Nonracemic 3°-carbamines from the asymmetric allylboration of N-trimethylsilyl ketimines with B-allyl-10-phenyl-9-borabicyclo[3.3.2]decanes

Article abstract of DOI:10.1021/ja062242q

The simple and efficient asymmetric synthesis of 3°-carbamines 7 from N-TMS enamines (3) and either enantiomeric form of β-allyl-10-(phenyl)-9-borabicyclo[3.3.2]decane (1) is reported. The high reactivity (<1 h, -78 °C) and enantioselectivity (60-98% ee) of these substrates can be attributed to the fact that the complexation of 3 with 1 facilitates its isomerization to the corresponding syn-N-TMS ketimine complex from which allylation can occur. In addition to providing the homoallylic amines 7 with predictable stereochemistry, the procedure also permits the efficient recovery of the chiral boron moiety (50-65%) as air-stable crystalline pseudoephedrine complexes 8, which are directly converted back to 1 with allylmagnesium bromide in ether (98%). Copyright

Full text of DOI:10.1021/ja062242q

Published on Web 06/15/2006
Nonracemic 3°-Carbamines from the Asymmetric Allylboration of
N-Trimethylsilyl Ketimines with B-Allyl-10-phenyl-9-borabicyclo[3.3.2]decanes
Eda Canales, Eliud Hernandez, and John A. Soderquist*
Department of Chemistry, UniVersity of Puerto Rico, Rio Piedras, Puerto Rico 00931-3346
Received April 2, 2006; E-mail: jas@janice.uprr.pr
The synthesis of nonracemic 3°-carbamines from the asymmetric
allylation of achiral ketimines represents an important synthetic
challenge. These amines can be prepared through the asymmetric
addition of Grignard and organolithium reagents to unsymmetrical
chiral N-sulfinyl ketimines.1 The asymmetric allylsilylation of
ketone-derived N-benzoylhydrazones was also demonstrated to
provide these nonracemic 3°-carbamines after the SmI2-mediated
reduction of the resulting homopropargylic hydrazines.2 While no
analogous asymmetric allylboration process is known for achiral
ketimines or related compounds, new allylboranes and processes
have been recently reported for the asymmetric allylboration of
ketones.3 Among these, the B-allyl-10-phenyl-9-borabicyclo[3.3.2]-
Mixtures of the anti-N-TMS ketimines (a-2) and 3 were prepared
through the Rochow protocol6 from nitriles and LiMe followed by
TMSCl (75-95%). These mixtures are thermally unstable, and
heating usually increases the amount of 3 and also gives rise to
minor amounts of the syn-ketimine s-2 (Table 1).
Table 1. N-TMS Ketimines and Enamines from Nitriles
decanes (9-BBDs) (1) contain a nearly ideal chiral pocket for the
highly enantioselective allylation of methyl ketones.3a In the present
study, we wish to report the asymmetric allylboration of N-TMS
ketimines 2 generated in situ from the reaction of N-TMS enamines
3 with 1. The new process can be viewed as occurring through an
initial complex 4 followed by isomerization to 5, allylation giving
6, which provides the desired 3°-carbamines 7 after a pseudoephe-
drine (PE) workup (Scheme 1).
R
series
a-2:3a
s-2:a-2:3b
Ph
a
b
c
d
e
f
g
h
i
94:6
16:22:62
4:4:92
5:48:47
2-MeOC6H4
4-MeOC6H4
t-Bu
70:30
40:60
80:20
60:40
45:55
74:26
60:40
81:19
60:40
87:13
c-Hx
4-BrC6H4
4-MeC6H4
3-Py
4-Me2NC6H4
4-ClC6H4
2-thienyl
15:35:50
5:36:59
4:9:87
j
k
10:26:64
0:70:30
Scheme 1
a The a-2:3 ratios were estimated from the 13C NMR analysis of the
peak areas for the TMS signals. Other characteristic signals for these
tautomers were also observed in each case. b The a-2:3 mixtures were heated
at reflux temperature (24-72 h), and the ratios of s-2, a-2, and 3 were
estimated as above (see Supporting Information).
Treatment of a-2a:3a (90:10) with a 1:1 mixture of 1 and MeOH
at -78 °C results in the clean formation of the desired N-boryl
homoallylic amine (11B NMR δ 51). An oxidative workup provided
7aR in 80% yield and 52% ee. The R configuration of 7aR is
consistent with the allylboration of PhCOMe with 1 (i.e., R, 96%
ee).3a The lesser ee for a-2a:3a versus PhCOMe parallels a similar
pattern observed in the allylboration of N-H aldimines versus
aldehydes with B-allyl-10-TMS-9-BBD.4e Our models for the key
pretransition states for these two processes are illustrated above
(cf. 9 and 10).
Clearly, 3 is not an obvious choice as a substrate for the
allylboration process. In fact, our plan was to follow an earlier
protocol which was successful for the allylboration of N-H aldimines
derived from the borane-mediated methanolysis of their N-TMS
precursors.4 Since the allylboration of the aldimines with the BBD
systems does not occur until the N-TMS derivatives are converted
to their N-H counterparts,4e we anticipated similar behavior, namely,
that 1 would smoothly allylate the N-H ketimines derived from 2
in a predictable manner (cf. 9 and 10).5
Seeking a more selective reaction protocol, we prepared (()-B-
Et-10-Ph-9-BBD (11) as a nonreacting model for 1. Its complexation
with PhMeCdNH (4 equiv) was examined by 11B NMR, revealing
that 11 (δ 83) was completely converted to its imine complex (δ
1). Unexpectedly, we also noted that 11 is partially complexed (11B
NMR δ -1, ∼5%) with the excess 90:10 a-2a:3a mixture at -78
°C even before the addition of MeOH. Moreover, using 4 equiv of
the 16:22:62 s-2:a-2:3 mixture increases the complexation with 11
to ∼90%.
9
8712
J. AM. CHEM. SOC. 2006, 128, 8712-8713
10.1021/ja062242q CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Allylboration of N-TMS Ketimines with 1
We view the larger TES versus TMS group as increasing the
relative amount of the minor 7fS enantiomer through this “upside-
down” isomer which avoids TMS-Ph repulsions. Moreover,
through the addition of EtMgBr to PhCN followed by TMSCl, we
prepared the N-TMS propiophenone enamines 3l as an 83:17 Z/E
mixture free of either ketimine tautomer. This mixture reacts rapidly
with (+)-1S (1 h, -78 °C) to give 7lR (67%) in 65% ee.9 Thus,
with the larger Et versus Me inward group, repulsions between the
BBD ring and this group apparently also increase the amount of 7
originating from this upside-down pathway, thereby lowering the
product ee.
yield of
7b(%)
% ee
3
1
8a
(abs. config.)c
a
b
c
d
e
f
g
h
i
R
R
R
R
S
63
52
48
58
64
61
65
50
75
58
55
50
66
65
67
71
82
74
80
92 (S)
94 (S)
92 (S)
98 (S)
70 (R)
70 (R)
84 (R)
60 (S)
94 (S)
64 (R)
60 (R)
S
S
R
R
S
j
k
60
65
S
Clearly the carbamines 7 are rare with only 7a being known in
nonracemic form.1a,2 With their ready availability through the
present methodology, we chose to further demonstrate their utility
through their conversion to the corresponding â3,3-amino acids and
â-amino aldehydes.1a Thus, acetylation of 7b gives 13b (80%)
whose ozonolysis (CH2Cl2, -78 °C) affords 14b (90%) and 15b
(57%) with oxidative (H2O2) and reductive (Me2S) workups,
respectively.
a Yield of crystalline (+)-8R from (-)-1R or (-)-8S from (+)-1S
reactions. b Isolated yield based upon 1. c The product ee’s were determined
by 31P NMR analysis of their Alexakis thiophosphoric triamides.7 The
absolute configurations of 7 were based upon the known rotation of 7a.1a,2
This suggested that a-2:3 mixtures may undergo allylboration
with 1 even without converting the N-TMS to the corresponding
N-H ketimine. The allylboration process was examined with (-)-
1R at -78 °C employing a 94:6 a-2a:3a mixture (2 equiv) with
the finding that the addition was complete in 16 h. Significantly,
the homoallylic amine 7a was formed in 92% ee and with the
opposite S absolute configuration from that obtained from PhMeCd
NH! Moreover, under these same conditions, the 16:22:62
s-2:a-2:3 mixture (2 equiv) also gave 7aS, again in 92% ee, with
the reaction being complete in <1 h. This reactivity is consistent
with the general process illustrated in Scheme 1, wherein 3 initially
forms a complex with 1 which rapidly isomerizes to the reacting 5
complex which leads to 6 and ultimately to 7. Clearly, 5 could
also form directly from s-2, but even in cases where this isomer is
not present, rapid allylboration occurs provided ample 3 is present
to react with 1, as illustrated in Scheme 1. Moreover, to gain addi-
tional support for our view of the process, the anti aldimine PhHCd
NTMS (2 equiv) was found to partially complex 1 (∼20% at -78
°C), but not its 10-TMS counterpart. However, this aldimine, despite
being less substituted than a-2a, does not undergo allylboration
with either 1 or its 10-TMS counterpart even after 1 week at 25
°C. These aldimines simply do not have access to their syn isomers
because the enamine-based process is not an option for them.
We carried out the allylboration of the 2/3 mixtures (g2 equiv
of 2/3) for 1 h at -78 °C with 1 to ultimately produce 8 (48-
65%) and the desired 3°-carbamine 7 (50-82%) in high ee (60-
98%) (Table 2). The complex 8 is easily recycled back to 1 (98%)
with allylmagnesium bromide in ether.
The asymmetric allylboration of ketimines with the BBD reagent
1 has been accomplished in a unique manner utilizing their N-TMS
enamines 3 to access the requisite syn-ketimine allylborane com-
plexes 5. The reagents 1 are readily prepared in either enantiomeric
form and are easily recycled providing the 3°-carbamines 7 in high
ee (60-98%). With the N-TMS substitution being readily hydro-
lyzed during workup, this new method has the advantage of
producing the free 3°-carbamines 7 for subsequent conversions.
Acknowledgment. The support of the NSF (CHE-0517194),
NIH (S06GM8102), and the U.S. Dept. Ed. GAANN Program
(P200A030197-04) is gratefully acknowledged. We thank Ms.
Eduvigis Gonzalez and Dr. Peter Baron for the X-ray structure of
(+)-8R.
Supporting Information Available: Experimental procedures,
analytical data, and selected spectra for 1-3, 7, 8, 13f, 14f, and 15g,
and derivatives and X-ray data for (+)-8R (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
As can be noted from these results, higher ee’s for 7 are generally
observed for aryl derivatives with electron-donating groups in the
aromatic ring. Sterically biased examples (e.g., 3d) also provide
excellent substrates for this process. For the 4-BrC6H4 (f) series,
we also prepared the mixture of N-triethylsilyl (TES) ketimine and
its enamine (81:19). This also underwent allylboration with (+)-
1S (1 h, -78 °C) to give 7fR (60%) in somewhat lower ee (50%)
than was observed with 3f (70% ee).
(1) (a) Hua, D. H.; Wu, S. W.; Chem, J. S.; Iguchi, S. J. Org. Chem. 1991,
56, 4. (b) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
(c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984.
(2) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686.
(3) (a) Canales, E.; Prasad, K. G.; Soderquist, J. A. J. Am. Chem. Soc. 2005,
127, 11572. (b) Wu, T. R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6,
2701. (c) Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2004, 126, 8910.
(4) (a) Chen, G.-M.; Ramachandran, P. V.; Brown, H. C. Angew. Chem., Int.
Ed. 1999, 38, 825. (b) Ramachandran, P. V.; Burghardt, T. E. Chem.s
Eur. J. 2005, 11, 4387. (c) Ramachandran, P. V.; Burghardt, T. E.; Ram
Reddy, M. V. J. Org. Chem. 2005, 70, 2329. (d) Ramachandran, P. V.;
Burghardt, T. E.; Bland-Berry, L. J. Org. Chem. 2005, 70, 7911. (e)
Hernandez, E.; Canales, E.; Gonzalez, E.; Soderquist, J. A. Pure Appl.
Chem. 2006, 7, 1389.
Simple MM calculations8 suggest that 3 strongly prefers (a series,
∼5 kcal/mol) to complex (-)-1R trans to the 10-Ph group (i.e.,
4). Tautomerism leads to either 5 or its rotamer 12.
(5) Chen, G.-M.; Brown, H. C. J. Am. Chem. Soc. 2000, 122, 4217.
(6) Chan, L.-H.; Rochow, E. G. J. Organomet. Chem. 1967, 9, 231.
(7) Alexakis, A.; Frutos, J. C.; Mutti, S.; Mangeney, P. J. Org. Chem. 1994,
59, 3326.
(8) Performed using the Spartan 04 MM program.
(9) With a 100% excess of E/Z-3l, the less sterically encumbered E-3l-1
complex is evidently formed and proceeds to product faster than with
Z-3l. Unreacted 3l is observed exclusively as the Z isomer.
JA062242Q
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