Nucleophilic addition to N-phosphinylimines by rare-earth-metal triflate/trifluoroacetic anhydride activation

Article abstract of DOI:10.1002/anie.200700694

(Chemical Equation Presented) Hydrated lanthanum triflate has been shown to be an effective and highly active Lewis acid catalyst for nucleophilic addition to N-phosphinylimines in the presence of trifluoroacetic anhydride (TFAA; see scheme). Unexpectedly

Full text of DOI:10.1002/anie.200700694

Communications
DOI: 10.1002/anie.200700694
Synthetic Methods
Nucleophilic Addition to N-Phosphinylimines by Rare-Earth-Metal
Triflate/Trifluoroacetic Anhydride Activation**
Winnie W. Ong, Aaron B. Beeler, Sarathy Kesavan, James S. Panek, and John A. Porco, Jr.*
Table 1: Catalyst evaluation.
The asymmetric addition of allyl metal and related reagents to
=
C N bonds is an active area in chemical synthesis.[1] Method-
ologies include allylation of imines with allyl boronates,[2] allyl
stannanes,[3] and chiral silanes.[4] Recently, N-diphenylphos-
phinylimines have emerged as useful acylimine equivalents in
[5]
À
a variety of asymmetric C C bond-forming reactions, and
we therefore considered their utility in asymmetric crotyla-
Entry
Additive
Catalyst
Yield of 3 [%][a]
tions.[6] Herein, we report the addition of chiral organosilanes
and other carbon nucleophiles to N-diphenylphosphinyl-
imines using rare-earth-metal triflate/trifluoroacetic anhy-
dride activation to unexpectedly afford trifluoroacetamide
products as well as preliminary mechanistic studies to probe
the reaction course.
1[b]
2[b]
3[b]
4[b]
5[b]
6[b]
7[c]
8[c,d]
–
–
–
BF3·OEt2
TiCl4
0
0
0
Sc(OTf)3
Sc(OTf)3
Sm(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3·nH2O
TFAA
TFAA
TFAA
TFAA
TFAA
56
37
50–75
86
93
We initiated our studies with the asymmetric crotylation
of N-diphenylphosphinylimine 1[7] using chiral organosilane 2.
After failed attempts in an initial evaluation of several Lewis
acids (see Table 1, entries 1–3), we considered alternative,
milder methods for activation of N-phosphinylimines. Pre-
vious studies by Yamamoto and co-workers have demon-
strated the effectiveness of scandium triflate (Sc(OTf)3) as a
catalyst for acylation of alcohols with acetic anhydride.[8]
Thus, we conducted studies probing the utility of Sc(OTf)3/
TFAA[9] for the activation of phosphinylimine 1 by acylation.
Initial results revealed that catalytic amounts of Sc(OTf)3 and
TFAA (2.0 equiv) (Table 1, entry 4) were effective for the
activation of N-phosphinylimine 1 towards addition of
crotylsilane 2 and unexpectedly afforded trifluoroacetamide
product 3 (56% yield). Control experiments established that
both Sc(OTf)3 and TFAA were required and that CH3CN was
an optimal solvent. Moreover, experiments[10] employing
0.2 equivalents of triflic acid[11] for the crotylation provided
3 in 27% yield after 48 h, thus establishing the importance of
the rare-earth-metal catalyst.
[a] Yield of isolated product after purification by chromatography on
silica gel. [b] Reaction was carried out in anhydrous CH3CN. [c] ACS-
grade CH3CN was employed. [d] La(OTf)3·nH2O purchased from Aldrich.
TFAA=trifluoroacetic anhydride.
To optimize the crotylation process, we next evaluated a
range of rare-earth-metal triflates.[12] While Sm(OTf)3
(Table 1, entry 5) afforded a modest yield (37%) of 3, we
found that La(OTf)3 produced 3 in moderate to good yields
(Table 1, entry 6).[10] Optimization studies later indicated that
use of ACS-grade acetonitrile (2400 ppm water)[13] cleanly
afforded 3 in 86% yield (Table 1, entry 7). Further optimiza-
tion led to the identification of La(OTf)3·nH2O,[14] which
catalyzed the reaction to afford 3 in 93% yield after 2 h
(Table 1, entry 8; d.r. > 20:1, e.r. > 97:3). The relative stereo-
chemistry of homoallylic trifluoroacetamide 3 was deter-
mined by conversion into a known crotylation product[4a,10]
and the absolute stereochemistry confirmed through conver-
sion into the corresponding mandelamide derivatives.[10,15,16]
The liberation of the phosphinate moiety from the N-
phosphinylimine substrate and formation of a trifluoroaceta-
mide product were not anticipated in the transformation. The
reaction outcome is consistent with in situ generation and
subsequent crotylation of a highly activated trifluoroacetyl-
imine[17] or its corresponding hydrate.[18] Unfortunately,
attempts to generate arylaldehyde-derived trifluoroacetyli-
mines using reported methods have thus far been unsuccess-
ful.[19] Initial mechanistic studies were undertaken to eluci-
date details of the La(OTf)3/TFAA activation of N-phosphi-
nylimines. 1H NMR studies[10] indicate rapid loss of the
phosphinylimine proton resonance (1H NMR, CD3CN, d =
9.33 ppm, JP, H = 32.1 Hz) within 10 min to afford an unidenti-
fied intermediate (1H NMR, CD3CN, br, d = 8.80 ppm). To
further probe this phenomenon, we carried out mass spec-
trometry experiments (ESI + ),[14b,20] which confirmed rapid
[*] W. W. Ong, Dr. A. B. Beeler, Dr. S. Kesavan, Prof. Dr. J. S. Panek,
Prof. Dr. J. A. Porco, Jr.
Center for Chemical Methodology and Library Development
Boston University
590 Commonwealth Avenue, Boston, MA 02215 (USA)
Fax: (+1)617-358-2847
E-mail: porco@bu.edu
[**] This work was generously supported by the NIGMS CMLD initiative
(P50 GM067041). We thank Professors Scott Schaus (Boston
University) and Jinquan Yu (Brandeis University) for helpful
discussions, Dr. Paul Ralifo (Boston University) for assistance with
NMR structure elucidation, CEM Corporation (Matthews, NC) for
assistance with microwave instrumentation, and Symyx Technolo-
gies, Inc. (Santa Clara, CA) for assistance with chemical reaction
planning software.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
7470
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 7470 –7472

Angewandte
Chemie
Table 2: Asymmetric crotylation using La(OTf)3/TFAA activation.
consumption of phosphinylimine 1 and suggested the pres-
ence of both hydrated species 4b and 5 (Scheme 1).[10]
Furthermore, upon addition of crotyl silane 2, direct-injection
mass spectral data supports the consumption of species 5.[10]
Based on our preliminary experimental data, we propose the
general reaction mechanism for activation of the phosphiny-
limine 1 as shown in Scheme 1. Phosphinylimine acylation
with TFAA may be promoted by lanthanum triflate through
either direct N-acylation[21] or acylation of the phosphinyl
Entry
1
R1
Product
Yield [%][a]
75
d.r.[b]
10:1
e.r.[c]
93:7
[22]
oxygen atom with subsequent O-to-N acyl transfer.
7
Hydration of 4a affords the observed tetrahedral intermedi-
ate 4b,[18] which may be followed by loss of diphenylphos-
phinic acid (HOPOPh2) to yield the lanthanum-coordinated
intermediate 5.[18b,c,23] 31P NMR and mass spectrometry
experiments (ESI + )[10] also suggest that symmetrical (diphe-
nylphosphinic anhydride)[24] or mixed anhydrides (trifluoro-
acetic diphenylphosphinic anhydride)[25] derived from the
liberated diphenylphosphinic acid and TFA become ligated to
LaIII as the reaction progresses.[26]
With an optimized protocol for crotylation in hand, we
next evaluated the scope of the substrate (Table 2). Electron-
rich aryl groups were found to be workable substrates in the
crotylation, affording good yields of homoallylic amide
products 7–9 (Table 2, entries 1–3). Electron-withdrawing
aryl groups were tolerated and generally afforded moderate
2
3
8
9
71
87
>20:1
96:4
15:1
89:11
4
5
6
7
10
11
12
13
99
87
80
53
15:1
15:1
10:1
10:1
96:4
99:1
91:9
99:1
[a] Yield of isolated product after chromatography on SiO2. [b] Diaste-
reomeric ratios determined using 1H NMR integration. [c] Enantiomeric
ratios determined by chiral HPLC analysis.
(88%). Alternatively, use of methylenecyclopentane as
the nucleophile afforded the imino (aza)-ene[29] product
16 in high yield (91%). These initial studies illustrate
the high reactivity of intermediates produced by
lanthanum triflate/anhydride activation of N-phosph-
inylimines towards a range of nucleophiles, underscor-
ing the significant potential for this catalyst system.
In summary, hydrated lanthanum triflate has been
shown to be an effective and highly active Lewis acid
catalyst for nucleophilic addition to N-phosphinyli-
mines in the presence of trifluoroacetic anhydride.
Unexpectedly, trifluoroacetamide products are pro-
duced in a novel process which likely involves consec-
utive acylation/hydration of N-phosphinylimine sub-
strates and subsequent nucleophilic addition. In initial
studies, asymmetric crotylation, Friedel–Crafts, and
(aza)-ene reactions have been demonstrated with this
activation system. Further development of additional
Scheme 1. Proposed mechanism for activation and nucleophilic addition of N-
phosphinylimines.
to good yields of crotylation products 10–11 (Table 2,
entries 4 and 5). The aryl framework was also extended
to cinnamaldehyde-derived phosphinylimines (Table 2,
entry 6).
A
cyclopropanecarboxaldehyde-derived
phosphinylimine substrate also produced a moderate
yield of 13 (Table 2, entry 7). Attempts to perform the
crotylation using other aliphatic phosphinylimines
were unsuccessful likely owing to competing imine–
enamine tautomerization.[27]
Further reactions employing the La(OTf)3/TFAA
catalytic system were investigated using alternative
carbon nucleophiles (Scheme 2). Treatment of N-
phosphinylimine 14[10] with La(OTf)3/TFAA in the
presence of excess furan (microwave, 608C) led to
efficient formation of the Friedel–Crafts[28] product 15 Scheme 2. Friedel–Crafts and (aza)-ene reactions.
Angew. Chem. Int. Ed. 2007, 46, 7470 –7472
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7471

Communications
15; e) S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35, 209;
f) S. Kobayashi, M. Sugiura, H. Kitagawa, W. W.-L. Lam, Chem.
Rev. 2002, 102, 2227.
reaction processes using rare-earth-metal triflate/trifluoro-
acetic anhydride activation is ongoing in our laboratories and
will be reported in due course.
[13] S. Ribe, P. Wipf, Chem. Commun. 2001, 299.
[14] For use of hydrated lanthanum triflate as catalyst, see: a) S.
Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc. 1998,
120, 8287; b) S. Yamasaki, T. Iida, M. Shibasaki, Tetrahedron
Lett. 1999, 40, 307; c) S. Yamasaki, T. Iida, M. Shibasaki,
Tetrahedron Lett. 1999, 55, 8857; d) M. Curine, E. Francesco,
M. C. Marcotullio, O. Rosati, Heterocycles 2001, 55, 1599.
[15] The d.r. of the mandelamide derivative was measured using
1H NMR and found to be greater than 95:1, corresponding to an
e.r. of greater than 95:1 for the crotylation.
[16] B. Trost, R. C. Bunt, S. R. Pulley, J. Org. Chem. 1994, 59, 4202.
[17] For the synthesis of aldimine-derived trifluoroacetylimines, see:
a) V. I. Naddaka, V. P. Garꢀkin, K. V. Obayan, Zh. Org. Khim.
1981, 17, 2020; for additional information on N-trifluoroketi-
mines, see: b) T. Hirata, M. Shiro, Y. Nagao, Heterocycles 1997,
44, 133; c) V. M. Koshelev, T. D. Truskanova, V. F. Cherstkov,
D. V. Romanov, N. V. Vasiliꢀev, Russ. Chem. Bull. 2005, 54, 1675.
[18] The Petasis reaction has been proposed to proceed through
Received: February 14, 2007
Published online: August 23, 2007
Keywords: anhydrides · lanthanum · phosphinylimines · silanes ·
.
synthetic methods
[1] a) H. Miyabe, M. Ueda, T. Naito, Synlett 2004, 1140; b) H. Ding,
G. K. Friestad, Synthesis 2005, 2815; c) G. K. Friestad, Eur. J.
Org. Chem. 2005, 3157.
[2] a) S. Sebelius, K. J. Szabo, Eur. J. Org. Chem. 2005, 2539; b) R. T.
Wu, M. J. Chong, J. Am. Chem. Soc. 2006, 128, 9646; c) M.
Sugiura, H. Keiichi, S. Kobayashi, N.-W. Tseng, M. Lautens, Org.
Synth. 2006, 83, 170.
[3] a) H. Nakamura, H. Iwama, Y. Yamamoto, J. Am. Chem. Soc.
1996, 118, 6641; b) H. Nakamura, H. Iwama, Y. Yamamoto,
Chem. Commun. 1996, 1459; c) N. Solin, J. Kjellgren, K. J. Szabo,
J. Am. Chem. Soc. 2004, 126, 7026.
[4] a) J. Schaus, N. Jain, J. S. Panek, Tetrahedron 2000, 56, 10263;
b) R. Berger, P. M. A. Rabbat, J. L. Leighton, J. Am. Chem. Soc.
2003, 125, 9596; c) R. Berger, K. Duff, J. L. Leighton, J. Am.
Chem. Soc. 2004, 126, 5686; d) D. Lipomi, J. S. Panek, Org. Lett.
2005, 7, 4701.
[5] a) P. Wipf, C. Kendall, C. R. J. Stephenson, J. Am. Chem. Soc.
2003, 125, 761; b) A. A. Boezio, J. Pytkowicz, A. Cote, A. B.
Charette, J. Am. Chem. Soc. 2003, 125, 14260; c) M. Petrini,
Chem. Rev. 2005, 105, 3949; d) K. A. Nolin, R. W. Ahn, F. D.
Toste, J. Am. Chem. Soc. 2005, 127, 12462; e) W. B. Jennings, C. J.
Lovely, Tetrahedron 1991, 47, 5561; f) C. Lauzon, J. N. Desros-
iers, A. B. Charette, J. Org. Chem. 2005, 70, 10579; g) P. Wipf,
C. M. Coleman, J. M. Janjic, P. S. Iyer, M. D. Fodor, Y. A. Shafer,
C. R. J. Stephenson, C. Kendall, B. W. Day, J. Comb. Chem. 2005,
7, 322; h) J. N. Desrosiers, A. CôtØ, A. A. Boezio, A. B. Charette,
Org. Synth. 2005, 83, 5.
[6] a) C. E. Masse, J. S. Panek, Chem. Rev. 1995, 95, 1293; b) R. T.
Beresis, J. S. Solomon, M. G. Yang, N. F. Jain, J. S. Panek, Org.
Synth. 1997, 75, 78.
[7] For preparation and reactions of N-phosphinylimines, see:
a) W. B. Jennings, C. J. Lovely, Tetrahedron Lett. 1988, 29,
3725; b) for an excellent review on phosphinylimines, see:
c) R. K. Orr, S. M. Weinreb, Synthesis 2005, 1205.
[8] a) K. Ishihara, M. Kubota, H. Yamamoto, J. Am. Chem. Soc.
1995, 117, 4413; b) H. Kurihara, H. Yamamoto, J. Org. Chem.
1996, 61, 4560; c) K. Ishihara, M. Kubota, H. Yamamoto, Synlett
1996, 265; for related studies employing La(NO3)3·6H2O as
catalyst, see: d) T. S. Reddy, M. Narasimhulu, N. Suryakiran,
K. C. Mahesh, K. Ashalatha, Y. Venkateswarlu, Tetrahedron
Lett. 2006, 47, 6825.
[9] For use of Sc(OTf)3/TFAA in aza-annulation, see: a) S. Danda-
pani, P. Lan, A. B. Beeler, S. Beischel, A. Abbas, B. Roth, J. A.
Porco, Jr., J. S. Panek, J. Org. Chem. 2006, 71, 8934.
[10] See the Supporting Information for complete experimental
details.
[11] a) R. Dumeunier, I. E. Marko, Tetrahedron Lett. 2004, 45, 825;
b) T. C. Wabnitz, J. Q. Yu, J. B. Spencer, Chem. Eur. J. 2004, 10,
484; c) D. C. Rosenfeld, S. Shekhar, A. Takemiya, M. Utsuno-
miya, J. F. Hartwig, Org. Lett. 2006, 8, 4179.
nucleophilic addition to
a hemiaminal intermediate, see:
a) N. A. Petasis, I. Akritopoulou, Tetrahedron Lett. 1993, 34,
583; on the basis of literature precedent, the reactive acylimine
may also undergo reversible hydration: b) W. J. Middleton, J.
Org. Chem. 1983, 48, 3845; c) A. R. Katritzky, S. C. Rao,
Synthesis 1990, 663.
[19] a) J. Vidal, S. Damestoy, L. Guy, J. -C. Hannachi, A. Aubry, A.
Collet, Chem. Eur. J. 1997, 3, 1691; b) S. Lou, B. M. Taoka, A.
Ting, S. E. Schaus, J. Am. Chem. Soc. 2005, 127, 11256.
[20] a) S. Watanabe, Y. Kobayashi, T. Arai, S. Takayoshi, H. Sasai, M.
Bougauchi, M. Shibasaki, Tetrahedron Lett. 1998, 39, 7353; b) T.
Nemoto, T. Ohshima, Takashi, K. Yamaguchi, M. Shibasaki, J.
Am. Chem. Soc. 2001, 123, 2725.
[21] For the formation of acyliminium ions by acylation of N-
substituted imines, see: B. E. Maryanoff, H. -C. Zhang, J. H.
Cohen, I. J. Turchi, C. A. Maryanoff, Chem. Rev. 2004, 104, 1431.
[22] a) Y. Tachibana, H. Kawasaki, N. Kihara, T. Takata, Toshikazu,
J. Org. Chem. 2006, 71, 5093; b) L. P. Miranda, W. D. F. Meuter-
mans, M. L. Smythe, P. F. Alewood, J. Org. Chem. 2000, 65, 5460.
[23] a) H. C. Aspinall, N. Greeves, B. G. McIver, Tetrahedron Lett.
1998, 39, 9283; b) V. K. Aggarwal, A. Mereu, G. J. Tarver, R.
McCague, J. Org. Chem. 1998, 63, 7183; c) H. C. Aspinall, J. S.
Bissett, N. Greeves, D. Levin, Tetrahedron Lett. 2002, 43, 323.
[24] P. M. Cullis, A. D. Kaye, S. Trippett, J. Chem. Soc. Chem.
Commun. 1987, 1464.
[25] a) J. Wasiak, J. Helinski, W. Dabkowski, Z. Skrzypczynski, J.
Michalski, Pol. J. Chem. 1995, 69, 1027.
[26] For the coordination of diphenylphosphinyl ligands with
lanthanum(III), see: a) H. C. Aspinall, S. R. Moore, A. K.
Smith, J. Chem. Soc. Dalton Trans. 1992, 53; b) B. Ryszard,
A. W. G. Platt, J. Fawcett, J. Chem. Soc. Dalton Trans. 1992, 675;
c) J. Fawcett, A. W. G. Platt, D. R. Russell, Polyhedron 2002, 21,
287; d) J. Fawcett, A. W. G. Platt, Polyhedron 2003, 22, 967; e) J.
Fawcett, A. W. G. Platt, S. Vickers, M. D. Ward, Polyhedron
2004, 23, 2561; f) S.-F. Tang, J.-L. Song, J.-G. Mao, Eur. J. Inorg.
Chem. 2006, 2011.
[27] a) W. B. Jennings, D. R. Boyd, J. Am. Chem. Soc. 1972, 94, 7187;
b) M. K. Schwarz, D. Tumelty, M. A. Gallop, J. Org. Chem. 1999,
64, 2219.
[28] a) K. A. Jørgensen, Synthesis 2003, 1117; b) D. Uraguchi, K.
Sorimachi, M. Terada, J. Am. Chem. Soc. 2004, 126, 11804; c) J.
Esquivias, R. G. Arrayꢁs, J. C. Carretero, Angew. Chem. 2006,
118, 645; Angew. Chem. Int. Ed. 2006, 45, 629.
[12] For use of rare-earth-metal triflates in organic synthesis, see:
a) S. Kobayashi, Synlett 1994, 689; b) K. Ishihara, M. Kubota, H.
Kurihara, H. Yamamoto, J. Am. Chem. Soc. 1995, 117, 4413;
c) K. Ishihara, M. Kubota, H. Kurihara, H. Yamamoto, J. Org.
Chem. 1996, 61, 4560; d) S. Kobayashi, Eur. J. Org. Chem. 1999,
[29] a) M. Yamanaka, A. Nishida, M. Nakagawa, Org. Lett. 2000, 2,
159; b) M. Terada, K. Machioka, K. Sorimachi, Angew. Chem.
2006, 118, 2312; Angew. Chem. Int. Ed. 2006, 45, 2254.
7472
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 7470 –7472