Irregularities in the effect of potassium phosphate in ynamide synthesis

Article abstract of DOI:10.1021/jo801935b

(Chemical Equation Presented) The yields of ynamides using Hsung's second generation protocol depend substantially on the quality of K₃PO ₄. Samples of K₃PO₄ from different suppliers were investigated by various techniques, revealing that the use of pure and anhydrous K₃PO₄ provides higher ynamide yields in comparison to samples contaminated with hydrates (K₃PO ₄·1.5H₂O and K₃PO₄· 7H₂O). With high quality K₃PO₄, a number of ynamides were synthesized in yields of 52-91%. In addition, we report that ynamides can undergo regioselective hydroamination with carbamates.

Full text of DOI:10.1021/jo801935b

SCHEME 1. Copper Catalyzed Ynamide Synthesis
Irregularities in the Effect of Potassium
Phosphate in Ynamide Synthesis
Karin Dooleweerdt,†,‡ Henrik Birkedal,† Thomas Ruhland,‡
and Troels Skrydstrup*,†
Department of Chemistry and the Interdisciplinary
Nanoscience Center, UniVersity of Aarhus,
Langelandsgade 140, 8000 Aarhus C, Denmark, and H.
Lundbeck A/S, Department of Medicinal Chemistry and
Support, OttiliaVej 9, 2400 Valby, Denmark
the Kinugasa reaction,7 DMDO oxidation,8 in the synthesis of
chiral enamides9 and benzofurans.10,11
In a project directed to using ynamides in cross coupling
reactions for the synthesis of heterocyclic systems, we were
recently confronted with the task of preparing these function-
alized alkynes exploiting Hsung′s second generation protocol
(Scheme 1).12,13 In this procedure, the ynamide is generated by
a copper catalyzed coupling between a bromoalkyne and a
protected amine such as a carbamate in the presence of either
anhydrous K3PO4 or K2CO3 as the base. Even though this
protocol has been optimized through several screenings, lack
of reproducibility of yields has been reported from the Tam
group.1e In our hands, we encountered similar problems in
particular when scaling up the reactions to above 1 mmol, which
we discovered was linked to the quality of the anhydrous K3PO4
obtained from commercial sources. Buchwald and co-workers
have reported analogous irregularities of anhydrous K3PO4 in
Cu-catalyzed amidation reactions.14 Since K3PO4 is frequently
used as a base in various transition metal catalyzed reactions,
we were therefore encouraged to have a closer look at the quality
of this base, from commercial sources, in ynamide synthesis.
ts@chem.au.dk
ReceiVed September 1, 2008
The yields of ynamides using Hsung′s second generation
protocol depend substantially on the quality of K3PO4.
Samples of K3PO4 from different suppliers were investigated
by various techniques, revealing that the use of pure and
anhydrous K3PO4 provides higher ynamide yields in com-
parison to samples contaminated with hydrates (K3PO4 ·
1.5H2O and K3PO4 · 7H2O). With high quality K3PO4, a
number of ynamides were synthesized in yields of 52-91%.
In addition, we report that ynamides can undergo regiose-
lective hydroamination with carbamates.
(3) (a) Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008, 10, 3829. (b) Istrate,
F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian, Y.; Gagosz, F. Org. Lett. 2008,
10, 925. (c) Hashmi, S. K.; Rudolph, M.; Bats, J. W.; Frey, W.; Rominger, F.;
Oeser, T. Chem.-Eur. J. 2008, 14, 6672. (d) Couty, S.; Meyer, C.; Cossy, J.
Angew. Chem., Int. Ed. 2006, 45, 6726. (e) Chechik-Lankin, H.; Livshin, S.;
Marek, I. Synlett 2005, 2098. (f) Tracey, M. R.; Zhang, Y.; Frederick, M. O.;
Mulder, J. A.; Hsung, R. P. Org. Lett. 2004, 6, 2209. (g) Couty, S.; Liegault,
B.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511. (h) Witulski, B.; Alayrac, C.;
Tevzadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257.
(4) Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis, A.
Org. Lett. 2005, 7, 1047.
(5) (a) Kurtz, K. C. M.; Frederick, M. O.; Lambeth, R. H.; Mulder, J. A.;
Tracey, M. R.; Hsung, R. P. Tetrahedron 2006, 62, 3928. (b) Frederick, M. O.;
Hsung, R. P.; Lambeth, R. H.; Mulder, J. A.; Tracey, M. R. Org. Lett. 2003, 5,
2663.
(6) Couty, S.; Meyer, C.; Cossy, J. Synlett 2007, 2819.
