Synthesis of amidines using N-allyl ynamides. A palladium-catalyzed allyl transfer through an ynamido-π-allyl complex

Article abstract of DOI:10.1021/ol802844z

A de novo transformation of N-allyl-N-sulfonyl ynamides to amidines is described featuring a palladium-catalyzed N-to-C allyl transfer via ynamido-palladium-π-allyl complexes.

Full text of DOI:10.1021/ol802844z

ORGANIC
LETTERS
2009
Vol. 11, No. 4
899-902
Synthesis of Amidines Using N-Allyl
Ynamides. A Palladium-Catalyzed Allyl
Transfer through an Ynamido-π-Allyl
Complex
Yu Zhang, Kyle A. DeKorver, Andrew G. Lohse, Yan-Shi Zhang, Jian Huang, and
Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received December 9, 2008
ABSTRACT
A de novo transformation of N-allyl-N-sulfonyl ynamides to amidines is described featuring a palladium-catalyzed N-to-C allyl transfer via
ynamido-palladium-π-allyl complexes.
Our involvement in the studies of Huisgen’s azide-[3 + 2]1-3
cycloadditions employing ynamides4-7 led us to an exciting
possibility. As shown in Scheme 1, under copper(I)-catalyzed
conditions,8 while triazolyl copper intermediates 1 could be
trapped with electrophiles other than proton to afford more
substituted triazoles 2,9,10 when R2 ) Ts, it could also readily
lose N2 in a retro-[3 + 2] manner to give ynamido-copper
complexes 3a in equilibrium with ketenimine-copper com-
plexes 3b. A series of elegant studies have since appeared
reporting nucleophilic trappings of 3 in both inter- and
intramolecular fashion, leading to amidines and ami-
dates.11-14 The potential of harvesting new reactivities from
(1) (a) Huisgen, R. Angew. Chem. 1963, 75, 604. (b) Huisgen, R. In
1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Pergamon Press:
Oxford, 1984; pp 1-176.
(6) For chemistry of ynamides in the last 2 years, see: (a) Couty, S.;
Liegault, B.; Meyer, C.; Cossy, J. Tetrahedron 2009, 65, ASAP. (b)
Deweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009,
11, 221. (c) Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J.
Org. Chem. 2008, 73, 9447. (d) Saito, N.; Katayama, T.; Sato, Y. Org.
Lett. 2008, 10, 3829. (e) Yasui, H.; Yorimitsu, H.; Oshima, K. Bull. Chem.
Soc. Jpn. 2008, 81, 373. (f) Yasui, H.; Yorimitsu, H.; Oshima, K. Chem.
Lett. 2008, 37, 40. (g) Istrate, F. M.; Buzas, A. K.; Jurberg, I. D.;
Odabachian, Y.; Gagosz, F. Org. Lett. 2008, 10, 925. (h) Mart´ınez-Espero´n,
M. F.; Rodr´ıguez, D.; Castedo, L.; Saa´, C. Tetrahedron 2008, 64, 3674. (i)
Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. (j)
Yavari, I.; Sabbaghan, M.; Hosseini, N.; Hossaini, Z. Synlett 2007, 20, 3172.
(k) Hashimi, A. S. K.; Salathe, R.; Frey, W. Synlett 2007, 1763. (l)
Rodr´ıguez, D.; Mart´ınez-Espero´n, M. F.; Castedo, L.; Saa´, C. Synlett 2007,
1963. (m) Couty, S.; Meyer, C.; Cossy, J. Synlett 2007, 2819. (n)
Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007, 129,
10096. (o) Tanaka, K.; Takeishi, K. Synthesis 2007, 2920. (p) Kohnen, A. L.;
Dunetz, J. R.; Danheiser, R. L. Org. Synth. 2007, 84, 88.
(2) For leading reviews, see: (a) Meldal, M.; Tornoe, C. W. Chem. ReV.
2008, 108, 2952. (b) Wu, P.; Fokin, V. V. Aldrichim. Acta 2007, 40, 7. (c)
Bock, V. D.; Hiemstra, H.; Van Maarseveen, J. H. Eur. J. Org. Chem. 2006,
51. (d) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Heterocycles 2003, 60,
1225. (e) Abu-Orabi, S. T. Molecule 2002, 7, 302. (f) Kolb, H. C.; Finn,
M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004
(3) For a review on organic azides, see: Bra¨se, S.; Gil, C.; Knepper, K.;
Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188
.
.
(4) (a) Zhang, X.; Li, H.; You, L.; Tang, Y.; Hsung, R. P. AdV. Syn.
Catal. 2006, 348, 2437. (b) Zhang, X.; Hsung, R. P.; You, L. Org. Biomol.
Chem. 2006, 6, 2679
.
(5) For reviews on ynamides, see: (a) Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
(b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (c)
Katritzky, A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455
.
10.1021/ol802844z CCC: $40.75
Published on Web 01/27/2009
2009 American Chemical Society

Scheme 1
.
Generating Ynamido-Metal Complexes
Table 1. Effect of Equivalents of Amine and Pd(0) Sources
ynamido-metal complexes captured our attention. Conse-
quently, we examined a different pathway that can provide
general access to ynamido-metal π-allyl complexes 5a and
5b from N-allyl-N-sulfonyl ynamides 4. We report here a
de novo synthesis of pharmacologically useful amidines15-18
from ynamides featuring a palladium-catalyzed N-to-C allyl
transfer through ynamido-π-allyl complexes.
a All are isolated yields.
(7) (a) Al-Rashid, Z. F.; Johnson, W. L.; Hsung, R. P.; Wei, Y.; Yao,
P.-Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780. (b) Yao, P.-Y.;
Zhang, Y.; Hsung, R. P.; Zhao, K. Org. Lett. 2008, 10, 4275. (c) Zhang,
X.; Hsung, R. P.; Li, H.; Zhang, Y.; Johnson, W. L.; Figueroa, R. Org.
Lett. 2008, 10, 3477. (d) Al-Rashid, Z. F.; Hsung, R. P. Org. Lett. 2008,
10, 661. (e) Oppenheimer, J.; Hsung, R. P.; Figueroa, R.; Johnson, W. L.
Org. Lett. 2007, 9, 3969. (f) You, L.; Al-Rashid, Z. F.; Figueroa, R.; Ghosh,
S. K.; Li, G.; Lu, T.; Hsung, R. P. Synlett 2007, 1656. (g) Li, H.; You, L.;
Zhang, X.; Johnson, W. L.; Figueroa, R.; Hsung, R. P. Heterocycles 2007,
74, 553. (h) Sagamanova, I. K.; Kurtz, K. C. M.; Hsung, R. P. Org. Synth.
2007, 84, 359. (i) Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung,
R. P.; Yao, P.-Y.; Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361.
(8) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.;
Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew.
Chem., Int. Ed. 2004, 43, 3928.
While identifying a suitable palladium catalyst for our
intended reaction pathway was not difficult, we found two
amidine products. As shown in Table 1, when treating
N-allyl-N-sulfonyl ynamide 6 with 5 mol % of Pd(PPh3)2Cl2
in the presence of c-hex-NH2 in THF at 65 °C, both amidines
7 and 8 were observed.19 Intriguingly, the ratio of 7 and 8
depended upon the amount of c-hex-NH2 that was used. A
greater amount of c-hex-NH2 (3-5 equiv) predominantly led
to the formation of 7 in which the allyl group is lost (entries
1 and 2), while 1.0 equiv of c-hex-NH2 and/or addition with
the use of syringe pump began to favor the formation of 8
in which the allyl group had undergone an N-to-C transfer
(entries 3 and 4).
(9) Zhang, X.; Hsung, R. P.; Li, H. Chem. Commun. 2007, 2420.
(10) For related studies on these triazolyl copper intermediates, see: (a)
Gerard, B.; Ryan, J.; Beeler, A. B.; Porco, J. A., Jr. Tetrahedron 2006, 62,
6405. (b) Wu, Y. M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005, 1314.
(c) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int. Ed. 2006,
45, 3154. See footnote 11. .
Moreover, a quick screening of palladium sources revealed
that the allyl transfer is catalyst dependent (Table 1). At 3.0
equiv of c-hex-NH2 in comparison with Pd(PPh3)2Cl2 (see entry
1), Pd(PPh3)4 gave exclusively allyl-transferred amidine 8 (entry
5), while Pd(dppe)Cl2 and Pd(dppf)Cl2 (entries 6 and 7) reverted
back to favor amidine 7 with Pd(dppf)Cl2 giving a better yield
(entry 7). Sensing that these contrasts could be due to the
differences either in the initial oxidation state of the palladium
metal or, more likely, their respective ligands, we examined
(11) For intermolecular additions, see: (a) Bae, I.; Han, H.; Chang, S.
J. Am. Soc. Chem. 2005, 127, 2038. (b) Cho, S. H.; Yoo, E. J.; Bae, I.;
Chang, S. J. Am. Chem. Soc. 2005, 127, 16046. (c) Yoo, E. J.; Bae, I.;
Cho, S. H.; Han, H.; Chang, S. Org. Lett. 2006, 8, 1347. (d) Kim, S. H.;
Jung, D. Y.; Chang, S. J. Org. Chem. 2007, 72, 9769. (e) Cho, S. H.; Chang,
S. Angew. Chem., Int. Ed. 2008, 47, 2836. (f) Kim, J.; Lee, S. Y.; Lee, J.;
Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454. (g) Yoo, E. J.; Ahlquist,
M.; Bae, I.; Sharpless, K. B.; Fokin, V. V.; Chang, S. J. Org. Chem. 2008,
73, 5520.
(12) For an intramolecular addition, see: Chang, S.; Lee, M.; Jung, D. Y.;
Yoo, E. J.; Cho, S. H.; Han, S. K. J. Am. Soc. Chem. 2006, 128, 12366.
(13) For a study using ynamides, see: Kim, J. Y.; Kim, S. H.; Chang,
S. Tetrahedron Lett. 2008, 49, 1745.
(14) For other leading examples of trapping complexes such as 3, see:
(a) Cui, S.-L.; Lin, X.-F.; Wang, Y.-G. Org. Lett. 2006, 8, 4517. (b) Xu,
X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9, 1585. (c) Jin, Y.;
Fu, H.; Yin, Y.; Jiang, Y.; Zhao, Y. Synlett 2007, 901. (d) Cui, S.-L.; Wang,
J.; Wang, Y.-G. Org. Lett. 2007, 9, 5023. (e) Cui, S.-L.; Wang, J.; Wang,
Y.-G. Org. Lett. 2008, 10, 1267. (f) For an earlier study on trapping of
ynamido-lithium complexes, see: Fromont, C.; Masson, S. Tetrahedron
1999, 55, 5405.
(17) Dunn, P. J. In ComprehensiVe Organic Functional Group Trans-
formations II, Amidines and N-Substituted Amidines; Katritzky, A. R.,
Taylor, R. J. K., Eds.; Pfizer Global Research and Development: Sandwich,
U.K., 2005; Vol. 5, pp 655-699.
(18) For recent examples of amidine synthesis, see: (a) Yu, R. T.; Rovis,
T. J. Am. Chem. Soc. 2008, 130, 3262. (b) Wang, J.; Xu, F.; Cai, T.; Shen,
Q. Org. Lett. 2008, 10, 445. (c) Malik, H.; Frederic, B.; Alexandre, M.;
Jean-Jacques, B. Org. Biomed. Chem. 2006, 4, 3142. (d) Katritzky, A. R.;
Cai, C.; Singh, S. K. J. Org. Chem. 2006, 71, 3375. (e) Kumagai, N.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43, 478.
(19) See the Supporting Information. On the basis of NOE experiments
(see the Supporting Information for details), these amidines adopt an
E-geometry with respect to the CdN bond.
(15) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203
.
(16) For a leading review on amidine derivatives serving as selective
muscarinic agonists in the treatment of Alzheimer’s diseases, see: Messer,
W. S., Jr.; Dunbar, P. G. In Muscarinic Agonists and the Treatment of
Alzheimer’s Disease; Landes Bioscience: Georgetown, TX, 1996; pp
131-153.
900
Org. Lett., Vol. 11, No. 4, 2009

Table 2. Amidine Synthesis Using Primary Aminesa
Table 3. Ynamide Substituent Effect
isolated
yield (%)
entry ynamides
R1
amidines
NR2
1
2
3
4
5
6
29a
29b
29c
29d
29e
29e
TBDPS
TBS
TES
(CH2)3OTBS
c-hex
c-hex
30a
30b
30c
30d
30e
30f
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
c-hex-NH
pyrrolidinyl
c-hex-NH
95
94
87
41
54
69
of a diverse array of amidines. First, we employed a range
of primary amines including allyl amine (entry 3 in Table
2), propargyl amine (entry 4), and anilines (entries 5-9).
Second, we examined a series of secondary amines including
the use of p-Ns-substituted ynamide (see 20 in Figure 1),
indoline (see 26), tetrahydroquinoline (see 27), and imidazole
(see 28).
a All reactions utilized ynamide 6, 5.0 mol % of Pd(PPh3)4, 1.0 equiv
of K2CO3, 3.0 equiv of RNH2, and THF [conc ) 0.05 M], 65 °C, 5-8 h.
b Isolated yields. c 1.0 equiv of amine was used. d Reaction time was 24 h.
Third, we explored ynamides 29a-e with variations on
the acetylenic substituent (Table 3). It is noteworthy that
while Pd(PPh3)4 was effective in promoting allyl transfer
when using primary amines, it was not useful for secondary
amines (with the exception of 22), and only the usage of
Pd2(dba)3 and xantphos led to allyl-transferred amidines.
Pd2(dba)3 along with 10 mol % of various phosphine ligands.
While BINAP was not useful (entry 8, potential ee was not
analyzed), we found that both xantphos20 and X-phos21 (entries
9 and 10) represent excellent ligand systems for promoting the
allyl transfer, with the former phosphine ligand (see entry 9)
providing a much faster reaction.
A proposed model consistent with our observations is
shown in Scheme 2. While all evidence points toward the
presence of ynamido-Pd-π-allyl complexes 5a in equilib-
rium with the ketenimine complex 5b through an oxidative
addition,22,23 the pathway clearly diverged thereafter depend-
ing upon the concentration of the amine HNR2 and the nature
of the ligand. We believe the first equivalent of HNR2
effectively gave the amidinyl Pd-π-allyl complexes 31a and
31b via nucleophilic addition to 5b. An ensuing reductive
elimination of 31a and/or 31b would lead to respective allyl
(20) For a leading reference on xantphos, see: Kranenburg, M.; van der
Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Organome-
tallics 1995, 14, 3081.
(21) For leading references on X-phos, see: (a) Huang, X.; Anderson,
K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 6653. (b) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc.
2007, 129, 12003.
(22) As shown below, a non-palladium-involved pathway would entail
an aza-Claisen type of rearrangement followed by trapping of the allyl-
ketenimine intermediate i with an external amine. However, while this
pathway is indeed a possibility, it requires much higher temperature and
longer reaction time. When carried out at 65-80 °C in THF, the reaction
was sluggish and slow.
Figure 1. Amine synthesis using secondary amines. (a) Reaction
conditions: 5.0 mol % of Pd2(dba)3, 10.0 mol % of xantphos, 1.0
equiv of K2CO3, 3.0 equiv of R2NH, THF (conc ) 0.05 M), 65
°C, 1.5-6 h. (b) Isolated yields. (c) 10.0 mol % of Pd2(dba)3, 20.0
mol % of xantphos, and 5.0 equiv of R2NH were used. (d) The
only successful example in using 5.0 mol % of Pd(PPh3)4.
For a recent account on a related thermal transformation using ynol
The generality of this allyl transfer could be established
very quickly via three perspectives, leading to the synthesis
ethers, see: Sosa, J. R.; Tudjarian, A. A.; Minehan, T. G. Org. Lett. 2008,
10, 5091
.
Org. Lett., Vol. 11, No. 4, 2009
901

Scheme 2
.
Proposed Mechanistic Model
Scheme 3. Pd(II) versus Pd(0) Source
angles such as xantphos20,26 that presumably promote
reductive elimination could be employed to favor the
formation of allyl-transferred amidines 32b.
Finally, the efficacy of oxidative addition likely plays a
role in the distribution between nonallyl- and allyl-transferred
amidines because the choice of Pd(0) source appears to be
critical. Specifically, a Pd(II) source could also serve as
π-Lewis acid to activate the ynamide, leading to keten-
iminium Pd complex 35 (Scheme 3). After addition of the
first equivalent of HNR2, deallylation of the resulting N-allyl
enamide 36 could take place with a second equivalent of
HNR2. This process could be promoted by either Pd(0) or
Pd(II), with the former initiating an oxidative addition while
the latter again serving to activate the ketene-aminal motif.
This assessment is consistent with the observation that
nonallyl transferred amidines 34 were the major product
when using Pd(II) sources.
We have described here a de novo transformation of
N-allyl-N-sulfonyl ynamides to a diverse array of amidines
featuring a palladium-catalyzed N-to-C allyl transfer via
ynamido-palladium-π-allyl complexes. Efforts in further
developingsyntheticmethodsinvolvingtheseynamido-palladium-π-
allyl complexes are underway.
transferred amidines 32a and 32b, and 32a appears to
tautomerize favorably to 32b.
However, this reductive elimination step appears to be less
favored when an excess of amine was used. Consequently,
Pd complexes 33 could be attained likely through a direct
nucleophilic attack on the Pd-π-allyl motif, thereby leading
to the loss of the respective allyl amines24 and, ultimately,
the formation of the nonallyl-transferred amidines 34 after
reductive elimination. In addition, this deallylative pathway
is also consistent with the fact that when using the more
nucleophilic secondary amines (relative to primary amines)25
and Pd(PPh3)4, nonallyl-transferred amine product predomi-
nated. Consequently, in all cases, either a controlled amount
of HNR2, a slow addition of HNR2, or more bulky ligands
such as X-phos21 and/or bidentate ligands with unique bite
Acknowledgment. We thank the NIH (GM066055) for
funding.
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.
(23) For leading reviews on Claisen rearrangements, see: (a) Hill, R. K.
In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York,
1984. (b) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 827.
(24) Because of their basicity, polarity, and/or volatility, the respective
allyl amine byproducts [R2NCH2CHdCH2] from de-allylation were difficult
to isolate. However, we were able to isolate the following allylated amine
ii when using piperizine.
OL802844Z
(26) Hartwig observed that in comparison with monodentate phosphine
ligands, the usage of bidentate ligands such as xantphos leads to a much
faster amidative cross-coupling. This is presumably due to the ability of
amido-type carbonyl groups to engage in tight complexation with the
palladium metal. As a result, when using xantphos, its unique bite angle
promotes reductive elimination. See: Fujita, K.-I.; Yamashita, M.; Pus-
chmann, F.; Alvarez-Falcon, M. M.; Incarvito, C. D.; Hartwig, J. F. J. Am.
(25) For a leading reference on relative nucleophilicity of amines, see:
Brotzel, F.; Chu, Y. C.; Mayr, H. J. Org. Chem. 2007, 72, 3679.
Chem. Soc. 2006, 128, 9044.
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Org. Lett., Vol. 11, No. 4, 2009