Copper(I) catalyzed regioselective asymmetric alkoxyamination of aryl enamide derivatives

Article abstract of DOI:10.1021/ol202367d

The copper(I) catalyzed reaction of an enamide with an iminoiodane, in the presence of an alcohol, triggers the direct alkoxyamination of the double bond. This transformation represents a straightforward access to α-amino aminals in a completely regio- an

Full text of DOI:10.1021/ol202367d

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5792–5795
Copper(I) Catalyzed Regioselective
Asymmetric Alkoxyamination of Aryl
Enamide Derivatives
Masafumi Nakanishi, Corinne Minard, Pascal Retailleau, Kevin Cariou, and
Robert H. Dodd*
Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, Avenue de la Terrasse,
91198 Gif-Sur-Yvette, France
robert.dodd@icsn.cnrs-gif.fr
Received September 1, 2011
ABSTRACT
The copper(I) catalyzed reaction of an enamide with an iminoiodane, in the presence of an alcohol, triggers the direct alkoxyamination of the
double bond. This transformation represents a straightforward access to R-amino aminals in a completely regio- and diastereoselective manner.
Use of a chiral Box ligand allows this reaction to be carried out in an enantioselective fashion.
Since the seminal work of Breslow,1 Mansuy,2 and Evans,3
iminoiodanes4 have gained notoriety as highly versatile nitre-
noid precursors, most notably to promote metal-catalyzed
alkene aziridination and alkane amidation through CꢀH
insertion. Over the past 25 years, research groups have striven
to broaden the usefulness of these reagents by designing more
practical and selective transformations.5 This challenge was
partly met by Evans who rapidly developed an enantioselec-
tive version3b of the copper-catalyzed aziridination reaction
and extended the substrate scope from alkenes to silyl enol
ethers.3c The latter are of particular interest since they allow
the formal R-amination of a carbonyl compound (Scheme 1,
eq 1).3,6 Curiously, enamines have practically never been used
as substrates for this type of reaction. We thus decided to
probe the reactivity of enamine derivatives 1 toward iminoio-
danes in the presence of copper catalysts. In particular, the
question arose as to whether an amino-aziridine such as 2
could be generated and, if so, how it would evolve upon reac-
tion with a nucleophile (Scheme 1, eq 2). Careful study of
the literature only revealed a handful of examples of
(1) Breslow, R.; Gellman, S. H. J. Chem. Soc., Chem. Commun. 1982,
1400–1401.
ꢀ
ꢀ
(2) (a) Mansuy, D.; Mahy, J.-P.; Dureault, A.; Bedi, G.; Battioni, P.
ꢀ
J. Chem. Soc., Chem. Commun. 1984, 1161–1163. (b) Mahy, J.-P.; Bedi,
G.; Battioni, P.; Mansuy, D. J. Chem. Soc., Perkin Trans. 2 1988, 1517–
1524.
(3) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem.
1991, 56, 6744–6746. (b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.;
Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328–5329.
(c) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994,
116, 2742–2753.
(6) (a) Nakanishi, M.; Salit, A.-F.; Bolm, C. Adv. Synth. Catal. 2008,
€
350, 1835–1840. (b) Adam, W.; Roschmann, K. J.; Saha-Moller, C. R.
Eur. J. Org. Chem. 2000, 557–561 and references therein.
(4) (a) Abramovitch, R. A.; Bailey, T. D.; Takaya, T.; Uma, V.
J. Org. Chem. 1974, 39, 340–345. (b) Yamada, Y.; Yamamoto, T.;
Okawara, M. Chem. Lett. 1975, 361–362. For a review see:(c) Dauban,
P.; Dodd, R. H. Synlett 2003, 1571–1586.
(5) For reviews, see ref 4c and (a) Tanner, D. Angew. Chem., Int. Ed.
Engl. 1994, 33, 599–619. (b) Li, A.-H.; Dai, L.-X. Chem. Rev. 1997, 97,
2341–2372. (c) McCoull, W.; Davies, F. A. Synthesis 2000, 1347–1365.
(7) (a) Warren, B. K.; Knaus, E. E. J. Med. Chem. 1981, 24, 462–464.
