Concise synthesis of α-trisubstituted amines from ketones using n -methoxyamines

Article abstract of DOI:10.1021/ol300622r

Three-component allylation and cyanation utilizing a ketone and an N-methoxyamine are reported. The high nucleophilicity of the N-methoxyamine and high electrophilicity of the corresponding iminium ion enable the concise synthesis of α-trisubstituted amin

Full text of DOI:10.1021/ol300622r

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2098–2101
Concise Synthesis of r-Trisubstituted
Amines from Ketones Using
N-Methoxyamines
Yusuke Kurosaki,† Kenji Shirokane,† Takeshi Oishi,‡ Takaaki Sato,*,† and
Noritaka Chida*,†
Department of Applied Chemistry, Faculty of Science and Technology, Keio University,
3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan, and School of Medicine,
Keio University, 4-1-1, Hiyoshi, Kohoku-ku, Yokohama 223-8521, Japan
takaakis@applc.keio.ac.jp; chida@applc.keio.ac.jp
Received March 12, 2012
ABSTRACT
Three-component allylation and cyanation utilizing a ketone and an N-methoxyamine are reported. The high nucleophilicity of the
N-methoxyamine and high electrophilicity of the corresponding iminium ion enable the concise synthesis of R-trisubstituted amines in a single step.
R-Trisubstituted amines are one of the most important
structural motifs, embedded in a number of biologically
active alkaloids such as halichlorine,1 FR901483,2 and
histrionicotoxin3 (Figure 1). The simplest approach to the
structure is nucleophilic addition to a ketimine 3 derived
from the condensation of a ketone 1 and a primary amine 2
(Scheme 1, 1 þ 2 f 3 f 4).4 However, this approach suffers
from several drawbacks: (1) poor electrophilicity of the
ketimine 3 due to electronic and steric effects compared
with aldimines, (2) the instability of ketimine 3, and (3)
R-deprotonation to form metal enamines. Functional group
tolerance is also problematic because poorly electrophilic
ketimines very often require reactive nucleophiles such as
Grignard reagents. To circumvent these problems, general
approaches have taken advantage of amines such as 5,
with a supporting functional group such as an N-sulfinyl
amine,4a,e an N-benzoylhydrazine,4b,f or an N-diphenylpho-
sphinoyl amide.4c,d,f These supporting functional groups
render the imines more stable as well as more reactive to
nucleophiles (1 þ 5 f 6 f 7). Although these methodolo-
gies are very practical and offer high stereoselectivity, they
require a three-step sequence that includes deprotection.
During our pursuit of new chemistry related to the
nitrogenꢀoxygen bond, wediscovered seemingly contradictory
† Department of Applied Chemistry, Faculty of Science and Technology,
Keio University.
‡ School of Medicine, Keio University.
(1) (a) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi,
Y.; Uemura, D. Tetrahedron Lett. 1996, 37, 3867–3870. (b) Arimoto, H.;
Hayakawa, I.; Kuramoto, M.; Uemura, D. Tetrahedron Lett. 1998, 39,
861–862. For a review, see: (c) Clive, D. L. J.; Yu, M.; Wang, J.; Yeh,
V. S. C.; Kang, S. Chem. Rev. 2005, 105, 4483–4514.
(2) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37–44.
(3) (a) Daly, J. W.; Karle, I.; Myers, C. W.; Tokuyama, T.; Waters,
J. A.; Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870–1875. For
a review, see: (b) Sinclair, A.; Stockman, R. A. Nat. Prod. Rep. 2007, 24,
298–326.
(4) For selected reviews on synthesis of R-trisubstituted amines
through nucleophilic addition to imines, see: (a) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995. (b) Sugiura, M.;
Kobayashi, S. Angew. Chem., Int. Ed. 2005, 44, 5176–5186. (c) Shibasaki,
M.; Kanai, M. Org. Biomol. Chem. 2007, 5, 2027–2039. (d) Shibasaki, M.;
Kanai, M. Chem. Rev. 2008, 108, 2853–2873. (e) Robak, M. T.; Herbage,
M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600–3740. (f) Kobayashi, S.;
Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626–2704.
(5) We reported sequential nucleophilic addition to N-methoxyamide
via an N-methoxyiminium ion; see: (a) Shirokane, K.; Kurosaki, Y.;
Sato, T.; Chida, N. Angew. Chem., Int. Ed. 2010, 49, 6369–6372.
Kibayashi and Vincent/Kouklovsky reported similar reactions of
N-alkoxylactams; see: (b) Iida, H.; Watanabe, Y.; Kibayashi, C.
J. Am. Chem. Soc. 1985, 107, 5534–5535. (c) Vincent, G.; Guillot, R.;
Kouklovsky, C. Angew. Chem., Int. Ed. 2011, 50, 1350–1353.
r
10.1021/ol300622r
Published on Web 04/04/2012
2012 American Chemical Society

properties of N-methoxyamine 8 (Scheme 1). In general,
the condensation of a highly nucleophilic amine derivative
with a carbonyl group tends to give a poorly electrophilic
iminium ion. However, the N-methoxyiminium ion 95,6
exhibited unexpectedly high electrophilicty despite the
high nucleophilicity of N-methoxyamine 8.7,8 Thus, the
condensation of 8 with ketone 1 could generate N-meth-
oxyiminium ion 9 with assistance of an acid, followed by
nucleophilic addition to the resulting iminium ion 9 to give
sterically hindered R-trisubstituted N-methoxyamine 10 in
a single step. In addition, the N-methoxy group was easily
removed with Zn in AcOH to give secondary amine 4.
Scheme 1. Synthesis of R-Trisubstituted Amines 4 or 7 from
Ketones 1
in the presence of a catalytic amount of Sc(OTf)3 (Table 1).9
The three-component reaction of N,N-disubstituted amine
12 is very challenging because of steric hindrance, which
suppresses the condensation with cyclohexanone 11. Indeed,
use of Cbz-protected amine 12a led to the generation of
tertiary alcohol 14 in 41% yield through the direct allylation
of ketone 11 (entry 1). N-Methyl-N-benzylamine 12b gave
neither R-trisubstituted amine 13b nor tertiary alcohol 14
(entry 2). On the contrary, the condensation of primary
N-benzylamine 12c with cyclohexanone 11, followed by
allylation, gave secondary amine 13c in low yield, probably
because allyltributylstannane did not possess sufficient nu-
cleophilicity for the imine (entry 3).10 N-Methoxyamine 12d
was then exposed to the same allylation conditions (entry 4).11
As we expected, N-methoxyamine 12d exhibited high
nucleophilicity and smoothly condensed with ketone 11
to generate a highly electrophilic N-methoxyiminium ion.
The allylation with allyltributylstannane then took place,
affording R-trisubstituted amine 13d in 85% yield, along
with a small amount of tertiary alcohol 14 in 7% yield. It is
noteworthy that ketone 11 and N-methoxyamine 12d were
used in an equal molar ratio.
Figure 1. Representative natural products containing R-trisub-
stituted amines.
The present investigation commenced with a three-com-
ponent allylation utilizing cyclohexanone 11, a variety of
N-substituted-N-benzylamines 12, and allyltributylstannane
(6) For selected examples on reactions via N-alkoxyiminium ions as
the key intermediates, see: (a) Hardegger, B.; Shatzmiller, S. Helv. Chim.
Acta 1976, 59, 2765–2767. (b) Plate, R.; van Hout, R. H. M.; Behm, H.;
Ottenheijm, H. C. J. J. Org. Chem. 1987, 52, 555–560. (c) Padwa, A.;
Dean, D. C. J. Org. Chem. 1990, 55, 405–406. (d) Hermkens, P. H. H.;
van Maarseveen, J. H.; Cobben, P. L. H. M.; Ottenheijm, H. C. J.;
Kruse, C. G.; Scheeren, H. W. Tetrahedron 1990, 46, 833–846. (e) Tiecco,
M.; Testaferri, L.; Tingoli, M.; Bagnoli, L. J. Chem. Soc., Chem.
Commun. 1995, 235–236. (f) McMills, M. C.; Wright, D. L.; Zubkowski,
J. D.; Valente, E. J. Tetrahedron Lett. 1996, 37, 7205–7208. (g) Grigg, R.;
Rankovic, Z.; Thoroughgood, M. Tetrahedron 2000, 56, 8025–8032. (h)
Yamashita, T.; Kawai, N.; Tokuyama, H.; Fukuyama, T. J. Am. Chem.
Soc. 2005, 127, 15038–15039. (i) Dondas, H. A.; Grigg, R.; Markandu,
J.; Perrior, T.; Suzuki, T.; Thibault, S.; Thomas, W. A.; Thornton-Pett,
M. Tetrahedron 2002, 58, 161–173. (j) Peng, Z.; Song, J.; Liao, W.; Ma,
R.; Chen, S.-H.; Li, G.; Ando, R. Lett. Org. Chem. 2006, 3, 455–458. (k)
Nemoto, H.; Ma, R.; Kawamura, T.; Kamiya, M.; Shibuya, M. J. Org.
Chem. 2006, 71, 6038–6043. (l) Zheng, X.; Wang, X.; Chang, J.; Zhao, K.
Synlett 2006, 3277–3283. (m) Nemoto, H.; Ma, R.; Moriguchi, H.;
Kawamura, T.; Kamiya, M.; Shibuya, M. J. Org. Chem. 2007, 72,
9850–9853. (n) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr,
M. A. J. Am. Chem. Soc. 2008, 130, 4196–4201.
(7) Oxime ethers are known to be less electrophilic than the corre-
sponding imines; see: (a) Enders, D.; Reinhold, U. Tetrahedron:
Asymmetry 1997, 8, 1895–1946. (b) Bloch, R. Chem. Rev. 1998, 98,
1407–1438.
(8) When a solution of N-methoxybenzylamine 12d, cyclohexanone
11, and CDCl3 was treated with Sc(OTf)3, 1H NMR analysis showed
that 12d and the N-methoxyiminium ion i existed as a ratio of 1.1:1 in
equilibrium after 1 h. Enamine derivative ii was not detected during the
analysis. This result might support the high electrophilicity of the
N-methoxyiminium ions.
(9) For selected reviews on allylation to iminium intermediates, see:
(a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293. (b)
Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39, 595–614.
(10) The use of more reactive nucleophiles including a Grignard
reagent gave secondary amines in good yields, although these ap-
proaches were not compatible with sensitive functional groups. For
ꢀ
ꢀ
selected examples, see: (a) Bonjoch, J.; Diaba, F.; Puigbo, G.; Sole, D.;
Segarra, V.; Santamarıa, L.; Beleta, J.; Ryder, H.; Palacios, J.-M.
´
Bioorg. Med. Chem. 1999, 7, 2891–2897. (b) Wright, D. L.; Schulte,
J. P., II; Page, M. A. Org. Lett. 2000, 2, 1847–1850. (c) Varlamov, A.;
ꢀ
Kouznetsov, V.; Zubkov, F.; Chernyshev, A.; Shurupova, O.; Mendez,
L. Y. V.; Rodrıguez, A. P.; Castro, J. R.; Rosas-Romero, A. J. Synthesis
´
2002, 771–783. (d) Dhudshia, B.; Tiburcio, J.; Thadani, A. N. Chem.
Commun. 2005, 5551–5553. (e) Kropf, J. E.; Meigh, I. C.; Bebbington,
M. W. P.; Weinreb, S. M. J. Org. Chem. 2006, 71, 2046–2055. (f) Kaden,
S.; Reissig, H.-U. Org. Lett. 2006, 8, 4763–4766. (g) Prusov., E.; Maier,
M. E. Tetrahedron 2007, 63, 10486–10496.
(11) For selected examples on the three-component reaction with an
aldehyde and an N-alkoxyamine via an N-methoxyiminium ion, see:
Reference 6g 6k, and 6m. For selected examples on the three-component
radical reactions with an aldehyde and an N-alkoxyamine, see: (a)
Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140–1157. (b) Cho, D. H.;
Jang, D. O. Chem. Commun. 2006, 5045–5047.
