Tandem nucleophilic addition/oxa-Michael reaction of ortho-formyl chalcones with dimethyl (diazomethyl)phosphonate for the synthesis of phosphine-containing 1,3-disubstituted phthalans

Article abstract of DOI:10.1016/j.tetlet.2020.152174

A novel base-promoted tandem reaction between ortho-formyl chalcones and dimethyl (diazomethyl)phosphonate has been discovered for the construction of a series of phosphine-containing 1,3-disubstituted phthalans with up to 99percent yields. This reaction was amenable to scale up to 1 mmol with 90percent yield. The alkyne, which was well-known as the product of Seyferth-Gilbert reagent with aldehyde, was not detected in this reaction.

Full text of DOI:10.1016/j.tetlet.2020.152174

Journal Pre-proofs
Tandem nucleophilic addition/oxa-Michael reaction of ortho-formyl chal‐
cones with dimethyl (diazomethyl)phosphonate for the synthesis of phos‐
phine-containing 1,3-disubstituted phthalans
Ximeng Wei, Guihua Chen, Yungui Peng
PII:
S0040-4039(20)30634-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152174
TETL 152174
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 January 2020
20 June 2020
23 June 2020
Please cite this article as: Wei, X., Chen, G., Peng, Y., Tandem nucleophilic addition/oxa-Michael reaction of
ortho-formyl chalcones with dimethyl (diazomethyl)phosphonate for the synthesis of phosphine-containing 1,3-
disubstituted phthalans, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152174
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Tandem nucleophilic addition/oxa-Michael reaction of
ortho-formyl chalcones with dimethyl
(diazomethyl)phosphonate for the synthesis of
phosphine-containing 1,3-disubstituted phthalans
Ximeng Wei, Guihua Chen,* Yungui Peng*
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, P. R. China
E-mail: pengyungui@hotmail.com (Y. Peng)
chgh603@swu.edu.cn (G. Chen)
Abstract: A novel base-promoted tandem reaction between ortho-formyl chalcones and dimethyl
(diazomethyl)phosphonate has been discovered for the construction of
a series of
phosphine-containing 1,3-disubstituted phthalans with up to 99% yields. This reaction was
amenable to scale up to 1 mmol with 90% yield. The alkyne, which was well-known as the
product of Seyferth-Gilbert reagent with aldehyde, was not detected in this reaction.
Key words: tandem reaction; ortho-formyl chalcones; dimethyl (diazomethyl)phosphonate;
phosphine-containing 1,3-disubstituted phthalans
1. Introduction
Seyferth-Gilbert1 homologation is the base promoted reaction of dimethyl
(diazomethyl)phosphonate2 with aldehydes and aryl ketones at low temperatures, which provides
an efficient method for the synthesis of alkynes. It is presumed that the mechanism of
Seyferth-Gilbert homologation involves the initial formation of intermediate II under strong bases
as shown in Scheme 1. Nucleophilic attack of intermediate II to aldehydes furnishes intermediate
III which undergoes cyclization to give intermediate IV. Intermediate IV undergoes elimination
of dimethyl phosphate and loss of nitrogen, leading to alkylidenecarbene VI which spontaneously
rearranges into the alkyne VII.
Scheme 1. Base-catalyzed Seyferth-Gilbert homologation
1

Seyferth-Gilbert homologation
O
O
O
P
O
O
P
O
P
MeO
MeO
H
R
OtBu
R
H
P
H
O
MeO
MeO
MeO
MeO
MeO
MeO
N2
II
N2
III
N2
I
N2
R
IV
-(OMe)2PO2
H
H
R
-N2
C
H
R
N2
C
R
VII
VI
V
This Work
O
O
O
O
O
O
O
O
O
(MeO)2P
(MeO)2P
(MeO)2P
N2
N2
N2
III
VIII
The Ohira3−Bestmann4 modification of the original Seyferth–Gilbert homologation employs
dimethyl 1-diazo-2-oxopropylphosphonate (the Bestmann–Ohira reagent) and a weak base at
ambient temperature to generate the same reactive specie (intermediate II) in situ, which can
subsequently react with aldehydes to give alkynes. Although many modifications have been
reported,5-8 dimethyl (diazomethyl)phosphonate anion (intermediate II) is always a crucial and
indispensable intermediate. Dimethyl (diazomethyl)phosphonate (Seyferth-Gilbert reagent) has
been proven to be an efficient and popular reagent for transforming aldehydes and aryl ketones
into alkynes through the Seyferth-Gilbert homologation. Considering our previous research
employing Seyferth-Gilbert reagent as C-nucleophiles,9 we conceived that if a suitable
intramolecular electrophile acceptor is located at proper position, the formed intermediate III
could undergo an electrophilic attack, avoiding formation of intermediate IV which can easily be
transformed into alkynes. Moreover, when ortho-formyl chalcone is used as a substrate,
phosphine-containing phthalan VIII could be obtained. Phthalans are frequently found in drug
molecules and natural products having fascinating pharmacological activities such as
antidepressive,10 antioxidant,11 antifungal,11, 12 antitumor,13 antihistaminic activity14 and anti-HIV
activity.15 Some representative phthalans are shown in Figure 1. Furthermore,
phosphine-containing heterocycle compounds have displayed broad application in medicinal
chemistry16 and material science17. The phosphine-containing phthalans which are composed of
dimethyl phosphonate and phthalans would have potential biological activities.
2

