Horner-wadsworth-emmons reagents as azomethine ylide analogues: Pyrrole synthesis via (3 + 2) cycloaddition

Article abstract of DOI:10.1021/ol102075y

Amido-substituted Horner-Wadsworth-Emmons reagents can serve as precursors to 1,3-dipoles for use in cycloaddition. These compounds are assembled in one pot via the TMSOTf-catalyzed Arbuzov reaction of imines, acid chlorides, and phosphites. The coupling of this synthesis with alkyne cycloaddition provides a three-component synthesis of pyrroles. The dipoles can be prepared with a diverse range of imines and acid chlorides, and (3 + 2) cycloaddition with unsymmetrical alkynes is highly regiospecific, providing a modular approach to form substituted pyrroles.

Full text of DOI:10.1021/ol102075y

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4916-4919
Horner-Wadsworth-Emmons Reagents
as Azomethine Ylide Analogues: Pyrrole
Synthesis via (3 + 2) Cycloaddition
Marie S. T. Morin,‡ Daniel J. St-Cyr,‡ and Bruce A. Arndtsen*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montreal,
Quebec H3A 2K6, Canada
bruce.arndtsen@mcgill.ca
Received August 31, 2010
ABSTRACT
Amido-substituted Horner-Wadsworth-Emmons reagents can serve as precursors to 1,3-dipoles for use in cycloaddition. These compounds are
assembled in one pot via the TMSOTf-catalyzed Arbuzov reaction of imines, acid chlorides, and phosphites. The coupling of this synthesis with
alkyne cycloaddition provides a three-component synthesis of pyrroles. The dipoles can be prepared with a diverse range of imines and acid chlorides,
and (3 + 2) cycloaddition with unsymmetrical alkynes is highly regiospecific, providing a modular approach to form substituted pyrroles.
1,3-Dipolar cycloaddition with azomethine ylides has found
broad application in the synthesis of five-membered ring
heterocycles.1 There are a range of methods available to
generate azomethine ylides, including the R-deprotonation
of activated imine precursors,2 the carbon-carbon ring
opening of aziridines,3 or the desilylation of in situ
generated N-R-silyliminium ions.4 While effective, these
methods typically require the initial buildup of a precursor
with the correct substituents prior to creating the dipole
or need specific activating groups to proceed in good
yields (e.g., imines with electron-withdrawing substitu-
ents). In addition, because of their symmetry, the regi-
oselectivity of azomethine ylide cycloaddition is substit-
uent dictated and will result in mixtures unless there is a
large electronic or steric bias between the two carbon-
bound units.1,5
A potential approach to address these issues of azomethine
ylide generation and selectivity is to design synthetic
equivalents.6 One commonly employed variant of azomethine
ylides is Hu¨isgen’s 1,3-oxazolium-5-oxides (i.e., Mu¨nch-
nones, 2, Figure 1),7 though these can also be challenging
to prepare unless they are derived from natural amino acids8,9
or formed via catalysis.10 As an alternative, we have recently
reported that Wittig-type reagents 3 can serve as precursors
to 1,3-dipoles via cyclization to form 4.11 These phosphorus-
based dipoles can be synthesized in a modular fashion from
imines, acid chlorides, and phosphonites. In addition, the PR3
‡ These authors contributed equally to this work.
(1) (a) Harwood, L. M.; Vickers, R. J. The Chemistry of Heterocyclic
Compounds: SyntheticApplications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles andNatural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley: New York, 2002; Vol. 59, Ch. 3. (b) Lown, J. W. General
Heterocyclic Chemistry Series:1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 1, Ch. 6. (c) Coldham, I.; Hufton,
R. Chem. ReV. 2005, 105, 2765. (d) Stanley, L. M.; Sibi, M. P. Chem. ReV.
2008, 108, 2887.
(2) (a) Kanemasa, S. Synlett 2002, 1371. (b) Husinec, S.; Savic, V.
Tetrahedron: Asymmetry 2005, 16, 2047. (c) Na´jera, C.; Sansano, J. M.
Angew. Chem., Int. Ed. 2005, 44, 6272.
(5) For examples: (a) Vedejs, E.; Grissom, J. W. J. Am. Chem. Soc.
1988, 110, 3238. (b) Fejes, I.; To¨ke, L.; Nyerges, M.; Siek Pak, C.
Tetrahedron 2000, 56, 639. (c) Li, G.-Y.; Chen, J.; Yu, W.-Y.; Hong, W.;
Che, C.-M. Org. Lett. 2003, 5, 2153. (d) Lo´pez-Pe´rez, A.; Adrio, J.;
Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 340. (e) Garner, P.;
(3) Hu¨isgen, R.; Scheer, W.; Huber, H. J. Am. Chem. Soc. 1967, 89,
1753.
¨
(4) (a) Padwa, A.; Chen, Y.-Y.; Dent, W.; Hildegard, N. J. Org. Chem.
1985, 50, 4006. (b) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235. (c)
Vedejs, E.; West, F. G. Chem. ReV. 1986, 86, 941.
Kaniskan, H. U.; Hu, J.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8,
3647. (f) Herna´ndez-Toribio, J.; Arraya´s, R. G.; Mart´ın-Matute, B.;
Carretero, J. C. Org. Lett. 2009, 11, 393
.
10.1021/ol102075y  2010 American Chemical Society
Published on Web 10/12/2010

c
-
Scheme 1.
Synthesis of Phosphonate Precursors 1a-ca
Figure 1. 1,3-Dipolar cycloaddition reagents.
a P(OEt)3 at 0 °C, 5 min. b (PhO)2POH in CH2Cl2 with 2,4,6-collidine,
0 °C f rt. c P(catechyl)OMe at rt, 15 h.
unit creates a strong electronic bias across the dipole,
providing a tool to control selectivity in cycloaddition
reactions.11c
and phosphites, are airstable, and can be broadly diversified.
In addition, the generation of dipole 6 can be coupled with
cycloaddition, providing one-pot access to pyrroles.
Amido-substituted phosphonates can be generated by the
reaction of in situ formed R-chloroamides with phosphites.13
For example, the reaction of p-tolyl(H)CdNBn and anisoyl
chloride in acetonitrile leads to the formation of R-chloroa-
mide 8 within minutes at ambient temparature (Scheme 1).
The subsequent addition of P(OEt)3 results in a rapid
Arbuzov reaction, generating phosphonate 7a in near quan-
titative yield. Other phosphites can also participate in this
reaction, yielding variously phosphorus-substituted products
(7b and 7c).
Amido-substituted phosphonate 7a can be deprotonated
with LiHMDS to generate the corresponding ylide 5a (Table
1). This product has the potential to cyclize in a fashion
similar to Wittig-type reagents 3 (Figure 1). However, in
situ 31P and 13C NMR data suggest 5a exists predominately
in an acyclic ylide structure. For example, 31P NMR analysis
reveals a signal at 34.4 ppm, which is typical of Horner-
Wadsworth-Emmons structures,14 while the amide 13C
NMR resonance (δ 176.8 ppm) is not perturbed as expected
for the 1,3-dipole.11 Despite these structural features, the
addition of the alkyne DMAD to 5a does result in a slow
cycloaddition reaction to form pyrrole (Table 1).15 5b and
5c react in a similar fashion, with the less sterically
encumbered catechyl-substituted 5c leading to the rapid
formation of pyrrole (<5 min, entry 3).
A challenge in the use of 4 is that it is generated via the
equilibrium reaction of imines, acid chlorides, and P(o-
catechyl)Ph, thereby limiting the scope of dipoles available
to those derived from stabilized precursors (e.g., R2 or R3 )
aryl, alkyl).11 In considering this issue, we became interested
in the potential of Horner-Wadsworth-Emmons reagents
such as 5 (Figure 1) to behave as 1,3-dipoles. Horner-
Wadsworth-Emmons reagents have become useful alterna-
tives to Wittig reagents in alkene synthesis due in large part
to the stability and availability of their precursors: phospho-
nates (e.g., 7, Scheme 1).12 The latter are generated via the
Arbuzov reaction of phosphites and electrophiles. As de-
scribed below, amido-substituted Arbuzov products can serve
as attractive precursors to 1,3-dipoles. These compounds are
formed in a nonequilbrium reaction of imines, acid chlorides,
(6) (a) Komatsu, M.; Minakata, S.; Oderaotoshib, Y. ArkiVoc 2006, 370,
and references therein. (b) Vedejs, E.; Grissom, J. W. J. Org. Chem. 1988,
53, 1876. (c) Pearson, W. H.; Clark, R. B. Tetrahedron Lett. 1999, 40,
4467. (d) Dondas, H. A.; Durust, Y.; Grigg, R.; Slater, M. J.; Sarker,
M. A. B. Tetrahedron 2005, 61, 10667. (e) Tsuge, O.; Kanemasa, S.;
Yamada, T.; Matsuda, K. J. Org. Chem. 1987, 52, 2523. (f) Hosomi, A.;
Miyashiro, Y.; Yoshida, R.; Tominaga, Y.; Yanagi, T.; Hojo, M. J. Org.
Chem. 1990, 55, 5308. (g) Takahashi, Y.; Miyashi, T.; Yoon, U. C.; Oh,
S. W.; Mancheno, M.; Su, Z.; Falvey, D. F.; Mariano, P. S. J. Am. Chem.
Soc. 1999, 121, 3926. (h) St. Cyr, D. J.; Martin, N.; Arndtsen, B. A. Org.
Lett. 2007, 9, 449. (i) Pearson, W. H.; Dietz, A.; Stoy, P. Org. Lett. 2004,
6, 1005.
(7) Huisgen, R.; Gotthardt, H.; Bayer, H. O.; Schaefer, F. C. Angew.
Chem., Int. Ed. 1964, 3, 136.
(8) (a) Gribble, G. W. In Oxazoles: Synthesis, Reactions, and Spectros-
copy, A; Palmer, D. C., Ed.; Wiley: New York, 2003; Vol. 60, Chapter 4.
(b) Gringrich, H. L.; Baum, J. S. In Oxazoles; Turchi, I. J., Ed.; Wiley:
New York, 1986; Vol. 45, p 731. (c) Potts, K. T. In 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.;Wiley: New York, 1984; Vol. 2,
p 1.
While the reaction in Table 1 provides a method to
generate pyrroles, there are several challenges in this
approach. First, the most effective phosphonate precursor,
the catechyl-substituted 7c, is formed slowly from P(o-
catechyl)OMe and 8, making it difficult to diversify this
reagent to other imines/acid chlorides. This can be addressed
(9) For other routes to Mu¨nchnones: (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) (a) Dhawan, R.; Dghaym, R.; Arndtsen, B. A. J. Am. Chem. Soc.
2003, 125, 1474. (b) Lu, Y.; Arndtsen, B. A. Angew. Chem., Int. Ed. 2008,
47, 5430. (c) Dhawan, R.; Dghaym, R. D.; St. Cyr, D. J.; Arndtsen, B. A.
Org. Lett. 2006, 8, 3627.
(13) (a) Stevens, C. V.; Vekemans, W.; Moonen, K.; Rammeloo, T.
Tetrahedron Lett. 2003, 44, 1619. (b) Couture, A.; Deniau, E.; Grandclau-
don, P. Synthesis 1994, 9, 953.
(11) (a) St. Cyr, D. J.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129,
12366. (b) Krenske, E. H.; Houk, K. N.; Arndtsen, B. A.; St. Cyr, D. J.
J. Am. Chem. Soc. 2008, 130, 10052. (c) St-Cyr, D. J.; Morin, M. S. T.;
Be´langer-Garie´py, B.; Arndtsen, B. A.; Krenske, E. H.; Houk, K. N. J.
Org. Chem. 2010, 75, 4261.
