A new access to 2-phosphonothiophenes

Article abstract of DOI:10.1016/j.tetlet.2014.01.018

2-Phosphonothiophenes are prepared via the reaction of β- chloroacroleins with diethyl mercaptomethylphosphonate.

Full text of DOI:10.1016/j.tetlet.2014.01.018

Accepted Manuscript
A new access to 2-phosphonothiophenes
Dariusz Cal
PII:
S0040-4039(14)00023-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.018
TETL 44049
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 October 2013
6 December 2013
6 January 2014
Please cite this article as: Cal, D., A new access to 2-phosphonothiophenes, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.01.018
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2
Graphical Abstract
Leave this area blank for abstract info.
A new access to 2-phosphonothiophenes
Dariusz Cal
O
R1
O
R1
NaH / THF
R1
R2
S
+
HS
P(OEt)2
R2
R2
Cl
P(OEt)2
P(OEt)2
S
O
O
O
R1 = Alk, Ar
R2 = Alk, Ar

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A new access to 2-phosphonothiophenes
Dariusz Cal
Department of Organic and Applied Chemistry, University of Łódź, Tamka 12, PL 91-403 Łódź, Poland, Tel.: +48 42 635 57 63; fax: +48 42 665 51 62; e-mail:
darekcal@uni.lodz.pl
ARTICLE INFO
ABSTRACT
Article history:
Received
2-Phosphonothiophenes are prepared via the reaction of -chloroacroleins with diethyl
mercaptomethylphosphonate.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
2-Phosphonothiophenes
Thiaheterocyclic phosphonates
-Chloroacroleins
3-Exo trig cyclization
Diethyl mercaptomethylphosphonate
The
reaction
of
-chloroacroleins
and
diethyl
mercaptomethylphosphonate was performed in THF as the
solvent and NaH as the base.17 In some cases, we managed to
isolate the aldehyde intermediate 2 (entries 3, 4 and 5). Attempts
to transform this intermediate into 3 by prolonged heating (entry
4) ended mainly with excessive decomposition. The cyclization
of aldehyde 2d (entry 6) was conducted under similar conditions
to those described for the reaction of compound 1d with methyl
mercaptoacetate,18 using EtOH as the solvent and EtONa as the
base. Thus, only the product of 3-exo trig cyclization 3d was
obtained, and in contrast to the nonphosphorylated variant,18 no
5-exo trig cyclization products were found. However, when -
chloroacrolein 1e was employed as the substrate (entry 7), two
products were obtained: 2-phosphonothiophene 3e and the
Heterocycles bearing a phosphonyl group have found a wide
range of applications in many research fields such as agricultural,
medicinal, and materials chemistry. As a representative class,
phosphonothiophenes are applied in medicine as potential
antibacterial agents,1 as antihypertensive agents, for asthma
treatment,2 as inhibitors of FBPase (inhibition of FBPase is
considered a promising way to reduce hepatic gluconeogenesis,
and therefore could be a potential approach to treat type 2
diabetes).3 In addition, they find various applications in materials
chemistry4 and as ligands for catalysis.5 Some synthetic
approaches to phosphonothiophenes have already been reported.6
The most commonly applied protocols include: the reaction of
thienyl halides with trialkyl phosphites (Arbuzov reaction),7 the
reaction -keto-phosphonates with active methylene nitriles and
subsequent treatment of the resulting phosphonoalkylidenes with
sulfur (Gewald reaction),8 the phosphonylation of metalated
thiophenes with dialkyl chlorophosphates,9 and a very recent
method based on a silver-catalyzed dehydrogenative cross-
coupling reaction of substituted thiophenes with dialkyl
phosphites.10
known
4,5,6,7-tetrahydrobenzo[b]thiophene
(5).19
The
phosphonothiophene 3e results from 3-exo trig cyclization, while
compound 5 is most likely formed by basic dephosphorylation20
of intermediate 4, which is itself the 5-exo trig cyclization
product (but is not separated and is unstable in the reaction
conditions) (Scheme 1).
