Copper-Catalyzed [3+2] Cycloaddition Reactions of Isocyanoacetates with Phosphaalkynes to Prepare 1,3-Azaphospholes

Article abstract of DOI:10.1002/anie.201812779

A novel copper-catalyzed synthetic method is described for phosphorous- and nitrogen-containing heterocycles such as 1,3-azaphospholes. Cycloaddition reactions of various isocyanoacetates with phosphaalkynes in the presence of copper bromide, bis(diphenylphosphino)methane (dppm), and potassium carbonate afford the corresponding 1,3-azaphospholes in high yields with complete selectivity. Some dppm-bridged dicopper complexes were identified as active species for the formation of 1,3-azaphospholes.

Full text of DOI:10.1002/anie.201812779

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Copper-Catalyzed [3+2] Cycloaddition Reactions of
Isocyanoacetates with Phosphaalkynes to Prepare 1,3-
Azaphospholes
Authors: Wenbin Liang, Kazunari Nakajima, Ken Sakata, and Yoshiaki
Nishibayashi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812779
Angew. Chem. 10.1002/ange.201812779
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10.1002/anie.201812779
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Heterocycles
Copper-Catalyzed [3+2] Cycloaddition Reactions of Isocyanoacetates
with Phosphaalkynes to Prepare 1,3-Azaphospholes**
Wenbin Liang, Kazunari Nakajima,* Ken Sakata* and Yoshiaki Nishibayashi*
Abstract: A novel copper-catalyzed synthetic method is described
for phosphorous- and nitrogen-containing heterocycles such as 1,3-
azaphospholes. Cycloaddition reactions of various isocyanoacetates
with phosphaalkynes in the presence of copper bromide, dppm, and
potassium carbonate afford the corresponding 1,3-azaphospholes in
high yields with a complete selectivity. Some dppm-bridged
dicopper complexes work as active species for the formation of 1,3-
azaphospholes.
isolated ring system.[5]
To develop a new method to construct such nitrogen- and
phosphorous-containing heterocycles, we envisaged that [3+2]
cycloaddition reactions between phosphaalkynes[6,7] and nitrogenous
counterparts under transition metal-catalysis might be an effective
strategy. Previously, Regitz and co-workers reported Rh-catalyzed
synthesis of 1,3-oxaphosphole derivatives via Rh-carbenoid
intermediates.[8] Recently, our group has succeeded in iron-
catalyzed [2+2+2] cycloaddition reactions to afford phosphabenzene
derivatives.[9] However, the utilization of phosphaalkynes under a
variety of transition metal catalysis has still been less explored.
As the nitrogenous counterparts, we have focused on alkyl
isocyanides because alkyl isocyanides are broadly utilized as
building blocks of various nitrogen-containing heterocycles.[10]
Actually, Yamamoto's and de Meijer's groups independently
reported copper-catalyzed [3+2] cycloaddition reactions of
isocyanoacetates with alkynes to give the corresponding pyrrole
derivatives (Scheme 1a).[11] This elegant construction of nitrogenous
5-membered rings such as pyrrole derivatives prompted us to
investigate cycaloaddition reactions of phosphaalkynes with
isocyanoacetates to afford the corresponding 1,3-azaphospholes.
Herein, we report copper-catalyzed [3+2] cycloaddition reactions of
phosphaalkynes with isocyanoacetates to afford the corresponding
1,3-azaphospholes (Scheme 1b).