(7) Zhang, X.; Hsung, R. P.; Li, H.; Zhang, Y.; Johnson, W. L.; Figueroa,
R. Org. Lett. 2008, 10, 3477.
(8) Al-Rashid, Z. F.; Hsung, R. P. Org. Lett. 2008, 10, 661.
(9) Song, Z.; Lu, T.; Hsung, R. P.; Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew.
Chem., Int. Ed. 2007, 46, 4069.
(10) Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung, R. P.; Yao,
P.-Y.; Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361.
(11) For a special issue dedicated to the chemistry of ynamides, see:
Tetrahedron-Symposium-In-Print: “Chemistry of Electron-Deficient Ynamines
and Ynamides.” Tetrahedron 2006, 62, Issue no. 16.
(12) (a) Sagamanova, I. K.; Kurtz, K. C. M.; Hsung, R. P. Org. Synth. 2007,
84, 359. (b) Zhang, X.; Zhang, Y.; Huang, J; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R.
J. Org. Chem. 2006, 71, 4170. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.;
Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151.
(13) For another protocol for copper catalyzed ynamide synthesis, see: (a)
Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser, R. L.
Tetrahedron 2006, 62, 3815. (b) Kohnen, A. L.; Dunetz, J. R.; Danheiser, R. L.
Org. Synth. 2007, 84, 88.
(14) (a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 4120. (b) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421. (c) Klapars, A.; Antilla, J.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727.
Small, reactive building blocks and synthons are paramount
in organic synthesis. Recently, ynamides have proven to be
versatile and useful reagents in a variety of synthetic organic
transformations including various cycloadditions,1 metathesis,2
transition metal catalyzed reactions,3 Pictet-Spengler-type
cyclizations,4 Saucy-Marbet rearrangements,5 epoxidations,6
† University of Aarhus.
‡ H. Lundbeck A/S.
(1) (a) Li, H.; You, L.; Zhang, X.; Johnson, W. L.; Figueroa, R.; Hsung,
R. P. Heterocycles 2007, 74, 553. (b) Tanaka, K.; Takeishi, K. Synlett 2007,
2920. (c) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser,
R. L. Tetrahedron 2006, 62, 3815. (d) Tracey, M. R.; Oppenheimer, J.; Hsung,
R. P. J. Org. Chem. 2006, 71, 8629. (e) Riddell, N.; Villeneuve, K.; Tam, W.
Org. Lett. 2005, 7, 3681. (f) Zhang, X.; Li, H.; You, L.; Tang, Y.; Hsung, R. P.
AdV. Synth. Cat. 2006, 348, 2437. (g) Zhang, X.; Hsung, R. P.; You, L. Org.
Biomol. Chem. 2006, 8, 2679. (h) Zhang, X.; Hsung, R. P.; You, L. Org. Biomol.
Chem. 2006, 14, 2679. (i) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc.
2005, 127, 5776.
(2) (a) Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun. 2007, 23, 2420. (b)
Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231.
10.1021/jo801935b CCC: $40.75
Published on Web 11/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9447–9450 9447

FIGURE 2. (a) Rescaled and offset FTIR data in the 475-650 cm-1
region. The vertical lines indicate the maximum peak positions for the
phosphate adsorption in the C and A samples, respectively. (b) Rescaled
and offset FTIR data in the 725-1300 cm-1 region.
FIGURE 1. Screening of K3PO4 from different suppliers and measure-
ment of their water contents.
Five samples (A-E)15 of anhydrous K3PO4 from different
suppliers were investigated by screening them in coupling
reactions of two bromoalkynes (1 and 2) with carbamates 3 and
4. The yields of the obtained ynamides 5 (screening 1) and 6
(screening 2) were in the range of 17-54% and 51-84%,
respectively. In screening 1, the carbamate 3, CuSO4 ·5H2O,
1,10-phenanthroline and K3PO4 were blanketed with argon,
heated to 70 °C in dry toluene (1 M based on 3) and when the
desired temperature was reached, bromoalkyne 1 was added in
dry toluene (1 M based on 3) and the reaction mixture was
stirred for 22 h. In screening 2, the Boc-protected amine 4,
CuSO4 ·5H2O, 1,10-phenanthroline and K3PO4 were weighed
out in an argon-filled glovebox. Dry toluene (0.5 M based on
4) was added and the reaction mixture was heated to 80 °C.
When the desired temperature was reached, a solution of 2 in
dry toluene (0.66 M based on 4) was added and the reaction
mixture was stirred for 67 h. The yields of ynamides 5 and 6 in
the screening of K3PO4-samples from the commercial sources
(A-E) are shown in Figure 1.
