H-phosphonate-mediated sulfonylation of heteroaromatic N-oxides: a mild and metal-free one-pot synthesis of 2-sulfonyl quinolines/pyridines

Article abstract of DOI:10.1039/c5cc04484g

A smart H-phosphonate-mediated synthetic strategy for the sulfonylation of heteroaromatic N-oxides has been developed, by which a large variety of 2-sulfonyl quinolines/pyridines were synthesized starting from easily available sulfonyl chlorides, diisopropyl H-phosphonate and pyridine/quinoline N-oxides in one pot under metal-free conditions at room temperature.

Full text of DOI:10.1039/c5cc04484g

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H-phosphonate-mediated sulfonylation of heteroaromatic N-
oxides: a mild and metal-free one-pot synthesis of 2-sulfonyl
quinolines/pyridines
Received 00th January 20xx,
Accepted 00th January 20xx
Kai Sun,a Xiao-Lan Chen,*a Xu Li,a Ling-Bo Qu,*ab Wen-Zhu Bi,a Xi Chen,a Hui-Li Ma,a Song-Tao
Zhang,a Bo-Wen Han,a Yu-Fen Zhao*ac and Chao-Jun Lid
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
smart H-phosphonate-mediated synthetic strategy for the heteroaromatic sulfone compounds via C-H activation under metal-
sulfonylation of heteroaromatic N-oxides has been developed, by free conditions is highly desired from a synthetic practicality
which a large variety of 2-sulfonyl quinolines/pyridines were viewpoint.
synthesized starting from easily available sulfonyl chlorides,
In the last decade, several processes for the sulfonylation of
diisopropyl H-phosphonate and pyridine/quinoline N-oxides in these heteroaromatic compounds have been developed as shown
one pot under metal-free conditions at room temperature.
in Scheme 1. Traditionally, sulfones are synthesized either by
oxidation of the corresponding sulfides10 as in the case of Scheme
1a11, or by alkylation or arylation of sulfinate salts12 as in the cases
of Scheme 1b-c9,13. However, these traditional methods shown in
Scheme 1a-c have associated limitations. For the oxidation method
shown in Scheme 1a, the ultimate starting materials are foul-
smelling benzenethoils and halopyridines. Halopyridines usually are
not commercially available and are problematic to prepare. The
arylation of sulfinate salts shown in Scheme 1b-c is achieved by
coupling reactions of halopyridines/quinoline with sulfinate salts
The possibility of direct introduction of a new functionality via
direct C-H bond transformation is a highly attractive strategy with
high atom economy in covalent synthesis.1 Substantial growth in
carbon-heteroatom bond formation based on the transition-metal-
catalyzed C-H bond activation has been observed.2 It is especially
worth emphasizing that nearly all the reported methods employed
metal, noble metal or even toxic metal catalysts for C-H bond
activation reactions.3 However, from environmental and economic
views, metal-free chemistry should be greatly encouraged.4 It is
worth noting that the development of effective C-S bond formation
reactions via direct C-H activation is under developed compared to
C-N5 and C-O6 bond formation. It is well known that, as an
extremely important structural moiety, quinoline (or pyridine)
moiety exists in a wide range of pharmaceutical interest products.7
However, it has been found that quinine, a naturally occurring
product for treatment of malaria, is easily detoxified in the body by
oxidation to the 2-hydroxy derivative which has much less
therapeutic activity. So lots of synthetic methods have been
focused on introducing groups into the 2-position in order to block
this mode of detoxification.8 Sulfones are not only versatile
synthetic intermediates, but also exhibit broad range of physical,
chemical and biological activities. They play an especially important
role in agricultural, industrial and pharmaceutical chemistry.9
under
metal
catalytic
conditions.
However,
both
halopyridines/quinolines and sulfinate salts have very limited
commercial availability. In particular, sulfinate salts are often
prepared from the corresponding sulfonyl chlorides.14 Recently,
Therefore,
a rapid, efficient, and practical access to those
a.College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, 450052, China. Fax: 86 371 67767051; Tel: 86 371 67767051; E-mail:
chenxl@zzu.edu.cn.
b.Chemistry and Chemical Engineering School, Henan University of Technology,
Zhengzhou, 450001, China.
c.Department of Chemistry, Xiamen University, Xiamen, 361005, China.
d.Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis,
McGill University, Montreal, Quebec H3A0B8, Canada.
