Syntheses of 3-oxo-λ5-benzophospholes by an intramolecular cyclization of phosphorus-ylide

Article abstract of DOI:10.1246/cl.170758

Three synthetic procedures have been developed for a new class of phosphorus ylide containing conjugate heterocycles, 3-oxo-λ⁵-benzophospholes. The key to the formation of the hetero-cycle is unusual intramolecular acylation of a phosphorus ylide forming an endocyclic ylide. Several types of 2-substituted benzophospholes are synthesized, some of which show fluorescence.

Full text of DOI:10.1246/cl.170758

Advance Publication Cover Page
5
Syntheses of 3-Oxo- -benzophospholes by an Intramolecular Cyclization of
Phosphorus-ylide
Minoru Hayashi,* Yasunobu Nishimura, and Yutaka Watanabe
Advance Publication on the web September 23, 2017
doi:10.1246/cl.170758
©
2017 The Chemical Society of Japan
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1
5
Syntheses of 3-Oxo-λ -benzophospholes by an Intramolecular Cyclization of Phosphorus-
ylide
Minoru Hayashi, * Yasunobu Nishimura, and Yutaka Watanabe
Department of Materials Science and Biotechnology, Graduate School of Science and Engineering,
Ehime University, 3 Bunkyo-cho, Matsuyama 790-8577, Japan
E-mail: mhayashi@ehime-u.ac.jp
1
2
3
4
5
6
7
Three synthetic procedures have developed for a new
O
O
O
class of phosphorus-ylide containing conjugate heterocycles,
5
3-oxo-λ -benzophospholes. The key to the heterocycle is
Lv
Lv
+
R
R
unusual intramolecular acylation of phosphorus-ylide
forming an endocyclic ylide. Several types of 2-substituted
benzophospholes are synthesized, some of which showed a
fluorescence.
P
X
P
R
P
(A)
(B)
(C)
3
3
3
2
3
4
Scheme 1. Intramolecular ylide-acylation approach.
8
9
Phosphorus-containing conjugate heterocycles have 35
To construct an oxophosphole ring (A), we planned to
recently received much attention due to their characteristic 36 apply an intramolecular acylation of
a
cis-β-
1
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0 properties. In the previous paper, we have reported a new
1 class of phospholes as symmetrical bis-phosphole 1 (Figure
2 1), containing carbonyl-stabilized phosphorus ylide in the
3 cycle. According to molecular orbital calculations at
4 B3LYP/6-31G(d) level, the ylide-containing phosphole 2 is
37 phosphinylacryloyl compound (B) having an ylide; a
3
38 leaving group (Lv) on the carbonyl carbon is essential. The
39 precursor (B) would be generated from the corresponding
40 phosphonium salt that would be prepared from a cis-
41 phosphanylacrylate (C) and haloalkane.
5 expected to show a characteristic property due to a narrow 42
Methyl ortho-phosphinylbenzoate was chosen as a
6 HOMO-LUMO gap and high lying HOMO, compared with
7 phosphole and phosphole oxide (Figure 2). However, no
8 general synthetic procedure for this type of ylide-containing
9 phospholes 2 is disclosed; the only existing compound
0 having this type of structure is bis-phosphole 1 despite
1 recent active research on several types of phospholes.
43 model substrate to test the plan without difficulties of
44 stereocontrolled synthesis of cis-β-phosphinylacrylates. In
5
45 addition, the resulted benz-annulated 3-oxo-λ -phosphole is
46 also an attractive derivative of 2 (Figure 2). Though only
47 limited examples have appeared for acylation of ylides with
4
-6
48 esters, we expected that the ylide fixed near the carbonyl
49 group would react with a methyl ester to form an endocyclic
2
Herein, we wish to report a new approach for
5
3 monocyclic benz-annulated 3-oxo-λ -phospholes by a new 50 ylide.
4 intramolecular acylation of phosphorus-ylide (Scheme 1).
51
5
As an initial attempt, methylphosphonium salt 3a was
7
2 reacted under usual ylide-generating conditions, followed
O
R
R
R'O C
CO R'
53 by heating for cyclization (Scheme 2).