O
P
O
O
S
S
O
O
H3C
tBu
tBu
NMe2
O
O
O
OH
O
O
OH
HO
N
NH
antioxidant, antifungal activity
antihistaminic activity
anti-HIV activity
O
Figure 1. Selected representative bioactive molecules containing a phthalan motif.
However, to the best of our knowledge, only one example of preparing non-alkynes via the
reaction of dimethyl (diazomethyl)phosphonate with ketones has been reported until now. Quite
active ketones were chosen as substrates, and strong bases which are the key to Seyferth-Gilbert
homologation were not used in this example.9c What’s more, utilizing dimethyl
(diazomethyl)phosphonate as a reagent for the transformation of aldehydes into non-alkynes has
not been realized at present. Although some research on the tandem reaction of ortho-formyl
chalcones with strong nucleophiles for the synthesis of phthalans have been reported,18 such a
novel tandem reaction of ortho-formyl chalcones with weakly nucleophilic dimethyl
(diazomethyl)phosphonate catalyzed by base has not been reported yet, and it still remains a
meaningful but challenging research project because of Seyferth-Gilbert homologation.
Herein, we report a novel tandem nucleophilic addition/oxa-Michael reaction of ortho-formyl
chalcones and dimethyl (diazomethyl)phosphonate for the synthesis of phosphine-containing
1,3-disubstituted phthalans.
2. Results and discussions
We started our investigation with ortho-formyl chalcone 1a and dimethyl
(diazomethyl)phosphonate 2a as substrates and examined the reaction parameters to identify
optimal conditions. When a mixture of ortho-formyl chalcone 1a (1.0 equiv.), dimethyl
(diazomethyl)phosphonate 2a (1.2 equiv.) and Cs2CO3 (0.1 equiv.) in toluene was stirred for 10 h
o
at -20 C, product 3a was isolated in 27% yield and 57:43 dr (Table 1, entry 1). The major
diastereoisomer can be isolated and the cis-stereochemistry was determined by NOESY NMR
analysis (see Supporting Information). The controlling reaction indicated that base was
indispensable for this tandem reaction (Table 1, entry 2). The effect of both inorganic and organic
bases on the reaction was then examined. The change of Cs2CO3 to K3PO4 slightly improved the
yield of 3a (Table 1, entry 3). Organic bases were also examined in this reaction (Table 1, entries
3

4-10). Although no reaction was observed when NEt3 or TMEDA was used, the use of DBU gave
the desired product in 92% yield and 70:30 dr (Table 1, entry 7). Subsequently, solvents screening
indicated that DCE (1,2-dichloroethane) was the best solvent, product 3a could be obtained in
94% yield and 61:39 dr (Table 1, entries 11-17). Finally, when the reaction temperature was
decreased to -30 oC, the yield of the product was further improved to 98% while by-products were
obviously decreased (Table 1, entry 18). Thus, on the basis of those screenings, the optimal
reaction conditions were established as ortho-formyl chalcones (0.1 mmol, 1.0 equiv.), dimethyl
(diazomethyl)phosphonate (0.12 mmol, 1.2 equiv.) and DBU (0.01 mmol, 0.1 equiv.) in DCE (1
ml, 0.1 M) at -30 oC.
Table 1. Optimization of reaction conditions a
O
O
O
Ph
H
P(OMe)2
Ph
base
solvent, -20 oC
O
+
O
N2
H
P(OMe)2
H
N2
3a
O
2a
1a
entry
base
solvent
yield(%)b
dr(3a)c
1
2
CS2CO3
-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Xylene
Et2O
40
NR
44
34
NR
NR
92
78
68
89
92
73
71
15
89
92
94
98
57:43
-
3
K3PO4
tBuOK
NEt3
60:40
62:38
-
4
5
6
TMEDA
DBU
DBN
TBD
-
7
70:30
70:30
64:36
62:38
69:31
62:38
64:36
50:50
63:37
61:39
61:39
61:39
8
9
10
11
12
13
14
15
16
17
18d
TMG
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
THF
CH3OH
CH3CN
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
a Unless otherwise noted, reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), base (0.01 mmol), solvent (1.0 mL),
4