The structure of phosphonothiophene 3a was confirmed by the
heteronuclear multiple bond correlation (HMBC) experiment, in
which the signal of the thiophene carbon atom C-2 correlates
with the signal of the methyl protons of the methyl group
attached to thiophene ring. In addition, the NOESY (nuclear
Overhauser effect spectroscopy) spectrum displays a correlation
between the protons of the methyl group attached to thiophene
ring and the methyl protons of the ethyl group. We observed that
the 13C NMR spectra of 3a-f exhibit four characteristic
phosphorus-carbon coupling constants for the carbons of the
thiophene ring: 209.5 ± 3.0 Hz, 6.3 ± 0.9 Hz, 17.0 ± 0.6 Hz and
11.5 ± 0.5 Hz, and based on the asigned structure of 3a (Table 2,
Considering the importance of heterocyclic phosphonates in
medicinal11 and coordination chemistry,12 we recently reported a
new strategy for the preparation of pyrazole-, thiazolidinone-,
pyrrole- and phthalazine-phosphonic acids.13 Herein,
a
convenient method for the synthesis of 2-phosphonothiophenes
from easily available (via the Vilsmeier reaction) -
chloroacroleins14 and diethyl mercaptomethylphosphonate15 is
reported.
The synthetic route to 2-phosphonothiophenes 3a-f is depicted
in Table 1.16
1
2
3
3
entry 1), they correspond to: JPC, JPCC, JPCCC, and JPCSC. The
NMR (HMQC and HMBC) analysis, in particular the observation
of typical coupling constants, and comparison with data obtained

2
Table 1
Synthesis of 2-phosphonothiophenes 3a-f
O
R1
R2
O
R1
NaH / THF
R1
R2
S
+
HS
P(OEt)2
R2
Cl
P(OEt)2
O
S
O
P(OEt)2
O
1
2
3
Entry
1
Aldehyde
Conditions
Product
Yielda (%)
41
O
NaH / THF, 4 h
3a
Ph
Me
1a
Cl
14a
(Z / E, 64 / 36)
2
3
O
NaH / THF, 38 h
NaH / THF, 4 h
3b
78
Ph
F3C
1b
Cl
14b
(Z / E, 60 / 40)
O
3c
32
19
Me
(E)-2c
Ph
1c
Cl
14c
(Z / E, 6 / 94)
4
5
1c
NaH / THF, 19 h
NaH / THF, 24 h
3c
33
8
(E)-2c
2d
Cl
92
6
O
3d
1d14d
6
7
2d
EtONa / EtOH, 14 h
NaH / THF, 19 h
3d
3e
5
60
49
24
O
Cl
1e14c
8
O
NaH / THF, 19 h
3f
68
Me
Et
1f
Cl
14c
(Z / E, 25 / 75)
a Isolated pure product.
2, entry 7),7a were useful tools for structural assignment of 2-
phonothiophenes 3b-f (Table 2, entries 2-6). For example, the
characteristic coupling constant P-CHarom for 3-exo trig cylization
product 3f , was 11.5 Hz instead of 6.3 ± 0.9 Hz, which would be
expected for hypothetical 5-exo trig cylization product 7 (Figure
1).
O
O
a
b
NaH / THF
+
HS
P(OEt)2
Cl
P(OEt)2
O
S
O
a
b
O
In conclusion, a simple and convenient process for the
preparation of 2-phosphonothiophenes from readily available
starting materials has been developed. In addition, we have
provided a simple method for determining the structures of 2-
phosphonothiophenes, based on the values of the 31P-13C
coupling constants.
P(OEt)2
O
P(OEt)2
O
S
S
4
O
Base
S
P(OEt)2
O
S
H
5
H
Me
Et
Me
Et
3JPCSC = 11.5 Hz
2JPCC = 6.7 + 1.3 Hz
S
S
P(OEt)2
S
P(OEt)2
P(OEt)2
O
O
O
3e
3f
7
Scheme 1. The formation of 3e by 3-exo trig cyclization
(path a), and 5 by 5-exo trig cyclization (path b).
