Phosphinative cyclopropanation of allyl phosphates with lithium phosphides

Article abstract of DOI:10.1039/d0cc04854b

A new cyclopropanation reaction of allyl phosphates with lithium phosphides has been developed to give cyclopropylphosphines through the formation of both a C-P bond and a cyclopropane ring at the same time, and high selectivity toward cyclopropanation over allylic substitution has been realized by conducting the reaction in the presence of HMPA.

Full text of DOI:10.1039/d0cc04854b

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Phosphinative cyclopropanation of allyl phosphates with lithium
phosphides
Received 00th January 20xx,
Accepted 00th January 20xx
Ryo Shintani,* Ayase Ohzono and Kentaro Shirota
DOI: 10.1039/x0xx00000x
A new cyclopropanation reaction of allyl phosphates with lithium
Phosphorus-substituted
cyclopropanes
such
as
phosphides has been developed to give cyclopropylphosphines cyclopropylphosphines constitute a useful class of compounds
through the formation of both a C–P bond and a cyclopropane ring that can be applied as ligands for transition metals in various
at the same time, and high selectivity toward cyclopropanation catalytic organic transformations.8 They are also found in
over allylic substitution has been realized by conducting the biologically active molecules such as antimalarial agents.9
reaction in the presence of HMPA.
Synthesis of these compounds always relies either on C–P
bond formation using pre-existing three-membered
carbocycles such as cyclopropanes8a,c–f,10 and cyclopropenes11
or on C–C bond-forming cyclopropanation using substrates
possessing preinstalled C–P bonds.8b,12 In contrast, despite its
potential versatility and efficiency of the overall process, no
reports have been made that achieves both C–P bond
formation and cyclopropane-ring formation at the same time,
as far as we are aware. In this context, herein we describe the
first such process by the reaction of allyl phosphates with
lithium phosphides in the presence of hexamethylphosphoric
triamide (HMPA) (Scheme 1b).
Cyclopropanation of allylic electrophiles by nucleophilic attack
at their -position represents one of the attractive approaches
for the synthesis of substituted cyclopropanes from relatively
simple precursors, although it requires suppression of
competing allylic substitution.1 Applicable nucleophiles to this
mode of cyclopropanation are typically enolate-type carbon
nucleophiles under palladium catalysis.2 On the other hand,
the use of heteroatom nucleophiles under palladium catalysis
is limited to intramolecular processes using nitrogen3 or
oxygen4 nucleophiles. Only boron5 and silicon (Scheme 1a)6
nucleophiles have been utilized as effective heteroatom
nucleophiles for intermolecular reactions so far under copper
catalysis and uncatalyzed stoichiometric conditions,
respectively. In addition, a photocatalytic process was recently
reported for the intramolecular synthesis of chlorinated
cyclopropanes by isomerization of cinnamyl chlorides through
a radical
Initially, we chose (E)-cinnamyl diethyl phosphate (1a) as a
model
substrate
and
treated
it
with
lithium
dicyclohexylphosphide (2a), which was prepared from
dicyclohexylphosphine and n-butyllithium, in various solvents
at 20 °C, and the products were analyzed after oxidation of
phosphorus with hydrogen peroxide (Table 1). The reaction in
toluene resulted in no formation of cyclopropanation product
3aa with 5% yield of allylic substitution product 4aa (entry 1).13
Selective formation of 4aa over 3aa was also observed with
improved chemical yields when the reaction was conducted in
acyclic ethereal solvents such as diethyl ether, tert-butyl
methyl ether, and cyclopentyl methyl ether, although the
formation of 3aa was also confirmed as a minor component
(3aa/4aa = 6/94–3/97; entries 2–4). The best result toward the
Scheme 1 (a) Silylative (previous work) and (b) phosphinative (this formation of 4aa was achieved by conducting the reaction in
work) cyclopropanation of allyl phosphates.
mechanism.7
cyclopentyl methyl ether (71% yield, 3aa/4aa = 3/97; entry 4).
