Chemoselective allene aziridination via Ag(I) catalysis

Article abstract of DOI:10.1021/ol303167n

Allene aziridination generates useful bicyclic methylene aziridine scaffolds that can be flexibly transformed into a range of stereochemically complex and densely functionalized amine-containing stereotriads. The scope of this chemistry has been limited by the poor chemoselectivity that often results when typical dinuclear Rh(II) catalysts are employed with homoallenic carbamates. Herein, Ag(I) catalysts that significantly improve the scope and yield of bicyclic methylene aziridines that can be prepared via allene aziridination are described.

Full text of DOI:10.1021/ol303167n

ORGANIC
LETTERS
2013
Vol. 15, No. 2
290–293
Chemoselective Allene Aziridination via
Ag(I) Catalysis
Jared W. Rigoli, Cale D. Weatherly, Brian T. Vo, Samuel Neale, Alan R. Meis, and
Jennifer M. Schomaker*
Department of Chemistry, University of Wisconsin;Madison, Madison, Wisconsin 53706,
United States
schomakerj@chem.wisc.edu
Received November 16, 2012
ABSTRACT
Allene aziridination generates useful bicyclic methylene aziridine scaffolds that can be flexibly transformed into a range of stereochemically
complex and densely functionalized amine-containing stereotriads. The scope of this chemistry has been limited by the poor chemoselectivity
that often results when typical dinuclear Rh(II) catalysts are employed with homoallenic carbamates. Herein, Ag(I) catalysts that significantly
improve the scope and yield of bicyclic methylene aziridines that can be prepared via allene aziridination are described.
The chemoselective amination of unsaturated com-
pounds can be a challenging endeavor. In the case of
alkene amination, the aziridination of a π-bond is often
Scheme 1. Rh-Catalyzed Amination of Homoallenic
Carbamates
favored over competing amination of an allylic CꢀH
bond.1,2 However, our recentstudies in allene aziridination
have uncovered several examples where the chemoselec-
tivity of the reaction depends more heavily on the structur-
al features of the allene than we had expected.1 As typical
Rh-based catalysts did not permit successful tuning of the
selectivity of allene amination, we needed an alternative
catalyst system that would favor aziridination over CꢀH
insertion (Scheme 1).
Bicyclic methylene aziridines 2a and 2b and allenic
amines 3 (Scheme 1, Figure 1) are valuable intermedi-
ates for the preparation of complex amine-containing
(1) (a) Adams, C. S.; Boralsky, L. A.; Guzei, I. A.; Schomaker, J. M.
J. Am. Chem. Soc. 2012, 134, 10807. (b) Boralsky, L. A.; Marston, D.;
Grigg, R. D.; Hershberger, J. C.; Schomaker, J. M. Org. Lett. 2011, 13,
stereotriads, tetrads, and heterocycles.1 In our previous
1924. (c) Weatherly, C. D.; Rigoli, J. W.; Schomaker, J. M. Org. Lett.
2012, 14, 1704. (d) Rigoli, J. W.; Boralsky, L. A.; Hershberger, J. C.;
Marston, D.; Meis, A. R.; Guzei, I. A.; Schomaker, J. M. J. Org. Chem.
2012, 77, 2446. (e) Grigg, R. D.; Schomaker, J. M.; Timokhin, V.
Tetrahedron 2011, 67, 4318.
(2) For selected references on Rh-catalyzed amination, see: (a)
Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598. (b)
Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc.
2001, 123, 6935. (c) Padwa, A.; Flick, A. C.; Leverett, C. A.; Stengel, T. J.
Org. Chem. 2004, 69, 6377. (d) Espino, C. G.; Fiori, K. W.; Kim, M.; Du
Bois, J. J. Am. Chem. Soc. 2004, 126, 15378. (e) Fiori, K. W.; Du Bois, J.