(14) Bottin-Strzalko, T.; Seyden-Penne, J.; Pouet, M.-J.; Simonnin, M.-
P. J. Org. Chem. 1978, 43, 4346.
(15) 5a also undergoes standard Wadsworth-Emmons reactions with
aldehydes. See Supporting Information and: (a) Couture, A.; Deniau, E.;
Grandclaudon, P. Tetrahedron Lett. 1993, 34, 1479. (b) Hendrickson, J. B.;
Rodriguez, C. J. Org. Chem. 1983, 48, 3344.
(12) (a) Warsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961,
83, 1733. (b) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
Org. Lett., Vol. 12, No. 21, 2010
4917

Table 1. Phosphonates in Alkyne Cycloaddition and Pyrrole
Table 2. Scope of Three-Component Pyrrole Synthesisa
Synthesisa
entry
compd
R
Lewis acid
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
7a
7b
7c
7c
7c
7c
7c
7c
7c
7c
7c
CO2Me
CO2Me
CO2Me
Me
Me
Me
Me
Me
Me
Me
-
-
-
24
0.5
<5 min
50
70
80
-
-
-
73
56
68
91
95
-
BF3·Et2O
TsCl
tBuPh2SiCl
SiCl4
TBSCl
TESCl
TMSCl
17
17
17
3
10
11
Me
3
a 0.2 mmol of 7 in 0.5 mL of CH2Cl2, -78 °C, 0.2 mmol of LiHMDS
solution; then 0.22 mmol of L.A. at rt, followed by 0.6 mmol of alkyne.
by the use of the slightly more nucleophilic P(o-catechyl)-
OTMS and addition of catalytic TMSOTf (eq 1). Under these
conditions, 7c is generated within 2 h at ambient temperature,
presumably via the in situ formation of a more electrophilic
N-acyl iminium triflate salt intermediate. This approach can
also be readily adapted to less reactive imines and acid
chlorides (vide infra).
A second issue with 5c is its inability to undergo
cycloaddition with less activated dipolarophiles (e.g., Table
1, entry 4). The low reactivity presumably arises from the
relatively electron-rich phosphorus unit in 5, which disfavors
a P-O interaction to generate the dipole. One approach to
favor cyclization of 5 is to neutralize the formal oxygen
anionic charge. As shown in Table 1, a number of Lewis
acids can serve this purpose (entries 7-11), with TMSCl
proving to be the most effective. In situ NMR analysis is
consistent with the Lewis acid favoring a dipolar form (6c).
This shows a significant perturbation of the amide carbonyl
resonance of 6c in the presence of TMSCl (at δ 146.8 ppm),
as well as an upfield shift in the 31P NMR resonance (δ -28.2
ppm, relative to 5c at 47.6 ppm). This latter is within the
range expected for pentacoordinate organophosphorus struc-
a (a) 0.20 mmol of imine/acid chloride, 0.5 h; TMSOP(Cat) (0.22 mmol),
TMSOTf (0.002 mmol), 2 h; (b) 0.20 mmol of LiHMDS; (c) TMSCl (0.20
mmol), alkyne (0.60 mmol). b (c) 55 °C. c Major isomer (66:34 ratio). d (a)
24 h. e 5% TMSOTf. f 0.80 mmol of LiHMDS. g 0.22 mmol of TMSOTf,
CH3CN, DBU. h (a) 12 h,55 °C. i (c) 0.40 mmol of TMSOTf.
4918
Org. Lett., Vol. 12, No. 21, 2010

tures16 and similar to crystallographically characterized
phosphorus dipoles.11
synthesis of 7d from commercial (o-catechyl)PCl, p-toluic
acid, and imine (Scheme 2). Notably, this approach avoids
The coupling of these optimized conditions for phospho-
nate formation, deprotonation, and dipolar cycloaddition
allows for a series of very rapid and selective reactions and
the assembly of polysubstituted pyrroles within hours at
ambient temperature (Table 2).17 Because of the stability of
the phosphonate intermediates, this transformation is straight-
forward to generalize. A range of C-aryl, -functionalized aryl,
and -heteroaryl-substituted imines can be used in this reaction
(entries 1-7), as can various aryl-substituted acid chlorides.
Electron-poor dipolarophiles are the most reactive with 6,
though aryl-acetylenes are also viable substrates (entry 6).
Alkynes can be replaced with electron-deficient alkenes,
which undergo acid loss to generate pyrroles upon cycload-
dition (entries 8 and 9). In addition to forming pyrroles, the
cycloadditions with unsymmetrical alkynes typically result
in a single isomeric product, where the electron-withdrawing
unit is directed away from the formerly phosphorus-bound
carbon. This is consistent with a phosphorus-induced elec-
tronic bias in these dipoles controlling regioselectivity.11c
The irreversibility of phosphonate formation can also allow
the use of less stable imine/acid chloride reagents. For
example, formaldimines can be employed in the coupling,
followed by subsequent cyclization and dipolar addition to
form 5-H substituted pyrroles (entry 10). Alternatively,
imines can be replaced with aromatic heterocycles such as
isoquinoline, which can be efficiently trapped to yield a
polycyclic pyrrole (entry 11).18 The acid chlorides can even
be replaced with chloroformates and chlorothioformates.
While these latter create less electrophilic analogues to 8,
their trapping can occur with P(o-catechyl)OTMS, providing
a route to 2-heteroatom-substituted pyrroles (entries 12-14).
The Arbuzov intermediates in this reaction can be ex-
ploited to create alternative routes to these dipoles. Burnaeva
and co-workers have reported that the reaction of imines with
benzoate-substituted phosphonites leads to amido-substituted
phosphonates.19 Performing this reaction with a catechyl-
substituted phosphorus reagent can provide a single-step
Scheme 2.
Pyrrole Synthesis from Carboxylic Acidsa
a 0.2 mmol of imine, 0.22 mmol of carboxylic acid, 0.22 mmol of (o-
catechyl)PCl, 1 mL of CH2Cl2, MW, 100 °C 2 h; 0.45 mmol of LiHMDS
solution,-78 °C to rt; 0.4 mmol of TMSCl, 0.6 mmol of alkyne, rt.
both the need to generate (o-catechyl)P(OTMS) and the use
of sensitive acid chloride (and iminium salt) precursors.
Coupling this synthesis with subsequent cycloaddition can
allow the overall synthesis of pyrroles in one pot from
carboxylic acids, imines, and alkynes.
In conclusion, amido-substituted Horner-Wadsworth-
Emmons reagents can serve as precursors to 1,3-dipoles and
participate in cycloaddition reactions with alkynes to form
pyrroles. Coupling the generation of these reagents with
cycloaddition can provide a modular method to construct
pyrroles directly from available building blocks. Studies
directed toward the reaction of these reagents with other
dipolarophiles, and the development of alternative approaches
to generate 6, are under investigation.
Acknowledgment. We thank NSERC, FQRNT, and the
CFI for their financial support.
Supporting Information Available: Synthesis and spec-
tral data for pyrrole products. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) (a) Ylides and Imines of Phosphorus; Johnson, A. W.; Wiley-
Interscience: New York, New York, 1993. (b) Handbook of Phosphorus-
31 NMR Data; Tebby, J. C., Ed.; CRC Press: Boston, 1991.
OL102075Y
(17) TMSCl is the formal byproduct of 7 formation with P(o-catechyl)-
OTMS; however, excess TMSCl is beneficial to the reaction (Table 2, entry
2 is in 37% yield without additional TMSCl).
(19) Mironov, V. F.; Gubaidullin, A. T.; Burnaeva, L. M.; Litvinov,
I. A.; Ivkova, G. A.; Romanov, S. V.; Zyablikova, T. A.; Konovalov, A. I.;
Konovalova, I. V. Russ. J. Gen. Chem. 2004, 74, 32.
(18) Van der Jeught, S.; Stevens, C. V. Chem. ReV. 2009, 109, 2672.
Org. Lett., Vol. 12, No. 21, 2010
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