Enantioselective 1,6-Conjugate Addition of Dialkyl α-Diazo Methylphosphonate to para-Quinone Methides

Article abstract of DOI:10.1002/adsc.202100881

An asymmetric 1,6-conjugate addition reaction of dialkyl diazomethylphosphonates to para-quinone methides promoted by phase-transfer catalysis has been developed. A series of chiral diarylmethylated diazomethylphosphonates were accessed with up to 85% yields and 99% ee enantioselectivities. The resulting products were further transformed into bioactive compounds, namely, a chiral dihydrocinnoline phosphonate and a chiral α-aminophosphonate, bearing diarylmethine stereogenic centers. (Figure presented.).

Full text of DOI:10.1002/adsc.202100881

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doi.org/10.1002/adsc.202100881
Enantioselective 1,6-Conjugate Addition of Dialkyl α-Diazo
Methylphosphonate to para-Quinone Methides
a
a
a
b,
a,
Yuan Chen, Rui Yu, Min Wang, Yanmin Huang, * and Yungui Peng *
a
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest
University, Chongqing 400715, People’s Republic of China
Fax: (+86)-023-68253157
E-mail: pengyungui@hotmail.com; pyg@swu.edu.cn
College of Chemistry and Life Science, Guangxi Teachers Education University, Nanning 530001, People’s Republic of China
b
E-mail: huangyanmin828@gxtc.edu.com
Manuscript received: July 15, 2021; Revised manuscript received: August 18, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100881
addition of a wide range of nucleophiles to p-QMs has
Abstract: An asymmetric 1,6-conjugate addition
been well-established, enabling the straightforward
synthesis of various diarylmethane compounds.
reaction of dialkyl diazomethylphosphonates to
[4]
para-quinone methides promoted by phase-transfer
catalysis has been developed. A series of chiral
diarylmethylated diazomethylphosphonates were ac-
cessed with up to 85% yields and 99% ee
enantioselectivities. The resulting products were
further transformed into bioactive compounds,
namely, a chiral dihydrocinnoline phosphonate and
a chiral α-aminophosphonate, bearing diarylmethine
stereogenic centers.
Despite great progress, obtaining chiral diarylmethine
units through asymmetric 1,6-conjugate addition to p-
QMs, especially using a chiral catalyst to activate the
carbonyl residue and realize stereocontrol, remains
challenging. This might be due to the long distance
between the carbonyl group and δ-position at which
nucleophile addition occurs, which makes enantiose-
[5]
lective control difficult. Since the seminal work of
[6a]
the Fan group, who achieved the asymmetric 1,6-
conjugate addition of malonates to p-QMs using
[
6a–c]
phase-transfer catalysis,
various nucleophiles or
Keywords: Asymmetric catalysis; conjugate addi-
tion; α-diazo methylphosphonate; para-quinone me-
thide; dihydrocinnoline phosphonate
[6d]
precursors, such as aldehyde, bis(pinacolato)diboron
[
6e,f]
6i,j]
[6g]
[6h]
[6l]
[
B (pin) ],
dicyanoolefins,
azlactones,
2
2
[
[6k]
oxindoles,
allenoates, and azaaryl acetamides,
The diarylmethine unit is a privileged substructure
widely found in natural products and medicinal
molecules, such as pheniramines, festerodines, tolter-
odines, and (+)-mimosifoliol, which can be used as
antihistamines, treatments for bladder syndrome, and
[1]
estrogen (Figure 1). The activity of some of these
bioactive compounds is closely related to the absolute
configuration of the diarylmethine stereogenic center.
Therefore, the development of asymmetric method-
ology to access various compounds with a diary-
lmethine stereogenic center enantioselectively has
received considerable attention in organic and pharma-
[2]
ceutical chemistry.
para-Quinone methides (p-QMs), which have a
unique structure bearing a hexadiene core and para-
carbonyl moiety, are extensively employed in modern
Figure 1. Bioactive diarylmethine units.
[3–6]
organic synthesis.
For example, the 1,6-conjugate
Adv. Synth. Catal. 2021, 363, 1–7
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[a]
have been successfully employed in asymmetric 1,6- Table 1. Optimization of reaction conditions.
conjugated additions to p-QMs promoted by different
catalytic strategies. The Seyferth-Gilbert reagent
(SGR, dimethyl-(diazomethyl)phosphonate), which
provides expedient access to phosphonate-functional-
ized molecules, has been applied in asymmetric
[
7]
reactions, such as the cyclopropanation of alkenes,
[8]
[
3+2] cycloaddition reactions with olefins
or
[9]
imines, 10]as nucleophiles in asymmetric aldol
[
[11]
reactions,
and the Mannich reaction.
To our
knowledge, using the SGR as a nucleophile in
asymmetric conjugate addition has yet to be explored.
Inspired by achievements in asymmetric reactions
involving p-QMs and the SGR, the development of an
alternative catalytic asymmetric 1,6-conjugate addition
of SGR with p-QMs for the synthesis of optically
active diarylmethylated diazophosphonates is highly
appealing. Herein, we report an efficient methodology
for the asymmetric 1,6-conjugate addition reaction of
SGR to p-QMs. Notably, the resulting products were
further transformed into promising potential bioactive
compounds or raw materials thereof, namely, a chiral
aryl-substituted dihydrocinnoline phosphonate and a
chiral α-aminophosphonate, with diarylmethine stereo-
genic centers.
[b]
[c]
Entry
Cat
T (°C)
Yield of 3 (%)
ee of 3 (%)
The reaction of p-QM 1a and dimethyl diazometh-
ylphosphonate (2a) was selected as the model reaction.
After initial trials, to our delight, the reaction
proceeded smoothly in the presence of phase-transfer
1
2
3
4
5
6
7
8
9
–
Ia
Ib
Ic
À 30
À 30
À 30
À 30
À 30
À 30
À 30
À 30
À 30
À 40
À 50
À 50
À 50
trace
95
92
89
92
90
91
90
91
87
85
85
80
–
48
55
60
65
71
70
80
76
82
85
88
92
[12]
catalyst Ia,
derived from a cinchona alkaloid,
Id
affording desired product 3aa in excellent yield (95%)
with moderate enantioselectivity (48% ee) (Table 1,
entry 2). Changing the phase-transfer catalyst counter
IIa
IIb
IIc
IId
IIc
IIc
IIc
IIc
À
À
ion from Br (Ia) to Cl (Ib) increased the enantiose-
lectivity from 48% to 55% ee (entries 2 vs. 1). Based
on the structure of catalyst Ib, replacing the MeO
group at the 6-position with either Ph (Ic) or naphthyl
1
0
1
1
1
2
d
e
(Id) groups improved the enantioselectivity, achieving 13
up to 65% ee (entries 4 and 5). To investigate the
influence of substituent electronic effects and steric
hindrance, the benzyl group in the ammonium part of
the catalyst was exchanged for a 3,5-di-tert-butyl-2,6-
dimethoxybenzyl group (IIa). Good stereocontrol
performance was observed as a result of the increased
steric hindrance, affording a higher enantioselectivity
of 71% ee (entry 6). Increasing the steric hindrance by
changing the benzyl group to a 3,5-di-tert-butyl-2,6-
[a]
Unless otherwise specified, the reaction was conducted with
a (0.22 mmol), 2a (0.2 mmol), Cs CO (1.5 equiv.), cat.
1
2
3
(
10 mol%), and solvent (1.5 mL).
[b]
[c]
Isolated yield.
Determined by HPLC analysis.
[
d]
e]
2
b was used.
[
2c was used.
1
t
diethoxybenzyl group (IIc) resulted in the best ing the R moiety from Me (2a) to Et (2b) and Bu
enantioselectivity obtained, at 80% ee (entry 8).
(2c). Improved enantioselectivity was observed with
1
Other catalysts were also investigated (See support- increasing steric hindrance at R , with an 80% yield
ing information (SI)), but no improvements were and 92% ee obtained when di-tert-butyl α-diazometh-
found. Using the best catalyst, the reaction conditions ylphosphonate (entries 12 and 13) was employed as the
were optimized. When the reaction temperature was nucleophile.
decreased from À 30 to À 50°C, the enantioselectivity
With optimal reaction conditions in hand, the
was improved from 80% to 85% ee (entries 8, 10, and substrate scope was examined, with the results shown
1). The effect of steric hindrance in the nucleophilic in Scheme 1. Generally, the reaction tolerated a wide
1
diazomethylphosphonates was investigated by chang- substrate scope. p-QMs with ortho-substituents on the
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ee (3sc and 3tc). When ethyl α-diazoacetate was
employed as nucleophile in the reaction, no desired
product was observed, the definite reason was not
clear.
To demonstrate potential applications of this meth-
odology in organic synthesis, the reaction of 1d and
2
c was performed on a larger scale (3 mmol),
proceeding smoothly to afford 3dc in 75% yield with
2% ee (Scheme 2). Treating 3dc with P(Bu) gave
9
3
corresponding hydrazone 4. Further protection of 4
with BzCl resulted in N-benzoylated hydrazone 6.
Reduction of 6 with NaBH4 led to substituted
hydrazine 7 in 85% yield and 91% ee. Cleavage of the
NÀ N bond in 7 with SmI generated chiral α-amino
2
[13]
phosphonate 8 (75% yield, 93% ee). These succes-
sive transformations showed no racemization, main-
taining high enantioselectivity (90% ee-93% ee). The
intramolecular cyclization of 4 mediated by CuI in the
presence NaOAc and N,N’-dimethylethylenediamine
(
5
DMEN) afforded chiral dihydrocinnoline phosphonate
[14]
.
Cinnoline derivatives have been employed in
agrochemical and pharmaceutical drugs as micro-
bicides, fungicides, herbicides, bactericides, antitumor
[15]
agents, and anti-inflammatory agents.
The absolute configuration of 3ac was determined
to be (R) by X-ray crystallographic analysis (Fig-
[a]
Scheme 1. Reaction scope.
phenyl ring afforded good yields (65%–85%) and
excellent enantioselectivities (90%–92% ee) (3bc–
3
ec). p-QMs with electron-withdrawing substituents
(3cc–3ec) gave lower yields than that with an
electron-donating substituent (3bc). p-QMs bearing
one or two meta- or para-substituents on the phenyl
ring were also suitable for this reaction (3fc–3nc).
However, when a strongly electron-withdrawing group
(
CF ) was present at the para-position of the p-QM
3
phenyl ring, the enantioselectivity decreased dramati-
cally, affording only 61% ee. Naphthyl-substituted p-
QM was also compatible with this protocol, giving
corresponding product 3pc in 78% yield with 85% ee.
p-QMs with heterocyclic substituents were also sur-
veyed. 3-Pyridinyl and thiophene-substituted p-QMs
furnished good yields (60%–75%) and enantioselectiv-
ities (73%–94% ee) (3qc and 3rc). Furthermore, 3-
indolyl and quinoline-derived p-QMs achieved good
yields and excellent enantioselectivities of up to 96%
Scheme 2. Gram-scale preparation of 3dc and further elabo-
ration.
[a]
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[16]
ure 2),
with other product configurations deduced using a phase-transfer catalyst. The resulting products
from this result.
Based on the experimental results and previous compounds or raw materials thereof, namely, a chiral
were transformed into potential biologically active
[6a–c,g,j]
reports,
we proposed a transition state model that dihydrocinnoline phosphonate and a chiral α-amino-
accounts for the stereocontrol outcome, as shown in phosphonate, bearing diarylmethine stereogenic cen-
Figure 3. The hydroxyl at the 9-position of the phase- ters.
transfer catalyst interacts with the oxygen of p-QM
through hydrogen bonding to activate it, and simulta-
neously interacts with the oxygen of diazophosphonate,
Experimental Section
bringing it close to the p-QM. The nucleophilic α- General Procedure for the Synthesis of Diarylmeth-
carbon of diazophosphonate then undergoes addition to ylated Diazophosphate 3
the p-QM at the δ-position from the Re-face. The
Chiral ammonium salts derived from cinchona alkaloids IIc
inorganic base, after exchange with the counter ion of
(
0.01 mmol), 1 (0.22 mmol), Cs CO (0.33 mmol) and anhy-
2 3
the phase-transfer catalyst to form complexation
through Coulombic interactions, concomitantly deprot-
onates the hydrogen of the α-carbon, assisting the
drous toluene (1.5 mL) were added to a dried reaction tube at
the nitrogen atmosphere, and the mixture was cooled to À 50°C.
Then the di-tert-butyl α-diazomethylphosphonate 2c
addition process and affording the phenolic anion (0.2 mmol) was added and stirred at À 50°C until the reaction
intermediate. This intermediate is then protonated to completion monitored by TLC. The reaction mixture was
give the 1,6-conjugate addition product.
directly purified on a silica gel chromatography column PE/EA
(
8/1 to 4/1) to give chiral functional diarylmethylated diazo-
In conclusion, we have disclosed a method for
accessing a series of chiral functionalized diarylmeth-
ylated diazomethylphosphonates with up to 85% yields
and 99% ee enantioselectivities through the asymmet-
ric 1,6-conjugate addition reaction of dialkyl
phosphate 3.
Acknowledgements
diazomethylphosphonates to para-quinone methides We are grateful for financial support from the National Science
Foundation of China (21472151), Natural Science Foundation
of Chongqing (cstc2019jcyj-msxmX0414), and Fundamental
Research
Funds
for
the
Central
Universities
(XDJK2019AA003).
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Enantioselective 1,6-Conjugate Addition of Dialkyl α-Diazo
Methylphosphonate to para-Quinone Methides
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Y. Chen, R. Yu, M. Wang, Y. Huang*, Y. Peng*