Copper-catalyzed amination of silyl ketene acetals with N-chloroamines

Article abstract of DOI:10.1021/ol302331k

A copper(I)/2,2′-bipyridyl complex catalyzes an amination reaction of silyl ketene acetals with N-chloroamines, presenting a new preparative method of α-amino esters.

Full text of DOI:10.1021/ol302331k

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5214–5217
Copper-Catalyzed Amination of Silyl
Ketene Acetals with N‑Chloroamines
Tomoya Miura,* Masao Morimoto, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University,
Katsura, Kyoto 615-8510, Japan
tmiura@sbchem.kyoto-u.ac.jp; murakami@sbchem.kyoto-u.ac.jp
Received August 21, 2012
ABSTRACT
A copper(I)/2,20-bipyridyl complex catalyzes an amination reaction of silyl ketene acetals with N-chloroamines, presenting a new preparative
method of R-amino esters.
Amines intrinsically possess a nucleophilic property.
Their nucleophilic substitution reactions present con-
ventional preparative methods of substituted amines.
Transition-metal-catalyzed cross-coupling reactions of
aryl halides with amines are also powerful methods for
the formation of CꢀN bonds.1 An alternative pathway to
substituted amines has recently become available by the
use of electrophilic amination reagents together with nu-
cleophilic organometallic species.2 For example, Johnson
and co-workers have reported their pioneering research
on copper- and nickel-catalyzed amination reactions of
diarylzinc compounds using N-hydroxyl(dialkyl)amine
derivatives as the amination reagent.2e,f N-Chloroamines
are also promising amination reagents with their easy
availability3 as well as high reactivity.4 Jarvo and co-
worker reported a nickel-catalyzed amination reaction of
diarylzinc compounds with N-chloro(dialkyl)amines,
which formed tertiary anilines.2k Similarly, secondary ani-
lines are produced by the reaction of in situ-generated
N-chloro(monoalkyl)amines with arylmagnesium reagents
in the presence of an excess amount of titanium(IV)
isopropoxide.2l,5 Furthermore, transition-metal-catalyzed
direct CꢀH amination reactions of aromatic compounds
with N-chloro(dialkyl)amines have been developed by
Miura,6 Yu,7 and Glorius.8,9 It is also possible to intro-
duce an amino group at the R-positions of carbonyl
compounds by the reaction of their lithium enolates with
N-chloroamines,10,11 although the substrate scope is lim-
ited probably due to the strongly basic reaction conditions
(1) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (b) Tasler, S.; Lipshutz, B. H. J. Org. Chem. 2003, 68,
1190. (c) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (d) Qiao, J. X.;