As seen from Figure 1, the obtained yields in screening 1
and 2 depend significantly on the commercial source of K3PO4.
K3PO4-samples B and C performed best followed by sample D
and E, while sample A was considerably less efficient. To
elucidate the reason to these significant variations, a selection
of characterization studies were performed on the K3PO4-
samples.
Analysis of the K3PO4-samples by powder X-ray diffraction
(PXRD) showed that they were mixtures of anhydrous K3PO4
and hydrates to different extents. In particular, sample A,
displaying the poorest performance, is composed mainly of a
mixture of K3PO4 ·1.5H2O, K3PO4 ·7H2O and only a very minor
fraction of anhydrous K3PO4 if any at all.16 On the other hand,
samples B and C consist of almost pure anhydrous K3PO4 with
minor impurities of K3PO4 ·7H2O and K3PO4 ·1.5H2O, which
correlates well with their performance in screening 1 and 2.
Samples D and E are mainly anhydrous K3PO4, but with clear
indications of hydrate impurities. These results suggest an
important correlation of the composition of the employed K3PO4
and the yield obtained in ynamide synthesis.
Infrared spectroscopy supports the above findings (Figure 2).
The phosphate signature vibrations around 560 and 1000 cm-1
were fitted to allow quantitative comparison of the IR signals.17
Samples B-D display a main absorption at 562 cm-1 (see
Figure 2a), whereas the main adsorption for sample A is lower.
PXRD data showed that sample A contained essentially no
anhydrous K3PO4. Hence, the lack of a main absorption at
approximately 562 cm-1 can be taken as an indicator of poor
material. Around 900-1000 cm-1, the phosphate group has a
series of strong IR-bands (see Figure 2b). This region was also
fitted. In all samples there is a minor, sharp absorption at 922
cm-1, except for sample A. The presence of a sharp, albeit weak,
absorption at 922 cm-1 can be taken as a signature of anhydrous
K3PO4. The main IR absorptions occur in a cluster of peaks
around 1030 cm-1. The overlaps between the hydrates and
anhydrous K3PO4 mean that simple inspection of the obtained
IR spectra alone is not sufficient for confident determination of
sample purity; instead we recommend the use of powder X-ray
diffraction.
To substantiate and quantify the above findings, the samples
were subjected to thermagravimetrical analysis (TGA). The
(16) For further information on the powder X-ray diffraction analysis, see
the Supporting Information.
(15) K3PO4 was obtained from the following sources: (A) from Sigma Aldrich
(P5629), (B) from Riedel-de Hae¨n through Sigma Aldrich/Fluka (04347), (C)
from Acros Organics (38768), (D) from Strem Chemicals (19-3800), and (E)
from Alfa Aesar (041587).
(17) Fits were done to a sum of Lorentzians including a background term
and possibly an auxiliary peak for leveling background to left/right of peak cluster
and/or describing details of neighboring peaks. See Supporting Information for
further details on the analysis by infrared spectroscopy.
9448 J. Org. Chem. Vol. 73, No. 23, 2008

TABLE 1. Synthesized Ynamides
samples were heated to 350 °C, while the mass of the sample
was measured simultaneously to visualize the water content in
the samples. The curve plotted against the right-hand y-axis in
Figure 1 illustrates the mass loss as measured by TGA.18 The
deviations among the K3PO4 samples A-E are significant and
varying in the range of 3-16%. The measured mass loss
correlates well with the performance of the K3PO4 samples in
the ynamide synthesis. Again sample A stands alone with a mass
loss of 16 wt%, followed by sample D (12 wt%) and E (6 wt%).
