A robust and modular synthesis of ynamides

Article abstract of DOI:10.1039/c4cc07876d

A flexible, modular ynamide synthesis is reported that uses trichloroethene as an inexpensive two carbon synthon. A wide range of amides and electrophiles can be converted to the corresponding ynamides, importantly including acyclic carbamates, hindered a

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A robust and modular synthesis of ynamides†
Steven J. Mansfield, Craig D. Campbell, Michael W. Jones and
Edward A. Anderson*
Cite this:DOI: 10.1039/c4cc07876d
Received 7th October 2014,
Accepted 29th October 2014
DOI: 10.1039/c4cc07876d
www.rsc.org/chemcomm
A flexible, modular ynamide synthesis is reported that uses trichloro-
ethene as an inexpensive two carbon synthon. A wide range of
amides and electrophiles can be converted to the corresponding
ynamides, importantly including acyclic carbamates, hindered amides,
and aryl amides. This method thus overcomes many of the limitations
of other approaches to this useful functionality.
Ynamides (1, Scheme 1) are versatile functionalities that are
finding use in an increasing array of transformations.1,2 Their
popularity can be attributed to the high regioselectivity of
reactions of the polarized and nucleophilic alkyne, and also
to the advent of several methods for their synthesis over the last
decade. At the forefront of these are copper-catalyzed couplings
of amides with alkynes3 or their derivatives,4 or dibromoalkenes
(Scheme 1, eqn (1)).5 Despite these important advances, limitations
remain for the preparation of certain ynamide derivatives. For
instance, whilst oxazolidinones are excellent substrates for copper-
catalyzed ynamide synthesis, acyclic carbamates and amides typically
Scheme 1 Copper-catalyzed ynamide formations, and the planned modular
approach to ynamides 1 via dichloroenamides 2.
are not.6 Furthermore, these reactions are usually ineffective for to dichloroacetylene would lead to a dichloroenamide 2, a direct
poorly nucleophilic amides, including those with branched precursor to an ynamide via elimination. This route would benefit
substituents adjacent to the nitrogen centre, and aniline deriva- from a late-stage diversifying introduction of the alkyne substituent
tives. Here we report a solution to these problems, in the form of (R2) in the course of ynamide synthesis, using readily available
a modular and flexible ynamide synthesis that proceeds in short electrophiles (i.e. 2 - 1). Notably, this obviates the need for a
reaction times and displays extensive substituent diversity, and preformed (halo)alkyne or dihaloalkene, as required in most
thus opens up new possibilities for the wider use of ynamides in ynamide synthesis methodology, which can restrict product scope.
organic synthesis.
Investigations into dichloroenamide synthesis began with
We hypothesized that dichloroacetylene, generated from sulfonamides 3a and 3b, the latter of which is a challenging
inexpensive trichloroethene (TCE) under mildly basic reaction substrate for ynamide formation using other methods (Table 1).
conditions, could serve as an excellent two carbon synthon for An initial screen of inorganic bases afforded good results with a
ynamide synthesis (eqn (2), Scheme 1).7,8 Addition of an amide slight excess of LiOH and TCE in DMF at 70 1C (entries 1 and 2),
albeit after extended reaction times; other base–solvent combina-
tions proved less effective (entries 3 and 4) or inconsistent (entries
5 and 6). The reaction time was significantly shortened by
increasing the concentration, and the amount of base and TCE,
which gave excellent yields of dichloroenamide (entries 7 and 8).9
Pleasingly, these conditions were further improved by using just
1.1 equiv. of TCE with Cs2CO3 (1.5 equiv.) in DMF at 50 1C, which
effected rapid and high yielding formation of both enamides 2a
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford,
UK. E-mail: edward.anderson@chem.ox.ac.uk; Web: http://anderson.chem.ox.ac.uk;
Fax: +44 (0)1865 285002
† Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data, copies of 1H and 13C NMR spectra for dichloroena-
mides and ynamides, and X-ray crystallographic data. CCDC 1022574 and
1022575. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c4cc07876d
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Table 1 Optimization of 1,2-dichloroenamide synthesis
Table 2 Synthesis of 1,2-dichloroenamides: reaction scopea
Yielda [%]
(conversion
TCE Base (equiv.),
Entry Substrate equiv. solvent ([M])
t (h) [%])
1
2
3
4
3a
3b
3a
3a
3a
3b
3a
3b
3a
1.5
1.5
1.5
1.5
1.5
1.5
3.0
3.0
1.1
1.1
1.1
LiOH (1.2), DMF (0.8)
LiOH (1.2), DMF (0.8)
KOH (1.2), DMSO (0.8) 72
K2CO3 (1.2), DMF (0.8) 48
KOH (1.2), MeCN (0.8) 48
KOH (1.2), MeCN (0.8) 48
K2CO3 (3.0), DMF (1.33)
K2CO3 (3.0), DMF (1.33)
Cs2CO3 (1.5), DMF (1.33) 0.75 90 (100)
Cs2CO3 (1.5), DMF (1.33) 90 (100)
48
48
79 (100)
63 (100)
n.d.b (o10)
n.d.b (o60)
90 (100)
5
6
n.d.b (o10)
93 (100)
7c
8c
9d
5
7
92 (100)
10d 3b
11d,e 3a
2
Cs2CO3 (1.5), DMF (1.33) 1.5 95 (100)
a
1
Isolated yield; conversion determined by H NMR spectroscopic analysis
of the crude reaction mixture. b Not determined. c Anhydrous DMF used.