(b) Ondrus, T. A.; Pednekar, P. P.; Knaus, E. E. Can. J. Chem. 1985, 63,
2362–2368. (c) Sunose, M. K.; Anderson, M.; Orpen, A. G.; Gallagher,
T.; Macdonald, S. J. F. Tetrahedron Lett. 1998, 39, 8885–8888.
(d) Katritzky, A. R.; Yao, J.; Bao, W.; Qi, M.; Steel, P. J. J. Org. Chem.
1999, 64, 346–350. (e) Kuznetsov, M. A.; Kuznetsova, L. M.; Schantl,
J. G.; Wurst, K. Eur. J. Org. Chem. 2001, 1309–1314.
(8) (a) Adam, W.; Reinhardt, D. Tetrahedron 1995, 51, 12257–12262.
(b) Sugisaki, C. H.; Carroll, P. J.; Correia, C. R. D. Tetrahedron Lett.
1998, 39, 8885–8888. (c) Snider, B. B.; Zeng, H. Org. Lett. 2000, 2, 4103–
4106. (d) Snider, B. B.; Zeng, H. Org. Lett. 2002, 6, 1087–1090. (e) Xiong,
H.; Hsung, R. P.; Shen, L.; Hahn, J. M. Tetrahedron Lett. 2002, 43,
4449–4453.
€
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(d) Muller, C.; Fruit, C. Chem. Rev. 2003, 103, 2905–2919. (e) Dıaz-Requejo,
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M. M.; Perez, P. J. Chem. Rev. 2008, 108, 3379–3394. (f) Padwa, A. In
Comprehensive Heterocyclic Chemistry, Vol. III; Katritzky, A. R., Ed.; Elsevier:
2008; Vol. 18, pp 1ꢀ97. (g) Collet, F.; Dodd, R. H.; Dauban, P. Chem.
Commun. 2009, 5061–3394. (h) Karila, D.; Dodd, R. H. Curr. Org. Chem.
2011, 15, 1507–1538.
r
10.1021/ol202367d
Published on Web 10/05/2011
2011 American Chemical Society

amino-aziridines7 and amino-epoxides,8 which are invari-
ably highly prone to nitrogen-assisted opening to generate
a zwitterion that can then be trapped by a nucleophile.7cꢀe,8
Similar intermediates have also been postulated in the case
of the reaction of indoles with nitrenoids which, after
reaction with an internal or external nucleophile, leads to
oxyamination adducts.9
nosylamine-derived iminoiodane (PhINNs) in the pre-
sence of a catalytic amount of copper(I) catalyst (Table 1,
entry 1). Despite all our efforts, the expected aziridine 2a
could never be observed. Assuming the high reactivity of
the latter was at play, we attempted to trap it in situ with a
nucleophile. Thus, when the same reaction was run in the
presence of 1 equiv of ethanol, the R-amino-aminal 3a was
isolated as a single diastereomer, albeit in low yield possibly
due to competing solvolysis of the iminoiodane (entry 2).14
Screening of reaction conditions quickly showed that
dichloromethane was the most suitable solvent for this
transformation and that running the reaction at a lower
temperature (ꢀ10 °C) allowed the formation of 3a with a
60% yield (entry 3). The presence of water proved detri-
mental as the reactants decomposed in the absence of
molecular sieves (entry 4).
Scheme 1. Initial Endeavor
Table 1. Reaction Conditions Optimization
In our initial design, the sequence envisioned would lead
to densely functionalized diamines such as 3 (Scheme 1)
present in various bioactive natural products. For in-
stance, marine indole derivatives trachycladindoles E and
F possess a cyclic hydroxy-guanidine moiety which is
crucial for cytotoxic activities.10 Within the vast family of
antitumor tetrahydroisoquinoline derivatives, many safra-
mycins and congeners11 display a cyclic R-amino hemi-
aminal or the corresponding R-aminonitrile.
The lack of practical procedures to easily prepare en-
amines, substrates reputed for their instability, may have
curbed the study of their reactivity toward nitrenoid
reagents. However, the recent development of efficient
coupling reactions between amines and alkene halides or
vinyl boron derivatives now provides rapid access to
diversely substituted enamines.12 In our hands, conditions
developed by Buchwald using vinyl halides12a were suc-
cessfully applied to a broad range of secondary amines and
anilines, including sulfonamides which had not been pre-
viously utilized in this kind of cross-coupling reaction. In
this study, sulfonamide based enamides appeared aschoice
substrates, due to their well-known robustness.13
entry
reaction conditions
yield (%)a
1
2
3
4
5
6
7
8
9
PhINNs (1 equiv), no EtOH, MeCN, rt, 2 h
PhINNs (1 equiv), MeCN, rt, 2 h
c. m.
17
PhINNs (1 equiv), DCM, ꢀ10 °C, 2 h
PhINNs (1 equiv), no MS, DCM, ꢀ10 °C, 24 h
PhINNs (1 equiv), DCM, rt, 12 h
60
c. m.
c. m.
54b
PhINNs (1.5 equiv), DCM, rt, 1 h
PhINTs (1 equiv), DCM, ꢀ10 °C, 24 h
PhIO þ NsNH2 (1 equiv), DCM, ꢀ10 °C, 2 h
PhINNs (1 equiv), no Cu, DCM, ꢀ10 °C, 24 h
traces
traces
NR
a Isolated yields; c. m.: complex mixture. b 1 mmol scale.
Running the reaction at higher temperature (rt) led to
significant decomposition of both the starting material and
the product (entry 5), a problem that could be overcome by
using an excess of iminoiodane (entry 6). Other iminoio-
danes such as PhINTs reacted sluggishly (entry 7) and
attempts to generate the iminoiodane in situ15 failed to
promote the reaction (entry 8), probably because of the
presence of ethanol in the reaction mixture. Finally, no
reaction occurred in the absence of the catalyst (entry 9).
Using our optimized conditions, we next studied the
scope of this reaction by first checking the influence of the
nitrogen protecting group on the reaction (Table 2). Over-
all, the reaction was found to be quite general, with
sulfonamides giving the best results (entries 1ꢀ5), as
opposed to the Boc-protected substrate (entry 6). The
reaction was also applicable to alkyl- and benzyl-protected
enamines (entries 7ꢀ10), which in the case of 3i, for
instance, allowed the incorporation of three orthogonal
protecting groups on the nitrogens.
Having several enamides in hand, our initial study began
with styrylsulfonamide 1a which was reacted with the
(9) (a) Padwa, A.; Stengel, T. Org. Lett. 2002, 4, 2137–2139.
(b) Padwa, A.; Flick, A. C.; Leverett, C. A.; Stengel, T. J. Org. Chem.
2004, 69, 6377–6386. (c) Sato, S.; Shibuya, M.; Kanoh, N.; Iwabuchi,
Y. Chem. Commun. 2009, 6264–6266. (d) Beaumont, S.; Pons, V.;
Retailleau, P.; Dodd, R. H.; Dauban, P. Angew. Chem., Int. Ed. 2010,
49, 1634–1637.
(10) Capon, R. J.; Peng, C.; Dooms, C. Org. Biomol. Chem. 2008, 6,
2765–2771.
~
(11) (a) Avendano, C.; de la Cuesta, E. Chem.;Eur. J. 2010, 16,
9722–9734. (b) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669–
1730 and references therein.
(12) (a) Jiang, L.; Job, G. E.; Klapars, A; Buchwald, S. L. Org. Lett.
2003, 5, 3667–3669. (b) See also: Dehli, J.; Bolm, C. Adv. Synth. Catal.
2005, 347, 239–242. (c) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon,
S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. (d) Lam,
P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003,
44, 4927–4931.
(14) White, R. E. Inorg. Chem. 1987, 26, 3916–3919.
(15) Dauban, P.; Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem.
ꢁ
(13) See Supporting Information for details.
Soc. 2001, 123, 7707–7708.
Org. Lett., Vol. 13, No. 21, 2011
5793

due to purely steric effects or to more subtle interactions,
the reactive intermediate apparently has a strong confor-
mational bias which has yet to be clearly identified. It
should also be pointed out that competition may exist
between the ethanolysis of the hypervalent iodine reagent14
and its reaction with the catalyst to form the nitrenoid
species. The high reactivity of the latter, coupled with the
nucleophilicity of the substrate, should ensure formation
of the expected aziridine 2 first and then the zwitterionic
iminium 9. This highly reactive intermediate would then be
immediately trapped by the nucleophile.18,19
Table 2. Substrate Scope for the Alkoxyamination
entry
R
PG
R0
product
yield (%)a
1
Ph
PhSO2
Ms
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Bn
iPr
tBu
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
4
60 (54)b,c
78
70 (80)b
70
2
Ph
Ph
Ph
Ph
Ph
Me
Bn
Bn
PMB
Ph
Ph
Ph
Ph
3
Ts
4
PMPS
Ns
5
50
Scheme 2. Possible Mechanistic Pathways
6
Boc
PhSO2
Ms
37
7
62
8
52
9
Ses
42
10
11
12
13
14
Ms
60c
37
Ms
Ms
5
63
Ms
6
58
Ms
7
42
a Isolated yields. b reactions run at rt with 1.5 equiv of PhI=NNs.
c 1 mmol scale.
We also explored whether other alcohols could be used
for the alkoxyamination (entries 11ꢀ14). Methanol gave a
rather low yield of product 4 (37%), probably due to the
moderate stability of the final product. In contrast, benzyl
and isopropyl alcohol provided acceptable yields of alkoxy-
amination products 5 (63%) and 6 (58%), respectively.
However, product formation diminished as the steric bulk
of the alcohol increased, tert-butanol affording only a 42%
yield of product 7.
Interestingly, this transformation is highly diastereose-
lective, therelativeR*S*stereochemistrybeing assignedby
X-ray crystallographic analysis of compound 3a.16 This
observed relative configuration raises a few mechanistic
issues. We assume that the iminoiodane firstreactswiththe
copper catalyst to generate the active nitrenoid species
which can thenreact withthe enamide 1 stereoselectively to
furnish aziridine 2 with a trans geometry (Scheme 2).3
From there, two regioisomeric zwitterions could then be
formed: generation of a benzylic cation would give 8 but,
more probably,7cꢀe,8 nitrogen assisted opening would lead
to 9. Depending on the reactive intermediate, addition of
the nucleophile in an SN2 or SN1 fashion can give rise to
four products, two being regioisomeric pairs of diastereo-
mers. In our case, only compound 3 is formed,17 thus
pointing to the preeminence of zwitterionic iminium 9 as
the reactive intermediate. However, the involvement of a
planar iminium such as 9 would tend to disfavor a stereo-
selective process. Whether the observed stereoselectivity is
The next step was to take advantage of the high diaster-
eoselectivity of this transformation to develop an enantio-
selective version starting from enamide 1b. We first
investigated the use of different types of chiral ligands
which have already been proven to be efficient for copper-
catalyzed asymmetricaziridinations.20 Tetradentateligand
11, although more suitable for complexing copper(II), was
tested but showed almost no reactivity (Table 3, entry 1).
We therefore chose to focus on bidentate ligands, starting
with diimine 12, which proved quite efficient in terms of
reactivity, affording 3b in 88% yield with a significant
enantioinduction (66% ee, entry 2). Turning then to bis-
oxazolidine ligands (13ꢀ17), the reactivity dropped
slightly using 13 (71% yield) but the selectivity was main-
tained (entry 3). Switching from a phenyl group to a tert-
butyl on the Box framework (14) now induced an excellent
enantioselectivity (91% ee) although with a slightly lower
yield (58%, entry 4).
(18) Indeed, addition of the ethanol after stirring the other reagents
and reactants for 1 h only led to complex mixtures, demonstrating the
necessity of intercepting the reactive intermediate as it forms.
(19) For examples of intermolecular trapping of an iminium, arising
from an enamine functionalization, by an alcohol, see: (a) Norton
Matos, M.; Afonso, C. A. M.; Batey, R. A. Tetrahedron 2005, 61,
1221–1244. (b) Matsubara, R.; Kawai, N.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2006, 45, 3814–3816. (c) Huang, X.; Shao, N.; Huryk, R.; Palani,
A.; Aslanian, R.; Seidel-Dugan, C. Org. Lett. 2009, 11, 867–870.
(d) Shao, N.; Huang, X.; Palani, A.; Aslanian, R.; Buevich, A.; Piwinski,
J.; Huryk, R.; Seidel-Dugan, C. Synthesis 2009, 2855–2872. (e) Terada,
M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2009, 48, 2553–
2556. (f) Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009,
11, 5546–5549.
(16) CCDC 810284 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(17) Preliminary molecular calculations did show that 3-R*S* was
the more stable of the four isomers.
(20) (a) For Box ligands, see ref 3b. (b) Diimine ligands: Li, Z.;
Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 5326–5327.
