Syntheses of α-stannylated and α-iodinated enamides via molybdenum-catalyzed hydrostannation

Article abstract of DOI:10.1021/ol4031028

α-Stannylated and α-iodinated enamides can easily be obtained by molybdenum-catalyzed regio- and stereoselective hydrostannation and subsequent tin-iodine exchange. These functionalized enamides are interesting building blocks for a wide range of cross-coupling reactions giving access to various types of α-substituted enamides.

Full text of DOI:10.1021/ol4031028

ORGANIC
LETTERS
2013
Vol. 15, No. 24
6246–6249
Syntheses of r‑Stannylated
and r‑Iodinated Enamides via
Molybdenum-Catalyzed Hydrostannation
Pulakesh Maity, Manuel R. Klos, and Uli Kazmaier*
Saarland University, Institute of Organic Chemistry, Campus, Bldg. C4.2, D-66123
Saarbruecken, Germany
u.kazmaier@mx.uni-saarland.de
Received October 29, 2013
ABSTRACT
R-Stannylated and R-iodinated enamides can easily be obtained by molybdenum-catalyzed regio- and stereoselective hydrostannation and
subsequent tinꢀiodine exchange. These functionalized enamides are interesting building blocks for a wide range of cross-coupling reactions
giving access to various types of R-substituted enamides.
Functionalized enamides are widespread in nature, e.g.
as peptide alkaloids such as frangulanin1 or the zizyphines
(Figure 1, A).2 A wide range of biologically active peptides
such as tentoxin (B)3 contain dehydroamino acids. Even
more unusual structures, such as vinylogous dehydro-
amino acids, are found in cyclic peptides such as cyclo-
theonamide C (C).4 The strong phytotoxin tentoxin acts as
an inhibitor of ATP synthase,5 and the family of the
cyclotheonamides are found to be strong inhibitors of
serine proteases, such as thrombin and trypsin.4 In addi-
tion to their occurrence in natural products, R-substituted
enamides are also found in a number of drugs. For
example, peptidyl allyl sulfones (D) are an interesting class
of cysteine protease inhibitors.6 There is no question that
straightforward protocols toward differently substituted
enamides are highly welcome. In addition, synthetic pro-
tocols should also focus on a stereoselective formation of
the enamide double bond, because in general only one
isomer shows biological activity, or at least a higher one
than the other isomer.
Especially for the synthesis of didehydroamino acids
and peptides, various protocols have been developed,
mainly based on elimination reactions or olefinations.7
But in general, control of the olefin geometry is not a trivial
issue. Allylic sulfones such as in D can be obtained by
isomerization of the corresponding vinyl sulfones under
basic conditions, but generally also here mixtures of iso-
mers are formed.6
Therefore, we were interested in developing a protocol
which allows the stereoselective synthesis of most of these
enamide structures from the same synthetic intermediates
(Scheme 1). R-Substituted enamides should be accessible
from R-halogenated enamides via cross-coupling chemis-
try. The required halogen derivatives can be obtained via
(1) Tschesche, R.; Last, H.; Fehlhaber, H.-W. Chem. Ber. 1967, 100,
3937–3943.
(2) (a) Tschesche, R.; Kaubmann, E. U. In The Alkaloids, Vol. 15;
Manske, R. H. F., Holmes, H. L., Eds.; Academic Press: New York,
1975; pp 165ꢀ206. (b) Lin, H.-Y.; Chen, C. H.; You, B. J.; Lin, K. C. S.
C.; Le, S.-S. J. Nat. Prod. 2000, 63, 1338–1343.
(3) Templeton, G. E. Microbial Toxins 1972, 8, 169–192.
(4) Nakao, Y.; Matsunaga, S.; Fusetani, N. Bioorg. Med. Chem.
1995, 3, 1115–1122.
(5) Meiss, E.; Konno, H.; Groth, G.; Hisabori, T. J. Biol. Chem. 2008,
283, 24594–24599.
(7) (a) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1988, 159–
172. (b) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243–
€
2266. (c) Bonauer, C.; Walenzyk, T.; Konig, B. Synthesis 2006, 1–20. (d)
Kazmaier, U. In Amino Acids, Peptides and Proteins in Organic Chem-
€
(6) Gotz, M. G.; Caffrey, C. R.; Hansell, E.; McKerrow, J. H.;
Powers, J. C. Bioorg. Med. Chem. 2004, 12, 5203–5211.
istry, Vol. 2; Hughes, A. B., Ed.; Wiley-VCH: Weinheim, 2009; pp 3ꢀ34.
r
10.1021/ol4031028
Published on Web 11/08/2013
2013 American Chemical Society