†Electronic Supplementary Information (ESI) available: [Detailed experimental
procedures analytical data.]. See DOI: 10.1039/x0xx00000x
Scheme 1. Comparison of previous work with this work
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Cui’s group developed
a
protocol to synthesize 2-(aryl (entries 1-5). A high yield of 3a was obtained when diisopropyl H-
sulfonyl)quinoline N-oxides in chemo- and regioselective manners phosphonate was employed (85%) (entry 2). The ideal amount of
via copper-catalyzed C-H bond activation, starting from quinoline N- diisopropyl H-phosphonate was then explored (entries 2 and 6-10).
oxides and sulfonyl chlorides (Scheme 1d).15 Although this The reaction did not proceed in the absence of any dialkyl H-
introduction of a new functionality via copper-catalyzed C-H bond phosphonate (entry 6). The yield increased from 43% to 85% as the
activation of quinoline N-oxides is an attractive strategy, amount of diisopropyl H-phosphonate increased from 0.5 to 1 equiv.
nevertheless, it required metal catalyst,
a relatively high (entries 7-8, 2), and decreased from 85% to 80% as the amount
temperature, and a rather long reaction time (24 h) to progress to continuously increased from 1 to 1.5 equiv (entries 2, 9-10). The
reaction. Moreover, PCl3, a harsh reagent, would usually be used if ideal amount of TsCl was also explored. It was found that the yield
one wanted to reduce the 2-(aryl sulfonyl)quinoline N-oxides increased from 45% to 85% with the increase of TsCl from 1 equiv
(Scheme 1d-I) to the corresponding 2-(aryl sulfonyl)quinolines to 2 equiv (entries 11-12, 2). However the yield began to decrease
(Scheme 1e-II).16 Herein, we disclose a highly efficient one-pot when the amount was above
procedure to build large variety of both 2-(aryl/alkyl investigation into the influence of various bases on the reaction was
2 equiv. (entry 13). Further
a
sulfonyl)pyridines and 2-(aryl/alkyl sulfonyl)quinolines, via a direct carried out (entries 2 and 14-18). Without base no product was
C-H functionalization of pyridine/quinoline N-oxides with H- formed (entry 18). The use of KOH brought about a highest yield
phosphonates under metal-free conditions (Scheme 1e). In a sharp (85%) (Table 1, Entry 2), whereas the other bases resulted in
contrast to Cui’s method, the prominent advantages of our one-pot relatively low yields of 3a: i.e., K2CO3 (trace), t-BuOK (43%), Et3N
method include a much reduced reaction time (1 h), a relatively (53%), Et2NH (28%) (entries 14-17). The investigation on the optimal
wide scope of reactants, metal free and room temperature reaction amount of KOH (Table 1, entries 2 and 19-22) indicated that 4 equiv
conditions, and
a
one-step procedure to the final sulfonyl of KOH (entry 2) was an appropriate amount. Further screening of
the solvents showed that THF was the best choice among those
pyridines/quinolines.
We initiated the meaningful study, starting with establishing tested solvents (entries 4 and 23–29). By the way, the reason why
optimal experimental conditions using the model reaction of the yield was so low in dioxane (Table 1, entry 23), and why the
quinoline N-oxide (1a) with TsCl (2a) in the presence of dialkyl H- yield was so high when the reaction was performed in ethanol
phosphonates under open-air conditions for
1 h at room (Table 1, entry 26) were further explored (For the reason, along
temperature, as summarized in Table 1. The influence of a variety with supplemental experiments, see supporting information).
of dialkyl H-phosphonates on the model reaction was investigated
Therefore, the best yield of 3a (85%) was obtained by employing 1
equiv diisopropyl H-phosphonate, 2 equiv TsCl, 4 equiv KOH in THF
(entry 2).
Table 1. Optimization of reaction conditionsa
Table 2. Scope of the sulfonylated quinoline and related derivatives
a Reaction conditions: 0.2 mmol of 1a, 0.2-0.4 mmol of 2a, H-phosphonate
(equiv), base and 7 mL of solvent in a 25 mL round-bottom flask at room
temperature for 1 h. b Isolated yields.
Reaction conditions: 0.2 mmol of 1, 0.4 mmol of 2, diisopropyl H-phosphonate
(1.0 equiv), KOH (4.0 equiv) and 7 mL of THF in a 25 mL round-bottom flask at
room temperature for 1 h.