2
P
2
O
O
P
R'O C
CO R'
2
2
R
OCH3
n-BuLi
R
O
CH3
2
2
5
6
5
2
CH3
Figure 1. Bis-3-oxo-l -phosphole 1.
THF
–78 to 50°C
P
PPh2
O
Ph Ph I-
2ꢀ
1ꢀ
0ꢀ
3a
5a
1
.39ꢀ
O
LUMO
-
-
-
-
-
-
-
-
1ꢀ
2ꢀ
3ꢀ
4ꢀ
5ꢀ
6ꢀ
7ꢀ
8ꢀ
-
0.97ꢀ
-1.12ꢀ
-0.97ꢀ
-5.09ꢀ
P
Ph
Ph
-
1.88ꢀ
E / eV
4
a
5
4
HOMO
-
5.04ꢀ
5
5
Scheme 2. An initial attempt of cyclization.
-
5.48ꢀ
-
6.08ꢀ
56
-6.64ꢀ
5
7
Unfortunately, 3-oxophosphole 4a was not isolated; 5a
O
O
5
8 was obtained instead after aqueous workup, where the
N
H
P
P
P
59 methyl group was actually transferred from the phosphorus
P
Me
O
Me Me
Me
Me Me 60 to the carbonyl carbon. It is reasonable to assume that 5a
2
2
2
2
3
3
7
8
9
0
1
6
6
6
1 was formed through 4a or an equivalent, and followed by
Figure 2. Comparison of the HOMO and LUMO energy levels
among pyrrole, phospholes and the ylide-containing phospholes
based on calculations at the B3LYP/6-31G(d) level.
8
2 hydrolysis resulted in a ring-opening. Actually, phenyl-
3 substituted 4b was isolated from 3b and nBuLi with
64 considerable amount of ring-opened side product 5b after
6
5 aqueous workup (Scheme 3). Survey of a base revealed that

2
9
1
2
3
4
5
6
7
8
9
LiH is the best suited for this ylide-cyclization. Use of an
O1
C7
excess amount of LiH is essential; the methoxide formed
during the initial cyclization may be insufficient to
deprotonate from the intermediate cyclic phosphonium salt
which is subsequently hydrolyzed to give the product 5a.
Since excess use of nBuLi causes unfavorable reaction with
an ester, less nucleophilic LiH is suitable for this cyclization.
C8
C1
P1
5
2-Aryl-3-oxo-λ -benzophospholes were obtained in fairly
good yields, regardless of the nature of the substituent
1
0 (Table 1).
O
2
5
n-BuLi / THF
78°C, 3 h,
1
1
OCH3
26
Figure 2. X-ray molecular structure of 4c. H atoms are
2
7
omitted for clarity. Thermal ellipsoids are drawn at the 30%
-
P
Ph
then rt, 1 h
28
29
30
31
probability level. Selected bond lengths [Å] and angles [°]: P-
C(1) 1.791(2), P-C(8) 1.741(2), C(7)-C(8) 1.431(3), C(7)-O
1.242(3), C(1)-P-C(8) 95.95(9), P- C(8)-C(7)-C(6) 5.7(2).
Ph Ph
Br–
3b
O
O
O
P
3
2
Next, we would prepare the salt from methyl ortho-
Ph
O–
Ph +
33 phosphinylbenzoate and BrCH CO Et at 120 °C.
2
2
P
PPh2
O
Ph
34 Surprisingly, cyclization proceeded during preparation of
35 the salt even in the absence of a base (Table 2, entry 1). The
36 yield was dramatically improved when the counter anion
Ph
Ph
Ph Ph
4
b (62%)
5b (34%)
6b
1
1
1
1
1
1
2
3
–
–
3
7 was changed from Br to Cl (entry 2). Heating at 120 °C in
8 halides or in xylenes is required for the preferential
Scheme 3. Formation of 4b by using n-BuLi.
3
4
5
Table 1. Synthesis of 2-Aryl-3-oxobenzophosphole (method
39 cyclization over other side reactions like a nucleophilic de-
40 methylation. Addition of a base is effective for milder
a
A).
O
2 2 3
41 conditions (entry 3). ClCH CN and ClCH COCH also
O
LiH
4
2 gave the corresponding oxobenzophospholes in good yields
(
3.0 equiv.)