J. Am. Chem. Soc. 2007, 129, 562.
studies, we have described the treatment of homoallenic
carbamates 1 with tetra-bridged dirhodium(II) carboxy-
late complexes to promote the formation of 2a and 2b as
the major products.1aꢀd However, good chemoselectivity
was reliant on the specific substitution of the allene and the
presence or absence of branching in the tether.1e Compet-
ing CꢀH insertion to yield 3 was exacerbated when the
allene was trisubstituted or branching in the tether between
r
10.1021/ol303167n
Published on Web 12/24/2012
2012 American Chemical Society

Several transition metals, including Rh, Cu, Ru, Fe, Co,
Au, and Ag, are known to promote CꢀN bond formation
via presumed nitrene intermediates (Figure 2).2ꢀ8 Recent
studies have shown that changing the identity of the metal
in the catalyst can control whether predominantly aziridi-
nation or CꢀH amination is observed when both CꢀH
and π-bonds are present.9,10 We focused on two substrates
4a and 4b that gave poor chemoselectivity in Rh-catalyzed
aziridination. Treatment of 4a with Rh2(esp)2 (esp = R,R,
R0,R0-tetramethyl-1,3-benzene-dipropionic acid, Table 1,
entry 1) gave only a 35% yield of 5a and significant CꢀH
insertion to 6a. Rh2(espn)2Cl (entry 2) performed better,
yet further attempts to improve the chemoselectivity by
changing the nature of the carboxylate ligands on the Rh
were unsuccessful.11 A series of Cu catalysts gave poor
reactivity, and attempts to isolate the iodinane prior to
amination were unsuccessful (see Supporting Information
for details). However, Cu(MeCN)4PF6 (entry 5) could be
induced to give low yields of amination products by
premixing 4a with PhIO before the addition of catalyst.12
However, this did not improve the results using Ru- and
Fe-based catalysts, even when 20 mol % of the metal was
employed (entries 6ꢀ7).3c,4a,5e While treatment of 4a with
AgOTf in the presence of PhIO gave very little 5a (entry 8),
the addition of dafone (4,5-diazafluoren-9-one, entry 9)
improved the conversion and, encouragingly, yielded
>20:1 chemoselectivity for aziridination over CꢀH inser-
tion. A series of bipyridine (bipy) ligands (entries 10ꢀ12)
also gave excellent chemoselectivity for aziridination with
good yields.8aꢀd Phen (entry 13) increased the yield to
79%, but the additional bulk in bathophen (entry 14) was
not necessary. To our surprise, switching to a terpyridine
ligand (terpy, entry 15) reversed the chemoselectivity
in favor of 6a.8a Interestingly, the nature of the Ag
Figure 1. Synthetic utility of bicyclic methylene aziridines and
potential natural product targets.
the allene and the nitrogen source was present.1e Efforts to
improve chemoselectivity by tuning Rh-based catalysts via
the ligand were disappointing. Thus, we needed to identify
another catalyst system capable of delivering predictable
and superior selectivity for allene aziridination, indepen-
dent of substrate structure.
(4) Harvey, M. E.; Musaev, D. G.; Du Bois, J. J. Am. Chem. Soc.
2011, 133, 17207 and references therein.
(5) For selected references on Fe-catalyzed amination, see: (a) Jung,
€
N.; Brase, S. Angew. Chem., Int. Ed. 2012, 51, 5538. (b) Cramer, S. A.;
Jenkins, D. M. J. Am. Chem. Soc. 2011, 133, 19342. (c) Klotz, K. L.;
Slominski, L. M.; Riemer, M. E.; Phillips, J. A.; Halfen, J. A. Inorg.
Chem. 2009, 48, 801. (d) Mahy, J.; Battioni, P.; Mansuy, D. J. Am. Chem.
Soc. 1986, 108, 1079. (e) Paradine, S. M.; White, M. C. J. Am. Chem. Soc.
2012, 134, 2036.
(6) Gao, G.; Harden, J. D.; Zhang, X. P. Org. Lett. 2005, 7, 3191.
(7) Li, Z.; Ding, X.; He, C. J. Org. Chem. 2006, 71, 5876.
(8) For selected references on Ag-catalyzed amination, see: (a) Cui,
Y.; He, C. J. Am. Chem. Soc. 2003, 125, 16202. (b) Cui, Y.; He, C. Angew.
