pubs.acs.

org/joc

P[N(i-Bu)CH2CH2]3N: Nonionic Lewis Base for Promoting the

Room-Temperature Synthesis of r,β-Unsaturated Esters, Fluorides,
Ketones, and Nitriles Using Wadsworth-Emmons Phosphonates
Venkat Reddy Chintareddy,† Arkady Ellern,‡ and John G. Verkade*,†
†
Department of Chemistry, Gilman Hall and ‡Molecular Structure Laboratory,
Iowa State University, Ames, Iowa 50011, United States

[email protected]
Received July 1, 2010

The bicyclic triaminophosphine P(RNCH2CH2)3N (R = i-Bu, 1c) serves as an effective promoter for the
room-temperature stereoselective synthesis of R,β-unsaturated esters, fluorides, and nitriles from a wide
array of aromatic, aliphatic, heterocyclic, and cyclic aldehydes and ketones, using a range of Wadsworth-
Emmons (WE) phosphonates. Among the analogues of 1c [R=Me (1a), i-Pr (1b), Bn (1d)], 1a and 1b per-
formed well, although longer reaction times were involved, and 1d led to poorer yields than 1c. Functionalities
such as cyano, chloro, bromo, methoxy, amino, ester, and nitro were well tolerated. We were able to isolate
and characterize (by X-ray means; see above) the reactive WE intermediate species formed from 2b and 1c.

Introduction chemicals such as perfumes, fragrances, insecticides, carotenoids,

pheromones, pharmaceuticals, and prostaglandins.1-3 WE reac-
The Wadsworth-Emmons (WE) reaction is versatile, having
tions are key steps in the total synthesis of biologically active
numerous applications in the synthesis of intermediates for fine
(2) (a) Johnson, A. W. In Ylides and Imines of Phosphorus; Wiley: New York,
(1) (a) Wadsworth, W. S.; Emmons., W. D. J. Am. Chem. Soc. 1961, 83, 1993; p 307. (b) Walker, B. J. In Organophosphorus Reagents in Organic
1733–1738. (b) Wadsworth, W. S. Org. React. 1977, 25, 73–253. (c) Iorga, B.; Synthesis; Cadogan, J. I. G., Ed.; Academic Press: London, 1979; Chapter 3,
Eymery, F.; Mouries, V.; Savignac, P. Tetrahedron 1998, 54, 14637–14677. p 155. (c) Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87–99. (d) Maryanoff,
(d) Rehwinkel, H.; Skupsch, J.; Vorbruggen., H. Tetrahedron Lett. 1988, 29, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927. (e) Nicolaou, K. C.; Harter,
1775–1776. (e) Allevi, P.; Ciuffreda, P.; Colombo, D.; Monti, D.; Speranza., G. M. W.; Gunzner, J. L.; Nadin, A. Liebigs Ann./Recueil 1997, 1283–1301.
J. Chem. Soc., Perkin Trans. 1 1989, 1281–1283. (f ) Jones, G.; Maisey, R. F. (f ) Janecki, T. Targets Heterocycl. Syst. 2006, 10, 301–320. (g) Figueras, F.;
Chem. Commun. 1968, 543–544. (g) Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, Kantam, M. L; Choudary, B. M. Curr. Org. Chem. 2006, 10, 1627–1637.
7, 4281–4283. (h) Davis, F. A.; Xu, H.; Wu, Y.; Zhang, J. Org. Lett. 2006, 8, (h) Motoyoshiya, J. Trends Org. Chem. 1998, 7, 63–73. (i) Heron, B. M.
2273–2276. (i) Yu, J. S.; Kleckley, T. S.; Wiemer, D. F. Org. Lett. 2005, 7, 4803– Heterocycles 1995, 41, 2357–2386. ( j) Gaich, T.; Weinstabl, H.; Mulzer, J. Synlett
4806. ( j) Kondekar, N. B.; Kumar, P. Org. Lett. 2009, 11, 2611–2614. 2009, 1357–1366. (k) Ando, K.; Narumiya, K.; Takada, H.; Teruya, T. Org. Lett.
(k) Mirzabekova, N. S.; Kuzmina, N. E.; Lukashov, O. I.; Sokolova, N. A.; 2010, 12, 1460–1463. (l) Markiewicz, J. T.; Schauer, D. J.; Lofstedt, J.; Corden,
Golosov, S. N.; Kazakov, P. V.; Perlova, T. G.; Potapova, V. V.; Kheinman, S. J.; Wiest, O.; Helquist, P. J. Org. Chem. 2010, 75, 2061–2064. (m) Crimmins,
V. A.; Ivanova, G. B. Russ. J. Org. Chem. 2008, 44, 1139–1149. (l) Miller, D. J.; M. T.; Shamszad, M.; Mattson, A. E. Org. Lett. 2010, 12, 2614–2617.
Yu, F.; Young, N. J.; Allemann, R. K. Org. Biomol. Chem. 2007, 5, 3287–3298. (3) (a) Choudary, B. M.; Lakshmi Kantam, M.; Venkat Reddy, Ch.; Bharathi,
(m) Lubkoll, J.; Millemaggi, A.; Perry, A.; Taylor, R. J. K. Tetrahedron 2010, B. J. Catal. 2003, 218, 191–200. (b) Shahak, I.; Almog, J. Synthesis 1970, 145–147.
66, 6606–6612. (n) Franchini, L.; Compostella, F.; Colombo, D.; Panza, (c) Kitamura, M.; Isobe, M.; Ichikawa, Y.; Goto, T. J. Org. Chem. 1984, 49, 3517–
L.; Ronchetti, F J. Org. Chem. 2010, 75, 5363–5366. (o) Sabitha, G.; 3527. (d) Wilson, Z. E.; Brimble, M. A. Org. Biomol. Chem. 2010, 8, 1284–1286.
Chandrashekhar, G.; Yadagiri, K.; Yadav, J. S. Tetrahedron Lett. 2010, (e) Weng, J.; Li, Y-B; Wang, R.-B.; Li, F.-Q.; Liu, C.; Chan, A.S. C.; Lu, G. J. Org.
51, 3824–3826. (p) Valizadeh, H.; Shockravi, A. Synth. Commun. 2009, 39, Chem. 2010, 75, 3125–3128. (f ) Cainelli, G.; Contento, M.; Manescalchi, F.;
4341–4349. (q) Elamparuthi, E; Linker, T Angew. Chem., Int. Ed. 2009, 48, Regnoli, R. J. Chem. Soc., Perkin Trans. 1 1980, 2516–2519. (g) Martyn, D. C.;
1853–1855. (r) Krawczyk, H.; Albrecht, L. Synthesis 2008, 3951–3956. Hoult, D. A.; Abell, A. D. Aust. J. Chem. 2001, 54, 391–396.

