A highly stereoselective addition of lithiated ynamides to Ellman-Davis chiral N-tert -butanesulfinyl imines

Article abstract of DOI:10.1021/ol400989x

A highly diastereoselective addition of lithiated ynamides to Ellman-Davis chiral imines is described. While additions of N-sulfonyl ynamides are highly stereoselective even without Lewis acids, the use of BF₃-OEt ₂ completely reversed the stereoselectivity. In addition, oxazolidinone-substituted ynamides behaved differently and functioned better with BF₃-OEt₂, and the chirality of the oxazolidinone ring exerts no impact on the selectivity.

Full text of DOI:10.1021/ol400989x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Highly Stereoselective Addition of
Lithiated Ynamides to EllmanÀDavis
Chiral N‑tert-Butanesulfinyl Imines
Xiao-Na Wang, Richard P. Hsung,* Rui Qi, Sierra K. Fox, and Ming-Can Lv
Division of Pharmaceutical Sciences and Department of Chemistry, University of
Wisconsin, Madison, Wisconsin 53705, United States
rhsung@wisc.edu
Received April 9, 2013
ABSTRACT
A highly diastereoselective addition of lithiated ynamides to EllmanÀDavis chiral imines is described. While additions of N-sulfonyl ynamides are highly
stereoselective even without Lewis acids, the use of BF3ÀOEt2 completely reversed the stereoselectivity. In addition, oxazolidinone-substituted
ynamides behaved differently and functioned better with BF3ÀOEt2, and the chirality of the oxazolidinone ring exerts no impact on the selectivity.
The chemistry of ynamides has evolved into a burgeon-
ing field that is attracting an immense amount of attention
from the synthetic community.1,2 Although new transfor-
mations involving ynamides have appeared in the litera-
ture at a rapid pace,3 new and improved protocols for
synthesizing ynamides,4,5 and more provocatively, struc-
tural relatives of ynamides6 have also been continuously
reported in recent years. To continue developing useful
methods for constructing N-heterocycles, we have been
exploring N-tethered intramolecular transformations
through usage of γ-amino-ynamides such as 1 [Scheme 1].7
(1) For current leading reviews on ynamides, see: (a) DeKorver,
K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P.
Chem. Rev. 2010, 110, 5064. (b) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem., Int. Ed. 2010, 49, 2840.
(2) For reviews partially accounting the chemistry of ynamides, see:
(a) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503.
(b) Domınguez, G.; Perez-Castells, J. Chem. Soc. Rev. 2011, 40, 3430. (c)
Weding, N.; Hapke, M. Chem. Soc. Rev. 2011, 40, 4525. (d) Madelaine,
C.; Valerio, V.; Maulide, N. Chem.;Asian J. 2011, 6, 2224.
(3) Given the volume, for ynamide chemistry published since September
of 2012, see: (a) Karmakar, R.; Mamidipalli, P.; Yun, S. Y.; Lee, D. Org.
Lett. 2013, 15, 1938. (b) Brioche, J.; Meyer, C.; Cossy, J. Org. Lett. 2013, 15,
1626. (c) Yun, S. Y.; Wang, K.-P.; Lee, N.-K.; Mamidipalli, P.; Lee, D.
J. Am. Chem. Soc. 2013, 135, 4668. (d) Heffernan, S. J.; Beddoes, J. M.;
Mahon, M. F.; Hennessy, A. J.; Carbery, D. R. Chem. Commun. 2013, 49,
2314. (e) Kong, Y.; Jiang, K.; Cao, J.; Fu, L.; Yu, L.; Lai, G.; Cui, Y.; Hu,
Z.; Wang, G. Org. Lett. 2013, 15, 422. (f) Yavari, I.; Nematpour, M.;
Sodagar, E. Synlett 2013, 24, 161. (g) Yavari, I.; Nematpour, M. Synlett
2013, 24, 165. (h) Bhunia, S.; Chang, C.-J.; Liu, R.-S. Org. Lett. 2012, 14,
5522. (i) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I.
Nature 2012, 490, 522. (j) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.;
Woods, B. P. Nature 2012, 490, 208. (k) Cao, J.; Kong, Y.; Deng, Y.; Lai,
G.; Cui, Y.; Hu, Z.; Wang, G. Org. Biomol. Chem. 2012, 10, 9556. (l)
Greenaway, R. L.; Campbell, C. D.; Chapman, H. A.; Anderson, E. A.
Adv. Synth. Catal. 2012, 354, 3187. (m) Jiang, Z.; Lu, P.; Wang, Y. Org.