Chem., Int. Ed. 2004, 43, 4210. (c) Li, Z.; Capretto, D. A.; Rahaman,
R. H.; He, C. Angew. Chem., Int. Ed. 2007, 46, 5184. (d) Li, Z.; He, C.
Eur. J. Org. Chem. 2006, 19, 4313. (e) Kumar, K. A.; Rai, L. K. M.;
Umesha, K. B. Tetrahedron Lett. 2001, 57, 6993. (f) Minakaa, S.; Kano,
D.; Fukuoka, R.; Oderaotoshi, Y.; Komatsu, M. Heterocycles 2003, 60,
289. (g) Gomez-Emeterio, B. P.; Urbano, J.; Diaz-Requejo, M. M.;
ꢀ
Perez, P. J. Organometallics 2008, 27, 4126. (h) Llaveria, J.; Beltran, A.;
ꢀ
Mar Dıaz-Requejo, M.; Matheu, M. I.; Castillon, S.; Perez, P. J. Angew.
ꢀ
Figure 2. Catalysts for chemoselective allene amination.
Chem., Int. Ed. 2010, 122, 7246.
(9) For selected examples of tuning the chemoselectivity of amination
using Rh and Ru catalysis, see: (a) Hayes, C. J.; Beavis, P. W.;
Humphries, L. A. Chem. Commun. 2006, 4501. (b) Fiori, K. W.; Du
Bois, J. J. Am. Chem. Soc. 2007, 129, 562. (c) Kornecki, K. P.; Berry, J. F.
Eur. J. Inorg. Chem. 2012, 3, 562.
(10) Control of chemoselectivity in carbene chemistry is well-devel-
oped. (a) Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857.
(b) Nadeau, E.; Ventura, D. L.; Brekan, J. A.; Davies, H. M. L. J. Org.
Chem. 2010, 75, 1927.
(3) For selected references on Cu-catalyzed amination, see: (a)
Nakanishi, M.; Salit, A.; Bolm, C. Adv. Synth. Catal. 2008, 350, 1835.
(b) Han, H.; Park, S. B.; Kim, S. K.; Chang, S. J. Org. Chem. 2008, 73,
2862. (c) Duran, F.; Leman, L.; Ghini, A.; Burton, G.; Dauban, P.;
Dodd, R. H. Org. Lett. 2002, 4, 2481. (d) Lebel, H.; Lectard, S.;
Parmentier, M. Org. Lett. 2007, 9, 4797. (e) Liu, R. M.; Herron, S. R.;
Fleming, S. A. J. Org. Chem. 2007, 72, 5587. (f) Gephart, R. T.; Warren,
T. H. Organometallics 2012, 31, 7728.
(11) Kornecki, K. P.; Berry, J. F. Chem. Commun. 2012, 48, 12097.
(12) We thank a reviewer for this suggestion.
Org. Lett., Vol. 15, No. 2, 2013
291

Table 1. Investigation of Catalysts for Chemoselective Allene
Amination Reactions
Table 2. Aziridination of R,R-Disubstituted Allene Carbamates
a Rh: 5 mol % catalyst, 2.0 equiv of PhIO, CH2Cl2, rt. Cu, Ru, Fe:
20 mol % catalyst, 2.0 equiv of PhIO, rt. Ag: 20 mol % AgOTf, 25 mol %
ligand, 4 A MS, 2.0 equiv of PhIO, CH2Cl2. b A = aziridination 5a,5b;
˚
I = insertion 6a,b. c NMR yields using mesitylene as the internal
standard. d 4a and PhIO were mixed for 1 h prior to adding the catalyst.
e Significant decomposition of the carbamate occurred. f 45% conver-
sion. g 60% conversion.
counteranion also had a significant impact on the reac-
tion. Substitution of AgOTf with AgOAc (entry 16) or
AgO2CCF3 (entry 17) gave almost exclusively CꢀH inser-
tion 6a, although the reactivity of the catalyst was dimin-
ished, as these anions can bind tightly to the metal.
