Organophotocatalytic Synthesis of Phosphoramidates

Article abstract of DOI:10.1002/adsc.201501068

We describe the use of visible light in conjunction with an organic dye for the synthesis of phosphoramidates. Cross dehydrogenative coupling reactions between phosphites and amines are reported using organic dyes and light as catalysts for the first time. It is not only a novel application of organic dyes but also fulfils the requirement of sustainability and green chemistry avoiding the use of chromatographic purification techniques. The product was simply isolated from the reaction mixture via an acid-base work-up procedure, rendering the pure product in good yields.

Full text of DOI:10.1002/adsc.201501068

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DOI: 10.1002/adsc.201501068
Organophotocatalytic Synthesis of Phosphoramidates
Marta Meazza,a Agnieszka Kowalczuk,a Luke Shirley,a Jung Woon Yang,a,b
Hao Guo,c,* and Ramon Riosa,b,*
a
Faculty of Natural and Environmental Science, School of Chemistry, University of Southampton, Highfield Campus,
Southampton SO17 1BJ, U.K.
E-mail: R.Rios-Torres@southampton.ac.uk
Department of Energy Science, Sungkyunkwan University, Suwon 440-746, Korea
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai, 200433, Fudan, Peopleꢀs Republic of China
b
c
E-mail: Hao_Guo@fudan.edu.cn
Received: November 22, 2015; Revised: December 10, 2015; Published online: February 11, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501068.
Abstract: We describe the use of visible light in
conjunction with an organic dye for the synthesis of
phosphoramidates. Cross dehydrogenative coupling
reactions between phosphites and amines are re-
ported using organic dyes and light as catalysts for
the first time. It is not only a novel application of
organic dyes but also fulfils the requirement of sus-
tainability and green chemistry avoiding the use of
chromatographic purification techniques. The prod-
uct was simply isolated from the reaction mixture
via an acid-base work-up procedure, rendering the
pure product in good yields.
functionalization for interesting scaffolds. In our re-
search group, we are interested in the development of
green organocatalytic reactions that allow us to build
new atom-atom s-bonds. To do this, photocatalytic re-
actions for CDC have attracted our attention. In-
spired by previous works of Rueping,[4] among others,
we envisioned that photocatalysis, using organic dyes,
could be contributing to the development of new re-
actions for the synthesis of phosphoramidates.
Phosphoramidates are very important structural
scaffolds in many biologically active molecules[5] and
industrially important products.[6] Moreover, in recent
years, phosphoramidates have become important
chiral ligands for several metal-catalyzed reactions.[7]
In medicinal chemistry, phosphoramidate ProTide
technology has been used to bypass the rate-limiting
step of the initial phosphorylation of nucleosides and
to act as a better inhibitor.[8] Recently, Zhou and co-
workers have used chiral phosphoramidates as orga-
nocatalysts for several reactions such as addition of
Keywords: cross dehydrogenative coupling (CDC)
reactions; dyes; green chemistry; phosphorami-
dates; photocatalysis
The quest for green procedures has become of para- oxindoles to nitrostyrenes[9] or the Michael addition
mount importance for organic chemists in the last of fluorinated silyl enol ethers[10] with excellent re-
decade. Discovery of benign, green and atom eco- sults, showing the importance of this type of function-
nomic processes is one of the corner stones for chem- al molecule as catalyst scaffold.
