P[N(i-Bu)CH2CH2]3N: Nonionic Lewis base for promoting the room-temperature synthesis of α,β-unsaturated esters, fluorides, ketones, and nitriles using Wadsworth - Emmons phosphonates

Article abstract of DOI:10.1021/jo1012515

The bicyclic triaminophosphine P(RNCH₂CH₂) ₃N (R = i-Bu, 1c) serves as an effective promoter for the room-temperature stereoselective synthesis of α,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 performed 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.

Full text of DOI:10.1021/jo1012515

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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
jverkade@iastate.edu
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-
tions are key steps in the total synthesis of biologically active
The Wadsworth-Emmons (WE) reaction is versatile, having
numerous applications in the synthesis of intermediates for fine
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Published on Web 10/14/2010
DOI: 10.1021/jo1012515
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2010 American Chemical Society

Chintareddy et al.
JOCArticle
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
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
FIGURE 1. Proazaphosphatranes used in this study.
Condensation of an aldehyde or a ketone with a phospho-
nate to give an R,β-unsaturated ester or nitrile (see scheme in
the abstract) is traditionally effected in the presence of strong
stoichiometric ionic bases such as KOH,4 Ba(OH)2,5 NaH,6
BuLi,6,7 benzyltrimethylammonium hydroxide (Triton B),6,8
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
FIGURE 2. Phosphonates employed in this work.
TABLE 1. Survey of Proazaphosphatranes in the Reaction of
p-Nitrobenzaldehyde with 2a in the Presence of 1 equiv of 1a
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1a
1b
1c
5.5
4.0
0.5
95 [99/1]
94 [99/1]
96 [99/1]; lit.: 89 [100/0],15a 74 [100/0],5d
95,19b 98 [99/1],18 90 [99/1]3a
60 [96/4]
1d
none
6.0
20.0
no reaction
aSee Experimental Section for conditions. bIsolated yields after
column chromatography. cE/Z ratios were determined by 1H NMR
spectroscopic integration.
employed as a base.12 Barrett et al. reported an application
of the nonionic base 1,1,3,3-tetramethylguanidine (TMG)
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[4.4.0]dec-5-ene (TBD) as a nonionic base for WE reactions
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promoter for WE reactions,14b and in 2008, Davies et al.
reported WE reactions using MeMgBr as base.14c Several
reports of solid reagents/catalysts for WE reactions have also
appeared, for example, SiO2-supported 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU),15 KF/alumina,16 MgAlO-t-Bu
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Lett. 1999, 1, 579–582.
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(b) Sano, S.; Teranishi, R.; Nagao, Y. Tetrahedron Lett. 2002, 43, 9183–9186.
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P. M.; Russell, A. J.; Smith, A. D.; Toms, S. M. Org. Lett. 2008, 10, 5437–
5440.
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Rambaud, M.; Kirschleger, B. Phosphorus, Sulfur Related Elem. 1983, 14, 385–
391.
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K.; Suzuki, Y. Tetrahedron Lett. 2010, 51, 2323–2325.
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TABLE 2. WE Reactions of Various Aldehydes with 2a in the Presence of 1 equiv of 1ca
aSee 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
reactions are also useful in solid phase syntheses using DBU
as base.19 Problems encountered in some of the aforemen-
tioned methods include longer reaction times arising from
moderate chemoselectivity (resulting in Knoevenagel adduct
formation or Cannizzarro and Meerwein-Pondorf-Verley
reductions13,16) and the lack of ketone participation.3a,14a,15
Heterogeneous catalysts such as MgAlO-t-Bu hydrotalcite,3a
MgLa mixed oxides,17 macroreticular anion-exchange resin
Amberlyst A-26 (OH- form),3f and nano MgO18 require 130 °C
to obtain reasonable yields of WE products, but heteroge-
neous metal oxide catalysts must be prepared in a process
requiring 450 °C for up to 6 h,3a,17 and activation of Ba(OH)2
as a catalyst requires 200 °C.5 An ionic liquid methodology has
been described that uses up to 5 equiv of LiOH H2O as a pro-
3
moter.9a Apart from this, to the best of our knowledge there
is no report of a catalyst that operates at room temperature
with wide functional group tolerance using a commercially
available catalyst.