On the other hand, a significant amount of desired
cyclopropane 3aa was obtained when the solvent was
switched to THF (3aa/(4aa+4aa’) = 43/57; entry 5), and a
slightly higher ratio was observed by conducting the reaction
at –78 °C instead of 20 °C (3aa/(4aa+4aa’) = 47/53;
Division of Chemistry, Department of Materials Engineering Science, Graduate
School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531,
Japan. E-mail: shintani@chem.es.osaka-u.ac.jp
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Table 1 Reaction of Allyl Phosphate 1a with Lithium Phosphide 2a
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mostly gave cyclopropanation product 3ma (97/3) as a mixture
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of stereoisomers (dr = 87/13; eqn(2))D. OWI: 1it0h.10r3e9g/Da0rdCCt0o48t5h4Be
substituents on the phosphorus atom of lithium phosphides,
other secondary alkyl groups such as cyclopentyl (2b) and
isopropyl (2c) groups could be used for the reaction with allyl
phosphate 1b to give cyclopropanation products 3bb–bc in
good yields with excellent selectivity (≥97/3; entries 12 and
13). In addition, both primary and tertiary alkyl groups were
effectively employed as well to give 3bd with perfect
selectivity and 3be with 89% selectivity (entries 14 and 15).
Unfortunately,
Yield of
Entry Additive
Solvent
Temp (°C)
3aa/4aab
3aa+4aa (%)a
1
2
3
4
5
6
7
8
None
None
None
None
None
None
DMPU
HMPA
Toluene
Et2O
20
20
20
5b
55b
73
0/100
6/94
tBuOMe
5/95
cPentOMe 20
71
86b
3/97
THF
THF
THF
THF
20
–78
–78
–78
43/57c
47/53d
60/40e
92/8g
Table
2 Cyclopropanation of Allyl Phosphates 1 with Lithium
91
Phosphides 2
86
77f
a Combined isolated yield. trans/cis > 99/1 for both 3aa and 4aa unless
b
c
d
otherwise noted.
4aa/4aa’ = 93/7.
Determined by 1H NMR. 4aa/4aa’ = 67/33.
e
f
4aa/4aa’ = 85/15.
Containing inseparable
g
dicyclohexyl(3-phenylpropyl)phosphine oxide (≤4%).
4aa/4aa’ =
Yield of
88/12.
Entry
R
R’
3a
3/4c
3+4 (%)b
1
2
3
3aa 77d
3ba 80
3ca 76
92/8e
97/3
99/1
2a
2a
entry 6). The different reaction outcomes between acyclic
ethers and THF may indicate that better coordination ability of
oxygen atom of THF to lithium phosphide 2a increased its
nucleophilicity, which facilitated the attack to less electrophilic
-carbon of 1a compared to its -carbon. Based on this
hypothesis, we decided to examine several Lewis bases as an
additive. Although nitrogen donors such as 4-
4
5
2a
2a
3da 86d
3ea 67 d
90/10f
90/10g
dimethylaminopyridine
(DMAP)
and
N,N,N’,N’-
6
2a
3fa 97
97/3h
tetramethylethylenediamine (TMEDA) showed no effect (data
not shown), the use of N,N’-dimethylpropyleneurea (DMPU)
improved the selectivity toward 3aa to some extent
(3aa/(4aa+4aa’) = 60/40; entry 7), and high selectivity of 3aa
was observed by using hexamethylphosphoric triamide
(HMPA) as an additive (3aa/(4aa+4aa’) = 92/8; entry 8).14
Under the conditions using HMPA as an additive,
cyclopropanation with lithium phosphide 2a effectively
proceeds for various allyl phosphates 1 (Table 2). For example,
in addition to parent cinnamyl phosphate 1a (entry 1),
cinnamyl phosphates 1b–e having substituents at para, meta,
or ortho positions could all be employed to give the
corresponding cyclopropanation products 3ba–ea in
reasonably high yields with 90–99% selectivity (entries 2–5).15
Naphthyl, thienyl, and alkenyl-substituted allyl phosphates 1f–i
also gave cyclopropanes 3fa–ia with high selectivity (90/10–
97/3; entries 6–9), but only allylic substitution took place for
alkyl-substituted allyl phosphate 1j under the current reaction
conditions (entry 10). On the other hand, more electron-
deficient allyl phosphate 1k readily underwent selective
cyclopropanation in the absence of HMPA, as expected from
its ability as a Michael acceptor (entry 11).16 The use of ,-
diphenyl allyl phosphate 1l also provided cyclopropanation
product 3la with relatively high selectivity (85/15; eqn (1)), and
the reaction of -methyl--phenyl allyl phosphate 1m with 2a
7
8
2a
2a
3ga 86
3ha 82
97/3i
90/10j
9k
2a
2a
2a
3ial 95
3ja 90
3ka 70
96/4
10m
11k
0/100n
100/0
12
13
1b
1b
3bb 70
3bc 82
100/0
97/3
14
15
16
1b
1b
1b
3bd 86
3be 88
3bf 80
100/0
89/11o
0/100
17
2f
3nf 76
100/0
a
b
c
trans/cis > 99/1.