d Reaction conducted at 50 1C. e Conducted with 4.1 g (15.7 mmol) of 3a.
and 2b (entries 9 and 10). The reaction remained efficient on
multigram scale (4.1 g of 3a, 95% yield, entry 11).
With optimized conditions in hand, we investigated the scope
of dichloroenamide formation (Table 2). We were delighted to
find that both unhindered and hindered N-alkyl sulfonamides
were highly competent substrates, affording dichloroenamides
2c–h in excellent yields. Similarly, sulfonamides of electron-rich,
electron-poor, and sterically hindered anilines also proved to
be outstanding substrates (2i–m), including the particularly
challenging but highly efficient reaction of 2,6-diisopropyl-
aniline sulfonamide (2m). The N-vinylation of a range of aromatic
azacycles was also successful, with indoles 2n–2q, benzotriazole 2r
and imidazole 2s all obtained in good yields; for 2q, the decreased
acidity of this indole starting material necessitated the use of
NaH as base.
This latter example suggested that a subtle balance of pKa
and nucleophilicity determines the reactivity of the substrate
towards dichlorovinylation. This indeed turned out to be the case
for the reactions of other amide derivatives: where unhindered
carbamate derivatives such as oxazolidinone 2t and methoxycarba-
mate 2u were readily obtained using Cs2CO3-promoted vinylation
conditions, substrates that are both less nucleophilic and weakly
acidic (such as ureas, hydrazides and tert-butyl carbamates)
required the use of either phase-transfer conditions,10 or NaH as
base for formation of the desired dichloroenamides (2w–2bb),
with all obtained in good to excellent yields. In virtually all
cases, only the (E)-stereoisomer of these bench-stable dichloro-
a
b
All yields are isolated yields. 3.0 equiv. K2CO3, 3.0 equiv. TCE,
c
d
anhydrous DMF, 70 1C. E/Z = 94: 6. 2.1 equiv. NaH, 1.0 equiv. TCE,
anhydrous DMF, rt. 0.2 equiv. (n-Bu)4NHSO4, 3.0 equiv. TCE, toluene,
25% aq. NaOH, rt. E/Z = 88:12.
e
f
Fig. 1 ORTEP diagram for (E)-dichloroenamide 2a (the alkene hydrogen is
retained for clarity).
enamide products was obtained (see Table 2), as determined to be efficient bases for this elimination process, with the former of
through X-ray crystallographic analysis of products 2a (Fig. 1) these requiring a more controlled addition of the base at À78 1C to
and 2t, with others assigned by analogy.11
avoid side-reactions. Following trapping of the alkynyllithium inter-
Having established mild, general and high yielding routes to mediate 4 with iodomethane, ynamide 1a was isolated in 85% yield.
1,2-dichloroenamides, we next surveyed conditions to effect their
This lithiated ynamide proved to be an extremely competent
conversion to functionalised ynamides (Table 3).12 After some nucleophile, giving high yields of a wide range of ynamides.
optimisation,13 we found either n-butyllithium or phenyllithium Products arising from reaction with primary alkyl iodides/bromides
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Table
scopea
3
Ynamide synthesis from dichloroenamide 2a: electrophile
Table 4 Ynamide synthesis: amide and electrophile scopea
a
b
c
All yields are isolated yields. 1.0 g scale. 1.2 equiv. BF3ÁOEt2
d
e
required. Transmetallation with ZnCl2ÁOEt2; then TBSOTf. Trans-
metallation with ZnCl2ÁOEt2; then PhI, Pd2(dba)3 (3 mol%), PPh3
(6 mol%).
a
b
c
All yields are isolated yields. 3.2 equiv. PhLi was used. 2.2 equiv.
n-BuLi was used.
(1a–c), and various carbonyl derivatives including aldehydes,
ketones and chloroformates (1d–f), were all formed successfully.14
The terminal ynamide 1g was obtained in excellent yield, including
on gram scale, via direct protonation of 4. The use of epoxides as
electrophiles offers a convenient entry to b-hydroxy ynamides, with
products 1h and 1i isolated in good yield. We also investigated the
selectivity of 1,2- versus 1,4-addition of the amidoacetylide anion
to a,b-unsaturated carbonyl derivatives; exclusive 1,2-addition
was observed with a,b-unsaturated ketones and aldimines (1j,k),
whereas clean 1,4-addition was accomplished following trans-
metallation to zinc (1l).15 This transmetallation also enabled
acetylenic arylation to be achieved in a single step from the
dichloroenamide by in situ Negishi coupling (1m).16 Finally, we
were gratified to observe smooth formation of thioynamide 1n,
a markedly stable double heteroatom-substituted alkyne, upon
trapping with a disulfide.
Following the success of this strategy, the generality of the process
was explored, with a particular focus on the formation of ynamides
inaccessible by other means. Most pleasingly, the protocol met with
wide success, providing access to an array of ynamides (Table 4). Whilst
these reactions could all be performed using PhLi, in a few instances
(1r, 1v) n-BuLi gave superior results. Thus, N-alkyl ensulfonamides were
smoothly converted to various ynamides 1o–s, including the efficient
syntheses of the N-tert-butyl ynamide 1s, for which no other method
has been reported. N-Aryl ynamides 1t–y were formed in excellent
yields, with a wide tolerance of electronic and steric effects, the latter
emphasised by the high yield of the 2,6-diisopropylphenyl ynamide 1w
(85%). In addition to sulfonyl ynamides, the chemistry is equally
effective with other electron-withdrawing functionalities: N-aryl urea
ynamide 1z, and the Boc-protected N-aryl and N-alkyl ynamides 1aa and
1bb, were all produced in high yields. The successful application of this
chemistry extended to the formation of azacyclic ynamines, as illu-
strated by indole 1cc and benzotriazole 1dd, which further underlines
the broad scope of the methodology.
In conclusion, a rapid, economic and modular route to ynamides
has been developed that overcomes limitations encountered with
other ynamide-forming procedures, and offers a reliable means to
prepare a diverse range of ynamides with extensive variation of all
substituents. The reaction is tolerant of a wide range of functionality
on the amide component, including successful reactions of carba-
mates, hindered amides, and aryl amides. Combined with a veritable
diversity of electrophile partners, this strategy can access previously
challenging or unattainable ynamides, without requiring preformed
alkyne or alkene coupling partners.
We thank the EPSRC (EP/H025839/1) for support.
Notes and references
1 For recent reviews of ynamide chemistry, see: (a) X.-N. Wang,
H.-S. Yeom, L.-C. Fang, S. He, Z.-X. Ma, B. L. Kedrowski and
R. P. Hsung, Acc. Chem. Res., 2013, 47, 560–578; (b) G. Evano,
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K. Jouvin and A. Coste, Synthesis, 2013, 17–26; (c) Y. Zhang,
K. A. DeKorver, H. Y. Li, A. G. Lohse, R. Hayashi, Z. J. Lu and
R. P. Hsung, Chem. Rev., 2010, 110, 5064–5106; (d) G. Evano, A. Coste
and K. Jouvin, Angew. Chem., Int. Ed., 2010, 49, 2840–2859; (e) For recent
5 (a) A. Coste, G. Karthikeyan, F. Couty and G. Evano, Angew. Chem.,
Int. Ed., 2009, 48, 4381–4385; (b) Y. Yang, X. Zhang and Y. Liang,
Tetrahedron Lett., 2012, 53, 6557–6560; (c) K. Jouvin, A. Coste,
A. Bayle, F. Legrand, G. Karthikeyan, K. Tadiparthi and G. Evano,
Organometallics, 2012, 31, 7933–7947; (d) M. G. Wang, J. Wu and
Z. C. Shang, Synlett, 2012, 589–594.
6 For limitations of bromoalkyne and 1,1-dibromoalkene methods,
see ref. 4d and 5c. Danheiser’s combination of carbamate anions
and bromoalkynes successfully affords ynamides at room tempera-
ture (20 h), albeit requiring a full equivalent of CuI and KHMDS; see
ref. 4b.
