Rhodium-Catalyzed Synthesis of Dialkyl(Heteroaryl)Phosphine Sulfides by Phosphinylation of Heteroaryl Sulfides

Article abstract of DOI:10.1002/adsc.201800630

Dialkyl(heteroaryl)phosphine sulfides were synthesized by the rhodium-catalyzed exchange reaction of heteroaryl aryl sulfides and tetraalkyldiphosphine disulfides. The reaction has a broad applicability, giving diverse dialkyl(heteroaryl)phosphine sulfides containing five- and six-membered heteroaryl groups. Various dialkyl(heteroaryl)phosphines were obtained by desulfurization. (Figure presented.).

Full text of DOI:10.1002/adsc.201800630

Title: Rhodium-catalyzed Synthesis of Dialkyl(heteroaryl)phosphine
Sulfides by Phosphinylation of Heteroaryl Sulfides
Authors: Mieko Arisawa, Takeru Tazawa, Wataru Ichinose, Haruki
Kobayashi, and Masahiko Yamaguchi
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800630
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10.1002/adsc.201800630
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Rhodium-catalyzed Synthesis of Dialkyl(heteroaryl)phosphine
Sulfides by Phosphinylation of Heteroaryl Sulfides
Mieko Arisawa,a,* Takeru Tazawa,a Wataru Ichinose,a Haruki Kobayashi,a and
Masahiko Yamaguchi a,*
a
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai,
980-8578, Japan
E-mail: arisawa@m.tohoku.ac.jp, yama@m.tohoku.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
dialkylphosphine oxides R2P(=O)H, which are not
easy to prepare and handle. The development of a
versatile synthesis method for heteroarylphosphines is
desired.
Abstract. Dialkyl(heteroaryl)phosphine sulfides were
synthesized by the rhodium-catalyzed exchange reaction
of heteroaryl aryl sulfides and tetraalkyldiphosphine
disulfides. The reaction has a broad applicability, giving
diverse dialkyl(heteroaryl)phosphine sulfides containing
five- and six-membered heteroaryl groups. Various
Described here is a rhodium-catalyzed synthesis of
dialkyl(heteroaryl)phosphines
from
heteroaryl
dialkyl(heteroaryl)phosphines
were
obtained
by
sulfides and tetraalkyldiphosphine disulfides (Scheme
1). Diverse dialkyl(heteroaryl)phosphine sulfides
containing five- and six-membered heteroaryl groups
desulfurization.
Keywords:
dialkyl(heteroaryl)phosphine
sulfides;
were
obtained
by
employing
stable
tetraalkyldiphosphine
disulfides;
phosphinylation;
tetraalkyldiphosphine disulfides as the phosphinyl
reagents. Dialkyl(heteroaryl)phosphine sulfides were
desulfurization; Rh catalysis
desulfurized
with
tributylphosphine
giving
dialkyl(heteroaryl)phosphines.
Aryl- and alkylphosphines are organophosphorus
compounds used as ligands of metal-catalysis and
reagents for organic synthesis,[1] and their
phosphonium salts are used as ionic liquids,
antibacterial agents, and catalysts.[2] It is therefore
critical to develop a versatile method to synthesize a
diversity of phosphines and phosphonium salts to
improve properties and to develop novel functions. In
particular, phosphines possessing heteroaryl groups
are attractive, because such compounds have
additional heteroatoms located in the vicinity of the
phosphorus atom.
A limited number of heteroarylphosphines,
however, are known. Reported methods of
synthesizing of heteroaryl diarylphosphines employed
diphenylphosphine oxides Ph2P(=O)H as the
phosphinyl reagents, and were generally conducted by
either 1) transition-metal-catalyzed substitution
reactions of electron-deficient six-membered
heteroaryl halides, mostly pyridines and quinolines,[3]
or 2) radical reactions of five-membered heteroaryl
compounds possessing structures capable of
Scheme
1.
Rhodium-catalyzed
synthesis
of
dialkyl(heteroaryl)phosphine sulfides by phosphinylation of
heteroaryl sulfides.
