Introducing a new class of N-phosphoryl ynamides via Cu(I)-catalyzed amidations of alkynyl bromides

Article abstract of DOI:10.1021/ol201947b

We describe here the first synthesis of N-phosphoryl ynamides featuring C- and P-chirality via copper(I)-catalyzed amidative cross-couplings between phosphoramidates and phosphordiamidates with alkynyl bromides. Also featured is a tandem aza-Claisen-hetero-[2 + 2] cycloaddition for the synthesis of N-phosphoryl azetidin-2-imines.

Full text of DOI:10.1021/ol201947b

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4862–4865
Introducing a New Class of N-Phosphoryl
Ynamides via Cu(I)-Catalyzed Amidations
of Alkynyl Bromides
Kyle A. DeKorver,* Mary C. Walton, Troy D. North, and Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry,
University of Wisconsin, Madison, Wisconsin 53705, United States
dekorver@wisc.edu rhsung@wisc.edu
Received July 19, 2011
ABSTRACT
We describe here the first synthesis of N-phosphoryl ynamides featuring C- and P-chirality via copper(I)-catalyzed amidative cross-couplings
between phosphoramidates and phosphordiamidates with alkynyl bromides. Also featured is a tandem aza-Claisenꢀhetero-[2 þ 2] cycloaddition
for the synthesis of N-phosphoryl azetidin-2-imines.
The chemistry of ynamides1 has continued to blossom,
with the number of publications increasing at an astonishing
rate.2 This surge of new and exciting chemistry is largely a
result of the ease of ynamide synthesis using copper-cata-
lyzed cross-coupling reactions3 (Scheme 1). However, with
the exception of Masson’s4 single example of trapping
lithiated ynamine 5 with diethyl chlorophosphate, all ex-
amples of ynamides to date utilize amide, carbamate, urea,
sulfonyl, and only recently, imide5 derived electron-with-
drawing groups (EWG) to harness the ynamide’s reactivity.
To the best of our knowledge, the amidative cross-coupling6
between an sp-C and a phosphoramidate7,8 has not been
reported. We describe herein the first general synthesis of a
(1) For current leading reviews on ynamides, see: (a) Evano, G.;
Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (b)
DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064.
(2) For ynamide papers published in 2011 alone, see: (a) Balieu, S.;
ꢀ
Toutah, K.; Carro, L.; Chamoreau, L.-M.; Rouseliere, H.; Courillon, C.
Tetrahedron Lett. 2011, 52, 2876. (b) Fadel, A.; Legrand, F.; Evano, G.;
Rabasso, N. Adv. Synth. Catal. 2011, 353, 263. (c) Schotes, C.; Mezzetti,
A. Angew. Chem. 2011, 123, 3128. (d) Barbazanges, M.; Meyer, C.;
Cossy, J.; Turner, P. Chem.ꢀEur. J. 2011, 17, 4480. (e) Pizzetti, M.;
Russo, A.; Petricci, E. Chem.ꢀEur. J. 2011, 17, 4523. (f) Garcia, P.;
Evanno, Y.; George, P.; Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.;
Gandon, V. Org. Lett. 2011, 13, 2030. (g) Kramer, S.; Friis, S. D.; Xin,
Z.; Odabachian, Y.; Skrydstrup, T. Org. Lett. 2011, 13, 1750. (h) Li, C.;
Zhang, L. Org. Lett. 2011, 13, 1738. (i) Wang, Y. P.; Danheiser, R. L.
Tetrahedron Lett. 2011, 52, 2111. (j) Mak, X, Y.; Crombie, A. L.;
Danheiser, R. L. J. Org. Chem. 2011, 76, 1852. (k) Davies, P. W.;
Cremonesi, A.; Martin, N. Chem. Commun. 2011, 379. (l) Xu, C.-F.;
Mei, Xu, M.; Jia, Y. X.; Li, C.-Y. Org. Lett. 2011, 13, 1556. (m) Chen, Z.;
Zheng, D.; Wu, J. Org. Lett. 2011, 13, 848. (n) Shindoh, N.; Takemoto,
Y.; Takasu, K. Heterocycles 2011, 82, 1133. (o) Saito, N.; Katayama, T.;
Saito, K. Heterocycles 2011, 82, 1181. (p) Kramer, S.; Odabachian, Y.;
(3) For leading reviews on the synthesis of ynamides, see: (a) Tracey,
M. R.; Hsung, R. P.; Antoline, J. A.; Kurtz, K. C. M.; Shen, L.; Slafer,
B. W.; Zhang, Y. In Science of Synthesis, Houben-Weyl Methods of
Molecular Transformations; Weinreb, S. M., Ed.; Georg Thieme Verlag
KG: Stuttgart, Germany, 2005; Chapter 21.4. (b) Mulder, J. A.; Kurtz,
K. C. M.; Hsung, R. P. Synlett 2003, 1379.
(4) Fromont, C.; Masson, S. Tetrahedron 1999, 55, 5405.
(5) Sueda, T.; Oshima, A.; Teno, N. Org. Lett. 2011, 13, 3996.
(6) For an intramolecular Cu-catalyzed cross-coupling between an
sp2-C and phosphoramidate, see: Yang, T.; Lin, C.; Fu, H.; Jiang, Y.;
Zhao, Y. Org. Lett. 2005, 7, 4781.
(7) For examples of phosphoramidates and phosphordiamidates as
pharmaceuticals, see: (a) Jeng, A. Y.; De Lombaert, S. Curr. Pharm. Des.
1997, 3, 597. (b) Colvin, O. M. Curr. Pharm. Des. 1999, 5, 555–8.
(8) For examples as insectides, see: (a) Milzner, K.; Reisser, F. Patent
CH 554376, 1974. (b) Anderson, J.; Homeyer, B.; Kuehle, E.; Scheinpflug,
H.; Zeck, W. M.; Simonet, D. E. Patent US 4603214, 1986.
€
Overgaard, J.; Rottlander, M.; Gagosz, F.; Skrydstrup, T. Angew.
Chem. 2011, 123, 5196. (q) Nissen, F.; Richard, V.; Alayrac, C.;
Witulski, B. Chem. Commun. 2011, 47, 6656. (r) Hashmi, A. S. K.;
Schuster, A. M.; Zimmer, M.; Rominger, F. Chem.ꢀEur. J. 2011, 17,
5511. (s) Gilboa, N.; Wang, H.; Houk, K. N.; Marek, I. Chem.ꢀEur. J.
€
2011, 17, 8000. (t) Chemla, F.; Dulong, F.; Ferreira, F.; Nullen, M. P.;
ꢁ
Perez-Luna, A. Synthesis 2011, 9, 1347. (u) Saito, N.; Saito, K.; Shiro,
M.; Sato, Y. Org. Lett. 2011, 13, 2718.
r
10.1021/ol201947b
Published on Web 08/17/2011
2011 American Chemical Society

novel class of N-phosphoryl ynamides capable of containing
both C- and P-chirality. The highly Lewis basic nature of the
phosphoryl moiety and the ability to tune its electronega-
tivity make the phosphoryl EWG ideal to further expand
both the phosphoramidates and alkynyl bromides (Table 2).
Phosphoramidate 7a led smoothly to ynamides 12a and 12b
in moderate yield (entries 1 and 2). However, with the
N-allyl phosphoramidate 7b, a thermal aza-Claisen9 rear-
rangement of the ynamide product and ensuing hydrolysis10
occurred readily at 75 °C leading to a low yield of the desired
ynamide 13 (entry 3). This issue could be overcome using
anhydrous coupling conditions (CuTC/DMEDA) and a
lower reaction temperature to give N-allyl ynamide 14 in
57% yield, with almost complete recovery of the unreacted
10a. In general, cyclic diol-derived phosphoramidates 10b
and 10c gave ynamides 15 and 16 with higher yields (entries
5ꢀ7), likely due to the increased hydrolytic stability11 of
both the amides and the ynamide products. Interestingly,
these cyclic N-phosphoryl ynamides adopt a chair config-
uration with the NꢀCtC in an axial orientation such that
the nitrogen lone pair is delocalized into the σ*[PdO] (see
X-ray of 15b in Figure 1).
Scheme 1. Current Ynamide Electron-Withdrawing Groups
the already vast scope of reactions one can accomplish using
ynamides. To this effect, we disclose an application toward
highly functionalized N-phosphoryl azetidin-2-imines
through a Staudinger-type ketenimineꢀimine [2 þ 2]
cycloaddition not possible with pre-existing ynamides.
Our initial efforts were in optimizing the copper-cata-
lyzed cross-coupling between phosphoramidate 7a and
alkynyl bromide 8 (Table 1). It was immediately clear that
the strength of the base played a significant role in the
reaction, with K3PO4 giving the best yield of ynamide 9
(entries 1ꢀ3). Unfortunately, the stronger KOt-Bu base
led to complete decomposition (entry 4). Also, the combi-
Figure 1. X-ray of ynamide 15b.
nation of CuSO4 5H2O and 1,10-phenanthroline was far
more efficient than both CuI and CuCN with DMEDA as
the ligand (entry 3 vs 5 and 6).
3
By using a 1:1 diastereomeric mixture of phosphorami-
dates 11, ynamides 17-eq and 17-ax differing only in the
stereochemistry at phosphorus could be obtained in ex-
cellent yield and separated by column chromatography
(Table 2, entry 8). X-ray crystallography and NOE analy-
sis was used to determine the conformation of the two
diastereomeric ynamides, revealing that 17-ax adopted a
configuration similar tothat of 15b, with the nitrogen atom
axial and delocalized into the σ*[PdO] while the two
oxygen lone pairs were delocalized into the σ*[PꢀN]
Table 1. Optimization of Coupling Conditionsa
(9) (a) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.;
Huang, J.; Hsung, R. P. Org. Lett. 2009, 11, 899. (b) DeKorver, K. A.;
Hsung, R. P.; Lohse, A. G.; Zhang, Y. Org. Lett. 2010, 12, 1840. (c)
DeKorver, K. A.; North, T. D.; Hsung, R. P. Synlett 2010, 2397. (d)
DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai, H.;
Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org. Chem. 2011, 76, 5092.
(10) During the formation of ynamide i bearing an N-allyl moiety, an
ensuing thermal aza-Claisen occurred followed by hydrolysis of the
resulting ketenimine to give ii.
entry
catalyst
ligand
base
yield (%)b
1
2
3
4
5
6
CuSO4 5H2O 1,10-phenanthroline K2CO3
38
59
3
CuSO4 5H2O 1,10-phenanthroline Cs2CO3
3
CuSO4 5H2O 1,10-phenanthroline K3PO4
68
3
CuSO4 5H2O 1,10-phenanthroline KOt-Bu
<5
3
Cul
DMEDA
DMEDA
K3PO4
K3PO4
25c
27c
CuCN
a Conditions: 15 mol % Cu, 30 mol % ligand, 2 equiv base, toluene
(concn = 0.4 M), 95 °C, 24 h. b Isolated yields. c Reactions run at
110 °C.
(11) For leading references, see: (a) Garrison, A. W.; Boozer, C. E. J.
ꢁ~
With an optimized protocol in hand, our next goal was
to access the tolerance of the reaction to functionality on
ꢁ
ꢁ~
Am. Chem. Soc. 1968, 90, 3486. (b) Nunez, A.; Berroteran, D.; Nunez, O.
Org. Biomol. Chem. 2003, 1, 2283.
Org. Lett., Vol. 13, No. 18, 2011
4863