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With the optimized reaction conditions in hand, we then
examined the substrate scope of quinoline N-oxides and sulfonyl
chlorides. The results were summarized in Table 2. As it can be seen,
a variety of aryl sulfonyl chlorides reacted well with quinoline N-
oxide itself, giving the resulting 2-(aryl sulfonyl)quinolines (3a-f) in
good yields. Two alkyl sulfonyl chlorides also reacted well with
quinoline N-oxide to afford the resulting 2-(alkyl sulfonyl)quinolines
(3g-h) in moderate yields. A series of substituted quinoline N-oxides
were tested as well, giving the corresponding products (3i-o) in
good yields. To our delight, the sulfonyl method could further be
applied to isoquinoline N-oxide, regioselectively producing three
corresponding products (3p-r). It’s especially worth mentioning
here that pyridine N-oxide and its substituted derivatives, and even
quinoxaline N-oxide (an aromatic ring with two heteroatoms)
smoothly went sulfonylation at the 2-position (3s-y). It can be seen
that both the electron-donating and -withdrawing groups of
sulfonyl chlorides and aromatic N-oxides were well compatible to
afford the desired products under the optimal reaction conditions.
Generally, the reaction efficiency was slightly sensitive to the
electronic property. The electron-donating (CH3, C(CH3)3) groups on
the phenyl ring of sulfonyl chlorides, compared to electron-
withdrawing groups (Cl, NO2) on the ring, gave relatively higher
yields as in the cases of 3a-b, d, l. The electron-donating groups
(CH3, OCH3) attached to aromatic N-oxides led usually to higher
yields than did the electron-withdrawing groups (Br, Cl), as in the
cases of 3n and 3o, 3u and 3x.
Scheme 2. Proposed reaction mechanism
undergoes a nucleophilic addition and elimination reaction, forming
an instable intermediate 6 and a chloride anion. The S-P bond of 6 is
weak owing to the strong electron withdrawing abilities of the
sulfonyl group and phosphoryl group at two sides of the bond.
Subsequently, the chloride anion quickly attacks the phosphorus
atom of 6, via an addition-elimination process, forming diisopropyl
chlorophosphate 2 along with sulfonyl anion 7. It can clearly be
seen that the sulfur in 5 is positively charged, whereas the sulfur in
7 is negatively charged. It is to say that, by reacting with dialkyl H-
phosphonate (1 or 1’), sulfonyl chloride 5, which initially acts as
electrophile, can quickly be transformed into nucleophile sulfonyl
anion 7 (S charge reversion process). Then, the oxygen atom of
quinoline N-oxide 8 attacks the phosphorus atom of 2 and triggers
another addition-elimination process. A chloride anion is expelled
and intermediate 9 is formed. Meanwhile an energetically favorable
six-membered ring is generated inside 9 owing to the formation of
an intramolecular hydrogen bond, by which the covalent C2-H of 9
is effectively activated. It can be seen that 9 is in resonance with 9’.
Then sulfonyl anion 7, acting as a nucleophile, attacks the carbon 2
of 9’, initiating an energetically favorable elimination of diisopropyl
phosphate 3 along with the formation of the target product 10. By
the way, tetraisopropyl diphosphate 4 is formed via intermolecular
dehydration of 3 under basic reaction condition.
Dialkyl H-phosphonates play
a
predominant role in
organophosphorus chemistry, since as important intermediates,
they are frequently employed to synthesize a large variety of
bioactive phosphorus-containing products.17 In order to know what
role dialkyl H-phosphonate played here in the reaction, the whole
reaction process was monitored by 31P NMR every 5 min. (Figure 1).
Beginning with diisopropyl H-phosphonate 1, the phosphorus-
containing intermediates and product, diisopropyl chlorophosphate
2, diisopropylphosphate 3 and tetraisopropyl diphosphate 4, were
all well tracked in the proper sequence as shown in Figure 1. A
plausible mechanism is proposed accordingly in Scheme 2. Dialkyl
H-phosphonates often exist in rapid equilibrium with a tautomeric
form known as tricoordinated phosphorus form and
tetracoordinated form, as in the case of 1’ and 1 shown in Scheme
2.17c Diisopropyl phosphite 1’ initially acts as nucleophile to attack
the sulfur atom of sulfonyl chloride 5, and then the reaction
Based on the above mechanism, we proposed another new
synthetic strategy (Scheme 3), by which
a group of 2-
sulfonylated quinolines were efficiently synthesized. The related
mechanism is shown in Scheme 3. Based on the well-known
Atherton-Todd reaction18, diisopropyl H-phosphate 1 can initially be
converted into dialkyl chlorophosphate 2 in the presence of carbon
tetrachloride and base (Scheme 3). Afterwards, following exactly
the same steps as described in Scheme 2, the final product 10 was
successfully obtained. The success of this synthetic method gave us
a further support for the mechanism shown in Scheme 2. Quite like
the first method, this reaction was also performed at room
temperature in short reaction time under metal-free conditions.