Synthesis of aryldialkylphosphine sulfides was
initially examined by the reaction of diaryl sulfides
and tetraethyldiphosphine disulfide[6] which was
accompanied by aryl diethyldithiophosphinates. When
equimolar
trifluoromethylbenzonitrile
amounts
of
2-[(4-tolyl)thio]-5-
1a and
tetraethyldiphosphine disulfide 2 were reacted in
refluxing THF for 3 h in the presence of RhH(PPh3)4
(5
mol%)
and
1,2-bis[di(4-
methoxyphenyl)phosphino]ethane (dmppe, 10 mol%),
2-diethylphosphinothioyl-5-
stabilizing
radical
intermediates,
mostly
benzothiazoles.[4] These conventional methods suffer
from the limited scope of the heteroaryl moiety.
Method to synthesize dialkyl derivatives of
heteroarylphosphines are still rare[5] and use
trifluoromethylbenzonitrile
3a
and
aryl
diethyldithiophosphinate 4a were obtained in 90% and
81% yields, respectively (Scheme 2). No reaction
occurred in the absence of the rhodium complex or
dmppe. The use of several bidentate ligands revealed
1
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10.1002/adsc.201800630
Advanced Synthesis & Catalysis
the high efficiency of dmppe for the reaction of 1 and
2: 1,2-bis(diphenylphosphino)ethane (yields of 3a and
Six-membered heteroaryl 4-chlorophenyl sulfides
containing 2-triazyl, 4-quinazolyl, and pyrimidyl
4a:
55%
and
37%),
1,2-bis[di(4-
groups
were
also
converted
to
the
methoxyphenyl)phosphino]benzene (24% and 43%),
1,2-bis(diphenylphosphino)benzene (both in amounts
heteroaryldiethylphosphine sulfides 6p–6v. For the
six-membered heteroaryl derivatives, the use of 4-
chloroaryl sulfides 5u and 5v improved the yields of
6u and 6v to 65% and 83% compared with the use of
4-tolyl sulfides which provided 6u and 6v in 35% and
trace),
1,3-bis(diphenylphosphino)propane
(not
detected), and 1,4-bis(diphenylphosphino)butane (not
detected). The monodentate ligands tris(4-
methoxyphenyl)phosphine
and
10%
yields,
respectively.
Various
tris(cyclohexyl)phosphine were ineffective. These
results showed that the bidentate phosphine ligands
with diarylphosphino groups separated by two carbon
atoms are essential, and that the yield increased using
dmppe possessing 4-methoxyphenyl groups.
Aryl 4-tolyl sulfides possessing two electron-
withdrawing groups gave the corresponding
aryldiethylphosphine sulfides 3a–3c, although no
reaction occurred with 4-[(4-tolyl)thio]benzonitrile.
The leaving arylthio moiety, can possess either 4-
electron-donating or 4-electron-withdrawing groups,
both of which provided 3a in high yields. It was also
noted that the octylthio derivative 1d was
phosphinylated in 90% yield. The Ar–S bonds of
diaryl and aryl alkyl sulfides were cleaved and
converted to the Ar–P bonds through rhodium
catalysis.
dialkyl(heteroaryl)phosphine sulfides were effectively
synthesized by dialkylthiophosphinylation of
heteroaryl sulfides using tetraalkyldiphosphine
disulfides. All the dialkyl(heteroaryl)phosphines
shown here are new compounds except for 6f,[7] which
has not been reported before.
Table
1.
Rhodium-catalyzed
synthesis
of
dialkyl(heteroaryl)phosphine sulfides from heteroaryl
sulfides.
6a R = Et 99%, 92%a
6h R = Et 92%
6b R = n-C3H7 89%
6c R = n-C4H9 97%
6d R = n-C3H7 and Ph
90%
6e X = H, R = Me 61%
6f X = H, R = Et 49%
6g X = MeO, R = Et
39%
6i R = Ph 66%
6n 40%b
6j R = Me 80%
6k R = Et 100%
6l R = n-C4H9 and Ph
99%
6m 99%
6o 40%c, 21%d
6q R = Et 93%
6r R = n-C3H7 99%
6s R = Ph 32%
6p 68%
Scheme
2.
Rhodium-catalyzed
synthesis
of
aryldialkylphosphine sulfides by phosphinylation of aryl
sulfides.
6u 65%, 35%a
6t 100%
6v 83%, 10%a
a) Heteroaryl 4-tolyl sulfide was used. b) Rh cat. (15 mol%)
and dmppe (30 mol%) were used. c) Rh cat. (50 mol%) and
dmppe (100 mol%) were used. d) o-Dichlorobenzene reflux
using Rh cat. (5 mol%) and dmppe (10 mol%), 3 h.
Various dialkyl(heteroaryl)phosphine sulfides 6a–
6o were synthesized by the reaction of five-membered
heteroaryl 4-chlorophenyl sulfides in high yields,
which involved 1,3-benzothiazolyl, 1,3-benzoxazolyl,
1,3-oxyazolyl, and 2-furyl derivatives (Table 1). When
an
equimolar
amount
of
5-chloro-2-(4-
A possible mechanism of the reaction is provided in
Scheme 3. The phosphine ligand in RhH(PPh3)4 is
exchanged with dmppe, and the reaction of
diphosphine sulfide provides rhodium(I) phosphide
intermediate A. Then, the oxidative addition of
chlorophenyl)thiobenzothiazole 5a and 2 were reacted
in refluxing THF for 3 h in the presence of RhH(PPh3)4
(5 mol%) and dmppe (10 mol%), 6a and 4c were
obtained in 99% and 91% yields, respectively. 6a and
4a were also obtained in 92% and 84% yields,
respectively, by the reaction of 4-tolyl sulfide.
Diphosphine disulfides such as tetramethyl, tetraethyl,
tetrapropyl, teterabutyl, and 1,2-dipropyl-1,2-
diphenyldiphosphine disulfides, as well as
tetraphenyldiphosphine disulfide reacted efficiently.
tetraalkyldiphosphine
disulfide
provides
the
bis(dialkylphosphinyl)rhodium(III) intermediate B.
The intermediate B undergoes a heteroaryl exchange
reaction with a heteroaryl aryl sulfide, forming
HetAr′–Rh(III)–P(S)R2 complex C and an aryl
2
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10.1002/adsc.201800630
Advanced Synthesis & Catalysis
dialkyldithiophosphinate,
and
equiv) in the presence of RhH(PPh3)4 (5 mol%) and
dmppe (10 mol%) in refluxing THF for 9 h, 2-
dialkyl(heteroaryl)phosphine sulfide is liberated by
reductive elimination with the regeneration of rhodium
catalyst. The rhodium(I) phosphide complex (X =
P(S)R2) may be formed as an active species.[8]
(diethylphosphinothioyl)benzothiazole
6f
was
obtained in 63% yield (Scheme 4). The heteroaryl
group
can
be
transferred
from
the
to
dimethylphosphinothioyl
dibutylphosphinothioyl
phenylphosphinothioyl
group
and
1-butyl-1-
giving
and
groups,
2-
9b,
phosphinothioylbenzothiazoles
respectively.
9a
Scheme 4. The heteroaryl exchange of heteroarylphosphine
sulfides via HetAr–P bond cleavage reaction.
It was also noted that the reaction of
heteroarylphosphine sulfides and disulfides provided
heteroaryl sulfides, which is the reverse reaction of the
dialkylphosphinylation of heteroaryl sulfides. When 2-
(dimethylthiophosphinyl)-1,3-benzothiazole 6e was
reacted with dioctyl disulfide 10 (1 equiv.) in refluxing
chlorobenzene for 3 h in the presence of RhH(PPh3)4
(10 mol%) and dmppBz (20 mol%), 2-octylthio-1,3-
benzothiazole 11 and octyl dimethyldithiophosphinate
12 were obatined in 46% and 45% yields, respectively
(Scheme 5). No reaction occurred in the absence of the
rhodium complex or dmppBz. The use of dmppe
decreased 11 in 25% yield. It is interesting to note that
the C–P bonds in heteroarylphosphines can be cleaved
and converted to C–S and P–S bonds, and that such a
method can be used for the synthesis of various
heteroaryl compounds.
