Asymmetric Synthesis of P-Stereogenic Phosphinic Amides via Pd(0)-Catalyzed Enantioselective Intramolecular C-H Arylation

Article abstract of DOI:10.1021/acs.orglett.5b00122

(Chemical Equation Presented). The palladium-catalyzed enantioselective intramolecular C-H arylation of N-(2-haloaryl)-P,P-diphenylphosphinic amides furnishes P-stereogenic phosphine oxide derivatives in 61-99% yield with 88-97% ee. The catalyst generated in situ from a TADDOL-derived phosphoramide ligand and Pd(dba)₂ is optimum in terms of yield and enantioselectivities.

Full text of DOI:10.1021/acs.orglett.5b00122

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of P‑Stereogenic Phosphinic Amides via Pd(0)-
Catalyzed Enantioselective Intramolecular C−H Arylation
Lantao Liu,*,† An-An Zhang,†,§ Yanfang Wang,‡,§ Fuqiang Zhang,† Zhenzhen Zuo,† Wen-Xian Zhao,†
Cui-Lan Feng,† and Wenjin Ma*,‡
†College of Chemistry and Chemical Engineering, Shangqiu Normal University, 298 Wenhua Road, Shangqiu, Henan 476000, China
‡School of Chemistry & Material Science, Shanxi Normal University, Linfen 041004, China
S
* Supporting Information
ABSTRACT: The palladium-catalyzed enantioselective intramolecular C−H arylation of N-(2-haloaryl)-P,P-diphenylphosphinic
amides furnishes P-stereogenic phosphine oxide derivatives in 61−99% yield with 88−97% ee. The catalyst generated in situ from
a TADDOL-derived phosphoramide ligand and Pd(dba)2 is optimum in terms of yield and enantioselectivities.
hiral phosphorus compounds constitute a class of
Cprominent compounds typically used as versatile ligands
or oganocatalysts in asymmetric catalysis.1 Particularly
attractive are those possessing chiral centers at phosphorus
atoms (P-stereogenic phosphines) which exhibit excellent
enantioselectivities in asymmetric catalysis, and some have
also been applied in the pharmaceutical industry. The
usefulness of the P-stereogenic phosphines has made their
stereoselective synthesis the subject of extensive research.2
Significant methods for stoichiometric asymmetric synthesis
of P-stereogenic phosphines have been developed on the basis
of the use of chiral auxiliaries3 and enantioselective
deprotonation of prochiral phospines.4 More efficient and
atom-economical pathways become accessible with the advent
of transition-metal-catalyzed methods such as enantioselective
cycloaddition of symmetrical dialkynylphosphine oxides,5
asymmetric ring-closing metathesis of symmetrical dialkenyl-
phosphine oxides,6 asymmetric alkylation,7 and arylation8 of
secondary phosphines as well as their catalytic asymmetric
conjugate addition to electron-deficient olefins.9 Very recently,
chiral Brønsted acid catalyzed phosphoramidic acid additions to
alkenes have been reported for the synthesis of C- and P-chiral
phosphoramidates.10 Despite these elegant approaches, cata-
lytic asymmetric methods for highly enantioselective synthesis
of P-stereogenic phosphines, especially the methods for P-
stereogenic phosphorus heterocycles, remain undeveloped.11
Asymmetric C−H direct functionalization has been a
challenging task in asymmetric catalysis.12 Recently, Pd(0)-
catalyzed enantioselective functionalization of enantiotopic C−
H bonds has been successfully applied to asymmetric
construction of quaternary carbon-stereogenic centers,13
silicon-stereogenic centers14 and planar chirality15 (eq 1).
The application of the asymmetric C−H functionalization
process to construct P-chiral phosphines would be highly
desirable but remains undeveloped.16 Herein, we report
asymmetric synthesis of phosphorus heterocycles with P-
stereogenic center through palladium-catalyzed enantioselective
intramolecular C−H arylation of N-(2-haloaryl)-P,P-dipheny-
phosphinic amides with excellent enantioselectivity under mild
conditions.17
The achiral substrate N-(2-bromophenyl)-N-methyl-P,P-
diphenylphosphinamide (1a) was prepared by the acylation
of 2-bromoaniline with diphenylphosphinic chloride and the
subsequent N-methylation with methyl iodide. When 1a was
treated with Pd(dba)2 (8 mol %), Cy3P (10 mol %), PivOH
(30 mol %), and Cs2CO3 (1.5 equiv) in toluene at 100 °C for
10 h, the C−H bond of the phenyl ring was cleaved and
arylated intramolecularly to generate racemic 2a in 98% isolated
yield (Scheme 1).
A plausible mechanistic pathway for the formation of 2a is
depicted in Scheme 2. Initially, oxidative addition of the
C(sp2)−Br bond onto palladium(0) generates arylpalladium
bromide A. The pivalate anion replaces the bromide ligand on
palladium to afford palladium pivalate B. Then, a C−H bond
Received: January 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00122
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Intramolecular C−H Arylation Reaction of 1a
Table 1. Selected Optimization of Reaction Conditions
Scheme 2. Proposed Mechanism
b
c
entry
L
addtive (mol %) t (°C) yield (%) ee (%)
1
(R)-BINAP
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (40)
AdOH (40)
TMBA (40)
PivOH (40)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
66
33
34
73
28
0
4
2
2
(R)-H8−BINAP
(R)-SEGPHOS
on the phenyl ring is cleaved to generate the seven-membered
di(aryl)palladium species C.17 Reductive elimination ensues to
furnish phosphorus heterocycle 2a possessing P-stereogenic
center along with regeneration of the palladium(0) species.
Then, various types of ligands were employed to realize the
asymmetric transformation, and the selected examples are listed
in Table 1. The commercial available bidentate ligand (R)-
BINAP gave 2a in 66% yield with only 4% ee (Table 1, entry
1). However, no promising result was observed when other
bidentate ligands, such as (R)-H8-BINAP, (R)-SEGPHOS,
(R,R)-DIOP, and (R,S)-PPFA, were used as chiral ligands
(Table 1, entries 2−5). We then turned our attention to
monodentate phosphoamidites ligands. To our disappointment,
BINOL-derived phosphoamidites L1−3 showed no enantiose-
lectivity either (Table 1, entries 6−8). Pleasingly, when
TADDOL-derived phosphoamidite L5 (R1 = Me) was used
as ligand, the reaction proceeded smoothly to afford 2a in 64%
yield with 82% ee (Table 1, entry 12). The better result (75%
yield with 86% ee) was obtained when L6 (R1 = Et) was used
as ligand (Table 1, entries 11). However, L7 (R1 = Ph)
exhibited poor reactivity and enantioselectivity (Table 1, entry
10), which indicates that the amine portion of the
phosphoamidites also has important influence on the reactivity
and enantioselectivity of the reaction. Further modification of
the amine portion with cylic substituents (piperidine or
morpholine) gave ligands L8 and L9 that were comparable to
L7 (Table 1, entries 13 and 14). Replacement of the phenyl
substituents by other aryl groups (3,5-dimethylphenyl, 4-
methoxyphenyl, 4-fluorophenyl, 2-naphthyl) had no positive
or even negative influence on the reactivity and enantiose-
lectivity (Table 1, entries 15−18).
3
13
3
4
(R,R)-DIOP
5
(R,S)-PPFA
L1
4
6
0
7
L2
50
0
1
8
L3
0
9
L4
30
64
75
26
84
73
40
75
50
69
60
52
98
56
13
99
42
82
86
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
L5
L6
L7
L8
77
85
73
53
86
82
92
92
93
91
97
95
L9
L10
L11
L12
L13
L6
L6
50
L6
60
L6
60
L6
60
d
24
L6
60
a
Reaction conditions: 1a (0.05 mmol) in 3 mL of toluene at the
b
c
indicated temperature. Isolated yield. The ee values were determined
by HPLC analysis. In hexane. dba = (E,E)-dibenzylideneacetone,
PivOH = pivalic acid, AdOH = adamantoic acid, TMBA = 2,4,6-
trimethylbenzoic acid.
d
aryl chloride (X = Cl) failed to take part in this reaction, aryl
iodide (X = I) reacted smoothly to give 2a in 95% yield with
93% ee which is comparable with the result of aryl bromide,
whereas no reaction occurred when unprotected amide (R =
H) was subjected to the optimized reaction conditions, the
The substrate scope was investigated under the optimized
conditions and the results are summarized in Table 2. Although
B
DOI: 10.1021/acs.orglett.5b00122
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a c
−
Table 2. Substrate Scope
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data for new com-
pounds, and details of X-ray crystallographic analysis for 2f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liult05@iccas.ac.cn.
*E-mail: ma_w_j@163.com.
Author Contributions
§A.-A.Z. and Y.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21202095, 21172139, 21271125)
and the Program for Science & Technology Innovation Talents
in Universities of Henan Province (14HASTIT016).
REFERENCES
■
(1) Recent selected reviews: (a) Luhr, S.; Holz, J.; Borner, A.
̈
ChemCatChem 2011, 3, 1708−1730. (b) Zhou, Q.-L., Ed. Privileged
Chiral Ligands and Catalysts; Wiley-VCH: Weinheim, 2011. (c) Ojima,
I., Ed. Catalytic Asymmetric Synthesis, 3rd ed.; Wiley: Hoboken, NJ,
2010. (d) Borner, A., Ed. Phosphorus Ligands in Asymmetric Catalysis;
Wiley-VCH: Weinheim, 2008; Vols. I-III. (e) Guiry, P. J.; Saunders, C.
P. Adv. Synth. Catal. 2004, 346, 497−537. (f) Tang, W.; Zhang, X.
Chem. Rev. 2003, 103, 3029−3070.
a
Reaction conditions: amide 1 (0.05 mmol, 1.0 equiv), Pd(dba)2 (8
mol %), L6 (10 mol %), Cs2CO3 (1.5 equiv), PivOH (40 mol %),
hexane (3 mL), 60 °C, 10 h. Isolated yield. Determined by chiral
HPLC.
(2) (a) Fabre, B. Acc. Chem. Res. 2010, 43, 1509−1518. (b) Tarafder,
K.; Surendranath, Y.; Olshansky, J. H.; Alivisatos, A. P.; Wang, L.-W. J.
Am. Chem. Soc. 2014, 136, 5121−5131. (c) Tropiano, M.; Kilah, N. L.;
Morten, M.; Rahman, H.; Davis, J. J.; Beer, P. D.; Faulkner, S. J. Am.
Chem. Soc. 2011, 133, 11847−11849. Reviews on P-stereogenic
phosphorus compounds: (d) Yao, Q.; Wang, A.; Pu, J.; Tang, Y. Chin.
J. Org. Chem. 2014, 34, 292−303. (e) Kolodiazhnyi, O. I. Tetrahedron:
b
c
amides with bulkier N-protecting groups furnish the desired
cyclic products 2b,c in good yield albeit with slightly lower
enantioselectivity. The substrates derived from substituted 2-
bromoanilines successfully took part in the reaction affording
the products 2d−l with excellent enantioselectivities ranging
from 92 to 97% ee. Compound 2m with an N-benzyl group was
obtained in excellent enantioselectivity but with poor yield.
Products 2n−p bearing groups at the para-position of the P-
phenyl ring can also be prepared by this method. Product 2q
containing a methyl group ortho to the phosphorus atom was
obtained with poor yield and excellent ee. Two isomers, 2r and
2r′, were obtained when substrate containing a methyl group
meta to the phosphorus atom was tested. Notably, various
useful substituents including −F, −CF3, −CN, and −Cl are well
tolerated. The absolute configuration of 2f was assigned as R by
X-ray crystallographic analysis.18
In conclusion, we have developed a concise way to synthesize
cyclic P-chiral phosphinic amides through Pd-catalyzed
enantioselective C−H bond arylation of prochiral N-(2-
haloaryl)-P,P-diphenylphosphinc amides. The method presents
an example of catalytic asymmetric construction of P-
stereocenters with excellent enantioselectivity by enantioselec-
tive C−H bond functionalization.
́
Asymmetry 2012, 23, 1−46. (f) Juge, S. Phosphorus, Sulfur Silicon. 2008,
183, 233−248. (g) Grabulosa, A.; Granell, J.; Muller, G. Coord. Chem.
Rev. 2007, 251, 25−90. (h) Wozniak, L. A.; Okruszek, A. Chem. Soc.
Rev. 2003, 32, 158−169. (I) Kolodiazhnyi, O. I. Tetrahedron:
Asymmetry. 1998, 9, 1279−1332. (j) Pietrusiewicz, K. M.; Zablocka,
M. Chem. Rev. 1994, 94, 1375−1411.
(3) (a) Selected examples: Nikitin, K.; Rajendran, K. V.; Muller-
̈
Bunz, H.; Gilheany, D. G. Angew. Chem., Int. Ed. 2014, 53, 1906−1909.
(b) Rast, S.; Mohar, B.; Stephan, M. Org. Lett. 2014, 16, 2688−2691.
(c) Han, Z. S.; Goyal, N.; Herbage, M. A.; Sieber, J. D.; Qu, B.; Xu, Y.;
Li, Z.; Reeves, J. T.; Desrosiers, J.-N.; Ma, S.; Grinberg, N.; Lee, H.;
Mangunuru, H. P. R.; Zhang, Y.; Krishnamurthy, D.; Lu, B. Z.; Song, J.
J.; Wang, G.; Senanayake, C. H. J. Am. Chem. Soc. 2013, 135, 2474−
2477. (d) Berger, O.; Montchamp, J.-L. Angew. Chem., Int. Ed. 2013,
́ ́
52, 11377−11380. (e) Zijlstra, H.; Leon, T.; Cozar, A. d; Guerra, C. F.;
Byrom, D.; Riera, A.; Verdaguer, X.; Bickelhaupt, F. M. J. Am. Chem.
Soc. 2013, 135, 4483−4491. (f) Leon, T.; Riera, A.; Verdaguer, X. J.
Am. Chem. Soc. 2011, 133, 5740−5743. (g) Gatineau, D.; Giordano,
L.; Buono, G. J. Am. Chem. Soc. 2011, 133, 10728−10731. (h) den
Heeten, R.; Swennenhuis, B. H. G.; van Leeuwen, P. W. N. M.; de
Vries, J. G.; Kamer, P. C. J. Angew. Chem., Int. Ed. 2008, 47, 6602−
6605. (i) Xu, Q.; Zhao, C.-Q.; Han, L.-B. J. Am. Chem. Soc. 2008, 130,
12648−12655. (j) Juge,
́
S.; Genet, J. P. Tetrahedron Lett. 1989, 30,
2783−2786. (k) Kaloun, E. B.; Merdes, R.; Genet, J. P.; Uziel, J.; Juge,
́
S. J. Organomet. Chem. 1997, 529, 455−463. (l) Bauduin, C.; Moulin,
D.; Kaloun, E. B.; Darcel, C.; Juge,
4301.
́
S. J. Org. Chem. 2003, 68, 4293−
C
DOI: 10.1021/acs.orglett.5b00122
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) (a) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc.
1995, 117, 9075−9076. (b) Genet, C.; Canipa, S. J.; O’Brien, P.;
Taylor, S. J. Am. Chem. Soc. 2006, 128, 9336−9337. (c) Gammon, J. J.;
Gessner, V. H.; Barker, G. R.; Granander, J.; Whitwood, A. C.;
Strohmann, C.; O’Brien, P.; Kelly, B. J. Am. Chem. Soc. 2010, 132,
13922−13927. (d) Wu, X.; O’Brien, P.; Ellwood, S.; Secci, F.; Kelly, B.
Org. Lett. 2013, 15, 192−195. (e) Imamoto, T.; Watanabe, J.; Wada,
Y.; Masuda, H.; Yamada, H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi,
K. J. Am. Chem. Soc. 1998, 120, 1635−1636. (f) Ohashi, A.; Kikuchi, S.
I.; Yasutake, M.; Imamoto, T. Eur. J. Org. Chem. 2002, 15, 2535−2546.
(5) Nishida, G.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem.,
Int. Ed. 2008, 47, 3410−3413.
(16) Racemic example: (a) Guan, J.; Wu, G.-J.; Han, F. S. Chem.
Eur. J. 2014, 20, 3301−3305. During preparation of this manuscript,
palladium(II)-catalyzed intermolecular C−H arylation reaction pro-
ducing phosphinic amides in excellent enantioselectivity has appeared:
(b) Du, Z.-J.; Guan, J.; Wu, G. J.; Xu, P.; Gao, L. X.; Han, F. S. J. Am.
Chem. Soc. 2015, 137, 632−635.
(17) The pivalate ligand would facilitate C−H activation via
concerted metalation−deprotonation mechanism: (a) Garcia-
Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am.
Chem. Soc. 2006, 128, 1066−1067. (b) Lafrance, M.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 16496−16497.
(18) CCDC1042046 (2f) contains the supplementary crystallo-
graphic data for this paper.
(6) Harvey, J. S.; Malcolmson, S. J.; Dunne, K. S.; Meek, S. J.;
Thompson, A. L.; Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V.
Angew. Chem., Int. Ed. 2009, 48, 762−766.
(7) (a) Chan, V. S.; Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 2786−2787. Via Pt(II): (b) Scriban, C.; Glueck,
D. S. J. Am. Chem. Soc. 2006, 128, 2788−2789. (c) Scriban, C.; Glueck,
D. S.; Golen, J. A.; Rheingold, A. L. Organometallics. 2007, 26, 1788−
1800.
(8) (a) Brauer, D. J.; Hingst, M.; Kottsieper, K. W.; Liek, C.; Nickel,
T.; Tepper, M.; Stelzer, O.; Sheldrick, W. S. J. Organomet. Chem. 2002,
645, 14−26. (b) Moncarz, J. R.; Laritcheva, N. F.; Glueck, D. S. J. Am.
Chem. Soc. 2002, 124, 13356−13357. (c) Brunker, T. J.; Anderson, B.
J.; Blank, N. F.; Glueck, D. S.; Rheingold, A. L. Org. Lett. 2007, 9,
1109−1112. (d) Blank, N. F.; Moncarz, J. R.; Brunker, T. J.; Scriban,
C.; Anderson, B. J.; Amir, O.; Glueck, D. S.; Zakharov, L. N.; Golen, J.
A.; Incarvito, C. D.; Rheingold, A. L. J. Am. Chem. Soc. 2007, 129,
6847−6858. (e) Korff, C.; Helmchen, G. Chem. Commun. 2004, 530−
531. (f) Chan, V. S.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc.
2007, 129, 15122−15123.
(9) (a) Huang, Y.; Li, Y.; Leung, P.-H.; Hayashi, T. J. Am. Chem. Soc.
2014, 136, 4865−4868. (b) Li, C.; Bian, Q.-L.; Xu, S.; Duan, W.-L.
Org. Chem. Front. 2014, 1, 541−545. (c) Huang, Y.; Pullarkat, S. A.; Li,
Y.; Leung, P.-H. Inorg. Chem. 2012, 51, 2533−2540. (d) Kovacik, I.;
Wicht, D. K.; Grewal, N. S.; Glueck, D. S.; Incarvito, C. D.; Guzei, I.
A.; Rheingold, A. L. Organometallics. 2000, 19, 950−953.
(10) Toda, Y.; Pink, M.; Johnston. J. Am. Chem. Soc. 2014, 136,
14734−14737.
(11) Reviews on catalytic asymmetric synthesis of P-stereogenic
compounds: (a) Harvey, J. S.; Gouverneur, V. Chem. Commun. 2010,
46, 7477−7485. (b) Glueck, D. S. Chem.Eur. J. 2008, 14, 7108−
7117. (c) Glueck, D. S. Synlett. 2007, 17, 2627−2634.
(12) For reviews on enantioselective C−H activation, see: (a) Delord,
W. J.; Colobert, F. Chem.Eur. J. 2013, 19, 14010−14017. (b) Zheng,
C.; You, S.-L. RSC Adv. 2014, 4, 6173−6214.
(13) (a) Albicker, M. R.; Cramer, N. Angew. Chem., Int. Ed. 2009, 48,
9139−9142. (b) Nakanishi, M.; Katayev, D.; Besnard, C.; Kundig, E. P.
Angew. Chem., Int. Ed. 2011, 50, 7438−7441. (c) Anas, S.; Cordi, A.;
Kagan, H. B. Chem. Commun. 2011, 47, 11483−11485. (d) Katayev,
D.; Nakanishi, M.; Buergi, T.; Kundig, E. P. Chem. Sci. 2012, 3, 1422−
̈
1425. (e) Saget, T.; Lemouzy, S. J.; Cramer, N. Angew. Chem., Int. Ed.
2012, 51, 2238−2242. (f) Martin, N.; Pierre, C.; Davi, M.; Jazzar, R.;
Baudoin, O. Chem.Eur. J. 2012, 18, 4480−4484. (g) Saget, T.;
Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 12842−12845.
(h) Larionov, E.; Nakanishi, M.; Katayev, D.; Besnard, C.; Kundig,
̈
E. P. Chem. Sci. 2013, 4, 1995−2005. (i) Saget, T.; Cramer, N. Angew.
Chem., Int. Ed. 2013, 52, 7865−7868. (j) Pedroni, J.; Boghi, M.; Saget,
T.; Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 9064−9067.
(k) Katayev, D.; Larionov, E.; Nakanishi, M.; Besnard, C.; Kundig,
̈
E. P. Chem.Eur. J. 2014, 20, 15021−15030.
(14) Shintani, R.; Otomo, H.; Ota, K.; Hayashi, T. J. Am. Chem. Soc.
2012, 134, 7305−7308.
(15) (a) Deng, R.; Huang, Y.; Ma, X.; Li, G.; Zhu, R.; Wang, B.;
Kang, Y.-B.; Gu, Z. J. Am. Chem. Soc. 2014, 136, 4472−4475. (b) Gao,
D.-W.; Yin, Q.; Gu, Q.; You, S.-L. J. Am. Chem. Soc. 2014, 136, 4841−
4844. (c) Ma, X.; Gu, Z. RSC Adv. 2014, 4, 36241−36244. (d) Liu, L.;
Zhang, A.-A.; Zhao, R.-J.; Li, F.; Meng, T.-J.; Ishida, N.; Murakami, M.;
Zhao, W.-X. Org. Lett. 2014, 16, 5336−5338.
D
DOI: 10.1021/acs.orglett.5b00122
Org. Lett. XXXX, XXX, XXX−XXX