However, the first synthetic strategy shown in Table 2 owns an
obvious advantage over this one here shown in Scheme 3 in
that it employed wildly available sulfonyl chlorides, rather than
sulfinate salts, as sulfonylation agents. As mentioned at the
beginning, sulfinate salts currently have very limited
commercial availability and are often prepared from sulfonyl
chlorides.14
Figure 1: 31P NMR stacks diagram. Reaction conditions: quinoline N-oxide (0.2
mmol), TsCl (0.4 mmol), diisopropyl H-phosphonate (0.2 mmol) and KOH (0.8
mmol) in THF (7 mL) at room temperature for 1 h. The whole process was
monitored by 31P NMR every 5 min (comp-1, 4.07 ppm, comp-2, 1.27 ppm, comp-
3, -1.08 ppm, comp-4, -14.42 ppm).
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Notes and references
1
2
X. Chen, K. M. Engle, D. H. Wang, J. Q. Yu, Angew. Chem. Int.
Ed., 2009, 48, 5094.
(a) I. P. Beletskaya, V. P. Ananikov, Chem. Rev., 2011, 111
1596; (b) T. W. Lyons, M. S. Sanford, Chem. Rev., 2010, 110
,
,
1147; (c) G. Y. Song, F. Wang, X. W. Li, Chem. Soc. Rev., 2012,
41, 3651; (d) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem.
Soc. Rev., 2011, 40, 5068.
3
(a) X. D. Tang, L. B. Huang, Y. L. Xu, J. D. Yang, W. Q. Wu, H. F.
Jiang, Angew. Chem. Int. Ed., 2014, 53, 4205; (b) B. Meunier,
S. P. Visser, S. Shaik, Chem. Rev., 2004, 104, 3947; (c) M.
Baik, M. Newcomb, R. Friesner, S. J. Lippard, Chem. Rev.,
2003, 103, 2385; (d) K. Mylvaganam, G. B. Bacskay, N. S.
Hush, J. Am. Chem. Soc., 2000, 122, 2041; (e) S. Chempath, A.
T. Bell, J. Am. Chem. Soc., 2006, 128, 4650; (f) G. Fu, X. Xu, X.
Lu, H. Wan, J. Am. Chem. Soc., 2005, 127, 3989; (g) G. J.
Wang, Y. Gong, M. H. Chen, M. F. Zhou, J. Am. Chem. Soc.,
2006, 128, 5974; (h) S. Feyel, J. Dobler, R. Hockendorf, M. K.
Beyer, J. Sauer, H. Schwarz, Angew. Chem. Int. Ed., 2008, 47
1946.
F. Recupero, C. Punta, Chem. Rev., 2007, 107, 3800.
(a) W. B. Wu, J. M. Huang, Org. Lett., 2012, 14, 5832; (b) C. H.
Tang, N. Jiao, J. Am. Chem. Soc., 2012, 134, 18924; (c) D.
Dhara, K. S. Gayen, S. Khamarui, P. Pandit, S. Ghosh, D. K.
Maiti, J. Org. Chem., 2012, 77, 10441.
,
4
5
6
7
(a) T. S. Jiang, G. W. Wang, J. Org. Chem., 2012, 77, 9504; (b)
S. Guin, S. K. Rout, A. Banerjee, S. Nandi, B. K. Patel, Org.
Lett., 2012, 14, 5294.
(a) R. Dayam, L. Q. Al-Mawsawi, Z. Zawahir, M. Witvrouw, Z.
Debyser, N. Neamati, J. Med. Chem., 2008, 51, 1136. (b) M.
P. Maguire, K. R. Sheets, K. McVety, A. P. Spada, A.
Zilberstein J. Med. Chem., 1994, 37, 2129.
Reaction conditions: quinoline N-oxides (1 mmol), sulfonate salts (1 mmol), diisopropyl
H-phosphonate (1 mmol), KOH (4 mmol) and CCl4 (0.5 mL) in THF (15 mL) at room
temperature for 1 h.
Scheme 3. A new synthetic strategy toward 2-sulfonyl quinolones
In conclusion, we have developed a straight forward method
by which a wide variety of N-heteroaromatic sulfones were
synthesized by a one-pot reaction of pyridine/quinoline N-
oxides with sulfonyl chlorides in the presence of diisopropyl H-
phosphonate for 1 h at room temperature. The study on the
mechanism indicates that sulfonyl chlorides (electrophile) can
be transformed into sulfonyl anions (nucleophile) in the
presence of dialkyl H-phosphonates. Meanwhile, dialkyl H-
8
9
N. G. Luthy, F. W. Bergstrom, H. S. Mosher, J. Am. Chem.
Soc., 1949, 71, 1109.
E. J. Emmett, B. R. Hayter, M. C. Willis, Angew. Chem. Int.
Ed., 2013, 52, 12679.
10 (a) F. Xue, D. Wang, X. Li, B. Wan, J. Org. Chem., 2012, 77
,
3071; (b) N. Furukawa, S. Ogawa, K. Matsumur, H. Fujihara,
J. Org. Chem., 1991, 56, 6341.
11 W. G. Trankle, M. E. Kopach, Org. Process Res. DeV., 2007,
11, 913.
12 (a) J. K. Crandall, C. Pradat, J. Org. Chem., 1985, 50, 1327;
phosphonates
can
be
transformed
into
dialkyl
(b) Y. Ju, D. Kumar, R. S. Varma, J. Org. Chem., 2006, 71
,
chlorophosphates (strong electrophile), which then could, in
the following step, react with quinoline/pyridine N-oxides to
form complexes. By the six-membered ring formed inside the
complexes, C2-H of N-heteroaromatic substrates could
therefore be greatly activated. These key reaction steps make
it possible to directly employ wildly available sulfonyl chlorides
and aromatic N-oxides to synthesize a large variety of N-
heteroaromatic sulfones under mild and metal-free reaction
conditions. The current substrate scope encompasses a wide
range of heteroaromatic N-oxides, including pyridine N-oxides,
quinoline N-oxides and quinoxaline N-oxide, as well as a
variety of sulfonyl chlorides, including aryl and alkyl sulfonyl
chlorides. Compared with literature methods, great
advantages of this strategy include a wide range of reaction
substrates, an efficient time-saving one-pot procedure,
extremely mild and metal-free reaction conditions. The
method will undoubtedly be a far superior alternative for the
synthesis of a variety of biologically and chemically significant
N-heteroaromatic sulfones. Further studies on the applications
of this strategy will be reported in due course.
6697. (c) K. M. Maloney, J. T. Kuethe, K. Linn, Org. Lett.,
2011, 13, 102; (d) B. Qu, L. P. Samankumara, J. Savoie, D. R.
Fandrick, N. Haddad, X. D. Wei, S. L. Ma, H. Lee, S. Rodriguez,
C. A. Busacca, N. K. Yee, J. J. Song, C. H. Senanayake, J. Org.
Chem., 2014, 79, 993. (e) A. Kar, I. A. Sayyed, W. F. Lo, H. M.
Kaiser, M. Beller, M. K. Tse, Org. Lett., 2007,
Richards-Taylor, D. C. Blakemore, M. C. Willis, Chem. Sci.,
2014, , 222. (g) S. Cacchi, G. Fabrizi, A. Goggiamani, L. M.
9, 3405; (f) C. S.
5
Parisi, R. Bernini, J. Org. Chem., 2004, 69, 5608.
13 W. Zhu, D. W. Ma, J. Org. Chem., 2005, 70, 2696.
14 W. E. Truce, A. M. Murphy, Chem. Rev., 1951, 48, 69.
15 Z. Y. Wu, H. Y. Song, X. L. Cui, C. Pi, W. W. Du, Y. J. Wu, Org.
Lett., 2013. 6, 1270.
16 D. Wenkert, R. B. Woodward, J. Org. Chem., 1983, 48, 283.
17 (a) J. Stawinski, A. Kraszewski, Acc. Chem. Res., 2002, 35
,
952; (b) Y. X. Gao, G. Wang, L. Chen, P. Xu, Y. F. Zhao, Z. B.
Zhou, L.B. Han; J. Am. Chem. Soc., 2009, 131, 7956; (c) K. D.
Troev; Chemistry and application of H-phosphonates, Elsevier
Science 2006, Vol. 84, pp 438.
18 E. M. Ceorgiev, J. Kaneti, K. D. Troev, M. Roundhill, J. Am.
Chem. Soc., 1993, 115, 10964.
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