(17) Kantam, M. L.;Kochkar, H.;Clacens, J.-M.;Veldurthy, B.;Garcia-Ruiz,
A.; Figueras, F. Appl. Catal. B 2005, 55, 177–183.
(18) Choudary, B. M.; Mahendar, K.; Ranganath, K. V. S. J. Mol. Catal.
A: Chem. 2005, 234, 25–27.
(19) (a) Yamazaki, K.; Kondo, Y. Chem. Commun. 2002, 210–211, and
references therein. (b) Bouziane, A.; Helou, M.; Carboni, B.; Carreaux, F.;
Demerseman, B.; Bruneau, C.; Renaud, J.-L. Chem.;Eur. J. 2008, 14, 5630–
5637.
We have previously reported that the commercially available20a
proazaphosphatranes 1a, 1b, and 1c (Figure 1) are exceed-
ingly strong nonionic bases that are useful in a wide variety of
important organic transformations20b-g as organocatalysts,
7168 J. Org. Chem. Vol. 75, No. 21, 2010

Chintareddy et al.
JOCArticle
as ligands in metal-assisted coupling reactions, and as stoi-
chiometric reagents.21
configured esters. An enolizable aliphatic acyclic and a
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
reported in the literature. An electron-donating amino-func-
tionalized aldehyde with phosphonate 2a resulted in an
excellent yield of R,β-ester 4g. Good to excellent yields of E
product were obtained in all cases. In the reaction in Table 2
that produced 4h, promoter 1c in protonated form was
recovered in 87% yield according to our previous report,23
thus enhancing the appeal of 1c for possible recovery in these
syntheses.
Results and Discussion
Here we report a convenient, efficient, and stereospecific
synthesis of R,β-unsaturated esters, fluorides, and nitriles
from a wide array of aromatic, heterocyclic, aliphatic, and
cyclic aldehydes and ketones, using a range of WE phospho-
nates 2a-2f (Figure 2) in the presence of a proazaphospha-
trane of type 1 (see scheme in the abstract). In screening
1a-1d in the reaction shown in Table 1, we found that 1d20c,d
did not perform as well as 1a-1c. Among the latter com-
pounds, 1c gave an excellent yield of product in the shortest
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
TABLE 3. WE Reactions of 2 with Various Ketones in the Presence of
1 equiv of 1ca
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 range of aldehydes in their reaction with 2a in the presence
of 1 equiv of 1c (Table 2). 4-Chlorobenzaldehyde and 4-bromo-
benzaldehyde provided good isolated product yields (products
4b and 4d, respectively), while 3-methoxybenzaldehyde (Table 2,
4c) gave a moderate yield of product. Electron-deficient,
acid-sensitive 4-cyanobenzaldehyde 4h and the ester-
functionalized aldehyde 4i gave excellent yields of trans-
aSee Experimental Section for conditions. bIsolated yields after
column chromatography. cE/Z ratios were determined by 1H NMR
spectroscopic integration. d2 equiv of 1c was used. eNo yield was
obtained using MgAlO-t-Bu hydrotalcite catalyst.