Lett. 2012, 14, 6266. (n) Gati, W.; Rammah, M. M.; Rammah, M. B.;
Evano, G. Beilstein J. Org. Chem. 2012,8, 2214. (o) Smith, D. L.; Chidipudi,
S. R.; Goundry, W. R.; Lam, H. W. Org. Lett. 2012, 14, 4934. (p)
Heffernan, S. J.; Carbery, D. R. Tetrahedron Lett. 2012, 53, 5180.
(4) For reviews on syntheses of ynamides, see: (a) Mulder, J. A.;
Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (b) Dehli, J. R.;
Legros, J.; Bolm, C. Chem. Commun. 2005, 43, 973. (c) Tracey, M. R.;
Hsung, R. P.; Antoline, J. A.; Kurtz, K. C. M.; Shen, L.; Slafer, B. W.;
Zhang, Y. In Science of Synthesis, Houben-Weyl Methods of Molecular
Transformations; Weinreb, S. M., Ed.; Georg Thieme Verlag KG: Stuttgart,
Germany, 2005; Chapter 21.4. (d) Evano, G.; Blanchard, N.; Mathieu Toumi,
M. Chem. Rev. 2008, 108, 3054. (e) Evano, G.; Jouvinb, K.; Coste, A.
Synthesis 2013, 17.
(5) For syntheses of ynamides published in 2012, see: (a) Jin, X.;
Yamaguchi, K.; Mizuno, N. Chem. Lett. 2012, 41, 866. (b) Jin, X.;
Yamaguchi, K.; Mizuno, N. Chem. Commun. 2012, 48, 4974. (c) Jouvin,
K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756. (d) Jouvin, K.;
Coste, A.; Bayle, A.; Legrand, F.; Karthikeyan, G.; Tadiparthi, K.;
Evano, G. Organometallics 2012, 31, 7933. (e) Tong, X.; Ni, G.; Deng,
X.; Xia, C. Synlett 2012, 23, 2497. (f) Wang, M.-G.; Wu, J.; Shang, Z.-C.
Synlett 2012, 23, 589. (g) Laouiti, A.; Jouvin, K.; Bourdreux, F.;
Rammah, M. M.; Rammah, M. B.; Evano, G. Synthesis 2012, 44, 1491.
r
10.1021/ol400989x
XXXX American Chemical Society

ynamides 4 to chiral imines such as EllmanÀDavis chiral
N-tert-butanesulfinyl imines 6.9,10 Metalated ynamides have
been added to a number of electrophiles,11 but to the best of
our knowledge, additions to chiral imines have not been
reported.1,12,13 This method would be ideal for constructing
new chiral ynamides. We wish to report here a highly stereo-
selective synthesis of chiral γ-amino-ynamides via the addi-
tion of lithiated ynamides to EllmanÀDavis chiral imines.
Scheme 1. Approaches to Chiral γ-Amino-Ynamides
Scheme 2. Initial Assessment of The Two Approaches
We recognized that the Cu-catalyzed protocol1,2,4 may
actually not be the most attractive approach because it
would require (a) optically enriched propargyl amines 3,
which are not always readily available, and (b) a deprotec-
tion protocol that may not be compatible with ynamides 2in
addition to being tedious.8 Yet, with N-protected propargyl
amines 5, the most direct access would be an addition of
metalated chiral ynamide 4* to achiral imines 5, which
would constitute a long-range stereochemical induction.
The more practical approach may be adding metalated
We quickly established that although synthetically fea-
sible, additions to imines using lithiated ynamides such as
7, which is substituted with an Evans chiral oxazolidinone
auxiliary, provided no significant diastereoselectivity in
γ-amino-ynamide 9 [Scheme 2].14 This effectively ends the
speculation of a possible 1,5-asymmetric induction. Yet,
for additions to EllmanÀDavis chiral imine 11a using
achiral ynamides such as 10, the selectivity was actually
promising, although the yield was not impressive.
(6) For syntheses of novel structural analogs of ynamides, see: (a) Yne-
Sulfoxyimines: Wang, L.; Huang, H.; Priebbenow, D. L.; Pan, F.-F.; Bolm,
C. Angew. Chem., Int. Ed. 2013, 52, 3478. (b) Yne-hydrazides: Beveridge,
R. E.; Batey, R. A. Org. Lett. 2012, 14, 540. (c) Yne-imines: Laouiti, A.;
Rammah, M. M.; Rammah, M. B.; Marrot, J.; Couty, F.; Evano, G. Org.