at -20 oC for 10 h. b Isolated yield of the diastereomeric mixture. c Determined by 1H NMR spectrum of the crude
reaction mixture. d The reaction was carried out at -30 oC.
With the optimized reaction conditions in hand, the scope and limitation of this tandem
reaction was then explored (Table 2). The electron-donating groups on the terminal aryl moiety,
such as p-Me (3b), p-OMe (3c), as well as halogen groups p-F (3d), p-Cl (3e), p-Br (3f), were
well-tolerated to furnish the desired products with excellent yields (88-99%). However, the
electron-withdrawing groups on the terminal aryl moiety resulted in a decrease in yields (3g-3j).
Especially, with a strong electron-withdrawing group p-NO2, the corresponding product was
obtained only in 56% yield (3i). This could presumably be because the activities of those
substituents are so high that a large number of side products were produced, although
electron-withdrawing substituents made oxa-Michael reaction work easier. Many side products
were obviously detected by TLC in the reactions when p-CN (3g), p-CF3 (3h) and p-NO2 (3i) were
tested. The electronic nature on the terminal aryl moiety has a great influence on products yields,
and the excessively high activity is detrimental to yield. Electron-withdrawing groups at ortho
position and meta position of the terminal aryl moiety provided the corresponding products in 94
and 76% yield, respectively (3k, 3m). Irrespective of the position of the substitution, such as p-Cl
(3e), m-Cl (3l), 3,4-di-Cl (3n), and 2,4-di-OMe (3o), the reaction worked well and led to
corresponding products with 84-95% yields.
The reaction also proceeded smoothly with heteroaryls (thiophenyl (3q), furyl (3r)), naphthyl
(3n), or aliphatic (3u) ketones. It should be noted that only trace of desired product was obtained
under standard conditions when ester (3v) was used as Michael acceptor. However, the
corresponding product was isolated in reasonable yield (72%) when 0.05 mmol DBU was used.
Furthermore, to expand the substrate scope, the substitutions on the central aryl moiety were also
tested, both electron-donating(3t) or electron-withdrawing group (3s) were well-tolerated to give
the desired products with good yields. The dr of products obtained above was all between 2: 1 and
1: 1. The experimental results showed that the large steric hindrance of the base and the low
activity of the substrate are beneficial to the diastereoselectivity.
Table 2. Substrate scope of the tandem reaction a
5