Ketones are well-known to be difficult substrates for WE
reactions.3a,9c,14a,15,17,18 As shown in Table 3, both aromatic
and aliphatic ketones reacted with phosphonate 2a or 2b in
the presence of 1 equiv of 1c at room temperature, affording
the desired products in poor to good yields, although time
requirements were longer than in the case of aldehydes. How-
ever, the E/Z ratio was higher for 5a than those in literature
reports3a,15,17 for this compound. It is noteworthy that some
of the literature procedures3a,15 reported failure of such reac-
tions, gave poor yields, or operated at higher temperatures
(typically at 130 °C3a,17,18). The reaction of acetophenone
with 2a resulted in a 47% yield of product 5a in the presence
of 1 equiv of 1c, but with 2 equiv, a 67% yield of product was
realized after 24 h. Similarly, benzophenone with 1 equiv of
(20) (a) Proazaphosphatranes 1a-1c are commercially available from
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–
4430. (c) Chintareddy, V. R.; Wadhwa, K.; Verkade, J. G. J. Org. Chem.
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.
Chem. 2009, 74, 5683–5686. (f ) Wadhwa, K.; Verkade, J. G. J. Org. Chem.
2009, 74, 4368–4371. (g) Venkat Reddy, Ch.; Verkade, J. G. J. Org. Chem.
2007, 72, 3093–3096. (h) Kisanga, P. B.; Verkade, J. G. Tetrahedron 2001, 57,
467–475.
(21) For reviews of proazaphosphatrane chemistry, see: (a) Verkade, J. G.
New Aspects of Phosphorus Chemistry II. Top. Curr. Chem. Majoral, J. P., Ed.,
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–
8052. Also see the Supporting Information for experimental details.
(22) Wang, Z.; Verkade., J. G. Heteroatom Chem. 1998, 9, 697–689.
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TABLE 4. WE Reactions of Aldehydes with 2b in the Presence of 1 equiv
of 1ca
TABLE 5. WE Reactions with Various Heterocyclic Aldehydes in the
Presence of 1 equiv of 1ca
aSee Experimental Section for conditions. bIsolated yields after
column chromatography. Only the E isomer was isolated. E/Z ratios
c
were determined by 1H NMR spectroscopic integration.
SCHEME 1. Synthesis of R,β-Unsaturated Nitriles in the Presence
of 1 equiv of 1ca
aSee Experimental Section for conditions. bIsolated yields after
column chromatography. Only the E isomer was isolated. E/Z ratios
c
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
as benzaldehyde and 2-napthaldehyde with phosphonate 2b
gave a good and excellent yield of the unsaturated esters 6a
and 6b, respectively. 4-Chlorobenzaldehyde and 4-bromo-
benzaldehyde provided excellent isolated product yields
(6c and 6d, respectively), while cyclohexanecarboxaldehyde
(6f) gave a moderate product yield. The electron-deficient,
acid-sensitive, ester-functionalized aldehyde gave an excel-
lent yield of trans-ester 6g.
Results for the use of heterocyclic aldehydes containing
oxygen, nitrogen, and sulfur as heteroatom in the WE reaction
with 2a or 2b in the presence of 1 equiv of 1c are presented in
Table 5. Good to excellent product yields were obtained with
good to excellent stereoselectivity. The two five-membered
heterocyclic aldehydes in Table 5 gave excellent isolated yields of
the corresponding products (entries 7b and 7c), whereas 7a was
isolated in good yield. The versatility of our protocol was
extended with phosphonate 2b with the heterocyclic aldehydes
furan-2-carboxaldehyde and pyridine-2-carboxaldehyde,
aSee Experimental Section for conditions. bIsolated yields after column
chromatography. Reaction times appear in parentheses. cIsolated yield of
E/Z mixture.
providing an 84% and 80% yield of R,β-unsaturated product,
respectively.
In Scheme 1 is illustrated the ability of 1c to promote
the synthesis of R,β-unsaturated nitriles via WE reactions
employing phosphonate 2e in its reaction with two different
ketones and an aldehyde. In the cases of cyclohexyl ketone
and benzaldehyde, our protocol is superior.
