Chemoselective alkynylation of N-sulfonylamides versus amides and carbamates-Synthesis of tetrahydropyrazines

Article abstract of DOI:10.1039/c3cc40529j

The chemoselective alkynylation of N-sulfonylamides versus amides and carbamates using TMS-EBX as an alkynylating agent leads to the formation of non-symmetrical tetrahydropyrazines from orthogonally protected diamines. The Royal Society of Chemistry 2013

Full text of DOI:10.1039/c3cc40529j

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Chemoselective alkynylation of N-sulfonylamides
versus amides and carbamates – Synthesis of
tetrahydropyrazines†
Cite this: Chem. Commun., 2013,
49, 3303
Received 21st January 2013,
Accepted 28th February 2013
Thomas Aubineau and Janine Cossy*
DOI: 10.1039/c3cc40529j
www.rsc.org/chemcomm
The chemoselective alkynylation of N-sulfonylamides versus amides
and carbamates using TMS-EBX as an alkynylating agent leads to
the formation of non-symmetrical tetrahydropyrazines from ortho-
gonally protected diamines.
Insertion of acetylenic moieties into organic molecules is of
great interest due to the specific properties of the triple bond.
Transfer of an alkyne group can be realized either by nucleo-
philic or electrophilic alkynylation. The electrophilic alkynyl-
ation has gained interest in the last decade, due to the design
of reagents, such as halogeno-alkynes, sulfone-substituted
alkynes, terminal acetylenic derivatives via in situ oxidation or
alkynyl iodonium salts (Fig. 1).1 In order to achieve the syn-
thesis of ynamines and ynamides,2 iodonium salts3 were found
to be useful reagents and several methods, along with various
salts, were developed since the first synthesis of ynamines
using alkynyl iodonium salts by Stang et al.4
More recently, Waser et al. reported the a-alkynylation of
activated carbonyl derivatives using trimethylsilyl ethynyl-1,2-
benziodoxol-3(1H)-one (TMS-EBX) (Ia),5 the structure of which
is presented in Scheme 1, and they have also shown the syn-
thetic potential of TIPS-EBX (Ib) in alkyne transfer to various
aromatic heterocycles under transition metal-catalyzed conditions.6
Scheme 1 Chemoselective alkynylation of N-sulfonylamides. Synthesis of
tetrahydropyrazines.
Herein, we would like to report that trimethylsilyl ethynyl-1,2-
benziodoxol-3(1H)-one (Ia) can react with N-sulfonylamides to give
the corresponding terminal ynamides but remains inactive towards
amides and carbamates. By taking advantage of this chemo-
selectivity, tetrahydropyrazines, precursors of piperazines fre-
quently encountered in numerous currently used drugs,7,8 were
synthesized from orthogonally protected diamines (Scheme 1).
At first, the chemoselective alkynylation of N-tosylamides
versus carbamates was achieved. Compounds 1–6 were pre-
pared and treated under basic conditions (NaH, 1 equiv.) in
DMF in the presence of TMS-EBX Ia (1 equiv.). Under these
conditions, N-tosylamides 1–3 were transformed into the
corresponding N-tosylynamides 8–10 in good to excellent yield
(74–93%). In contrast, carbamates 4–6 were nonreactive under
these conditions. Interestingly, when diamine 7 was treated
with NaH and TMS-EBX Ia, ynamide 11 was the only product
isolated in 88% yield. The results are reported in Table 1.
Fig. 1 Electrophilic alkynylation reagents.
´
Laboratoire de Chimie Organique associe au CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France. E-mail: janine.cossy@espci.fr; Fax: +33 1-4079-4660
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data. See DOI: 10.1039/c3cc40529j
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3303--3305 3303

