Access to 2,5-diamidopyrroles and 2,5-diamidofurans by Au(I)-catalyzed double hydroamination or hydration of 1,3-diynes

Article abstract of DOI:10.1021/ol1008685

(Figure presented) A Au(I)-catalyzed hydroamination or hydration of 1,3-diynes to access 2,5-diamidopyrroles and 2,5-diamidofurans has been developed. This method can also be expanded to 2,5-disubstituted furans and 1,2,5-trisubstituted pyrroles including the formation of deuterated heterocycles and ¹⁸O-labeled furans.

Full text of DOI:10.1021/ol1008685

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2758-2761
Access to 2,5-Diamidopyrroles and
2,5-Diamidofurans by Au(I)-Catalyzed
Double Hydroamination or Hydration of
1,3-Diynes
Søren Kramer,† Julie L. H. Madsen,† Mario Rottla¨nder,‡ and Troels Skrydstrup*,†
Center for Insoluble Protein Structures (inSPIN), Department of Chemistry and the
Interdisciplinary Nanoscience Center, Aarhus UniVersity, Langelandsgade 140,
8000 Aarhus C, Denmark, and DiVision of Medicinal Chemistry, H. Lundbeck A/S
OttiliaVej 9, 2500 Valby, Denmark
ts@chem.au.dk
Received April 15, 2010
ABSTRACT
A Au(I)-catalyzed hydroamination or hydration of 1,3-diynes to access 2,5-diamidopyrroles and 2,5-diamidofurans has been developed. This
method can also be expanded to 2,5-disubstituted furans and 1,2,5-trisubstituted pyrroles including the formation of deuterated heterocycles
and 18O-labeled furans.
Due to the high importance of pyrroles and furans in
biologically active molecules, a number of synthetic ap-
proaches have been devised and published as alternatives to
the classical methods represented by the Knorr, Paal-Knorr,
and Hantzsch protocols.1-3 A significant number of these
strategies rely on the application of alkynes with carefully
chosen functionalities nearby. Such a setup would allow for
an intramolecular cyclization to the desired heterocycles,
often relying on the use of gold catalysis.4,5 Recently,
terminal alkynes have been exploited for the synthesis of
symmetrical 2,5-disubstituted furans by a Ru(II)-catalyzed
head-to-head dimerization followed by an intramolecular
cyclization.6 In addition, a Rh(I)-catalyzed head-to-tail
dimerization of terminal propargyl amides followed by a
Au(III)-catalyzed cyclization have successfully been shown
for accessing 1,2,4-trisubstituted pyrroles.7
Another approach to symmetrical and nonsymmetrical
furans and pyrroles would involve the addition of water or
an amine to 1,3-diynes. Access to a variety of diyne starting
(3) Representative examples of alternative strategies: (a) Kobatake, T.;
Yoshida, S.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2010, 49,
2340. (b) Liu, W.; Jiang, H.; Huang, L. Org. Lett. 2010, 12, 312. (c) Mizuno,
A.; Kuzama, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2009, 48, 8318. (d)
Wang, J.-Y.; Wang, X.-P.; Yu, Z.-S.; Yu, W. AdV. Synth. Catal. 2009, 351,
2063. (e) Lygin, A. V.; Larionov, O. V.; Korotkov, V. S.; Meijere, A.
Chem.sEur. J. 2009, 15, 227. (f) Liu, X.-T.; Huang, L.; Zheng, F.-J.; Zhan,
Z.-P. AdV. Synth. Catal. 2008, 350, 2778. (g) Martin, R.; Larsen, C. H.;
Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 3379. (h) St. Cyr, D. J.;
Martin, N.; Arndtsen, B. A. Org. Lett. 2007, 9, 449. (i) Martin, R.; Rivero,
M. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079. (j)
Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004,
6, 2957. (k) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238. (l) Gilchrist,
T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491.
† Aarhus University.
‡ H. Lundbeck A/S.
(1) (a) Knorr, L. Chem. Ber. 1884, 17, 2863. (b) Paal, C. Chem. Ber.
1884, 17, 2756. (c) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474
.
(2) Recent reviews on pyrrole and furan synthesis: (a) Russel, J. S.;
Pelkey, E. T.; Yoon-Miller, S. J. P. Prog. Heterocycl. Chem. 2009, 21,
145. (b) Hou, X.-L.; Yang, Z.; Yeung, K.-S.; Wong, H. N. C. Prog.
Heterocycl. Chem. 2009, 21, 179
.
10.1021/ol1008685  2010 American Chemical Society
Published on Web 05/12/2010

materials can be obtained under mild conditions by the well-
established Glaser coupling.8 The corresponding nonsym-
metrical diynes can be obtained by the Negishi, the
Codiat-Chodkiewicz, or the Yu-Jiao protocols.9 Only a few
examples of direct pyrrole synthesis from 1,3-diynes exist
in the literature.10,11 In these cases, high temperatures and
often stoichiometric Cu salts are required, and rarely are
exceptional yields reported. Furthermore, to the best of our
knowledge, only one example of a furan synthesis from a
1,3-diyne has been reported using water as the nucleophile.
However, the use of HgO makes this a less appealing
strategy.12
In this communication, we report a Au(I)-catalyzed
hydration or hydroamination of 1,3-diynes to access 2,5-
diamidofurans and 2,5-diamidopyrroles, as well as 2,5-
disubstituted furans and 1,2,5-trisubstituted pyrroles.13-15
This protocol not only includes full atom economy but also
provides straightforward access to isotopically labeled furan
and pyrrole analogues.
Scheme 2. Regioselectivity of the First Addition Step
monoaddition providing the undesired regioselectivity (path
b).17 These substrates would lead to the nontrivial 2,5-
diamidopyrroles and 2,5-diamidofurans. Furthermore, these
products represent electron-rich pyrroles, which are usually
difficult to synthesize. Previous approaches to amidopyrroles
have exploited the direct amidation of pyrroles; however,
the yields are generally moderate.18
The double hydroamination of the dimerized ynamides was
indeed very effective and highly regioselective using
We have previously shown how the polarization of alkynes
influences the reactivity and regioselectivity of a Au(I)-
catalyzed hydroamination (Scheme 1).16 On the basis of these
19
(Ph3P)AuNTf2 as the catalyst, hence securing excellent
yields of the desired 2,5-diamidopyrroles (Table 1). A variety
of anilines were successfully applied. The position of the
substituent did not seem to change the reaction time, except
for the anilines with electron-withdrawing groups in the para-
position, which required longer reaction time for completion
(entries 3 and 4). Furthermore, utilization of an N-deuterated
aniline afforded a 3,4-dideuteropyrrole (entry 8). Both
aliphatic and aromatic substituents on the ynamides were
tolerated. Applying water instead of anilines successfully
afforded the corresponding 2,5-diamidofurans (Table 2).
Although a temperature increase is required, excellent
regioselectivity is still observed. The yields are slightly lower
due to a competing hydrolysis of the intermediate, which
Scheme 1. Regioselectivity Based on Alkyne Polarization
(10) One example in: (a) Levallo, V.; Frey, G. D.; Donnadieu, B.;
Soleilhavoup, M.; Bertrand, G. Angew. Chem., Int. Ed. 2008, 47, 5224. (b)
Matsumoto, S.; Kobayashi, T.; Ogura, K. Heterocycles 2005, 66, 319. One
example in: (c) Ackermann, L.; Born, R. Tetrahedron Lett. 2004, 45, 9541.
(d) Schulte, K. A.; Reisch, J.; Walker, H. Chem. Ber. 1965, 98, 98.
(11) Au(I)-catalyzed pyrrole synthesis from 1,5-diynes: Duan, H.;
Sengupta, S.; Petersen, J. L.; Akhmedov, N. G.; Shi, X. J. Am. Chem. Soc.
2009, 131, 12100.
observations, we expected dimerized terminal ynamides (1)
to be ideal substrates for pyrrole synthesis (Scheme 2, path
a) as they would minimize the detrimental and irreversible
(4) Recent gold-catalyzed pyrrole and furan synthesis from alkynes: (a)
Saito, A.; Konishi, T.; Hanzawa, Y. Org. Lett. 2010, 12, 372. (b) Davies,
P. W.; Martin, N. Org. Lett. 2009, 11, 2293. (c) Aponick, A.; Li, C.-Y.;
Malinge, J.; Marques, E. F. Org. Lett. 2009, 11, 4624. (d) Egi, M.; Azechi,
K.; Akai, S. Org. Lett. 2009, 11, 5002. (e) Chen, D.-D.; Hou, X.-L.; Dai,
L.-X. Tetrahedron Lett. 2009, 50, 6944. (f) Shu, X.-Z.; Liu, X.-Y.; Xiao,
H.-Q.; Ji, K.-G.; Guo, L.-N.; Liang, Y.-M. AdV. Synth. Catal. 2008, 350,
243. (g) Istrate, F. M.; Gagosz, F. Org. Lett. 2007, 9, 3181. (h) Binder,
J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151. (i) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (j) Liu, Y.; Song, F.;
Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
(12) Kost, A. N.; Shchegolev, A. A.; Terentev, P. B. J. Gen. Chem.
USSR 1962, 32, 2567.
(13) Selected gold-catalyzed hydration of alkynes: (a) Marion, N.;
Ramo´n, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448. (b) Leyva,
A.; Corma, A. J. J. Org. Chem. 2009, 74, 2067. (c) Mizushima, E.; Sato,
K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed. 2002, 41, 4563.
(14) Selected gold-catalyzed hydroaminations of alkynes: (a) Bertrand,
G.; Donnadieu, B.; Kinjo, R.; Frey, G. D.; Zeng, X. J. Am. Chem. Soc.
2009, 131, 8690. (b) Zeng, X.; Frey, G. D.; Kousar, S.; Bertrand, G.
Chem.sEur. J. 2009, 15, 3056. (c) Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che,
C.-M. Org. Lett. 2007, 9, 2645. (d) Mizushima, E.; Hayashi, T.; Tanaka,
M. Org. Lett. 2003, 5, 3349.
(5) Recent reviews on gold catalysis: (a) Fu¨rstner, A. Chem. Soc. ReV.
2009, 38, 3208. (b) Michelet, V.; Toullec, P. Y.; Geneˆt, J. P. Angew. Chem.,
Int. Ed. 2008, 47, 4268. (c) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem.
ReV. 2008, 108, 3326. (d) Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008,
108, 3239. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008,
108, 3351. (f) Skouta, R.; Li, C.-J. Tetrahedron 2008, 64, 4917.
(6) Zhang, M.; Jiang, H.-F.; Neumann, H.; Beller, M.; Dixneuf, P. H.
Angew. Chem., Int. Ed. 2009, 48, 1681.
(15) During our work, a similar approach to germoles was published:
Matsuda, T.; Kadowaki, S.; Yamaguchi, Y.; Murakami, M. Org. Lett. 2010,
12, 1056.
(16) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottla¨nder, M.;
Skrydstrup, T. Org. Lett. 2009, 11, 4208.
(7) Peng, H. M.; Zhao, J.; Li, X. AdV. Synth. Catal. 2009, 351, 1371.
(8) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. (b) Glaser, C.
Ann. Chem. Pharm. 1870, 154, 137.
(17) Recent review on ynamides: Evano, G.; Coste, A.; Jouvin, K.
Angew. Chem., Int. Ed. 2010, 49, 2840.
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Org. Lett., Vol. 12, No. 12, 2010
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Table 1. Gold-Catalyzed Synthesis of 2,5-Diamidopyrroles
Table 2. Access to 2,5-Diamidofurans via Gold Catalysis
a Isolated yield after column chromatography. b Reaction time was 1.5 h.
to DCE or THF and increasing the temperature to 60 °C
did not improve the conversion. At this temperature,
SPhosAuNTf2, (PhO)3PAuOTf, and IPrAuOTf in either
toluene or THF only showed traces of conversion. Only with
catalyst 5 in toluene at 80 °C was acceptable conversion
obtained (Table 3). However, electronic activation of the
Table 3. Synthesis of 1,2,5-Trisubstituted Pyrroles
a Isolated yields after column chromatography. b Reaction time was 1 h.
c The product was 90% deuterated, which was also the case for the starting
material.
a Isolated yields after column chromatography. Conversion of diyne in
parentheses. b Phenylhydrazine was used instead of aniline.
eliminates the free sulfonamide. Again, both aliphatic and
aromatic substituents on the ynamide were tolerated. Fur-
thermore, incorporation of 18O proved possible by application
of H218O (entry 2).
Encouraged by these results, we set out to expand the
scope to include diaryl/alkyl pyrroles; however, this proved
more difficult.20 Only 10% conversion was observed with a
5-fold increase in catalyst loading from the conditions used
for the 2,5-diamidopyrrole synthesis. Changing the solvent
diyne significantly improves the reactivity. This is exempli-
fied by entries 1 and 2, where 10.0 equiv of aniline is required
to bring the first example to comparable conversion with that
of entry 2. Unfortunately, the yield with aliphatic side chains
was low (entry 3). Interestingly, the same conditions made
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Org. Lett., Vol. 12, No. 12, 2010

it possible to synthesize a highly nitrogen-substituted pyrrole
in moderate yield (entry 4) starting from phenylhydrazine.
This method also made it possible to synthesize nonsym-
metrical furans (entries 5 and 6).
Finally, we examined the possibility of exploiting 1,3-
diynes to access pyrazoles as well. This was possible using
phenylhydrazine as the nucleophile; however, the two
regioisomers were obtained in 28% and 20% yield, respec-
tively (Scheme 3).22 Again, the alkyne polarization is lower
In contrast to the dimerized ynamides, water proved to be
a better match as a nucleophile for the diaryl/alkyl diynes.
For these hydrations, SPhosAuNTf2 was superior to
(Ph3P)AuNTf2 which was also shown by Corma et al.13b
Applying the conditions shown in Table 4, we obtained a
Scheme 3. Pyrazole Synthesis from a 1,3-Diyne
Table 4. Full Incorporation of Water Gives Access to Both
Symmetrical and Nonsymmetrical 2,5-Disubstituted Furans
than for the dimerized ynamides (1), and interestingly, in
the case of 8b, the hydrazine cyclizes in a 5-exo-dig fashion
with the alternative nitrogen nucleophile in contrast to that
obtained in the case of 6d (Table 4, entry 4).
In summary, we have discovered a novel route to 2,5-
diamidopyrroles and 2,5-diamidofurans. Furthermore, we
have shown that the same procedure can be used for the facile
synthesis of 2,5-disubstituted furans, 1,2,5-trisubstituted
pyrroles, and a pyrazole including examples of nonsym-
metrical furans, as well as deuterium and 18O-incorporation.
This approach is particularly useful as there is easy access
to the starting materials in high-yielding reactions under mild
conditions.
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foun-
dation, H. Lundbeck A/S, the OChem graduate school, and
Aarhus University.
a Isolated yields after column chromatography. b Reaction performed
with 2 mol % of catalyst.
Supporting Information Available: Experimental pro-
cedures and characterizataion data for all the prepared
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
73% isolated yield of furan 7a (entry 1). Although a 93%
conversion from 1,4-diphenylbuta-1,3-diyne was observed,
the low polarization of the alkynes led to a 16% yield of the
undesired regioisomer, which was collected as the ꢀ-hy-
droxy-R,ꢀ-unsaturated ketone (entry 1).21 However, when
increasing the polarization by introducing p-methoxy sub-
stituents on the phenyl rings, only traces of the regioisomer
were detected. Furthermore, in this case the catalyst loading
could be lowered to 2 mol % (entry 2). When the nucleophile
was changed to D2O, full incorporation of deuterium on the
3 and 4 position of the furan ring was observed (entry 3).
OL1008685
(20) The optimization table is included in the Supporting Informa-
tion.
(21) The first addition creates an enol (Scheme 2), which tautomerizes
to the ketone. This affords an electron-poor alkyne, hence directing the
second addition to the ꢀ-carbon.
(22) Several attempts using hydrazine, Boc-hydrazine, and 1,2-di-Boc-
hydrazine followed by deprotection were unsuccessful. In addition, no clean
reaction was obtained with the dimerized ynamides.
Org. Lett., Vol. 12, No. 12, 2010
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