The reaction of the bulky phosphonate 2c with various
aldehydes and a ketone also proceeded efficiently (Scheme 2)
in moderate to excellent yields. The formation of R-fluoro
esters shown in Scheme 3 is especially attractive for the
synthesis of biologically important molecules.24,12a As seen
in Scheme 3, Z isomer formation is enhanced using an
R-fluoro ester substrate. Electron-neutral and electron-rich
aldehydes participated with equal ease. The ketones shown
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SCHEME 2. Synthesis of Bulky Esters Using 1 equiv of 1ca
SCHEME 3. Synthesis of R-Fluoro Esters Using 1 equiv of 1ca
aSee 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
aSee Experimental Section for conditions. bIsolated yield of E/Z
mixture. Reaction times appear in parentheses. cE/Z ratio was
determined by 19F NMR spectroscopy.
(24) See for example: (a) Suzuki, Y.; Sato., M. Tetrahedron Lett. 2004, 45,
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,
4639–4642. (e) Kitazume, T.; Tanaka, G. J. Fluorine Chem. 2000, 106, 211–
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.
SCHEME 4. Some Test Examples with Different Phosphonates
Using 1 equiv of 1ca
(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.;
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.
Chem. 1980, 45, 1270–1276. (g) Bottin-Strzalko, T.; Seyden-Penne, J.; Pouet,
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,
M. P.; Seyden-Penne, J.; Bottin-Strzalko, T. Mag. Reson. Chem. 1985, 23,
48–51. ( j) Bonfanti, J.-F.; Craig, D. Tetrahedron Lett. 2005, 46, 3719–3723.
(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.
(m) Ando, K. J. Org. Chem. 1999, 64, 6815–6821.
aSee Experimental Section for conditions. bIsolated yield after col-
umn chromatography, isolated yield of E isomer. cE/Z ratio was
determined by 1H NMR spectroscopy.
a 2% conversion by GC-MSanalysisunder the same reaction
conditions.
The pathway of the WE reaction has been extensively
discussed in the literature.1,2,3a,26 Seyden-Penne26f et al.
reported the presence of carbanions in lithium or potassium
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FIGURE 3. Molecular structure of 12 (H atoms are omitted for clarity).
salts of M[(C2H5O)2P(O)CHCOOCH3], which were charac-
terized using proton, carbon, and phosphorus NMR, and IR
spectroscopies. Brandt,26l Motoyoshiya,26h and Ando26m et al.
reported computational studies on the WE reaction pathway.
In the present work we found that the active methylene group
of trimethyl phosphonoacetate (pKa ∼18-19 in DMSO,1g
∼12 in H2O27) is deprotonated by 1c (pKa 33.53 in CH3CN28).
By cooling an acetonitrile/hexanes solution of a 1:1 mixture of
these two components at freezer temperature for 1-3 h, it
became possible to grow colorless crystalline needles of 12 that
melted at room temperature (see Supporting Information for
conditions). The molecular structure shown by X-ray means
(Figure 3) was determined at -70 °C (see Supporting Informa-
tion for details). It should be noted, however, that water is
stoichiometrically formed in the WE reaction. Thus water in the
presence of 1c is likely to be in equilibrium with [H1c]þ[OH-]
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.
than the 122.7(2)o we observed by X-ray means; the former
value being well outside of 3ꢀ the standard deviation of the
latter. It is not presently clear why this discrepancy exists,
although crystal packing effects could be responsible. It is
interesting to note that the apparent partial double bond
nature of the carbon-carbon and phosphorus-carbon linkages
in the WE intermediate anion is reflected in both the calculated
and the X-ray-determined bond length values. However,
a similar departure from the expected nature of the PdO and
CdO bonds does not seem to affect these linkages as measured
by both the calculation and the X-ray determination of their
lengths.