7166 J. Org. Chem. 2010, 75, 7166–7174 Published on Web 10/14/2010 DOI: 10.1021/jo1012515
r 2010 American Chemical Society
Chintareddy et al.
JOC Article
molecules such as Maytansine (anticancer),3c Leukotriene B4
(leukocyte function promoter),2e Aurodox (antibiotic),2e Lipoxin
A4 (anti-inflammatory mediator), 2e Amphoteronolide B
(aglycone of the antibiotic amphotericin), 2e X-14547A
(antibiotic), 2e providencin (anticancer), 2j macrolides
(antibiotics),2k trichostatic acid (anticancer),2l Brevenal (breve-
toxin inhibitor),2m and Berkelic acid3d (a natural product FIGURE 1. Proazaphosphatranes used in this study.
with selective activity against ovarian cancer). The WE reac-
tion is also a key step in the synthesis of Oseltamivir, a widely
used antiviral drug for the treatment and prevention of influ-
enza.3e With inherent advantages, such as the use of inexpensive
triethylphosphite as a starting material for the synthesis of
phosphonates, ease of product separation, and excellent reacti-
vity of the phosphonate reagent, the WE reaction has enjoyed a
broader scope of utility than the Wittig reaction.2a,3
Condensation of an aldehyde or a ketone with a phospho-
nate to give an R,β-unsaturated ester or nitrile (see scheme in FIGURE 2. Phosphonates employed in this work.
the abstract) is traditionally effected in the presence of strong
stoichiometric ionic bases such as KOH,4 Ba(OH)2,5 NaH,6 TABLE 1. Survey of Proazaphosphatranes in the Reaction of
BuLi,6,7 benzyltrimethylammonium hydroxide (Triton B),6,8 p-Nitrobenzaldehyde with 2a in the Presence of 1 equiv of 1a
LiOH,9a-d Et3N-LiBr,9e,f KHMDS/18-crown-6,8,10a K2CO3/
KHCO3/phase transfer conditions,10b and KOtBu/18 crown-6.11
N-Ethylpiperidine assisted by Sn(OSO2CF3)2 has also been