ꢀ
~
Lett. 2012, 14, 6. (d) Ynimides: Souto, J. A.; Becker, P.; Iglesias, A.; Muniz,
K. J. Am. Chem. Soc. 2012, 134, 15505. (e) Ynimides: Sueda, T.; Oshima,
A.; Teno, N. Org. Lett. 2011, 13, 3996. (f) Ynimides: Sueda, T.; Kawada, A.;
Urashi, Y.; Teno, N. Org. Lett. 2013, 15, 1560. (g) Diamino-acetylenes:
Petrov, A. R.; Daniliuc, C. G.; Jones, P. G.; Tamm, M. Chem.;Eur. J.
2010, 16, 11804. (h) Amidinyl-ynamides: Li, J.; Neuville, L. Org. Lett. 2013,
15, 1752.
(7) DeKorver, K. A.; Hsung, R. P.; Song, W.-Z.; Walton, M. C.;
Wang, X.-N. Org. Lett. 2012, 14, 3214.
(8) For an example of coupling using unprotected secondary pro-
pargylic amines, see: Hashmi, A. S. K.; Schuster, A. M.; Zimmer, M.;
Rominger, F. Chem.;Eur. J. 2011, 17, 5511.
Table 1. A Temperature Effect on Stereoselectivity
(9) For reviews, see: (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A.
Chem. Rev. 2010, 110, 3600. (b) Ferreira, F.; Botuha, C.; Chemla, F.;
Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162. (c) Lin, G.-Q.; Xu,
M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem. Res. 2008, 41, 831. (d)
Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869. (e) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (f) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (g) Sorochinsky,
A. E.; Soloshonok, V. A. J. Fluorine Chem. 2010, 131, 127.
(10) Given the volume on additions to EllamnÀDavis chiral imines,
for leading examples using metallated acetylides, see: (a) Wang, B.;
Zhang, P.-P. Tetrahedron Lett. 2012, 53, 119. (b) Ye, L.; He, W.; Zhang,
L. Angew. Chem., Int. Ed. 2011, 50, 3236. (c) Chen, B.-L.; Wang, B.; Lin,
G.-Q. J. Org. Chem. 2009, 75, 941. (d) Hodgson, D. M.; Kloesges, J.;
Evans, B. Synthesis 2009, 1923. (e) aHarried, S. S.; Croghan, M. D.;
Kaller, M. R.; Lopez, P.; Zhong, W.; Hungate, R.; Reider, P. J. J. Org.
additive time
dr
entry
R=
temp [°C] [equiv]
[h] product yielda [S:R]b
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
À 78
À
À
À
À
À
15
15
15
9
15-S
15-S
15-S
15-S
15-S
15-S
63
60
67
69
35
94
7:1
À 78 to À50
À 78 to À40
À 78 to À40
À 78 to rt
11:1
21:1
25:1
g25:1
18:1
ꢀ
Chem. 2009, 74, 5975. (f) Voituriez, A.; Perez-Luna, A.; Ferreira, F.;
Botuha, C.; Chemla, F. Org. Lett. 2009, 11, 931. (g) Chen, X.-Y.; Qiu,
X.-L.; Qing, F.-L. Tetrahedron 2008, 64, 2301. (h) Turcaud, S.; Berhal,
F.; Royer, J. J. Org. Chem. 2007, 72, 7893. (i) Patterson, A. W.; Ellman,
J. A. J. Org. Chem. 2006, 71, 7110. (j) Davis, F. A.; Nolt, M. B.; Wu, Y.;
Prasad, K. R.; Li, D.; Yang, B.; Bowen, K.; Lee, S. H.; Eardley, J. H.
J. Org. Chem. 2005, 70, 2184. (k) Barrow, J. C.; Ngo, P. L.; Pellicore,
J. M.; Selnick, H. G.; Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051.
(l) Shaw, A. W.; deSolms, S. J. Tetrahedron Lett. 2001, 42, 7173. (m)
Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66, 8772.
(11) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc.
2003, 125, 2368. (b) Rodriguez, D.; Martinez-Esperon, M. F.; Castedo,
15
9
À 78 to À40 TMEDA
[0.25]
7
Ph
À 78 to À40 TMEDA
[1.0]
9
15-S
g95 20:1
8
9
n-hex
c-hex
À 78 to À40
À 78 to À40
À
À
À
9
9
9
16-S
17-S
18-S
68
77
63
20:1
20:1
10 p-MeOPh À 78 to À40
g25:1
a Isolated yields. b Ratios determined by 1H and/or 13C NMR. The desig-
nation of (S) or (R) refers to the stereochemistry at the γ-C in the product.