Figure 1. Determination of the structure of 3f based on
measurement of the P – CHarom coupling constant.
for 3a and with an example in the literature (compound 6, Table

3
4. (a) Bair, J. S.; Harrison, G. R. J. Org. Chem. 2007, 72, 6653-
Table 2
6661; (b) Gerbier, P.; Guerin, C.; Henner, B.; Unal, J.-R.; J.
Mater. Chem. 1999, 9, 2559-2565; (c) Rueff, J.-M.; Perez, O.;
Pautrat, A.; Barrier, N.; Hix, G. B.; Hernot, S.; Couthon-Gourves,
H.; Jaffres, P.-A. Inorg. Chem. 2012, 51, 10251-10261; (d)
Hanson, E. L.; Schwartz, J.; Nickel, B.; Koch, N.; Danisman, M.
F. J. Am. Chem. Soc. 2003, 125, 16074-16080; (e) Ogawa, T.;
Usuki, N.; Ono, N. J. Chem. Soc., Perkin Trans. 1, 1998, 2953-
2958; (f). Advincula, R. C. Dalton Trans. 2006, 2778–2784; (g)
Edder, C.; Frechet, J. M. J. Org. Lett., 2003, 5, 1879-1882.
5. Monteforte, M.; Cauteruccio, S.; Maiorana, S.; Benincori, T.;
Forni, A.; Raimondi, L.; Graiff, C.; Tiripicchio, A.; Stephenson,
G. R.; Licandro, E.; Eur. J. Org. Chem. 2011, 5649-5658.
6. For a review, see: Ivonin, S. P.; Tolmachev, A. A.; Pinchuk, A. M.
Curr. Org. Chem. 2008, 12, 25-38; (b) Bansal, R. K.; Drabowicz,
J.; Enchev, D. D.; Gudat, D.; Gupta, N.; Heugebaert, T. S. A.;
Keglevich, G.; Krasowska, D.; Łopusinski, A.; Sasaki, S.;
Stevens, C. V. Phosphorus Heterocycles II, (Springer Berlin
Heidelberg 2010), Chap. 1, pp. 1-21.
Coupling constants (P – C) of the carbons of the
thiophene ring of 2-phosphonothiophenes 3a-f and 6.
Entry 2-Phosphonothiophene P - C coupling constant (in bold)
123.5 (d, 1JPC = 211.6 Hz, C-2)
143.1 (d, 2JPCC = 5.4 Hz, C-3)
140.2 (d, 3JPCCC = 16.4 Hz, C-4)
138.8 (d, 3JPCSC = 11.1 Hz, C-5)
130.5 (d, 1JPC = 206.5 Hz, C-2)
5
1
2
Ph
4
S 1
2
3a
3
Me
P(OEt)2
O
5
Ph
4
S 1
2
3b
132.2 (dq, 2JPCC = 7.2 Hz, 2JFCC
36.4 Hz, C-3)
=
3
F3C
P(OEt)2
144.9 (dq, 3JPCCC = 16.6 Hz, 3JFCCC
O
7. (a) Yao, Q.; Levchik, S. Tetrahedron Lett. 2006, 47, 277–281 (b)
Erker, T.; Handler, N. Synthesis 2004, 668-670.
8. Chebila, E.; Chamakhia, M.; Touil, S. J. Sulfur Chem. 2011, 32,
249-256.
9. (a) Graham, S. L.; Scholz, T. H. J. Org. Chem. 1991, 56, 4260-
4263; (b) Jones, P.; Bottomley, M. J.; Carfi, A.; Cecchetti, O.;
Ferrigno, F.; Lo Surdo, P.; Ontoria, J. M.; Rowley, M.; Scarpelli,
R.; Schultz-Fademrecht, C.; Steinkuhler, C. Bioorg. Med. Chem.