7 For the synthesis of relatively unstable ynamines from dialkylamide
anions and dihaloacetylenes, see: (a) H. G. Viehe and M. Reinstein,
Angew. Chem., Int. Ed., 1964, 3, 506; (b) H. G. Viehe, Angew. Chem.,
Int. Ed., 1967, 6, 767–778; (c) R. van der Heiden and L. Brandsma,
Synthesis, 1987, 76–77; (d) R. V. Joshi, Z. Q. Xu, M. B. Ksebati,
D. Kessel, T. H. Corbett, J. C. Drach and J. Zemlicka, J. Chem. Soc.,
´
examples of ynamide methodology, see: C. Theunissen, B. Metayer,
N. Henry, G. Compain, J. Marrot, A. Martin-Mingot, S. Thibaudeau and
G. Evano, J. Am. Chem. Soc., 2014, 136, 12528–12531; ( f ) S. N. Karad and
R.-S. Liu, Angew. Chem., Int. Ed., 2014, 53, 9072–9076; (g) B. Peng,
X. Huang, L.-G. Xie and N. Maulide, Angew. Chem., Int. Ed., 2014, 53,
8718–8721; (h) H. A. Laub, G. Evano and H. Mayr, Angew. Chem., Int. Ed.,
2014, 53, 4968–4971; (i) Z. Xin, S. Kramer, J. Overgaard and
T. Skrydstrup, Chem. – Eur. J., 2014, 20, 7926–7930; ( j) H. V. Adcock,
T. Langer and P. W. Davies, Chem. – Eur. J., 2014, 20, 7262–7266;
(k) P. Zhang, A. M. Cook, Y. Liu and C. Wolf, J. Org. Chem., 2014, 79,
4167–4173; (l) M. D. Santos and P. W. Davies, Chem. Commun., 2014, 50,
6001–6004; (m) A. M. Cook and C. Wolf, Chem. Commun., 2014, 50,
3151–3154; (n) S. K. Pawar, D. Vasu and R.-S. Liu, Adv. Synth. Catal.,
2014, 356, 2411–2416.
´
Perkin Trans. 1, 1994, 1089–1098; (e) J. Balsells, J. Vazquez,
`
2 (a) For work from our group, see: C. D. Campbell, R. L. Greenaway,
O. T. Holton, H. A. Chapman and E. A. Anderson, Chem. Commun.,
2014, 50, 5187–5189; (b) P. R. Walker, C. D. Campbell, A. Suleman,
G. Carr and E. A. Anderson, Angew. Chem., Int. Ed., 2013, 52,
9139–9143; (c) R. L. Greenaway, C. D. Campbell, H. A. Chapman
and E. A. Anderson, Adv. Synth. Catal., 2012, 354, 3187–3194;
(d) R. L. Greenaway, C. D. Campbell, O. T. Holton, C. A. Russell
and E. A. Anderson, Chem. – Eur. J., 2011, 17, 14366–14370.
3 (a) T. Hamada, X. Ye and S. S. Stahl, J. Am. Chem. Soc., 2008, 130,
833–835; (b) X. J. Jin, K. Yamaguchi and N. Mizuno, Chem. Commun.,
2012, 48, 4974–4976.
A. Moyano, M. A. Pericas and A. Riera, J. Org. Chem., 2000, 65,
7291–7302; ( f ) L. M. Geary and P. G. Hultin, Org. Lett., 2009, 11,
5478–5481.
8 For the equivalent chemistry of potassium alkoxides: A. Moyano,
F. Charbonnier and A. E. Greene, J. Org. Chem., 1987, 52, 2919–2922.
9 For reaction of phenols under these conditions, see: Z. S. Sales and
N. S. Mani, J. Org. Chem., 2009, 74, 891–894.
10 (a) For the formation of dichloroacetylene under these conditions, see:
A. Jonczyk and K. Michalski, Synlett, 2002, 1703–1705; (b) J. Pielichowski
and D. Bogdal, J. Prakt. Chem., 1989, 331, 145–148.
