Practical synthesis of N -Boc- and N -Cbz-α-amido stannanes from α-amido sulfones using TMSSnBu3 and CsF

Article abstract of DOI:10.1021/ol200599d

Chemical equations presented. In the presence of TMSSnBu₃ and CsF, stannylation of N-Boc- and N-Cbz-α-amido sulfones proceeded very well to afford the corresponding α-amido stannanes in moderate-to-high yields. This reaction tolerated α-aryl-,

Full text of DOI:10.1021/ol200599d

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2354–2357
Practical Synthesis of N-Boc- and
N-Cbz-r-Amido Stannanes from r-Amido
Sulfones Using TMSSnBu3 and CsF
Tsuyoshi Mita,* Yuki Higuchi, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
tmita@pharm.hokudai.ac.jp; biyo@pharm.hokudai.ac.jp
Received March 7, 2011
ABSTRACT
In the presence of TMSSnBu3 and CsF, stannylation of N-Boc- and N-Cbz-R-amido sulfones proceeded very well to afford the corresponding R-
amido stannanes in moderate-to-high yields. This reaction tolerated R-aryl-, alkenyl-, and alkyl-substituted R-amido sulfones as well as substrates
containing either an ester or cyano moiety, which might be reactive with lithium or magnesium stannides employed in conventional stannylation.
R-Amino stannanes are robust and useful synthetic in-
termediates because of their high stability and the latent
nucleophilic character of their sp3 carbons adjacent to the
nitrogen, which usually possess a positive charge in classi-
cal organic chemistry. Taking advantage of this umpolung
reactivity,1 several transformations that use R-amino stan-
nanes have been developed (Scheme 1): These include the
SnÀLi exchange reaction triggered by n- or sec-BuLi and
the subsequent reaction with many electrophiles, such as
aldehydes, ketones, CO2, chloroformates, chlorophos-
phates, silyl chlorides, alkyl halides, and deuterides, which
were all incorporated into the R-position of the bis-pro-
tected nitrogen (eq 1).2 Palladium- or copper-catalyzed
Stille-type couplings3 have also been reported (eq 2).4 This
methodology was successfully applied in the synthesis of
carbapenem derivatives by Merck researchers5 using Vedejs’
R-amino stannane.6 Recently, our research group developed
Scheme 1. Various Transformations of R-Amino Stannanes
(1) For reviews on umpolungof amine reactivity, see: (a) Seebach, D.;
Enders, D. Angew. Chem., Int. Ed. 1975, 14, 15. (b) Beak, P.; Reitz, D. B.
Chem. Rev. 1978, 78, 275.
(2) For selected examples of tinÀlithium exchange of R-amino
stannane followed by its functionalizations, see: (a) Pearson, W. H.;
Lindbeck, A. C. J. Org. Chem. 1989, 54, 5651. (b) Pearson, W. H.;
Lindbeck, A. C. J. Am. Chem. Soc. 1991, 113, 8546. (c) Chong, J. M.;
Park, S. B. J. Org. Chem. 1992, 57, 2220. (d) Wu, S.; Lee, S.; Beak, P.
J. Am. Chem. Soc. 1996, 118, 715. (e) Park, Y. S.; Beak, P. J. Org. Chem.
1997, 62, 1574. (f) Iula, D. M.; Gawley, R. E. J. Org. Chem. 2000, 65,
6196. (g) Ncube, A.; Park, S. B.; Chong, J. M. J. Org. Chem. 2002, 67,
3625. (h) Fraser, D. S.; Park, S. B.; Chong, J. M. Can. J. Chem. 2004, 82,
87. (i) Coeffard, V.; Beaudet, I.; Evain, M.; Grognec, E. L.; Quintard,
J.-P. Eur. J. Org. Chem. 2008, 3344. (j) Stead, D.; Carbone, G.; O’Brien,
P.; Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010,
132, 7260.
a highly efficient carboxylation of N-Boc-R-amidostannanes
using CO2 as a C1 unit mediated by CsF, which provided
the corresponding R-amino acids in moderate-to-high
yields (eq 3).7
Although many powerful transformations that use R-
amino stannanes have been reported thus far, the
(3) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636.
For a review on Stille coupling, see: (b) Espinet, P.; Echavarren, A. M.
Angew. Chem., Int. Ed. 2004, 43, 4704 and references cited therein.
r
10.1021/ol200599d
Published on Web 04/06/2011
2011 American Chemical Society