The allenic carbamate 4b was also a challenging sub-
strate for aziridination. When Rh2(esp)2 was employed as
the catalyst, an 80% yield of 6b was obtained (entry 18),1e
highlighting the impact of substrate structure on the
chemoselectivity of Rh-catalyzed CꢀN bond formation.
Neither Rh2(espn)2 (entry 19) nor Cu-, Fe-, or Ru-based
catalysts (entries 20ꢀ22) improved the outcome. However,
employing a dafone ligand in the presence of AgOTf
(entry 24) reversed the chemoselectivity to 2.7:1 in favor
of aziridination. Bipyridine ligands (entries 25ꢀ27) im-
proved the chemoselectivity further, resulting in good
yields of the aziridine 5b and A:I selectivities ranging from
3.1:1 to 6.4:1. Phen and bathophen (entries 28ꢀ29) gave
comparable yields, in contrast to the aziridination of the
more sterically demanding 4a (entries 13ꢀ14). As in the
case of 4a, a 2,20:60,200-terpyridine ligand (entry 30) resulted
inareversalof thechemoselectivity, providing a5b:6bratio
of 1:6.6. To our knowledge, these results represent the first
examples of reagent-controlled amination of unsaturated
substrates with Ag(I) catalysis.
a
˚
Rh conditions: 3 mol % catalyst, 2 equiv of PhIO, 4 A MS, CH2Cl2,
rt. b Reaction conditions: 20 mol % AgOTf, 25 mol % ligand, 2 equiv of
˚
PhIO, 4 A MS, CH2Cl2, rt.
using Rh2TPA4 (TPA = triphenylacetate). Interestingly,
the E:Z ratio was not greatly affected by the nature of the
catalyst. AgOTf/phen also performed on par with Rh
when a 1,3,3-trisubstituted homoallenic carbamate was
employed (entry 2), and other 1,3-disubstituted allene
carbamates (entries 3ꢀ4, 8) gave good to excellent yields
ofthe methylene aziridines8c, 8d, and 8h. The presence of a
polar carboxyethyl group in 7h (entry 8) resulted in very
different behavior depending on whether a Rh- or Ag-
based catalyst was employed. While Ag gave the E methy-
lene aziridine as the expected stereoisomer, Rh2(esp)2
unexpectedly yielded the Z isomer as the major product.
In addition to the 1,3,3-trisubstituted homoallenic
carbamate 7b, other highly substituted allenes bearing
A series of allenes containing R,R-dimethyl groups
(Table 2) were investigated with Ag(I) catalysts as an
attractive alternative to Rh catalysts. Gratifyingly, treat-
ment of 7a with AgOTf/phen gave an excellent yield of 8a
(entry 1), which compared well with our previous results
292
Org. Lett., Vol. 15, No. 2, 2013

dramatic in the case of 4b, with a change in the A:I ratio of
1:17 to 5.9:1 (entry 4). Surprisingly, the 1,3,3-trisubstituted
allene carbamates 5a and 8lꢀm (entries 5ꢀ7) exhibited
much greater chemoselectivity for aziridination using
AgOTf/phen catalysts compared to conventional Rh cat-
alysts. This was counterintuitive, as we expected the in-
creased steric congestion around the allene to favor more
of the CꢀH insertion product. The ability to prepare such
highly substituted bicyclic methylene aziridines represents
a valuable step forward in our ability to prepare densely
functionalized and complex nitrogen-containing stereo-
triads using these reactive scaffolds (Figure 1).
Table 3. Chemoselective Aziridination of Homoallenic
Carbamates Using Ag(I) Catalysis
In conclusion, we have demonstrated that the scope and
utility of allene aziridination can be greatly increased by
employing readily available and tunable Ag(I)-based cat-
alysts. These complexes promote aziridination with super-
ior chemoselectivity over conventional Rh-based catalysts,
and the resultant bicyclic methylene aziridines are being
studied as scaffolds for the synthesis of complex amines.
However, the reasons for the high chemoselectivity exhib-
ited by Ag(I) catalysts compared to Rh2(L)n are not yet
clear.13 One major difference between the two systems is
that Rh2(L)n complexes adopt only paddlewheel or
“lantern-type” geometries, while Ag(I) complexes can adopt
a variety of coordination geometries depending on the
ligand, solvent, counteranion, and concentration of the
reaction.3aꢀc,14,15 Studies to address our hypothesis that the
coordination geometry of the Ag catalyst impacts chemo-
selectivity are underway and will be reported in due course.
Acknowledgment. Funding was provided by the Uni-
versity of Wisconsin;Madison. We thank Professor John
Berry of the University of Wisconsin;Madison for a sample
of Rh2(espn)2. The NMR facilities at UW;Madison are
funded by the NSF (CHE-9208463, CHE-9629688) and
NIH (RR08389-01).
a
˚
Rh conditions: 3 mol % catalyst, 2 equiv of PhIO, 4 A MS, CH2Cl2,
rt. b Reaction conditions: 20 mol % AgOTf, 25 mol % ligand, 2 equiv of
PhIO, 4 A MS, CH2Cl2, rt. c A = aziridination; I = insertion. d 73%
˚
conversion. e dr E = 1:1; dr Z = 3:1.
Supporting Information Available. Experimental pro-
cedures and full characterizations are available for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
R,R-dimethyl branching (entries 5ꢀ7) gave good yields of
methylene aziridines 8eꢀg.
The next challenge for Ag(I)-based catalysts was to
explore the chemoselectivity of amination in substrates
where CꢀH insertion was a competing process (Table 3).
When 1,3-disubstituted allenes 7i and 7j were employed
(entries 1ꢀ2), AgOTf in the presence of bipyridine and
phenanthroline ligands gave comparable to slightly im-
proved yields of bicyclic methylene aziridines. The benefit
of substituting Ag catalysts for Rh became apparent when
substitution was present in the tether between the allene
and the carbamate (entries 3ꢀ4). AgOTf/phen increased
the aziridination/insertion (A:I) ratio from 1:1 to 9:1 in the
amination of 7k to 8k (entry 3). This effect was even more
(14) For selected references illustrating the coordination geometries
that can be adopted by Ag(I) complexes, see: (a) Hung-Low, F.; Renz,
A.; Klausmeyer, K. K. Polyhedron 2009, 28, 407. (b) Hung-Low, F.;
Renz, A.; Klausmeyer, K. K. J. Chem. Crystallogr. 2011, 41, 1174. (c)
Du, J.; Hu, T.; Zhang, S.; Zeng, Y.; Bu, X. CrystEngComm 2008, 10,
1866. (d) Zhang, H.; Chen, L.; Song, H.; Zi, G. Inorg. Chim. Acta 2011,
366, 320. (e) Xiong, K.; Wu, M.; Zhang, Q.; Wei, W.; Yang, M.; Jiang,
F.; Hong, M. Chem. Commun. 2009, 1840. (f) Hung-Low, F.; Renz, A.;
Klausmeyer, K. K. J. Chem. Cryst. 2009, 39, 438. (g) Schultheiss, N.;
Powell, D. R.; Bosch, E. Inorg. Chem. 2003, 42, 5304. (h) Levason, W.;
Spicer, M. D. Coord. Chem. Rev. 1987, 75, 45. (i) Silver in Organic
Chemistry; Harmata, M., Ed.; John Wiley & Sons: Hoboken, NJ, 2010. (j)
Ma, Z.; Xing, Y.; Yang, M.; Hu, M.; Liu, B.; Guedes de Silva, M. F. C.;
Pombeiro, A. J. L. Inorg. Chim. Acta 2009, 362, 2921. (k) Hou, L.; Dan, L.
Inorg. Chem. Commun. 2005, 8, 128.
(15) Evidence for a dinuclear Cu complex containing a bridging
nitrene: Badiei, Y. M.; Krishnaswamy, A.; Melzer, M. M.; Warren,
T. H. J. Am. Chem. Soc. 2006, 128, 15056.
(13) Ag(I) catalysts have been shown to cyclopropanate sterically
congested olefins in contrast to Rh(II) catalysts: Thompson, J. L.;
Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 6090.
The authors declare no competing financial interest.
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