Lett. 2008, 18, 3456–3461.
10. Xiang, C.-B.; Bian, Y.-J.; Mao X.-R.; Huang, Z.-Z. J. Org. Chem.,
2012, 77, 7706-7710.
11. (a) Moonen, K.; Laureyn, I.; Stevens, Ch. Chem. Rev. 2004, 104,
6177-6215; (b) Elayadi, H.; Smietana, M.; Pannecouque, C.;
Leyssen, P.; Neyts, J.; Vasseur, J. J.; Lazrek, H. B. Bioorg. Med.
Chem. Lett. 2010, 20, 7365-7368.
12. (a) Brunet, E.; Juanes, O.; Jiménez, L.; Rodríguez-Ubis, J. C.
Tetrahedron Lett. 2009, 50, 5361-5363; (b) Villemin, E.; Elias, B.;
Robiette, R.; Robeyns, K.; Hernet, M.-F.; Habib-Jiwan, J.-L.;
Marchand-Brynaert, J. Tetrahedron Lett. 2011, 52, 5140-5144.
13. (a) Bartnik, R.; Cal, D. Phosphorus Sulfur Silicon Relat. Elem.
2010, 185, 1858-1861; (b) Cal, D. Phosphorus Sulfur Silicon
Relat. Elem. 2010, 185, 2233-2237; (c) Cal, D.; Zagórski, P.
Phosphorus Sulfur Silicon Relat. Elem. 2011, 186, 2295-2302; (d)
Cal, D. Tetrahedron Lett. 2012, 52, 3774-3776.
14. (a) Huet, F. Synthesis; 1985, 496-497; (b) Alvernhe, D.; Grief, D.;
Langlois, B.; Laurent, A.; Le Drean, I.; Pulst, M.; Selemi, A.;
Weissenfels, M. Bull. Soc. Chim. Fr. 1994, 131, 167-172 (c)
Gagan, J. M. F.; Lane, A. G.; Lloyd, D. J. Chem. Soc. C. 1970,
2484-2488; (d) La Frate, A. L.; Gunther, J. R.; Carlson, K. E.;
Katzenellenbogen, J. A. Bioorg. Med. Chem. 2008, 16; 10075-
10084.
= 2.1 Hz, C-4)
139.1 (d, 3JPCSC = 11.0 Hz, C-5)
125.0 (d, 1JPC = 210.3 Hz, C-2)
146.4 (d, 2JPCC = 6.6 Hz, C-3)
134.4 (d, 3JPCCC = 16.5 Hz, C-4)
140.3 (d, 3JPCSC = 11.0 Hz, C-5)
125.0 (d, 1JPC = 211.0 Hz, C-1)
146.4 (d, 2JPCC = 6.9 Hz, C-10b)
139.9 (d, 3JPCCC = 16.4 Hz, C-3a)
139.2 (d, 3JPCSC = 11.9 Hz, C-3)
123.2 (d, 1JPC = 211.3 Hz, C-1)
144.9 (d, 2JPCC = 6.5 Hz, C-7a)
136.7 (d, 3JPCCC = 17.5 Hz, C-3a)
138.26 (d, 3JPCSC = 11.2 Hz, C-3)
122.1 (d, 1JPC = 212.4 Hz, C-2)
150.0 (d, 2JPCC = 6.5 Hz, C-3)
133.7 (d, 3JPCCC = 17.2 Hz, C-4)
139.8 (d, 3JPCSC = 11.5 Hz, C-5)
125.9 (d, 1JPC = 218.15 Hz, C-2)
134.6 (d, 2JPCC = 8.0 Hz, C-3)
128.1 (d, 3JPCCC = 19.47 Hz, C-4)
138.3 (d, 3JPCSC = 13.06 Hz, C-5)
5
3
4
5
6
7
Me
Ph
4
S 1
3c
3
2
P(OEt)2
O
O
S2
(EtO)2P
1
3
10
10a
3a
3d
3e
10b
9
8
4
6a
5
6
7
4
3
3a
5
6
S 2
1
7a
7
P(OEt)2
O
5
Me
Et
4
S 1
2
3f
3
P(OEt)2
O
5
4
3
S 1
2
67a
15. Makomo, H.; Masson, S.; Saquet, M.; Tetrahedron 1994, 50,
10277-10288.
