Palladium-Catalyzed Migratory Insertion of Isocyanides for Synthesis of C-Phosphonoketenimines

Article abstract of DOI:10.1021/acscatal.6b01253

An efficient method for the synthesis of C-phosphonoketenimines through palladium-catalyzed migratory insertion of isocyanides has been developed for the first time. This procedure tolerates wide functional groups and has a good atom economy. Further tran

Full text of DOI:10.1021/acscatal.6b01253

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Letter
Palladium-Catalyzed Migratory Insertion of
Isocyanides for Synthesis of C-Phosphonoketenimines
Qiang Yang, Chong Li, Ming-Xing Cheng, and Shang-Dong Yang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01253 • Publication Date (Web): 15 Jun 2016
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Palladium-Catalyzed Migratory Insertion of Isocyanides for
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Synthesis of C-Phosphonoketenimines
Qiang Yang,† Chong Li,† MingꢀXing Cheng,† ShangꢀDong Yang*†‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China.
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy
of Sciences, Lanzhou, 730000, P. R. China.
ABSTRACT: An efficient method for the synthesis of Cꢀphosphonoketenimines through palladiumꢀcatalyzed migratory insertion
of isocyanides has been developed for the first time. This procedure tolerates wide functionalꢀgroups and has a good atom econoꢀ
my. Further transformations of the products which are useful building blocks for the βꢀaminophosphonates, βꢀ
aminovinylphosphonates and Cꢀphosphorylated tetrazoles indicate potential synthetic utility.
KEYWORDS: Cꢀphosphonoketenimines, palladium, isocyanides, phosphonylated, synthetic method
Ketenimines are an important class of compounds as useful
synthetic intermediates or synthons in chemistry. Since
Staudinger reported the first ketenmines in 1920,1 much of the
knowledge of these analogous compounds has been flourished
within the last hundred years.2 Due to their unique properties
related to the presence of an ethyleneꢀlike CꢀC double bond
and an azomethineꢀlike CꢀN double bond, ketenimines have
opened a wide range of available reaction paths. It has been
proved that ketenimines can undergo many useful reactions
such as nucleophilic additions, radical additions, biradical
cyclizations, electrocyclizations, sigmatropic rearrangements
and cycloaddition reactions.2cꢀd,3 On the other hand, isocyaꢀ
nides4 which may function as a nucleophile, an electrophile
and a radical are ideal reagents for the synthesis of
ketenimines.2d,5
ed by Kolodyazhnyi and Yakovlev in 1980 (Scheme 1, path
b).13c Among these approaches suffer from limitations
such as complicated procedures and narrow substrate scope.
Considering the importance of ketenimines and continuing our
research interest in synthesis of newꢀstyle organophosphorus
compounds,15 for the first time, we report an efficient method
to synthesize stable ketenimines beaing a phosphoryl group
through palladiumꢀcatalyzed migratory insertion of isocyaꢀ
nides with αꢀhalophosphonates and αꢀhalophosphine oxides.
Scheme 1. Methods for the Synthesis of C-
Phosphonoketenimines
Organophosphorus compounds,6 such as phosphonates and
phosphine oxines, are useful in medicinal chemistry,7 agriculꢀ
tural chemistry,8 materials,9 biochemistry10 and organic synꢀ
thesis.11 Considering these diverse applications, development
of new and efficient methods to synthesis of organophosphoꢀ
rus compounds has became an intensive topic of organic synꢀ
thetic chemistry.12 A ketenimine bearing a phosphoryl group
as a multifunctional substituent has been reported years ago.13
Compared with partial ketenimines which are difficult to isoꢀ
late just as intermediates in reactions,2g,14 phosphonoꢀ
ketenimines are more stable and easier to control. Notably
introduction of a phosphoryl group bonded to the ketenimine
would be expected to improve not only the reactivity of the
ketenimine but also its value as a synthetic reagent.13a Howevꢀ
er, such reports are particularly rare, especially for the transiꢀ
tion metal catalyst reports are none. In 1979, Ohshiro and Moꢀ
The investigation was started from tertꢀbutyl isocyanide
(1a) with diethyl (bromo(phenyl)methyl)phosphonate (2aa) in
the presence of 10 mol % Pd(OAc)2 and two equivalents of
K2CO3 in 1,4ꢀdioxane under argon atmosphere at 85 ºC (see
the Supporting Information, Table S1, entry 1). To our delight,
diethyl (2ꢀ(tertꢀbutylimino)ꢀ1ꢀphenylvinyl)phosphonate (4a)
was isolated in 23% yield. Encouraged by this result, we furꢀ
ther screened solvents, catalysts and bases and used different
ratio of 1a and 2aa under an argon atmosphere extensively.