View Article Online
Communication
ChemComm
Table 1 Chemoselective synthesis of sulfonynamides
Table 2 Synthesis of tetrahydropyrazines
Entry
1
Diamines
Tetrahydropyrazines (yield)a
Entry
1
Amines
Ynamides (yield)a
2
3
2
3
4
5
6
4
5
c
—
c
—
c
—
6
7
a
b
Yield obtained on a 0.2 mmol scale. 83% yield obtained on a 1 mmol
c
scale. No conversion.
7
8
9
It has been shown previously that amides can react with
ynamides in the presence of a base to yield ketene N,N-acetals
via an hydroamidation process.9–11 To obtain similar cyclized
products, compound 7 was examined and, under optimized
conditions [NaH (2 equiv.) then TMS-EBX (1 equiv.) in DMF; see
ESI†], compound 21 was the only product isolated with a yield
of 56% (Table 2, entry 1). This product is the result of a formal
6-endo-dig cyclization, which is usually formed under copper-
catalyzed conditions.12,13
10
Replacing the N-tosyl group by an N-mesitylene sulfonyl
group as in diamine 12 did not affect the yield as the corre-
sponding tetrahydropyrazine 22 was obtained in 51% yield
(Table 2, entry 2). However, switching to a mesyl or a nosyl
group decreased the yield of the cyclized products 23 and 230 to
26% and 38% respectively (Table 2, entry 3). The influence of
a
b
Yield obtained on a 0.2 mmol scale. 81% yield obtained on a 1 mmol
scale.
the second protecting group was next examined. N-Tosyl, An interesting beneficial effect was observed when the N-benzoyl
N-benzoyl protected diamine 14 afforded the corresponding group was replaced by an alkanoyl group. Thus, when diamine
tetrahydropyrazine 24 in 46% yield (Table 2, entry 4). Substitu- 17, substituted by an octanoyl group, was treated with Ia,
tion of the benzoyl group by one electron-withdrawing group tetrahydropyrazine 27 was isolated in a good yield of 67%
did not affect the yield of the corresponding tetrahydropyrazine (Table 2, entry 7). Similarly, cyclopentane-carboxamide 18 was
(Table 2, entry 5). However substitution of the aromatic ring with transformed to 28 in 70% yield (Table 2, entry 8). The best
two chlorine atoms decreased the yield to 29% (Table 2, entry 6). result was obtained with the isobutyric amide 19 which was
c
3304 Chem. Commun., 2013, 49, 3303--3305
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
either carbene C can be trapped by the remaining amide to
form a transient vinylic carbanion leading to D (Path a), or it
can undergo a rearrangement to produce intermediate ynamide
E which can produce F after cyclization and hydrolysis (Path b).
The discrimination between the two pathways was trouble-
some, as the silyl group (R = TMS) tends to be cleaved under
basic conditions. However, treatment of ynamide 11 with NaH
in DMF produced tetrahydropyrazine 21 with full conversion of
11. In addition, when 7 was treated with one equivalent of NaH
and then with Ph-EBX Ic, ynamine 31 was formed and then
cyclized to tetrahydropyrazine 32 when treated with a second
equivalent of NaH. It is worth noting that tetrahydropyrazine 32
was also obtained as the major product14 when diamine 7 was
treated directly with two equivalents of NaH. These results are
in full agreement with Path b (Scheme 3).
Scheme 2 Possible pathways for the formation of tetrahydropyrazines.
Eventually, the tetrahydropyrazines can be easily trans-
formed to the corresponding piperazines by reduction using
Pd/C under an hydrogen atmosphere (25 bar) and tetrahydro-
pyrazine 29 was indeed effectively transformed to piperazine 33
in 85% yield (Scheme 4).
In summary, ethynyl-1,2-benziodoxol-3(1H)-ones (R-EBX) I
have been found to be good and chemoselective alkynylating
reagents of N-tosyl amides. This selectivity applied to ortho-
gonally protected diamines can be useful to synthesize non-
symmetrical tetrahydropyrazines which can then be involved in
the synthesis of important therapeutic agents.
Notes and references
1 J. P. Brand and J. Waser, Chem. Soc. Rev., 2012, 41, 4165–4179.
2 For reviews, see: K. A. DeKorver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu,
Y. Zhang and R. Hsung, Chem. Rev., 2010, 110, 5064–5106; G. Evano,
A. Coste and K. Jouvin, Angew. Chem., Int. Ed., 2010, 49, 2840–2859;
G. Evano, K. Jouvin and A. Coste, Synthesis, 2013, 17–26.
3 V. V. Zhdankin and P. J. Stang, Tetrahedron, 1998, 54, 10927–10966.
4 P. Murch, B. L. Williamson and P. J. Stang, Synthesis, 1994,
1255–1256.
Scheme 3 Mechanistic investigations.
5 D. Fernandez Gonzalez, J. P. Brand and J. Waser, Chem.–Eur. J.,
2010, 16, 9457–9461.
6 J. P. Brand, C. Chevalley, R. Scopelliti and J. Waser, Chem.–Eur. J.,
2012, 18, 5655–5666.
Scheme 4 Hydrogenation of tetrahydropyrazines to piperazines.
7 C. J. Dinsmore and D. C. Beshore, Org. Prep. Proced. Int., 2002, 34,
367–404.
8 For some examples of tetrahydropyrazines and application to the
synthesis of biologically active compounds, see: D. C. Horwell,
R. A. Lewthwaite, M. C. Pritchard, G. S. Ratcliffe and J. R. Rubin,
Tetrahedron, 1998, 54, 4591–4606; S. Kitamura, H. Fukushi,
T. Miyawaki, M. Kawamura, N. Konishi, Z. Terashita and T. Naka,
J. Med. Chem., 2001, 44, 2438–2450; J. Dimaio and B. Belleu, J. Chem.
Soc., Perkin Trans. 1, 1989, 1687–1689; H. Kour, S. Paul, P. P. Singh,
M. Gupta and R. Gupta, Tetrahedron Lett., 2013, 54, 761–764.
9 A. Coste, F. Couty and G. Evano, Org. Lett., 2009, 11, 4454–4457.
10 H. Naito, T. Hata and H. Urabe, Tetrahedron Lett., 2008, 49,
2298–2301.
11 K. Dooleweerdt, H. Birkedal, T. Ruhland and T. Skrydstrup, J. Org.
Chem., 2008, 73, 9447–9450.
12 Y. Fukudome, H. Naito, T. Hata and H. Urabe, J. Am. Chem. Soc.,
2008, 130, 1820–1821.
13 A similar result has been obtained from 1,1-dibromo-1-alkenes:
H. Xiu, S. Gu, W. Chen, D. Li and J. Dou, J. Org. Chem., 2011, 76,
2448–2458.
converted to its corresponding tetrahydropyrazine 29 in 83%
yield (Table 2, entry 9).
This method was also found to be suitable for the construc-
tion of seven-membered heterocycles. 1,3-Diaminopropane 20
was smoothly transformed to the corresponding tetrahydro-1,4-
diazepine 30 in 57% yield (Table 2, entry 10).
On the basis of these results and precedent studies on the
behaviour of ynamides and hypervalent iodine derivatives,
a possible mechanism is depicted in Scheme 2. As described
previously,5 the reaction of a carbanion with TMS-EBX led to
the formation of an intermediate carbene. Therefore, for bis-
amide B, formed by treatment of diamine A with two equiv. of
NaH, the more nucleophilic N-tosyl amide is supposed to react
with R-EBX I to produce carbene C. Two pathways can take place; 14 Impurities are also found and could not be separated from 32.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3303--3305 3305