Phospha-Muenchnones: Electronic structures and 1,3-dipolar cycloadditions

Article abstract of DOI:10.1021/jo1008383

The reaction of imines, acid chlorides, PR₃, and base generates a new class of 1,3-dipoles: phospha-Muenchnones. These 1,3-dipoles can undergo cycloadditions with alkynes followed by loss of phosphine oxides to form pyrroles. Cycloaddition reac

Full text of DOI:10.1021/jo1008383

pubs.acs.org/joc
€
Phospha-Munchnones: Electronic Structures and 1,3-Dipolar
Cycloadditions
†
Daniel J. St-Cyr, Marie S. T. Morin, Francine Belanger-Gariepy,
†
‡
ꢀ
ꢀ
Bruce A. Arndtsen,*,† Elizabeth H. Krenske,§ and K. N. Houk*,§
†Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada,
‡
ꢀ
Deꢀpartement de Chimie, Universiteꢀde Montreꢀal, 2900, Boulevard Edouard-Montpetit, Montreꢀal, QueꢀbecH3T1J4,
Canada, and §Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095
bruce.arndtsen@mcgill.ca; houk@chem.ucla.edu
Received May 2, 2010
The reaction of imines, acid chlorides, PR3, and base generates a new class of 1,3-dipoles: phospha-
€
Munchnones. These 1,3-dipoles can undergo cycloadditions with alkynes followed by loss of phosphine
oxides to form pyrroles. Cycloaddition reactivity is dependent upon the PR3 employed, with PhP-
(catechyl) (catechyl = o-O2C6H4) providing the most rapid cycloadditions and optimal pyrrole yields.
1H, 13C, and 31P NMR analysis and computations indicate that electron-poor catechyl-substituted
phosphonites and phosphites favor a cyclic 1,3-dipolar structure, while more electron-rich phosphines
instead favor the valence tautomeric acyclic ylides. X-ray crystallographic studies confirm this. Density
functional theory calculations support the wide variety of P-O interactions induced by different PR3
groups and indicate that the most efficient concerted 1,3-dipolar cycloadditions are those for dipoles
whose ground-state geometry is most like the transition-state geometry. Reactions of these dipoles with
monosubstituted alkynes bearing an electron-withdrawing group are calculated to occur by stepwise
mechanisms. The presence of the phosphorus unit creates a large electronic bias across the 1,3-dipole,
allowing for regioselective cycloadditions with substituted alkynes.
Introduction
synthesis but also makes substrate variation difficult to
achieve.
1,3-Dipolar cycloaddition is a versatile route to five-mem-
bered heterocycles. An impressive array of 1,3-dipoles have
emerged over the past several decades, including such well-
known substrates as nitrones, azomethine ylides, nitrile ylides,
€
One example of the latter type of dipoles is Munchnones,
or 1,3-oxazolium 5-oxides (1), which were first reported by
Huisgen in 1964.3,4 Munchnones typically extrude CO2 upon
€
cycloaddition with alkynes, leading to pyrroles. This reactivity
has been exploited in the synthesis of biologically relevant
pyrroles,5 pyrrolines,5,6 imidazoles,7 and imidazolines.8
substituted azides, Sydnones, and Munchnones.1-4 While cer-
€
tain 1,3-dipoles are relatively easily generated (e.g., substituted
azides), many others require a multistep synthesis to assemble
the precursors, followed by the use of reactive reagents to create
the dipole.1 This not only adds further steps to the overall
(5) (a) For reviews of M€unchnones, see: Gribble, G. W. In Oxazoles:
Synthesis, Reactions, and Spectroscopy, A; Palmer, D. C., Ed.; Wiley: New
York, 2003; Vol. 60, Chapter 4. (b) Gingrich, H. L.; Baum, J. S. In Oxazoles, The
Chemistry of Heterocyclic Compounds; Turchi, I. J., Ed.; Wiley: New York,
1986; Vol. 45, Chapter 4.
(1) (a) The Chemistry of Heterocyclic Compounds: Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, H., Eds.; Wiley: New York, 2002; Vol. 45. (b) 1,3-
Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984.
(2) (a) Stewart, F.; H., C. Chem. Rev. 1964, 64, 129. (b) Lewis, W. G.;
Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn, M.
G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 1053.
(6) For examples: (a) Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am.
ꢀ
Chem. Soc. 2007, 129, 12638. (b) Belanger, G.; April, M.; Dauphin, E.; Roy,
S. J. Org. Chem. 2007, 72, 1104. (c) Peddibhotla, S.; Tepe, J. J. J. Am. Chem.
Soc. 2004, 126, 12776.
(7) For examples, see: (a) Croce, P. D.; Rerraccioli, R.; La Rosa, C.
Tetrahedron 1999, 55, 201. (b) Siamaki, A. R.; Arndtsen, B. A. J. Am. Chem.
Soc. 2006, 128, 6050.
(3) Lawson, A.; Miles, D. H. Chem. Ind. (London) 1958, 461.
(4) (a) Huisgen, H.; Gotthardt, H.; Bayer, H. O. Angew. Chem., Int. Ed.
Engl. 1964, 3, 135. (b) Huisgen, H.; Gotthardt, H.; Bayer, H. O.; Schaefer, F.
C. Angew. Chem., Int. Ed. Engl. 1964, 3, 136.
(8) (a) Dghaym, R. D.; Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int.
Ed. 2001, 40, 3228. (b) Fisk, J. A.; Mosey, R. A.; Tepe, J. J. Chem. Soc. Rev.
2007, 36, 1432.
DOI: 10.1021/jo1008383
r
Published on Web 05/18/2010
J. Org. Chem. 2010, 75, 4261–4273 4261
2010 American Chemical Society

St-Cyr et al.
JOCArticle
SCHEME 1. Generation and Cycloaddition of 212
€
Munchnones are most commonly generated via the dehydration
meric structures are conceivable. For example, conformations
where there is no potential for cyclic P-O interaction (such as 3)
can only be phosphorus ylides, while 2 could be a blend of
phosphorus ylide and 1,3-dipolar azomethine ylide. Consistent
with the latter structure, catechyl-substituted phosphonites un-
dergo a multicomponent coupling with imines and acid chlorides
to generate 2, which reacts with alkynes to yield pyrroles in
of the corresponding R-amido acids,4,5,9 and multistep syntheses
are required if these precursors derive from non-natural amino
€
acids. In addition, cycloaddition of Munchnones with unsym-
metrical substrates (e.g., unsymmetrical alkynes or alkenes)
often leads to a mixture of regioisomeric products, unless there
is a large steric or electronic bias between R2 and R3.5,10 The
regioisomers can be difficult to separate, and yields are limited.
€
analogy to Munchnones. The new compounds 2 have also been
We recently reported a one-pot synthesis of Munchnones that
characterized theoretically.13
€
involves the palladium-catalyzed coupling of imines, acid chlor-
ides, and carbon monoxide.11 This procedure enables various
We now report a detailed study of these new 1,3-dipoles and
their transformations. This includes the observation that the
structure, and 1,3-dipolar cycloaddition reactivity, are very sen-
sitive to the nature of the PR3 group. X-ray structural analysis
has allowed the full characterization of a cyclic dipole, 2b, ob-
tained from the catechyl-containing phosphonite PhP(o-O2-
C6H4) (PhP(catechyl)), as well as an acyclic ylide, 3a, obtained
from PPh3. Density functional theory calculations provide
explanations of the effects of P-substituents on dipole structure
and reactivity. We also examine the mechanisms, scope, and
selectivities of the cycloadditions of 2 and their application to the
regioselective synthesis of diversely substituted pyrroles.
€
Munchnone-derived products to be constructed in a modular
fashion, where the R2C-N(R1)-CR3 unit arises from the imine
and acid chloride fragments. The synthesis is efficient, but the
scope of products can be limited (particularly when employing
unstable reagents such as enolizable imines, C- or N-functiona-
lized imines, or R-acidic acid chlorides), and cycloadditions with
unsymmetrical dipolarophiles still result in a mixture of regioi-
someric products.
Results and Discussion
I. Influence of PR3 on Cycloaddition Reactivity. As we have
previously communicated,12 compounds 2/3can be generated by
the in situ reaction of imines with acid chlorides, followed by PR3
and base. However, the ability of these intermediates to react
with alkynes to generate pyrroles is dependent upon the nature
of the PR3 group. For example, the reaction of p-Tol(H)CdNBn
(p-Tol = p-CH3C6H4, Bn = CH2Ph) and p-methoxybenzoyl
chloride, followed by PPh3, results in the near-quantitative
formation of the phosphonium salt 5 within minutes at ambient
temperature. However, the addition of LiHMDS followed by
dimethyl acetylenedicarboxylate does not result in pyrrole for-
mation, even at elevated temperatures (Table 1, entry 1). In
contrast, the same series of steps with PPh(o-O2C6H4)
(PPh(catechyl)) provides a high yield of pyrrole within 5 min
at ambient temperature (entry 2).
€
FIGURE 1. Modular design of Munchnone analogues.
€
We discovered that a synthetic equivalent to Munchnones can
be generated when the carbonyl fragment in 1 (A = CO,
Figure 1) is replaced with an R3P unit (2, Scheme 1).12 The
13
€
ꢀ
phospha-Munchnones 2 have also been called Montrealones.
Dipole 2 is the valence tautomer of an amido-substituted phos-
phorus ylide in circumstances where the ylide adopts a suit-
able conformation to enable P-O interaction. Compound 2 is
represented as a resonance hybrid, but separate, valence tauto-
A range of other phosphorus reagents were examined.
Relatively electron-rich alkyl-substituted phosphines can be
incorporated into 2/3 (entries 3 and 4), but they are unable to
mediate cycloaddition with DMAD. Electron-poor phosphites
are also unable to mediate pyrrole formation (entries 6 and 7),
but this is because poor nucleophilicity (triphenylphosphite) or
competing Arbuzov product formation (triethyl phosphite)14,15
€
(9) For recent alternative Munchnone syntheses, see: (a) Merlic, C. A.;
Baur, A.; Aldrich, C. C. J. Am. Chem. Soc. 2000, 122, 7398. (b) Alper, H.;
Tanaka, M. J. Am. Chem. Soc. 1979, 101, 4245. (c) Keating, T. A.;
Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574.
(10) For representative examples, see: (a) Funabiki, K.; Ishihara, T.;
Yamanaka, H.. J. Fluorine Chem. 1995, 71, 5. (b) Anderson, W. K.; Corey.,
P. F. J. Org. Chem. 1977, 42, 559. (c) Texier, F.; Mazari, M.; Yebdri, O.;
ꢀ
Tonnard, F.; Carrie, R. Bull. Soc. Chim. Fr. 1991, 128, 962.
(11) (a) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468.
(b) Dhawan, R.; Dghaym, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2003, 125,
1474. (c) For an alternative isocyanide-mediated approach, see: St. Cyr, D.
J.; Martin, N.; Arndtsen, B. A. Org. Lett. 2007, 9, 449.
(12) St. Cyr, D. J.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129, 12366.
(13) Krenske, E. H.; Houk, K. N.; Arndtsen, B. A.; St. Cyr, D. J. J. Am.
Chem. Soc. 2008, 130, 10052.
(14) (a) Colle, K. S.; Lewis, E. S. J. Org. Chem. 1978, 43, 571. (b) Arbuzov
reaction review: Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415.
(15) For routes to alkoxy-substituted Wittig reagents, see: (a) Aggarwal,
V. K.; Fulton, J. R.; Sheldon, C. G.; de Vicente, J. J. Am. Chem. Soc. 2003,
125, 6034. (b) Kolodiazhnyi, O. I. Phosphorus Ylides: Chemistry and Applica-
tion in Organic Synthesis; Wiley-VCH: Weinheim, 1999. (c) Johnson, A. W.
Ylides and Imines of Phosphorus; Wiley-Interscience: New York, 1993.
4262 J. Org. Chem. Vol. 75, No. 12, 2010