OCH3
R
R
43 (entries 4-6). The vicinity of the ylide and the ester is
44 essential for this non-basic cyclization; aliphatic
THF
P
P
50°C
Ph
Ph
Ph Ph
Br–
4
2 2 2 2
5 phosphanylester, Ph PCH CH CO Et, did not give the
3
4
46 cyclic ylide in ClCH CN; only the corresponding
1
6
2
b
Entry
R
Ph
Time (h)
Product
4b
4c
4d
4e
4f
4g
4h
4i
Yield (%)
47 phosphonium salt was formed even under the elevated
48 temperature.
4
c
1
2
3
4
5
6
7
8
19
3.5
12
5.5
8
74
p-CNC
m-CNC
6
H
4
83
60
60
78
52
9
0
6
H
4
a
5
Table 2. Non-basic synthesis of 4 (method B).
p-MeOC
6
H
4
O
O
m-MeOC
o-MeOC
p-tBuC
2-Pyridyl
6
H
4
CO CH3
2
6
H
4
6
5
X
Z
OCH3
Z
c
Z
6
H
4
72
d
PPh2
120 °C
P
24
82
P
Ph
Ph Ph
X–
Ph
4j-l
1
1
1
2
2
2
2
2
7
8
9
0
1
a) 3 prepared in situ was used without purification. b) Isolated yields.
2
3
1
10
3j-l
c) NMR yield determined by P NMR. d) Hydrobromide was used 51
with 4.0 equiv. of LiH.
Entry
X
Z
Conditions
Product Yield
b
(%)
c
1
2
3
4
5
6
7
Br CO
2
2
2
Et
Et
Et
120°C, 4.5 h
120°C, 2.5 h
4j
4j
4j
4k
4l
7
Recrystallization of 4c from EtOAc/n-Hexane gave a
2 single crystal suitable for X-ray diffraction study (Figure
3 2). The oxophosphole ring in 4c is quite similar to that of
c
c
Cl
Cl
Cl
Cl
Cl
Cl
CO
CO
C(O)CH
CN
CN
Ph
78
78
70
d
11
80°C, 2 h
120°C, 3.5 h
120°C, 2 h
2
3
4 1.
100
80
e
120°C, 1 h
4l
4b
f
120°C, 6 h
-
5
5
5
5
5
5
5
5
2
3
4
5
6
7
8
a) A halide (XCH
2
Z) was used as a solvent. b) Isolated yields. c)
3
1
10
NMR yield determined by P NMR.
2 3
d) K CO (2.0 equiv.) was
added as a base. e) Xylenes were used as a solvent. Chloroacetonitrile
(3 equiv.) was used as a halide. f) Benzylphosphonium benzoate 6b
was isolated instead of 4b.
On the contrary, methyl ortho-phosphinylbenzoate in
9 benzyl chloride did not afford 4b under the same conditions

3
1
2
3
4
5
6
7
8
9
(entry 7), probably due to low acidity of α-proton to 30
generate the ylide on heating. Indeed, heating at more 31
In conclusion, we have developed three synthetic
32 methods for 3-oxo-λ -benzophospholes, some of which
1
1
2
3
5
elevated temperature in vacuo was found to be effective.
It is very curious that bromide is suitable in this case.
33 showed a fluorescence property. Since this approach starts
Several substrates with aryl, heteroaryl, and alkenyl
34 from two parts of the phosphole ring, the present methods
5
substituents are successfully converted to the corresponding 35 opened the route toward wide variety of 3-oxo-λ -
3-oxobenzophospholes in good yields (Table 3). The results
are comparable to those of method A, except the case of p-
anisyl substrate (entry 5), where the electron-donating
36 benzophospholes with tunable functionality. In addition, the
37 stable ylidic structure of 4 allows alkylation and acylation of
38 the carboxyl oxygen to form the phosphole-type structure
39 with phosphonium salt and further structural conversion
40 could be available. The further conversions are now under
41 investigation.
1
1
1
1
0 nature of the substituent inhibited the salt from generating
1 the ylide at that temperature.
2
3
a
Table 3. Non-basic cyclization in vacuo (method C).