SCHEME 5. Equilibrium Formed by 1c and 1 equiv of Trimethyl
Phosphonoacetate with 31P NMR Chemical Shifts Measured
in C6D6
TABLE 6. Pertinent Bond Lengths in 12
av length calcd length X-ray determined
bond (pm)a
(pm)b
140.5
124.5
149.9
173.6
length (pm)
138.6(4)
122.9(3)
146.8(2)
170.7(3)
bond character
partial double bond
double bond
C-C 154
CdC 134
C-O 143
CdO 120
P-O 163
PdO ca. 150
P-C 180b
PdC 1.66c
double bond
partial double bond
aFrom Huheey, J. E.; Keiter, E. A.; Keiter, R. L. Inorganic Chemistry,
4th ed.; Harper Collins College Publishers: New York, 1993, except
where indicated otherwise. bP-C mean length from Interatomic Dis-
tances and Configurations in Molecules and Ions; Sutton, L. E., Ed.;
Chemical Society: London, Special Publication No. 11, 1958, and No.
18, 1965. cPdC length in a simple ylide: (a) Pauling, L. The Nature of the
Chemical Bond, 3rd ed.; Cornell University Press: Ithaca, NY, 1960;
p 224. (b) Bart, J. C. J. Chem. Soc. B 1969, 350-365.
In the solid state, 12 is composed of the transannulated
protonated proazaphosphatrane H1cþ cation and the free
intermediate [(MeO)2P(O)CHC(O)OMe]- anion, suggesting
that the equilibrium between equimolar trimethyl phospho-
noacetate and 1c involves the formation of the ionic salt 12
(Scheme 5 and Figure 3). The room-temperature 31P NMR
spectrum consists of four major peaks at 131 (sharp), 43 (broad),
23 (broad), and -8.0 (sharp) ppm, which we assign to 1c, the
anion of 12, the trimethyl phosphonoacetate molecule, and the
cation of 12, respectively. The assignments of the broad peaks
accord well with those made earlier for equilibria reached in
DME with trimethyl phosphonoacetate in the presence of
LiOt-Bu or LiOCH(CF3)2.1g,29 The assignment for the fourth
peak is consonant with the 31P chemical shift we observed
From Table 6 it is seen that our experimental values for
pertinent bond lengths of the anion of 12 match well those
calculated by others for the gas phase global minimum of this
anion at the B3LYP/6-31þG* level.26l The large P-C-C
angle noted by these authors (128°) is significantly larger
(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,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
(28) Kisanga, P. B.; Verkade, J. G. J. Org. Chem. 2000, 65, 5431–5432.
7172 J. Org. Chem. Vol. 75, No. 21, 2010

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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
we assign the first peak to 1c on the basis of the spectrum of this
compound in C6D6 measured separately. The breadth of the
43 and 23 ppm peaks is consistent with an equilibrium between
the neutral and anionic forms of the phosphonoacetate. After
warming the NMR tube to 50 °C for 30 min, major sharp peaks
at 26.5, 14, and 9.2 ppm arose at the expense of the peaks at 131, 43,
and 23 ppm resonances. The prominent upfield peak for the cation
of 12 persisted in all of the 31P spectra discussed here. The intensity
changes suggested that 1c was being consumed by a reaction with
the anion of 12. After 1 h at 50 °C, the NMR spectrum had not
changed appreciably, but after 2 h, the peak for 1c had almost
disappeared and the broad peaks at 43 and 23 had grown quite
small, leaving prominent sharp peaks at 26.5, 14, and 9.5 ppm, in
addition to a large sharp peak at 7.9 pm for the cation of 12. After
16 h at 50 °C, the only prominent peaks remaining were the ones at
26, 14, and 10 ppm in addition to the cation peak at 7.7 ppm, and
the peak at 23 ppm had grown considerably smaller.