Scheme 2. Synthesis of Ynamides
While a variety of R-additions are reported for yna-
mides, to the best of our knowledge so far only a few
examples describe more or less R-regioselective Pd-cata-
lyzed hydrostannations.13 While high R-selectivities are
generally observed in the hydrostannation of alkynyl
oxazolidinones, the results obtained with other amides
such as tosylated ynamides are significantly worse. Also,
the yields are moderate in most cases, depending on the
ynamide structure.
Figure 1. Enamide-containing natural products and drugs.
metalꢀhalogen exchange from a suitable R-metalated
enamide, which should be available from the correspond-
ing ynamide via regioselective transition metal catalyzed
hydrometalation.8
Our group is also involved in hydrostannation chemis-
try. We developed Mo(CO)3(CNt-Bu)3 (MoBl3) as a new
highly regioselective catalyst for the R-hydrometalation of
terminal propargyl alcohol derivatives.14 The stannylated
allyl alcohol derivatives obtained can be used, e.g., for the
synthesis of stannylated amino acids and peptides.15
Highly R-regioselective reactions are also observed with a
variety of terminal alkynes bearing electron withdrawing
groups such as sulfones,16 or phosphonates.17 So far, the
goodresults obtained were limited toterminalalkynes, and
therefore, we were interested to determine if ynamides as
disubstituted alkynes are also suitable substrates for our
catalyst system. To prove this option, we synthesized a set
of tosyl- and Boc-protected ynamides 1 (Table 1) accord-
ing to Scheme 2.11 This protocol was suitable for these
protecting groups, but failed with N-alkyl acetamides or
trifluoroacetamides. In this case only a dimerization of the
bromoalkyne was observed. But with the ynamides 1 in
hand, we investigated the molybdenum-catalyzed hydro-
stannation (Table 1). The reactions were carried out in a
CO atmosphere, because in previous investigations we
observed that CO is beneficial for the lifetime of the
catalyst, and higher yields are obtained especially with
“critical”substratessuchas1,2-disubstituted alkynes.18 To
our complete satisfaction, also with the ynamides 1 the
hydrostannation proceeded cleanly in a highly regio- and
stereoselective fashion giving rise to the (E)-R-stannylation
Scheme 1. R-Substituted Enamides from Ynamides
The ynamides required evolved to an interesting class of
functionalized alkynes over recent years, and several prac-
tical syntheses toward these compounds have been devel-
oped.9 Some of the most popular approaches are based
on Cu-catalyzed or Cu-mediated couplings of amides with
bromoalkynes.10 Especially in the presence of 1,10-
phenanthroline as a ligand, a wide range of amide sub-
strates can be coupled under rather mild conditions
(Scheme 2).11 The bromoalkynes required can easily be
obtained from the corresponding alkyne and NBS/
12
AgNO3. The ynamides are versatile synthetic building
blocks undergoing a wide range of reactions, such as R- or
β-additions, cycloadditions, cycloisomerizations, orreduc-
tions, to name only a few.9
ꢀ
(13) (a) Miniere, S.; Cintrat, J.-C. J. Org. Chem. 2001, 66, 7385–7388.
(8) Reviews: (a) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. Rev.
2000, 100, 3257–3282. (b) Trost, B. M.; Ball, Z. T. Synthesis 2005, 853–
887.
(b) Timbart, L.; Cintrat, J.-C. Chem.;Eur. J. 2002, 8, 1637–1640. (c)
Naud, S.; Cintrat, J.-C. Synthesis 2003, 1391–1397. (d) Buissonneaud,
D.; Cintrat, J.-C. Tetrahedron Lett. 2006, 47, 3139–3143.
(14) (a) Kazmaier, U.; Schauss, D.; Pohlman, M. Org. Lett. 1999, 1,
1017–1019. (b) Kazmaier, U.; Pohlman, M.; Schauss, D. Eur. J. Org.
Chem. 2000, 2761–2766. (c) Braune, S.; Kazmaier, U. J. Organomet.
Chem. 2002, 641, 26–29. (d) Braune, S.; Pohlman, M.; Kazmaier, U.
J. Org. Chem. 2004, 69, 468–474.
(15) (a) Kazmaier, U.; Schauss, D.; Raddatz, S.; Pohlman, R.
Chem.;Eur. J. 2001, 7, 456–464. (b) Kazmaier, U.; Schauss, D.; Pohl-
man, M. Synthesis 2000, 914–916. (c) Deska, J.; Kazmaier, U. Angew.
Chem., Int. Ed. 2007, 46, 4570–4573.
(16) Kazmaier, U.; Wesquet, A. O. Synlett 2005, 1271–1274.
(17) Jena, N.; Kazmaier, U. Eur. J. Org. Chem. 2008, 3852–3858.
(18) (a) Wesquet, A. O.; Kazmaier, U. Adv. Synth. Catal. 2009, 1395–
1404. (b) Bukovec, C.; Wesquet, A. O.; Kazmaier, U. Eur. J. Org. Chem.
2011, 1047–1056.
(9) Recent reviews: (a) Evano, G.; Coste, A.; Jouvin, K. Angew.
Chem. 2010, 122, 2902–2921. Angew. Chem., Int. Ed. 2010, 49, 2840–
2859. (b) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064–5106.
(10) (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, 2368–2369. (b) Dunetz, J. R.; Danheiser, R. L. Org. Lett.
2003, 5, 4011–4014. (c) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc.
2005, 127, 5776–5777.
(11) (a) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.;
Vera, E. L. Org. Lett. 2004, 6, 1151–1154. (b) Zhang, X.; Zhang, Y.;
Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen,
M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006,
71, 4170–4177.
(12) Li, L.-S.; Wu, Y.-L. Tetrahedron Lett. 2002, 43, 2427–2430.
Org. Lett., Vol. 15, No. 24, 2013
6247