Lam, P. Y. S. Synthesis 2011, 829. (e) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2011, 2, 27.
(2) For reviews on transition-metal-catalyzed reactions of organo-
metallic reagents with electrophilic nitrogen sources, see: (a) Narasaka,
K.; Kitamura, M. Eur. J. Org. Chem. 2005, 4505. (b) Barker, T. J.; Jarvo,
E. R. Synthesis 2011, 3954. For recent examples, see: (c) Tsutsui, H.;
Hayashi, Y.; Narasaka, K. Chem. Lett. 1997, 317. (d) Erdik, E.;
Daskapan, T. J. Chem. Soc., Perkin Trans. 1 1999, 3139. (e) Berman,
A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680. (f) Berman,
A. M.; Johnson, J. S. Synlett 2005, 1799. (g) Liu, S.; Yu, Y.; Liebeskind,
L. S. Org. Lett. 2007, 9, 1947. (h) He, C.; Chen, C.; Cheng, J.; Liu, C.;
Liu, W.; Li, Q.; Lei, A. Angew. Chem., Int. Ed. 2008, 47, 6414. (i) Liu, S.;
Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (j) Zhang, Z.; Yu,
Y.; Liebeskind, L. S. Org. Lett. 2008, 10, 3005. (k) Barker, T. J.; Jarvo,
E. R. J. Am. Chem. Soc. 2009, 131, 15598. (l) Barker, T. J.; Jarvo, E. R.
Angew. Chem., Int. Ed. 2011, 50, 8325. (m) Matsuda, N.; Hirano, K.;
Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 3642. (n) Rucker,
R. P.; Whittaker, A. M.; Dang, H.; Lalic, G. Angew. Chem., Int. Ed.
2012, 51, 3953. (o) Rucker, R. P.; Whittaker, A. M.; Dang, H.; Lalic, G.
J. Am. Chem. Soc. 2012, 134, 6571. (p) Xiao, Q.; Tian, L.; Tan, R.; Xia,
Y.; Qiu, D.; Zhang, Y.; Wang, J. Org. Lett. 2012, 14, 4230. (q) Yan, X.;
Chen, C.; Zhou, Y.; Xi, C. Org. Lett. 2012, 14, 4750. (r) Matsuda, N.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2012, 77, 617.
(3) N-Chloroamines are readily prepared by treatment of secondary
amines with an aqueous solution of sodium hypochlorite or with N-
chlorosuccinimide. (a) Broka, C. A.; Eng, K. K. J. Org. Chem. 1986, 51,
5043. (b) Zhong, Y.-L.; Zhou, H.; Gauthier, D. R., Jr.; Lee, J.; Askin, D.;
Dolling, U. H.; Volante, R. P. Tetrahedron Lett. 2005, 46, 1099.
(4) For a review on reactions of N-chloroamines with other nucleo-
philes, see: Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337.
(5) For electrophilic aminations of Grignard reagents with N-chloro-
(dialkyl)amines, see: (a) Sinha, P.; Knochel, P. Synlett 2006, 3304. (b)
Hatakeyama, T.; Yoshimoto, Y.; Ghorai, S. K.; Nakamura, M. Org.
Lett. 2010, 12, 1516.
(6) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc.
2010, 132, 6900.
(7) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2012, 14, 272.
(8) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656.
r
10.1021/ol302331k
Published on Web 10/02/2012
2012 American Chemical Society

