Intramolecular hydroamination of aminoalkynes with silver-phenanthroline catalysts

Article abstract of DOI:10.1021/ol801458g

(Chemical Equation Presented) Intramolecular hydroamination of several aminoalkynes catalyzed by silver-phenanthroline complexes is reported. This catalyst system complements previous protocols by employing air- and moisture-stable complexes without compromising activity or reaction control. Some of the hydroamination products are subject to a useful aerobic oxidation. Silver-phenanthroline complexes have successfully demonstrated efficacy in the desymmetrization of a prochiral diyne.

Full text of DOI:10.1021/ol801458g

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3903-3906
Intramolecular Hydroamination of
Aminoalkynes with
Silver-Phenanthroline Catalysts
Jeffrey M. Carney, Patrick J. Donoghue, William M. Wuest, Olaf Wiest, and
Paul Helquist*
Department of Chemistry and Biochemistry and the Walther Cancer Research Center,
UniVersity of Notre Dame, Notre Dame, Indiana 46556
phelquis@nd.edu
Received June 27, 2008
ABSTRACT
Intramolecular hydroamination of several aminoalkynes catalyzed by silver-phenanthroline complexes is reported. This catalyst system
complements previous protocols by employing air- and moisture-stable complexes without compromising activity or reaction control. Some
of the hydroamination products are subject to a useful aerobic oxidation. Silver-phenanthroline complexes have successfully demonstrated
efficacy in the desymmetrization of a prochiral diyne.
Nitrogen heterocycles are important because of their
presence in a variety of biologically relevant compounds.1
Therefore, the synthesis of these heterocycles is of paramount
interest. Among the more versatile means for incorporation
of nitrogen into organic compounds is the metal-catalyzed
hydroamination reaction,2–4 with N-heterocycles arising from
intramolecular hydroamination of a carbon-carbon double
or triple bond by a tethered amine or amine derivative. The
search for appropriate metal catalysts and corresponding
ligand systems for these reactions has been the subject of
extensive research.2–7 The hydroamination of alkynes has
been reported as both an intra- and intermolecular4 reaction
proceeding in the presence of various metals, including
lanthanides,5 transition metals,6 and some alkaline earth
metals.7 The use of late transition metals as catalysts is
thought to facilitate the attack of nitrogen nucleophiles onto
unsaturated carbon moieties through activation of the double
or triple bond such that the electron-rich alkene or alkyne is
transformed into an electrophile.3a As a clear indication of
their utility, alkyne hydroaminations have been employed
as key steps in total syntheses of a number of natural
products.8
Previous processes for the catalytic hydroamination are
often limited by use of air- or moisture-sensitive catalysts
or the prohibitive cost of metal complexes. Despite the
relatively low cost of silver compared to more precious
(1) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (b) Higashio, Y.;
Shoji, T. Appl. Catal., A 2004, 260, 251.
(2) Roesky, P. W.; Mu¨ller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708,
and references therein
.
(3) (a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675. (b) Pohlki,
(7) (a) Crimmin, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem. Soc.
2005, 127, 2042. (b) Datta, S.; Roesky, P. W.; Blechert, S. Organometallics
2007, 26, 4392.
F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104. (c) Severin, R.; Doye, S. Chem.
Soc. ReV. 2007, 36, 1407
.
(4) For a review of transition-metal-catalyzed intermolecular hydroami-
(8) (a) Mujahidin, D.; Doye, S. Eur. J. Org. Chem. 2005, 2689. (b) Patil,
N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101. (c)
Trost, B. M.; Fandrick, D. R. Org. Lett. 2005, 7, 823. (d) Kno¨lker, H.-J.;
Agarwal, S. Tetrahedron Lett. 2005, 46, 1173. (e) Trost, B. M.; Tang, W.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 14785. (f) Parker, K. A.; Fokas,
D. J. Am. Chem. Soc. 2006, 71, 449.
nations, see: Nobis, M.; Driessen-Ho¨lscher, B. Angew. Chem., Int. Ed. 2001,
40, 3983
.
(5) (a) Li, Y.; Fu, P.-F.; Marks, T. J. Organometallics 1994, 13, 439.
(b) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673
(6) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935.
.
10.1021/ol801458g CCC: $40.75
Published on Web 07/29/2008
2008 American Chemical Society

metals, silver-catalyzed hydroaminations have not been as
extensively studied.9 Many types of supporting ligands may
be used in these reactions, and although 1,10-phenanthrolines
have broad utility,10 their use in hydroaminations has not
been demonstrated.11 This fact, as well as our previous
development of methods for the synthesis of functionalized
phenanthrolines,12 has prompted us to investigate the use of
this ligand class in these reactions. We wish to report the
results of these studies whereby silver-1,10-phenanthroline
complexes function as efficient and recyclable catalysts for
the intramolecular hydroamination of aminoalkynes.
The efficacy of the parent 1,10-phenanthroline as a ligand
in the hydroamination of 5-phenyl-4-pentyn-1-amine (1a)
was initially tested in a brief qualitative screening of several
metal catalyst candidates, including Ni, Yb, Sm, Ti, Cu, Au,
and Ag. These preliminary experiments found that there was
a metal dependence of whether the imine 2a or the isomeric
enamine 3a was obtained as the major product (Scheme 1).
With this knowledge, we attempted a more quantitative
screening of selected metal catalysts in the hydroamination
of 1a (Table 1). The advantage of silver-phenanthroline
Table 1. Screening of Metal-Phenanthroline Complexes
entry
catalyst
AgOTf
Ag(phen)OTf
Ag(phen)OTf
Ag(phen)OTf
Ag(phen)OTf
Pd(acac)2
mol % time (h) temp (°C) % yielda
1
2
3
4b
5
6
7
8
9
10
10
4
4
1
10
15
10
10
4
4
4
4
4
70
70
70
70
70
100
100
25
55
95
82
84
71
0d
c
Pd(phen)(acac)2
NaAuCl4
Au(phen)Cl2NO3
6
4
4
69
46
59
25
a Yields were calculated from 1H NMR spectra using mesitylene as an
internal standard. b Result from catalyst that was collected by filtration after
reaction in entry 3, washed with CH2Cl2, and reused. c Reactions run in
d6-dimethyl-sulfoxide. d In the absence of supporting ligand, Pd(acac)2
formed Pd black and did not catalyze the cyclization.
Scheme 1. Initial Metal-Catalyzed Hydroamination Screening
(phen) complexes over the naked silver salt was demonstrated
with the increase in yield of 2a (entry 1 vs entry 2, Table
1). In palladium-catalyzed reactions, the benefit of phenan-
throline was seen in its ability to stabilize the metal in the
This initial screening found that both Ag and Pd favored
formation of 2a, whereas Yb, Sm, and Ni preferentially gave
tautomeric enamine 3a (data not shown). For purposes of
this study, we chose to focus on the use of those metals that
led to selective formation of cyclic imines as highly versatile
products.
reaction mixture (entry
6 vs entry 7, Table 1).
Au(phen)Cl2NO3 provided good reactivity in the intramo-
lecular hydroamination (reactions proceeded at 25 °C), but
the yield of 2a was lower than for the other two metals
studied (entries 8 and 9). Enamine 3a was not observed in
any of the reactions in Table 1.
(9) (a) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4253.
(b) Koseki, Y.; Kusano, S.; Nagasaka, T. Tetrahedron Lett. 1998, 39, 3517.
(c) Mu¨ller, T. E.; Grosche, M.; Herdtweck, E.; Pleier, A.-K.; Walter, E.;
Yan, Y.-K. Organometallics 2000, 19, 170. (d) Robinson, R. S.; Dovey,
M. C.; Gravestock, D. Tetrahedron Lett. 2004, 45, 6787. (e) van Esseveldt,
B. C. J.; Vervoort, P. W. H.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org.
Chem. 2005, 70, 1791. (f) Luo, Y.; Li, Z.; Li, C.-J. Org. Lett. 2005, 7,
2675. (g) Robinson, R. S.; Dovey, M. C.; Gravestock, D. Eur. J. Org. Chem.
2005, 505. (h) Sun, J.; Kozmin, S. A. Angew. Chem., Int. Ed. 2006, 45,
4991. (i) Harrison, T. J.; Kozak, J. A.; Corbella-Pane´, M.; Dake, G. R. J.
Org. Chem. 2006, 71, 4525. (j) Lingaiah, N.; Babu, N. S.; Reddy, K. M.;
Prasad, P. S. S.; Suryanarayana, I. Chem. Commun. 2007, 278. (k) Prior,
A. M.; Robinson, R. S. Tetrahedron Lett. 2008, 49, 411. (l) Ding, Q.; Yu,
X.; Wu, J. Tetrahedron Lett. 2008, 49, 2752.
Overall, silver complexes provided 2a in higher yields than
either palladium or gold. There were also other benefits to
the Ag(phen)-based catalysts that led us to choose silver as
the catalyst for further studies. The reactions run in aceto-
nitrile using phenanthroline complexes were heterogeneous
at 25 °C but became homogeneous above 35 °C. After the
reaction mixture was cooled, the phenanthroline complex
could be recovered by filtration, whereas AgOTf could not
be recycled as readily because of its solubility at 25 °C. No
loss of activity was observed in a second run (entry 4, Table
1), and Ag(phen)OTf was also active using a catalyst loading
as low as one mole percent (entry 5, Table 1), but the rate
was too slow for the reaction to go to completion under
the normal conditions. In addition to its recyclability, the
silver-phenanthroline complex was air- and moisture-stable
(10) (a) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994,
33, 497. (b) Pallenberg, A. J.; Marschner, T. M.; Barnhart, D. M. Polyhedron
1997, 16, 2711. (c) Chelucci, G.; Thummel, R. P. Chem. ReV. 2002, 102,
3129. (d) Schoffers, E. Eur. J. Org. Chem. 2003, 1145. (e) Luman, C. R.;
Castellano, F. N. Phenanthroline Ligands. In ComprehensiVe Coordination
Chemistry II; McCleverty, J. A., Meyer, T. J., Eds.; Elsevier: Oxford, 2004;
Vol. 1, pp 25-39.
(11) For some examples of phenanthroline-based ligands in other
cyclization reactions, see: (a) Zhang, Q.; Lu, X.; Han, X. J. Org. Chem.
2001, 66, 7676. (b) Ragaini, F.; Rapetti, A.; Visentin, E.; Monzani, M.;
Caselli, A.; Cenini, S. J. Org. Chem. 2006, 71, 3748. (c) 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. For an example of a silver-phenanthroline C-H amination, see:
(d) Li, Z.; Capretto, D. A.; Rahaman, R.; He, C. Angew. Chem., Int. Ed.
2007, 46, 5184.
(12) (a) O’Neill, D. J.; Helquist, P. Org. Lett. 1999, 1, 1659. (b)
Weitgenant, J. A.; Mortison, J. D.; O’Neill, D. J.; Mowery, B.; Puranen,
A.; Helquist, P. J. Org. Chem. 2004, 69, 2809. (c) Weitgenant, J. A.;
Mortison, J. D.; Helquist, P. Org. Lett. 2005, 7, 3609. (d) Plummer, J. M.;
Weitgenant, J. A.; Noll, B. C.; Lauher, J. W.; Wiest, O.; Helquist, P. J.
Org. Chem. 2008, 73, 3911.
3904
Org. Lett., Vol. 10, No. 17, 2008

for at least 6 months after preparation,13 a benefit over other
catalysts for which strict anhydrous and anaerobic conditions
are necessary.
obtained when the reaction times were extended (Scheme
2).14 Although this oxidation occurred readily for the
Complexes of silver-1,10-phenanthroline and silver-2,9-
dimethyl-1,10-phenanthroline (neocuproine, dmp) were syn-
thesized by reaction of the ligands with silver triflate, and
these catalysts were studied in the hydroamination of a series
of primary aminoalkynes (Table 2). These reactions were
Scheme 2. Hydroamination and Facile Benzylic Oxidation
Table 2. Silver-Catalyzed Hydroamination of Aminoalkynes
2-benzylpyrroline 2a, it was not observed for the corre-
sponding 2-benzyltetrahydropyridine 2b or for the non-benzyl
substituted products 2c-e. In previous work, imines similar
to 2a have been formed under Ag-catalyzed conditions, but
detection of compounds analogous to 4 were not discussed.9e
Hydroamination of the alkynes above leads to imine
products that lack chirality. To demonstrate that such
reactions could potentially generate chiral products,15 we
have done a preliminary study of a desymmetrization of a
prochiral diyne 5, using an achiral catalyst prior to future
efforts to develop appropriate chiral catalysts. The substrate
5 was synthesized as shown in Scheme 3. Under the
entry
substrate
R′
time (h)
product
% yielda
1
2
3
4
5
6
1a
1a
1b
1c
1d
1e
H
CH3
H
CH3
CH3
CH3
4
6
6
4
5
2a
2a
2b
2c
2d
2e
95 (87)
95
77 (70)
95
78
90
10
Scheme 3. Synthesis of Prochiral Diyne 5
a Yields were calculated from 1H NMR spectra using mesitylene as an
internal standard. Isolated yields shown in parentheses where applicable.
carefully monitored to minimize reaction times. A catalyst
loading of 10 mol % was standardized, despite the demon-
stration of the potential for lower loadings, because this
loading allowed for the complete conversion of starting
material within a reasonable reaction time. Replacement of
phenanthroline with neocuproine showed no effect on
activity, thus demonstrating tolerance for substitution at the
2 and 9 positions of the phenanthroline scaffold.
In general, 5-aminopentyne derivatives cyclized more
efficiently than their 6-aminohexyne counterparts (entries 1,
2, and 4 as compared to entries 3 and 5, Table 2). The
catalysts were effective in the cyclization of terminal and
disubstituted alkynes, including an unactivated methyl
substituted alkyne (entry 6). Because of its volatility,
2-methyl-1-pyrroline (2c) was isolated as its N-methyl
pyrrolinium derivative by reaction with iodomethane in
acetonitrile.
conditions optimized for the simple aminoalkynes, 5 was
cyclized to form the racemic but desymmetrized cyclic imine
6. Interestingly, it was found that the prochiral diyne
underwent cyclization under much milder conditions than
the previous alkynes. When Ag(phen)OTf and Ag(dmp)OTf
complexes were used to catalyze this reaction, a temperature
(15) (a) Kadota, I.; Shibuya, A.; Lutete, L. M.; Yamamoto, Y. J. Org.
Chem. 1999, 64, 4570. (b) Lutete, L.; Kadota, I.; Yamamoto, Y. J. Am.
Chem. Soc. 2004, 126, 1622. (c) Bajracharya, G. B.; Huo, Z.; Yamamoto,
Y. J. Org. Chem. 2005, 70, 4883. (d) Patil, N. T.; Lutete, L. M.; Wu, H.;
Pahadi, N. K.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 4270.
(16) For examples of desymmetrization in hydroamination reactions, see:
(a) Lebeuf, R.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2006, 8, 4755.
(b) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 4253. For
examples of desymmetrization in other cyclization reactions, see: (c)
Goumans, T. P. M.; Ehlers, A. W.; Lammertsma, K. Organometallics 2005,
24, 3200. (d) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005,
7, 4553. (e) Antoniotti, S.; Genin, E.; Michelet, V.; Geneˆt, J.-P. J. Am.
Chem. Soc. 2005, 127, 9976. (f) Lertpibulpanya, D.; Marsden, S. P.;
Rodriguez-Garcia, I.; Kilner, C. A. Angew. Chem., Int. Ed. 2006, 45, 5000.
(g) Messerle, B. A.; Vuong, K. Q. Organometallics 2007, 26, 3031.
In addition to the desired imine product 2a, a useful
product of oxidation, 2-benzoyl-1-pyrroline (4), could be
(13) The catalyst was stored at 25 °C in the dark with no precautions to
avoid exposure to air.
(14) Although the hydroamination reactions were initially set up under
argon, no rigorous measures were taken to exclude adventitious oxygen
during the long reaction times. For a similar oxidation of a benzylic imine,
see: Kim, S.; Lee, Y. M.; Lee, J.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.; Kim,
D. J. Org. Chem. 2007, 72, 4886. For comparison of spectroscopic data of
4, see: Schieberle, P. J. Agric. Food Chem. 1995, 43, 2442. In a similar
Pd-catalyzed reaction, a byproduct of identical molecular weight was also
observed; however, it was thought to be PhCC(CH2)3NO. Richmond, M. K.;
Scott, S. L.; Yap, G. P. A.; Alper, H. Organometallics 2002, 21, 3395.
Org. Lett., Vol. 10, No. 17, 2008
3905

of 35 °C was found to be adequate for formation of imine 6
(Table 3). Reactions using these catalysts in d6-DMSO
allowed for shorter reaction times when compared to those
in d3-acetonitrile.
Scheme 4. Further Elaboration of Diyne 5
Table 3. Desymmetrization of Prochiral Diyne 5
catalysta
solvent
temp (°C)
time (h)
% yieldb
Ag(phen)OTf
Ag(phen)OTf
Ag(dmp)OTf
Ag(dmp)OTf
CD3CN
CD3CN
CD3CN
(CD3)2SO
70
35
35
35
4
2
4
2
72
67 (48)
67
catalytic alkyne hydroamination with an alternative to
sensitive or cost-prohibitive catalysts. Studies of secondary
amines in these reactions and of the enantioselective desym-
metrization of prochiral diynes and related dienes by
employing chiral ligand complexes are currently underway
and will be reported in due course.
67
a phen ) 1,10-phenanthroline; dmp ) 2,9-dimethyl-1,10-phenanthroline.
b Yields were calculated from 1H NMR spectra using mesitylene as an
internal standard. Isolated yields shown in parentheses where applicable.
A consequence of the initial formation of an imine 6 is
the differentiation of the identical alkynes in diyne 5.16
Fundamentally distinct reactions are applicable to the now
different functional groups in imine 6. As was the case with
pyrroline 2a, extended heating of the reaction mixture results
in the conversion of pyrroline 6 to the corresponding
R-ketoimine 7 (Scheme 4). This facile oxidation allows for
complex functionality to be obtained in one step. In turn,
the remaining alkyne can be employed in reactions typical
of this group, such as Lindlar hydrogenation to give cis-
alkene 8 (Scheme 4).
In conclusion, silver-phenanthroline complexes have been
shown to be effective catalysts for the intramolecular
hydroamination of a variety of primary aminoalkynes. In
addition to being air- and moisture-stable, the complexes are
readily recyclable. These complexes provide the field of
Acknowledgment. The authors would like to acknowledge
the members of CHEM 248 L laboratory course during the
Spring of 2004 for their participation in the initial metal-
phenanthroline catalyst screening. We would also like to
thank the Walther Cancer Research Center, Proctor &
Gamble, a Wolff and a Podrasnak Fellowship for financial
support for J.M.C. and the Schmitt Foundation for financial
support of P.J.D.
Supporting Information Available: Experimental details
for all reactions and characterization data for compounds
2a-e and 4-8. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL801458G
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Org. Lett., Vol. 10, No. 17, 2008