St-Cyr et al.
JOCArticle
TABLE 1. Effect of PR3 on Pyrrole Synthesisa
TABLE 2. Effect of PR3 Reagent and Dipolarophile on Cycloaddition
Yieldsa
no.
PR3
31P of 2 (ppm)
additive
yieldb (%)
1
2
3
4
5
PPh3
10.2
-16.9
22.5
0
85
0
0
0
PhP(catechyl)
PCy3
PMe3
P(NMe2)3
P(OEt)3
P(OPh)3
-1.9
51.3
c
6
7
8
9
10
11
12
P(OEt)3
P(OPh)3
P(OCH2CF3)3
PF(catechyl)
PPh2Cl
44.4
TMSOTf
0
94
92
61
30.2, -44.0 (1.2:1) TMSOTf
47.0, -21.3 (1.8:1) TMSOTf
-22.0d
TMSOTf
TMSOTf
e
aImine (41.9 mg, 0.200 mmol), acid chloride (34.1 mg, 0.200 mmol), 0.7
mL of CD2Cl2, rt, 1 h; followed by additive (0.200 mmol), PR3 (0.200
mmol), rt; LiHMDS solution (0.22 mL, 0.220 mmol), -78 °Ctort;DMAD
(74 μL, 0.60 mmol), rt, 5 min. bIsolated. cArbuzov product obtained.
d1
J
= 1296.2 Hz. e5 was formed, but deprotonation failed to yield 2.
PF
aImine (41.9 mg, 0.200 mmol), acid chloride (34.1 mg, 0.200 mmol),
0.7 mL of CHCl3, 30 min; followed by PR3 (0.300 mmol), DBU (60 μL,
0.4 mmol); alkyne (0.600 mmol), 15 min. bIsolated. cImine/acid chloride/
PR3 for 72 h [P(OPh3)] or 0.5 h [P(OCH2CF3)3] prior to DBU.16 d6 equiv
of alkene.
SCHEME 2. Mechanism of Formation of 2
2/3, shown in Table 1, correlate with the 1,3-dipolar reactiv-
ities. In general, intermediates that are unreactive toward
alkynes (entries 1 and 3-8) have 31P NMR resonances in the
typical region for related Wittig-type reagents,17 while inter-
mediates that undergo 1,3-dipolar cycloaddition have up-
field resonances (δ -16.9 to -44.0; entries 2 and 9-11).
Interestingly, two different signals are observed with the
phosphites P(OPh)3 and P(OCH2CF3)3, implying that two
structures are present in solution.18 These data suggest that
the electronic and steric features of the PR3 unit can sig-
nificantly influence the ground state structure and both the
cyclic species 2 and the acyclic species 3 may exist in solution.
II. NMR and X-ray Crystallographic Characterization of
2b and 3a. We have isolated and examined the structure of an
example of each type of intermediate: an acyclic intermedi-
ate, 3a, generated with PPh3, and a cyclic intermediate, 2b,
generated with PhP(catechyl).
NMR and X-ray Characterization of PPh3-Based 3a. The
triphenylphosphine-based 3a (R1 = Me, R2 = R3 = Ph) can
be isolated in 82% yield after BuLi deprotonation of in situ
generated 5a (Scheme 2). The carbonyl unit derived from the
acid chloride has a 13C NMR signal at 176.1 ppm. This is in a
similar region to that expected for a simple amide and shows
none of the perturbation expected for an interaction of the
amide oxygen with the organophosphorus unit. The 31P
NMR signal of 3a, at 11.0 ppm, matches that observed when
hampers the formation of phosphonium salt 5 (Scheme 2). This
problem is eliminated by the addition of TMSOTf, which shifts
the 4/6 equilibrium (Scheme 2, X = Cl) toward the reactive N-
acyliminium form 4 (X = OTf). Use of TMSOTf allowed
formation of pyrroles from commercially available triphenyl
phosphite and tris(trifluoroethyl) phosphite (entries 9 and
10)16 and even from the very weakly nucleophilic PF-
(catechyl) (although in low yield; entry 11). The slightly
more electron-rich counterparts, P(OEt)3 (entry 8) and P-
(NMe2)3 (entry 5), however, did not mediate cycloaddition.
While several PR3 groups lead to high yields of pyrrole from
DMAD, the yields are more variable for other alkynes. For
example, methyl propiolate reacts with each of the substrates
that were found to be reactive in Table 1 but only gives a high
yield of pyrrole with PPh(catechyl) (Table 2, entry 3). Similar
results are observed with 1,1-chlorocyanoethylene (entries 4-6).
We postulated that the PR3 reagent must strike a balance
between having sufficient nucleophilicity to attack the N-
acyliminium salt 4 and being sufficiently electron poor to
accept chelation of the amide oxygen and generate the 1,3-
dipole 2. The 31P NMR chemical shifts of the intermediates
(17) Phosphorus ylides typically show 31P NMR = δ þ40 to -9 ppm,
while five-coordinate phosphorus appears at δ þ10 to -90 ppm . Handbook
of Phosphorus-31 NMR Data; Tebby, J. C., Ed.; CRC Press: Boston, 1991;
and ref 15c.
(16) Compound 2 can also be prepared from P(OPh)3 and P(OCH2CF3)3
by waiting several hours before base addition, instead of via TMSOTf
addition (Yield 2: P(OCH2CF3)3 = 90%, P(OPh3) = 98%, PhP(catechyl)
= 91%). ClCH2CF3 formation from 5 (R = OCH2CF3, X = Cl, Scheme 2)
is slow at rt.
(18) The ratios of these two 31P NMR signals are temperature dependent,
consistent with their presence in dynamic equilibrium.
J. Org. Chem. Vol. 75, No. 12, 2010 4263

St-Cyr et al.
JOCArticle
generated in situ (Table 1), falling in the typical region for
PPh3-based Wittig reagents.17
The acyclic structure of 3a was confirmed by X-ray
crystallography.19,20 Slow diffusion of diethyl ether into a
benzene solution of 3a provided crystals suitable for X-ray
analysis. The resulting ORTEP is shown in Figure 2. Com-
pound 3a adopts an acyclic, Wittig-like structure in the
ground state, with no interaction between phosphorus and
the amide oxygen. The amide carbonyl oxygen O(3) is
˚
oriented away from phosphorus, at a distance of 4.443 A.
The carbonyl and C(13)-N(1) bond lengths and angles are
˚
typical of simple amides [C(13)-O(3), 1.229 A; N(1)-C(13),
1.366 A].21 A torsion of 78.3° around C(13)-N(1)-C(14)-P
˚
places the nitrogen lone pair nearly perpendicular to the
P-C(14) π-system, minimizing the destabilizing interaction
with the carbanion lone pair at C(14). The P-C(14) bond
FIGURE 2. X-ray crystal structure of 3a (ORTEP view). Hydro-
gens have been removed for clarity, and displacement ellipsoids are
˚
length of 1.719 A and the pseudotetrahedral configuration at
˚
scaled to the 30% probability level. Selected bond lengths (A)
phosphorus are both similar to those in related phosphorus
ylides.15,22
NMR and X-ray Structural Characterization of PPh-
and angles (deg): P(1)-C(14), 1.7189(14); P(1)-C(1), 1.8101(14);
P(1)-C(7), 1.8107(14); P(1)-C(28), 1.8296(14); N(1)-C(13),
1.3660(18); N(1)-C(14), 1.4356(18); N(1)-C(15), 1.4652(18);
O(3)-C(13), 1.2286(18); C(14)-C(22), 1.4529(19); C(13)-C(16),
1.501(2); C(14)-P(1)-C(1), 112.55(7); C(14)-P(1)-C(7), 109.36(7);
C(14)-P(1)-C(28), 118.36(7); C(1)-P(1)-C(7), 106.98(7); C(1)-P-
(1)-C(28), 101.94(6); C(7)-P(1)-C(28), 106.87(6); C(13)-N(1)-C-
(14), 123.89(12); C(13)-N(1)-C(15), 117.45(12); C(14)-N(1)-
C(15), 118.35(11); O(3)-C(13)-N(1), 121.87(13); O(3)-C(13)-
C(16), 120.21(13); N(1)-C(13)-C(16), 117.89(12); N(1)-C(14)-
C(22), 118.25(12); N(1)-C(14)-P(1), 118.12(10); C(22)-C(14)-
P(1), 122.09(10).
(catechyl)-Based 2b. The PPh(catechyl)-based 2b (R1
=
Me, R2=R3=Ph) was isolated by precipitation from aceto-
nitrile and has 13C and 31P NMR data quite distinct from
those of 3a. The 13C NMR resonance of the carbonyl unit
shows a strong upfield shift, to 149.2 ppm, suggesting dis-
ruption of the amide substructure. The 31P NMR resonance,
at -18.9 ppm, is upfield of classic Wittig-type reagents,
falling instead in the diagnostic range for five-coordinate
organophosphorus compounds.17
shorter than those typically observed in cyclic RnP
O
3 3 3
The crystal structure (Figure 3) confirms that 2b repre-
sents a new class of 1,3-dipole in the ground state. The
phosphorus center adopts a five-coordinate, pseudotrigonal
bipyramidal geometry, with the axial sites occupied by one
catechyl oxygen [O(1)] and the O(3) oxygen from the former
amide unit. There is a strong interaction between the former
Lewis acid/base adducts.25 The carbonyl C(13)-O(3) bond
shows diminished double-bond character (1.317 A, com-
26
˚
˚
pared with 1.229 A in 3a), and the N(1)-C(13) bond shows
increased double-bond character (1.316 A, compared with
˚
1.366 A in 3a),27 consistent with a strong iminium contribu-
˚
amide oxygen and phosphorus (P-O(3)=1.789 A).23,24 This
tion to the former amide moiety.
The P(1)-C(14) bond length in 2b is similar to that in
and is even slightly
˚
˚
bond is longer than typical P-Oaxial bonds (1.689 A) but
15c
˚
classical Wittig reagents (1.706 A)
˚
shorter than that in 3a (1.719 A). The C(1)-P(1)-O(2)
equatorial bond angle is compressed from the ideal 120° to
105.7°. These features are consistent with P(1)dC(14) multi-
ple bonding, which is expected to perturb the P(1)-O(2) and
P(1)-C(1) σ-bonds in the trigonal plane due to hyperconju-
gation with the C(14) carbanion.28
(19) Solid-state 31P NMR confirms consistency between the solution-
phase and solid-state structures; see the Experimental Section.
(20) For examples of related amino-substituted phosphorus ylides, see:
(a) Paterson, I.; Cowden, C.; Watson, C. Synlett 1996, 3, 209. (b) Canac, Y.;
Conejero, S.; Soleilhavoup, M.; Donnadieu, B.; Bertrand, G. J. Am. Chem.
Soc. 2006, 128, 459.
(21) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A.
G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, 12, S1–S19.
(22) For the crystal structure of Ph3PdC(H)Ph, see: Yufit, D. S.;
Howard, J. A. K.; Davidson, M. G. J. Chem. Soc., Perkin Trans. 2 2000, 2,
249.
€
Structural Comparison of 2b to Munchnones. Structural
data for 2b and the analogously substituted Munchnone
€
1a29a are shown in Figure 4.
(23) For related phosphorus complexes, see: (a) Burger, K.; Fuchs, A.
Nitrogen, Oxygen and Sulfur Ylide Chemistry; Clark, S. J., Ed.; Oxford
University Press: Oxford, UK, 2002; Chapter 4, pp 286-292. (b) Onys'ko, P.
P.; Rassukana, Y. V.; Sinitsa, A. D. Curr. Org. Chem. 2008, 12, 2. (c) Stieglitz, G.;
Neumueller, B.; Dehnicke, K. Z.; Naturforsch., B Chem. Sci. 1993, 48, 730. (d)
Matsukawa, S.; Kojima, S.; Kajiyama, K.; Yamamoto, Y.; Akiba, K.-Y.; Re, S.;
Nagase, S. J. Am. Chem. Soc. 2002, 124, 13154. (e) Satoshi Kojima, S.; Takagi,
R.; Akiba, K. J. Am. Chem. Soc. 1997, 119, 5970. (f) Naya, S.-i.; Nitta, M. J.
Chem. Soc., Perkin Trans. 2 2002, 5, 1017. (g) Kano, N.; Kikuchi, A.;
Kawashima, T. Chem. Commun. 2001, 2096.
€
The Munchnone ring in 1a is virtually planar, whereas in
2b, the oxygen is 0.050 A out of the plane formed by the
remaining ring atoms. The substitution of PR3 for the
carbonyl unit yields a wider C-N-C angle (113.8° vs
109.6°), increasing the steric crowding about the ring in 2b.
Outside of these differences, however, the pattern of bond
˚
21
˚
(24) Examples of R3PdX (X = O, S, NR) with intramolecular coordina-
(26) The C-O single bond is >1.30 A.
˚
ꢀ
tion: (a) Chuit, C.; Reye, C. Eur. J. Inorg. Chem. 1998, 1, 1847. (b) Holmes,
(27) The 1.316 A C-N bond length is shorter than the average for amides
˚
˚
R. R. Acc. Chem. Res. 1998, 31, 535. (c) Kumaraswamy, S.; Muthiah, S. K. C.
K. J. Am. Chem. Soc. 2000, 122, 964. (d) Schomburg, D.; Wermuth, U.;
Schmutzler, R. Phosphorus, Sulfur Silicon Relat. Elem. 1986, 26, 193.
(25) For examples, see: (a) Cavell, R. G; Vande Griend, L. Inorg. Chem.
1986, 25, 4699. (b) Cavell, R. G.; The, K. I.; Van de Griend, L. Inorg. Chem.
1981, 20, 3813. (c) Lacour, J.; Vial, L.; Bernardinelli, G. Org. Lett. 2002, 4,
2309. (d) Burford, N.; Kennepohl, D.; Cowie, M.; Ball, R. G.; Cavell, R. G.
Inorg. Chem. 1987, 26, 650–657. (e) Chandrasekaran, A.; Day, R. O.;
Holmes, R. R. Inorg. Chem. 2001, 40, 6229.
(1.34 A, see ref 21) and longer than the <1.30 A of related iminium
structures: (a) Li, P.; Xu, J. C. J. Chem. Soc., Perkin Trans. 2 2001, 1, 113.
(b) Krill, J.; Shevchenko, I. V.; Fischer, A.; Jones, P. G.; Schmutzler, R.
Chem. Ber. Recl. 1997, 130, 1479.
(28) Leyssens, T.; Peeters, D. J. Org. Chem. 2008, 73, 2725.
(29) (a) Toupet, L.; Texier, F.; Carrie, R. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 1991, C47, 328. (b) Boyd, G. V.; Davies, C. G.;
Donaldson, J. D.; J. Silver, J.; Wright, P. H. J. Chem. Soc., Perkin Trans. 2
1975, 12, 1280.
4264 J. Org. Chem. Vol. 75, No. 12, 2010

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FIGURE 5. Limiting resonance structures of 2b.
FIGURE 3. X-ray crystal structure of 2b C6H6 (ORTEP view).
3
Hydrogens and solvent have been removed for clarity, and displace-
ment ellipsoids are scaled to the 30% probability level. Selected bond
˚
FIGURE 6. Geometry of 2d (bond lengths in A).
˚
lengths (A) and angles (deg): P(1)-O(2), 1.6772(19); P(1)-C(14),
structures for 2b, these data favor dipolar structures A and B
1.706(3); P(1)-O(1), 1.7281(18); P(1)-O(3), 1.7894(18); P(1)-C(1),
1.824(3); O(3)-C(13), 1.317(3); N(1)-C(13), 1.316(3); N(1)-C(14),
1.434(3); N(1)-C(15), 1.475(4); C(13)-C(16), 1.462(4); C(14)-
C(22), 1.473(4); O(2)-P(1)-C(14), 126.90(12); O(2)-P(1)-O(1),
90.71(9); C(14)-P(1)-O(1), 93.09(11); O(2)-P(1)-O(3), 85.77(9); C-
(14)-P(1)-O(3), 86.78(11); O(1)-P(1)-O(3), 175.48(9); O(2)-P(1)-
C(1), 105.66(12); C(14)-P(1)-C(1), 126.96(13); O(1)-P(1)-
C(1), 92.85(11); O(3)-P(1)-C(1), 90.83(11); C(13)-O(3)-P(1),
114.86(17); C(13)-N(1)-C(14), 113.8(3); C(13)-N(1)-C(15),
124.5(2); C(14)-N(1)-C(15), 120.5(2); N(1)-C(13)-O(3), 112.5(2);
N(1)-C(13)-C(16), 128.2(3); O(3)-C(13)-C(16), 119.2(3); N(1)-C-
(14)-C(22), 118.3(3); N(1)-C(14)-P(1), 111.9(2); C(22)-C(14)-P(1),
129.6(2).
€
(Figure 5), analogous to Munchnones. Compound 2b mirrors
not only the reactivity, but also the ground-state structure, of
5
€
Munchnones.
III. Computational Studies of Geometries. To explore the
sensitivity of dipole structure and stability to substituent
effects, we performed density functional theory calculations
at the B3LYP/6-31þG(d) level in Gaussian 03.30 In previous
studies on the parent dipole 2d,13 a range of ab initio and
density functional methods gave very similar geometries
˚
(P-O distances ranging from 2.51 to 2.57 A) and differences
in energy ΔHcyc-acyc between the cyclic form 2d and acyclic
form 3d (ΔHcyc-acyc in the range -1.7 to -3.1 kcal mol-1).
Two views of 2d at the B3LYP/6-31þG(d) level are shown in
˚
Figure 6. The long P-O distance of 2.55 A and substantial
pyramidalization at the ylidic carbon CP (average bond angle
116.5°) indicate that it is best regarded as an acylaminopho-
sphonium ylide containing an electrostatic P-O interaction
and not a covalently bound heterocycle.
1
€
FIGURE 4. Structural comparison of Munchnone 1a (R = Me,
R2 = Ph, R3 = p-methoxyphenyl)29a and 2b (R1 = Me, R2 = R3 =
Ph), with approximate ring bond lengths.
lengths in 2b is remarkably similar to that in 1a. Both structures
3
˚
show lengthened C(R )-O bonds (1.317 and 1.337 A) and
3
˚
shortened C(R )-N bonds (1.316 and 1.332 A), consistent with
significant C(R3)-N iminium character. The C(14)-N(1)
bonds (1.434 and 1.411 A) are close to single-bond length,
A range of substituted derivatives of 2d are shown in
Figure 7, together with the corresponding energy differences
between their cyclic and acyclic forms. A methyl group at
24
˚
while the P-C(R2) and C(dO)-C(R2) bonds are intermediate
between single and double bond values, at 1.706 and 1.375 A,
˚
nitrogen (2e) shortens the P-O bond by 0.11 A and stabilizes
˚
the cyclic form by 3.4 kcal mol-1. A phenyl group at the
respectively.15c,24 In considering the various viable resonance
˚
ylidic carbon (2f) shortens the P-O bond by 0.09 A, while a
phenyl group at the carbonyl carbon (2g) shortens the P-O
bond by 0.18 A. Together (2h), these two groups have an
(30) Gaussian 03, Revision C.02: Frisch, M. J.; Trucks, G. W.; Schlegel, H.
B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian, Inc., Wallingford CT, 2004.
˚
˚
additive effect on the P-O distance (shortened by 0.27 A)
and stabilize the cyclic form by 4.7 kcal mol-1 over the
acyclic form. The most substantial geometrical effects are
exerted, however, bythesubstituentsatphosphorus. Figure7
shows derivatives containing PPh3, PMe3, P(OMe)3, P-
(OCH2)3CH, and PPh(catechyl) groups. The P-O distances
in the cyclic isomers range from an essentially nonbonded
˚
arrangement for PPh3 (2i) (3.92 A) to a substantially covalent
bond for PPh(catechyl) (2m) in the O-axial conformation
˚
(1.97 A). The PMe3, P(OMe)3, and P(OCH2)3CH derivatives
˚
have P-O distances of 3.05, 2.86, and 2.00 A, respectively.
J. Org. Chem. Vol. 75, No. 12, 2010 4265