P(OPh)2
16. Reactions
mercaptomethylphosphonate: To a suspension of NaH (0.024 g,
1.0 mmol) in THF (5 mL) at
oC was added diethyl
of
-chloroacroleins
1a-f
with
diethyl
O
0
mercaptomethylphosphonate (0.184 g, 1.0 mmol) and the resultant
solution was stirred for 15 min. To the solution was added acrolein
1a-f (0.9 mmol) and the mixture was stirred at room temperature
under an argon atmosphere (time given in Table 1). In the case of
3b, an additional portion of NaH (0.015 g, 0.6 mmol) was added
after a period of 19 h and stirring was continued for an additional
19 h. The solution was poured into cold H2O (or brine in the case
of 3b) / Et2O mixture (1:4, v/v, 40 mL), the organic fraction was
collected, and the aqueous fraction was extracted with Et2O (2 x
30 mL).The combined organic fractions were dried (Na2SO4) and
filtered, and the solvent was removed in vacuo. The residue was
chromatographed on silica gel (Et2O, 100%) to afford 3a-f, 2c,d,
Acknowledgments
The author thanks M. Kucharska, K. Szadkowska and J.
Kaczyński from the University of Łódź for technical support.
References and notes
and
2-Diethoxyphosphoryl-3-methyl-4-phenylthiophene (3a): Yield:
5.19
1. Wiles, J. A. ; Phadke, A. S.; Bradbury, B. J.; Pucci, M.
J.;Thanassi, J. A.; Deshpande, M. J. Med. Chem. 2011, 54, 3418-
3425.
2. Esch, P.; Rovenszky, F.; Towart, R..; Christoph, T.; Hartman, M.;
Kealey, G. T. E. PCT Int. Appl. WO 00 34,287 2000; Chem.
Abstr. 2000, 133, 43508d.
3. Dang, Q.; Brown, B. S.; Liu, Y.; Rydzewski, R. M.; Robinson, E.
D.; van Poelje, P. D.; Reddy, M. R.; Erion, M. D. J. Med. Chem.
2009, 52, 2880-2898.
1
3
41%; yellow oil: H NMR (CDCl3, 600 MHz): δ = 1.36 (t, JHH
=
7.3 Hz, 6H, 2CH3), 2.54 (s, 3H, CH3), 4.10-4.22 (m, 4H, 2CH2O),
4
7.32-7.44 (m, 5H, C6H5), 7.59 (d, JPH = 8.6 Hz, 1H, CH); 13C
3
NMR (CDCl3, 151 MHz): δ = 14.5 (d, JPC = 2.0 Hz, CH3), 16.3
3
2
(d, JPC =7.7 Hz, 2CH3), 62.6 (d, JPC = 4.4 Hz, 2CH2), 123.5 (d,
1JPC= 211.6 Hz, C-2), 127.3 (CHarom), 128.5 (CHarom), 128.6
3
(CHarom), 135.5 (Carom), 138.8 (d, JPC = 11.1 Hz, C-5), 140.2 (d,
3JPC = 16.4 Hz, C-4), 143,1 (d, JPC = 5.4 Hz, C-3); 31P NMR
2
(CDCl3, 243 MHz): δ = 11.96; HRMS (CI) Calcd for C15H19O3PS:

4
3
310.0793.