ists nowadays.[1] One of the most promising eco-
Despite the importance of phosphoramidates, their
friendly processes is the use of light in combination synthesis requires harsh conditions and/or the use of
with a photosensitizer to catalyze organic reactions. halides or precious transition metals. Typical method-
Advantages to use light as a source of energy are that ologies for the synthesis of phosphoramidates are de-
it is a renewable source, clean, non-toxic and cheap. scribed as follows: (i) they were conventionally syn-
For these reasons, the use of photocatalysis has grown thesized by the reaction of amine with the appropri-
exponentially in recent years.[2]
ate phosphorus halide.[11] Generally, these kinds of
For similar reasons, cross dehydrogenative cou- phosphorus reagents are moisture sensitive and ther-
plings (CDCs) have become a hot topic of interest for mally unstable; (ii) Other methods require the use of
chemists.[3] CDCs present some advantages such as no potentially explosive and toxic reagents or need
requirement of prefunctionalized starting materials multi-step synthesis. For example, the Staudinger-
and typically highly efficient, atom-economic process- phosphite reaction uses azides or phosphoryl
es, which should be an excellent way to shorten the azides.[12] In addition; highly toxic chlorinating agents
common synthetic routes or to introduce late-stage were used as solvents, for example, CCl4 in the
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Marta Meazza et al.
Table 1. Screening of parameters.[a]
Entry Dye Green light Solvent Temp. [oC] Yield [%][b]
Scheme 1. Previous works and our work.
1
2
3
4
5
6
7
8
I
II
yes
yes
CH3CN r.t.
CH3CN r.t.
CH3CN r.t.
toluene r.t.
CHCl3 r.t.
EtOAc r.t.
DMSO r.t.
toluene 70
CH3CN 70
CH3CN r.t.
CH3CN r.t.
n.r.
n.r.
36
40
26
13
17
54
95
III yes
III yes
III yes
III yes
III yes
III yes
III yes
Atherton–Todd reaction, to generate the reactive
phosphorus halide species. In order to overcome the
above-mentioned limitations, some examples of direct
catalytic approaches were recently reported based on
the concept of CDCs process: (i) copper-catalyzed
aerobic oxidative coupling between amines and phos-
phonates with excellent results were developed by the
groups of Hayes and Mizuno independently in 2013
[Scheme 1, Eq. (1)];[13] (ii) Prabhu and co-workers re-
ported the use of I2 as catalyst with (over)stoichiomet-
ric amounts of H2O2 as oxidant to obtain phosphor-
amidates in good yields [Scheme 1, Eq. (2)].[14] From
a practical and green chemistry point of view, howev-
er, general solutions such as the elimination of the
9
10
11
–
yes
n.r.
n.r.
III no
[a]
Reaction conditions: 1a (0. 362 mmol), 2a (0.724 mmol),
dye I–III (20 mol%), air (1 atm), green light, solvent
(1.5 mL).
Isolated yields.
[b]
use of precious transition metals or stoichiometric ox- obtained in acetonitrile at room temperature (Table 1,
idants are still highly desirable. entries 3 and 4). On the other hand, the use of chloro-
Herein, we report a simple, non-toxic, and transi- form, EtOAc, and DMSO as solvents gave lower
À
tion metal-free, P N bond-forming CDC reactions yields (Table 1, entries 5–7). In order to improve the
between phosphites and amines for the synthesis of reaction rate and the yields, the reaction was carried
phosphoramidates in a one-pot manner using an or- out in either toluene or acetonitrile at 708C. Acetoni-
ganic dye as photocatalyst and air as oxidant under ir- trile gave a striking difference in terms of the yield
radiation of green light-emitting diodes (LEDs) compared with toluene, giving the desired product in
[Scheme 1, Eq. (3)]. Moreover, the large-scale pro- almost quantitative yield (95%) (Table 1, entry 9).
duction of the desired product is demonstrated with- Control reactions demonstrated that no reaction oc-
out the need of chromatographic purification.
curred in the absence of organic dye III or light
We initially commenced with the CDC reaction be- source (Table 1, entries 10 and 11).
tween diethyl phosphite 1a and p-anisidine 2a in ace-
Having the optimal conditions in hand, we focused
tonitrile under aerobic conditions, catalyzed by sever- our attention on the reaction scope of a variety of ar-
al organic dyes at room temperature (Table 1). The omatic and aliphatic amines with 1a.
reaction furnished phosphoramidate 3a with low con-
As shown in Scheme 2, the presence of electron-do-
version at room temperature. Among organic dyes, nating substituents, such as 4-OMe (3a), 3,4,5-OMe
Rose Bengal (III) was proven to be the best dye in (3m), on the aromatic ring of the anilines produced
combination with green light for this study whereas the corresponding phosphoramidates in high yields,
other dyes such as Eosin Y (I) or Methylene Blue whilst that of a 2-OMe substituent gave slightly lower
(II), surprisingly, did not render any product (Table 1, yields. When methyl-substituted anilines were em-
entries 1 and 2). After screening of several solvents, it ployed, the final products were obtained in almost
was found that toluene gave comparable result to that quantitative yields (p-methylaniline-derived product
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Organophotocatalytic Synthesis of Phosphoramidates
Scheme 2. Substrate scope of aromatic amines.
3c, 97%; m-methylaniline-derived product 3d, 99%;
o-methylaniline-derived product 3e, 98%) regardless
of the substituent position. When an electron-with-
drawing substituted aniline (3k) and sterically con-
gested 1-naphthylamine (3l) were used, moderate
yields were achieved. We also examined the function-
al group tolerance with halogenated aromatics (3f–j).
All of the halogenated anilines produced the desired
products with extremely high yields under our reac-
tion conditions: 4-F (3f) 73%; 4-Cl (3g) 74%; 4-Br
(3h) 87%; 4-I (3i) 96%; 2-F (3j) 93%.
The only limitation of the present methodology is
the use of terminal vinylaniline because of its sensi-
tive radical nature which may give oligo- or polymeri-
zation by radical cations, or the use of heteroaromatic
amines such as 2-aminothiazole that decomposes
under the reaction conditions. It is noteworthy that
the pure products were obtained in most cases after
a simple acid-base work-up procedure without any
need for additional purification techniques.
Next, we investigated the reaction scope with more
challenging aliphatic amine substrates. Previously, ali-
phatic amines have been introduced in similar CDC
reactions with diethyl phosphite under organic dye-
À
À
Scheme 3. Competitive reactions between C P and N P
bond formation.
catalyzed photoredox reactions by the group of Ruep- Eq. (2) and Scheme 4]. These results are dependent
ing. However, the Kabachnik–Fields (K-F) product on the stabilization of tertiary or primary amine radi-
À
(i.e., a-amino phosphonate) was observed via C P cal cations, followed by the subsequent deprotonation
bond formation during the course of the reaction efficiency of proton at the a-position of amine radical
[Scheme 3, Eq. (4)].
cations by base (e.g., superoxide anion), which is gov-
In contrast to the work of Rueping, phosphorami- erned by the pKa value of the relevant acidic protons.
date products (3p and 3q) were selectively rendered For example, when tetrahydroisoquinoline was used,
À
in reasonable yields (42–59%) via N P bond forma- a mixture of the K-F product and the phosphorami-
tion when the reaction was performed in toluene date was found (14:1 ratio). Unfortunately, no prod-
under our optimized reaction conditions [Scheme 3, uct was observed when the reaction was tested with
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Marta Meazza et al.
(SET) process. The radical anion dye V is re-oxidized
to the ground-state dye by molecular oxygen, forming
the superoxide anion 5. Next, the superoxide anion 5
reacts with the phosphite 1a to liberate the phospho-
ryl radical 7 and hydrogen peroxide anion 6. The final
target molecule 3 is produced by the reaction of phos-
phoryl radical 7 and amine radical cation 4, followed
by the deprotonation of the protonated phosphorami-
date 8 by hydrogen peroxide anion 6.
Scheme 4. Substrate scope of aliphatic amines.
To verify the stabilization of amine radical cation
species, we decided to perform the reaction with an
secondary amines such as morpholine, piperidine or equal molar ratio of p-anisidine and p-cyanoaniline in
pyrrolidine. a single flask under the optimal reaction conditions.
Next, we studied the reaction with different phos- Gratifyingly, the phosphoramidate 3a derived from p-
phorus sources. As it is shown in Scheme 5, the reac- anisidine was exclusively formed, indicating that
tions with diphenyl phosphite (1b) or dibenzyl phos- a better ability of electron-donating group such as
phite (1c) render a mixture of products.
-OMe to stabilize amine radical cation preferentially
A proposed mechanism for the reaction is outlined (Scheme 7). In order to prove the radical nature of
in Scheme 6. The organic dye (Rose Bengal, III) ac-
cepts a photon from the visible-light source to popu-
late the excited-state dye (IV), which removes one
electron from the nitrogen atom of 2 to generate
amine radical cation 4 by a single-electron transfer
Scheme 7. Selective formation of phosphoramidate product
3a via stabilization of the amine radical cation species by
controlling the electronic properties of the substituents on
the aromatic ring of anilines.
Scheme 5. Substrate scope of phosphites.
the intermediates, the reaction was conducted with
1 equiv. of TEMPO. Under these conditions no prod-
uct was obtained, showing clearly that an intermedi-
ate radical is formed. Another fact that validates our
mechanistic proposal of the formation of intermediate
4 is the mixture of phosphoramidation and K-F prod-
ucts when tetrahydroisoquinoline was used.
The recyclability of Rose Bengal was also exam-
ined. The organic dye catalyst was recovered and
reused after completion of the reaction by simple
acid-base extraction. The recovered catalyst exhibited
similar results to those obtained in the first cycle: first
cycle (74% yield) and second cycle (67% yield).
Finally, we applied this protocol to the large-scale
production of the phosphoramidate 3i derived from
p-iodoaniline (Scheme 8). The reaction was repeated
on a 5.00 g scale of diethyl phosphite 1a with 2 equiv.
of p-iodoaniline 2i. The product 3i was isolated in
82% yield without any assistance by chromatographic
purification.
In summary, we have developed a new methodolo-
gy for the synthesis of phosphoramidates catalyzed by
organic dyes and light (a renewable energy) with ex-
cellent results. This methodology complements and
Scheme 6. Plausible mechanism for the synthesis of phos-
phoramidates.
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Organophotocatalytic Synthesis of Phosphoramidates
R.R., M.M., and L.S. thank EU for a CIG grant FP7-MC-
CIG-618237.
References
Scheme 8. Large-scale production of 3i.
[1] B. M. Trost, Angew. Chem. 1995, 107, 285–307; Angew.
Chem. Int. Ed. Engl. 1995, 34, 259–281.
[2] For reviews on photoredox catalysis, see: a) C. K. Prier,
D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013,
113, 5322–5363; b) T. P. Yoon, M. A. Ischay, J. Du, Nat.
Chem. 2010, 2, 527–532.
[3] a) R. Narayan, K. Matcha, A. P. Antonchick, Chem.
Eur. J. 2015, 21, 14678–14693; b) C.-J. Li, Z. Li, Pure
Appl. Chem. 2006, 78, 935–945.
improves the existing technologies eliminating the use
of metals or halide reagents and, importantly, the re-
quirement of tedious purification steps. For these rea-
sons, we believe that this new process fulfills all the
requirements of green chemistry and opens a new
gate to the development of more sustainable method-
ologies based on these observations. Further studies
towards the use of more reactive dyes and expanding
the scope of the reaction to other interesting com-
pounds (alcohols, amides, thiols, etc.) are ongoing in
our laboratory.
[4] M. Rueping, S. Zhu, R. M. Koenigs, Chem. Commun.
2011, 47, 8679–8681.
[5] a) D. R. Phillips, M. Uramoto, K. Isono, J. A. McClos-
key, J. Org. Chem. 1993, 58, 854–859; b) J. I. Guijarro,
J. E. Gonzµlez-Pastor, F. Baleux, J. L. San Millµn,
M. A. Castilla, M. Rico, F. Moreno, M. Delepierre, J.
Biol. Chem. 1995, 270, 23520–23532; c) R. A. Dwek,
Chem. Rev. 1996, 96, 683–720; d) M. J. Berridge, R. F.
Irvine, Nature 1989, 341, 197–205; e) M. J. Berridge,
R. F. Irvine, Nature 1984, 312, 315–321.
Experimental Section
[6] a) P. Garcia, Y. Y. Lau, M. R. Perry, L. L. Schafer,
Angew. Chem. Int. Ed. 2013, 52, 9144–9148; b) T.-M.
Nguyen, S. Chang, B. Condon, R. Slopek, E. Graves,
M. Yoshioka-Tarver, Ind. Eng. Chem. Res. 2013, 52,
4715–4724.
[7] a) S. E. Denmark, G. L. Beutner, Angew. Chem. 2008,
120, 1584–1663; Angew. Chem. Int. Ed. 2008, 47, 1560–
1638; b) O. Molt, T. Schrader, Synthesis 2002, 2633–
2670.
General Procedure
In a closed vial were added in this sequence: the organic
dye Rose Bengal (73 mg, 0.072 mmol, 20 mol%), the amine
(0.724 mmol, 2 equiv.), the solvent (1.5 mL) and diethyl
phosphite (47 mL, 0.362 mmol, 1 equiv.). The reaction mix-
ture was stirred at 708C in the photoreactor under green
light (see Table 1 for reaction times). CHCl3 was added to
the crude mixture and the organic phase was washed with
0.5M HCl (3”20 mL), then with saturated aqueous
NaHCO3 solution (3”20 mL). The organic phases were
dried over MgSO4, filtered and the solvent was evaporated
under vacuum to afford the desired phosphoramidate.
[8] R. F. Roush, E. M. Nolan, F. Lçhr, C. T. Walsh, J. Am.
Chem. Soc. 2008, 130, 3603–3609.
[9] M. Ding, F. Zhou, Y.-L. Liu, C.-H. Wang, X.-L. Zhao,
J. Zhou, Chem. Sci. 2011, 2, 2035–2039.
[10] J.-S. Yu, F.-M. Liao, W.-M. Gao, K. Liao, R.-L. Zuo, J.
Zhou, Angew. Chem. 2015, 127, 7489–7495; Angew.
Chem. Int. Ed. 2015, 54, 7381–7385.
Acknowledgements
[11] F. R. Atherton, H. T. Openshaw, A. R. Todd, J. Chem.
Soc. 1945, 660–663.
H.G. and R.R. acknowledge International Science & Tech-
nology Cooperation Program of China (2014DFE40130) for
financial support. M.M. and RR acknowledge the European
Regional Development Fund (ERDF) for co-financing the
AI-CHEM – Chem project (No. 4061) through the INTER-
REG IV A France (Channel) – England cross-border cooper-
ation Programme. M.M., A.K., L.S. and R.R. are grateful
for the EPSRC Core Capability Funding (EP/K039466/1).
J. W. Y. thanks the NRF Nano·Material Technology Develop-
ment Program (2012M3A7B4049652) for financial support.
[12] a) R. L. Letsinger, M. E. Schott, J. Am. Chem. Soc.
1981, 103, 7394–7396; b) J. Nielsen, M. H. Caruthers, J.
Am. Chem. Soc. 1988, 110, 6275–6276; c) I. Wilkening,
G. del Signore, C. P. R. Hackenberger, Chem. Commun.
2008, 2932–2934.
[13] a) J. Fraser, L. J. Wilson, R. K. Blundell, C. J. Hayes,
Chem. Commun. 2013, 49, 8919–8921; b) X. Jin, K. Ya-
maguchi, N. Mizuno, Org. Lett. 2013, 15, 418–421.
[14] J. Dhineshkumar, K. R. Prabhu, Org. Lett. 2013, 15,
6062–6065.
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