(4) (a) Grabarnick, M.; Zamir, S. Org. Process Res. Dev. 2003, 7, 237–243.
(b) Arai, S.; Hamagushi, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2997–
3000. (c) Texier-Boullet, F.; Foucaud, A. Synthesis 1979, 884.
(5) (a) Sinisterra, J. V.; Marinas, J. M.; Riquelme, F.; Arias, M. S. 1 t (h) yield (%)b [E/Z]c
Tetrahedron 1988, 44, 1431–1440. (b) Sinisterra, J. V.; Mouloungui, Z.; 1a 5.5 95 [99/1]
Delmas, M.; Gaset, A. Synthesis 1985, 1097–1100. (c) Climent, M. S.; 1b 4.0 94 [99/1]
Marinas, J. M.; Mouloungui, Z.; LeBigot, Y.; Delmas, M.; Gaset, A.;
Sinisterra., J. V. J. Org. Chem. 1989, 54, 3695–3701. (d) Marinas, J. M.; 1c 0.5 96 [99/1]; lit.: 89 [100/0],15a 74 [100/0],5d
Fuentes, A.; Sinisterra, J. V. Tetrahedron Lett. 1987, 28, 2951–2954. 95,19b 98 [99/1],18 90 [99/1]3a
(6) (a) Yu, W.; Su, M.; Jin, Z. Tetrahedron Lett. 1999, 40, 6725–6728. 1d 6.0 60 [96/4]
(b) Sanders, T. C.; Golen, J. A.; Williard, P. G.; Hammond, G. B. J. Fluorine none 20.0 no reaction
Chem. 1997, 85, 173–175. (c) Pihko, P. M.; Salo, T. M. Tetrahedron Lett. a
See Experimental Section for conditions. bIsolated yields after
2003, 44, 4361–4364. (d) Marshall, J. A.; Hagan, C. P.; Flynn., G. A. J. Org.
Chem. 1975, 40, 1162–1166. (e) Ando, K. Synlett 2001, 1272–1274. (f ) Ando, column chromatography. cE/Z ratios were determined by 1H NMR
K. J. Org. Chem. 1998, 63, 8411–8416. (g) Breuer, E.; Bannet, D. M. spectroscopic integration.
Tetrahedron Lett. 1977, 18, 1141–1144. (h) Ando, K. J. Org. Chem. 1997,
62, 1934–1939. (i) Tay, M. K.; About-Jaudet, E.; Collignon, N.; Teulade,
M. P.; Savignac, P. Synth. Commun. 1988, 18, 1349–1362. ( j) Kapferer, T.; employed as a base.12 Barrett et al. reported an application
Brueckner, R. Eur. J. Org. Chem. 2006, 2119–2133. (k) Pinna, G. A.;
Cignarella, G.; Ruiu, S.; Loriga, G.; Murineddu, G.; Villa, S.; Grella,
of the nonionic base 1,1,3,3-tetramethylguanidine (TMG)
G. E.; Cossu, G.; Fratta, W. Bioorg. Med. Chem. 2003, 11, 4015–4026. in combinatorial chemistry involving WE reactions,13 and
(l) Groundwater, P. W.; Garnett, I.; Morton, A. J.; Sharif, T.; Coles, S. J.; Simoni et al. described the use of 1,5,7-triazabicyclo-
Hursthouse, M. B.; Nyerges, M.; Anderson, R. J.; Bendell, D.; McKillop, A.;
Zhang, W. J. Chem. Soc, Perkin Trans. 1 2001, 2781–2787. (m) Charette, [4.4.0]dec-5-ene (TBD) as a nonionic base for WE reactions
A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001, 123, 12168–12175. in refluxing THF.14a In 2002, Nagao et al. used i-PrMgBr as
(n) Banerjee, S.; Nayek, A.; Sinha, S.; Bhaumik, T.; Ghosh, S. J. Mol. Catal. promoter for WE reactions,14b and in 2008, Davies et al.
A: Chem. 2006, 254, 85–92. (o) Green, M. P.; Prodger, J. C.; Hayes, C. J.
Tetrahedron Lett. 2002, 43, 6609–6611. (p) Kelkar, S. V.; Reddy, G. B.; reported WE reactions using MeMgBr as base.14c Several
Kulkarni, G. H. Indian J. Chem., Sect. B 1991, 30B, 504–507. (q) Kelkar, reports of solid reagents/catalysts for WE reactions have also
S. V.; Arbale, A. A.; Joshi, G. S.; Kulkarni, G. H. Synth. Commun. 1990, 20,
839–847. (r) Matthias, A.; Penman, K. G.; Matovic, N. J.; Bone, K. M.;
appeared, for example, SiO2-supported 1,8-diazabicyclo-
De Voss, J. J.; Lehmann, R. P. Molecules 2005, 10, 1242–1251. (s) Schelkun, [5.4.0]undec-7-ene (DBU),15 KF/alumina,16 MgAlO-t-Bu
R. M.; Yuen, P.-W.; Wustrow, D. J.; Kinsora, J.; Su, T.-Z.; Vartanian, M. G.
Bioorg. Med. Chem. Lett. 2006, 16, 2329–2332.
(7) Mulzer, J.; Martin, H. J.; List, B. Tetrahedron Lett. 1996, 37, 9177– (12) (a) Sano, S.; Ando, K.; Yokoyama, K.; Nagao, Y. Synlett 1998, 777–
9178. 779. (b) Sano, S.; Yokoyama, K.; Teranishi, R.; Shiro, M.; Nagao, Y. Tetra-
(8) (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105–4108. (b) Still, W. C.; hedron Lett. 2002, 43, 281–284. (c) Sano, S.; Yokoyama, K.; Fukushima, M.;
Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408. Yagi, T.; Nagao, Y. Chem. Commun. 1997, 559–560.
(9) (a) Kryshtal, G. V.; Zhdankina, G. M.; Zlotin, S. G. Mendeleev (13) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org.
Commun. 2002, 12, 176–178. (b) Lattanzi, A.; Orelli, L. R.; Barone, P.; Lett. 1999, 1, 579–582.
Massa, A.; Iannece, P.; Scettri, A. Tetrahedron Lett. 2003, 44, 1333–1337. (14) (a) Simoni, D.; Rossi, M.; Rondanin, R.; Mazzali, A.; Baruchello,
(c) Bonadies, F.; Gardilli, A.; Lattanzi, A.; Orelli, L. R.; Scettri, A. Tetra- R.; Malagutti, C.; Roberti, M.; Invidiata, F. P. Org. Lett. 2000, 2, 3765–3768.
hedron Lett. 1994, 35, 3383–3386. (d) Bonadies, F.; Scettri, A.; Campli, C. D. (b) Sano, S.; Teranishi, R.; Nagao, Y. Tetrahedron Lett. 2002, 43, 9183–9186.
Tetrahedron Lett. 1996, 37, 1899–1900. (e) Rathke, M. W.; Nowak, M. (c) Claridge, T. D. W.; Davies, S. G.; Lee, J. A.; Nicholson, R. L.; Roberts,
J. Org. Chem. 1985, 50, 2624–2626. (f ) Heimgaertner, G.; Raatz, D.; Reiser, P. M.; Russell, A. J.; Smith, A. D.; Toms, S. M. Org. Lett. 2008, 10, 5437–
O. Tetrahedron 2005, 61, 643–655. 5440.
(10) (a) Motoyoshiya, J.; Kusaura, T.; Kokin, K.; Yokoya, S.; Takagushi, (15) (a) Jin, Y. Z.; Yasuda, N.; Inanaga, J. Green Chem. 2002, 4, 498–500.
Y.; Narita, S.; Aoyama, H. Tetrahedron 2001, 57, 1715–1721. (b) Villieras, J.; (b) Ando, K.; Yamada, K. Tetrahedron Lett. 2010, 51, 3297–3299. (c) Ando,
Rambaud, M.; Kirschleger, B. Phosphorus, Sulfur Related Elem. 1983, 14, 385– K.; Suzuki, Y. Tetrahedron Lett. 2010, 51, 2323–2325.
391. (16) (a) Moison, H.; Texier-Boullet, F.; Foucaud, A. Tetrahedron 1987,
(11) (a) Tago, K.; Kogen, H. Tetrahedron 2000, 56, 8825–8831. (b) Appel, 43, 537–542. (b) Texier-Boullet, F.; Villemin, D.; Ricard, M.; Moison, H.;
R.; Loos, R.; Mayr, H. J. Am. Chem. Soc. 2009, 131, 704–714. Foucaud, A. Tetrahedron 1985, 41, 1259–1266.

J. Org. Chem. Vol. 75, No. 21, 2010 7167

JOC Article Chintareddy et al.

TABLE 2. WE Reactions of Various Aldehydes with 2a in the Presence of 1 equiv of 1ca

a
See Experimental Section for conditions. bIsolated yields after column chromatography. Only the E isomer was isolated. cE/Z ratios were determined
by 1H NMR spectroscopic integration.

hydrotalcite,3a a MgLa mixed oxide,17 and nano MgO.18 WE MgLa mixed oxides,17 macroreticular anion-exchange resin
reactions are also useful in solid phase syntheses using DBU Amberlyst A-26 (OH- form),3f and nano MgO18 require 130 °C
as base.19 Problems encountered in some of the aforemen- to obtain reasonable yields of WE products, but heteroge-
tioned methods include longer reaction times arising from neous metal oxide catalysts must be prepared in a process
moderate chemoselectivity (resulting in Knoevenagel adduct requiring 450 °C for up to 6 h,3a,17 and activation of Ba(OH)2
formation or Cannizzarro and Meerwein-Pondorf-Verley as a catalyst requires 200 °C.5 An ionic liquid methodology has
reductions13,16) and the lack of ketone participation.3a,14a,15 been described that uses up to 5 equiv of LiOH 3 H2O as a pro-
Heterogeneous catalysts such as MgAlO-t-Bu hydrotalcite,3a moter.9a Apart from this, to the best of our knowledge there
is no report of a catalyst that operates at room temperature
(17) Kantam, M. L.; Kochkar, H.; Clacens, J.-M.; Veldurthy, B.; Garcia-Ruiz, with wide functional group tolerance using a commercially
A.; Figueras, F. Appl. Catal. B 2005, 55, 177–183.
(18) Choudary, B. M.; Mahendar, K.; Ranganath, K. V. S. J. Mol. Catal.
available catalyst.
A: Chem. 2005, 234, 25–27. We have previously reported that the commercially available20a
(19) (a) Yamazaki, K.; Kondo, Y. Chem. Commun. 2002, 210–211, and proazaphosphatranes 1a, 1b, and 1c (Figure 1) are exceed-
references therein. (b) Bouziane, A.; Helou, M.; Carboni, B.; Carreaux, F.;
Demerseman, B.; Bruneau, C.; Renaud, J.-L. Chem.;Eur. J. 2008, 14, 5630– ingly strong nonionic bases that are useful in a wide variety of
5637. important organic transformations20b-g as organocatalysts,
7168 J. Org. Chem. Vol. 75, No. 21, 2010
Chintareddy et al.
JOC Article
as ligands in metal-assisted coupling reactions, and as stoi- configured esters. An enolizable aliphatic acyclic and a
chiometric reagents.21 sterically bulky aldehyde gave an excellent and moderate
product ester yield, respectively (entries 4j and 4k). Interestingly,
the yield of the conjugated ester 4f exceeded that previously
Results and Discussion
reported in the literature. An electron-donating amino-func-
Here we report a convenient, efficient, and stereospecific tionalized aldehyde with phosphonate 2a resulted in an
synthesis of R,β-unsaturated esters, fluorides, and nitriles excellent yield of R,β-ester 4g. Good to excellent yields of E
from a wide array of aromatic, heterocyclic, aliphatic, and product were obtained in all cases. In the reaction in Table 2
cyclic aldehydes and ketones, using a range of WE phospho- that produced 4h, promoter 1c in protonated form was
nates 2a-2f (Figure 2) in the presence of a proazaphospha- recovered in 87% yield according to our previous report,23
trane of type 1 (see scheme in the abstract). In screening thus enhancing the appeal of 1c for possible recovery in these
1a-1d in the reaction shown in Table 1, we found that 1d20c,d syntheses.
did not perform as well as 1a-1c. Among the latter com-
TABLE 3. WE Reactions of 2 with Various Ketones in the Presence of
pounds, 1c gave an excellent yield of product in the shortest 1 equiv of 1ca
time. Why 1c is the best promoter is not clear since its basicity
is less than (but close to) that of 1b, although it is perhaps
less sterically encumbered than 1b. As expected, no reaction
occurred in the absence of a proazaphosphatrane given
the mildness of our conditions. It may be mentioned that
we observed earlier that 1a promoted a few WE reac-
tions, but the scope of this transformation was not investi-
gated.22 Pleasingly, Cannizarro and MPV reductions were not
observed in the reactions in Table 1, in contrast to their frequent
occurrence in the presence of ionic bases such as NaOH and
LDA.13
We initially tested 1c in the reaction of p-nitrobenzalde-
hyde with 2a using 12.5 mol % of 1c, resulting in a 78% yield
of product (E/Z=99/1) in 7 h. Increasing the mol % of 1c to
25, 50, and 100 resulted in an 86%, 90%, and 95% isolated
yield of product (E/Z = 99/1 in each case) in 3.0, 1.0, and 0.5 h,
respectively. Product yields did not appear to correlate with
steric or basicity trends of the proazaphosphatranes. The
effect of organic solvent polarity on this reaction was exam-
ined by allowing p-nitrobenzaldehyde to react with triethyl
phosphonoacetate 2a for 0.5 h in the presence of 1 equiv of 1c
at room temperature. The effect of solvent polarity was
minimal as shown by the excellent isolated product yields
shown for 3 in polar solvents such as tetrahydrofuran (THF)
and 1,4-dioxane (96% and 94% yields, respectively) and for
the nonpolar solvents toluene and benzene (94% and 95%
yields, respectively).
To evaluate the scope of the transformation, we employed a
See Experimental Section for conditions. bIsolated yields after
a range of aldehydes in their reaction with 2a in the presence column chromatography. cE/Z ratios were determined by 1H NMR
of 1 equiv of 1c (Table 2). 4-Chlorobenzaldehyde and 4-bromo- spectroscopic integration. d2 equiv of 1c was used. eNo yield was
obtained using MgAlO-t-Bu hydrotalcite catalyst.
benzaldehyde provided good isolated product yields (products
4b and 4d, respectively), while 3-methoxybenzaldehyde (Table 2, Ketones are well-known to be difficult substrates for WE
4c) gave a moderate yield of product. Electron-deficient, reactions.3a,9c,14a,15,17,18 As shown in Table 3, both aromatic
acid-sensitive 4-cyanobenzaldehyde 4h and the ester- and aliphatic ketones reacted with phosphonate 2a or 2b in
functionalized aldehyde 4i gave excellent yields of trans- the presence of 1 equiv of 1c at room temperature, affording
the desired products in poor to good yields, although time
(20) (a) Proazaphosphatranes 1a-1c are commercially available from requirements were longer than in the case of aldehydes. How-
Aldrich, and 1a and 1b can also be obtained from Strem Chemicals. (b)
Venkat Reddy, Ch.; Urgaonkar, S.; Verkade, J. G. Org. Lett. 2005, 7, 4427– ever, the E/Z ratio was higher for 5a than those in literature
4430. (c) Chintareddy, V. R.; Wadhwa, K.; Verkade, J. G. J. Org. Chem. reports3a,15,17 for this compound. It is noteworthy that some
2009, 74, 8118–8132. (d) Wadhwa, K.; Chintareddy, V. R.; Verkade, J. G. J.
Org. Chem. 2009, 74, 6681–6690. (e) Wadhwa, K.; Verkade, J. G. J. Org. of the literature procedures3a,15 reported failure of such reac-
Chem. 2009, 74, 5683–5686. (f ) Wadhwa, K.; Verkade, J. G. J. Org. Chem. tions, gave poor yields, or operated at higher temperatures
2009, 74, 4368–4371. (g) Venkat Reddy, Ch.; Verkade, J. G. J. Org. Chem. (typically at 130 °C3a,17,18). The reaction of acetophenone
2007, 72, 3093–3096. (h) Kisanga, P. B.; Verkade, J. G. Tetrahedron 2001, 57,
467–475. with 2a resulted in a 47% yield of product 5a in the presence
(21) For reviews of proazaphosphatrane chemistry, see: (a) Verkade, J. G. of 1 equiv of 1c, but with 2 equiv, a 67% yield of product was
New Aspects of Phosphorus Chemistry II. Top. Curr. Chem. Majoral, J. P., Ed., realized after 24 h. Similarly, benzophenone with 1 equiv of
2002, 233, 1-44. (b) Verkade, J. G.; Kisanga, P. B. Tetrahedron 2003, 59, 7819–
7858. (c) Verkade, J. G.; Kisanga, P. B. Aldrichimica Acta 2004, 37, 3–14.
(d) Urgaonkar, S.; Verkade, J. G. Spec. Chem. 2006, 26, 36–39. (23) Kisanga, P.; D’Sa, B.; Verkade, J. G. Tetrahedron 2001, 57, 8047–
(22) Wang, Z.; Verkade., J. G. Heteroatom Chem. 1998, 9, 697–689. 8052. Also see the Supporting Information for experimental details.

J. Org. Chem. Vol. 75, No. 21, 2010 7169

JOC Article Chintareddy et al.

TABLE 4. WE Reactions of Aldehydes with 2b in the Presence of 1 equiv TABLE 5. WE Reactions with Various Heterocyclic Aldehydes in the
of 1ca Presence of 1 equiv of 1ca

a
See Experimental Section for conditions. bIsolated yields after
column chromatography. Only the E isomer was isolated. cE/Z ratios
were determined by 1H NMR spectroscopic integration.

SCHEME 1. Synthesis of R,β-Unsaturated Nitriles in the Presence

of 1 equiv of 1ca

a
See Experimental Section for conditions. bIsolated yields after
column chromatography. Only the E isomer was isolated. cE/Z ratios
were determined by 1H NMR spectroscopic integration.

2a gave a 43% yield of product 5c in 24 h, whereas in 36 h

using 2 equiv of 1c, a 61% product yield was obtained. Inter-
estingly, the reaction of acetophenone with 2b gave exclu-
sively the E isomeric product (5f) in 73% isolated yield.
We then investigated reactions of phosphonate 2b with a
variety of aldehydes (Table 4). Except for cyclohexyl alde-
hyde, the yields and E/Z ratios are good to excellent. For the
reaction involving 3-methoxybenzaldehyde, an extended
reaction time was required. Electron-neutral aldehydes such a
as benzaldehyde and 2-napthaldehyde with phosphonate 2b See Experimental Section for conditions. bIsolated yields after column
chromatography. Reaction times appear in parentheses. cIsolated yield of
gave a good and excellent yield of the unsaturated esters 6a E/Z mixture.
and 6b, respectively. 4-Chlorobenzaldehyde and 4-bromo-
benzaldehyde provided excellent isolated product yields providing an 84% and 80% yield of R,β-unsaturated product,
(6c and 6d, respectively), while cyclohexanecarboxaldehyde respectively.
(6f) gave a moderate product yield. The electron-deficient, In Scheme 1 is illustrated the ability of 1c to promote
acid-sensitive, ester-functionalized aldehyde gave an excel- the synthesis of R,β-unsaturated nitriles via WE reactions
lent yield of trans-ester 6g. employing phosphonate 2e in its reaction with two different
Results for the use of heterocyclic aldehydes containing ketones and an aldehyde. In the cases of cyclohexyl ketone
oxygen, nitrogen, and sulfur as heteroatom in the WE reaction and benzaldehyde, our protocol is superior.
with 2a or 2b in the presence of 1 equiv of 1c are presented in The reaction of the bulky phosphonate 2c with various
Table 5. Good to excellent product yields were obtained with aldehydes and a ketone also proceeded efficiently (Scheme 2)
good to excellent stereoselectivity. The two five-membered in moderate to excellent yields. The formation of R-fluoro
heterocyclic aldehydes in Table 5 gave excellent isolated yields of esters shown in Scheme 3 is especially attractive for the
the corresponding products (entries 7b and 7c), whereas 7a was synthesis of biologically important molecules.24,12a As seen
isolated in good yield. The versatility of our protocol was in Scheme 3, Z isomer formation is enhanced using an
extended with phosphonate 2b with the heterocyclic aldehydes R-fluoro ester substrate. Electron-neutral and electron-rich
furan-2-carboxaldehyde and pyridine-2-carboxaldehyde, aldehydes participated with equal ease. The ketones shown
7170 J. Org. Chem. Vol. 75, No. 21, 2010
Chintareddy et al.
JOC Article
SCHEME 2. Synthesis of Bulky Esters Using 1 equiv of 1ca SCHEME 3. Synthesis of R-Fluoro Esters Using 1 equiv of 1ca

a
See Experimental Section for conditions. bIsolated yields after column
chromatography. Reaction times appear in parentheses. Only the E isomer
was isolated. cE/Z ratio was determined by 1H NMR spectroscopy.

in Scheme 3 also reacted with phosphonate 2d, providing a

good yield of product at room temperature. It is worth
noting here that the products 9a-d in Scheme 3 are prepared
by our method for the first time except 9c, although such bulky
esters have been synthesized previously via the Mizoroki-
Heck reaction.25
Synthesis of an R,β-unsaturated ketone using acetyl phospho-
nate 2f proceeded in good yield (Scheme 4), whereas no reaction
occurred for alkyl phosphonate 2g with 4-chlorobenzaldehyde
using 1 equiv of 1c. Not surprisingly, the acid-containing phos-
phonate 2h (which could be expected to protonate 1c) gave only
a
See Experimental Section for conditions. bIsolated yield of E/Z
mixture. Reaction times appear in parentheses. cE/Z ratio was
(24) See for example: (a) Suzuki, Y.; Sato., M. Tetrahedron Lett. 2004, 45, determined by 19F NMR spectroscopy.
1679–1681. (b) Bargiggia, F.; Santos, S. D.; Piva, O. Synthesis 2002, 427–437.
(c) Ziemer, F.; Willms, L.; Bauer, K.; Bieringer, H.; Rosinger, C.; Demassey,
J. U.S. Patent 5,972,839 (Hoechst Schering AgrEvo GmbH); Chem. Abstr.
1999, 129, 105502. (d) Thenappan, A.; Burton, D. J. J. Org. Chem. 1990, 55, SCHEME 4. Some Test Examples with Different Phosphonates
4639–4642. (e) Kitazume, T.; Tanaka, G. J. Fluorine Chem. 2000, 106, 211– Using 1 equiv of 1ca
215. (f ) Engman, M.; Diesen, J. S.; Paptchikhine, A.; Andersson, P. G. J. Am.
Chem. Soc. 2007, 129, 4536–4537. (g) Sano, S.; Kuroda, Y.; Saito, K.; Ose,
Y.; Nagao, Y. Tetrahedron 2006, 62, 11881–11890. (h) Miyake, N.; Kitazume,
T. J. Fluorine Chem. 2003, 122, 243–246. (I) Suzuki, Y.; Sato, M. Tetrahedron
Lett. 2004, 45, 1679–1681. ( j) Sano, S.; Saito, K.; Nagao, Y. Tetrahedron Lett.
2003, 44, 3987–3990.
(25) For selected references on Mizoroki-Heck reactions see: (a) Nadri, S.;
Joshaghani, M.; Rafiee, E. Appl. Catal. A 2009, 362, 163–168. (b) Mohanty, S.;
Suresh, D.; Balakrishna, M. S.; Mague, J. T. Tetrahedron 2007, 64, 240–247.
(c) Dawood, K. M. Tetrahedron 2007, 63, 9642–9651. (d) Mino, T.; Shirae, Y.;
Sasai, Y.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2006, 71, 6834–6839. (e) Han,
Y.; Lee, L. J.; Huynh, H. V. Organometallics 2009, 28, 2778–2786. (f ) Kantchev,
E. A. B.; Peh, G-R; Zhang, C.; Ying, J. Y. Org. Lett. 2008, 10, 3949–3952.
(g) Han, Y.; Huynh, H. V.; Koh, L. L. J. Organomet. Chem. 2007, 692, 3606–
3613. (h) Huynh, H. V.; Neo, T. C.; Tan, G. K. Organometallics 2006, 25, 1298–
1302. (i) Martinez, R.; Voica, F.; Genet, J.-P.; Darses, S. Org. Lett. 2007, 9,
3213–3216.
(26) For mechanistic studies, see: (a) Izod, K. Coord. Chem. Rev. 2002,
227, 53–173. (b) Abdou, W. M.; Khidre, M. D.; Khidre, R. E. Eur. J. Med.
Chem. 2009, 44, 526–532. (c) Strzalko, T.; Seyden-Penne, J.; Froment, F.;
Corset, J.; Simonnin, M. P. Can. J. Chem. 1988, 66, 391–396. (d) Strzalko, T.;
Seyden-Penne, J.; Froment, F.; Corset, J.; Simonnin, M. P. J. Chem. Soc.,
Perkin Trans 2 1987, 6, 783–789. (e) Kitamura, M.; Isobe, M.; Ichikawa, Y.; a
See Experimental Section for conditions. bIsolated yield after col-
Goto, T. J. Org. Chem. 1984, 49, 3517–3527. (f ) Bottin-Strzalko, T.; Corset,
J.; Froment, F.; Pouet, M. J.; Seyden-Penne, J.; Simonnin, M. P. J. Org. umn chromatography, isolated yield of E isomer. cE/Z ratio was
Chem. 1980, 45, 1270–1276. (g) Bottin-Strzalko, T.; Seyden-Penne, J.; Pouet, determined by 1H NMR spectroscopy.
M-J; Simonnin, M. P. J. Org. Chem. 1978, 43, 4346–4351. (h) Motoyoshiya,
J.; Kusaura, T.; Kokin, K.; Yokoya, S.-I.; Takaguchi, Y.; Narita, S.;
Aoyama, H. Tetrahedron 2001, 57, 1715–1721. (i) Webb, G. A.; Simonnin,
a 2% conversion by GC-MS analysis under the same reaction
M. P.; Seyden-Penne, J.; Bottin-Strzalko, T. Mag. Reson. Chem. 1985, 23, conditions.
48–51. ( j) Bonfanti, J.-F.; Craig, D. Tetrahedron Lett. 2005, 46, 3719–3723. The pathway of the WE reaction has been extensively
(k) Arnett, E. M.; Wernett, P. C. J. Org. Chem. 1993, 58, 301–303. (l) Brandt,
P.; Norrby, P.-O.; Martin, I.; Rein, T. J. Org. Chem. 1998, 63, 1280–1289. discussed in the literature.1,2,3a,26 Seyden-Penne26f et al.
(m) Ando, K. J. Org. Chem. 1999, 64, 6815–6821. reported the presence of carbanions in lithium or potassium
J. Org. Chem. Vol. 75, No. 21, 2010 7171
JOC Article Chintareddy et al.