product 2 as the only product in good to high yield. The
R-stannylated enamides are stable compounds which
could easily be purified by flash chromatography. Subse-
quent tinꢀiodine exchange gave access to the correspond-
ing R-iodinated enamides 3,19 also in high to excellent
yields and with full retention of the olefin geometry. By this
protocol two interesting synthetic intermediates (2 and 3)
became available in a straightforward manner.
the optimized reaction conditions for aryl stannane. And
indeed, the required R-fluorinated enamide 4a could be
obtained, although in moderate yields (Scheme 3). Classi-
cal Stille coupling reactions,26 e.g. with benzyl and aryl
halides, proceeded well and gave access to R-alkylated and
arylated enamides with clean (Z)-olefin geometry.
Scheme 3. Fluorination and Cross-Coupling of Stannylated
Enamide 2a
Table 1. Synthesis of R-Stannylated and R-Iodinated Enamides
yield
[%]
yield
[%]
entry
1
R
R0 EWG
2
3
1
2
3
4
1a n-Hex
1b c-Pr
Me Ts
Me Ts
2a
2b
2c
87
68
71
83
3a
3b
3c
3d
96
96
87
98
1c (CH2)2OTBDPS Me Ts
1d Ph Bn
Boc 2d
Comparable cross-coupling reactions could also be car-
ried out with the R-iodinated enamides 3 (Scheme 4). An
excellent yield was obtained in the Sonogashira coupling
with phenyl acetylene, and also Suzuki and Stille couplings
gave rise to the desired products in acceptable yields.
If vinyl stannane was used as a coupling partner, an
amide-substituted 1,3-diene was formed, which could be
subjected to further modifications such as DielsꢀAlder
reactions.
Because our group is mainly interested in the develop-
ment of new protocols for the synthesis of unusual amino
acids and peptides,27 we wanted to also apply the
R-iodinated enamides in the synthesis of R,β-unsaturated
amino acids and peptides (Table 2).
The corresponding dehydroamino acid esters could
easily be obtained from the iodides under carbonylative
conditions in alcohol as solvent. Good results were ob-
tained with the tosyl-protected enamides. But in many
cases the N-tosyl group is not easily removable, and there-
fore we also investigated the reaction of N-Boc-protected
ynamide 3d. Unfortunately, in this case the yield was lower
(entry 4).
To prove if our protocol is also suitable for the synthesis
of dehydrodipeptides, we reacted some of the iodides with
amino acid esters as nucleophiles in the carbonylation
reaction. DMF was used as solvent in this case to avoid
side reactions of the solvent. The yields obtained were
comparable to the analogous esterifications.
To evaluate the synthetic potential of these building
blocks, we investigated the reaction behavior of the stan-
nylated ynamides 2. As shown in Table 1, the tinꢀiodine
exchange proceeds in almost quantitative yield and the
corresponding bromine and chlorine exchange can be
performed in analogous manner using the corresponding
halogens or N-halosuccinimides.20 While these reactions
are well established, in comparison, the introduction of
fluorine is not a trivial issue. In principle, F2,21 CsSO4F,22
23
and XeF2/AgPF6 can be used as fluorination reagents,
but these reagents are not easy to handle and are very
expensive. The most suitable fluorination reagent prob-
ably is selectfluor,24 especially in the presence of Ag-
catalysts. This protocol was optimized for the synthesis
of fluorinated aromatic ring systems by Ritter et al.25 It is
proposed that, in this case, the aryl stannane used is
transmetalated to the corresponding arylsilver derivative
which on oxidation by the selectfluor and reductive elim-
ination provides the required aryl fluoride. We were inter-
ested to see if such a protocol might also be suitable for the
synthesis of R-fluorinated enamides. Therefore, we sub-
jected exemplarily one of our stannylated enamides (2a) to
(19) R-Iodinated enamides are also accessible by hydroiodination of
ynamides: Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547–1550.
(20) (a) Mitchell, T. N.; Reimann, W. Organometallics 1986, 5, 1991–
1997. (b) Tiefenbacher, K.; Arion, V. B.; Mulzer, J. Angew. Chem. 2007,
46, 2690–2693.
(21) Bryce, M. R.; Chambers, R. D.; Mullins, S. T.; Parkin, A. Bull.
Soc. Chem. Fr. 1986, 930–932.
(22) Hodson, H. F.; Madge, D. J.; Widdowson, D. A. Synlett 1991,
831–832.
(26) (a) Stille, J. K. Angew. Chem. 1986, 98, 504–519. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 508–523. (b) Peng, Y.; Li, W.-D. Z. Eur. J. Org.
Chem. 2010, 6703–6718.
(23) Tius, M. A.; Kawakani, J. K. Tetrahedron 1995, 51, 3997–4010.
(24) Matthews, D. P.; Miller, S. C.; Jarvi, E. T.; Sabol, J. S.;
McCarthy, J. R. Tetrahedron Lett. 1993, 34, 3057–3060.
(25) Furuya, T.; Strom, A. E.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
1662–1663.
(27) (a) Kazmaier, U.; Maier, S. Org. Lett. 1999, 1, 1763–1766. (b)
Deska, J.; Kazmaier, U. Angew. Chem. 2007, 119, 4654–4657. Angew.
Chem., Int. Ed. 2007, 46, 4570–4573. (c) Kazmaier, U. In Frontiers in
Asymmetric Synthesis and Application of alpha-Amino Acids; Soloshonok,
V. A., IzawaK., Eds.; ACS Books: WA, 2009; pp 157ꢀ176.
6248
Org. Lett., Vol. 15, No. 24, 2013