Found:
310.0785
600 MHz) : δ = 1.32 (t, JHH = 7.1 Hz, 6H, 2CH3), 2.07 (s, 3H,
2
2-Diethoxyphosphoryl-4-phenyl-3-(trifluoromethyl)thiophene
CH3), 2.56 (d, JPH = 14.7 Hz, 2H, CH2), 4.08-4.13 (m, 4H,
2CH2O), 7.29-7.49 (m, 5H, C6H5), 9.18 (s, 1H, CHO); 13C NMR
(CDCl3, 151 MHz): δ = 12.6 (CH3), 16.4 (d, 3JPC = 5.5 Hz, 2CH3),
25.8 (d, JPC = 146.4 Hz, CH2P), 62.8 (d, JPC = 6.6 Hz, 2CH2O),
128.8 (CHarom), 129.3 (Carom), 129.5 ( CHarom), 130.3 (CHarom),
133.5 (C-2), 159.9 (C-3), 189.9 (C-1); 31P NMR (CDCl3, 243
MHz): δ = 21.97; HRMS (CI) Calcd for C15H21O4PS: 328.0898.
Found: 328.0898. The E configuration was confirmed by a
NOESY experiment in which a correlation between the aldehyde
(3b): Yield: 78%; yellow oil: 1H NMR (CDCl3, 600 MHz): δ =
3
1.38 (t, JHH = 7.2 Hz, 6H, 2CH3), 4.15-4.27 (m, 4H, 2CH2), 7.42
(s, 5H, C6H5), 7.58 (dq, 5JHF = 1.4 Hz, 4JPH = 8.2 Hz, 1H, CHarom.);
1
2
13C NMR (CDCl3, 151 MHz): δ = 16.3 (d, JPC = 6.6 Hz, 2CH3),
3
2
1
3
63.2 (d, JPC = 5.5 Hz, 2CH2), 122.0 (dq, JFC = 270.9 Hz, JPC
=
=
1
2.7 Hz, CF3), 128.5 (CHarom), 128.7 (CHarom), 130.5 (d, JPC
206.5 Hz, C-2.), 132.2 (dq, JFC = 36.4 Hz, JPC = 7.2 Hz, C-3),
2
2
3
3
133.4 (Carom), 139.1 (d, JPC = 11.0 Hz, C-5.), 144.9 (dq, JPC
=
3
16.6 Hz, JFC = 2.1 Hz, C-4); 31P NMR (CDCl3, 243 MHz): δ =
9.01; HRMS (CI) Calcd for C15H16F3O3PS: 364.0510. Found:
364.0515.
and
aromatic
protons
was
observed.
5-(Diethoxyphosphorylmethylsulfanyl)-8,9-dihydro-7H-
benzo[7]anulene-6-carbaldehyde (2d): Yield: 92%; yellow oil: 1H
NMR (CDCl3, 600 MHz): δ =1.29-1.39 (m, 6H, 2CH3), 2.11-2.16
(m, 2H, CH2), 2.18-2.27 (m, 2H, CH2) 2.61-2.71 (m, 4H, 2CH2),
4.05-4.22 (m, 4H, 2CH2O), 7.28-7.30 (m, 1H, CHarom), 7.34-7.39
(m, 2H, 2CHarom), 7.72-7.74 (m, 1H, CHarom), 10.53 (s, 1H, CHO);
2-Diethoxyphosphoryl-4-methyl-3-phenylthiophene (3c): Yield:
32%; yellow oil: H NMR (CDCl3, 600 MHz): δ = 1.39 (t, JHH
1
3
=
7.1 Hz, 6H, 2CH3), 2.35 (s, 3H, CH3), 4.14-4.25 (m, 4H, 2CH2O),
7.38-7.51 (m, 6H, CHarom); 13C NMR (CDCl3, 151 MHz) : δ = 14.7
3
2
3
(CH3), 16.3 (d, JPC = 6.7 Hz, 2CH3), 62.6 (d, JPC = 5.5 Hz,
13C NMR (CDCl3, 151 MHz): δ = 16.4 (d, JPC = 5.6 Hz, 2CH3),
1
1
2CH2O), 125.0 (d, JPC = 210.3 Hz, Carom), 128.1 (CHarom), 128.7
23.6 (C-7), 26.8 (d, JPC = 149.5 Hz, CH2P), 31.6 (C-9), 34.8 (C-
(CHarom), 129.0 (CHarom), 133.6 (d, 3JPC = 1.9 Hz, Carom), 134.4 (d,
3JPC = 16.5 Hz, C-4), 140.3 (d, 3JPC = 11.0 Hz, C-5), 146.4 (d, 2JPC
= 6.6 Hz, C-3); 31P NMR (CDCl3, 243 MHz): δ = 12.01; HRMS
(CI) Calcd for C15H19O3PS: 310.0793. Found: 310.0803.
8), 62.6 (d, 2JPC = 6.6 Hz, 2CH2O), 126.9 (C-2), 128.7 (C-4), 129.7
(C-1), 130.1 (C-3), 135.9 (C-4a), 142.9 (C-6), 143.4 (C-9a), 153.9
(d, JPC = 3.3 Hz, C-5), 189.4 (d, JPC = 9.1Hz, CHO); 31P NMR
3
5
(CDCl3, 243 MHz): δ = 22.44; HRMS (CI) Calcd for C17H23O4PS:
(5,6-Dihydro-4H-2-thia-benzo[e]azulen-1-yl)phosphonic
acid
354.1055.
Found:
354.1042.
diethyl ester (3d): Yield: 6%; yellow oil: 1H NMR (CDCl3, 600
Cyclization of aldehyde 2d: To a solution of NaOEt in EtOH,
prepared from Na (0.002 g, 0.09 mmol) and dry EtOH (1.0 mL),
was added aldehyde 2d (0.100 g, 0.28 mmol) and the resultant
solution was stirred at room temperature under an argon
atmosphere for 12 h. The solution was poured into ice H2O (5 ml)
and the mixture was extracted with Et2O (3 x 20 mL). The
combined organic fractions were dried (Na2SO4) and filtered, and
the solvent was removed in vacuo. The residue was
chromatographed on silica gel (Et2O, 100%) to afford 3d (0.057 g,
60%).
3
MHz): δ =1.38 (t, JHH = 7.1 Hz, 6H, 2CH3), 2.21-2.26 (m, 2H,
CH2), 2.67 (t, 3JHH = 6.6 Hz, 2H, CH2), 2.69 (t, 3JHH = 7.2 Hz, 2H,
CH2), 4.14-4.25 (m, 4H, 2CH2O), 7.28-7.31 (m, 3H, CHarom), 7.47-
7.50 (m, 2H, CHarom); 13C NMR (CDCl3, 151 MHz): δ = 16.3 (d,
3JPC = 6.6 Hz, 2CH3), 27.0 (C-4), 32.1 (C-5), 33.0 (C-6), 62.6 (d,
1
2JPC = 5.5 Hz, 2CH2O), 125.0 (d, JPC = 211.0 Hz, C-1), 126.7
(CHarom), 128.2 (CHarom), 128.4 (CHarom), 129.7 (CHarom), 133.8 (d,
3
3JPC = 2.2 Hz, C-10a), 139.2 (d, JPC = 11.9 Hz, C-3), 139.9 (d,
2
3JPC = 16.4 Hz, C-3a), 140.8 (C-6a), 146.4 (d, JPC = 6.9 Hz, C-
10b); 31P NMR (CDCl3, 243 MHz): δ = 12.22. HRMS (CI) Calcd
17. Similar reaction conditions were applied to the preparation of
thiophenes functionalized with carboethoxy- and trifluoromethyl-
substituents: (a) Arnaud, R.; Bensadat, A.; Ghobsi, A.; Laurent,
A.; Le Drean, I.; Lesniak, S.; Selemi, A. Bull. Soc. Chim. Fr.
1994, 131, 844-853; (b) Bartnik, R.; Bensadat, A.; Cal, D.; Faure,
R.; Khatimi, N.; Laurent, A.; Laurent, E.; Rizzon, C. Bull. Soc.
