], which
exhibit characteristic reactivities in various catalytic transfor-
mations.1 Specifically, formimidoylmetal species [M-C(=NR)-
H], which can be produced through isocyanide 1,1-insertion into
metal–H bonds, are expected to be “formyl anion (HCO–)”
equivalents. In fact, about fifty years ago, Saegusa, Ito, and co-
workers reported the copper-catalyzed 1,1-hydrosilylation of
cyclohexyl isocyanide with trimethylsilane to yield (N-
cyclohexylformimidoyl)trimethylsilane (Figure 1a). This reac-
tion should involve silylation of catalytically generated
formimidoylcopper(I) species. In this regard, Saegusa, Ito, and
co-workers showed for the first time the high synthetic potential
of isocyanide 1,1-insertion into a metal–H bond as a means of
generating reactive “formyl anion” equivalents.2 Surprisingly,
however, for a period of about a half century after this discovery,
catalytic reactions involving 1,1-insertion of isocyanides into
metal–H bonds or the formation of formimidoylmetal species
were not explored except for the copper-catalyzed indole-
forming reductive cyclization of a 2-alkenylaryl isocyanide
reported by Chatani and co-workers in 2010,3 while it was well
documented that various hydride complexes of early or middle
transition metals (groups 3–5 transition metals and lanthanides)
reacted with isocyanides in a stoichiometric manner to form η1-
or η2-formimidoylmetal complexes.1 As for copper, Sadighi and
co-workers recently reported the synthesis of an η1-
formimidoylcopper(I) complex through the stoichiometric
reaction of benzyl isocyanide with isolated copper(I) hydride
dimers coordinated with N-heterocyclic carbene ligands, but its
reactivity was not revealed.4
b) This work
R1N
H
O
R1N
H
H3O+
R3
Cu(I)/L*
1
via
+
+
HSiY3
R NC
H
R2
LG
CuL*
LiOtBu
R3 R2
R3 R2
Figure 1. Isocyanides as precursors for formyl anion equivalents.
In our earlier studies on the copper-catalyzed enantioselective
allylic substitution reactions of prochiral primary allylic phos-
phates with terminal alkyne or azole pronucleophiles, we syn-
thesized some phenol-carbene chiral ligands and found them
particularly efficient for enantioselective catalysis owing to the
functional roles of the phenolic hydroxyl groups.13a,b The phenol-
carbene chiral ligands were also useful for copper-catalyzed
enantioselective allylic substitution with allylboronate rea-
gents.13c
The three-component coupling reaction of PhMe2SiH (0.18
mmol), cyclohexyl isocyanide (1a) (0.165 mmol) and (Z)-3-
phenyl-2-buten-1-ol derivative 2a (0.15 mmol) occurred effi-
ciently and cleanly in the presence of a stoichiometric amount of
LiOtBu (0.195 mmol) and a catalytic amount of CuCl (10
mol%) and a chiral imidazolium salt (L1·HBF4, 10 mol%) in
THF at 25 °C to produce α-quaternary N-cyclohexylformimide
(S)-3aa. This hydrolytically unstable compound was trans-
formed to the corresponding α-quaternary aldehyde (S)-4a upon
purification by silica gel chromatography. The yield of the
purified (S)-4a was 93% based on 2a, and its enantiomeric
excess was as high as 96% (Table 1, entry 1). The γ-
regioselectivity giving the γ,γ-double-branched product (3aa)
over the achiral linear product (structure not shown) was exclu-
sive (branched/linear >99:1). The enantioselectivity was further
increased to 97% ee by lowering the reaction temperature to
0 °C (entry 2). The reaction in the presence of only 0.2 equiv of
LiOtBu (relative to 2a), which should be consumed as a
Brønsted base to form an oxy anion form of the L1 ligand (L1–
Here, we report a highly regio- and enantioselective copper-
catalyzed asymmetric three-component coupling reaction of
isocyanides, hydrosilanes, and γ,γ-disubstituted primary allylic
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H) (10 mol%), under otherwise identical conditions resulted in poly(methylhydrosiloxane) (1c) gave a low product yield (42%)
1
no reaction (entry 3).
albeit a high level of enantioselectivity (95% ee). Trialkylsilanes
2
3
4
5
6
7
8
9
such as Et3SiH or tBuMe2SiH did not participate in the reaction.
