β-Silylated homopropargylic amines via the asymmetric allenylboration of aldimines

Article abstract of DOI:10.1021/ol070074g

(Chemical Equation Presented) The asymmetric synthesis of α-trimethylsilylpropargylic carbamines (7) through the addition of allenylboranes 4 to N-H aldimines is reported. The insertion of TMSCHN ₂ into enantiomerically pure B-alkynyl-10-TMS-9-

Full text of DOI:10.1021/ol070074g

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1081-1084
â
-Silylated Homopropargylic Amines via
the Asymmetric Allenylboration of
Aldimines
Ana Z. Gonzalez and John A. Soderquist*
Department of Chemistry, UniVersity of Puerto Rico,
Rio Piedras, Puerto Rico 00931-3346
jas@janice.uprr.pr
Received January 10, 2007
ABSTRACT
The asymmetric synthesis of
r-trimethylsilylpropargylic carbamines (7) through the addition of allenylboranes 4 to N-H aldimines is reported.
The insertion of TMSCHN2 into enantiomerically pure B-alkynyl-10-TMS-9-borabicyclo[3.3.2]decanes 3 followed by a sterically driven 1,3-
suprafacial borotropic shift proceeds with complete stereospecificity to produce 4 in diastereomerically and enantiomerically pure form. These
reagents give 7 (51−85%, syn/anti >99%, 92−9% ee) permitting the recovery of 8 (53−63%). Allenylboranes 4 also provide a convenient route
to optically pure allenylsilanes 13 (55−94%) through their protonolysis.
Homopropargylic amines constitute an important class of
nitrogen-containing building blocks whose asymmetric syn-
thesis represents a challenging task. Their racemic synthesis
through the allenylation of N-substituted imines is ac-
complished employing a variety of allenylmetallics, including
B-allenyl-9-BBN.1,2 However, until now, the asymmetric
allenylboration of imines has not been reported.
highly selective route to 2 through the allenylboration of N-H
aldimines, generated from either their N-TMS or N-DIBAL
precursors. As a representative example, we chose to add
N-TMS benzaldimine to 1 in the presence of 1 equiv of
MeOH. This affords 2 efficiently (91%) in good optical
purity (73% ee) (Scheme 1). This observed selectivity of 1
Recently, we have developed a number of new organobo-
rane reagents for asymmetric conversions which contain the
remarkably versatile 10-trimethylsilyl-9-borabicyclo[3.3.2]-
decane (10-TMS-9-BBD) ring system. For example, either
aldehydes or N-H aldimines provide effective substrates for
asymmetric allylation with these reagents.3 This suggested
that the corresponding B-allenyl reagent 14 might provide a
Scheme 1
(1) Yamamoto, Y.; Ito, W.; Maruyama, K. J. Chem. Soc., Chem.
Commun. 1984, 1004.
(2) Brown. H. C.; Khire, U. R.; Narla, G.; Racherla, U. S. J. Org. Chem.
1995, 60, 544.
(3) (a) Burgos, C.; Canales, E.; Matos, K.; Soderquist, J. A. J. Am. Chem.
Soc. 2005, 127, 8044. (b) Hernandez, E.; Canales, E.; Gonzalez, E.;
Soderquist, J. A. Pure Appl. Chem. 2006, 78, 1389 and references cited
therein.
with benzaldimine compared to benzaldehyde (93% ee) is
consistent with a general trend wherein aldehydes provide
(4) Lai, C.; Soderquist, J. A. Org. Lett. 2005, 7, 799.
10.1021/ol070074g CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/13/2007

higher selectivities than do their imine counterparts. This
diminution in selectivity can be attributed to the lesser size
difference between the atoms which are coordinated to the
boron atom, that is, the allenyl sp2 carbon vs either the iminyl
NH or the smaller aldehydic O. This suggested that by
increasing the effective size of the allenyl group, the
selectivity of the allenylboration could be enhanced. Fortu-
nately, we had recently discovered a novel entry to more
substituted B-allenyl-10-TMS-9-BBDs (4) in optically pure
form.5 These result from a stereospecific CH(TMS) insertion
into B-alkynyl-10-TMS-9-BBDs (3) followed by a sterically
driven suprafacial 1,3-borotropic shift of the resulting
propargylborane to give 4 as a single diastereomer (Scheme
2). For aldehydes, 4 (94-99% ee) is more enantioselective
than is 1 (93-95% ee).
THF triggers the smooth allenylboration process (12 h,
-78 °C). Following the complete formation of 6, the mixture
was concentrated and the appropriate enantiomer of PE and
acetonitrile were added. Transesterification occurs in 12 h
at reflux temperature ultimately providing 8 (53-63%),
which can be recycled for the regeneration of 4. The R-TMS
propargylic carbamines 7 were isolated in high yields (51-
85%) and excellent selectivity (>99% syn, 92-99% ee).
While 4b (R1 ) (CH2)3Cl) is particularly selective (99% ee),
even 4a (R1 ) Me) adds to acetaldimine to provide 7h in
92% ee (Table 1, entry 8).
Table 1. Allenylboration of N-H Aldimines with 4a
entry
4
R2 in 5
7
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
b
b
b
b
d
c
2-C4H3S
CH(CH3)2
4-MeOC6H4
Ph
Ph
Ph
a
b
c
d
e
f
51
66
72
85
84
78
77
83
99
99
99
99
99
99
94
92
Scheme 2
a
a
Ph
CH3
g
h
a Isolated yields after column chromatography. b Product ee determined
utilizing 31P NMR after the conversion of 7 to their phosphoramide
derivatives through the alexakis procedure.7
The remarkable enantioselectivity observed for this process
can be attributed to the difference in size between the
R-substituted allenic carbon and the incoming aldimine
(Figure 1). We examined pre-transition state complexes A
Readily available through simple Grignard procedures,
several alkynylboranes (3) were prepared (R1 ) Me (a),
(CH2)3Cl (b), c-C3H5 (c), (CH2)4CH3 (d)) from the enantio-
merically pure crystalline complexes 8 (Scheme 2). In this
process, pseudoephedrine (PE) can be recovered (81%)
through the addition of HCl to the insoluble Mg+2 salts
formed as byproducts from this metathesis. Addition of
TMSCHN2 to 3 results in an antiperiplanar 1,2-BfC alkynyl
group migration to give an R-silylated propargylborane,
which undergoes a sterically driven 1,3-suprafacial borotropic
rearrangement to ultimately give 4.5
Figure 1. Proposed models for the observed stereochemistry in
the allenylboration of N-H aldimines with (-)-4R.
(anti/cis) and B (anti/trans) computationally, which reveals
that A is favored over B. This is because the unfavorable
steric interactions of the allenyl CHR1 moiety with the 10-
TMS substitution are absent in A. This model is consistent
with the diminution in enantioselectivity observed with a
reduction in the size of R1 to methyl (94%, Table 1, entry
7).8
Allenylation with 4 was conducted with the N-H imines
derived from either N-TMS or N-DIBAL aldimines 5.6
Addition of 1 equiv of methanol to a mixture of 4 and 5 in
(5) Canales, E.; Gonzalez, A.; Soderquist, J. A. Angew. Chem., Int. Ed.
2007, 46, 397.
(6) N-TMS aldimines: (a) Hart, D. J.; Kania, K.-I.; Thomas, D. G.; Yang,
T. K. J. Org. Chem. 1983, 48, 289. N-DIBAL aldimines: (b) Itsuno. S.;
Wantanabe, K.; Kroda, S.; Yokoi, A.; Ito, K.; Itsuno, S. J. Organomet.
Chem. 1999, 581, 103.
(7) Alexakis, A.; Furtos, J. C.; Mutti, S.; Mangeney, P. J. Org. Chem.
1994, 59, 3326.
1082
Org. Lett., Vol. 9, No. 6, 2007

The syn relative stereochemistry of the R-TMS-propargylic
carbamines 7 was confirmed from the single-crystal X-ray
structure of 7d (Figure 2). This is also consistent with our
the nonracemic homoallylic amine 12. This process retains
the two contiguous stereogenic centers with the introduction
of the Z-allylsilane functionality (Scheme 3).
Scheme 4
Figure 2. Single-crystal X-ray structure of 7d hydrochloride
Allenylboranes smoothly undergo protonolysis with acetic
acid to provide the corresponding allenes.11 Taking advantage
of the high optical purity of our allenylboranes 4, we chose
to explore their conversion to optically pure allenylsilanes
13. These are useful for several transformations such as their
findings in the allenylboration of aldehydes with 4.5 The
absolute stereochemistry of these amines 7 was obtained
through the conversion of (1R, 2R)-7g (from 4Sa) to
1-amino-1-phenylpentane 11. In contrast to their carbinol
counterparts which easily undergo elimination, â-TMS
carbamines react with TBAF (1 equiv) to produce a 34:66
mixture of propargylic (9) and allenic (10) carbamines.9
Catalytic hydrogenation of this mixture with exactly 2 equiv
of H2 provides (1S)-11. The assignment of the absolute
configuration of 11 was based upon its specific rotation
compared to the literature value (see Scheme 3).10 The S
Table 2. Asymmetric Synthesis of Allenylsilanes 13
b
entry
R1
4
13
yield (%)a
[R]D
1
2
3
4
Me
Sa
Rb
Sc
Rd
a
b
c
55
86
87
94
+94.0
-107.4
+40.6
(CH2)3Cl
c-C3H5
C5H11
d
-39.6
a Isolated yields after column chromatography. b Specific rotations were
determined in either CDCl3 or CH2Cl2 solution. See Si for the conditions
employed for each example.
Scheme 3
addition to aldehydes and for cycloadditions.12 Allenylsilanes
are usually prepared through the organocuprate addition to
propargyl carbamates or mesylates.13 Other methods for the
synthesis of allenylsilanes include the palladium-catalyzed
bis-silylation of optically active propargylic alcohols14 and
(9) For some synthetic modifications of allenic amines see: (a) Fukuhara,
K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145. (b) Ohno, H.; Toda, A.;
Miwa, Y.; Taga, T.; Fujii, N.; Ibuka, T. Tetrahedron Lett. 1999, 40, 349.
For the synthesis of optically active allenic carbamines see: (c) Shen, L.;
Hsung, R. P.; Zhang, Y.; Antoline, J.; Zhang, X. Org. Lett. 2005, 7, 3081.
(10) Itsuno, S.; Yanaka, H.; Hachisuka, C.; Ito, K. J. Chem. Soc., Perkin
Trans. 1 1991, 1341.
(11) Pelter, A.; Smith, K.; Brown, H. C. In Borane Reagents; Katritzky,
A. R., Meth-Cohn, O., Rees, C. W., Eds; Academic Press: San Diego,
CA, 1988; Chapter 1, pp 40-41 and 73-74.
(12) For additions to aldehydes see: (a) Kobayashi, S.; Nishio, K. J.
Am. Chem. Soc. 1995, 117, 6392. (b) Marshall, J. A.; Adams, N. D. J.
Org. Chem. 1997, 62, 8976. (c) Marshall, J. A.; Maxson, K. J. Org. Chem.
2000, 65, 630. For [2 + 2] cycloadditions see: (d) Akiyama, T.; Daidouji,
K.; Fuchibe, K. Org. Lett. 2003, 5, 3691. (e) Shepard, M. S.; Carreira, E.
M. J. Am. Chem. Soc. 1997, 119, 2597. For [3 + 2] additions see: (f)
Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y. J. Am. Chem. Soc. 1985,
107, 7233. (g) Yadav, V. K.; Srinamurthy, V. Org. Lett. 2004, 6, 4495.
(13) (a) Fleming, I.; Takaki, K.; Thomas, A. P. J. Chem. Soc., Perkin
Trans. I 1987, 2269. (b) Fleming, I.; Terrett, N. J. Organomet. Chem. 1984,
264, 99. (c) Guintchin, B. K.; Bienz, S. Organometallics 2004, 23, 4944.
configuration for 11 is consistent with the stereochemistry
expected from the favored pre-transition state complex A.
As a useful application of 7, we carried out the semire-
duction of 7g to provide a particularly convenient entry to
(8) The equilibrium distance between the γ-allenyl carbon atom and the
iminyl carbon is ∼3.4 ∆. Constricting this distance to 3.0 ∆, increases this
energy difference (A vs B, R1 ) Me, R2 ) Ph) to >1 kcal/mol.
Org. Lett., Vol. 9, No. 6, 2007
1083

the palladium-catalyzed hydrosilylation of enynes.15 Axially
chiral allenylboranes are known and their protonolysis does
produce optically active allenes.16 Addition of 1 equiv of
glacial acetic acid to 4 affords 13 in good yields (55-97%)
after 6 h at 25 °C. Since this reaction proceeds with retention
of configuration either enantiomer of the allenylsilane can
be synthesized depending on the enantiomer of 4 employed.
In summary, the allenylborane reagents 4 are simply
prepared from the enantiomerically pure air-stable crystalline
complexes 8 through a two-step operation involving a
Grignard procedure to give the alkynylborane 3 followed
by treatment with TMSCHN2 to result in an insertion/
rearrangement that gives 4 in both diasteromerically and
enantiomerically pure form. This method also permits the
recovery of pseudoephedrine (81%). Reagents 4 cleanly add
to N-H imines (5) (12 h, -78 °C), efficiently producing
R-TMS-propargylic carbamines (7) following a non-oxidative
pseudoephedrine workup that regenerates 8 (53-63%) for
recycling. Depending upon the enantiomeric form of 4
employed, either enantiomer of 7 can be prepared with
predictable stereochemistry. The addition of 4 to N-H imines
proved to be a highly selective process (92-99% ee) for
the synthesis of the homopropargylic amines 7, even for the
more challenging substrates such as acetaldimine. Reagents
1 can also be transformed into the corresponding optically
pure allenylsilanes 13 through simple protonolysis in good
to excellent yields (55-94%).
Acknowledgment. The support of the NSF (CHE-
0517194), NIH SCORE (S06GM8102), and U.S. Department
of Education GAANN Program (P200A030197-04) is grate-
fully acknowledged. We wish to thank Dr. Hong Zhao
(University of Puerto Rico) for determining the X-ray
structure of 7d hydrochloride.
Supporting Information Available: Full experimental
procedures, characterization data, selected spectra for 2-4,
7-13, and derivatives and X-ray crystallographic data for
7d hydrochloride. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Suginome, M.; Matsumotu, A.; Ito, Y. J. Org. Chem. 1996, 61,
4884.
(15) Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001,
123, 12915.
(16) (a) Matsumoto, Y.; Naito, M.; Uozumi, Y.; Hayashi, T. J. Chem.
Soc., Chem. Commun. 1993, 1468. (b) Shimizu, M.; Kurahashi, T.;
Kitagawa, H.; Hiyama, T. Org. Lett. 2003, 5, 225-227. (c) Midland, M.
M.; McDowell, D. C. J. Organomet. Chem. 1978, 156, C5.
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