as well as competing side reactions such as a chlorina-
tion reaction. We envisaged that an analogous amination
reaction of carbonyl compounds would become feasible
under milder conditions if it is assisted by transition-metal
catalysts. Herein we report that a copper(I)/2,20-bipyridyl
complex successfully catalyzes an amination reaction of
silyl ketene acetals with N-chloroamines to afford R-amino
esters.
We initially attempted a direct amination reaction of
methyl phenylacetate with N-chloromorpholine (2a, 1.3
equiv) in the presence of CuI (10 mol %) and 2,20-bipyridyl
(10 mol %). Various bases (2.0 equiv) such as NEt(i-Pr)2,
K2CO3, and K(Ot-Bu) were examined, and the desired
methyl 2-morpholino-2-phenylacetate (3aa) was formed in
6% (NMR) yield at best when K2CO3 was used. Then,
methyl phenylacetate was replaced by its activated form,
trimethylsilyl ketene acetal 1a (E/Z = 76:24). An amina-
tion reaction proceeded in the absence of a base, and after
12 h, 3aa was obtained in 39% yield together with methyl
2-chloro-2-phenylacetate (4aa, 29% yield) (Scheme 1).
4aa (5% yield) was obtained together with the recov-
ered 1c (95%).
Various N-chloroamines 2 were subjected to the amina-
tion reaction of 1c (E/Z = 7:93) (Table 1). Cyclic N-
chloroamines 2bꢀf reacted smoothly to give the corre-
sponding products 3cbꢀcf in yields ranging from 60 to
83% (entries 1ꢀ5). Acyclic N-chloroamines 2gꢀi were also
competent amination reagents (entries 6ꢀ8). On the other
hand, the reaction with N-chloro(dibenzyl)amine (2j) gave
the product 3cj in only 28% yield due to a competing
chlorination reaction of 1c (entry 9).
Table 1. Cu(I)-Catalyzed Amination Reaction of Silyl Ketene
Acetal 1c with Various N-Chloroamines 2bꢀja
Scheme 1. Effect of Silyl Group
Other sterically bulkier silyl groups were examined, and
3aa was obtained in 80% isolated yield when triisopropyl-
silyl ketene acetal 1c (E/Z = 82:18) was employed. It
seemed that bulkier silyl groups disfavored the formation
of 4aa to improve the yield of 3aa. A similar result was
observed with 1c of an opposite E/Z ratio (7:93).12,13 In
the absence of a copper catalyst, only a small amount of
(9) For transition-metal-catalyzed direct CꢀH amination with other
electrophilic nitrogen sources, see: (a) Tan, Y.; Hartwig, J. F. J. Am.
Chem. Soc. 2010, 132, 3676. (b) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.;
Zhang, Q. J. Am. Chem. Soc. 2011, 133, 1694. (c) Yoo, E. J.; Ma, S.; Mei,
T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7652. (d)
Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 2860.
(e) Liu, X.-Y.; Gao, P.; Shen, Y.-W.; Liang, Y.-M. Org. Lett. 2011, 13,
4196. (f) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang,
S. J. Am. Chem. Soc. 2012, 134, 9110.
(10) (a) Horiike, M.; Oda, J.; Inouye, Y.; Ohno, M. Agric. Biol.
Chem. 1969, 33, 292. (b) Oguri, T.; Shioiri, T.; Yamada, S. Chem. Pharm.
Bull. 1975, 23, 167. See also: (c) Smulik, J. A.; Vedejs, E. Org. Lett. 2003,
5, 4187 and references therein.
a Conditions: 1c (0.20 mmol), 2 (0.26 mmol), CuI (10 mol %), and
2,20-bipyridyl (10 mol %) in CH3CN (2 mL) at rt for 12 h, unless
otherwise noted. b Isolated yields (averages of 2 runs). c Using 0.30 mmol
of 2g. d Chlorination product was obtained in 40% yield.
(11) For reviews on R-amination of carbonyl compounds, see: (a)
Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem. 2004, 1377.
(b) Erdik, E. Tetrahedron 2004, 60, 8747. (c) Ciganek, E. Org. React.
2008, 72, 1.
(12) Other copper catalysts such as CuCl, CuBr, Cu(OAc), CuCN,
CuCl2, Cu(acac)2, and Cu(OAc)2 gave inferior results.
Next, the scope of silyl ketene acetals 1 was examined
using 2a (Table 2). Whereas the reaction of R-alkyl-substi-
tuted silyl ketene acetals was sluggish,14 R-aryl-substituted
(13) When N-benzoyloxymorpholine was used instead of N-chloro-
morpholine (2a) under the same reaction conditions, 3aa was obtained in
80% yield.
(14) R-Methyl-substituted silyl ketene acetal gave the desired product
in 23% yield.
Org. Lett., Vol. 14, No. 20, 2012
5215

substrates successfully participated in the reaction. All
three substrates 1dꢀf with isomeric tolyl substituents
afforded the corresponding products 3daꢀfa in good
yields (entries 1ꢀ3). Both electron-withdrawing and
-donating groups were allowed for the aryl substituent
(entries 4ꢀ6). Thienyl-substituted substrate 1j also gave
the product 3ja in 67% yield (entry 7).
exemplified in eq 3.15 The R-amino ester 3ck was obtained
in 73% yield directly from 1,2,3,4-tetrahydroisoquino-
line (7k).
Table 2. Cu(I)-Catalyzed Amination Reaction of Various Silyl
Ketene Acetals 1dꢀj with 4-Chloromorpholine 2aa
Upon the basis of experimental precedents in the litera-
ture, three plausible pathways are conceived for produc-
tion of 3 from 1 and 2 (Scheme 2). In pathway (I), silyl
Scheme 2. Proposed Mechanisms for the Formation of 3 from 1
and 2
entry
1 (R, E/Z)
3
yield (%)b
1
2
3
4
5
6
7
1d (4-MeC6H4, 84:16)
1e (3-MeC6H4, 81:19)
1f (2-MeC6H4, 68:32)
1g (4-MeOC6H4, 87:13)
1h (4-CF3OC6H4, 15:85)
1i (4-ClC6H4, 45:55)
1j (3-thienyl, 58:42)
3da
3ea
3fa
3ga
3ha
3ia
3ja
83
79
70
89
55c
72
67
a Conditions: 1 (0.20 mmol), 2a (0.26 mmol), CuI (10 mol %), and
2,20-bipyridyl (10 mol %) in CH3CN (2 mL) at rt for 12 h, unless
otherwise noted. b Isolated yield. c Using 0.36 mmol of 2a.
The commercially available t-butyldimethylsilyl ketene
acetal 5 produced glycine derivative 6e in 59% yield (eq 1).
ketene acetal 1 initially undergoes transmetalation16 with
copper(I) to generate nucleophilic copper(I) enolate A.17
The following reaction with N-chloroamine 2 gives R-
amino ester 3. Pathway (II) involves single-electron trans-
fer (SET) from copper(I) to N-chloroamine 2.18 The
resulting aminyl radical intermediate B couples with silyl
ketene acetal 1. SET back to copper(II) produces R-amino
ester 3 together with triisopropylchlorosilane and copper(I).
In pathway (III), N-chloroamine 2 initially undergoes
oxidative addition to copper(I) to generate amino copper-
(III) species D.2h Transmetalation with silyl ketene acetal
1 furnishes copper(III) enolate E, and reductive elimina-
tion ensues.
The facile availability of N-chloroamines from second-
ary amines permits a one-pot two-step synthesis starting
from amines on gram scale (eq 2). Treatment of morpho-
line (7a, 0.68 g, 7.8 mmol) with N-chlorosuccinimide
(NCS, 1.04 g, 7.8 mmol) in CH3CN at room temperature
for 30 min generated N-chloromorpholine (2a) quantita-
tively. Then, 1c (1.85 g, 6.0 mmol), CuI (10 mol %), and
2,20-bipyridyl (10 mol %) were sequentially added to the
reaction mixture, which was further stirred at room tempera-
ture for 12 h. The product 3aa (1.14 g, 4.8 mmol) was isolated
in 80% yield based upon 1c. The one-pot synthesis demon-
strates another advantage from the practical standpoint.
Whereas a catalytic reaction of 1c with 2a using CuI/
1,10-phenanthroline gave 3aa in 72% yield, a stoichio-
metric reaction of 2a with copper/1,10-phenanthroline
enolate A, generated according to the Hartwig’s procedure,
(15) When cyclohexylamine was treated with 1c under the same one-
pot reaction conditions, the desired R-amino ester was obtained in 20%
yield.
(16) For transmetalation between Cu(I) and trimethylsilyl ketene
acetals in the presence of a base, see: (a) Oisaki, K.; Suto, Y.; Kanai, M.;
Shibsaki, M. J. Am. Chem. Soc. 2003, 125, 5644. (b) Li, D.; Ohmiya, H.;
Sawamura, M. J. Am. Chem. Soc. 2011, 133, 5672.
(17) Huang, Z.; Hartwig, J. Angew. Chem., Int. Ed. 2012, 51, 1028.
€
(18) (a) Heuger, G.; Kalsow, S.; Gottlich, R. Eur. J. Org. Chem. 2002,
This one-pot two-step method was useful particularly
when an N-chloroamine was too unstable to be isolated, as
1848. (b) Tsuritani, T.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2003,
68, 3246.
5216
Org. Lett., Vol. 14, No. 20, 2012

yielded only 8% of 3aa together with methyl phenylace-
tate (56% yield) and 4,40-bimorpholine (43% yield based
upon 2a) (eq 4).
under mild reaction conditions. This reaction provides an
efficient synthetic route to R-amino esters, which are sub-
structures found in a variety of bioactive compounds.
Acknowledgment. This work was supported in part by
MEXT (Grant-in-Aid for Scientific Research on Innova-
tive Area Nos. 22105005 and 24106718, Scientific Research
(B) No. 23350041, Young Scientists (A) No. 23685019)
and Takeda Science Foundation. M.M. is grateful for the
JSPS Research Fellowship for Young Scientists.
Inaddition, the reactionof 1cwith2aunder thestandard
conditions but in the presence of TEMPO (1.0 equiv)
afforded 3aa in almost same yield (72%). Thus, we prefer
pathway (III) as the most likely mechanistic scenario,
albeit with no experimental evidence to support it.
Supporting Information Available. Experimental de-
tails and spectra data for new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
In summary, we have developed a copper-catalyzed ami-
nation reaction of silyl ketene acetals with N-chloroamines
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
5217