Sample B and C perform best with mass losses of only 3-4
wt%. In short, K3PO4-samples B and C provide the highest
yields in our screenings. When investigated more closely they
appear to consist to a high degree of pure anhydrous K3PO4.19,20
With these results in hand, a variety of ynamides were
synthesized using the commercial source of K3PO4 (samples B
or C) with highest purity (Table 1). The yields for the coupling
between aryl bromoalkynes and 2-oxazolidinones were obtained
in the range of 52-72% (entries 1-3), where the major
byproducts of this reaction arose from competing Glaser-type
homocoupling.21 Ynamide 5 could be isolated in a similar yield
when K2CO3 was employed in place of K3PO4. Earlier we have
been unable to obtain ynamide 7 in a satisfactory yields. When
the reaction scale was increased from 1-2 mmol to 5-10, the
yields dropped to 40%. After changing the source of K3PO4 A
to B we have been able to obtain a 72% yield on a 50 mmol
scale. Ynamide 8 was isolated in a 66% yield equivalent to the
60-71% obtained by Hsung et al. in the coupling of (bromo-
ethynyl)benzene with (R)-4-benzyloxazolidin-2-one.12a With the
more acidic sulfonamide, a high yield of 88% (10 mmol scale,
improved from 73%) was secured (entry 4). In the case of the
TIPS-substituted bromoalkynes (entries 4-8), no Glaser prod-
ucts were observed and the yields were therefore generally
higher, attaining 91% (entries 5 and 6). In this case ynamide
10 was obtained in 91% yield on a 56 mmol scale; this result
correlates well with the yield of 89% obtained by Hsung and
co-workers in the coupling of (bromo-ethynyl)-triisopropylsilane
with (R)-4-benzyloxazolidin-2-one on a 48 mmol scale.12a,b
Earlier we have only been able to isolate 10 in 40% yield. In
the case of 11 we have succeeded in increasing the yield from
51% to a very good yield (91%). Satisfactory yields were also
furnished in representative couplings of the bromoalkyne of
TBDMS-protected propargylic alcohol with an oxazolidinone
and a sulfonamide (entries 9 and 10). When coupling a
sulfonamide to a non functionalized alkyne, such as 1-bromo-
hex-1-yne (entry 11) the ynamide product was obtained in a
64% yield.
a Reaction conditions: Argon atmosphere, nucleophile (1 equiv),
bromoalkyne (1.1 equiv), CuSO4 ·5H2O (10 mol%), 1,10-phenanthroline
(20 mol%), K3PO4 (2 equiv), toluene (0.5 M based on nucleophile), 70
°C. b All yields are isolated yields after column chromatography on
silica gel. c Reaction conditions: Argon atmosphere, nucleophile (1.2
equiv), bromoalkyne (1 equiv), CuSO4 ·5H2O (20 mol%),
1,10-phenanthroline (40 mol%), K3PO4 (2.4 equiv, toluene (0.33 M
based on nucleophile), 80 °C. d Reaction conditions: Argon atmosphere,
nucleophile (1 equiv), bromoalkyne (1.5 equiv), CuSO4 ·5H2O (10
mol%), 1,10-phenanthroline (20 mol%), K3PO4 (2 equiv), toluene (0.5
M based on nucleophile), 70 °C.
Finally, we briefly report an unexpected regioselective
hydroamination as side reaction that was discovered during our
investigations. In the coupling reaction between 1 and 3, we
isolated small amounts of the ketenaminal 16 (Scheme 2). To
examine whether this product was arising from the addition of
carbamate to the ynamide, we therefore treated both ynamides
5 and 7 with 1.1 equivalents of 2-oxazolidinone (3) and a 2-fold
SCHEME 2. Base-Mediated Hydroamination of Ynamide
(18) For further information on the results achieved by T.G.A., see the
Supporting Information.
(19) The use of CuSO4 ·5H2O as the catalyst for ynamide synthesis provides
contamination of the reaction mixture with water. However, with the loadings
of K3PO4 used for each reaction, at least 1.7 equiv. of anhydrous K3PO4 would
be present.
(20) In the case of K3PO4 received as ”chunks” and not a powder, the yields
can be increased to some extent by grinding of the material. But it is not sufficient
to convert it into a more effective K3PO4. Drying has been attempted at 150 °C
for several hours with no success.
(21) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. (b) Siemsen, P;
Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632.
excess of K3PO4 (Scheme 2). The reactions gave exclusively
one regioisomer in both cases providing the hydroamination
products 16 and 17 in 59 and 68% yield, respectively. Further
work is underway to investigate the scope of this reaction.
J. Org. Chem. Vol. 73, No. 23, 2008 9449

Vacuo. After column chromatography (Et2O in pentane in a gradient
from 0-2%) the title compound was obtained as a brown oil (654
mg, 1.69 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ (ppm)
7.38-7.28 (m, 5H), 4.57 (s, 2H), 1.49 (s, 9H), 1.02 (s, 3H), 1.01
(s, 18H). 13C NMR (100 MHz, CDCl3) δ (ppm) 154.3, 136.5, 128.7,
128.6 (2C), 127.9 (2C), 98.0, 82.6, 68.6, 53.2, 28.3 (3C), 18.8 (6C),
11.5 (3C). HRMS (ES) calcd for C23H37NO2SiNa (MNa+) 410.2486,
found 410.2482.
In summary, we have identified a possible reason for the
irregularities in the Hsung protocol seen by us and others, when
using K3PO4 as the base. The yields of the ynamide synthesis
appear to depend highly on the purity of the base. The qualities
of K3PO4 from five different commercial sources were examined
by powder X-ray diffraction, thermagravimetrical analysis and
IR-spectroscopy. Highest yields of ynamides are obtained in
the case of pure and anhydrous K3PO4. In addition, we have
found that ynamides in certain cases can be converted into
ketenaminals with carbamates by a regioselective hydroamina-
tion reaction.
3,3′-(2-(4-tert-Butylphenyl)ethene-1,1-diyl)dioxazolidin-2-
one (15). 7 (243 mg, 1.00 mmol), 2-oxazolidinone (96 mg, 1.1
22
mmol), K3PO4 (651 mg, 2.00 mmol), and dry toluene (0.5 M
based on 16) were mixed and then heated to 70 °C and stirred for
24 h. The reaction mixture was then cooled to room temperature,
diluted with EtOAc, filtered through a thin pad of Celite and
concentrated in Vacuo. After column chromatography (1:1 EtOAc
in pentane) the title compound was obtained as a colorless solid
(194 mg, 0.587 mmol, 59%). 1H NMR (400 MHz, CDCl3) δ (ppm)
7.38 (dt, 2H, J ) 8.4 Hz, 2.0 Hz), 7.28 (dt, 2H, J ) 8.4 Hz, 2.4
Hz), 6.11 (s, 1H), 4.47 (dd, 2H, J ) 9.2 Hz, 7.6 Hz), 4.43 (dd, 2H,
J ) 8.4 Hz, 6.8 Hz), 4.08 (dd, 2H, J ) 9.2 Hz, 7.6 Hz), 3.74 (dd,
2H, J ) 9.6 Hz, 8.4 Hz), 1.32 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ (ppm) 156.8, 155.3, 151.5, 130.2, 129.2, 127.9 (2C), 125.9 (2C),
117.8, 63.5, 62.6, 47.8, 45.1, 34.8, 31.4 (3C). HRMS (ES) calcd
for C18H22N2O4Na (MNa+) 353.1477, found 353.1473. mp )
161-163 °C.
Experimental Section
General Procedure for the Cu-Catalyzed Coupling of an
Amide or Carbamate with a Bromoalkyne. Ynamides are
synthesized according to literature procedure.12b Carbamate or
amide (1 equiv), CuSO4 ·5H2O (0.10 equiv), 1,10-phenanthroline
22
(0.20 equiv), and K3PO4 (2 equiv) were heated to 70 °C in dry
toluene (1 M based on carbamate) under an atmosphere of argon,
then bromoalkyne (1.1-1.5 equiv) was added in dry toluene (1 M
based on carbamate) followed by stirring until the carbamate was
consumed or the reaction has stopped as determined by thin layer
chromatography. The reaction mixture was allowed to cool to room
temperature, diluted with EtOAc, filtered through a thin pad of
Celite and then concentrated in Vacuo. The obtained crude material
was purified by flash chromatography on silica gel.
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foundation,
The Lundbeck Foundation, the Carlsberg Foundation, H. Lun-
dbeck A/S, and the University of Aarhus. H.B. is a Skou
associate professor funded by the Danish Natural Sciences
Research Council. This support is gratefully acknowledged.
Procedure for the Cu-Catalyzed Coupling of tert-Butyl-
benzyloxycarbamate with (Bromoethynyl)triisopro-pylsilane.
Ynamide 6 was synthesized according to literature procedure.3a
4
(2.40 mmol, 497 g), CuSO4 ·5H2O (2.40 mmol, 497 g), 1,10-
23
phenanthroline (0.80 mmol, 144 mg), and K3PO4 (4.80 mmol,
Supporting Information Available: Experimental details of
all new and known ynamides and spectroscopic data of all
ynamides and unknown compounds, powder X-ray diffraction,
thermal gravimetrical and infrared spectroscopy data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1.02 g) were mixed in an argon-filled glovebox and then heated to
80 °C in dry toluene (0.66 M based on 2, then 2 (2.0 mmol, 523
mg) was added in dry toluene (0.66 M) followed by stirring for
67 h. The reaction mixture was cooled to room temperature, diluted
by EtOAc, filtered through a pad of Celite and concentrated in
(22) K3PO4 obtained from Riedel de-Hae¨n (B).
(23) K3PO4 obtained Acros Organics (C).
JO801935B
9450 J. Org. Chem. Vol. 73, No. 23, 2008