Other chiral carbene ligands bearing a naphthol or phenol
group were less effective (Table 1, entries 4–6).13 Thus, replac-
ing the N-2,4-dicyclohexyl-6-methylphenyl of L1 with a N-
mesityl group [(S,S)-L2] decreased the enantioselectivity to a
moderate level (72% ee) (entry 4). The change of the naphthol
group of L1 to a phenol group [(S,S)-L3] also reduced the enan-
tioselectivity (81%) (entry 5). The combination of phenol and N-
mesityl groups [(S,S)-L4] resulted in significant reductions in
product yield (22%) and enantioselectivity (32%) (entry 6).
Table 2. Scope of isocyanides and allylic phosphates.a
CuCl/L1
(2.5–10 mol %)
R2
R1N
O
H3O+
HSiMe2Ph
R1NC
+
+
R3
H
H
LiOtBu
THF
0 ˚C, 24 h
R3 R2
R3 R2
1
X
(1.2 equiv) (1.1 equiv)
(Z)-2
3
4
entry isocyanide
allylic substrate
formimide or yield ee
aldehyde
(S)-4a
(%) (%)
99
1b
BnCN (1b)
(Z)-2a
89
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PMPN
The use of phenol- or naphthol-carbenes was essential not
only for the enantiocontrol but also for the catalytic activity
(Table 1, entries 7–10). No reaction occurred with O-methyl-
protected ligand L5 (entry 7). Thus, the OH group in L1 was
essential. The ring-unsaturated C2-symmetric carbene ligand
(L6) having 1-(mesityl)ethyl groups at both nitrogen atoms gave
nearly racemic product with low yield (25%), whereas the
branch regioselectivity was exclusive (entry 8).14 The ring-
saturated C2-symmetric carbene ligand [(S,S)-L7], which has
two stereogenic carbon centers in the imidazolidine ring and two
mesityl groups at both nitrogen atoms, induced virtually no
reaction (entry 9).15 The N-hydroxyalkyl-substituted carbene
ligand (L8) having a stereogenic center in the N-alkyl side arm
promoted no reaction (entry 10).16 Thus, having the alkanol in
place of the arenol was not suitable.
MeO
NC
H
2
(Z)-2a
94
99
Ph Me
(S)-3ca
1c
3b
4c
5d
6e
1c
1c
1c
1c
(Z)-2a
(S)-4a
94
81
90
84
99
99
99
98
(Z)-2a (2 g, 7.04 mmol)
(Z)-2a (0.3 mmol)
(Z)-2a (0.6 mmol)
Et
(S)-3ca
(S)-3ca
(S)-3ca
PMPN
H
Ph
7
8
1c
1c
90
89
96
97
O
Ph Et
(S)-3cb
(Z)-2b OP(OEt)2
PMPN
Cy
H
Ph
(Z)-2c
O
Ph Cy
(R)-3cc
OP(OEt)2
X
Me
Table 1. Screening of conditions.a
H
Me
R
O
R
Me
CyN
H
O
CuCl (10 mol %)
L (10 mol %)
silica
gel
OP(OEt)2
Ph
+
+
CyNC
HSiMe2Ph
(1.2 equiv)
O
H
LiOtBu
THF
temp, 24 h
Ph Me
(S)-3aa
Ph Me
(S)-4a
1a
OP(OEt)2
9
1c
10b 1c
R = m-MeO [(Z)-2d] X = N-PMP [(S)-3cd] 93
R = m-MeO [(Z)-2d] X = O [(S)-4d] 93
R = m-THPO [(Z)-2e] X = N-PMP [(S)-3ce] 90
R = p-F [(Z)-2f] X = N-PMP [(S)-3cf] 90
R = p-EtO2C [(Z)-2g] X = N-PMP [(S)-3cg] 92
98
98
99
96
97
95
98
(1.1 equiv)
Cy = cyclo-Hexyl
Ph Ph
(Z)-2a
Ph
Ph
N
Ph
N
Ph
R
11
12
13
14
15
1c
1c
1c