ꢀ
L.; Saa, C. Synlett 2007, 1963. (c) Yne-hydrazides: Beveridge, R. E.;
Batey, R. A. Org. Lett. 2012, 14, 540.
B
Org. Lett., Vol. XX, No. XX, XXXX

Subsequently, we observed that N-sulfonyl-substituted
ynamides appear to work better in this asymmetric addi-
tion. Addition of lithiated ynamide 13 to 11a at À78 °C
afforded 15 with a dr of 7:1 in favor of the (S)-isomer
[entry 1, Table 1]. There appears to be a noticeable tem-
perature effect; when the same addition was carried
out at À50 °C [entry 2] or À40 °C [entries 3 and 4], the
selectivity improved significantly. Although the selectiv-
ity was the highest when the reaction was run at rt, the
yield suffered [entry 5]. An additive such as TMEDA
enhanced the yield, but at the expense of diastereoselec-
tivity [entries 6 and 7]. The generality of this asymmetric
addition can be revealed through the use of chiral imines
(Ss)-11cÀd [entries 8À10]. The (S) stereochemistry was
confirmed using the single crystal X-ray structure of
15-S [Figure 1].
The success in achieving a high level of diastereoselec-
tivity led us to examine the effects of Lewis acids, and we
found a complete reversal of stereoselectivity when using
1.2 to 2.0 equiv of BF3ÀOEt2 [entries 3 and 4, Table 2].15
The extent of reversal appears to depend on the amount
of BF3ÀOEt2 used [entries 14]. This phenomenon appears
to be unique with BF3ÀOEt2, as not all monodentate
Lewis acids would present such a reversal [entries 5À7].
Yet, bidentate Lewis acids were poor promoters overall
[entries 7À12] with TiCl4, SnCl4, and Cu(OTf)2 appearing
to impede the reaction [entries 7, 8, and 12]. Again, chiral
γ-amino-ynamides 16-RÀ18-R could be obtained through
additions to (Ss)-11cÀd in the presence of BF3ÀOEt2
[entries 13À15].
A rationale of this stereochemical switch is shown in
Figure 2. The S-selectivity in the absence of a Lewis acid is
likely derived from a ZimmermanÀTraxler type chelated
transition state. Yet, a synclinal or antiperiplanar ap-
proach takes place with BF3ÀOEt2 coordinating to the
sulfinyl O-atom, thereby effectively breaking up the chela-
tion especially when using g1.0 equiv. It has been sug-
gested that other Lewis acids such as AlMe2Cl could
coordinate to the imino lone pair, and thus, are not
effective in deterring the pro-S-TS.9
Figure 1. X-ray structure of 15-S.
Figure 2. Chelation-TS versus open-TS.
Table 2. Reversal of Stereoselectivity Using BF3ÀOEt2
Consequently, variations on the sulfonamide substitu-
tions were examined, and we found an interesting effect
on the selectivity. Most notably, the para-nitro substit-
uent eroded the selectivity significantly in the absence of
BF3ÀOEt2 [see 20-S in Figure 3]. This loss of selectivity is
likely due to the nitro group competing for the Li-chelation
in the pro-SÀTS, thereby suggesting that the sulfonamido
group can impact the selectivity. This phenomenon also
entry
R=
Lewis acid [equiv] product yielda dr [S:R]b
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
BF3-OEt2 [0.25]
BF3-OEt2 [0.50]
BF3-OEt2 [1.2]
BF3-OEt2 [2.0]
AlCl3 [1.2]
15-R/S 66
15-R/S 78
1:1
2
1:1.5
e1:25
e1:25
2:1
3
15-R
15-R
15-S
15-S
15-S
15-R
15-R
g95
(12) For an elegant account on additions of lithiated ynol-ethers to
EllmanÀDavis chiral imines, see: Verrier, C.; Carret, S.; Poisson, J.-F.
Org. Lett. 2012, 14, 5122.
(13) For additions of lithiated ynol-ethers to imines, see: (a) Mak,
X. Y.; Ciccolini, R. P.; Robinson, J. M.; Tester, J. W.; Danheiser, R. L.
J. Org. Chem. 2009, 74, 9381. (b) Hashmi, A. S. K.; Rudolph, M.; Huck,
J.; Frey, W.; Bats, J. W.; Hamzic, M. Angew. Chem., Int. Ed. 2009, 48,
5848.