St-Cyr et al.
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FIGURE 7. Geometries and cyclic-acyclic energy differences of various derivatives of 2 (bond lengths in A; ΔHcyc-acyc in kcal mol-1).
˚
OMe lone pair and the intracyclic P-O antibonding orbital
CHART 1
˚
weakens the intracyclic P-O interaction by 0.68 A. These
features also operate in the PPh(catechyl) derivative 2m.
The Ph-axial conformer of 2m is 0.6 kcal mol-1 more stable
˚
than the O-axial form, but its P-O distance is almost 1 A
longer. The smaller energy difference between the two con-
formers of 2m compared with 2n reflects the geometrical
preference of the catechyl group to occupy an equatorial/
axial arrangement rather than bridging two pseudoequatorial
positions.
Taking into account the effects of the C- and N-substituents
on the P-O bond, the calculated structures are in close
agreement with the X-ray crystal structures of the PPh3
and PPh(catechyl) derivatives 3a and 2b.
The apicophilicity of an alkoxy group at phosphorus in the
dipoles 2 differs from that in typical 5-coordinate phosphorus
derivatives. For example, whereas the phosphorane 7 (Chart 1)
is 7.9 kcal mol-1 more stable with both OMe groups axial than
with one axial and one equatorial, the ylide 2n is 7.7 kcal mol-1
more stable with OMe equatorial. In 2n-Oeq, negative hyper-
conjugation between the carbanion lone pair and the antiper-
iplanar P-OMe σ* orbital results in net stabilization, even
though simultaneous negative hyperconjugation between an
IV. Structural Effects on Cycloaddition Barriers. Insights
into the widely diverging 1,3-dipolar cycloaddition efficien-
cies for different PR3 groups are provided by the transition
states for cycloadditions with ethylene. Three representative
transition-state (TS) geometries are shown in Figure 8. In the
TS for the parent dipole 2d, the bond developing at the
˚
carbonyl carbon is 0.2 A shorter than that at the ylidic
carbon. A similarly polarized but more asynchronous TS is
found for the PPh(catechyl) derivative 2m. In contrast, the
PPh3-containing dipole 2i shows more advanced bond devel-
opment at the ylidic carbon, consistent with the Wittig
reagent-like structure of the reactant dipole.
4266 J. Org. Chem. Vol. 75, No. 12, 2010

St-Cyr et al.
JOCArticle
˚
FIGURE 8. Transition structures for concerted cycloaddition of 2d, 2i, and 2m (O-axial) with ethylene (bond distances in A; barriers in
kcal mol-1).
and acetylene,31 as well as for cycloadditions of azides with
alkenes and alkynes.32 For those acyclic 1,3-dipoles, bending
about the central atom contributes the major fraction of the
dipole distortion energy,33 whereas for the ylidic dipoles in
Figure 9 the major geometrical change required to reach the
TS is P-O compression; there is a correlation of R2 = 0.57
between dipole distortion energy and the change in P-O
distance on going from reactant to TS.
V. Cycloadditions with Substituted Alkynes. Although
concerted transition states are found for the reactions of 2
with ethylene, it is possible that cycloadditions with electron-
deficient alkynes follow stepwise mechanisms. In Figure 10
are shown the two regioisomeric transition states for the
reaction of 2o with cyanoacetylene. The favored cycloaddi-
tion mechanism is a stepwise pathway in which 2o adds
nucleophilically to the terminal carbon of cyanoacetylene,
forming a CN-stabilized carbanion that then closes onto the
iminium group to provide the bicyclic product. Formation of
the opposite regioisomer could occur by a concerted me-
chanism but is disfavored by 6.8 kcal mol-1 (ΔΔHq). High
regioselectivity is exerted through electronic control.
FIGURE 9. Plot of activation energies vs distortion energies for
concerted cycloadditions of 1,3-dipoles with ethylene.
Consistent with experiment, the PPh3-containing dipole
has a high activation energy of ΔHq = 31.7 kcal mol-1, while
We also investigated the possibility that the carbanion in
the zwitterionic intermediate may add to phosphorus instead
of to the carbonyl group. Subsequent scission of the original
P-C bond could lead to a CN-stabilized ylide that then
undergoes an intramolecular Wittig reaction with the amide
carbonyl. However, in the parent species 2d, the activation
energy for ring closure onto phosphorus is 4.7 kcal mol-1
higher than for closure onto carbonyl, and for the more
highly substituted 2o, steric crowding at phosphorus renders
such a pathway unfeasible.
the activation energy for the PPh(catechyl) derivative is 16.2
kcal mol-1. The activation energies for the three TSs in
Figure 8 follow the same trend as the degree to which the
P-O bond must shorten to reach the TS; for PPh3, the dipole
˚
must decrease its P-O separation by 1.16 A, whereas for
˚
PPh(catechyl) a shortening of only 0.17 A is required. More
generally, the activation energies (ΔEq) for cycloadditions of
1,3-dipoles such as 2 with ethylene correlate with the energy
(ΔEdistq) required to distort the reactants from their ground-
state geometries to their TS geometries. In Figure 9 is shown
q
a plot of ΔEq versus ΔEdist for eight representative ylidic
VI. Cycloaddition Regioselectivities. There is a much great-
€
€
dipoles, along with those for the parent Munchnone and
er electronic bias across the dipole in 2 than in Munchnones.
azomethine ylide. There is a very close correlation (R2 =
0.98) between ΔEq and ΔEdistq. Similar correlations have
previously been noted for 1,3-dipolar cycloadditions of
azomethine, nitrilium, and diazonium betaines with ethylene
For example, the charges at the ylidic carbon and carbonyl
carbon in 2d, calculated by the natural bond orbital
method,34 are -0.78 and þ0.46, respectively, compared to
€
-0.33 and þ0.38 for the parent Munchnone. This feature
suggests that regioselective cycloadditions may be possible.
(31) (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646–
10647. (b) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187–
10198.
(32) (a) Ess, D. H.; Jones, G. O.; Houk, K. N. Org. Lett. 2008, 10, 1633–
1636. (b) Schoenebeck, F.; Ess, D. H.; Jones, G. O.; Houk, K. N. J. Am.
Chem. Soc. 2009, 131, 8121–8133.
(33) Xu, L.; Doubleday, C. E.; Houk, K. N. Angew. Chem., Int. Ed. 2009,
48, 2746–2748.
(34) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. NBO
Version 3.1.
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FIGURE 10. Regioisomeric transition structures for cycloaddition of 2o with cyanoacetylene (bond distances in A; barriers in kcal mol-1).
˚
TABLE 3. Cycloaddition Regioselectivity with 2a
component are often the determining feature for cycloaddi-
tion selectivity. With 2, exchanging the acid chloride and
imine substituents allows access to regioisomeric pyrroles
(Table 3, entries 4-6). Derivatives of 2 bearing either
electron-rich or electron-poor aryl or alkyl substituents each
undergo cycloaddition with terminal alkynes to form a single
regioisomer of the pyrrole (vide infra).
A diverse range of polysubstituted pyrroles can be accessed.
Examples are shown in Table 4. Variation of the imine
component provides examples including N-aryl-, alkyl-, allyl-,
and benzyl-substituted pyrroles (entries 1-4 and 14-16) and a
range of C-aromatic and C-heteroaromatic derivatives
(entries 4-7, 12, 15, and 16). Less stable imines, such as those
with enolizable C-alkyl groups and even formaldehyde-derived
imines (entries 9 and 10), can also be used to generate 2-alkyl-
and 2-H-pyrroles. The former is notable, since the iminium salts
generated from enolizable imines are prone to enamide forma-
tion and are not viable in our previously reported palladium-
€
11a
catalyzed Munchnone synthesis. The rapid attack of the
phosphonite on the in situ generated iminium salt 4 likely
allows their use with 2. Smaller imine C-alkyl groups, e.g.,
n-butyl, were not successful. Isoquinoline can be employed as a
less reactive imine equivalent, leading to the direct formation of
naphthyl-fused pyrrole (entry 11), though in lower yields. From
the acid chloride component, aryl, heteroaryl (entries 4, 12, and
13), and alkyl (entries 6, 8, and 16) units may be incorporated.
Cycloadditions can be performed with a range of alkynes,
including DMAD, alkyl propiolates, and unsaturated ke-
tones (entry 12). Compound 2 reacts most efficiently with
electron-poor dipolarophiles, although some more electron-
rich alkynes (acetylene, propargyl ethers: entries 7 and
13-15) are also viable substrates.38 In general, the cycload-
ditions of 2 provide a modular strategy to build up a diversity
of substituted pyrroles in one-pot reactions.
aTable 2 procedure.36 b19 h.
The calculated activation energies for cyanoacetylene
(section V) indicate that high stereoselectivity can be ex-
pected for suitably substituted dipolarophiles.
We have explored this possibility by using dipoles in which
the aromatic units on the imine carbon (R2) and acid chloride
(R3) vary only in the para-substituents. As shown in Table 3,
the reaction of 2 with methyl propiolate results in a single
regioisomer of the pyrrole, where the alkyne ester functional
group has been directed toward the former acid chloride
substituent (entry 1).35,36 Similar results are observed with
1-chloro-1-cyanoethylene (entry 2) and the internal alkyne in
entry 3, both of which provide the product expected from the
electronic bias in 2. Notably, the electronic bias in 2 is
independent of the substituents, including those on the
phosphorus unit (Table 2). This contrasts with the reactivity
Conclusions
Suitably substituted phosphonites or phosphites react with
imines and acid chloridestogeneratea new classof 1,3-dipolar
of Munchnones,5,10 and indeed many other 1,3-dipoles1 and
39
cycloaddition reagent, the phospha-Munchnones 2. These
€
€
Diels-Alder substrates,37 where the substituents on the 4π
(38) Lower pyrrole yields are due to the instability of the 1,3-dipole over
long reaction times with less activated dipolarophiles. The 2 is prone to
decompose to form (Cat)PhPdO under these conditions, leading to lower
yields.
11a
€
(35) A ca. 2:1 mixture of these pyrroles is generated via Munchnones.
(36) The regiochemistry of all pyrrole products was determined either by
comparison to previously reported compounds or via 1D and 2D NOE NMR
experiments. See the Experimental Section and the Supporting Information
for spectra and full details.
(37) The Diels-Alder Reaction: Selected Practical Methods; Fringuelli, F.,
Taticchi, A., Eds.; Wiley: Baffins Lane, 2002.
(39) For the closest related example,
a trifluoromethyl-substituted
[1,4,2]oxazaphospholine has been shown to behave as a dipole precursor
(Burger, K.; Fehn, J.; Moll, E. Chem. Ber. 1971, 104, 1826). However, a
simple phosphorus ylide (e.g., 2) has not been used as a 1,3-dipole.
4268 J. Org. Chem. Vol. 75, No. 12, 2010