Combined isolated yield.
Containing inseparable dicyclohexyl(3-arylpropyl)phosphine
Determined by 1H
d
NMR.
e
f
g
oxide (2–4%). 4aa/4aa’ = 88/12. 4da/4da’ = 89/11. 4ea/4ea’ =
65/35. h 4fa/4fa’ = 50/50. i 4ga/4ga’ = 96/4. j 4ha/4ha’ = 80/20. k The
reaction was conducted in the absence of HMPA. l trans/cis = 96/4.
m
2 | J. Name., 2012, 00, 1-3
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n
o
The reaction time for the first step was 30 min. 4ja/4ja’ = 94/6.
4be/4be’ = 62/38.
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DOI: 10.1039/D0CC04854B
the use of lithium diphenylphosphide (2f) gave only allylic
substitution product 4bf from substrate 1b under the present
reaction conditions (entry 16), but somewhat electron-
deficient 4-methoxycarbonyl-substituted cinnamyl phosphate
1n completely reversed the selectivity to give cyclopropane
3nf as the sole product in 76% yield (entry 17). It is worth
noting that the present phosphinative cyclopropanation of (E)-
allyl phosphates gives trans-cyclopropanes
3 with no
formation of the corresponding cis-isomers in most cases as
exemplified in the reaction of (E)-1a with 2d (Scheme 2a). On
the other hand, the reaction of (Z)-1a gave a mixture of trans-
3ad and cis-3ad in favor of the cis-isomer along with some
allylic substitution product 4ad (Scheme 2b). These results
indicate that addition of phosphide nucleophile and following
three-membered ring formation take place more or less in a
concerted manner on the opposite sides of the alkene with
each other, rather than discrete formation of a carbanion
intermediate in a stepwise fashion.
Scheme 2 Comparison of reactions using (a) E- and (b) Z-cinnamyl
phosphates.
although the reaction had to be conducted at a higher
temperature. In contrast, cinnamyl chloride 7 having a much
stronger leaving group resulted in the formation of allylic
substitution product. These results, along with the trend
observed in Table 2, indicate that the selectivity between
cyclopropanation and allylic substitution seems to be partly
controlled by the balance between electrophilicity at the -
position, which is mainly governed by the substituent at the -
position, and the leaving group ability at the -position.
In summary, we have developed a new cyclopropanation
reaction of allyl phosphates with lithium phosphides to give
cyclopropylphosphines through the formation of both a C–P
bond and a cyclopropane ring at the same time. High
selectivity toward cyclopropanation over allylic substitution
has been realized by conducting the reaction in the presence
of HMPA. We have also demonstrated the importance of
choice of leaving groups and future studies will be directed
toward further understanding of the origin of selectivity as
well as development of cyclopropanation reactions with other
nucleophiles.
We subsequently examined the effect of the nature of
leaving groups to gain further insight into the origin of
selectivity in the present reaction. Cinnamyl tert-butylsulfinate
5, presumably having a slightly weaker leaving group ability
than 1a based on the pKa values of their conjugate acids
(tBuS(O)(OH): 2.7517 versus (EtO)2P(O)(OH): 1.3918), was found
to react with 2a to give cyclopropanation product 3aa in 77%
yield with a somewhat higher selectivity of 99/1 under the
same reaction conditions (eqn (3)). Selective cyclopropanation
(90/10) was also observed for the reaction of cinnamyl phenyl
ether 6 with an even weaker leaving group (pKa value of
phenol: 10.019),
Support has been provided in part by the Naito Foundation.
We thank Mr. Tomohiro Tsuda for the help of X-ray
crystallographic analysis.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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than
a
lithium phosphide, and HMPA presumably
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC04854B
A new cyclopropanation reaction of allyl phosphates with lithium phosphides has been
developed to give cyclopropylphosphines through the formation of both a C–P bond and
a cyclopropane ring at the same time, and high selectivity toward cyclopropanation over
allylic substitution has been realized by conducting the reaction in the presence of HMPA.