N-propargylamides via the asymmetric Michael addition of B-alkynyl-10-TMS-9-borabicyclo[3.3.2]decanes to N-acylimines

Article abstract of DOI:10.1021/ol0611595

The asymmetric synthesis of N-propargylamides through Michael addition of the alkynylborane 1 to N-acylimines is reported. The N-acetylimines provide the best substrates for the process exhibiting high selectivity (56-95% ee) with predictable stereochemis

Full text of DOI:10.1021/ol0611595

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3331-3334
N-Propargylamides via the Asymmetric
Michael Addition of B-Alkynyl-10-TMS-9-
borabicyclo[3.3.2]decanes to
N-Acylimines
Ana Z. Gonzalez, Eda Canales, and John A. Soderquist*
UniVersity of Puerto Rico, Department of Chemistry, Rio Piedras,
Puerto Rico 00931-3346
jas@janice.uprr.pr
Received May 11, 2006
ABSTRACT
The asymmetric synthesis of N-propargylamides through Michael addition of the alkynylborane 1 to N-acylimines is reported. The N-acetylimines
provide the best substrates for the process exhibiting high selectivity (56 95% ee) with predictable stereochemistry. In several cases, 5
crystallizes in essentially pure form (97 99% ee) and a single-crystal X-ray structure was also obtained for 5g (R1 R2 Me, R3 o-Cl
C6C4). The process regenerates 4 for its direct conversion back to 1 and facilitates the efficient recovery of the pseudoephedrine.
−
−
)
)
)
−
With more than 75% of drugs and drug candidates containing
the nitrogen functionality, it is not surprising that the
asymmetric synthesis of amines is the focus of continuing
research. Versatile, multifunctional amines such as propar-
gylic amines are of interest because they provide useful
building blocks for the synthesis of more complex systems.1,2o
Many organometallic routes to propargylic amines have been
reported,2 but until recently, the organoborane-based alky-
nylation of imines was an unknown process.3 Recently, we
reported several highly useful asymmetric organoborane
conversions with the remarkably stable and versatile 10-
substituted-9-borabicyclo[3.3.2]decanes (10-R-9-BBDs).4 As
an extension of those studies, we chose to evaluate the
potential of B-alkynyl-10-trimethylsilyl-9-BBDs (1) to un-
dergo 1,4-addition to N-acylaldimines as a convenient entry
to nonracemic propargylic amides (5) (Scheme 1).
(1) (a) Dai, L.; Lin, Y.; Hou, X.; Zhou, Y. Pure Appl. Chem. 1999, 71,
1033. (b) Chung, J. L.; Wasicak, T. Tetrahedron Lett. 1990, 31, 3957. (c)
Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; Stone, B. P. R.; Parsons, R.
L.; Pesti, J., Jr.; Magnus, N. A.; Fortunak, J. M.; Confalone, P. N.; Nugent,
W. A. Org. Lett. 2000, 2, 3119.
(2) Organometallic-mediated propargylamine synthesis. Al: (a) Blanchet,
J.; Bonin, M.; Micoulin, L.; Husson, H. P. J. Org. Chem. 2000, 65, 6423.
Cu: (b) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (c) Koradin,
C.; Polbon, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 2535. (d)
Gommermann, N.; Polbon, K.; Koradin, C.; Polbon, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763. (e) Li, C.-J.; Li, Z. J. Am. Chem. Soc.
2004, 126, 11810. (f) Bernaud, F.; Vracken, E.; Mangeney, P. Org. Lett.
2003, 5, 2567. Zr: (g) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2003, 42, 4244. (h) Traverse, J. F.; Hoveyda, A.
H.; Snapper, M. L. Org. Lett. 2003, 5, 3273. Li: (i) Mecozzi, T.; Petrini,
M. J. Org. Chem. 1999, 64, 8970. (j) Enders, D.; Schankat, J. HelV. Chim.
Acta 1995, 78, 970. (k) Huffman, M. A.; Yasuda, N.; DeCamp, A. E.;
Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590. (l) Murai, T.; Mutoh,
Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968. Zn: (m)
Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121,
11245. (n) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6(9), 1497. For a
review, see: (o) Blanchet, J.; Bonin, M.; Micouin, L. Org. Prep. Proc. Int.
2002, 34, 467.
(3) Gonzalez, A.; Canales, E.; Soderquist, J. A. Presented at the 229th
National Meeting of the American Chemical Society, San Diego, CA,
March, 2005; Paper ORGN 933. During the preparation of the present
manuscript, a similar process with alkynylboronates derived from 3,3′-
disubstituted binaphthols was reported: Wu, T. R.; Chong, J. M. Org. Lett.
2006, 8, 15.
10.1021/ol0611595 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/29/2006

situ conversion to the corresponding N-H derivatives through
a borane-mediated methanolysis, allylation was rapid even
at -78 °C. In contrast to the rapid six-center allylation
process, the four-center alkynylation of aldehydes, N-TMS,
or N-H aldimines with 1 does not occur (1 week, 25 °C).
By contrast, we felt that N-acylaldimines (2) could exhibit
greater reactivity because these substrates can serve as
Michael acceptors for 1.9 Among the available routes to these
systems,10 the Wu¨rthwein acylation of N-TMS aldimines with
acid chlorides was particularly attractive and was employed
for the synthesis of 2 for this study.11,12
Scheme 1
We initially examined the role played by the acyl group
with respect to both the efficiency of the addition and its
enantioselectivity. Addition of 2 equiv of various N-acyl-
aldimines 2 to 1a (R1 ) Me) results in the complete
formation of the borinic ester intermediate 3 (11B NMR δ ∼
57) in 12 h at 25 °C.13 However, the alkynylation of the
N-carbamoyl derivative (Table 1, entry 6) was very slow (1
Table 1. Michael Additions of 1R to N-Acylaldimines (2)a
entry
R2
R3
5
yield (%)b
ee (%)c
1
2
3
4
5
6
Ph
Ph
Ph
i-Pr
Me
OEt
2-C4H3O
Ph
2-C4H3S
Ph
Ph
Ph
a
b
c
d
e
f
89
73
85
86
72
42
83
70
83
94
95
39
Alkynylboranes have been known to add to nonconjugated
aldehydes and more slowly to ketones to give the corre-
sponding propargyl alcohols.5 With conjugated enones, 1,4-
addition is observed resulting in â-alkynyl ketones.6 More
recently, this was developed into an effective asymmetric
process employing chiral alkynylboronic esters.5b This
preference for 1,4- vs 1,2-addition can be attributed to a
favorable six-membered ring cyclic transition state for the
alkynylation of the enone in its cisoid form. In a general
sense, conjugate additions are highly useful processes,7 with
several of these methods involving organoboranes.6,8
a For entries 2-6, the B-propynyl derivative 1aR (R1 ) Me) was used.
For the known 5a, the B-heptynyl derivative 1eR (R1 ) n-C5H11) was
employed to verify the product stereochemistry. b Isolated yields after
column chromatography. c Product ee determined by HPLC analysis with
a Chiracel OD column.
Recently, we examined the allylation of N-TMS imines
employing 10-R-9-BBD reagents.4e,f For the aldimines, the
N-TMS derivatives were unreactive. However, with their in
week, 25 °C) and gave a low product yield and ee. From
these results, we selected the N-acetylaldimines (R2 ) Me)
for the present study because these were both easy to prepare
and gave high product ee’s (e.g., Table 1, 5e).
(4) (a) Hernandez, E.; Soderquist, J. A. Org. Lett. 2005, 7, 5397. (b)
Lai, C.; Soderquist, J. A. Org. Lett. 2005, 7, 799. (c) Burgos, C.; Canales,
E.; Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 8044. (d)
Canales, E.; Prasad, G.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127,
11572. (e) Hernandez, E.; Canales, E.; Gonzalez, E.; Soderquist, J. A. Pure
Appl. Chem. 2006, 7, 1389. (f) Canales, E.; Hernandez, E.; Soderquist, J.
A. J. Am. Chem. Soc., 2006, 128, 8712-8713.
(5) (a) Brown, H. C.; Molander, G. A.; Singh, S. M.; Racherla, U. S. J.
Org. Chem. 1985, 50, 1577. (b) Evans, J. C.; Goralski, C. T.; Hasha, D. L.
J. Org. Chem. 1992, 57, 2941. (c) Corey, E. J.; Cimprich, K. A. J. Am.
Chem. Soc. 1994, 116, 3151.
Readily available through simple Grignard procedures,
several alkynylboranes 1 were prepared (R1 ) Me (a),
(8) For early Michael additions with trialkylboranes, see: (a) Brown,
H. C.; Rogic´, M. M.; Rathke, M. W.; Kabalka, G. W. J. Am. Chem. Soc.
1967, 89, 5907. (b) Brown, H. C.; Kabalka, G. W.; Rathke, M. W.; Rogic´,
M. M. 1968, 90, 4165. For recent asymmetric Michael additions with
areneboronic acids, see: Paquin, J.; Defieber, C.; Stephenson, C. R. J.;
Carreira, E. M. J. Am. Chem Soc. 2005, 127, 10850 and references therein.
(9) For additions to N-acylimines, see: (a) Hermanns, N.; Dahmen, S.;
Bolm, C.; Bra¨se, S. Angew. Chem., Int. Ed. 2002, 41, 3692. (b) Dahmen,
S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940. (c) Mecozzi, T.; Petrini,
M. Tetrahedron Lett. 2000, 2709. (d) Mecozzi, T.; Petrini, M.; Profeta, R.
J. Org. Chem. 2001, 66, 8264. (e) Petrini, M.; Profeta, R.; Righi, P. J. Org.
Chem. 2002, 67, 4530. (f) Kanazawa, A. M.; Denis, J.; Greene, A. E. J.
Chem. Soc., Chem. Commun. 1994, 2591. (g) Chao, W.; Waldman, J. H.;
Weinreb, S. M. Org. Lett. 2003, 5, 2915. (h) Sigman, M. S.; Jacobsen, E.
N. J. Am. Chem. Soc. 1998, 120, 4901.
(6) (a) Sinclair, J. A.; Molander, G. A.; Brown, H. C. J. Am. Chem. Soc.
1977, 99, 954. (b) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc.
2000, 122, 1822.
(7) For Michael additions, see: Al: (a) Yoshino, T.; Okamoto, S.; Sato,
F. J. Org. Chem. 1991, 56, 3205. (b) Arai, T.; Sasai, H.; Aoe, K.; Okamura,
K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. 1996, 35, 104. La: (c)
Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 7557. (d) Sasai, H.; Arai, T.; Satw, Y.; Houk,
K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194. Organocatalysis:
(e) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
8331. (f) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 661. (g) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002,
124, 13394. (h) Sammis, G.; Jabobsen, E. N. J. Am. Chem. Soc. 2003, 125,
4442. (i) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204.
(j) Jha, S. C.; Joshi, N. N. Tetrahedron: Asymmetry 2001, 12, 2463. (k)
Myers, J. K.; Jacobsen, E. J. J. Am. Chem. Soc. 1999, 121, 8959. For a
review, see: (l) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 2, 171.
(10) (a) Chao, W.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 9199.
(b) Back, T. G.; Brunner, K. J. Org. Chem. 1989, 54, 1904.
(11) Kupfer, R.; Meier, S.; Wu¨rthwein, E. Synthesis 1984, 688.
(12) All N-acyl (carbamoyl) imines were synthesized with the Wu¨rthwein
method without further purification immediately prior to the addition to 1.
(13) Use of 1.0 equiv of 2 in these processes provides 5 with similar
selectivities and reaction yields but with significantly longer reaction times
(ca. 1 week, 25 °C).
3332
Org. Lett., Vol. 8, No. 15, 2006

C(Me)dCH2 (b), (CH2)3Cl (c), c-C3H5 (d), (CH2)4CH3 (e))
to introduce differing alkynyl substitution into the products
5. Nonenolizable aldehydes were used to ultimately produce
2 through their N-TMS aldimines. Following the complete
formation of 3, the mixture was concentrated and the
appropriate enantiomer of pseudoephedrine (PE) and aceto-
nitrile were added. Transesterification occurs in 48 h at reflux
temperature, ultimately providing 4 (35-65%) for the
regeneration of 1. The N-propargylamides 5 were isolated
in good yields (61-82%) and high selectivity (56-95% ee).
Interestingly, in several cases, the enantiomeric excess of 5
was significantly upgraded to 97-99% through recrystalli-
zation from hexane/ethyl acetate (see Table 2, entries 2, 4,
Scheme 2
Table 2. Asymmetric Michael Addition of 1 to 2
a
entry
R1
R3
5
yield (%)b
ee (%)c
1
2
3
4
5
6
7
Me
Me
(CH2)3Cl
Ph
o-ClC6H4
p-MeOC6H4
e
g
h
i
j
k
l
72
54
81
61
61
82
50
95
70 (97)d
82
stereochemistry. This is also consistent with the above
selectivity observed for 5a.
C(Me)dCH2 p-MeOC6H4
84 (>99)d
74 (>99)d
56
c-C3H5
c-C3H5
Me
o-ClC6H4
Ph
t-Bu
To provide a potential explanation for the observed product
stereochemistry, we chose to examine eight possible dia-
stereomeric pre-transition-state cisoid syn-O-acetylbenzaldi-
mine complexes with 1 employing simple MM calculations.
We constrained the R-alkynyl carbon-iminyl carbon distance
to 3Å (Figure 1, dotted lines in red) which gave the lowest-
68
a For entries 1 and 3-5, the (10R) enantiomers of 1 were used. For entries
2, 6, and 7, the (10S) enantiomers of 1 were used. b Isolated yields after
column chromatography. c Product ee determined by HPLC analysis with
a Chiracel OD column. d Enantiomeric excess after recrystallization of 5.
and 5). The single-crystal X-ray structure of 5g reveals
intermolecular H-bonding between the amide hydrogen and
the carbonyl oxygen of an adjacent molecule.14 This second-
ary structure can account for the observed ee enhancement
through the recrystallization of 5.
This process can be conducted with the in situ formation
of the N-acetylaldimine in the presence of 1. Because neither
the acetyl chloride nor the N-TMS aldimine reacts with 1,
this three-component process of 5e is nearly as efficient
(67%) as the reaction of 2 with 1 (i.e., Table 2, entry 1,
72%).
Figure 1. Proposed models for the observed stereochemistry of
the alkynylation of 2 with (-)-1R.
The absolute stereochemistry of 5a was assigned from the
reported value for its rotation.2a Thus, (+)-(1R)-5a was
obtained from (-)-1eR. The BBD systems have been
previously demonstrated to give both predictable and con-
sistent selectivities in other asymmetric transformations.4
However, to further confirm the stereochemical assignments
of 5, we carried out the catalytic hydrogenation of 5g (from
1aS) which gave 6, quantitatively (Scheme 2). This N-
butylamide was also prepared by the asymmetric allylbora-
tion of N-H 2-chlorobenzaldimine (from its N-TMS precur-
sor, MeOH, and (+)-7S) which gave the known homoallylic
amine 8, with S stereochemistry.4e Following the acetylation
of 8 to give 9, its hydrogenation provides 6 (80%). With
both procedures producing the same (-) enantiomeric form
of 12, it is clear that N-propargylamide 5g also has the (1S)
energy complexes for the formation of R and S aminoboranes
3 from (-)-1R, of which R is lower in energy (∼2.5 kcal/
mol) than S. This semiquantitative model for the process is
consistent with the general observation that the carbonyl
oxygen coordinates the boron atom cis to the 10-TMS in
the BBD system in a wide range of asymmetric processes.
We view the reaction as occurring through a B-O coordi-
nated six-membered transition state in which the close
proximity of the now more electrophilic imine carbon
facilitates the transfer of the nucleophilic alkynyl group.
Finally, the deprotection of 5j can be smoothly achieved
with chlorine and triphenyl phosphite as reported by Prati.15
This impressive procedure provides the free amine 10 in 87%
yield (Scheme 3).
(14) These intermolecular interactions are apparent from the crystal-
lographic data included in the Supporting Information.
(15) Spaggiari, A.; Blaszczak, L. C.; Prati, F. Org. Lett. 2004, 6, 3885.
Org. Lett., Vol. 8, No. 15, 2006
3333

cases through a simple recrystallization. Moreover, deacety-
lation of 5 easily provides the corresponding amines (e.g.,
10). This borane-mediated Michael alkynylation of 2 pro-
vides a highly attractive method for the asymmetric synthesis
of propargylamides and amines.
Scheme 3
Acknowledgment. The support of the NSF (CHE-
0517194), NIH SCORE (S06GM8102), and U.S. Department
Ed. GAANN Program (P200A030197-04) is gratefully
acknowledged. We wish to thank Dr. Gellert Mezei (Uni-
versity of Puerto Rico) for determining the X-ray structure
of 5g.
In summary, the reagents 1 are cleanly prepared from the
enantiomerically pure air-stable crystalline complexes 4
through simple Grignard procedures which also permit the
recovery of pseudoephedrine (81%). Reagents 1 cleanly add
to N-acylimines (2) (12 h, 25 °C), efficiently producing
N-propargylamides (5) following a nonoxidative pseu-
doephedrine workup which regenerates 4 (35-65%). De-
pending upon the enantiomeric form of 1 employed, either
enantiomer of 5 can be prepared with predictable stereo-
chemistry. The N-acetyl derivatives of 2 provide good to
excellent selectivities (56-95% ee) in the formation of 5,
and these values were easily enhanced to >97% ee in several
Supporting Information Available: Full experimental
procedures, characterization data, selected spectra for 1,
4-10, and derivatives, and X-ray crystallographic data for
5g (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0611595
3334
Org. Lett., Vol. 8, No. 15, 2006