St-Cyr et al.
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TABLE 4. Generality of Regioselective Pyrrole Synthesisa
aTable 2 procedure.36 b33 h. cLiHMDS at -78 °C, CH2Cl2. dImine/acid chloride at -78 °C; AgOTf (1 equiv) added. eImine/acid chloride/PR3 for 16 h
prior to base. fTMSOTf (1 equiv) added. g1 atm, 50 °C.
dipoles are formally the valence tautomers of amido-sub-
stituted Wittig reagents. NMR, X-ray structural, and com-
putational analyses indicate that either form may be
preferred, depending upon the PR3 unit. Electron-poor
phosphites and phosphonites more favorably accept oxy-
gen chelation to create the cyclized dipole 2, while electron-
rich phosphines adopt the acyclic Wittig-type structure 3.
The electronegativity of the PR3 unit is not the only factor,
however; P(OPh)3 and P(OCH2CF3)3 are less able to stabi-
lize the cyclic form than the more electron-rich PPh(catechyl).
Presumably, angle strain involving the catechyl group
imparts “strain release Lewis acidity”40 to the PPh(catechyl)
unit, as previously noted for other main group Lewis acids.41
Angle strain is relieved upon chelation to oxygen, as the
catechyl unit then occupies the axial and equatorial sites of
the phosphorus trigonal bipyramid. A smaller destabiliza-
tion of the P-O bond due to negative hyperconjugation
might also be expected for the Ph-equatorial PPh(catechyl)
group, compared with P(OPh)3. The lower steric bulk of
the bidentate catechyl unit likely further strengthens
chelation and favors the approach of an alkyne during
cycloaddition.
The significant electronic bias introduced by the PR3
group provides a unique tool to control the cycloaddition
regioselectivity. Highly regioselective cycloadditions have
been achieved for a diverse range of pyrroles, where the
electron-withdrawing group on the dipolarophile is generally
directed away from the phosphorus unit during cycloaddi-
tion. The regioselective 1,3-dipolar cycloaddition reactivity,
together with the easy and modular synthetic protocol,
set 2 apart from previously studied 1,3-dipoles such as
(40) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835.
(41) (a) Westheimer, F. H. Acc. Chem. Res. 1968, 1, 70. (b) Kinnaird, J.
W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc.
2002, 124, 7920. (c) Nelson, S. G.; Kim, B.-K.; Peelen, T. J. J. Am. Chem. Soc.
2000, 122, 9318. (d) Chuit, R. J. P.; Corriu, C.; Reye, J. C.; Young Chem. Rev.
1993, 93, 1371. (e) Negrebetsky, V. V; Taylor, P. G.; Kramarova, E. P.;
Shipov, A. G.; Pogozhikh, S. A.; Ovchinnikov, Y. E.; Korlyukov, A. A.;
Bowden, A.; Bassindale, A. R.; Baukov, Y. I. J. Organomet. Chem. 2008, 693,
1309–1320. (f) Kawashima, T.; Takami, H.; Okazaki, R. J. Am. Chem. Soc.
1994, 116, 4509.
€
Munchnones.
J. Org. Chem. Vol. 75, No. 12, 2010 4269

St-Cyr et al.
JOCArticle
Experimental Section
122.7 (d, JCP = 0.5 Hz), 113.0 (d, JCP = 0.8 Hz). 31P NMR (81
MHz, CDCl3): δ (ppm) 180.1. 31P NMR (81 MHz, CD2Cl2): δ
(ppm) 174.2. HRMS (ESIþ) for C12H10O2Pþ: calcd 217.04129,
found 217.04192 (error m/z = 2.8 ppm).
General Procedures. All reactions were performed in a drybox
or under nitrogen using standard Schlenk techniques. Reagents
were used as received, including PhPCl2, catechol, DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene), LiHMDS (lithium bis(trim-
ethylsilyl)amide) 1.0 M in hexane or THF, TMSOTf (trim-
ethylsilyl trifluoromethanesulfonate), DMAD (dimethyl acetyl-
enedicarboxylate), aldehydes, amines, and acid chlorides with
the following exceptions: Solid PPh3, PCy3, and NaF were dried
by heating under high vacuum. Liquid P(OEt)3, P(OCH2CF3),
Synthesis of (o-O2C6H4)PF [FP(catechyl)]. To dry NaF (3.05
g, 50 mmol) in a 50 mL flask under nitrogen were added neat o-
phenylene phosphorochloridite (2.38 mL, 20 mmol) and 15-
crown-5 (0.40 mL, 2.0 mmol). The reaction is complete within 3
h. The product was very volatile and could be selectively distilled
from the 15-crown-5 in the crude mixture by vacuum transfer;
the crude was frozen (N2 (liq)) and placed under static high
vacuum. It was allowed to warm to room temperature without
additional heating with collection into a liquid nitrogen-cooled
flask. The room-temperature product was obtained as an oil
(1.76 g, 56% yield) with spectral properties consistent with the
literature.46 1H NMR (300 MHz, CDCl3): δ (ppm) 7.26-7.19
(m, 2H), 7.15-7.05 (m, 2H). 13C NMR (75 MHz, CDCl3): δ
(ppm) 143.8 (d, JCP = 6.9 Hz), 123.7, 113.3. 31P NMR (202
MHz, CDCl3): δ (ppm) 124.7 (d, JPF = 1306.6 Hz). 31P NMR
(81 MHz, CD3CN): δ (ppm) 124.8 (d, JPF = 1296.2 Hz).
Synthesis of 3a. In the glovebox, PhHCdNMe (1.19 g, 10.0
mmol) and benzoyl chloride (1.41 g, 10.0 mmol) were mixed in
ca. 2 mL of acetonitrile and allowed to stand for 30 min.
Triphenylphosphine (2.63 g, 10.0 mmol) was added as a CH2Cl2
(ca. 5 mL) solution. The solvent was removed in vacuo and the
crude re-evaporated from THF and dissolved in THF (100 mL).
Outside the glovebox, n-BuLi (4.1 mL, 10.3 mmol, as 2.5 M
hexanes solution) was added dropwise at -78 °C. Stirring
overnight at room temperature and concentration in vacuo
yielded 4.0 g of solid product (82%). Crystallization conditions:
In the glovebox, a benzene solution of 3a (100 mg) was con-
centrated until viscous, partially precipitated with Et2O, and
gravity filtered through dry Celite. Et2O was slowly diffused into
the resulting saturated solution of 3a using base bath, water, and
acetone cleaned vials, yielding crystals suitable for X-ray ana-
˚
and P(NMe2)3 were dried over 4 A molecular sieves. P(OPh)3
was dried by reflux under high vacuum (ca. 140 °C, ca. 50 mtorr)
followed by storage over 4 A molecular sieves. Dichloromethane
˚
and acetonitrile were distilled from CaH2 under nitrogen.
Diethyl ether was distilled from sodium benzophenone
ketyl. Chloroform and deuterated chloroform were dried over
˚
4 A molecular sieves. Imines were prepared as per standard
literature procedures.42 NMR spectra (1H, 13C, and 31P) were
recorded on 200, 300, 400, or 500 MHz spectrometers (for
solution-phase spectra) and on a 300 MHz spectrometer (for
solid state spectra). Reported JC-P and JC-F values were
verified by obtaining 13C NMR spectra at both 300 and 500
MHz. In the X-ray crystallography, nonbonding distance cal-
culations were obtained using the Mercury 1.4.2 CIF visualiza-
tion software. Pyrroles of Table 3, entries 1 and 5, and Table 4,
entries 2, 4-12, and 14, were characterized by comparison to
previous literature reports.11c,12,47
Computational Methods. Density functional theory calcula-
tions were performed at the B3LYP/6-31þG(d) level43 in
Gaussian 03.30 Species were characterized as minima or transi-
tion states on the basis of vibrational frequency analyses and
IRC calculations.44 Conformational searches were carried out
in order to identify the lowest energy structure for each species.
Zero-point energy and thermal corrections were derived
(unscaled) from the B3LYP/6-31þG(d) frequencies. Population
analyses were performed with the natural bond orbital
method.34
Synthesis of PhP(o-O2C6H4) [PhP(catechyl)]. A modified
version of the literature procedure was followed.45 To catechol
(11.01 g, 100 mmol) under nitrogen in a 500 mL Schlenk flask
was added Et2O (100 mL) followed by pyridine (16.2 mL, 200
mmol). The mixture was cooled to 0 °C, PhPCl2 (13.6 mL, 100
mmol) was added dropwise over 15-45 min with vigorous
stirring, and the mixture stirred at ambient temperature for 2
h. The flask was fitted to an air-free filtration assembly for the
removal of the pyridine hydrochloride precipitate. The filtrate
was concentrated in vacuo without exposure to air and distilled
(84-88 °C, 115 mTorr) to afford 12.9 g (60%) of a clear colorless
oil (additional filtration may be necessary at this stage), which
1
lysis. H NMR (400 MHz, CDCl3): δ (ppm) 7.97-7.83 (very
broad s, 2H), 7.60-6.85 (m, 20H), 6.73-6.50 (m, 3H), 3.28 (s,
3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 176.1, 145.8 (d,
1JC-P = 28.7 Hz), 138.2, 133.9, 133.8, 132.2 (d, 4JC-P = 2.9 Hz),
129.1 (d, 2 or 3JC-P = 12.0 Hz), 128.8 (d, JC-P = 6.9 Hz), 128.4
(broad s), 127.3, 126.9, 118.7 (d, JC-P = 6.6 Hz), 115.7, 56.2 (d,
1JC-P = 144.5 Hz), 39.6. 31P NMR (81 MHz, CDCl3): δ (ppm)
11.0. 31P NMR (121 MHz, solid state): δ (ppm) 12.2. HRMS
(ESIþ) for C33H29NOPþ: calcd 486.19813, found 486.19744
(error m/z = 1.4 ppm).
Synthesis of 2b. In the glovebox, PhHCdNMe (596 mg, 5.00
mmol) and benzoyl chloride (773 mg, 5.50 mmol) were mixed in
ca. 1 mL acetonitrile and allowed to stand for 30 min. An
acetonitrile solution (ca. 2 mL) of PhP(catechyl) (1.51 g, 7.00
mmol) was added followed by DBU (1.52 g, 10.0 mmol), and the
mixture was diluted with acetonitrile to ca. 10 mL total volume
and cooled at ca. - 40 °C overnight to improve product
precipitation. Filtration, washing with cold acetonitrile, and
removal of trace solvent residues in vacuo for ca. 12 h provides
1.76 g of product (80% yield). Crystallization conditions: In the
glovebox, 2b (100 mg) was partially precipitated from a dichlor-
omethane solution (ca. 1 mL, 15 min dissolution time) by
benzene addition. Gravity filtration through a ca. 0.5 cm pad
of dry Celite (do not prewet with solvent), addition of a few
drops of CH2Cl2, and slow evaporation from an uncapped 1
dram vial (cleaned with base bath, water, and acetone) undis-
˚
was stored in the glovebox over 4 A molecular sieves. Alterna-
tively, the product was also moderately stable when stored in the
freezer outside the glovebox. It was noted that PhP(catechyl)
can become malodorous with aging, though this does not
compromise its reactivity. This reaction was sensitive to slight
variations in experimental conditions. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.62-7.56 (m, 2H), 7.48-7.35 (m, 3H),
7.18-7.11 (m, 2H), 7.03-6.97 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ (ppm) 146.5 (d, JCP = 6.8 Hz), 141.7 (d, JCP = 49.0
Hz), 131.7, 128.5 (d, JCP = 22.6 Hz), 128.4 (d, JCP = 5.1 Hz),
1
(42) Layer, R. Chem. Rev. 1963, 63, 489.
turbed yielded needle crystals suitable for X-ray analysis. H
(43) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Stephens, P.
J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98,
11623–11627. (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–
789.
(44) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161.
(45) (a) Berlin, K. D.; Nagabhushanam, M. J. Org. Chem. 1964, 29, 2056.
(b) Wieber, M.; Hoos, W. R. Tetrahedron Lett. 1968, 51, 5333. (c) Weiber,
M.; Hoos, W. R. Monatsh. Chem. 1970, 101, 776.
NMR (300 MHz, C6D6): δ (ppm) 8.01 (dd, J = 17, 8.1 Hz, 2H),
7.42 (d, J = 6.9 Hz, 2H), 7.29-7.19 (m, 2H), 7.17-7.00 (m, 6H),
6.95-6.80 (m, 4H), 6.60 (broad s, 3H), 2.56 (s, 3H). 13C NMR
(46) Farooq, O. New J. Chem. 2000, 24, 81.
(47) Padwa, A.; Haffmanns, G.; Tomas, M. J. Org. Chem. 1984, 49, 3314.
4270 J. Org. Chem. Vol. 75, No. 12, 2010

St-Cyr et al.
JOCArticle
(75.5 MHz, DMSO-d6): δ (ppm) 149.2, 148.1, 145.7, 143.1 (d,
Synthesis of C-Alkyl Imine Derived Pyrroles (Table 4, Entry 9).
To (CH3)2CHHCdNCH2C6H5 (32.2 mg, 0.200 mmol) in di-
chloromethane (0.5 mL) under nitrogen at -78 °C was added p-
toluoyl chloride (26 μL, 0.50 mmol) via syringe. The -78 °C bath
was then replaced for a -15 °C bath (ethylene glycol/dry ice), and
PhP(catechyl) (36 μL, 0.22 mmol, d = 1.34 g/mL) was injected,
followed by AgOTf (51.4 mg, 0.200 mmol, acetonitrile solution).
The mixture was warmed to room temperature and then recooled
to -78 °C, and LiHMDS (200 μL, 0.20 mmol, 1.0 M solution in
THF) was added dropwise. Dimethyl acetylenedicarboxylate was
injected (98 μL, 0.8 mmol), and the mixture allowed to warm to rt
over 0.5 h. The solution was concentrated in vacuo followed by
column chromatography (ethyl acetate/hexanes as eluent) to
yield 49.9 mg product (61% yield).
Pyrrole Regiochemistry. For pyrroles of Tables 3 and 4,
entries 2-6, a series of 1D and 2D NOE NMR experiments
were used to assign regiochemistry. For pyrroles of Table 3,
entries 1, 2, and 4, and Table 4, entries 2-6, a correlation was
observed between pyrrole C4-H and the adjacent aromatic
substituent on C5. For pyrroles of Table 3, entries 3, 5, and 6,
a correlation was observed between the methyl ester protons and
adjacent aromatic group. See the Supporting Information for
spectra.
3
1JC-P = 225.1 Hz), 136.4 (d, JC-P = 19.1 Hz), 134.6 (d,
2 or 3
4JC-P = 5.5 Hz), 130.9, 129.5, 128.81, 128.80 (d,
J
=
=11.5 Hz), 128.0, 126.6, 125.9,
C-P
2 or 3
17.9 Hz), 128.2 (d,
J
C-P
122.6, 119.9, 111.3 (broad d, 3JC-P = 11.8 Hz), 110.8 (broad d,
3JC-P =6.1 Hz), 76.2 (d, 1JC-P = 262.1 Hz), 38.1 (d, 3JC-P
=
7.9 Hz). 31P NMR (81 MHz, C6D6): δ (ppm) - 19.6. 31P NMR
(81 MHz, CDCl3): δ (ppm) -18.9. 31P NMR (121 MHz, solid
state): δ (ppm) -22.2. HRMS (ESIþ) for C27H23NO3Pþ: calcd
440.14101, found 440.14096 (error m/z = 0.1 ppm).
X-ray Crystallographic Studies of 3a and 2b. X-ray crystal-
lographic data were collected from a single-crystal sample,
which was mounted on a loop fiber. Data were collected using
a Bruker Platform diffractometer, equipped with a Bruker
SMART 4K charged-coupled device (CCD) area detector using
the program APEX2 and a Nonius FR591 rotating anode
equipped with a Montel 200 optics. Upon isolation, the crystals
were covered in paratone-N and placed under a 150 K N2 stream
on the goniometer head of a Bruker microstar area detector
system (graphite-monochromated Cu KR radiation, λ =
˚
1.54178 A). The structures were solved by direct methods
(SHELXL). All non-hydrogen atoms were refined anisotropi-
cally unless stated, and hydrogen atoms were treated as idealized
contributions (Riding model).
Spectroscopic Data for Pyrroles. Table 3, Entry 1. Isolated
yield: 89%. 1H NMR (500 MHz, CDCl3): δ (ppm) 7.26 (d, J =
6.5 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.19-7.11 (m, 5H), 6.88
(d, J = 6.5 Hz, 2H), 6.79 (s, 1H), 6.69-6.65 (m, 2H), 5.06 (s,
2H), 3.81 (s, 3H), 3.71 (s, 3H), 2.36 (s, 3H). 13C NMR (125.7
MHz, CDCl3): δ (ppm) 165.5, 159.8, 140.2, 138.6, 137.8, 135.3,
132.1, 130.0, 129.45, 129.42, 128.6, 127.3, 126.2, 124.3, 113.8,
113.6, 110.7, 55.4, 51.1, 48.6, 21.5. HRMS (ESIþ) for
C27H26NO3þ: calcd 412.19072, found 412.19040 (error m/z =
0.8 ppm). Anal. Calcd for C27H25NO3: C, 78.81; H, 6.12; N,
3.40. Found: C, 78.47; H, 6.29; N, 3.35.
General Procedure for PR3 Screening (Table 1). In the glove-
box, (4-CH3C6H4)HCdNCH2C6H5 (41.9 mg, 0.200 mmol) and
p-methoxybenzoyl chloride (34.1 mg, 0.200 mmol) were mixed
in ca. 0.1 mL of CD2Cl2, allowed to stand for 1 h, diluted to ca.
0.7 mL with CD2Cl2, and transferred into a septum-sealed
NMR tube. Outside the glovebox, TMSOTf (36.3 μL, 0.200
mmol), phosphorus(III) reagent (0.200 mmol), and LiHMDS
(0.22 mL, 0.22 mmol, 1.0 M hexanes solution, dropwise at -78
°C) were injected in order with inversion to promote mixing.
Room-temperature 1H and 31P NMR data on 2/3 were ob-
tained. The addition of dimethyl acetylenedicarboxylate (74 μL,
1
Table 3, Entry 2. Isolated yield: 92%. H NMR (300 MHz,
1
0.60 mmol) was immediately followed by H NMR analysis,
CDCl3): δ (ppm) 7.30 (d, J = 9.0 Hz, 2H), 7.22-7.11 (m, 7H),
6.91 (d, J = 9.0 Hz, 2H), 6.70-6.61 (m, 2H), 6.54 (s, 1H), 5.13 (s,
2H), 3.81 (s, 3H), 2.35 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
(ppm) 160.1, 142.5, 138.1, 137.7, 136.3, 131.0, 129.2, 128.6,
128.5, 127.3, 125.7, 121.9, 117.4, 114.2, 111.5, 92.8, 55.2, 48.8,
21.2. HRMS (ESIþ) for C26H22N2Oþ: calcd 379.18049, found
379.18019 (error m/z = 0.8 ppm).
showing complete conversion in all reactive dipoles within 1-5
min. The pyrrole product was isolated by column chromatog-
raphy (ethyl acetate/hexanes eluent).
Typical Procedure for Pyrrole Synthesis (Table 4, Entry 1). In
the glovebox, (4-MeOPh)HCdN(CH2CHCH2) (88 mg, 0.50
mmol) and p-methoxybenzoyl chloride (85 mg, 0.50 mmol) were
mixed in ca. 0.1 mL chloroform and allowed to stand for 30 min.
PhP(catechyl) (162 mg, 0.75 mmol), DBU (152 mg, 1 mmol),
and ethyl propiolate (147 mg, 1.5 mmol) were added in order as
solutions in chloroform, bringing the final volume to 1 mL. The
reaction is complete in many cases once all additions have been
made. The solution was concentrated in vacuo followed by
column chromatography (ethyl acetate/hexanes as eluent) to
yield 165 mg of product (0.420 mmol, 84% yield). The pyrrole
products are generally fluorescent blue spots with Rf ca. 0.2 on
TLC with 5-30% ethyl acetate/hexanes as eluent. Pyrrole
regioisomers were distinguished by a combination of NMR
experiments (NOE, COSY, HMQC, HMBC at 2-3 then 4-5
bond setting).
Synthesis of Alkyl-Acid Chloride Derived Pyrroles (Table 4,
Entry 6). In the glovebox, PhHCdN(CH2C6H5) (97.6 mg, 0.50
mmol) and isobutyryl chloride (53.3 mg, 0.50 mmol, 0.5 mL)
were mixed in ca. 0.1 mL of CH2Cl2 and allowed to stand for 30
min. PhP(catechyl) (108 mg, 0.5 mmol) was added and the
mixture diluted to ca. 0.7 mL final volume with CH2Cl2. Outside
the glovebox, the mixture was cooled to -78 °C under nitrogen,
and LiHMDS (500 μL, 0.5 mmol, 1.0 M solution in THF) was
added dropwise. Methyl propiolate was injected (125 μL, 1.5
mmol), the cooling bath removed, and the mixture allowed to
warm to rt over 0.5 h. The solution was concentrated in vacuo
followed by column chromatography (ethyl acetate/hexanes
eluent) to yield 113 mg product (0.339 mmol, 67% yield).
1
Table 3, Entry 3. Isolated yield: 52%. H NMR (500 MHz,
CDCl3): δ (ppm) 7.20-7.07 (m, 9H), 6.85 (d, J = 8.5 Hz, 2H),
6.62-6.66 (m, 2H), 4.88 (s, 2H), 3.81 (s, 3H), 3.64 (s, 3H), 2.36 (s,
3H), 2.24 (s, 3H). 13C NMR (125 MHz, CDCl3): δ (ppm) 166.2,
159.2, 138.9, 138.4, 137.4, 132.3, 131.7, 130.8, 128.9, 128.1,
126.7, 125.9, 124.8, 118.6, 113.2, 112.7, 55.1, 50.4, 48.2, 21.2,
11.8. HRMS (ESIþ) for C28H28NO3þ: calcd 426.20637, found:
426.20605 (error m/z = 0.8 ppm).
1
Table 3, Entry 4. Isolated yield: 92%. H NMR (500 MHz,
CDCl3): δ (ppm) 7.31-7.17 (m, 2H), 7.23-7.13 (m, 7H), 6.84 (d,
J = 8.5 Hz, 2H), 6.68-6.60 (m, 2H), 6.51 (s, 1H), 5.11 (s, 2H),
2.80 (s, 3H), 2.36 (s, 3H). 13C NMR (75 MHz, CDCl3): δ (ppm)
159.5, 142.5, 139.0, 137.6, 136.0, 130.7, 129.44, 129.43, 128.4,
127.2, 126.7, 125.7, 123.8, 117.4, 113.9, 111.5, 92.7, 55.2, 48.8,
21.2. HRMS (ESIþ) for C26H22N2Oþ: calcd 379.18049, found
379.18024 (error m/z = 0.7 ppm).
1
Table 3, Entry 5. Isolated yield: 91%. H NMR (400 MHz,
CDCl3): δ (ppm) 7.24 (d, J = 8.4 Hz, 2H), 7.20-7.10 (m, 7H),
6.86 (d, J = 7.6 Hz, 2H), 6.74 (s, 1H), 6.69-6.61 (m, 2H), 5.02 (s,
2H), 3.80 (s, 3H), 3.70 (s, 3H), 2.36 (s, 3H). 13C NMR (125.7
MHz, CDCl3): δ (ppm) 165.5, 159.5, 140.2, 138.6, 138.3, 135.0,
130.9, 130.7, 129.1, 128.9, 128.5, 127.2, 126.1, 125.3, 114.1,
113.6, 110.5, 55.5, 51.1, 48.6, 21.6. HRMS (ESIþ) for
C27H26NO3þ: calcd 412.19072, found 412.19030 (error m/z =
1.0 ppm).
J. Org. Chem. Vol. 75, No. 12, 2010 4271

St-Cyr et al.
JOCArticle
1
Table 3, Entry 6. Isolated yield: 47%. H NMR (500 MHz,
CDCl3): δ (ppm) 7.21-7.08 (m, 9H), 6.86 (d, J = 8.0 Hz, 2H),
6.63-6.55 (m, 2H), 4.87 (s, 2H), 3.80 (s, 3H), 3.64 (s, 3H), 2.36 (s,
3H), 2.23 (s, 3H). 13C NMR (125 MHz, CDCl3): δ (ppm) 166.2,
159.0, 139.0, 138.3, 137.6, 132.2, 132.0, 130.4, 129.6, 128.5,
128.0, 126.7, 125.9, 124.1, 118.7, 113.6, 112.5, 55.1, 50.4, 48.1,
21.3, 11.7. HRMS (ESIþ) for C28H28NO3þ: calcd 426.20637,
found 426.20627 (error m/z = 0.2 ppm).
HRMS (ESIþ) for C24H27NO2Naþ: calcd 384.19340, found
384.19341 (error m/z = 0.1 ppm).
Table 4, Entries 8 and 9. Isolated yields: 83 and 61%,
1
respectively. H NMR (400 MHz, CDCl3): δ (ppm) 7.32-7.20
(m, 3H), 7.18-7.07 (m, 4H), 6.86 (d, J = 7.2 Hz, 2H), 4.97 (s,
2H), 3.86 (s, 3H), 3.62 (s, 3H), 3.02-2.90 (m, 1H), 2.32 (s, 3H),
1.20 (d, J = 7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ (ppm)
167.6, 165.3, 140.6, 138.7, 137.7, 136.9, 130.6, 129.1, 129.0,
128.1, 127.7, 125.7, 113.8, 113.4, 52.1, 51.6, 48.0, 26.7, 21.59,
21.55. HRMS (ESIþ) for C25H28NO4þ: calcd 406.20129, found
406.20093 (error m/z = 0.9 ppm).
1
Table 4, Entry 1. Isolated yield: 84%. H NMR (400 MHz,
CDCl3): δ (ppm) 7.37 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz,
2H), 7.00-6.90 (m, 4H), 6.68 (s, 1H), 5.66-5.54 (m, 1H), 5.02 (d,
J = 10.4 Hz, 1H), 4,66 (d, J = 17,2 Hz, 1H), 4.42-4.32 (m, 2H),
4.13 (q, J = 7.2, 2H), 3.846 (s, 3H), 3.838 (s, 3H), 1.16 (t, J = 6.8,
3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 165.1, 159.8, 159.5,
139.3, 134.7, 134.5, 132.2, 130.9, 125.5, 124.7, 116.6, 114.0,
113.8, 113.5, 110.2, 59.5, 55.5, 55.4, 47.2, 14.5. HRMS (ESIþ)
for C24H26NO4þ: calcd 392.18564, found 392.18520 (error
m/z = 1.1 ppm).
Table 4, Entry 10. Isolated yield: 44%. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.42-7.33 (m, 3H), 7.32-7.23 (m, 6H),
6.98-6.92 (m, 2H), 4.93 (m, 2H), 3.81 (m, 3H), 3.67 (m, 3H).
13C NMR (125 MHz, CDCl3): δ (ppm) 165.5, 164.1, 137.3,
136.3, 130.4, 130.0, 128.8, 128.3, 128.0, 127.0, 126.9, 115.5,
115.0, 51.7, 51.5, 51.2. HRMS (ESIþ) for C21H20NO4þ: calcd
350.13869, found 350.13827 (error m/z = 1.2 ppm).
1
Table 4, Entry 11. Isolated yield: 30%. 1H NMR (300 MHz,
CDCl3): δ (ppm) 8.55 (d, J = 7.9 Hz, 1H), 7.59-7.49 (m, 3H),
7.48-7.42 (m, 1H), 7.42-7.35 (m, 2H), 7.07-7.00 (m, 2H), 6.79 (d,
J = 7.4 Hz, 1H), 4.02 (s, 3H), 3.88 (s, 3H), 3.72 (s, 3H). 13C NMR
(75.5 MHz, CDCl3): δ (ppm) 168.0, 165.3, 160.5, 132.5, 129.8,
128.5, 128.4, 128.2, 127.8, 127.4, 125.5, 124.5, 121.9, 121.5, 117.1,
114.4, 114.2, 109.2, 52.6, 52.8, 52.0. HRMS for C23H20NO5þ: calcd
390.13360, found 390.13434 (error m/z = 1.9 ppm).
Table 4, Entry 2. Isolated yield: 89%. H NMR (500 MHz,
CDCl3): δ (ppm) 7.38-7.26 (m, 4H), 7.21 (d, J = 7.0 Hz, 2H),
6.95 (d, J = 8.0 Hz, 2H), 6.69 (s, 1H), 5.65-5.55 (m, 1H), 5.01
(d, J = 10.0, 1H), 4.65 (d, J = 17.5 Hz, 1H), 4.39 (s, 2H), 3.85 (s,
3H), 3.68 (s, 3H), 2.39 (s, 3H). 13C NMR (125.7 MHz, CDCl3): δ
(ppm) 165.5, 159.9, 139.8, 137.8, 134.8, 134.7, 132.2, 130.1,
129.45, 129.36, 124.4, 116.7, 113.6, 113.4, 110.3, 55.4, 51.0,
47.2, 21.5. HRMS (ESIþ) for C23H24NO3þ: calcd 362.17507,
found 362.17471 (error m/z = 1.0 ppm).
Table 4, Entry 12. Isolated yield: 60%. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.54 (d, J = 7.6 Hz, 2H), 7.40-7.10 (m, 11H),
7.05-6.95 (m, 2H), 6.93-6.80 (m, 4H), 5.26 (s, 2H). 13C NMR
(75.5 MHz, CDCl3): δ (ppm) 192.0, 139.2, 137.8, 136.1, 132.3,
131.4, 130.1, 130.0, 129.2, 128.9, 128.5, 128.1, 127.7, 127.1,
126.1, 49.1. HRMS (ESIþ) for C32H20NO7þ: calcd 530.12343,
found 530.12378 (error m/z = 0.7 ppm).
1
Table 4, Entry 3. Isolated yield: 90%. H NMR (400 MHz,
CDCl3):δ(ppm) 7.38(d, J= 8.4 Hz, 2H), 7.30 (d, J= 8.0 Hz, 2H),
7.24 (d, J = 7.6 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.69 (s, 1H),
5.68-5.55 (m, 1H), 5.03 (d, J = 10.4 Hz, 1H), 4.67 (d, J = 17.2 Hz,
1H), 4.39 (s, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 2.42 (s, 3H). 13C NMR
(100.6 MHz, CDCl3): δ (ppm) 165.2, 159.3, 139.6, 138.2, 134.44,
134.38, 130.7, 130.5, 129.1, 128.7, 125.1, 116.4, 113.8, 113.0, 109.9,
55.3, 50.8, 46.9, 21.5. HRMS (ESIþ) for C23H24NO3þ: calcd
362.17507, found 362.17487 (error m/z = 0.6 ppm).
Table 4, Entry 13. Isolated yield: 32%. 1H NMR (300 MHz,
CDCl3): δ (ppm) 7.48 (s, 1H), 7.44-7.35 (m, 2H), 7.18-7.07 (m,
2H), 6.51-6.46 (m, 2H), 6.44-6.40 (m, 1H), 6.19 (d, J = 3.3 Hz,
1H), 4.14 (q, J = 7.2 Hz, 2H), 1.162 (t, J = 7.2 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ (ppm) 162.2 (d, 1JC-F = 246.9 Hz), 147.9,
141.4, 134.9, 131.0 (d, 2JC-F = 7.9 Hz), 129.6 (d, 4JC-F = 3.4 Hz),
125.0, 115.3 (d, 3JC-F = 21.5 Hz), 111.1, 109.4, 109.3, 106.3, 40.2,
16.4. HRMS (ESIþ) for C16H15NOFþ: calcd 256.11322, found
256.11293 (error m/z = 1.1 ppm).
1
Table 4, Entry 4. Isolated yield: 74%. H NMR (300 MHz,
CDCl3): δ (ppm) 7.53 (s, 1H), 7.42-7.31 (m, 2H), 7.16-7.04 (m,
2H), 6.87 (d, J = 3.4 Hz, 1H), 6.54-6.50 (m, 1H), 6.48 (s, 1H),
5.92-5.76 (m, 1H), 5.14 (d, J = 10.6 Hz, 1H), 4,79 (d, J = 17.3
Hz, 1H), 4.72-4.63 (m, 2H). 13C NMR (75.5 MHz, CDCl3): δ
(ppm) 164.7, 161.4, 143.8, 143.0, 136.0, 133.8, 131.6, 131.5,
127.30, 127.26, 117.1, 117.0, 116.1, 115.8, 112.5, 111.9, 111.1,
92.4, 48.8. HRMS (ESIþ) for C18H14FN2Oþ: calcd 293.10846,
found 293.1091 (error m/z = 2.0 ppm).
Table 4, Entry 14. Isolated yield: 42%. 1H NMR (500 MHz,
CDCl3): δ (ppm) 7.22-7.07 (m, 5H), 7.04-6.93 (m, 6H), 6.77 (d,
J = 9.0 Hz, 2H), 6.47 (s, 1H), 6.45 (s, 1H), 3.79 (s, 3H), 2.30 (s,
3H). 13C NMR (125 MHz, CDCl3): δ (ppm) 158.4, 136.0, 135.8,
135.6, 133.7, 132.0, 130.4, 129.8, 128.62, 128.56, 127.8, 126.0,
113.9, 109.5, 109.3, 55.3, 21.0. HRMS (ESIþ) for C24H22NOþ:
calcd 340.16959, found 340.16952 (error m/z = 0.2 ppm). Note:
rapid H-D exchange in CDCl3 yielded extra carbon and MS
signals. 13C NMR (125 MHz, CDCl3): δ (ppm) 135.9, 135.5,
109.4, 109.2. HRMS (ESIþ) for C24H21DNOþ: calcd 341.17587,
found 341.17587 (error m/z = 0.0 ppm).
1
Table 4, Entry 5. Isolated yield: 69%. H NMR (500 MHz,
CDCl3): δ (ppm) 7.42-7.34 (m, 3H), 7.30 (d, J = 7.5 Hz, 2H),
7.15-7.09 (m, 2H), 6.58 (s, 1H), 4.05 (q, J = 7.5 Hz, 2H), 2.42 (s,
3H), 1.03 (t, J = 7.4 Hz). 13C NMR (125 MHz, CDCl3): δ (ppm)
142.5, 139.3, 132.4, 129.6, 129.5, 127.5, 127.4, 127.3, 126.7, 126.5,
117.0, 113.3, 92.8, 40.4, 21.3, 16.2. HRMS (ESIþ) forC18H17N2Sþ:
calcd 293.11070, found 293.11030 (error m/z = 1.3 ppm).
1
Table 4, Entry 6. Isolated yield: 67%. H NMR (400 MHz,
CDCl3): δ (ppm) 7.35-7.22 (m, 8H), 6.93 (d, J = 7.2 Hz, 2H),
6.72 (s, 1H), 5.19 (s, 2H), 3.83 (s, 3H), 3.25-3.13 (m, 1H), 1.29
(d, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ (ppm)
165.3, 146.2, 138.4, 133.6, 132.7, 129.3, 128.8, 128.4, 127.6,
127.3, 125.5, 111.6, 111.4, 50.9, 48.3, 26.7, 20.1. HRMS (ESIþ)
for C22H24NO2þ: calcd 334.18016, found 334.17984 (error
m/z = 1.0 ppm). Anal. Calcd for C22H23NO2: C, 79.25; H,
6.95; N, 4.20. Found: C, 79.12; H, 7.18; N, 4.07.
Table 4, Entry 15. Isolated yield: 35%. 1H NMR (500 MHz,
CDCl3): δ (ppm) 7.99 (s, 1H), 7.97-7.91 (m, 3H), 7.68 (d, J = 8.0
Hz, 1H), 7.64-7.46 (m, 6H), 7.43-7.36 (m, 1H), 6.45 (s, 1H), 6.39
(s, 1H), 4.25 (q, 2H, J = 7.0 Hz), 0.91 (t, 3H, J = 7.0 Hz). 13
C
NMR (125 MHz, CDCl3): δ (ppm) 136.3, 135.9, 134.0, 133.4,
132.3, 131.5, 129.0, 128.4, 127.95, 127.94, 127.7, 127.4, 127.3, 127.0,
126.3, 125.8, 110.1, 109.7, 40.1, 16.1. HRMS (ESIþ) for C22H20Nþ:
calcd 298.15903, found 298.15869 (error m/z = 1.1 ppm). Note:
rapid H-D exchange in CDCl3 yielded extra carbon and MS
signals. 13C NMR (125 MHz, CDCl3): δ (ppm) 136.2, 135.8, 110.0,
109.6. HRMS (ESIþ) for C22H19DNþ: calcd 299.16530, found
299.16490 (error m/z = 1.3 ppm).
Table 4, Entry 7. Isolated yield: 24%. 1H NMR (500 MHz,
CDCl3): δ (ppm) 7.36 (d, J = 8.0 Hz, 2H), 7.32-7.00 (m, 6H),
6.30 (s, 1H), 4.92 (s, 2H), 3.97 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H),
2.41 (s, 3H), 2.34 (q, J = 7.5 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H),
0.87 (t, 3H, J = 7.0 Hz). 13C NMR (125 MHz, CDCl3): δ (ppm)
174.7, 137.6, 136.8, 134.4, 130.76, 130.74, 130.5, 129.1, 129.0,
116.3, 116.2, 109.8, 60.08, 60.06, 39.7, 27.7, 21.24, 21.17, 16.2, 9.1.
Table 4, Entry 16. Isolated yield: 63%. 1H NMR (300 MHz,
CDCl3): δ (ppm) 7.23-7.13 (m, 3H), 6.89 (d, J = 8.4 Hz, 2H),
6.66 (d, J = 6.9 Hz, 2H), 6.52 (d, J = 8.7 Hz, 2H), 5.21 (s, 2H),
4272 J. Org. Chem. Vol. 75, No. 12, 2010

St-Cyr et al.
JOCArticle
3.89 (s, 3H), 3.56 (s, 3H), 2.89 (s, 6H), 1.34 (s, 9H). 13C NMR (75
MHz, CDCl3): δ (ppm) 170.0, 164.0, 149.9, 141.0, 138.6, 137.1,
131.0, 128.1, 126.7, 125.3, 118.5, 115.4, 111.4, 111.1, 52.1, 50.8,
49.6, 40.0, 33.6, 30.6. HRMS (ESIþ) for C27H33N2O4þ: calcd
449.24348, found 449.24374 (error m/z = 0.6 ppm).
ATS, and UCLA IDRE for computer resources. We also
thank Warren Powell for assistance with the IUPAC name of
€
the phospha-Munchnones 2 reported in the previous com-
munication of this work.
Supporting Information Available: CIF files for 3a and 2b,
NMR spectra of products, and B3LYP/6-31þG(d) geometries.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. We thank the NSF, NSERC, FQRNT,
DuPont, the CFI, and the Australian-American Fulbright
Commission for financial support and the NCSA, UCLA
J. Org. Chem. Vol. 75, No. 12, 2010 4273