Chim. Fr. 1997, 134, 725-734.
18. De, A.; Bhattacharya, S.; Jash, S. S.; Mukherjee, S.; Saha, U.; Sen,
P. K. J. Heterocycl. Chem. 1992, 29, 1213-1217.
19. Noe, C. R.; Knollmueller, M.; Wagner, E. Monatsh. Chem. 1986,
117, 621-630.
for
C17H21O3PS:
336.0949.
Found:
336.0958.
1-Diethoxyphosphoryl-4,5,6,7-tetrahydro-2-benzothiophene (3e):
Yield: 49%; yellow oil: 1H NMR (CDCl3, 600 MHz): δ = 1.35 (t,
3JHH = 7.1 Hz, 6H, 2CH3), 1.80-1.89 (m, 4H, CH2), 2.64-2.66 (m,
2H, CH2 ), 2.81-2.83 (m, 2H, CH2 ), 4.07-4.20 (m, 4H, 2CH2O),
7.34 (d, 4JPH = 8.4 Hz, 1H, CHarom); 13C NMR (CDCl3, 151 MHz):
3
δ = 16.3 (d, JPC = 6.7 Hz, 2CH3), 22.6 (CH2), 23.3 (CH2), 25.29
(CH2), 25.31 (CH2), 62.4 (d, 2JPC = 4.9 Hz, 2CH2O), 123.2 (d, 1JPC
= 211.3 Hz, C-1), 136.7 (d, 3JPC = 17.5 Hz, C-3a), 137.8 (d, 3JPC
=
2
11.2 Hz, C-3), 144.9 (d, JPC = 6.5 Hz, C-7a); 31P NMR (CDCl3,
243 MHz): δ = 13.00; HRMS (CI) Calcd for C12H19O3PS:
20. To the best of our knowledge, the dephosphorylation of
phosphonothiophenes has not been reported yet. There are
examples of basic decarboxylation of thiophene derivatives or
basic dephosphorylation of phosphonopyrrole in the literature: (a)
Lütjens, H.; Zickgraf, A.; Figler, H.; Linden, J.; Olsson, R.
A.;Scammells, P. J.; J. Med. Chem.; 2003, 46; 1870-1877; (b)
Griffin, C. E.; Peller, R. P.; Peters, J. A. J. Org. Chem. 1965, 30,
91–96.
274.0793.
Found:
274.0791.
2-Diethoxyphosphoryl-3-ethyl-4-methylthiophene (3f): Yield:
1
3
68%; yellow oil: H NMR (CDCl3, 600 MHz): δ = 1.31 (t, JHH
=
7.5 Hz, 3H, CH3), 1.34-1.37 (m, 6H, 2CH3), 2.18 (s, 3H, CH3),
2.80 (q, 3JHH = 7.5 Hz, 2H, CH2 ), 4.08-4.20 (m, 4H, 2CH2O), 7.37
4
(d, JPH = 8.4 Hz, 1H, CHarom); 13C NMR (CDCl3, 151 MHz): δ =
13.3 (CH3), 15.3 (CH3), 16.3 (d, 3JPC = 7.0 Hz, 2CH3), 21.7 (CH2),
2
1
62.4 (d, JPC = 5.3 Hz, 2CH2O), 122.1 (d, JPC = 212.4 Hz, C-2),
3
3
133.7 (d, JPC = 17.2 Hz, C-4), 139.8 (d, JPC = 11,5 Hz, C-5),
150.0 (d, JPC = 6.5 Hz, C-3); 31P NMR (CDCl3, 243 MHz): δ =
2
12.77; HRMS (CI) Calcd for C11H19O3PS: 262.0793 . Found:
262.0789.
(E)-3-(Diethoxyphosphorylmethylsulfanyl)-2-methyl-3-
1
phenylprop-2-enal (2c): Yield: 8%; yellow oil: H NMR (CDCl3,