U
nsaturated heterocyclic compounds whose skeletons involve two
distinct heteroatoms are important motifs in materials science and
coordination chemistry due to unique electronic properties
originated from the two heteroatoms.[1] Five-membered ring
skeletons containing nitrogen and phosphorous atoms i.e. 1,3-
azaphosphole and its derivatives have attracted particular interest,
because 1,3-azaphospholes exhibit markedly different natures from
the phosphorous-only five-membered cycles, phospholes. In general,
phospholes are non-planar, non- (or less) aromatic, and unstable
under aerobic conditions.[1b,2] In sharp contrast, the phosphorous
atom in 1,3-azaphospholes forms delocalized π-bonds. Hence, 1,3-
azaphospholes are planar, aromatic, and usually inert under air and
moisture.[1,3] Despite such attractive nature, synthetic methods for
1,3-azaphospholes have been limited. Actually, a number of arene-
fused 1,3-azphospholes have been prepared,[3,4] but there have been
a few examples for the synthesis of 1,3-azaphospholes with the
(a) Previous work: synthesis of pyrroles
H
N
cat. [Cu]
CO2R3
R2
CO2R3
R1
R2
+
CN
alkyne
isocyanoacetate
[*]
W. Liang, Prof. Dr. Y. Nishibayashi
R1
Department of Systems Innovation, School of Engineering, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8656 (Japan)
E-mail: ynishiba@sys.t.u-tokyo.ac.jp
pyrrole
(b) This work: synthesis of 1,3-azaphospholes
cat. [Cu]
Dr. K. Nakajima
H
N
CO2R2
R1
CO2R2
Frontier Research Center for Energy and Resources, School of
Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo,
113-8656 (Japan)
R1
+
CN
P
P
phosphaalkyne
isocyanoacetate
1,3-azaphosphole
E-mail: nakajima@sys.t.u-tokyo.ac.jp
Prof. K. Sakata
Scheme 1. Copper-catalyzed [3+2] cycloaddition reactions using isocyanides.
Faculty of Pharmaceutical Sciences, Toho University, Miyama,
Funabashi, Chiba 274-8510 (Japan)
E-mail: ken.sakata@phar.toho-u.ac.jp
At first, investigation of reaction conditions was carried out in
the cycloaddition reaction of 1-adamantylposphaethyne (1a) with
ethyl isocyanoacetate (2a) as typical substrates. Typical results are
shown in Table 1. The reaction of 1 equiv of 1a with 2 equiv of 2a
in the presence of CuI (10 mol%), dppm (1,1-
bis(diphenylphosphino)methane, 10 mol%), and K2CO3 (60 mol%)
was carried out in 1,4-dixoane at 100 ºC for 18 h. After the reaction,
[**] This work was supported by CREST, JST (JPMJCR1541). We thank
JSPS KAKENHI Grant Numbers 26288044, 15H05798, 26870120,
16K05767, and 16KT0160 from the Japan Society for the Promotion
of Science (JSPS) and the Ministry of Education, Culture, Sports,
Science and Technology of Japan (MEXT).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.((Please delete if not
appropriate))
the
corresponding
4-(1-adamantyl)-5-ethoxycarbonyl-1H-1,3-
azaphosphole (3a) was obtained in 62% yield (Table 1, entry 1).
Other copper salts such as CuBr, CuCl, and CuOTf·1/2C6H6 were
1
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10.1002/anie.201812779
Angewandte Chemie International Edition
also examined, and the highest yield of 3a (92% yield) was obtained
when CuBr was used as a catalyst (Table 1, entries 2-4). When
amounts of CuBr and dppm were reduced to 5 mol%, the yield
lowered, unfortunately (Table 1, entry 5). Then, effect of the ligand
to CuBr was investigated. Dppe (1,2-bis(diphenylphosphino)ethane),
dppp (1,3-bis(diphenylphosphino)propane), PPh3 and dtbpy (4,4'-di-
tert-butyl-2,2'-bipyridyl) were less effective ligands than dppm
(Table 1, entries 6-9). A small amount of isomeric product 3a' was
observed when dppe, PPh3, and dtbpy were used as ligands (Table 1,
entries 6, 8, and 9). Finally, we confirmed that the combination of
CuBr, dppm, and K2CO3 is necessary to obtain 3a in good yield
(Table 1, entries 10-12).
Figure 1. ORTEP drawing of 3a. Selected bond lengths (Å) and angles (º): P1-
C1, 1.715(2); P1-C3, 1.7757(19); N1-C1, 1.337(3); C2-C3, 1.392(3); N1-C2,
1.379(2); N1-O1’, 2.827(2); C1-N1-C2, 114.85(16); P1-C1-N1, 112.97(14); N1-
C2-C3, 112.10(17); C1-P1-C3, 89.92(9); P1-C3-C2, 110.14(13); N1-H22-O1',
154.93 (11).