Table 2. Synthesis of N-Phosphoryl Ynamides from Diolsa
Figure 2. X-rays of diastereomeric ynamides 17-eq and 17-ax.
1,3-diol counterparts (Scheme 2). To illustrate this point,
the synthesis of ynamide 19a from L-proline derived phos-
phordiamidate 18 proceeded in a meager 13% yield even
after 48 h at 110 °C using the previously optimized condi-
tions. Though some starting material could be recovered
after the reaction, the majority had decomposed. Unfortu-
nately, anhydrous conditions using CuTC and DMEDA
for 1R,2R-(ꢀ)-pseudoephedrine derived amide 20 also
resulted in no formation of the desired ynamide 21, though
70% of the starting material could be recovered.
Scheme 2. Attempts at Ynamide Synthesis from Amino Alco-
hols
a Conditions: 15 mol % CuSO4 5H2O, 30 mol % 1,10-phenanthro-
3
line, 1.3 equiv alkynyl bromide, 2 equiv K3PO4, toluene (concn = 0.4
M), 75ꢀ100 °C, 24 h. b Isolated yields. c 20 mol % CuTC, 40 mol %
DMEDA, 50 °C, 48 h and 95% based on recovered 10a. Using condi-
tions from Table 2, yield was 75%. d 48 h reaction time.
After much struggle, it was discovered that the addition
of 10 equiv of NEt3 to the reaction mixture allowed for
isolation of the desired ynamides 19a and 19b in low but
synthetically useful yields under anhydrous conditions
(Table 3). Furthermore, ynamide formation from the
two separable diastereomers of 20 led to 23 and 24 in
moderate yields. The stereochemistry of phosphordiami-
dates 18, 20a, and 20b was determined by NOE analysis
(see Supporting Information). The racemic 1,3-amino
alcohol derived phosphoramidate 22 led to ynamides 25a
and 25b resembling a phosphoryl version of Evans’ chiral
auxiliary in moderate yields without the addition of NEt3.
We had set out to investigate this new class of N-
phosphoryl ynamidestosolvea problem we hadpreviously
encountered while developing a thermal aza-Claisen re-
arrangement of N-sulfonyl, N-allyl ynamides, allowing for
their use as precursors to ketenimines.9 Despite our best
(Figure 2). Unfortunately, the X-ray of 17-eq was con-
voluted by the cocrystallization of both enantiomers in a
90:10 ratio as an example of whole molecule disorder.
Regardless, it was evident that 17-eq adopted a chair
configuration with the nitrogen atom equatorial and de-
localized into the π*[PdO] with the two oxygen lone pairs
delocalized into the σ*[PdO].
Next, we turned our attention to preparing ynamides
bearing a chiral phosphoryl group, which is especially
exciting as the phosphorus atom directly attached to the
nitrogen of the ynamide can itself be chiral. Amino alco-
hols represent an obvious choice for preparing such chiral
auxiliaries. Unfortunately, from the onset it was immedi-
ately apparent that the reactivity of 1,2-amino alcohol
derived phosphordiamidates was very different from their
4864
Org. Lett., Vol. 13, No. 18, 2011