11 The structures of 2a and 2t were determined by single crystal X-ray
diffraction. See the ESI† (CIF) for more details; CCDC 1022574 and
1022575.
4 (a) M. O. Frederick, J. A. Mulder, M. R. Tracey, R. P. Hsung, J. Huang,
K. C. M. Kurtz, L. C. Shen and C. J. Douglas, J. Am. Chem. Soc., 2003, 125,
2368–2369; (b) J. R. Dunetz and R. L. Danheiser, Org. Lett., 2003, 5, 12 (a) Although 2,2-dichloroenamides have been shown to be precur-
4011–4014; (c) Y. Zhang, R. P. Hsung, M. R. Tracey, K. C. M. Kurtz and
E. L. Vera, Org. Lett., 2004, 6, 1151–1154; (d) X. Zhang, Y. Zhang, J. Huang,
R. P. Hsung, K. C. M. Kurtz, J. Oppenheimer, M. E. Petersen,
I. K. Sagamanova, L. Shen and M. R. Tracey, J. Org. Chem., 2006, 71,
4170–4177; (e) K. Dooleweerdt, H. Birkedal, T. Ruhland and T. Skrydstrup,
sors to ynamides, their synthesis (via dichloroolefination of forma-
mides using excess PPh3/CCl4) is significantly more challenging;
see: D. Bru¨ckner, Synlett, 2000, 1402–1404; (b) D. Bru¨ckner, Tetra-
hedron, 2006, 62, 3809–3814; (c) S. Couty, M. Barbazanges, C. Meyer
and J. Cossy, Synlett, 2005, 905–910.
J. Org. Chem., 2008, 73, 9447–9450; ( f ) F. M. Istrate, A. K. Buzas, 13 See the ESI† for details of reaction optimisation for ynamide
I. D. Jurberg, Y. Odabachian and F. Gagosz, Org. Lett., 2008, 10,
925–928; (g) K. Jouvin, F. Couty and G. Evano, Org. Lett., 2010, 12,
3272–3275; (h) W. Jia and N. Jiao, Org. Lett., 2010, 12, 2000–2003; 14 (a) D. Rodrıguez, M. F. Martınez-Esperon, L. Castedo and C. Saa,
synthesis, and for the isolation of a chloroynamide intermediate
from treatment of 2a with 1.2 equiv. PhLi or LiHMDS.
´
´
´
´
(i) K. Jouvin, J. Heimburger and G. Evano, Chem. Sci., 2012, 3, 756–760;
( j) For an iron-catalyzed approach, see: B. Yao, Z. Liang, T. Niu and
Y. Zhang, J. Org. Chem., 2009, 74, 4630–4633; (k) Y. Tokimizu, S. Oishi,
N. Fujii and H. Ohno, Org. Lett., 2014, 16, 3138–3141; (l) For large scale
Synlett, 2007, 1963; (b) R. Qi, X. N. Wang, K. A. DeKorver, Y. Tang,
C. C. Wang, Q. Li, H. Li, M. C. Lv, Q. Yu and R. P. Hsung, Synthesis,
2013, 1749–1758; (c) X. N. Wang, R. P. Hsung, R. Qi, S. K. Fox and
M. C. Lv, Org. Lett., 2013, 15, 2514–2517; see also ref. 1k and m.
applications, see: A. L. Kohnen, J. R. Dunetz and R. L. Danheiser, Org. 15 (a) S. Kim and M. L. Joo, Tetrahedron Lett., 1990, 31, 7627–7630; (b) For a
Synth., 2007, 84, 88–101; (m) I. K. Sagamanova, K. C. M. Kurtz and
R. P. Hsung, Org. Synth., 2007, 84, 359–367; (n) A. Coste, F. Couty and
G. Evano, Org. Synth., 2010, 87, 231–244; (o) For pioneering work using 16 (a) M. F. Martınez-Esperon, D. Rodrıguez, L. Castedo and C. Saa,
review, see: S. Fujimori, T. F. Knopfel, P. Zarotti, T. Ichikawa, D. Boyall
and E. M. Carreira, Bull. Chem. Soc. Jpn., 2007, 80, 1635–1657.
´
´
´
´
alkynyliodonium salts, see: B. Witulski and T. Stengel, Angew. Chem.,
Int. Ed., 1998, 37, 489–492.
Tetrahedron, 2006, 62, 3843–3855; (b) D. Rodriguez, L. Castedo and
C. Saa, Synlett, 2004, 783–786.
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