4
g95
11
41
30
0
5
6
AlMe2Cl [1.2]
LiClO4 [1.2]
TiCl4 [1.2]
g25:1
g25:1
À
7
8
9
SnCl4 [1.2]
0
À
10
11
12
13
14
15
Ti (i-PrO)2Cl2 [1.2] 15-S
26
35
0
4:1
(14) See Supporting Information.
(15) For leading examples of related reversals of stereoselectivity, see:
Zn(OTf)2 [1.2]
Cu(OTf)2 [1.2]
BF3-OEt2 [1.2]
BF3-OEt2 [1.2]
15-S
15-R
16-R
17-R
18-R
g25:1
À
ꢀ
(a) Louvel, J.; Chemla, F.; Demont, E.; Ferreira, F.; Perez-Luna, A.;
ꢀ
Voituriez, A. Adv. Synth. Catal. 2011, 353, 2137. (b) Viso, A.; Fernandez
n-hex
c-hex
93
90
g95
e1:25
e1:25
e1:25
ꢀ
de la Pradilla, R.; Flores, A.; Garcıa, A.; Tortosa, M.; Lopez-Rodrıguez,
M. L. J. Org. Chem. 2006, 71, 1442. (c) Jiang, W.; Chen, C.; Marinkovic,
D.; Tran, J. A.; Chen, C. W.; Arellano, L. M.; White, N. S.; Tucci, F. C.
J. Org. Chem. 2005, 70, 8924. (d) Kuduk, S. D.; DiPardo, R. M.; Chang,
R. K.; Ng, C.; Bock, M. G. Tetrahedron Lett. 2004, 45, 6641. (e) Also see
ref 13.
p-MeOPh BF3-OEt2 [1.2]
a Isolated yields. b Ratios determined by 1H and/or 13C NMR.
Org. Lett., Vol. XX, No. XX, XXXX
C

occurred when the R substituent is a Ph group as shown in
22-S. Yet, a complete reversal of stereochemistry took
place when using BF3ÀOEt2 regardless of sulfonamide
substitutions.
Scheme 4. MatchingÀMismatching with Chiral Ynamide 7
Figure 3. Effects of the sulfonyl substitutions. Isolated yields
reported. Ratios determined by 1H and/or 13C NMR.
Scheme 4, the addition of lithiated 7 to either (Rs)-11a or
(Ss)-11a led to their respective addition products 24 and 26
in good yield and high diastereoselectivity. While the
relative stereochemistry at the γ-C of 24 was unambigu-
ously assigned based on its X-ray structure, 26 was as-
signed through its derivative obtained via an unusual
5-endo-dig S-cyclization.16 These reactions suggest that
the chirality on the oxazolidinone ring does not play a role
in the asymmetric induction. It is noteworthy that 24 and
26 represent de novo ynamides that are rich in chirality.
We have described here a highly diastereoselective
addition of lithiated ynamides to EllmanÀDavis chiral
N-tert-butanesulfinyl imines that expands synthetic
tools for constructing chiral ynamides. Our work
demonstrates that additions of N-sulfonyl ynamides
are highly stereoselective even without Lewis acids,
although the use of BF3ÀOEt2 could alter the stereo-
chemical outcome. Additions of oxazolidinone-substituted
ynamidesappeartorequireBF3ÀOEt2, but the chiralityon
the oxazolidinone ring does not impact the selectivity.
Applications of these de novo chiral γ-amino-ynamides in
developing new synthetic transformations are currently
underway.
Success with these N-sulfonyl-substituted ynamides
prompted us to return to oxazolidinone-substituted yna-
mides that were found to be unsuccessful earlier. Both
selectivity and efficiency could be rescued through the use
of 1.2 equiv BF3ÀOEt2 and gave the desired addition
product 23-R in quantitative yield [Scheme 3]. The X-ray
structure of 23-R confirms that the stereochemical out-
come is the same as those from using N-sulfonyl ynamides.
Scheme 3. Reexamining the Addition of Ynamide 10
When using chiral ynamide 7, we anticipated a potential
matched and mismatched scenario. However, as shown in
Acknowledgment. We thank the NIH [GM066055] for
funding and Dr. Victor Young of The University of
Minnesota for X-ray structural data.
(16) An acid promoted 5-endo-dig cyclization concomitant with the
loss of the t-Bu group led to isothiazole i and 2,3-dihydro-isothiazole
S-oxide ii in 25% and 31% yield, respectively. The single crystal X-ray
structure of ii provided the stereochemical assignment of 26 (Ss,R) and
confirmed that an inversion at the “S” center had taken place in ii.
Supporting Information Available. Experimental pro-
cedures, X-ray data, and NMR spectra and characteriza-
tions. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX