Palladium-catalyzed C-H arylation using phosphoramidate as a directing group at room temperature

Article abstract of DOI:10.1021/ol4009987

This communication describes the first phosphoramidate directing group for synthetically useful arylation. Remarkably, the nature of a new directing group drives selective C-H bond activation to afford diverse N-aryl phosphoramidates in good to excellent yields at room temperature.

Full text of DOI:10.1021/ol4009987

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed CÀH Arylation Using
Phosphoramidate as a Directing Group at
Room Temperature
Bathoju Chandra Chary,† Sunggak Kim,*,† Youngchul Park,‡ Jinsik Kim,‡ and Phil Ho Lee*,‡
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore and
Department of Chemistry, Kangwon National University, Chuncheon 200-701,
Republic of Korea
sgkim@ntu.edu.sg; phlee@kangwon.ac.kr
Received April 10, 2013
ABSTRACT
This communication describes the first phosphoramidate directing group for synthetically useful arylation. Remarkably, the nature of a new
directing group drives selective CÀH bond activation to afford diverse N-aryl phosphoramidates in good to excellent yields at room temperature.
The development of methods for new CÀC and
CÀheteroatom bond formation is a critical challenge in
organic chemistry, and in this regard, a CÀH bond activa-
tion reaction represents one of the most promising ap-
proaches over the past few years.1 In order for a CÀH
bond activation reaction to be of a general synthetic
nature, the desired CÀH bond in an organic molecule
must be selectively activated over all the CÀH bonds
present in the molecule. Especially in benzene derivatives,
because there is a slight difference in reactivity between the
CÀH bonds, a system to control regioselectivity is highly
necessary. To overcome uncontrolled site selectivity, a
number of examples of CÀC and CÀheteroatom bond
forming reactions have been reported through introduc-
tion of a directing group in recent years. The most widely
used directing groups in Pd(II)-catalyzed CÀH activation
(2) For carboxylic acids in Pd(II)-catalyzed CÀH activations, see: (a)
Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315.
(b) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010,
49, 6169. (c) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 14137. (d) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 6097. (e) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am.
Chem. Soc. 2008, 130, 17676. (f) Mei, T.-S.;Giri, R.; Maugel, N.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2008, 47, 5215. (g) Miura, M.; Tsuda, T.; Satoh, T.;
Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998, 63, 5211.
(3) For carboxylic amides, see: (a) Ano, Y.; Tobisu, M.; Chatani, N.
Org. Lett. 2012, 14, 354. (b) Ano, Y.; Tobisu, M.; Chatani, N. J. Am.
Chem. Soc. 2011, 133, 12984. (c) Rakshit, S.; Grohmann, C.; Besset, T.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (d) Guimond, N.;
Gouliaras, C.; Fagnou, K. J. J. Am. Chem. Soc. 2010, 132, 6908. (e)
Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972. (f) Tobisu, M.;
Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (g) Wang, D.-H.; Wasa,
M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. (h) Li, B.-J.;
Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115. (i)
Shi, Z.; Li, B. X.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang,
Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (j) Zaitsev, V.; Dauglulis, O.
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† Nanyang Technological University.
‡ Kangwon National University.
(1) (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
633. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094. (c) Phipps, R. J.; Gaunt, M. J. Science 2009, 323,
1593. (d) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009,
42, 1074. (e) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.,
Int. Ed. 2009, 48, 9792. (f) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (g) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147. (h) Ackermann, L. Chem. Rev. 2011, 111, 1315. (i)
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Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011,
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r
10.1021/ol4009987
XXXX American Chemical Society

reactions utilize carboxylic derivatives2À6 along with
N-heterocycles7 and aniline derivatives.8 Although use of a
directing group has become a practical strategy for allow-
ing selective functionalization, the development of new
practical directing groups is still a significant issue in the
field of straightforward reactions.
Recently, Pd-catalyzed arylation of aryl phosphates olefina-
tion of aryl hydrogen phosphates were reported.13 Herein,
we disclose the first protocol for the Pd(II)-catalyzed CÀH
arylation14 of N-aryl phosphoramidates using di(aryl)-
iodonium triflate (Ar2IOTf) as an aryl reagent (Scheme 1).
Because the carbon species and their phosphorus coun-
terparts have analogous characters regarding reactivity
and biological activity,9 we imagined that functionaliza-
tion of N-aryl phosphoramidatesvia CÀH bond activation
would be an advantage over other methods. In addition,
N-aryl phosphoramidates are among the most prominent
synthetic derivatives due to versatile functionalities for
further transformations.10 Despite this interest in phos-
phoramidates, synthetic methods for N-aryl phosphora-
midate derivatives are still limited.11 A strategy using N-
aryl phosphoramidates as a directing group for CÀH bond
activation, therefore, represents a relevant example for
efficient synthesis of functional molecules which could be
transformed into useful building blocks as well. As far as
we know, N-aryl phosphoramidates have not been used in
the transition-metal-catalyzed CÀH activation reactions.12
Scheme 1. Pd-Catalyzed CÀH Arylation Using Phosphoramidates
We initiated the study by examining the reaction between
N-tolyl phosphoramidate 1a and Ph2IOTf in 1,4- dioxane at
60 °C (Table 1). The reaction was first carried out in the
absence of additives which did not yield any desired product
2a (Table 1, entry 1). Unfortunately, the arylation of 1a did
not proceed under both basic and solely acidic conditions,
and 1a remained quantitatively (entries 2À4). To trigger the
reaction, we extensively tested various additives which are
known to positively influence Pd-catalyzed CÀH activation
reactions (see the Supporting Information). However
Ag2CO3 and Cu(OAc)2 proved to be incompatible with the
reaction conditions (entries 5 and 6). Gratifyingly, we ob-
served that arylation of N-aryl phosphoramidate proceeded
in the presence of catalytic amounts of both TfOH and Cu2O
(3 equiv), giving the arylated product 2a in 25% yield in 1,4-
dioxane at 60 °C after 16 h (entry 7). After surveying various
copper salts to enhance the catalytic turnover, we found that
CuO showed the highest efficiency (78%) compared with
other salts (entry 9). The best result was obtained by using the
catalyst Pd(OAc)2 (5 mol %), TfOH (20 mol %), and CuO
(3 equiv) in 1,4-dioxane at room temperature after 3 h,
(5) For ureas, see: (a) Nishikata, T.; Abela, A. R.; Lipshutz, B. H.
Angew. Chem., Int. Ed. 2010, 49, 781. (b) Nishikata, T.; Abela, A. R.;
Huang, S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 4978. (c)
Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, F. G.; Tyler, S. N. G.;
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Chem., Int. Ed. 2009, 48, 1830. (d) Houlden, C. E.; Hutchby, M.; Bailey,
ꢀ
C. D.; Ford, F. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn,
K. I. J. Am. Chem. Soc. 2008, 130, 10066.
(6) For esters: Xiao, B.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L.
J. Am. Chem. Soc. 2010, 132, 468.
(7) For pyridine derivatives, see: (a) Chernyak, N.; Dudnik, A. S.;
Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 8270. (b) Hull,
K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047.
(c) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett.
2006, 8, 2523. For oxazoline derivatives, see: (a) Chen, X.; Li, J.-J.; Hao,
X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78. (b)
Giri, R.; Wasa, M.; Breazzano, S. P.; Yu, J.-Q. Org. Lett. 2006, 8, 5685.
(c) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112.
(8) (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leewen, P. W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586. (b) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin,
A. C. Org. Lett. 2012, 14, 728. (c) Chen, J.; Song, G.; Pan, C.-L.; Li, X.
Org. Lett. 2010, 12, 5426.
Table 1. Optimization of the Pd-Catalyzed CÀH Arylationa
(9) (a) Dillon, K. B.; Mathey, F.; Nixon, J. F. In Phosphorus: The
Carbon Copy; John Wiley & Sons: Chichester, 1998. (b) Quin, L. D. In A
Guide to Organophosphorus Chemistry; John Wiley & Sons: New York,
2000; Chapter 11.
(10) (a) Ciufolini, M. A.; Spencer, G. O. J. Org. Chem. 1989, 54, 4739.
(b) Yadav, L. D. S.; Rai, A.; Rai, V. K.; Awasthi, C. Tetrahedron Lett.
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Tetrahedron Lett. 2007, 48, 8037. (d) Yadav, L. D. S.; Srivastava, V. P.;
Patel, R. Tetrahedron Lett. 2008, 49, 5652. (e) Basavaiah, D.; Reddy,
B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447. (f) Rai, A.; Yadav,
L. D. S. Org. Biomol. Chem. 2011, 9, 8058. (g) Minami, T.; Ogata, M.;
Hirao, I. Synthesis 1982, 231.
(11) (a) Lukanov, L. K.; Venkov, A. P.; Mollov, N. M. Synthesis
1985, 971. (b) Harger, M. J. P.; Westlake, S. Tetrahedron 1982, 38, 3073.
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hedron Lett. 2006, 47, 6281.
(12) For the use of phosphinites and phosphites as directing groups,
see: (a) Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc. 1986, 108, 2728. (b)
Oi, S.; Watanabe, S.-i.; Fukita, S.; Inoue, Y. Tetrahedron Lett. 2003, 44,
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M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112.
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entry
additive
temp (°C)
yield (%)
1
À
60
60
60
60
60
60
60
100
60
25
25
<1
<1
<1
<1
<1
<1
25
71
78
84b
<1c
2
NaOAc
3
AcOH
4
TfOH
5
TfOH, Ag2CO3
TfOH, Cu(OAc)2
TfOH, Cu2O
TfOH, CuO
TfOH, CuO
TfOH, CuO
TfOH, CuO
6
7
8
9
10
11
a Conditions: 1a (0.3 mmol), 5 mol % Pd(OAc)2, Ph2IOTf (1.2 equiv),
NaOAc, AcOH and TfOH (20 mol % each), Ag2CO3, Cu(OAc)2, Cu2O
and CuO (3 equiv each), and 1,4-dioxane (1.2 mL), 16 h. b 3 h. c Reaction
was carried out without Pd(OAc)2 catalyst.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Arylation of N-Aryl Phosphoramidatesa
Scheme 3. Arylation of N-Alkyl-N-aryl Phosphoramidatesa
a Conditions: 3 (0.3 mmol), 5 mol % Pd(OAc)2, Ph2IOTf (1.2 equiv),
20 mol % TfOH, CuO (3 equiv), and 1,4-dioxane (1.2 mL). b 10 mol %
Pd(OAc)2 was used. c Reaction was carried out at 60 °C.
a Conditions: 1 (0.3 mmol), 5 mol % Pd(OAc)2, Ph2IOTf (1.2 equiv),
20 mol % TfOH, CuO (3 equiv), and 1,4-dioxane (1.2 mL). b 10 mol %
Pd(OAc)2 was used. c Reaction was carried out at 60 °C.
functionalization on the aromatic ring, which provided
2d in 80% yield. The arylation of phosphoramidates
(1e and 1f) having an electron-donating methyl or ethyl group
on the meta position of phenyl ring proceeded smoothly to
give their corresponding products (2e and 2f) in 86% and
89% yields, respectively. The 4-tert-butyl substituted sub-
strate (1g) underwent monophenylation, which produced
2g in 76% yield. Similar results were obtained for methoxy
and ethoxy substituted arenes (2h, 2i, and 2j). Moreover,
subjecting the meta and para dimethoxy-substitutedN-aryl
phosphoramidate 1l to the Pd catalyst afforded the desired
CÀH phenylated product 2l in 82% yield. However,
phenoxy-substituited substrate 1k was less reactive and
the phenylated product 2k was isolated in 70% yield. The
tolerance of the bromo group is especially useful due to
further functionalization.
which gave rise to 2a in 84% yield (entry 10). Notably, the
arylation of phosphoramidates revealed that the reaction
carried out at room temperature vs high temperatures
provided a slightly higher yield (entries 8À10). A control
reaction in the absence of the palladium catalyst was carried
out with each reagent including the CuO additive and did not
yield any arylated product (entry 11). When we complemen-
tarily examined iodobenzene and phenylboronic acid as aryl
reagents, they provided none of the CÀH activated product.
In addition, diethyl phosphoramidate gave the best result
among methyl, isopropyl, and cyclic phosphoramidates (see
the Supporting Information).
As summarized in Scheme 2, various substrates were
applied to the standard conditions to determine the scope
and limitations of the present methodology. Arylation of
electron-neutral substrate 1b afforded the desired mono-
phenylated product 2b selectively. Phosphoramidate 1c
having an ortho ethyl group was converted to the corre-
sponding CÀH phenylated compound 2c in 91% yield
at room temperature. In the substrate containing a ben-
zylic CÀH bond site, this condition was selective for
With these results in hand, we obtained Pd-catalyzed
product 4a selectively, indicating that a N-alkyl-N-aryl
phosphoramidate was a good substrate for selective
CÀH bond functionalization (Scheme 3). Likewise, phos-
phoramidate 3b having a para methyl group proceeded
smoothly to give rise to the corresponding CÀH pheny-
lated compound 4b in 75% yield. The phosphoramidates
(3c and 3d) with a methoxy group on the meta and para
position of the phenyl ring furnished 4c (83%) and 4d
(75%). N-Aryl-N-methyl phosphoramidates with a chlo-
ride or bromide group on the phenyl ring also afforded the
desired products (4e, 4f, and 4g) in good yields. The halide
(14) (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S.
J. Am. Chem. Soc. 2006, 128, 4972. (b) Phipps, R. J.; Grimster, N. P.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Arylation of N-Aryl Phosphoramidate with Ar2-
IOTfa
Scheme 5. A Plausible Mechanism
Remarkably, the chloride substituent was also well toler-
ated on the oxidant. Phosphoramidate 1c was reacted with
di-(4-chlorophenyl)iodonium triflate to provide 5e in 53%
yield together with the starting material (1c, 32%).
On the basis of the preliminary studies,15 the mechanism
of this catalysis is proposed as shown in Scheme 5. Co-
ordination of N-aryl phosphoramidates to the Pd(II)
catalyst and subsequent CÀH activation form the six-
membered palladacycle A. Then, the aryl Pd(II) intermedi-
ate (A) could be oxidized to the Pd(IV) species (B) by
Ar2IOTf. Although the precise role of the copper salt still
remains to be elucidated, it may be reasonable to postulate
that CuO plays a constructive role as a base for generation
of intermediate A. It tentatively supports this possible path-
way for which a stoichiometric amount of CuO is required to
achieve full conversion; using 20 mol % of CuO gave only
22% desired product 2a (see Supporting Information).
In summary, we have developed a novel protocol to
effect CÀH arylation that takes place at room temperature
using synthetically useful N-aryl phosphoramidates as a
new directing group with di(aryl)iodium triflate (Ar2IOTf)
for the first time. The present method also could be applied
for N-alkyl-N-aryl phosphoramidates. A stoichiometric
amount of CuO was crucial for efficient Pd(II) catalysis
for the arylation of phosphoramidates.
a Conditions: 1 or 3 (0.3 mmol), 5 mol % Pd(OAc)2, Ar2IOTf
(1.2 equiv), 20 mol % TfOH, CuO (3 equiv), and 1,4-dioxane (1.2 mL).
b Recovery yield of starting material.
functionality affords a handle tointroduce other groupson
the phenyl ring via coupling reactions. The naphthalene-
based substrate (3h) gave corresponding product 4h in
75% yield without any difficulties as well albeit at 60 °C.
Similarly, N-ethyl-N-(3-methylphenyl) phosphoramidate
(3i) worked well. N-Butyl-N-phenyl phosphoramidate (3j)
was also an efficient substrate toward the Pd-catalyzed
arylation. These results suggested that the present method
could be applied in not only N-aryl- but also N-alkyl-N-
aryl-phosphoramidates.
Next, we evaluated the reactivity of this transformation
with a couple of hypervalent iodine coupling partners
(Scheme 4). The Ar2IOTf containing electron-donating
methyl substituent was observed to be compatible with
the Pd-catalyzed CÀH arylation of N-aryl phosphoami-
dates. Under the optimum reaction conditions, treatment
of phosphoramidate 1c and 1f having an ortho or meta
ethyl group with di-(4-methylphenyl)iodonium triflate
afforded the desired product 5a and 5b in 81% and 78%
yields, respectively. In addition, N-alkyl-N-aryl phosphor-
amidates were good substrates for selective CÀH aryla-
tion. Exposure of 3a and 3i to the Pd catalyst in the
presence of di-(4-methylphenyl)iodonium triflate (1.2 equiv)
gave rise to 5c and 5d in 80% and 81% yields, respectively.
Acknowledgment. S.K. acknowledges financial support
from Nanyang Technological University, and P.H.L. thanks
the NCRL (2012-0001245) funded by the National Research
Foundation of Korea. P.H. thanks Prof. E. J. Yoo (KNU)
for helpful discussions and manuscript preparation.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) (a) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924.
(b) Spencer, J.; Chowdhry, B. Z.; Mallet, A. I.; Rathnam, R. P.; Adatia,
T.; Bashall, A.; Rominger, F. Tetrahedron 2008, 64, 6082. (c) Deprez,
N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234. (d) Xiao, B.;
Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc.
2010, 132, 468.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX