Sequential Pd-catalyzed asymmetric allene diboration/α- aminoallylation

Article abstract of DOI:10.1021/ja057020r

Pd-catalyzed enantioselective diboration of prochiral allenes provides adducts which participate in highly selective allylation reactions with primary imines. The allylation product is a vinyl boronate which may be oxidized to give nonracemic Mannich prod

Full text of DOI:10.1021/ja057020r

Published on Web 12/07/2005
Sequential Pd-Catalyzed Asymmetric Allene Diboration/r-Aminoallylation
Joshua D. Sieber and James P. Morken*
Department of Chemistry, Venable and Kenan Laboratories, The UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
Received October 21, 2005; E-mail: morken@unc.edu
Table 1. Enantioselective Diboration/Allylation of Allenes and
Imines
The significance of chiral amines in organic chemistry has
stimulated aggressive research into the development of catalytic
enantioselective additions to imines. Because of the particular
importance of â-amino acids and â-amino ketones, the enantio-
selective catalytic Mannich1 and allylation2 reactions have attracted
much attention. While spectacular successes have been recorded
in each of these areas, many obstacles persist. For instance, both
Lewis acid-catalyzed and organo-catalytic direct Mannich reactions
require aryl or sulfonyl imines for effective reaction. Post-reaction
removal of the resulting nitrogen appendage requires conditions
which may not be compatible with resident substrate functionality.
The catalytic allylation of imines is less developed than the Mannich
reaction, and recent examples also require specialized substrates.
For instance, an outstanding recent example by Kobayashi requires
a glyoxal-derived acyl hydrazone.2e In this report, we describe a
convenient approach to chiral addition products that proceeds
directly on ammonia-derived imines.3 In its most convenient form,
this process operates as a multicomponent R-aminoallylation4
involving an allene, a diboron reagent, an aldehyde, and an ammonia
source. Other attractive features of this transformation are that
chirality arises from catalytic amounts of palladium and a readily
available chiral ligand, it runs at room temperature and employs
commercially available inexpensive diboron reagents, and it
provides access to both optically enriched (87-97% ee) Mannich
products and uncommon allylation products.
entry
R
R1
methoda
% yieldb
% ee 3c,d
% ceee
1
Ph
Ph
Ph
Ph
A
B
A
B
A
68
59
68
69
70
97
96
97
96
92
99
98
99
98
94
2
3
4
5
6
7
8
9
2-furyl
(E)-hexenyl
PhCH2CH2 Ph
A
B
A
B
A
64
59
69
56
70
93
92
92
91
89
95
94
94
93
91
PhCH2CH2 2-furyl
PhCH2CH2 (E)-hexenyl
Cy
Cy
Cy
Ph
A
B
A
B
A
46
30
66
39
59
91
91
92
93
87
98
98
99
100
94
2-furyl
(E)-hexenyl
Recently, our laboratory has engaged in the development of
catalytic asymmetric reactions which produce reactive chiral
intermediates that may provide access to diverse arrays of complex
organic structures quickly and efficiently. Along these lines, we
have focused on developing catalytic asymmetric diboration
processes5 and, most recently, have studied the asymmetric di-
boration of prochiral allenes.6 This transformation affords chiral
diboron adducts (1, Table 1) that contain both allylboronate and
vinylboronate functional groups. These reactive intermediates are
effective in the asymmetric allylation of aldehydes, and excellent
levels of chirality transfer are observed.7 Considering the above-
mentioned significance of chiral amines in organic chemistry, it
was important to examine the reactivity of diboron intermediates
1 with imine electrophiles.
a Method A: Imine generated in situ from N-(TMS)aldimine and MeOH.
Method B: Imine generated in situ from aldehyde and NH4OAc in MeOH
with 4 Å MS. b Yield of â-amidoketone after silica gel chromatography;
average of two experiments. c Enantiomeric excess determined by chiral
HPLC or SFC analysis of â-amidoketone. d Optical purity of the diboron
intermediate for R ) Ph, PhCH2CH2, and Cy was 98, 98, and 93% ee,
respectively. e Defined as (% ee 3 ÷ % ee 1) × 100.
reaction mixture was treated with a silylimine and methanol (method
A) or the reaction mixture was treated with a methanolic solution
of an aldehyde and solid ammonium acetate (method B).9 After
protection with Ac2O and oxidation with H2O2, the â-amidoketone
product was isolated in good yield and excellent enantiomeric
excess. Considering the selectivity in the allene diboration reaction,
the level of chirality transfer in the subsequent allylation reaction
often approaches 99%.
As depicted in Table 1, high levels of chirality transfer generally
result from the one-pot synthesis of â-amidoketones from allenes.
In general, the products can be obtained in similar yields and
enantiomeric excesses using either method A or method B.
However, for cyclohexyl allene, method B proved to be less
efficient. This was due, in part, to competitive allylation of the
aldehyde present in the reaction pot. Similar to the reaction with
benzaldimine, which proceeded with 99% conservation of ee (%
cee), the reaction utilizing phenyl allene and furfuraldimine (entry
2) gave essentially complete chirality transfer. However, a slight
drop in chirality transfer was observed when an R,â-unsaturated
imine was employed in the reaction (entry 3). While 2-phenethyl-
Initial experiments directed toward development of a tandem
allene diboration/imine allylation were performed using purified 1
and silyl, benzyl, and sulfonyl imines derived from benzaldehyde.
When these electrophiles were treated with bisboronate 1, no
1
reaction was observed by H NMR analysis even after heating to
60 °C in CDCl3. Suspecting that steric demands imposed by the
pinacol groups might prohibit the reaction of substituted imines,
the reaction of unsubstituted imines was examined. Upon mixing
1 with N-trimethylsilylbenzaldimine, followed by the addition of
1.1 equiv of H2O to cleave the N-Si bond,8 rapid consumption
(<15 min) of the starting material occurred. On the basis of this
observation, a one-pot tandem allene diboration/imine allylation
process was developed. Upon executing allene diboration, the
9
74
J. AM. CHEM. SOC. 2006, 128, 74-75
10.1021/ja057020r CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Figure 1. Allylation transition structures.
be useful in other transformations and allow access to structurally
diverse organic compounds. Further applications of this chemistry
are currently under investigation.
Acknowledgment. This work was supported by the NIH (GM
59417). The authors thank Dr. Peter White for X-ray crystal-
lography.
Supporting Information Available: Experimental procedures and
physical data (1H and 13C NMR, IR, MS, X-ray, chiral HPLC, SFC).
This material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 2. X-ray structure of intermediate 4.
allene afforded compound 1 (R ) PhCH2CH2) in 98% ee, the
chirality transfer in reactions utilizing this allene is not as high as
with phenyl allene, and therefore, the allylation selectivity is slightly
diminished (entries 4 and 5). A similar diminution in chirality
transfer occurred in all three allylations involving the R,â-
unsaturated imine (entries 3, 6, and 9). The diboration of cyclohexyl
allene afforded 1 (R ) Cy) in 93% ee. The levels of chirality
transfer when utilizing this allene were on par with those observed
for phenyl allene (entries 7, 8, and 9).
Due to the fact that the enantiomer of the ligand used in the
diboration reaction led to intermediate 1RdPh with the (S) config-
uration and that the final â-amidoketone product was isolated with
the (R) configuration, it appears likely that the allylation proceeds
through a transition state structure similar to A (Figure 1), which
would be expected for type I allylmetal compounds.10,11 In this
model, it seems reasonable that the R group of 1 would sit in a
pseudoaxial position due to the significant A(1,2) strain present in
diastereomeric transition structure B. According to these models,
E-imines would be expected to react through structure C, where
several penalizing 1,3-diaxial interactions would deter the process,
as is observed. Upon reaction through structure A, one would expect
to observe the Z-configured olefin in the allylation intermediate.
In fact, it was possible to crystallize the allylation intermediate 4
(Figure 2) directly from the reaction mixture, and the X-ray analysis
of this compound is shown in Figure 2. As anticipated, the structure
contains the (Z) configuration at the olefin, thereby offering
structural evidence for the above proposal.
References
(1) For representative catalytic asymmetric Mannich reactions with activated
nucleophiles, see: (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem.
Soc. 1997, 119, 7153. (b) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am.
Chem. Soc. 1998, 120, 2474. (c) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D.
Angew. Chem., Int. Ed. 2001, 40, 2271. (d) Ferraris, D.; Young, B.; Cox,
C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.; Lectka, T.
J. Am. Chem. Soc. 2002, 124, 67. (e) Wenzel, A. G.; Jacobsen, E. N. J.
Am. Chem. Soc. 2002, 124, 12965. (f) Kobayashi, S.; Hamada, T.; Manabe,
K. J. Am. Chem. Soc. 2002, 124, 5640. (g) Akiyama, T.; Itoh, J.; Yakota,
K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. (h) Matsubara,
R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 1679.
(i) Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
7768. (j) Josephson, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2004, 126, 3734. For a review on catalytic direct Mannich reactions,
see: (k) Cordova, A. Acc. Chem. Res. 2004, 37, 102.
(2) (a) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc. 1998,
120, 4242. (b) Ferraris, D.; Dudding, T.; Young, B.; Drury, W. J., III;
Lectka, T. J. Org. Chem. 1999, 64, 2168. (c) Fang, X.; Johannsen, M.;
Yao, S.; Gathergood, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
1999, 64, 4844. (d) Gastner, T.; Ishitani, H.; Akiyama, R.; Kobayashi, S.
Angew. Chem., Int. Ed. 2001, 40, 1896. (e) Ogawa, C.; Sugiura, M.;
Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 6491. (f) Fernandes, R.
A.; Yamamoto, Y. J. Org. Chem. 2004, 69, 735.
(3) (a) Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
7182. The allylation of silylimines is thought to proceed through the
intermediacy of unsubstituted imines (see ref 8). For asymmetric allylations
of silylimines with chiral boron reagents, see: (b) Itsuno, S.; Watanabe,
K.; Matsumoto, T.; Kuroda, S.; Yokoi, A.; El-Sheway, A. J. Chem. Soc.,
Perkin Trans. 1 1999, 2011. (c) Itsuno, S.; Watanabe, K.; Ito, K.; El-
Sheway, A. A.; Sarhan, A. A. Angew. Chem., Int. Ed. Engl. 1997, 36,
109.
(4) Reviews involving R-aminoalkylation: (a) von Wangelin, A. J.; Neumann,
H.; Go¨rdes, D.; Klaus, S.; Stru¨bing, D.; Beller, M. Chem.sEur. J. 2003,
9, 4286. (b) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int.
Ed. 1998, 37, 1044.
In addition to the preparation of Mannich addition products, the
allylation intermediate could be subjected to non-oxidative condi-
tions (Scheme 1). For instance, the vinylboronate could be
protonated12 to afford the homoallylic amide in good yield, without
loss of enantiopurity, and as one olefin isomer by NMR spectros-
copy. It is notable that these Z-configured allylation adducts are
not obtainable directly by any other methodology. As an alternative
transformation, the allylation adduct was subjected to Boc protection
conditions, and the vinyl boronate was then treated with iodo-
benzene under Suzuki-Miyaura cross-coupling conditions.13 Here,
the trisubstituted allylation product was isolated in good yield
without loss of stereochemical purity.
In conclusion, we have developed a one-pot synthesis of
â-amidoketones from allenes in good yields and high enantio-
selectivities. In addition, the sequence provides access to useful
vinylboronate intermediates that can be isolated, characterized, and
converted to allylation adducts. These compounds may prove to
(5) (a) Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003,
125, 8702. (b) Miller, S. P.; Morgan, J. B.; Nepveux, F. J.; Morken, J. P.
Org. Lett. 2004, 6, 131.
(6) Pelz, N. F.; Woodward, A. R.; Burks, H. E.; Sieber, J. D.; Morken, J. P.
J. Am. Chem. Soc. 2004, 126, 16328.
(7) Woodward, A. R.; Burks, H. E.; Chan, L. M.; Morken, J. P. Org. Lett.
2005, 7, 5505-5507.
(8) (a) Chen, G.-M.; Brown, H. C. J. Am. Chem. Soc. 2000, 122, 4217. (b)
Chen, G. M.; Ramachandran, P. V.; Brown, H. C. Angew. Chem., Int.
Ed. 1999, 38, 825.
(9) Allylation of unsubstituted imines, generated from aldehydes and ammonia
or ammonium hydroxide, has been described. See ref 3a.
(10) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 2.
(11) For stereocontrolled addition of R-chiral allylboronates to carbonyls, see:
(a) Hoffmann, R. W. Pure Appl. Chem. 1988, 60, 123. (b) Hoffmann, R.
W.; Niel, G.; Schlapbach, A. Pure Appl. Chem. 1990, 62, 1993 and
references therein.
(12) (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370. (b)
Brown, H. C.; Zweifel, G. J. J. Am. Chem. Soc. 1961, 83, 3834.
(13) Reviews: (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Kohta,
S.; Lahirir, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
JA057020R
9
J. AM. CHEM. SOC. VOL. 128, NO. 1, 2006 75