Direct Catalytic Asymmetric Cyclopropylphosphonation Reactions of N,N-Dialkyl Groups of Aniline Derivatives by Ru(II)-Pheox Complex

Article abstract of DOI:10.1021/acs.orglett.8b01788

Novel catalysis involving phosphonomethylation of N-methylaniline and asymmetric cyclopropylphosphonation reactions of N,N-diethylaniline derivatives with diazomethylphosphonates are reported. Optically active cyclopropylphosphonate derivatives were directly synthesized from diazomethylphosphonates and N,N-diethylaniline derivatives catalyzed by a Ru(II)-Pheox complex in one step in good yields and high diastereoselectivities (up to trans/cis = > 99:1<) and enantioselectivities (up to 99% ee). D-labeling mechanistic studies of phosphonomethylation and cyclopropylphosphonation suggested that an enamine or iminium intermediate was generated in the reaction process.

Full text of DOI:10.1021/acs.orglett.8b01788

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Catalytic Asymmetric Cyclopropylphosphonation Reactions
of N,N-Dialkyl Groups of Aniline Derivatives by Ru(II)-Pheox
Complex
Chi Thi Loan Le, Seiya Ozaki, Soda Chanthamath, Kazutaka Shibatomi, and Seiji Iwasa*
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi
441-8580, Japan
S
* Supporting Information
ABSTRACT: Novel catalysis involving phosphonomethylation of
N-methylaniline and asymmetric cyclopropylphosphonation reac-
tions of N,N-diethylaniline derivatives with diazomethyl-
phosphonates are reported. Optically active cyclopropylphosphonate
derivatives were directly synthesized from diazomethylphosphonates
and N,N-diethylaniline derivatives catalyzed by a Ru(II)-Pheox
complex in one step in good yields and high diastereoselectivities (up
to trans/cis = > 99:1<) and enantioselectivities (up to 99% ee). D-
labeling mechanistic studies of phosphonomethylation and
cyclopropylphosphonation suggested that an enamine or iminium
intermediate was generated in the reaction process.
hosphonates are an important group of compounds in
pharmaceutical and biological fields because these func-
P
tional groups are commonly found in biological systems.
Furthermore, the cyclopropane ring is an important structure
in biologically active compounds1 and a versatile unit that can
be transferred to an array of other bioactive compounds.2
Therefore, cyclopropylphosphonate derivatives have numerous
applications in a wide range of natural and artificial compounds
in the pharmaceutical industry3 and, in recent studies, the
synthesis of cyclopropylphosphonates has been extended to
improve pharmaceutical properties.
After the pioneering work by Seyferth et al.,4 transition-
metal-catalyzed asymmetric cyclopropylphosphonation of
alkenes with diazomethylphosphonate derivatives was quickly
developed, and several excellent results have been reported.5
Highly effective and stereocontrolled syntheses of phosphonate
functionalized cyclopropanes have been reported using chiral
transition metal complexes such as Rh(II) and Ru(II) catalysts.
In 2013, Lindsay et al.6 described the catalytic asymmetric
synthesis of diacceptor cyclopropylphosphonate derivatives
from α-cyano-diazomethylphosphonates in the presence of
Rh2(S-IBAZ)4 as a chiral catalyst under mild conditions and
reported excellent yields and enantioselectivities with electron-
rich alkenes. Recently, we reported the highly stereoselective
cyclopropanation of olefins with diethyl diazomethyl-
phosphonate using a Ru(II)-Pheox catalyst (Figure 1a).
Importantly, the cyclopropanation of electron-deficient olefins
such as α,β-unsaturated esters, ketones, and amides were also
performed under mild conditions to afford the corresponding
cyclopropylphosphonates in high yields (up to 93%) and with
excellent diastereo- and enantioselectivity (up to 99:1 dr and
99% ee).7
Figure 1. Research background.
Herein, we examined N-methyl and N-allylaniline with
diethyl diazomethylphosphonate using a Ru(II)-Pheox catalyst
to synthesize β-amino cyclopropylphosphonate and observed
no cyclopropanation product. However, we isolated an
interesting phosphonomethylation reaction product on the
−CH3 group8 of the aniline, along with trace amounts of
Received: June 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01788
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phosphonation on the aromatic ring as a minor product
(Figure 1b(1)). Thus, here, we describe a novel phosphono-
methylation of N-methylaniline and asymmetric cyclopropyl-
phosphonation reactions of N,N-diethylaniline derivatives with
diazomethyl phosphonates using Ru(II)-pheox derivatives as
chiral catalysts (Figure 1b(2) and b(3)).