42
O
43
Supporting
Information
is
available
on
O
4
4 http://dx.doi.org/10.1246/cl.******.
in vacuo
OCH3
R
45
46
1
90°C, 4.5 h
P
P
R
ACKNOWLEDGMENT
This work was partly
Ph
Ph Ph
Br–
Ph
47 supported by Grant-in-Aid for Scientific Research (C)
48 (20550046) and Ehime University COE incubation program.
49 We also thank Advanced Research Support Center
3
4
1
4
b
Entry
R
Ph
Product
4b
4m
4c
4d
4e
4n
4h
4i
4o
Yield (%)
51 (80)
with LiH
74
-
83
60
60
-
60
82
-
c
1
2
3
4
5
6
7
8
9
5
5
5
5
0 (ADRES), Ehime University for the measurements of NMR
2-Naphthyl
p-CNC
m-CNC
81
90
80
16
1 spectra and X-ray crystallographical analyses.
6
H
4
2
3
6
H
4
Dedicated to the late Professor Yoshihiko Ito on the
th
p-MeOC
6
H
4
c
p-BrC
p-tBuC
2-Pyridyl
β-(E)-Styryl
p-CN-(E)-Styryl
6
H
4
57 (80)
54 occation of the 10 anniversary of his sudden death.
6
H
4
72
54
53
72
55
d
56 References and Notes
1
0
4p
-
5
7
1
Selected recent papers for the synthesis and application of
phospholes, a) T. Chatterjee, V. S. Shetti, R. Sharma, M.
Ravikanth, Chem. Rev. 2017, 117, 3254-3328. b) M. P. Duffy,
W. Delaunay, P.-A. Bouit, M. Hissler, Chem. Soc. Rev. 2016,
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Higashiyama, S. Yamaguchi, J. Am. Chem. Soc. 2017, 139,
1
1
1
1
1
2
2
2
2
2
2
2
2
2
5
6
7
8
9
a) 3 was prepared in toluene and was used without purification after
5
8
removal of the solvent. b) Isolated Yields. c) NMR yield determined 59
3
1
10
6
6
6
6
6
0
1
2
3
4
by P NMR was shown in parantheses. d) Hydrobromide was used.
On the contrary to the previous bis-phosphole 1 (λmax =
10374-10381.
Organometallics 2017, 36, 2637-2645.
d) N. Yoshikai, M. Santra, B. Wu,
e) Y. Unoh, Y.
0 680 nm), the benzophospholes 4 prepared here have
1 absorbtion in shorter wavelength range (Table 4). 65
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D. Szieberth, C. Lescop, L. Nyulaszi, M. Hissler, R. Reau, J.
5
2 Preliminary
results
of
the
obtained
3-oxo-λ - 66
6
6
6
7
7
8
9
0
3 benzophospholes revealed that some of the products showed
4 a faint fluorescence both in solution (Table 4) and solid
5 phase. Unfortunately, the fluorescence was weak and its Φ
6 was measured as 0.03 (4l).
F
71
7
8
72
a
7
7
7
3
4
5
Table 4. UV-Vis and fluorescence data of 4.
4
R
λmax
nm)
ε
λmax
3
-1
-1
(
(x10 cm M
12
)
(FL, nm)
b
76
77
78
79
80
81
82
83
84
85
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
Ph
p-CNC
m-CNC
p-MeOC
m-MeOC
o-MeOC
p-tBuC
2-Pyridyl
CO Et
C(O)CH
CN
2-Naphthyl
p-BrC
345
360
342
343
345
350
346
-
-
-
-
-
-
-
-
b
6
H
4
21
11
b
6
H
4
b
6
H
4
4.8
9.5
9.8
8.0
12
b
6
H
4
b
6
H
4
b
6
H
4
b
342 c
d
2
338 , 300 6.3 (301)
452
450
c
d
3
344 , 306 5.7 (301)
8
8
8
8
9
9
6
7
8
9
0
1
Am. Chem. Soc. 2012, 134, 6524-6527.
r) Y. Ren, T.
c
d
346 , 301 5.1 (301)
465
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b
361
345
377
408
15
12
15
25
-
-
-
-
b
6
H
4
b
β-(E)-Styryl
p-CN-(E)-Styryl
b
2
9
a) CHCl
3
solution. b) No fluorescence was observed. c) λirr = 333 nm.
92
9
3

4
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
4
Sato, L. Ilies, Y. Itoh, Y. Sato, E. Nakamura, Org. Lett. 2008, 28
10, 2263-2265. w) T. Sanji, K. Shiraishi, T. Kashiwabara, M. 29
Tanaka, Org. Lett. 2008, 10, 2689-2692. x) A. Fukazawa, M. 30
Hara, T. Okamoto, E.-C. Son, C. Xu, K.Tamao, S. Yamaguchi, 31
Org. Lett. 2008, 10, 913-916. y) Fukazawa, A.; Yamada, H.; 32
Yamaguchi, S., Angew. Chem. Int. Ed. 2008, 47, 1-5. z) Dienes, 33
Y.; Englert, U.; Baumgartner, T., Z. Anorg. Allg. Chem. 2009, 34
Cooke, P., J. Org. Chem. 1973, 38, 4082-4084.
9
Details of survey of a base are found in SI. 4a could not be
isolated even when LiH (3 equiv.) was used instead of nBuLi in
Scheme 2; 5a was formed as a main product instead.
10 Some of the products were difficult to separate from the
phosphane oxide of the starting phosphine by a column
chromatography.
635, 238-244.
Nishimura, Y.; Kawamura, Y.; Watanabe, Y.; Hayashi, M. J. 36
Org. Chem. 2010, 75, 3875-3877.
Johnson, A. W., In Ylid Chemistry, Academic Press: New York 38
1966 pp45-48, pp102-104.
Reaction with methylenephosphorane; see, Wittig, G.; 40
Schollkopf, U., Chem. Ber. 1954, 87, 1318.
Intramolecular ylide-ester cyclization to form exocyclic ylides; 42
see, House, H. O.; Babad, H., J. Org. Chem. 1963, 28, 90-92.
35
37
39
41
43
11 Crystal data: 4c: C27
group P2 /n (No.14); a = 13.299(5), b = 11.774(5), c =
13.454(5); b = 96.221(6); V = 2094.3(14) Å ; Z = 4; m(MoKa) =
H18NOP; M = 403.39; monoclinic; space
2
3
4
5
6
1
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
5
-
1
0.150 mm ; T = 288 K; 9932 reflections collected; Rint
=
2
0.0251; R(F) = 0.0525 for 3598 data with I > 2s(I), wR(F ) =
0.1308 for all 4738 independent data. CCDC-759534 contains
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic
Date
Centre
via
Reaction with reactive esters; see, a) Trippett, S.; Walker, D. 44
M., J. Chem. Soc. 1961, 1266-1272; b) Subramanyam, V.; 45
Silver, E. H.; Soloway, A. H., J. Org. Chem. 1976, 41, 1272- 46
12731; c) Uijttewaal, A. P.; Jonkers, F. L.; van der Gen, A., J. 47
Org. Chem. 1978, 43, 3306-3311; d) Uijttewaal, A. P.; Jonkers, 48
F. L.; van der Gen, A., J. Org. Chem. 1979, 44, 3157-3168; e) 49
Bégué, J.-P.; Bonnet-Delpon, D.; Mesureur, D.; Née, G.; Wu, S. 50
www.ccdc.cam.ac.uk/data_request/cif.
12 In vacuo condition (ca 0.1 to 1 mmHg using a rotary oil pump)
is necessary because the formed HBr and MeOH should be
removed to complete the ylide formation under equilibrium.
2
Heating under N at 190°C gave ring-opened 5b exclusively
after aqueous workup, probably because the intermediate cyclic
phosphonium salt was not converted to 4b without removal of
HBr.
–W., J. Org. Chem. 1992, 57, 3807-3814.
51
7
8
Vedejs, E.; Meier, G. P.; Snoble, K. A. J., J. Am. Chem. Soc. 52
13 3b·Cl gave the expected oxophosphole in 19% at 190°C; the
main product was phosphonium benzoate 6b.
1981, 103, 2823-2831.
53
This type of degradation of a phosphorane is known; see,