straightforward synthesis of R-amino stannanes from sim-
ple imines4d,8 or an equivalent, such as an R-amino sulfone9
or an R-acetoxy amine,4a have all employed strongly
nucleophilic organometallic species such as LiSnBu3,
Et2ZnLiSnBu3, ClMgSnBu3, RZnSnBu3, and Bu3Sn-
LiCuCN (Scheme 2). These methods lack functional
group tolerability and often need a low reaction
temperature.
synthetically more useful N-Boc-R-amido sulfones could
not be stannylated even when using several potential
organometallic stannides that contained lithium, zinc, or
magnesium as the countercation. Also, the stannylation
would proceed through a radical mechanism, which re-
quired at least 2 equiv of alkali metal stannide. Hence, we
have circumvented these problems by using the reagent
combination of TMSSnBu3 and CsF12 and disclose, here-
in, the first mild and general stannylation of N-Boc- and
N-Cbz-R-amido sulfones.
First, different solvents for the stannylation of N-Boc-R-
amido sulfone 1a were investigated in the presence of
TMSSnBu3 (1.1 equiv) and CsF (3 equiv) at 60 °C (Table
1). When the reaction was performed in THF, the desired
R-amido stannane 2a was obtained exclusively in 96%
yield (entry 1). The use of 1,4-dioxane decreased the yield
(67%) and unidentified products were generated (entry 2).
When CH3CN, DMSO, and DMF (entries 3À5) were
used, the protiodestannylation product 3a was produced
as a byproduct.7
Scheme 2. Synthetic Strategy of R-Amino Stannanes
Table 1. Solvent Screening
During the course of our study on R-amino acid synth-
esis from N-Boc-R-amido sulfone and CO2,7 the combined
use of CsF and TMSSnBu3,10 both commercially available
and stable chemicals, was found to be very effective for the
preparation of N-Boc-R-amido stannanes from the corre-
sponding N-Boc-R-amido sulfones, where the tributylstan-
nyl anion was being generated in situ.10 Moreover, N-Boc-
R-amido sulfones can be readily prepared in stable crystal-
line form from the corresponding aldehydes and sodium
sulfinate according to Engberts’ method.11 A precedented
example of the stannylation of N-Cbz-R-amido sulfones,
reported by Pearson and co-workers,9b showed that the
substrate scope was not satisfactory and that the
yield (%)a
entry
solvent
THF
time (h)
2a
3a
1
2
3
4
5
2
96
67
58
24
58
<1
<1
27
47
22
1,4-dioxane
CH3CN
DMSO
2
0.5
0.5
1
DMF
a Yields were determined by 1H NMR analysis using 1,1,2,2-tetra-
chloroethane as an internal standard.
(4) (a) Nativi, C.; Ricci, A.; Taddei, M. Tetrahedron Lett. 1990, 31,
2637. (b) Ye, J.; Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc. 1994, 116, 1.
(c) Falck, J. R.; Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995, 117, 5973.
(d) Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666.
(5) Jensen, M. S.; Yang, C.; Hsiao, Y.; Rivera, N.; Wells, K. M.;
Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2000,
2, 1081.
Having decided the optimal solvent for suppressing the
generation of protiodestannylation product 3a, various R-
amido sulfones were subjected to this stannylation (Figure 1).
All R-amido stannanes 2aÀ2r were purified by column
chromatography using 10% K2CO3/silica gel as a station-
ary phase to remove organotin impurities following Har-
rowven’s novel method reported recently.13 Substrates
(1aÀ1g) possessing electron-donating and -withdrawing
groups on an aromatic ring were all tolerated regardless of
the location of the groups on the ring, with not only N-Boc-
amido sulfone 1a but also N-Cbz-amido sulfone 1b being
effectively stannylated. It is noteworthy that cyano and ester
(6) Vedejs, E.; Haight, A. R.; Moss, W. O. J. Am. Chem. Soc. 1992,
114, 6556.
(7) Mita, T.; Chen, J.; Sugawara, M.; Sato, Y. Angew. Chem., Int. Ed.
2011, 50, 1393. We also disclosed herein one-pot synthesis of R-amino
acids from R-amino sulfones using CsF and TMSSnBu3.
(8) (a) Kells, K. W.; Chong, J. M. Org. Lett. 2003, 5, 4215. (b) He, A.;
Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 6586.
(9) (a) MacLeod, D.; Quayle, P.; Davies, G. M. Tetrahedron Lett.
1990, 31, 4927. (b) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am.
Chem. Soc. 1993, 115, 2622.
(10) For its application to organic synthesis, see: (a) Mori, M.;
Kaneta, N.; Isono, N.; Shibasaki, M. Tertahedron Lett. 1991, 43,
6139. (b) Mori, M.; Isono, N.; Kaneta, N.; Shibasaki, M. J. Org. Chem.
1993, 58, 2972. (c) Honda, T.; Mori, M. Chem. Lett. 1994, 1013. (d)
Kinoshita, A.; Mori, M. Chem. Lett. 1994, 1475. (e) Imai, A. E.; Sato, Y.;
Nishida, M.; Mori, M. J. Am. Chem. Soc. 1999, 121, 1217.
(11) (a) Engberts, J. B. F. N.; Strating, J. Recl. Trav. Chim. Pays-Bas
1965, 84, 942. (b) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org.
Chem. 1994, 59, 1238. (c) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64,
8970.
(12) TMSSnBu3 reacted with an aldehyde in the presence of
CsFÀCsOH. See: Busch-Petersen, J.; Bo, Y.; Corey, E. J. Tetrahedron
Lett. 1999, 40, 2065.
(13) 10% K2CO3/silica gel was employed as a stationary phase
on column chromatography to remove organotin residues. See:
Harrowven, D. C.; Curran, D. P.; Kostiuk, S. L.; Wallis-Guy, I. L.;
Whiting, S.; Stenning, K. J.; Tang, B.; Packard, E.; Nanson, L. Chem.
Commun. 2010, 46, 6335.
Org. Lett., Vol. 13, No. 9, 2011
2355