aza-Claisen rearrangement are the reason we initially under-
took this project, they are by no means the only types of
transformations possible with these N-phosphoryl ynamides.
Table 3. Ynamides from Amino Alcoholsa
Scheme 3. Toward the Synthesis of N-Phosphoryl Azetidin-2-
imines
We have described here the first practical synthesis of a
new class of ynamides utilizing a variety of chiral and achiral
diol and amino alcohol-derived phosphates as the required
electron-withdrawing group. As one example of the type of
chemistry one may accomplish with such ynamides, we have
demonstrated a diastereoselective Staudinger-type keteni-
mineꢀimine [2 þ 2] cycloaddition using N-phosphoryl
ynamides as the synthetic precursor to give highly functio-
nalized N-phosphoryl azetidin-2-imines. Investigations are
currently underway to further develop these tandem se-
quences as well as to explore the use of the N-phosphoryl as
a chiral auxiliary14,15 and a temporary tether.16
a Conditions: 1.3 equiv alkynyl bromide, 20 mol % CuTC, 40 mol %
DMEDA, 3 equiv Cs2CO3, 10 equiv NEt3, dioxane (concn = 0.4 M), 95
°C, 6ꢀ24 h. b Isolated yields. c Same catalyst, but with 3:1 toluene/
EtOAc (concn = 0.4 M), 2 equiv K3PO4, 95 °C, 24 h.
efforts, the nucleophilic trapping of the N-sulfonyl keteni-
mines was severely limited due to a very rapid intramole-
cular 1,3-sulfonyl shift yielding nitriles. Since amide,
carbamate, and urea-derived ynamides failed to undergo
such an aza-Claisen in our hands, we turned our attention
to phosphoryl-based electron-withdrawing groups. We
were delighted to see that during the coupling of N-allyl
phosphoramidate 7b, some ketenimine hydrolysis product
was isolated.10 Furthermore, heating of N-allyl ynamide
26b resulted in no formation of nitrile 28b, meaning the
aza-Claisen is operational, but a 1,3-phosphoryl shift is not
(Scheme 3). This afforded us the opportunity to use the in
situ generated ketenimine derived from 26b in a Staudinger-
type ketenimineꢀimine [2 þ 2] cycloaddition12 to give
azetidin-2-imine13 30 bearing a quaternary carbon center
with 4:1 diastereoselectivity, which was confirmed by NOE.
While these types of tandem reactions initiated by an
Acknowledgment. We thank NIH (GM066055) for
funding. K.A.D. thanks the American Chemical Society
for a Division of Medical Chemistry Predoctoral Fellow-
ship. We thank Dr. Vic Young and Mr. Gregory T. Rohde
of the University of Minnesota for providing X-ray struc-
tural analysis.
Supporting Information Available. Experimental pro-
cedures as well as NMR spectra and characterizations for
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Molt, O.; Schrader, T. Synthesis 2002, 2633.
(15) Preliminary efforts at utilizing chiral amino-alcohol derived
N-phosphoryl ynamides in Lewis acid catalyzed reactions have been
problematic thus far due to instability of the ynamides to acidic condi-
tions. We are currently exploring their use in thermally driven pathways.
(16) For leading reviews on utilizing phosphorous as a temporary
tether, see: (a) McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R.
Chem. Rev. 2004, 104, 2239. (b) Thomas, C. D.; McParland, J. P.;
Hanson, P. R. Eur. J. Org. Chem. 2009, 32, 5487.
(12) For a review of ketenimine cycloadditions, see: Alajarin, M.;
Vidal, A.; Tovar, F. Targets Heterocycl. Syst. 2000, 4, 293.
(13) (a) Arnold, B.; Regitz, M. Angew. Chem., Int. Ed. 1979, 4, 320.
(b) Van Camp, A.; Goosens, D.; Moya-Portuguez, M.; Marchand-
Brynaert, J.; Ghosez, L. Tetrahedron Lett. 1980, 21, 3081. (c) Alajarin,
M.; Molina, P.; Vidal, A. Tetrahedron Lett. 1996, 37, 8945. (d) Whiting,
M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3157.
Org. Lett., Vol. 13, No. 18, 2011
4865