1c
1c
R
Cy
N
N
N
N
BF4
OH
R
BF4
OMe
Cy
R
BF4
OH
R = p-Cl [(Z)-2h]
R = p-Me [(Z)-2i]
X = N-PMP [(S)-3ch] 88
(S,S)-L3•HBF4 (R = Cy)
(S,S)-L4•HBF4 (R = Me)
(S,S)-L1•HBF4 (R = Cy)
(S,S)-L2•HBF4 (R = Me)
(S,S)-L5•HBF4
X = N-PMP [(S)-3ci]
95
Ph
Ph
X
Me
Ph
N
N
N
N
N
H
2-Naphthyl
N
PF6
OH
L8•HPF6
Me
BF4
(S,S)-L7•HBF4
O
PF6
L6•HPF6
OP(OEt)2
(Z)-2j
16
1c
17b 1c
X = N-PMP [(S)-3cj]
X = O [(S)-4j]
90
90
97
97
(Z)-2j
entry
1
ligand
temp. (˚C)
yield (%) of 4a
ee (%) of 4a
Me
L1·HBF4
L1·HBF4
L1·HBF4
L2·HBF4
L3·HBF4
L4·HBF4
L5·HBF4
L6·HPF6
L7·HBF4
L8·HPF6
25
0
93
88
0
96
97
–
O
18 1c
(R)-3ca
86
66
Ph
OP(OEt)2
(E)-2a
2
3b
25
25
25
25
25
25
25
25
X
Me
4
89
90
22
0
72
81
32
–
H
Me
Ph
Ph
5
X
6
19b 1a X = (EtO)2P(O)O [(Z)-2k] X = O [(R)-4k]
20
21b 1c X = (EtO)2P(O)O [(Z)-2k] X = O [(R)-4k]
89
83
84
84
86
7
1c X = (EtO)2P(O)O [(Z)-2k] X = N-PMP [(R)-3ck] 90
8
25
0
4
90
60
9
–
22b,f 1a X = Cl [(Z)-2k’]
X = O [(R)-4k]
10
0
–
Me
O
aReaction conditions: PhMe2SiH (0.18 mmol), 1a (0.165 mmol), (Z)-2a
(0.15 mmol), CuCl/L (10 mol %), LiOtBu (entries 1, 2, 4–6, 10, 0.195
mmol; entry 3, 0.03 mmol; entries 7–9, 0.18 mmol), THF (0.6 mL), 24 h.
Yield of isolated product. Constitutional isomer ratio branched/linear
>99:1 (determined by 1H NMR analysis of the crude product). 3aa was
hydrolyzed with silica gel. The enantiomeric excess was determined by
HPLC analysis. b20 mol% of LiOtBu was used.
R3
H
R3 Me
Cl
23b,f 1a R3 = Me2C=CHCH2CH2 [(Z)-2l’]
24b,f 1a R3 = TBSO CH2CH2 [(Z)-2m’]
(R)-4l
60
46
88
84
(R)-4m
aReaction conditions: PhMe2SiH (0.18 mmol), 1 (0.165 mmol), 2 (0.15
mmol), CuCl/L1 (10 mol %), LiOtBu (0.195 mmol), THF (0.6 mL), 0 ˚C,
24 h. Yield of isolated product. Constitutional isomer ratio branched/linear
>99:1 (determined by 1H NMR analysis of the crude product). The enanti-
Siloxane-type hydrosilane (Me2HSi)2O was as effective as
ee),
PhMe2SiH
(0
°C,
84%
yield,
97%
but
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omeric excess was determined by HPLC analysis. bEntries 3, 10, 17, 21: 3
quaternary stereogenic center with excellent enantioselectivity
(entry 8). Various functional groups such as methoxy, THP ether,
fluoro, ethoxy carbonyl and chloro substituents were tolerated at
the meta- or para-positions of the aromatic γ-substituent of the
allylic phosphate (entries 9–14). The p-tolyl- and 2-naphthyl-
substituted allylic substrates were also suitable (entries 15–17).
was hydrolyzed with 2 M HCl aq. Entry 1, 19, 22–24: 3 was hydrolyzed
with silica gel. cReaction over 36 h. d5 mol % of CuCl/L1 was used. Reac-
tion over 48 h. e2.5 mol % of CuCl/L1 was used. Reaction over 72 h.
fPoly(methylhydrosiloxane) was used.
1
2
3
4
5
6
7
8
Other isocyanides also participated in the enantioselective re-
action with PhMe2SiH and allylic phosphate 2a under identical
conditions (Table 2). The reaction of benzyl isocyanide (1b)
occurred with excellent enantioselectivity, affording, after
hydrolysis, aldehyde (S)-4a with 99% ee in 89% yield (entry 1).
The reaction of 4-methoxyphenyl isocyanide (1c) gave the
corresponding N-arylformimide [(S)-3ca] with 99% ee in 94%
yield (entries 2 and 3).
The reaction of (E)-2a with E-configuration under the opti-
mized conditions provided the antipode of the product derived
from the corresponding (Z)-isomer (branched/linear > 99:1)
(Table 2, entry 18). This result suggests that Z alkenes are more
favorable substrates than E alkenes and that the substitution
pattern at the β carbon is more important than that at the
γ carbon for enantioselection by the catalyst.
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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56
57
58
59
60
The potential for scaling up the copper-catalyzed reaction was
examined. Thus, the reaction of PhMe2SiH (1.19 g, 8.44 mmol),
1c (1.06 g, 7.74 mmol), and 2a (2 g, 7.04 mmol) yielded 1.51 g
(81%) of (S)-3ca with 99% ee (Table 2, entry 4). The Cu load-
ing could be reduced to 5 or 2.5 mol% with the high level of
enantioselectivity retained (entries 5 and 6).
Furthermore, the copper catalyst system was applicable for
the reaction of allylic substrates having two alkyl substituents at
the γ-position albeit with somewhat decreased enantioselectivi-
ties (Table 2). Thus, the reactions of allylic phosphate 2k having
methyl and phenylethyl groups with 1a or 1c occurred under the
optimal reaction conditions with exclusive branch selectivities,
affording the corresponding products [(R)-4k and (R)-3ck] in
aldehyde or imine forms, respectively (entries 19–21). The
Table 2 also summarizes the results of the reactions of various
(Z)-γ,γ-disubstituted allylic phosphates having aryl and alkyl
substituents at the γ-position under the CuCl-L1 catalyst system.
4-Methoxyphenyl isocyanide (1c) was used as an isocyanide
reagent because N-(4-methoxyphenyl)formimide products were
more hydrolytically stable than N-alkylformimides. The former
could be isolated by chromatography on silica gel. The N-(4-
methoxyphenyl)formimides were readily converted to the corre-
sponding aldehydes upon acidic hydrolysis (2 M HCl aq). The
methyl group of 2a could be replaced with an ethyl group with
virtually no deviation in enantioselectivity (entry 7). Remarka-
bly, the allylic phosphate [(Z)-2c], with a sterically more de-
manding cyclohexyl group at the γ-position, also participated in
the reaction to produce a significantly sterically congested
combination of chloride as
a
leaving group and
poly(methylhydrosiloxane) as a hydrosilane caused an increase
in enantioselectivity (86% ee) (entry 22). Alkene [(Z)-2l’] and
silyl ether [(Z)-2m’] moieties in the aliphatic γ-substituent of the
allylic chloride were compatible with the reaction (entries 23
and 24). The reaction of γ-monosubstituted allylic substrates did
not give the corresponding formimide products with tertiary
stereogenic centers, but gave trisubstituted alkenes and conju-
gate dienes that were produced through isomerization of the
three-component coupling products and elimination reaction of
the allylic substrates, respectively.
Ph
Ph
a) Copper hydride pathway
N
N
Ar
R2
LiOtBu
HSiY3
CuI
O
R3
A
H
O
Ph
Ph
C
Ph
Ph
Y3Si
+
– Y3SiOtBu
2
OP(OEt)2
N
R1N
H
CuCl/L1
LiOtBu
R1NC (1)
N
N
Ar
R1NC (1)
B
N
N
Ar
R1
– tBuOH
– LiCl
O
CuI
C
I
Cu
Ph
Ph
O
R3 R2
3
+
formal SN2'
Li
N
N
H
Ar
N
N
A
HSiY3
LiOtBu
C
R1
Cu
Cδ+
O
O
Li +
R1
– Y3SiOtBu
LiOP(OEt)2
– N
Si
O
H
b) Hydrosilicate pathway
D
tBu
R1
Figure 2. Possible reaction pathways.
This copper-catalyzed three-component coupling presumably
goes through the formation of lithium ar-
per(I) hydride species (B).17 Next, isocyanide insertion into the
Cu–H bond accompanied by transmetalation between the ar-
yloxysilane moiety and LiOtBu forms
yloxo(formimidoyl)cuprate (C).
a
yloxo(formimidoyl)cuprate species (C) followed by its formal
SN2’ reaction with allylic substrate 2 (Figures 2a and 2b). For
the formation of the formimidoylcopper(I) species (C), two
types of reaction pathways are conceivable. One involves isocy-
anide 1,1-insertion into a Cu–H bond (copper hydride pathway,
Figure 2a), and the other is direct reaction of hydrosilane, isocy-
anide-Cu(I) complex (A) and LiOtBu (hydrosilicate pathway,
Figure 2b).
a
lithium ar-
On the other hand, the hydrosilicate pathway (Figure 2b) does
not form a Cu–H bond. Thus, the complex A recruits LiOtBu
through an O···Li+···O ionic bridge to activate the hydrosilane
reagent, forming a hydrosilicate species D. The nucleophilic
hydrosilicate moiety attacks the positively charged isocyanide
terminal carbon that is in close proximity, producing lithium
aryloxo(formimidoyl)cuprate C.
In the copper hydride pathway (Figure 2a), the reaction of
CuCl, L1, LiOtBu, and isocyanide 1 forms (L1–H)-Cu(I)-
isocyanide complex A, in which the chiral carbene ligand coor-
dinates to Cu as an anionic C,O-bidentate ligand (L1–H).
Transmetalation between A and a hydrosilane produces a cop-
Although we do not rule out either reaction pathway at pre-
sent, the hydrosilicate pathway (Figure 2b) better explains the
critical roles of the ligand hydroxyl group (Table 1, entry 1 with
L1 vs. entry 7 with L5) because the naphthoxo group directly
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participatre in the formation of the formimidoylcopper structure
provides a new strategy for asymmetric synthesis using isocya-
only in the hydrosilicate pathway.18
nides as reagents for umpolung C1 synthons. Studies for ex-
panding this strategy toward using different coupling partners
will be carried out in our laboratory.
1
2
3
4
5
6
7
8
When the lithium aryloxo(formimidoyl)cuprate intermediate
(C) assumed above reacts with the prochiral allylic substrate (2)
in a formal SN2’ manner, either the Cu atom or the imidoyl
C(sp2) atoms may attack the γ carbon of 2 (Figure 2). Further-
more, the possibility for the intervention of bond formation
between the aryloxo O atom of L1 and the α or γ carbon atoms
of 2 should not be ruled out. This complicated situation hampers
the development of a model to explain the highly efficient
enantioselection by the Cu-L1 catalyst at present. However, it is
likely that the Li+ ion, bridging the isocyanide N and aryloxo O
atoms in C, plays an essential role in the enantioselection. Thus,
a Li+ ion located at a well-defined position in a chiral environ-
ment would fix the rotation of the formimidoyl ligand around
the Cu–C(imidoyl, sp2) axis and assist the reaction of C with 2
in a cooperative manner through binding to the leaving group,
limiting possible enantioselectivity-determining transition state
conformers.
ASSOCIATED CONTENT
Supporting Information. Experimental details and characteriza-
tion data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
9
AUTHOR INFORMATION
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Corresponding Authors
ohmiya@sci.hokudai.ac.jp; sawamura@sci.hokudai.ac.jp
ORCID
Hirohisa Ohmiya: 0000-0002-1374-1137
Masaya Sawamura: 0000-0002-8770-2982
ACKNOWLEDGMENT
This work was supported by Grants-in-Aid for Scientific Research
(B) (No. 15H03803), JSPS, to H.O. and by CREST and ACT-C,
JST, to M.S. K.H. thanks JSPS for scholarship support.
The enantioenriched α-quaternary formimide and aldehyde
obtained by the enantioselective copper catalysis were used to
demonstrate the synthetic utility of this methodology (Figure 3).
Formimide (S)-3ca was readily converted to primary alcohol
(S)-5a through acidic hydrolysis followed by NaBH4 reduction
(Figure 3a). Reduction of (S)-3ca with NaBH4 followed by
removal of the PMP group through treatment with cerium am-
monium nitrate afforded primary amine (S)-6a (Figure 3b). The
NaBH4 reduction of (S)-3ca and N-allylation followed by ring-
closing alkene metathesis produced the N-heterocyclic six-
membered ring compound (S)-7a (Figure 3c). The α-quaternary
aldehyde could be transformed to 2,2-disubstituted 3-
butenonitrile [(S)-8j] or 2,5-dienoate [(R)-9a] via Horner-
Wadsworth-Emmons reaction (Figures 3d and e).
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HCl NaBH4
(S)-5a
97% in 2 steps
HO
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NaBH4 CAN
(S)-6a
83% in 2 steps
H2N
(b)
Ph Me
H2O
CH3CN
Ph Me
EtOH
(S)-3ca, 99% ee
Me
Ph
allyl bromide
K2CO3, DMF
NaBH4
EtOH
Grubbs-II
CH2Cl2
(S)-7a
79% in 3 steps
(c)
(d)
N
PMP
O
NC
1) NH2OH•HCl
NaOAc, EtOH
H
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(18) Preliminary NMR or FTIR studies on stoichiometric reactions with CuCl,
L1, LiOtBu, PhMe2SiH, and benzyl isocyanide (1b) (1/1/3/1/1) in THF-d8
(for NMR) or THF (for FTIR) at room temperature indicated coordination
of the isocyanide (1b) to Cu in an asymmetric environment (2JH–H = 17.2
2-Naphthyl Me
2-Naphthyl Me
2) CDI, THF
(S)-8j, 84%
(S)-4j, 97% ee
O
(EtO)2P(O)CH2CO2Et
LiCl, DBU, CH3CN
EtO2C
H
(e)
Ph Me
(R)-9a, 85%
Ph Me
(S)-4a, 99% ee
Figure 3. Derivatizations of α-quaternary formimide and aldehydes.
In conclusion,
a
copper-catalyzed asymmetric three-
component coupling reaction of isocyanides, hydrosilanes, and
γ,γ-disubstituted primary allylic phosphates occurred with exclu-
sive regioselectivity and with high enantioselectivities to yield
chiral α-quaternary formimides, which were readily converted
to the corresponding aldehydes. This enantioselective copper
catalysis was enabled by our original chiral naphthol-carbene
ligand as a functional supporting ligand for Cu. Various func-
tional groups were tolerated in the substrates. The formimidoyl
group and vinyl group in the three-component coupling products
can be used as handles for further transformations. Mechanistic
studies by intermediate analysis and theoretical calculations are
underway. The enantioselective copper catalysis presented here
Hz (AB quartet) for CNCH2Ph; Δ νCN
+22 cm–1), interaction of
(isocyanide)
LiOtBu with the Cu-isocyanide complex, and the formation of
a
formimidoyl species (δ 9.98 (s) for –N=C(R)–H; νC=N 1680 cm–1) upon
addition of the hydrosilane (See Supporting Information). During these
spectroscopic experiments, no evidence of the formation of Cu–H species
was obtained. Although definitive information concerning the formation
of formimidoyl species was not obtained due to complex and dynamic na-
ture of the reaction mixtures, these spectroscopic results are in support of
the hydrosilicate pathway.
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