Figure 1. Reagents and conditions: Reaction was run using 1 (0.1 mmol), 1.1 equiv of TMSSnBu3, and 3 equiv of CsF in THF (2 mL) at
60 °C. Isolated yields are shown unless otherwise noted. a Yield was determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane
as an internal standard. b Reaction was performed at 0 °C. c Tetramethylammonium fluoride (TMAF) was used instead of CsF.
Bs = benzenesulfonyl. Ts = toluenesulfonyl.
functionalities in substrates 1f and 1g remained intact during
the stannylation. Moreover, both R- and β-naphthyl amido
sulfones (1hÀ1i) as well as heteroaromatic substrates (1jÀ1l)
were applicable. Stannylations of R-amido sulfones bearing
a vinyl group as well as a variety of alkyl chains (1mÀ1r)
also produced the corresponding R-amido stannanes in
moderate-to-good yields. However, the reaction of R-amido
sulfone 1n yielded a dimer 4n as a byproduct, the generation
of which could be suppressed by using tetramethylammo-
nium fluoride (TMAF) instead of CsF. All substrates shown
in Figure 1 could be transformed into the corresponding
R-amido stannanes with a slight excess of TMSSnBu3
(1.1 equiv), which is a synthetic advantage due to this contri-
buting to a reduction in the amount of potentially toxic
organotin reagents needed to effect a satisfactory reaction.
In order to gain a mechanistic insight into this process,
the reaction was performed without TMSSnBu3 (Scheme
3, eq 1). As a result, imine 5a was generated in 57% yield
along with recovery of 1a (39%) when using 1.5 equiv of
CsF. Furthermore, complete conversion to imine 5a was
achieved with an increased amount of CsF (3.0 equiv).
During this imine formation, which might be an equili-
brium favoring imine 5a, CsF works as a base to facilitate
the deprotonationÀelimination sequence. Based on these
observations, stannylation of 1a is most likely to proceed
via imine 5a, which was further supported by the fact that this
stannylation required a nearly equal amount of TMSSnBu3
and 3 equiv of CsF. However, when imine 5a was itself used
instead of 1a, stannylation did not proceed efficiently, afford-
ing 2a in only 29% yield along with benzaldehyde produced
via imine hydrolysis as well as some unidentified peaks
observed by 1H NMR analysis (eq 2). Due to the inherent
instability of N-Boc-imine, a high concentration of imine 5a
under the reaction conditions promoted its decomposition,
Scheme 3. Imine Formation and Stannylation of Imine 5a
2356
Org. Lett., Vol. 13, No. 9, 2011

and rapid stannylation of 5a is therefore necessary as soon as
imine 5a is generated through an equilibrium.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Young Scientists (B) from Japan
Society for the Promotion of Science (JSPS; Grant No.
22750081) and Tosoh Corporation.
In summary, we have developed a practical stannylation
of N-Boc- and N-Cbz-R-amido sulfones with synthetically
useful yields (49À89%). We believe that this method is
milder and tolerates more functionally than previously
reported methods that employ organometallic stannides.
Considerable effort toward the development of enantiose-
lective variants of this transformation is now ongoing.
Supporting Information Available. Details of experi-
mental procedures and physical properties of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 9, 2011
2357