Scheme 4. Cross-Coupling of R-Iodinated Enamide 3a
Scheme 5. Cross-Couplings of Enamides 2 and 3
Last but not least we subjected some of our stannylated
enamides 2 to a tinꢀlithium exchange by treatment with
n-BuLi. Our initial plan was to treat the vinyl lithium
species formed with electrophiles such as aldehydes or R,β-
unsaturated carbonyls. But none of these coupling prod-
ucts were obtained; we were not even able to trap the vinyl
lithium intermediate with D2O. The lithiated intermediate
was too reactive and underwent an intramolecular attack
on the electron-poor aromatic ring system of the tosyl
protecting group. The corresponding benzo-fused sul-
tames 14 were obtained in good to high yield (Scheme 6).
Scheme 6. Synthesis of Benzosultames 14
Table 2. Synthesis of R,β-Dehydroamino Acids and Peptides
In conclusion, we could show that R-stannylated and
iodinated enamides can easily be obtained from ynamides
by molybdenum-catalyzed regio- and stereoselective hy-
drostannation and subsequent tinꢀiodine exchange. These
functionalized enamides are interesting building blocks for
a wide range of cross-coupling reactions, giving access to
various types of functionalized enamides. Further investi-
gations, especially concerning synthetic applications, are
currently in progress.
yield
product [%]
entry
3
R
R0 EWG R00
1
2
3
4
5
6
7
8
3a n-Hex
3b c-Pr
Me Ts
Me Ts
11a
78
67
69
35
85
63
64
71
11b
3c (CH2)2OTBDPS Me Ts
11c
3d Ph
Bn
Boc
11d
3b c-Pr
Me Ts
i-Bu
i-Bu
i-Pr
Bn
12b
Acknowledgment. Financial support from the Deutsche
Forschungsgemeinschaft is gratefully acknowledged.
3c (CH2)2OTBDPS Me Ts
3c (CH2)2OTBDPS Me Ts
3c (CH2)2OTBDPS Me Ts
12c-1
12c-2
12c-3
Supporting Information Available. Experimental pro-
cedures as well as analytical and spectroscopic data for all
new compounds, as well as copies of NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
To enlarge the structural diversity, we also used the
building blocks 2 and 3 in carbonylative Stille couplings,
giving rise to tosylamide substituted divinyl ketones 13,
which might be interesting building blocks for further
modifications (Scheme 5).
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 24, 2013
6249