Org. Lett., Vol. 14, No. 8, 2012
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Table 1. Three-Component Allylation of Cyclohexanone 11 and
N-Substituted Benzylamines 12a
Scheme 2. Three-Component Allylation or Cyanation of
Ketones and N-Methoxyaminesa
yields (%)
entry
12
13
14
1
2
3
4
12a: R = Cbz
12b: R = Me
12c: R = H
0
0
41
0
9
0
12d: R = OMe
85
7
a Conditions: 11 (1.0 equiv), 12 (1.0 equiv), CH2dCHCH2SnBu3
(3.0 equiv), Sc(OTf)3 (0.3 equiv), CH2Cl2 (2.0 M), rt.
Once we confirmed the unique properties of N-methox-
yamine in the presence of Sc(OTf)3, we then surveyed the
scope of the three-component allylation with various
ketones (Scheme 2, method A). The allylation of 4-tert-
butylcyclohexanone took place from the equatorial side to
give 15 in a highly diastereoselective manner.12 One of the
conspicuous features in our methodology is functional
group tolerance. Because N-methoxyiminium ion 9 shown
in Scheme 1 exhibited high electrophilicity, a strong nu-
cleophile such as a Grignard reagent was not necessary.
Thus, the allylation of ethyl 4-oxocyclohexanecarboxylate
afforded 16 without affecting the ethyl ester (65%, dr =
3.2:1). Sterically hindered N-methoxyamine resulted in a
decrease in yield (17: 34%). We then applied the reaction
conditions to acyclic ketones. While the allylation of
5-nonanone gave 18 in low yield due to the large steric
hindrance, 2-nonanone provided R-tertiary amine 19 in
75% yield. Unfortunately, the aromatic ketone failed
to react even when an electron-withdrawing group was
introduced on the aromatic ring.
The three-component reaction was applicable to the cya-
nation with TMSCN and TMSOTf (Scheme 2, method B).13
In contrast to the allylation, when using 4-tert-butyl-cyclo-
hexanone, the cyanide group attacked from the axial side
probably due to its small size (21: 73%, dr = 4.6:1). The
reaction proceeded in the presence of the ethyl ester (22:52%,
dr = 2.2:1). The branched N-methoxyamine led to a low
yield as well as the allylation (23: 32%). The cyanation of
sterically hindered ketones tended to give better yields than
the allylation, inasmuch as 5-nonanone and 2-nonanone both
afforded the products in good yield (24: 65%, 25: 88%).
a Conditions: <method A> ketone (1.0 equiv), N-methoxyamine
(1.0 equiv), CH2dCHCH2SnBu3 (3.0 equiv), Sc(OTf)3 (0.3 equiv),
CH2Cl2 (2.0 M), rt or <method B> ketone (1.0 equiv), N-methoxyamine
(1.0 equiv), TMSCN (3.0 equiv), TMSOTf (1.0 equiv), CH2Cl2 (2.0 M), rt.
bThe reaction was performed at 80 °C.
The cyanation proceeded even with an aromatic ketone,
which was not a suitable substrate in the allylation (26: 62%).
We then turned our attention to a two-component
allylation using N-methoxyamine 27,14 which would result
in a single-step synthesis of 2,2-disubstituted piperidines
(Scheme 3).15 The reaction of cyclohexanone with Sc(OTf)3
in MeCN gave spiro-R-trisubstituted amine 28 in 84%
yield. When using 4-tert-butylcyclohexanone, the allylsilane
approached the N-methoxyiminium ion from the equatorial
face, giving 29 in 73% yield as a single diastereomer.16
We then attempted the reaction with acyclic ketones. The
allylation of 2-nonanone proceeded in high yield, but
poor diastereoselectivity (30: 87%, dr = 1.6:1). In the
case of an aromatic ketone, the best result was obtained
with 3.0 equiv of TFA instead of Sc(OTf)3, leading to high
(14) In general, the poorly nucleophilic allylsilane gave a lower yield
than the allylstannane in the three-component reaction. The allylsilane
was employed in the two-component reaction due to the high stability.
(15) For selected examples on the two-component reaction with
N-monosubstituted amines, see: (a) Monfray, J.; Gelas-Mialhe, Y.;
Gramain, J.-C.; Remuson, R. Tetrahedron: Asymmetry 2005, 16, 1025–
1034. (b) Amorde, S. M.; Jewett, I. T.; Martin, S. F. Tetrahedron 2009,
65, 3222–3231.
(16) The structure of 29 was determined by single-crystal X-ray
analysis (CCDC 864124). These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(12) The allylation of 4-tert-butyl-cyclohexanone with ammonia or a
primary amine tended to proceed via an equatorial attack (dr =
2.0ꢀ6.7:1); see: Reference 10b and 10d.
(13) For selected recent reviews on Strecker reaction, see: (a)
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–1094. (b) Ohfune,
€
Y.; Shinada, T. Bull. Chem. Soc. Jpn. 2003, 76, 1115–1129. (c) Groger, H.
Chem. Rev. 2003, 103, 2795–2827. (d) Vilaivan, T.; Bhanthumnavin, W.;
Sritana-Anant, Y. Curr. Org. Chem. 2005, 9, 1315–1392. (e) Friestad,
G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–2569.
2100
Org. Lett., Vol. 14, No. 8, 2012

Scheme 3. Two-Component Allylation for the Construction of
2,2-Disubstituted Piperidinesa
Scheme 4. Transformations of N-Methoxyamines
to the procedure reported by Varlamov, Kouznetsov, and
Zubkov, nitrone 34 was then transformed to spiroamine 35
as a single diastereomer through 1,3-dipolar cycloaddition,
followed by cleavage of the NꢀO bond.10c
a Conditions: ketone (1.0 equiv), N-methoxyamine 27 (1.0 equiv),
Sc(OTf)3 (1.0 equiv), MeCN (0.1 M), rt. bThe reaction was performed at
80 °C. cThe reaction was performed at 50 °C. dThe reaction was
In conclusion, we have developed novel multicompo-
nent reactions to access R-trisubstituted amines in a single
step by taking advantage of the high nucleophilicity of
N-methoxyamines as well as the high electrophilicity of the
N-methoxyiminium ions. The resulting N-methoxyamines
could undergo a variety of further transformations, lead-
ing to useful secondary amines. Studies on the enantiose-
lective variant of this reaction are in progress.
e
performed at 60 °C with TFA (3.0 equiv) instead of Sc(OTf)3. TFA
(1.0 equiv) was used instead of Sc(OTf)3.
diastereoselectivity (31: 57%, dr = 20:1). A ketoester could
be used for this two-component reaction with 1.0 equiv of
TFA and provided R,R-disubstituted amino acid derivative
32 in 53% yield as a single diastereomer.
Acknowledgment. This research was supported by a
Grant-in-Aid for Young Scientists (B) from MEXT
(21750049) and the Otsuka Pharmaceutical Co. Award
in Synthetic Organic Chemistry, Japan. We thank Prof.
Takeshi Noda and Mr. Takuya Shimogaki, Kanagawa
Institute of Technology, for their assistance with mass
spectrometric analysis.
As shown in Scheme 4, N-methoxyamines are readily
converted into potentially useful amines. As a demonstra-
tion, we first cleaved the N-methoxy group of 13d with Zn in
AcOH, affording secondary amine 33 in 97% yield. One of
the unique transformations related to N-methoxyamines is
direct oxidation to nitrones.17 Thus, the treatment of 13d
with mCPBA at ꢀ50 °C led to the formation of nitrone 34 in
90% yield without affecting the terminal olefin. According
Supporting Information Available. Experimental pro-
cedures; copies of 1H and 13C NMR spectra of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) For selected examples on the direct oxidation of N-alkoxya-
mines to nitrons, see: (a) Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.;
Trybulski, E. J.; Wong, S. C.; Ali, S. A. J. Am. Chem. Soc. 1979, 101,
2435–2442. (b) Ali, S. A.; Wazeer, M. I. M. Tetrahedron Lett. 1993, 34,
137–140. (c) Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.;
Kita, T.; Hashimoto, Y. Org. Lett. 2002, 4, 177–180.
The authors declare no competing financial interest.
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