O
O
O
R2
H
DBU (10 mol %)
DCE, -30 oC
R2
P(OMe)2
R1
R1
O
O
N2
H
P(OMe)2
O
H
N2
1
2
3
O
3a
: R = H, 98% yield, 1.5:1 dr
3f
: R = Br, 88% yield,1.4:1 dr
3b
3c
3d
: R = Me, 99% yield, 1.7:1 dr
: R = OMe, 97% yield,1.5:1 dr
: R = Cl, 91% yield, 1.5:1 dr
: R = F, 92% yield, 1.6:1 dr
3g
3h
3i
3j
: R = CN, 72% yield, 1.4:1dr
: R = CF3, 82% yield, 1.4:1 dr
: R = NO2, 56% yield, 1.2:1 dr
: R = Ph, 84% yield, 1.3:1 dr
O
R
P(OMe)2 3e
N2
O
O
O
O
NO2
NO2
Cl
O
O
O
P(OMe)2
O
P(OMe)2
O
P(OMe)2
N2
N2
N2
O
3k
3n
3q
: 94% yield, 1.5:1 dr
3l
3m
3p
3s
: 95% yield, 1.4:1 dr
: 76% yield, 1.4:1 dr
O
O
O
Cl
O
O
O
O
Cl
P(OMe)2
O
P(OMe)2
P(OMe)2
N2
N2
N2
O
O
O
: 86% yield, 1.4:1 dr
: 89% yield, 1.5:1 dr
3o
: 84% yield, 1.9:1 dr
O
O
O
S
O
Ph
O
O
O
F
P(OMe)2
P(OMe)2
P(OMe)2
N2
N2
N2
O
O
O
: 86% yield, 1.8:1 dr
: 81% yield, 1.5:1 dr
3r
: 95% yield, 1.5:1 dr
O
O
O
O
O
Ph
O
O
P(OMe)2
P(OMe)2
P(OMe)2
N2
O
N2
O
N2
O
b
3t
: 98% yield, 1.7:1 dr
3u
: 94% yield, 2.0:1dr
3v 72
:
% , 1.7:1 dr
a Unless otherwise noted, reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), DBU (0.01 mmol), DCE (1.0 mL),
o
1
at -30 C for 10 h. Isolated yield of the diastereomeric mixture. Dr was determined by H NMR spectroscopy of
the crude reaction mixture. b 0.05 mmol DBU was used for 40 h.
For practical utility, a scale up reaction with 1a was also performed on 1.0 mmol scale,
providing 3a in 90% yield and 1.5:1 dr (Scheme 2).
Scheme 2. Scale up reaction
6

O
O
O
Ph
H
P(OMe)2 DBU (10 mol %)
Ph
O
+
DCE, -30 oC
O
N2
H
P(OMe)2
O
H
N2
1a
2a
(1 mmol)
(1.2 mmol)
3a (
90% yield; 1.5:1 dr)
In order to further demonstrate the utility of the synthetic approach presented herein and of
the resulting phosphine-containing 1,3-disubstituted phthalans, the derivatization of product 3a
was performed as shown in Scheme 3. Treatment of 3a with Oxone gave the hemiacetal 4 with
71% yield and 1.1:1 dr. When 3a was treated with m-CPBA in CH2Cl2, the phthalide 5 was
formed in 53% yield.
Scheme 3. Synthetic Utility of the Product 3a
O
O
O
Ph
Ph
Ph
H
H
H
Oxone, NaHCO3
m-CPBA (5 eq.)
CH2Cl2, rt
O
O
O
toluene/H2O/acetone
H
OH
H
0 o
C
O
P(OMe)2
O
N2
3a
1.5:1 dr
4
5
71% yield, 1.1:1 dr
53% yield
3. Conclusions
In conclusion, we have developed a novel tandem nucleophilic addition/oxa-Michael reaction
of ortho-formyl chalcones with dimethyl (diazomethyl)phosphonate under the same reaction
conditions as Seyferth-Gilbert homologation, which provided an effective tool to prepare
phosphine-containing 1,3-disubstituted phthalans with high functional group tolerance in excellent
yields. A shortcoming of this method is that diastereoselectivity is not well controlled. Taking into
account the potential chemical and biological interest of phosphine-containing 1,3-disubstituted
phthalans, this method may eventually find application in the synthesis of bioactive products.
Further studies directed towards the enantioselective version of this reaction and the application of
the strategy to natural product synthesis is currently under investigation in our laboratory.
Acknowledgements
We thank the National Natural Science Foundation of China (No. No. 21472151 and 21502156),
Natural Science Foundation of Chongqing (No. cstc2019jcyj-msxmX0414) and Fundamental
Research Funds for the Central Universities (No. XDJK2019AA003) for financial support.
7

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Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
9

Highlights
 A
tandem
reaction
of
ortho-formyl
chalcones
with
dimethyl
(diazomethyl)phosphonate.
 Phosphine-containing 1,3-disubstituted phthalans were formed in excellent yields.
 Seyferth-Gilbert reagent was used for transforming aldehydes into non-alkynes.
 Seyferth-Gilbert homologation product was not detected.
Graphical Abstract
O
O
O
R2
H
P(OMe)2
R2
DBU (10 mol %)
DCE, -30 oC
R1
R1
O
O
N2
H
P(OMe)2
O
H
N2
R2 = aryl, heteroaryl,
alkyl, alkoxyl
22 examples
Up to 99% yield
Scale up to 1 mmol
10