Table 2. Reactions of 1a with isocyanoacetates (2).[a]
Table 1. Reactions of ethyl 1-adamantlyphosphaethyne (1a) with
isocyanoaceate (2a) under various conditions.[a]
CuBr (10 mol%)
dppm (10 mol%)
CO2R K2CO3 (0.6 equiv)
H
N
[Cu] (10 mol%)
ligand (10 mol%)
CO2Et K2CO3 (0.6 equiv)
CO2R
CN
+
P
Ad
H
N
P
CO2Et
CN
+
1,4-dioxane
100 °C, 18 h
P
Ad
2a, 2 equiv
Ad
1a
3
P
solvent
100 °C, 18 h
ligand
isolated yield (%)
2a, 2 equiv
Ad
1a
3a
O
O
O
O
H
N
H
N
H
entry
[Cu]
yield (%)[b]
N
OMe
OnPr
OtBu
OnBu
P
P
P
1
CuI
dppm
dppm
dppm
dppm
dppm
dppe
dppp
62
92
8
Ad
Ad
Ad
2
CuBr
CuCl
CuOTf•1/2C6H6
CuBr
CuBr
CuBr
CuBr
CuBr
-
3b, 86%
3c, 91%
3d, 80%
3
O
H
N
H
N
O
H
N
4
68
33
33[d]
25
39[f]
38[f]
0
O
OiPr
P
5[c]
6
P
P
Ad
Ad
Ad
3g, 77%
3f, 82%
3e, 78%
7
R = H: 3h, 78%
O
O
H
N
[e]
O
8
PPh3
H
N
p-Me: 3i, 77%
m-Me: 3j, 72%
o-Me: 3k, 70%
m-Cl: 3l, 59%
m-OMe: 3m, 66%
p-Ph: 3n, 70%
9
dtbpy
dppm
-
O
P
P
Ad
10
11
12[g]
Ad
R
3o, 71%
CuBr
CuBr
15[d]
0
O
O
dppm
H
N
O
O
H
N
H
N
H
N
Ad
O
tBu
tBu
PPh2
P
PPh2
PPh2
O
O
P
CO2Et
Ad
P
P
O
Ad
3p, 75%
unsuccessful isocyanides:
Ad
P
N
H
PPh2
dppm
PPh2
dppp
PPh2
dppe
N
N
Ad
3r, 42%[b]
3q, 69%
dtbpy
3a’
[a] All reactions of 1a (0.20 mmol) with 2a (0.40 mmol) were carried out in the
presence of Cu salt (0.020 mmol), a ligand (0.020 mmol), and K2CO3 (0.12
mmol) in 1,4-dioxane (2 mL) at 100 ºC for 18 h. [b] Isolated yield. [c] 5 mol% of
CuBr and 5 mol% of dppm were used. [d] 10:1 mixture of 3a and 3a'. [e] 20
mol% of PPh3. [f] 12:1 mixture of 3a and 3a'. [g] Without K2CO3.
O
O
O
CN
CN
CN
Ts
CN
P
CN
nPr
X
R
OEt
OEt
X = OPh
X = NMe2
R = Me
R = p-C6H4OMe
[a] All reactions of 1a (0.20 mmol) with 2 (0.40 mmol) were carried out in the
presence of CuBr (0.020 mmol), dppm (0.020 mmol), and K2CO3 (0.12 mmol) in
1,4-dioxane (2 mL) at 100 ºC for 18 h. [b] 0.40 mmol of 1a and 0.20 mmol of
hexane-1,6-diyl bis(isocyanoacetate) was used.
The detailed molecular structure of 3a was determined by X-ray
crystallographic analysis,[12] and an ORTEP drawing is shown in
Figure 1. To the best of our knowledge, single crystal X-ray
analyses on non-anellated 1,3-azaphospholes have not been reported,
although some theoretical studies have revealed structures of 1,3-
azaphospholes.[13] Comparison of the bond lengths and angles of the
obtained X-ray structure with those of calculated structures indicates
that the structure of 3a is in consistent with 1H-1,3-azaphosphole
rather than 3H-1,3-azaphosphole. Furthermore, the short N1–O1'
bond length suggests existence of an intermolecular hydrogen
bonding between N1-H22 moiety and O1' atom.
Under the optimized reaction conditions, the use of various
isocyanoacetates was investigated. Typical results are shown in
Table 2. Isocyanoacetates bearing primary, secondary, and tertiary
alkyl ester moieties were successfully converted into the
corresponding 1,3-azaphospholes in excellent yields (3b-g).
Introduction of functionalized benzene rings and naphthalene ring
was also successful to give 3h-o in high yields. Noteworthy is that
the alkene and alkyne moieties were well tolerant in the present
reaction system to afford 3p and 3q because these functional groups
2
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10.1002/anie.201812779
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dioxane at 80 ºC for 2 h, affording a bromide-bridged trimetallic
copper complex (4) in 95% yield (Scheme 2a). Next, we
investigated reactions of CuBr with 1 equiv of dppm in the presence
of 0.5 equiv and 1 equiv of isocyanoacetate 2a. In these reactions,
the corresponding dimetallic copper complexes bearing mono- and
bis-isocyanide coordination (5 and 6) were obtained in 89% and
60 % yields, respectively (Scheme 2b and 2c). Detailed molecular
structures of 4, 5, and 6 were determined by X-ray crystallographic
analysis.[12]
have been usually involved in the metal-mediated cyclization
reactions with isocyanides.[10,11] A double cyclization reaction of
hexane-1,6-diyl bis(isocyanoacetate) was also successful to give 3r
in 42% yield without the formation of the corresponding mono-
cyclization product. We also tested other isocyanides bearing phenyl
ester, amide, alkyl ketone, aryl ketone, sulfonate, phosphonate and
simple alkyl moieties instead of the ester moiety, however, no
desired products were obtained in all cases.[14]
Next, we investigated reactions with other phosphaalkynes.
Typical results are shown in Table 3. A phosphaalkyne bearing 3,5-
dimethyladamantyl group was transformed successfully to give 3s in
67% yield. Introduction of phenyl (3t), alkoxyphenyl (3u-x),
alkylphenyl (3y-ac), and biphenyl (3ad) groups to the
phosphaethyne skeleton gave the corresponding products in high
yields. The reaction of 3,3,3-triphenyl-1-phosphaprop-1-yne also
afforded the corresponding tetraarylmethane-type product (3ae) in
20% yields, respectively. We also tested the use of
trimethylsilylphosphaethyne, however, no desired 1,3-azaphosphole
was observed. This is probably due to the thermal instability of
trimethylsilylphosphaethyne[15] under the current heating conditions.
P
(a)
CuBr + dppm
1 equiv 1 equiv
Br
Br
P
Cu
P
Cu
Br
1,4-dioxane
80 ºC, 2 h
P
Cu
P
P
4, 95%
(P = PPh2)
(b)
P
P
P
P
CuBr + dppm
+ CN
CO2Et
Cu
Cu
1,4-dioxane
rt, 16 h
Br
Br
1 equiv 1 equiv
2a, 0.5 equiv
N
CO2Et
5, 89%
(P = PPh2)
(c)
Br
Table 3. Reactions of phosphaalkynes (1) with 2a.[a]
P
P
P
P
CuBr + dppm
+ CN
CO2Et
Cu
Cu
1,4-dioxane
rt, 16 h
Br
CuBr (10 mol%)
dppm (10 mol%)
CO2Et K2CO3 (0.6 equiv)
1 equiv 1 equiv
2a, 1 equiv
H
N
N
N
EtO2C
CO2Et
CO2Et
CN
+
P
R
6, 60%
(P = PPh2)
P
1,4-dioxane
100 °C, 18 h
2a, 2 equiv
R
1
3
isolated yield (%)
N
CO2Et
(d)
2a
0.5 equiv
(vs Cu atom)
2a
0.5 equiv
(vs Cu atom)
H
N
H
N
H
4
5
6
CO2Et
CO2Et
Ph
1,4-dioxane
100 ºC, 2 h
1,4-dioxane
rt, 16 h
P
P
P
65%
83%
OMe
3s, 67%
3t, 80%
3u, 76%
Scheme 2. Preparation of copper complexes.
H
N
H
H
N
N
CO2Et
CO2Et
CO2Et
P
P
P
IR measurements of 5 and 6 were carried out to reveal the nature
of coordinated isocyanoacetate 2a. Absorbance signals attributable
to the C–N stretching of 2a on 5 and 6 were observed at 2188 and
2186 cm-1, respectively. These values are higher than that of free
isocyanoacetate 2a (2164 cm-1). In copper-isocyanide complexes,
the isocyanides have been known to work as not only σ-donor but
also π-acceptor toward the Cu atom.[16] The high frequency shift of
the IR signals of 5 and 6 indicates that back-donation is weak in
these complexes and 2a is activated with electrophilic manner to
promote deprotonation of the copper-isocyanide complexes leading
the formation of Cu-enolate complexes (vide infra).
OEt
OnPr
OnBu
3v, 71%
3w, 77%
3x, 75%
H
N
H
N
H
N
CO2Et
CO2Et
CO2Et
P
P
P
Me
Et
3y, 62%
3z, 86%
3aa, 80%
H
N
H
N
H
N
CO2Et
CO2Et
CO2Et
P
P
P
iPr
tBu
Ph
To explain the relationship between copper complexes 4, 5 and
6, we carried out the following stoichiometric reactions (Scheme 2d).
At first, the reaction of trimetallic complex 4 with 0.5 equiv of
isocyanoacetate 2a (0.5 equiv based on the Cu atom of 4) gave
mono-isocyanide complex 5 in 65% yield. Furthermore, 5 was
further treated with 0.5 equiv of 2a (0.5 equiv based on the Cu atom
of 5) to give bis-isocyanide complex 6 in 83% yield. These results
clearly indicate that all copper complexes 4, 5, and 6 are possible
species in the reaction system, but 6 may be a dominant species
under the catalytic reaction conditions containing an excess amount
of isocyanoacetate 2a.
3ab, 75%
3ac, 81%
3ad, 57%
H
N
CO2Et
unsuccessful
phosphaalkyne:
P
Ph
Ph Ph
3ae, 20%
P
SiMe3
[a] All reactions of 1 (0.20 mmol) with 2a (0.40 mmol) were carried out in the
presence of CuBr (0.020 mmol), dppm (0.020 mmol), and K2CO3 (0.12 mmol) in
1,4-dioxane (2 mL) at 100 ºC for 18 h.
To examine the reactivity of the isolated complexes 4, 5, and 6,
the following catalytic and stoichiometric reactions were examined
(Scheme 3). At first, we carried out catalytic reactions of 1a with 2a
in the presence of 4, 5, and 6 as catalysts under the typical reaction
conditions (Scheme 3a). In all cases, a similar catalytic activity was
To obtain information on reactive copper species, preparation of
some copper complexes was investigated (Scheme 2). At first, we
carried out the reaction of CuBr with 1 equiv of dppm in 1,4-
3
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10.1002/anie.201812779
Angewandte Chemie International Edition
the initial copper complex together with D, which is converted into
the corresponding 1,3-azaphosphole 3 via aromatization by a
hydrogen shift.
P
P
observed. Next, we investigated the stoichiometric reaction of 6
with 3 equiv of 1a, where corresponding 1,3-azaphosphole 3a was
obtained in 73% yield based on 2a ligands in 6 (Scheme 3b). These
results of the catalytic and stoichiometric reactions indicate the
dimetallic complex 6 is involved as a catalytic active species.
Separately, we confirmed that the dimetallic structure is maintained
during the catalytic reaction. The mass spectrum of ESI-MS analysis
on the reaction mixture of the catalytic reaction showed signals of
m/z = 1201 and 975, which correspond to dimetallic species such as
[Cu2Br(dppm)2(2a)2] (cationic part of 6) and [Cu2Br(dppm)2] (part
of 5 or 6), respectively. In contrast, no signals derived from
monometallic Cu-dppm fragments such as [Cu(dppm)] and
[CuBr(dppm)] were observed from a reaction mixture.
P
P
P
P
P
P
P
P
P
P
TSII-III
TSIII-IV
Cu Cu
VA
Cu Cu
Cu Cu
N
(7.0)
•
(15.2)
N
CO2Et
N
Br
Br
Br
P
P
P
CO2Et
CO2Et
Ad
Ad
III
Ad
(3.9)
II
(1.2)
(-8.7)
IV
P
P
P
P
P
P
P
P
P
P
TSII′-III′
TSIII′-IV′
P
P
Cu Cu
Cu Cu
VA
P
Cu Cu
P
(15.6)
(4.1)
P
•
Ad
Br
Br
Ad
Ad
CO2Et
Br
N
N
N
CO2Et
CO2Et
(0.0)
(0.9)
(-8.7)
II′
III′
IV′
P
P
P
P
H
N
Cu Cu
CO2Et
•
N
Br
P
CO2Et
(21.0)
P
Ad
P
P
(a)
VA
P
P
[Cu] (10 mol% Cu atom)
H
Ad
Cu Cu
TS[3+2]-A
N
K2CO3 (0.6 equiv)
CO2Et
•
CN
CO2Et
+
Br
P
Ad
N
P
P
P
CO2Et
Ad
P
P
I
1,4-dioxane
100 °C, 18 h
H
N
2a, 2 equiv
Ad
Cu Cu
1a
CO2Et
•
+
P
3a
N
Br
CO2Et
(0.0)
P
Ad
Ad
[Cu]
yield
P
VB
4
5
6
64%
53%
86%
TS
[3+2]-B (19.8)
P
P P P
P
P P P
Cu Cu
•
VA
Cu Cu
Br
P
N
CO2Et
•
H
N
(b)
Br
N
CO2Et
K2CO3 (0.6 equiv)
CO2Et
Ad
6
+
P
Ad
I′
Ad
P
TS′[3+2]-A (23.9)
1,4-dioxane
100 °C, 18 h
+
P
Ad
1a, 3 equiv
P
P P P
(0.3)
3a, 73% yield
Cu Cu
Br
VB
•
N
Scheme 3. Stoichiometric and catalytic reactivity of copper complexes.
CO2Et
Ad
P
P = PPh2
TS′
[3+2]-B (22.0)
H
+
P
P
P
P
N
CO2R2
R1
CO2R2
CN
Cu
Cu
[Cu] =
P
Br
Figure 2. Reaction pathway examined by B3LYP-D3 level DFT calculations.
Relative free energies DG298K (kcal mol-1) are in parentheses.
L
2
3
P = PPh2
L = vacant site or 2a
The pathway from B to C shown in Scheme 4 was examined by
using B3LPY-D3 level DFT calculations (Figure 2) (For the
computational details, see Supporting Information). The structure of
dimetallic copper-enolate complex (I) suggests that a copper center
accepts the bridging bromide and provides a vacant site to the other
copper center. The coordination of 1-adamantylphosphaethyne 1a to
the vacant site in I is followed by a nucleophilic attack of the
enolate carbon to phosphaalkyne to afford the six-membered ring
complex III (II → TSII-III → III). The relative Gibbs free energy
(DG298K) of the transition state TSII-III is 15.2 kcal mol-1. Then, the
P-C bond formation gives the complex IV via the transition state
TSIII-IV. The DG298K of TSIII-IV and IV are 7.0 and -8.7 kcal mol-1,
respectively. The addition of phosphaalkyne to enolate in the
[Cu]
[Cu]
N
CO2R2
R1
H
N
P
CO2R2
A
D
H+
H+
[Cu]
[Cu]
CO2R2
CN
•
N
CO2R2
[Cu]
N
CO2R2
P
R1
B
B’
C
R1
P
opposite direction occurs via the same mechanism (II′
III′ TSIII′-IV′ IV′), although the initial complex II′ and the
transition state TSIII′-IV′ are lower in free energy than II and TSIII-IV
→
TSII′-III′
1
→
→
→
,
Scheme 4. Plausible reaction pathway.
respectively. On the other hand, we found other transition states that
undergo direct [3+2] cyclization without coordination of
phosphaalkyne to the copper (TS[3+2]-A, TS[3+2]-B, TS'[3+2]-A, and
TS'[3+2]-B). In these cases, the activation barriers (19.8 - 23.9 kcal
mol-1) are higher than that of TSII-III, and the orientation of the P≡C
bond is not selective because of the small difference in free energy
Based on the experimental results, a plausible reaction pathway
is shown in Scheme 4. At first, coordination of isocyanoacetate 2 to
a dimeatallic copper species forms copper-isocyanoacetate complex
(A). Subsequent deprotonation of A gives the corresponding copper-
enolate complex presumably as a mixture of B and B'. Then, the
reaction of B or B' with phosphaalkyne 1 proceeds to form the
corresponding copper complex (C). Finally, protonolysis of C gives
between TS[3+2]-A and TS[3+2]-B or between TS'[3+2]-A and TS'[3+2]-B
.
Thus, the bimetallic copper structure with a vacant site enables the
coordination of both isocyanide and phosphaalkyne toward the same
4
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10.1002/anie.201812779
Angewandte Chemie International Edition
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copper center and the formation of energetically unfavorable 1,3-
azaphosphole ring is achieved (VA is higher in free energy than VB
by 4.6 kcal mol-1).
Finally, we examined further synthetic applications of 1,3-
azaphosphole 3a (Scheme 5). Treatment of 3a with NaH and
subsequent propionyl chloride gave the N-acylation product (7) in
81% yield. In this case, no P-acylation product was observed. On
the other hand, reduction of ester moiety was succeeded by the
reaction of 3a with LiAlH4 to afford the corresponding alcohol (8)
in 65% yield.
[5]
O
Et
H
N
NaH
1.1 equiv
O
CO2Et
Ad
N
CO2Et
+
P
Cl
Et
P
THF, 0 °C to rt
17 h
Ad
[6]
[7]
2 equiv
7, 81%
3a
OH
H
N
H
N
CO2Et
+
LiAlH4
P
P
THF, 0 °C, 2 h
then H+
Ad
Ad
2 equiv
8, 65%
3a
Scheme 5. Transformations of 1,3-azaphosphole 3a.
In summary, we have developed a new synthetic method to
construct 1,3-azaphospholes by the reactions of phosphaalkynes
with isocyanoacetates in the presence of copper-dppm complex as a
catalyst. Metal-catalyzed cycloaddition reactions of phosphaalkynes
with nitrogenous counterparts offered an efficient strategy to
construct the phosphorous- and nitrogen-containing heterocycles.
Additionally, DFT calculations revealed the detailed reaction
pathway and the origin of selectivity. We believe the present study
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phosphaalkynes as building blocks of phosphorous- and other
heteroatom containing heterocycles.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
[12] CCDC 1833424 (3a), 1833425 (4), 1833426 (5), and 1833427 (6)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Keywords: phosphaalkyne • isocyanide • copper catalyst •
cycloaddition • azaphosphole
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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5
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10.1002/anie.201812779
Angewandte Chemie International Edition
Entry for the Table of Contents
Layout 2:
Heterocycles
Br
P
P
P
P
Wenbin Liang, Kazunari Nakajima,* Ken
Sakata,* and Yoshiaki
Nishibayashi*__________ Page – Page
Cu
Cu
cat.
Br
H
N
L
L
CO2R2
R1
CO2R2
R1
+
CN
P
P
[3+2] cycloaddition
Copper-Catalyzed [3+2] Cycloaddition
Reactions of Isocyanoacetates with
Phosphaalkynes to Prepare 1,3-
Azaphospholes
A novel copper-catalyzed synthetic method is described for phosphorous- and
nitrogen-containing heterocycles such as 1,3-azaphospholes. Cycloaddition
reactions of various isocyanoacetates with phosphaalkynes in the presence of
copper bromide, dppm, and potassium carbonate afford the corresponding 1,3-
azaphospholes in high yields with a complete selectivity. Some dppm-bridged
dicopper complexes work as active species for the formation of 1,3-azaphospholes.
6
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