Scheme 3. Proposed reaction mechanism.
Dialkyl(heteroaryl)phosphine
sulfides
were
desulfurized using tributylphosphine (Table 2).[9]
When
2-(dibutylphosphinothioyl)-5-
6c was reacted with
chlorobenzothiazole
tributylphosphine (1.2 eq.) in refluxing o-
dichlorobenzene for 10 h, the corresponding 2-
(dibutylphosphinyl)-5-chlorobenzothiazole 8a was
obtained
in
99%
yield.
Thus,
various
dialkyl(heteroaryl)phosphines with six- and five-
membered heteroarenes 8a-8g were synthesized, all of
which are new compounds except for 8d.[3d]
Table 2. Synthesis of dialkyl(heteroaryl)phosphines.
8b 80%
8f 55%
8a 99%
8c X = Ph, R = Et 84%
8d X = H, R = Ph 95%
Scheme 5. The reaction of heteroarylphosphine sulfides and
disulfides.
In summary, diverse dialkyl(heteroaryl)phosphine
sulfides containing five- and six-membered
heteroarenes were synthesized from heteroaryl aryl
sulfides and tetraalkyldiphosphine disulfides in high
yields. The dialkyl(heteroaryl)phosphine sulfides were
converted to dialkyl(heteroaryl)phosphines by
desulfurization. The substrates, heteroaryl aryl
sulfides, can be synthesized by a conventional
nucleophilic substitution reaction of heteroaryl halides
and arylthiols.[10] Alternatively, we developed a
rhodium-catalyzed heteroaryl exchange reaction of
heteroaryl aryl ethers and aryl thioesters[11] and a C–H
8g 67%
8e 90%
It was noted that the HetAr–P bonds in the
dialkyl(heteroaryl)phosphine sulfides were cleaved
under the rhodium-catalyzed conditions, and the
heteroaryl exchange of heteroarylphosphine sulfides
occurred in the presence of diphosphine disulfides.
When 2-(dimethylthiophosphino)benzothiazole 6e
was reacted with tetraethyldiphosphine disulfide (3
3
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10.1002/adsc.201800630
Advanced Synthesis & Catalysis
arylthiolation reaction of heteroarenes and –
arylthioketones.[12] Related metal-catalyzed C–H
arylthiolation reactions were also reported.[13] Novel
dialkyl(heteroaryl)phosphines obtained by this method
may be used to develop novel catalysts and materials.
[3] For examples, a) M. Sun, Y.-S. Zang, L.-K. Hou, X.-X.
Chen, W. Sun, S.-D. Yang, Eur. J. Org. Chem. 2014,
6796-6801; b) H.-Y. Zhang, M. Sun, Y.-N. Ma, Q.-P.
Tian, S.-D. Yang, Org. Biomol. Chem. 2012, 10, 9627-
9633; c) Y.-L. Zhao, G.-J. Wu, Y. Li, L.-X. Gao, F.-S.
Han, Chem. Eur. J. 2012, 18, 9622-9627; d) Using the
phosphinylation
of
oxadiazoles
by
chlorodiphenylphosphine, L.-H. Zou, Z.-B. Dong, C.
Bolm, Synlett, 2012, 23, 1613-1616.
Experimental Section
Typical procedures for synthesis of 3a
[4] a) W. Lin, F. Su, H.-J. Zhang, T.-B. Wen, Eur. J. Org.
Chem. 2017, 1757-1759; b) K. Luo, Y.-Z. Chen, W.-C.
Yang, J. Zhu, L. Wu, Org. Lett. 2016, 18, 452-455; c) K.
Luo, Y.-Z. Chen, L.-X. Chen, L. Wu, J. Org. Chem.
2016, 81, 4682-4689; d) L. Li, J.-J. Wang, G.-W. Wang,
J. Org. Chem. 2016, 81, 5433-5439; e) Dialkyl
benzothiazol-2-ylphosphonates, X.-L. Chen, X. Li, L.-B.