FIGURE 3. Molecular structure of 12 (H atoms are omitted for clarity).

salts of M[(C2H5O)2P(O)CHCOOCH3], which were charac- than the 122.7(2)o we observed by X-ray means; the former
terized using proton, carbon, and phosphorus NMR, and IR value being well outside of 3 the standard deviation of the
spectroscopies. Brandt,26l Motoyoshiya,26h and Ando26m et al. latter. It is not presently clear why this discrepancy exists,
reported computational studies on the WE reaction pathway. although crystal packing effects could be responsible. It is
In the present work we found that the active methylene group interesting to note that the apparent partial double bond
of trimethyl phosphonoacetate (pKa ∼18-19 in DMSO,1g nature of the carbon-carbon and phosphorus-carbon linkages
∼12 in H2O27) is deprotonated by 1c (pKa 33.53 in CH3CN28). in the WE intermediate anion is reflected in both the calculated
By cooling an acetonitrile/hexanes solution of a 1:1 mixture of and the X-ray-determined bond length values. However,
these two components at freezer temperature for 1-3 h, it a similar departure from the expected nature of the PdO and
became possible to grow colorless crystalline needles of 12 that CdO bonds does not seem to affect these linkages as measured
melted at room temperature (see Supporting Information for by both the calculation and the X-ray determination of their
conditions). The molecular structure shown by X-ray means lengths.
(Figure 3) was determined at -70 °C (see Supporting Informa-
tion for details). It should be noted, however, that water is SCHEME 5. Equilibrium Formed by 1c and 1 equiv of Trimethyl
stoichiometrically formed in the WE reaction. Thus water in the Phosphonoacetate with 31P NMR Chemical Shifts Measured
presence of 1c is likely to be in equilibrium with [H1c]þ[OH-] in C6D6
wherein the hydroxide ion is a potentially catalytically active
species that can also deprotonate the phosphonate substrate as
1c is converted to its protonated analogue.

TABLE 6. Pertinent Bond Lengths in 12

av length calcd length X-ray determined
bond (pm)a (pm)b length (pm) bond character
C-C 154
CdC 134 140.5 138.6(4) partial double bond
C-O 143
CdO 120 124.5 122.9(3) double bond
P-O 163
PdO ca. 150 149.9 146.8(2) double bond
P-C 180b
PdC 1.66c 173.6 170.7(3) partial double bond
a
From Huheey, J. E.; Keiter, E. A.; Keiter, R. L. Inorganic Chemistry, In the solid state, 12 is composed of the transannulated
4th ed.; Harper Collins College Publishers: New York, 1993, except protonated proazaphosphatrane H1cþ cation and the free
where indicated otherwise. bP-C mean length from Interatomic Dis-
tances and Configurations in Molecules and Ions; Sutton, L. E., Ed.; intermediate [(MeO)2P(O)CHC(O)OMe]- anion, suggesting
Chemical Society: London, Special Publication No. 11, 1958, and No. that the equilibrium between equimolar trimethyl phospho-
18, 1965. cPdC length in a simple ylide: (a) Pauling, L. The Nature of the noacetate and 1c involves the formation of the ionic salt 12
Chemical Bond, 3rd ed.; Cornell University Press: Ithaca, NY, 1960; (Scheme 5 and Figure 3). The room-temperature 31P NMR
p 224. (b) Bart, J. C. J. Chem. Soc. B 1969, 350-365.
spectrum consists of four major peaks at 131 (sharp), 43 (broad),
23 (broad), and -8.0 (sharp) ppm, which we assign to 1c, the
From Table 6 it is seen that our experimental values for anion of 12, the trimethyl phosphonoacetate molecule, and the
pertinent bond lengths of the anion of 12 match well those cation of 12, respectively. The assignments of the broad peaks
calculated by others for the gas phase global minimum of this accord well with those made earlier for equilibria reached in
anion at the B3LYP/6-31þG* level.26l The large P-C-C DME with trimethyl phosphonoacetate in the presence of
angle noted by these authors (128°) is significantly larger LiOt-Bu or LiOCH(CF3)2.1g,29 The assignment for the fourth
peak is consonant with the 31P chemical shift we observed
(27) The reported pKa of triethyl phosphonoacetate in water is 11.9:
Sokolov, M. P.; Gazizov, I. G.; Mavrin, G. V. Zh. Obshch. Khim. 1989, 59,
1043–1047. (29) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
(28) Kisanga, P. B.; Verkade, J. G. J. Org. Chem. 2000, 65, 5431–5432. S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.