5794
Org. Lett., Vol. 13, No. 21, 2011

the yield, especially in the case of the strongly electron-
withdrawing nosyl which provides only low yields of
product because of either destabilization of the iminium
intermediate or lowering of the nucleophilicity of the
enamine (entries 3,4). The reactivity of Boc-protected 1f
is improved in the presence of the ligand (entry 7, compare
with Table 2, entry 6), even if the enantioselectivity is
moderate. Finally, both N-benzyl substrates 1h,j exhibit
analogous behavior, showcasing a moderate yield but a
satisfying ee (entries 8,9).
Table 3. Screening of the Chiral Ligands for the Enantioselective
Alkoxyamination
entry
ligand
time
temp (°C)
yield (%)a
ee (%)b
Table 4. Substrate Scope for the Asymmetric Alkoxyamination
1
2
3
4
5
6
7
8
9
11
12
13
14
14
15
16
17
14
3 days
5 h
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
rt
traces
88
nd
66
66
91
91
74
83
78
87c
3 days
3 days
2 hc
2 hc
2 hc
71
58
56
63
temp
yield
(%)a
ee
73
entry
SM
PG/R
time
(°C)
(%)b
3 days
0.5 hc
58
60
1
2
3
4
5
6
7
8
9
1d
1d
1e
1e
1a
1c
1f
PMPS/Ph
PMPS/Ph
Ns/Ph
3 days
15 h
3 days
36 h
24 h
1 h
ꢀ10
rt
50
71
17
34
74
71
61
43
47
90
86
93
94
85
87
67
83
82
a Isolated yields. b Determined by chiral HPLC. c Reactions run with
1.5 equiv of PhIdNNs.
ꢀ10
rt
Ns/Ph
SO2Ph/Ph
Ts/Ph
rt
From there, the R0 substituent was varied thus changing
the dihedral angle of the ligand (entries 6ꢀ8),21 but no real
improvements in either yields or enantioselectivities were
observed. Finally it should be noted that the reaction time
can be decreased to 2 h by using an excess of iminoiodane
(compare entries 4 and 5) and that running the reaction at
rt is only slightly detrimental to the ee (87%), whereas both
the reaction time (30 min) and the yield (60%) are im-
proved (compare entries 9 and 5). Because ligand 14
provides the highest enantioselectivities for alkoxyamina-
tion and has the advantage of being commercially avail-
able, it was used for the subsequent studies.
These enantioselective reaction conditions were then
applied to the other substrates 1a,cꢀf,h,j. For compounds
1d and 1e, at ꢀ10 °C, slow conversion and lower yields
were observed, although the ee’s were satisfactory (90%
and 93%, respectively, Table 4, entries 1,3). Taking ad-
vantage of our previous experience concerning the influ-
ence of the temperature (see Table 3), we ran the same ex-
periments at rt (entries 2,4). The reaction times were
greatly shortened (15 and 36 h instead of 3 days) and
the yields were improved while the ee’s remained in the
same range. The other N-phenyl enamides (1a,c) behaved
in a similar manner with good yields (74% and 71%) and
ee’s (85% and 87%) (entries 5ꢀ6). Overall, the electronic
character of the sulfonyl group seems to only influence
rt
Boc/Ph
24 h
6 h
rt
1h
1j
Ms/Bn
rt
Ms/PMB
24 h
rt
a Isolated yields. b Determined by chiral HPLC.
In conclusion, we disclose here a novel and efficient
catalytic osmium-free direct asymmetric oxyamination22
of enamine derivatives. Mediated by an iminoiodane, this
oxidative difunctionalization allows the formation of
R-amino aminals. The precise mechanism of this reaction,
especially with respect to the actual involvement of an
aziridine intermediate and of nitrenoid species, still re-
mains to be explored, as are applications toward natural
product total synthesis.
Acknowledgment. We wish to thank the Institut de
Chimie des Substances Naturelles for financial support
and fellowships (M.N., C.M.).
Supporting Information Available. Experimental pro-
cedures and characterization of all compounds and crys-
tallographic data for compound 3a. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(22) Donohoe, T. J.; Callens, C. K. A.; Flores, A.; Lacy, A. R.; Rathi,
A. H. Chem.;Eur. J. 2011, 17, 58–76.
(21) Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875–5878.
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