toyoshiya
reported
the
first
synthesis
of
Cꢀ
phosphonoketenimines (Scheme 1, path a).13a Then an alternaꢀ
tive preparation of Cꢀphosphonoketenimines had been reportꢀ
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Unfortunately, we had done our best to increase the yield of 4a
initial
finding,
we
switched
2aa
to
diethyl
3
4
5
6
7
8
9
but
(chlro(phenyl)methyl)phosphonate (2ab) which had lower
reaction activity. To our surprise, we were pleasant to get the
yield of 4a in 84% (Table 1, entry 1) under existing condiꢀ
tions. Following other solvents such as toluene, 1,4ꢀdioxane
and CH3CN were also screened, and DCE was found to be
the best choice (Table 1, entries 2ꢀ4). A variety of Pd were
also tested, and results showed that Pd(C3H5)Cl2 was still the
most suitable catalyst (Table 1, entries 5ꢀ7). Though Pd(dba)2
could also give the product 4a in 82%, it was extremely sensiꢀ
tive to the air. Changing the base to K3PO4, K2CO3 or KOAc
did not have a marked effect on the reaction outcome (Table 1,
entries 8ꢀ10). Reducing the loading of [Pd(C3H5)Cl]2 deꢀ
creased efficiency of reaction (Table 1, entries 11ꢀ12). Deꢀ
creasing the reaction temperature was also unfavorable (Table
1, entries 13). Next, we tested the influence of H2O and O2. It
is noteworthy that H2O had little effect on the reaction (Table
1, entry 14).14k,16 However, when the reaction was conducted
in air, we could hardly detect the product (Table 1, entry
15). What’s more, palladium and base were essential for the
transformation indicated by the control experiments (Table 1,
entries 16ꢀ17).
Having the optimized reaction conditions in hand, the scope
of various isocyanides was tested. As shown in Scheme 2,
alkyl isocyanides such as tertꢀbutylꢀ (1a), cyclohexylꢀ (1b),
1,1,3,3ꢀtetramethylbutylꢀ (1c) and 1ꢀadamantylꢀisocyanide
(1d) led to the desired products in moderate to good yields
(55%−84%). Electronꢀpoor aromatic isocyanide (1e) also
smoothly afforded the phosphonoketenimine. Unfortunately,
benzyl isocyanide (1f) could not react in our reaction under the
standard conditions.
Table 1. Optimization of Reaction Conditionsa
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aReaction conditions: 1a (0.2 mmol), 2ab (0.3 mmol), [Pd], base
(1.4 equiv), solvent (2mL), Temperature, Ar, 30h. bIsolated yields
c
d
based on 1a. 1 equivalent H2O was added. Under air atmosꢀ
phere. en.r. = no reaction.
just got in 55% under the reaction conditions with
[Pd(C3H5)Cl]2 (5 mol %), Cs2CO3 (1.4 equiv) and 1a/2aa
(1.0/1.5) in 1,2ꢀdichloroethane under Ar atmosphere at 85 ºC
(see the Supporting Information, Table S1, for details). While
we have done this reaction, we detected that some debrominꢀ
ated byꢀproducts of diethyl benzylphosphonate has also been
produced simultaneously in the reaction system. This discovꢀ
ery prompted us to consider that the carbon bromine bond of
2aa is too active to decompose. In light of this
Scheme 3. Synthesis of C-Phosphonoketenimines from tert-
Butyl Isocyanide 1a and α-Halobenzylphosphonates and α-
Halophosphine oxides a,b
Scheme 2. Investigation of Various Isocyanides and α-
Chlorobenzylphosphonate 2aba,b
aReaction conditions:
1
(0.2 mmol), 2ab (0.3 mmol),
[Pd(C3H5)Cl]2 (5 mol %), Cs2CO3 (1.4 equiv), 1,2ꢀdichloroethane
(2 mL), 85 ºC, Ar, 30h. bIsolated yields of 4 based on 1.
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aReaction conditions: 1a (0.2 mmol), 3a-3p (0.3 mmol) or 3q
(0.15 mmol) , [Pd(C3H5)Cl]2 (5 mol %), Cs2CO3 (1.4 equiv), 1,2ꢀ
dichloroethane (2 mL), 85 ºC, Ar, 30h. bIsolated yields of 5 based
on 1a.
aReaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), [Pd(C3H5)Cl]2
(5 mol %), Cs2CO3 (1.4 equiv), 1,2ꢀdichloroethane (2 mL), 85 ºC,
Ar, 30h. bIsolated yields of 4 based on 1a.
Next, we subsequently investigated
a series of αꢀ
to excellent yields. Generally, the substrates with electronꢀ
withdrawing groups, such as fluorꢀ (3c, 3k), trifluoromethylꢀ
(3f) and nitroꢀ (3g) gave higher yields of the desired products
than that of electronꢀdonating groups (3a-b, 3h, 3j). Although
chloroꢀ or bromo substrates on aromatic ring (3d-e, 3i, 3m)
can undergo oxidative addition onto Pd(0), they were tolerated
and had little effect on the yields of products under our conꢀ
ditions. In addition, pyridine, thiophene and furan substrates
(3nꢀ3p) were also compatible with the reaction. In particular,
compound 3q with two groups of αꢀchlorobenzylphosphonates
could also run smoothly to afford the product (5q).
Importantly, the reactions can also be extended to syntheꢀ
size other ketenimines (scheme 5). Such as ethyl 2ꢀchloroꢀ2ꢀ
phenylacetate (6), αꢀbenzoyl benzyl chloride (7) and (chloroꢀ
methylene)dibenzene (8) afforded ketenimines (9-11) in modꢀ
erate to good yields.
chlorophosphonates and αꢀchlorophosphine oxides (Scheme
3). To our delight, the procedure tolerated a variety of
phosphonates such as dimethylꢀ, diisopropylꢀ, dibutylꢀ and
dibenzyl phosphonates, which all converted into the desired
products
Chlorobenzyldiphenylphosphine
(4gꢀ4j)
in
good
oxide
yields.
and
αꢀ
αꢀ
chlorobenzyldinaphthylphosphine oxide also afforded excelꢀ
lent yields of the products (4k, 4l). Other phosphonates, such
as diisopropyl phenylphosphinate (2ob) and chiral (1S, 2S,
5R)ꢀ(–)ꢀmenthoxylphenylphosphinate (2pb), were also comꢀ
patible with the reaction and obtained the desired products (4o,
4p) in good yields. Additionally, the reaction could also be
carried out with αꢀbromophosphonates and αꢀbromophosphine
oxides leading the yields up to 85 % (4k). It is worth noting
that αꢀphosphoryl benzyl chloride got much higher yields of
the products than αꢀphosphoryl benzyl bromide except dibenꢀ
zyl (halo(phenyl)methyl)phosphonate (2j).
To further explore the substrate scope, we tested the scope
with regard to substrates on the aromatic ring (Scheme 4).
Substrates at the orthoꢀ, metaꢀ, and para position with a range
of electronꢀrich and electronꢀpoor functional groups were tolꢀ
erated and afforded the desired products (5aꢀ5m) in moderate
Scheme 5. Synthesis of other keteniminesa
Scheme 4. Synthesis of C-Phosphonoketenimines from tert-
Butyl Isocyanide 1a and Diethyl (chloro(aryl)methyl)
phosphonate a,b
aReaction conditions: 1a (0.2 mmol), 6-8 (0.3 mmol),
[Pd(C3H5)Cl]2 (5 mol %), Cs2CO3 (1.4 equiv), 1,2ꢀdichloroethane
(2 mL), 85 ºC, Ar, 30h. bIsolated yields of 9-11 based on 1a.
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Since phosphonoketenimines are a significant class of reacꢀ
which might be intermediate D tautomeric produced intermeꢀ
diate E. The above results evidence that this transformation
possibly involving the intermediate C, D, and E.
tive species and useful synthetic intermediates,5a we illustrated
some synthetic utilities with our reaction product (Scheme 6).
As a transformation, βꢀaminophosphonates which have interꢀ
esting and diverse biological and biochemical properties17
could be easily obtained by hydrolysis of phosphonoꢀ
ketenimines (eq 1).11b Besides the obvious hydrolysis, phosꢀ
phonoketenimines could also be used for nucleophilic addiꢀ
tion reaction (eq 2).13b,13d In addition, more useful heterocycle
formations could be reached using phosphonoketenimines as
annulation reagents. For instance, diethyl (2ꢀ(tertꢀbutylimino)ꢀ
1ꢀphenylvinyl)ꢀphosphonate (4a) reacted with trimethylsilyl
azide in tertꢀbutanol afforded Cꢀphosphonylated tetrazole in
excellent yield (eq 3). 5a
O
Ph
P(OEt)2
Pd(tBuNC)2
[CꢀX]
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Figure 1. Analytical Data of ESI-MS
Scheme 8. Proposed Mechanism
Scheme 6. Transformations of C-Phosphonoketenimines
In order to explore the possible mechanism, several reacꢀ
tions were performed as shown in scheme 7 (see the Supportꢀ
ing Information, Scheme S1, for details). Benzyl, as we all
know, is easy not only to occur oxidative addition by the tranꢀ
sition metal, but also to generate benzyl radical. Thus we carꢀ
ried out our reactions in a series of radicalꢀtrapping experiꢀ
ments. Such as (1ꢀcyclopropylvinyl)benzene (eq.1) and diethyl
2,2ꢀdiallylmalonate (eq. 2) had little effect on the yield of the
4a. These evidences indicate that the radical pathway isn’t
involved in the reactions.
On the basis of these results and previous reports,18 a proꢀ
posed reaction mechanism was shown in Scheme 8. First, palꢀ
ladium(II) and isocyanide afforded palladium(0)ꢀisocyanide
intermediate B in situ. Second, intermediate B reacted with 2
to give a αꢀphosphonylated palladiumꢀbenzyl intermediate C
by oxidative addition. Subsequently, intermediate C was
smoothly converted to αꢀphosphonylated benzylimidoyl inꢀ
termediate D by 1,1ꢀinsertion of isocyanide 1. Finally, the
desired product 4 was obtained by βꢀhydride elimination of
intermediate D and given palladium(0)ꢀisocyanide B to recyꢀ
cle into the reaction. Meanwhile, intermediate D could also
proceed by leaving ligands to form intermediate E, followed
by βꢀhydride elimination to give the desired product 4 and
recycle into the reaction.
Scheme 7. Investigation of the Reaction Mechanism
In
summary,
an
effective
synthesis
of
Cꢀ
phosphonoketenimines via palladiumꢀcatalyzed migratory
insertion of isocyanides has been developed for the first time.
The reactions are operationally simple, tolerate wide functionꢀ
al groups and have a good atom economy. This research opens
a new door to synthesize new ketenimines. Further transforꢀ
mations of the Cꢀphosphonoketenimines also indicate potential
synthetic utility.
To further understand the catalytic cycle of the palladiumꢀ
catalyzed for synthesis of Cꢀphosphonoketenimines, the model
reaction was monitored by mass spectrometry experiment
(Figure 1). First, the ESI/MS showed a set of signal peaks at
m/z 499.1413, which corresponds to [C−X]+. The signal might
mean that Pd(0)(tBuNC)2 could react with 2 by oxidative
addition to form intermediate C. Another set of signal peaks at
m/z 582.2149 might be the intermediate D, which resulted
from the migratory insertion of 1 with intermediate C. Howꢀ
ever, we found a very weak signal peaks at m/z 416.0665,
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures,
spectra data for all compounds, copies of H, 13C, 31P and 19F
1
NMR spectra (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Synthesis of Organophosphines, Phosphonates, and Related Comꢀ
Corresponding Author
pounds,in Practical Functional Group Synthesis,;John Wiley & Sons,
Inc, Hoboken, NJ, 2016. (f) Demmer, C. S.; KrogsgaardꢀLarsen, N.;
Bunch, L. Chem. Rev. 2011, 111, 7981ꢀ8006.
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*yangshd@lzu.edu.cn.
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
We are grateful for the NSFC (Nos. 21272100 and 21472076)
financial support.
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