7172 J. Org. Chem. Vol. 75, No. 21, 2010

Chintareddy et al.
JOC Article
SCHEME 6. Possible Pathways for the Destruction of 1c in the Presence of 12

separately for this cation as the chloride salt in CDCl3,20h and MgAlO-t-Bu hydrotalcite,3a MgLa mixed oxides,17 and
we assign the first peak to 1c on the basis of the spectrum of this nano MgO18 catalysts that operate at 130 °C. The reaction
compound in C6D6 measured separately. The breadth of the conditions for our protocol are compatible with aryl sub-
43 and 23 ppm peaks is consistent with an equilibrium between strates bearing a variety of functional groups on the phenyl
the neutral and anionic forms of the phosphonoacetate. After ring such as, cyano, chloro, bromo, methoxy, amino, ester,
warming the NMR tube to 50 °C for 30 min, major sharp peaks and nitro. Several desirable features of 1c as a promoter in
at 26.5, 14, and 9.2 ppm arose at the expense of the peaks at 131, 43, addition to its commercial availability, are its optimum steric
and 23 ppm resonances. The prominent upfield peak for the cation properties provided by the iso-butyl groups, the electron-
of 12 persisted in all of the 31P spectra discussed here. The intensity richness of the phosphorus arising from the donating capa-
changes suggested that 1c was being consumed by a reaction with bility of all three virtually planar nitrogens adjacent to the
the anion of 12. After 1 h at 50 °C, the NMR spectrum had not phosphorus, and the possibility for augmented phosphorus
changed appreciably, but after 2 h, the peak for 1c had almost basicity arising from transannular bonding between the
disappeared and the broad peaks at 43 and 23 had grown quite bridgehead nitrogen and the phosphorus atom30 during its
small, leaving prominent sharp peaks at 26.5, 14, and 9.5 ppm, in catalytic cycle. Under room-temperature reaction condi-
addition to a large sharp peak at 7.9 pm for the cation of 12. After tions, the generally excellent chemo- and stereoselectivity,
16 h at 50 °C, the only prominent peaks remaining were the ones at wide scope, and good to excellent product yields encountered
26, 14, and 10 ppm in addition to the cation peak at 7.7 ppm, and with promoter 1c make our methodology particularly attrac-
the peak at 23 ppm had grown considerably smaller. tive compared with other catalyst systems usually employed
The three prominent peaks for the final products could be in WE reactions. The molecular structure of 12 determined
accounted for by the reactions depicted in Scheme 6 wherein the by X-ray means strongly supports the intermediacy of such a
proazaphosphatrane (1c in the present instance) is nucleo- species in the WE reaction. To the best of our knowledge, 12
philically attacked at an N-C carbon in Path A by Nu or represents the first structurally characterized example of a
Nu0 (see Scheme 5 for definitions of these symbols) or at the WE intermediate by noncalculational means.
phosphorus by these nucleophiles (Path B). Here the anio-
nic charges are balanced by the cation of 12. The two Experimental Section
anionic products of Path A could well have coincident 31P
NMR chemical shifts in view of the large separation be- General Procedure for the Synthesis of r,β-Unsaturated Esters,
Ketones, Fluorides, and Nitriles. An oven-dried Schlenk flask
tween the Nu and Nu0 moieties and the phosphorus. The
equipped with a magnetic stirring bar was charged with aldehyde
much smaller separation between these fragments and the (1 mmol) and phosphonate (1.2 mmol). The flask was capped with
phosphorus in the two products of Path B could give rise to a rubber septum, degassed under reduced pressure, and refilled
two 31P NMR chemical shifts. with argon. Then THF (2 mL) was introduced through a cannula.
Proazaphosphatrane 1 (1-2 mmol, as indicated in the footnotes of
Conclusions the tables and schemes) was then added to the flask under argon
atmosphere. Proazaphosphatranes 1a, 1b, and 1d were dissolved in
In summary, as shown in Tables 1-5 and Schemes 1-4, 2 mL of THF before addition to the Schlenk flask containing the
our methodology is eminently suitable for synthesizing WE aldehyde and phosphonate. Finally, the Schlenk flask was again
products via the reaction of a variety of phosphonates with degassed under reduced pressure and refilled with argon. The
aromatic, aliphatic, cyclic, and heterocyclic aldehydes in the reaction mixture was stirred at room temperature until the starting
aldehyde had been completely consumed as judged by TLC. After
presence of 1c as a promoter. Good to excellent yields were
completion of the reaction, the crude reaction mixture was loaded
obtained in the vast majority of cases. In the 69 instances for onto a small silica gel column and filtered with ethyl acetate/
which literature yields are available for these reactions hexanes (1:1), and the crude product was subjected to 1H NMR
involving aldehyde or ketone substrates (see corresponding spectroscopy to determine the E/Z ratio. The crude product was
parenthesized data in Tables 1-5 and Schemes 1-3), our then purified by silica gel column chromatography using an eluent
yields were comparable in 24 cases, higher in 31, and lower in
14 cases. It is worthy to note here that our protocol gave (30) Karpati, T.; Veszpremi, T.; Thirupathi, N.; Liu, X.; Wang, Z.; Ellern,
better or comparable yields even at room temperature over A.; Nyulaszi, L.; Verkade, J. G. J. Am. Chem. Soc. 2006, 128, 1500–1512.

J. Org. Chem. Vol. 75, No. 21, 2010 7173

JOC Article Chintareddy et al.

mixture of hexanes and ethyl acetate. The yields reported are Supporting Information Available: General considerations;
isolated yields of E isomers unless otherwise stated. procedure for recovery of 1c; 1H, 13C, 31P, and 19F NMR
spectroscopic data and copies of corresponding spectra; details
of the X-ray data collection, structure solution, and structure
Acknowledgment. The National Science Foundation is refinement; tables of crystal data, atomic coordinates, bond
gratefully acknowledged for financial support of this research distances, and bond angles for 12 and its CIF file. This
in the form of a grant (0750463). We also thank Dr. Weiping Su material is available free of charge via the Internet at http://
for kindly providing a sample of 1d. pubs.acs.org.

7174 J. Org. Chem. Vol. 75, No. 21, 2010