MgAlO-t-Bu hydrotalcite,3a MgLa mixed oxides,17 and
nano MgO18 catalysts that operate at 130 °C. The reaction
conditions for our protocol are compatible with aryl sub-
strates bearing a variety of functional groups on the phenyl
ring such as, cyano, chloro, bromo, methoxy, amino, ester,
and nitro. Several desirable features of 1c as a promoter in
addition to its commercial availability, are its optimum steric
properties provided by the iso-butyl groups, the electron-
richness of the phosphorus arising from the donating capa-
bility of all three virtually planar nitrogens adjacent to the
phosphorus, and the possibility for augmented phosphorus
basicity arising from transannular bonding between the
bridgehead nitrogen and the phosphorus atom30 during its
catalytic cycle. Under room-temperature reaction condi-
tions, the generally excellent chemo- and stereoselectivity,
wide scope, and good to excellent product yields encountered
with promoter 1c make our methodology particularly attrac-
tive compared with other catalyst systems usually employed
in WE reactions. The molecular structure of 12 determined
by X-ray means strongly supports the intermediacy of such a
species in the WE reaction. To the best of our knowledge, 12
represents the first structurally characterized example of a
WE intermediate by noncalculational means.
The three prominent peaks for the final products could be
accounted for by the reactions depicted in Scheme 6 wherein the
proazaphosphatrane (1c in the present instance) is nucleo-
philically attacked at an N-C carbon in Path A by Nu or
Nu0 (see Scheme 5 for definitions of these symbols) or at the
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 31
P
General Procedure for the Synthesis of r,β-Unsaturated Esters,
Ketones, Fluorides, and Nitriles. An oven-dried Schlenk flask
equipped with a magnetic stirring bar was charged with aldehyde
(1 mmol) and phosphonate (1.2 mmol). The flask was capped with
a rubber septum, degassed under reduced pressure, and refilled
with argon. Then THF (2 mL) was introduced through a cannula.
Proazaphosphatrane 1 (1-2 mmol, as indicated in the footnotes of
the tables and schemes) was then added to the flask under argon
atmosphere. Proazaphosphatranes 1a, 1b, and 1d were dissolved in
2 mL of THF before addition to the Schlenk flask containing the
aldehyde and phosphonate. Finally, the Schlenk flask was again
degassed under reduced pressure and refilled with argon. The
reaction mixture was stirred at room temperature until the starting
aldehyde had been completely consumed as judged by TLC. After
completion of the reaction, the crude reaction mixture was loaded
onto a small silica gel column and filtered with ethyl acetate/
NMR chemical shifts in view of the large separation be-
tween the Nu and Nu0 moieties and the phosphorus. The
much smaller separation between these fragments and the
phosphorus in the two products of Path B could give rise to
two 31P NMR chemical shifts.
Conclusions
In summary, as shown in Tables 1-5 and Schemes 1-4,
our methodology is eminently suitable for synthesizing WE
products via the reaction of a variety of phosphonates with
aromatic, aliphatic, cyclic, and heterocyclic aldehydes in the
presence of 1c as a promoter. Good to excellent yields were
obtained in the vast majority of cases. In the 69 instances for
which literature yields are available for these reactions
involving aldehyde or ketone substrates (see corresponding
parenthesized data in Tables 1-5 and Schemes 1-3), our
yields were comparable in 24 cases, higher in 31, and lower in
14 cases. It is worthy to note here that our protocol gave
better or comparable yields even at room temperature over
1
hexanes (1:1), and the crude product was subjected to H NMR
spectroscopy to determine the E/Z ratio. The crude product was
then purified by silica gel column chromatography using an eluent
(30) Karpati, T.; Veszpremi, T.; Thirupathi, N.; Liu, X.; Wang, Z.; Ellern,
A.; Nyulaszi, L.; Verkade, J. G. J. Am. Chem. Soc. 2006, 128, 1500–1512.
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mixture of hexanes and ethyl acetate. The yields reported are
isolated yields of E isomers unless otherwise stated.
Supporting Information Available: General considerations;
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
refinement; tables of crystal data, atomic coordinates, bond
distances, and bond angles for 12 and its CIF file. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. The National Science Foundation is
gratefully acknowledged for financial support of this research
in the form of a grant (0750463). We also thank Dr. Weiping Su
for kindly providing a sample of 1d.
7174 J. Org. Chem. Vol. 75, No. 21, 2010