Qu, Y.-C. Tang, W.-P. Mai, D.-H. Wei, W.-Z. Bi, L.-K.
Duan, K. Sun, J.-Y. Chen, D.-D. Ke, Y.-F. Zhao, J. Org.
Chem. 2014, 79, 8407-8416.
In a two-necked flask were placed RhH(PPh3)4
(57.6 mg, 5 mol%), dmppe (51.8 mg, 10 mol%), [2-
cyano-4-(trifluoromethyl)phenyl] 4-tolylsulfide (1.0
mmol, 293.0 mg), and tetraethyldiphosphine disulfide
(1.0 mmol, 242.0 mg) in THF (2.0 mL) under an argon
atomosphere, and the mixture was heated at reflux for
3 h. The solvent was removed under reduced pressure,
and the residue was purified by flash column
chromatography on silica gel giving 3a (263.1 mg,
90%) and 4a (198.0 mg, 81%).
[5] H.-J. Zhang, W. Lin, Z. Wu, W. Ruan, T.-B. Wen, Chem.
Typical procedures for synthesis of 6a
Commun. 2015, 51, 3450-3453. Also see ref. 4a, 4b, and
4d.
In a two-necked flask were placed RhH(PPh3)4
(28.8 mg, 5 mol%), dmppe (25.9 mg, 10 mol%), 5-
chlorobenzothiazolyl 4-chlorophenyl sulfide (0.5
mmol, 155.5 mg), and tetraethyldiphosphine disulfide
(0.5 mmol, 121.0 mg) in THF (1.0 mL) under an argon
atomosphere, and the mixture was heated at reflux for
3 h. The solvent was removed under reduced pressure,
and the residue was purified by flash column
chromatography on silica gel giving 6a (142.6 mg,
99%) and 4c (125.7 mg, 95%).
[6] K. A. Pollart, H. J. Harwood, J. Org. Chem. 1962, 27,
4444-4447.
[7] Compound 6f has been synthesized by the Arbuzov
rearrangement reaction, see:. a) M. N. Danchenko, A. D.
Sinitsa, Zhurnal Obschchei Khimii, 1987, 57, 1919-1920.
We also previously reported the synthesis of 6f, see: b)
M. Arisawa, T. Watanabe, M. Yamaguchi, Tetrahedron
Lett., 2011, 52, 2410-2412. This work significantly
expanded
the
scope
to
various
dialkyl(heteroaryl)phosphine sulfides.
Acknowledgements
[8] It is likely that rhodium phosphide species was formed
from RhH(PPh3)4, dmppe, and tetraalkyldiphosphine
disulfides in the initial step, see: a) L.-B. Han, T. D.
Tilley, J. Am. Chem. Soc., 2006, 128, 13698-13699. b)
M. Arisawa, T. Yamada, S. Tanii, Y. Kawada, H.
Hashimoto, M. Yamaguchi, Chem. Commun., 2016, 52,
13580-13583.
This research was supported by the Platform Project for
Supporting Drug Discovery and Life Science Research from
AMED under Grant Number JP18am0101100, JSPS KAKENHI
Grant Numbers 17K19112, 15H00911, Tohoku University Center
for Gender Equality Promotion (TUMUG), and Morinomiyako
Project for Empowering Women in Research.
[9] M. Yamamura, N. Kano, T. Kawashima, Bull. Chem.
Soc. Jpn. 2012, 85, 110-123.
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4
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10.1002/adsc.201800630
Advanced Synthesis & Catalysis
COMMUNICATION
Rhodium-catalyzed
Synthesis
Sulfides
of
by
Dialkyl(heteroaryl)phosphine
Phosphinylation of Heteroaryl Sulfides
Adv. Synth. Catal. Year, Volume, Page – Page
Mieko Arisawa,a,* Takeru Tazawa,a Wataru
Ichinose,a Haruki Kobayashi,a and Masahiko
Yamaguchi a,*
5
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