results are summarized in Table 2. Surprisingly, the cyclo-
propanation product was obtained via a C−H insertion
Table 2. Ru(II)-Pheox Catalyst Screening of
a
Cyclopropanation
After the novel reaction of N-methyl aniline with
diazomethylphosphonate catalyzed by Ru(II)-Pheox was
observed, we were encouraged to develop a novel catalytic
process using N,N-dimethylaniline as a substrate to further
examine the reaction. A brief optimization of the phosphono-
methylation reaction of N,N-dimethylaniline catalyzed by
Ru(II)-Pheox (Table 1) and the synthesis of a series of
b
c
entry
catalyst
yield (%) ee (%)
1
2
3
4
5
6
7
8
9
3c
3d
3e
3f
3g
3h
26
37
20
19
19
41
30
34
49
96
87
94
94
94
94
82
51
96
Table 1. Catalyst Screening for the Phosphonomethylation
a
of N,N-Dimethylaniline with Diazomethylphosphonate
3i: R1 to R3 = OMe, R4 = H, R5 = tBu
3j: R1 to R3 = OMe, R4 = H, R5 = iPr
3k: R1 to R3 = OMe, R4 = H, R5 = Ph
a
Reaction conditions: to Ru(II)-Pheox (3%) in CH2Cl2 (2.0 mL), a
b
entry
catalyst
yield (%)
solution of diazomethylphosphonate 2a (0.2 mmol) in CH2Cl2 (2.0
mL) was added under Ar. Isolated yield. Determined by chiral
HPLC analysis.
b
c
1
2
3
4
5
6
7
8
3a: Rh2(OAc)4
trace
52
53
27
41
72
71
15
3b: R1 to R5 = H
3c: R1 to R4 = H, R5 = Ph
3d: R1 to R4 = F, R5 = Ph
3e: R2 = NO2, R1 = R3 = R4 = H, R5 = Ph
3f: R3 = OMe, R1 = R2 = R4 = H, R5 = Ph
3g: R1 = OMe, R2 = R3 = R4 = H, R5 = Ph
3h: R1 = R3 = OMe, R2 = R4 = H, R5 = Ph
reaction with high enantioselectivity without the formation of
a methylphosphonation product in the case of N,N-diethyl-p-
bromoaniline 5b. As can be seen from Table 2 (entry 1), 96%
ee as a sole trans diastereomer in a 26% yield was obtained
with the dimer as a minor product. Various electronic effects
on the aromatic ring bonding with Ru(II) and chiral
environment on the oxazoline ring were examined for the
cyclopropylphosphonation reaction (Table 2, entries 2−6).
The Ru(II)-Pheox catalyst bearing an electron-donating group
on the benzene ring bonding with Ru(II) and a phenyl group
providing a chiral environment was found to be the most
efficient catalyst for this reaction in terms of yield and
stereoselectivity (Table 2, entry 9). For all of the reaction
conditions listed in Table 2, only the trans-isomers were
observed.
a
Reaction conditions: to Ru(II)-Pheox 3(3%) in CH2Cl2 (2.0 mL) a
solution of diazomethylphosphonate 2a (0.2 mmol) in CH2Cl2 (2.0
b
mL) was added under Ar. Isolated yield.
Scheme 1. Procedure for the Synthesis of a Series of Ru(II)-
Pheox Catalysts
Based on the optimized conditions, we next explored the
scope and generality of the direct catalytic asymmetric
cyclophosphonation reaction of diazomethylphosphonate and
N, N-diethyl aniline derivatives, and the results are summarized
in Table 3. N,N-Diethyl aniline as well as p-bromo- and
chloroaniline were reacted with diazomethylphosphonate in
the presence of the Ru(II)-Pheox catalyst 3k to afford their
corresponding cyclopropane products in high enantioselectiv-
ities up to a 49% yield and 97% ee (Table 3, entries 1, 3, 5, and
6). N-Benzyl-N-ethylaniline gave a slightly lower enantiose-
lectivity and yield (Table 3, entry 8) than the other substrates.
In addition, we examined N,N-diethyl-p-OMe substituted
aniline, and the product was found to be unstable during the
workup and purification process, which might be due to
cyclopropane ring opening. Furthermore, the methyl ester
substituent of the diazophosphonate showed 10% to 20%
higher yields compared to the ethyl ester (Table 3, entries 1, 3
and entries 2, 4). The minor products in these reactions were
difficult to isolate.
Ru(II)-Pheox catalysts (Scheme 1) were performed.
Rh2(OAc)4 and other transition metals such as Fe(II), Cu(I),
and Cu(II) are well-known carbene transfer catalysts, but had
almost no effect on the C−H insertion reaction (Table 1, entry
1). Phosphonomethylation product 4 was obtained in the
highest yield (72%) in the presence of electron-rich functional-
group-substituted Ru(II)-Pheox 3f (Table 1, entry 6).
Furthermore, the electron-rich substituents on the phenyl
group bonding with Ru(II) were more effective than the
electron-withdrawing groups (Table 1, entries 3−7).
The optimized reaction conditions from Table 1 were then
applied to N,N-diethylaniline to further understand the
reaction process. First, the reaction of N,N-diethyl-p-
bromoaniline 5b with dimethyl diazomethylphosphonate 2b
was performed using a series of Ru(II)-Pheox catalysts, and the
We used dibenzyl diazomethylphosphonate for cyclo-
propane reactions in the presence of catalyst 3k (Scheme 2).
Notably, the cyclopropanation products (6j and 6k) gave the
B
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Letter
reactions. First, mixtures of the Ru(II)-Pheox catalyst and
aniline derivative and the Ru(II)-Pheox catalyst, aniline
derivative, and olefin without diazophosphonate were tested,
but afforded no reaction under the identical reaction
conditions listed above. Second, the cyclopropylphosphonation
reaction was conducted with hydrogen acceptors such as
norbornene, stilbene, 1,2-diphenylethyne, acetophenone, and
p-nitroacetophenone, but no reducing product was observed
(see Supporting Information). These results suggest that a
transition metal hydride9 was not formed during the reaction.
Remarkably, the other diazo compounds, such as diazoesters,
also showed no reaction for N,N-diethylaniline. Then, a D-
labeled N,N-diethylaniline derivative was applied to determine
the mechanism for this reaction. The deuterated aniline
[D10]-5b was synthesized and reacted with dibenzyl
diazomethylphosphonate 2c in the presence of catalyst 3k to
afford the corresponding partially deuterated cyclopropyl
product [D8]-5j in a 27% yield with the minor product
[D2]-7 in a 30% yield. This indicated that two protons from
N-ethyl group of N-ethylaniline were transformed into the
byproduct (Scheme 3) and suggested the formation of an
Table 3. Substrate Scope of Cyclopropanation
Scheme 3. Preliminary Mechanistic Studies
imine or enamine intermediate8a for the cyclopropyl-
phosphonation via olefin insertion reaction of the Ru-carbene
complex. From this information, a plausible mechanism was
summarized (Scheme 4). First, the reaction of Ru(II)-pheox
catalyst and diazophosphonate generates a metal−carbene
complex, which coordinates with the nitrogen of aniline
immediately to activate intermediate I1. Then, the Ru
phosphonate intermediate I2 and iminium intermediate I3
are formed. The iminium intermediate I3 is easily converted to
the enamine and reacted with the Ru-carbene intermediate to
afford the corresponding cyclopropylphosphonation product.
Simultaneously, the intermediate I2 attracts hydrogen to form
intermediate I4, and then reductive elimination occurs to
generate the corresponding benzyl methyl phosphonate and
end of the catalytic cycle (Scheme 4A). The process involved a
C−H activation reaction when the substrates were aniline
derivatives with a −CH3 group (Scheme 4B).
The highly stereoselective cyclopropanation of ethylaniline
derivatives with diazomethylphosphonates catalyzed by the
Ru(II)-Pheox complex was determined to occur without the
formation of cis-isomer products. Although the cyclopropana-
tion yields are moderate because of the multistep reaction,
excellent enantioselectivities are noteworthy. Obviously, our
previous report regarding the cyclopropanation of vinyl-amine
derivatives with diazomethylphosphonate in the presence of a
Ru(II)-Pheox complex also achieved high yields.10a However,
the synthetic procedure for the vinyl-amine derivatives
involved many steps with a low yield and required long
cyclopropanation times.10 Here, we demonstrated direct
cyclopropylphosphonate derivatives simultaneously from an
N-ethylaniline derivative.
a
b
c
Isolated yield. Determined by chiral-phase HPLC analysis. Catalyst
loading: 3 mol %.
same high enantioselectivity, 96% ee. Meanwhile, the minor
product 7 in both reactions was isolated in 42% yield.
The results reported above, such as the direct methyl-
phosphonation of N-methyl aniline, direct catalytic asymmetric
cyclopropylphosphonation of N-ethyl aniline derivatives, and
the formation of benzyl methylphosphonate as a side product,
encouraged us to further explore the mechanisms of these
Scheme 2. Byproduct of Cyclopropanation
C
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Scheme 4. Plausible Mechanism Based on D-Labeling
Experiment
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Iwasa@ens.tut.ac.jp.
ORCID
Chi Thi Loan Le: 0000-0001-7793-6841
Kazutaka Shibatomi: 0000-0001-6368-4823
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research (B, No. 26288087) from the Japan Society for the
Promotion of Science.
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cyclopropylphosphonation reactions of N,N-diethylaniline
derivatives with diazomethylphosphonates. The catalytic
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and N-ethylaniline derivatives by Ru(II)-pheox complexes
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active cyclopropylphosphonate analogues. Furthermore, we
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intermolecular C−H insertion reactions of diethyl
diazomethylphosphonate to form an inactivated methyl
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ASSOCIATED CONTENT
* Supporting Information
■
S
(10) (a) Chanthamath, S.; Nguyen, D. T.; Shibatomi, K.; Iwasa, S.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01788.
Experimental procedures; spectral data (PDF)
D
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