A simple one-pot preparation of N-allenyl amides, ureas, carbamates and sulfonamides using a DMSO/tBuOK protocol

Article abstract of DOI:10.1016/j.tetlet.2014.11.093

A one-pot transformation of amides, ureas, carbamates and sulfonamides into synthetically useful N-allenyl analogues using a ^tBuOK/DMSO protocol is reported. The procedure is experimentally simple and robust, and provides N-allenyl analogues, c

Full text of DOI:10.1016/j.tetlet.2014.11.093

Tetrahedron Letters 56 (2015) 350–352
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Tetrahedron Letters
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A simple one-pot preparation of N-allenyl amides, ureas, carbamates
and sulfonamides using a DMSO/tBuOK protocol
⇑
Thomas W. Bousfield , Marc C. Kimber
Department of Chemistry, Loughborough University, Leicestershire LE11 3TU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot transformation of amides, ureas, carbamates and sulfonamides into synthetically useful N-alle-
nyl analogues using a tBuOK/DMSO protocol is reported. The procedure is experimentally simple and
robust, and provides N-allenyl analogues, commonly used within the literature, in yields comparable
to the benchmark two-step approach.
Received 1 October 2014
Revised 17 October 2014
Accepted 20 November 2014
Available online 27 November 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Amide
Allenamide
Propargyl bromide
One-pot
Lactam
N-Allenyl amides (allenamides), of the general structure 4, have
become an increasingly widespread and valuable synthon, with the
number of reports of their use increasing yearly (Scheme 1).1 While
synthetic approaches to these substrates have been well docu-
mented,1a it is the base-catalysed rearrangement of propargyl
amides that has presented itself as the stand-alone method of
choice for their synthesis.2,3 However, one of the drawbacks of this
method is the reliance on the formation and isolation of the prop-
argyl amide (3), which is in turn derived from an amide (1) and
propargyl bromide (2) under basic conditions.
To date, there have been two reports of the direct conversion of
amides into allenamides of the type 4 using this base-mediated
approach. In 2004, Pellón4 demonstrated that acridone (5) could
be transformed into the N-allenyl analogue (6) by heating
propargyl bromide (2) in an aqueous KOH/butanone solution in
the presence of a phase-transfer catalyst, while in 2005, Plumet5
demonstrated that lactams (7) could be transformed into their
N-allenyl analogues (8) using THF/KOH at room temperature.
In continuation of our interest in allenamides6 in Au-catalysed
transformations,7–12 we present a technically simple, yet robust
‘one-pot’ approach to synthesizing these valuable building blocks
using an adapted protocol of Heaney and Ley.13 We reported in
20106c that treatment of 2-oxazolidinone (9) and excess propargyl
bromide (2) with a mixture of DMSO/tBuOK was sufficient for full
conversion into the N-allenyl carbamate 10 in an isolated yield of
68% (Scheme 2).
Herein, we demonstrate the generality of this procedure for the
synthesis of a selection of N-allenyl amides, ureas, carbamates and
sulfonamides that have been used extensively in the literature, and
importantly, on an appreciable scale (20 mmol) (Table 1).14–17
Firstly, the synthesis of 10 could be confidently scaled up to
20 mmol with no discernable decrease in the isolated yield (entry
1). Using this procedure,14 the cyclic lactams 11a–c were converted
in moderate to good yields under these DMSO/tBuOK conditions
(entries 2–4), however, unlike the work of Plumet, the larger ring
size did not result in diminished isolated yields of the allenamide,
as highlighted by 12c (entry 4). Imidazolin-2-ones 13a and b were
smoothly converted into their respective N-allenyl ureas, with 14b
being the first reported example of a bis-N-allenyl urea, to our
knowledge (entries
5 and 6). All three chiral oxazolidinones
15a–c could be cleanly converted into N-allenyl carbamates 16a–c
(entries 7–9), and pleasingly N-methyl p-toluenesulfonamide (17)
could be transformed into N-allenyl sulfonamide 18 in a good yield
of 68% (entry 10). The previous route to this commonly used
N-allenyl sulfonamide 18 relied on sulfonamide formation on
N-methylpropargyl amine, and as such, this new approach
represents a significantly cheaper and technically easier method
for its synthesis.7e Acridone (5) could be transformed into its
N-allenyl analogue 19, but its purification proved difficult and this
is reflected in a poor overall isolated yield of only 12% (entry 11).
Finally, imidazole (20) gave the desired N-allenyl analogue 2118
in a good yield of 54% (entry 12).
⇑
Corresponding author. Tel.: +44 (0) 01509 22 2570.
E-mail address: M.C.Kimber@lboro.ac.uk (M.C. Kimber).
Tel.: +44 (0) 01509 22 2570.
http://dx.doi.org/10.1016/j.tetlet.2014.11.093
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

T. W. Bousfield, M. C. Kimber / Tetrahedron Letters 56 (2015) 350–352
351
base
Br
base-catalysed
rearrangement
R
N
R
N
R
N
EWG
H
EWG
EWG
2
3
4
1
2004
2005
, 46, 6029
Pellón - Heterocycles
, 63, 23
Plumet- Tetrahedron Lett.
O
O
KOH/butanone
KOH/THF
O
O
N
NH
2
, PTC/heat
N
2, RT
(
)
( )
n
n
N
H
5
6
7: n = 1-5
8: n = 1-5
Scheme 1. Base-facilitated synthesis of N-allenyl analogues.
In conclusion, we have developed
a
convenient, scalable
KOtBu (1.5 equiv.)/DMSO
O
O
(20 mmol) and robust ‘one-pot’ method for the synthesis of
N-allenyl amides, ureas, carbamates and sulfonamides. The iso-
lated yields for the synthesized N-allenyl analogues shown in
Table 1 are on par with the benchmark procedure of Hsung,3 and
furthermore, this procedure is experimentally simple. We there-
fore envisage this ‘one-pot’ approach being attractive in instances
when synthesizing these building blocks on large scale is required.
O
NH
O
N
2
(1.1 equiv.)
RT, 16 h
103a
9
[68%]
(5 mmol scale)
Scheme 2. One-pot synthesis of 10 from 9 and 2.
Table 1
Scope of the ‘one-pot’ synthesis of N-allenyl analoguesa
Acknowledgment
Entry
Amide
N-Allenyl analogue
Yieldb (%)
65
We gratefully acknowledge financial support from the Depart-
ment of Chemistry at Loughborough University.
O
O
O
O
NH
N
1
9
O
103a
O
References and notes
2
48
11a: n = 1
NH
N
1. For reviews on allenamides, see: (a) Lu, T.; Lu, Z.; Ma, Z.-X.; Zhang, Y.; Hsung, R.
P. Chem. Rev. 2013, 113, 4862; (b) Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem.
Res. 2003, 36, 773; (c) Standen, P. E.; Kimber, M. C. Curr. Opin. Drug Discovery
Dev. 2010, 13, 645; (d) De Agostino, A.; Prandi, C.; Tabasso, S.; Venturello, P.
Molecules 2010, 15, 2667.
12a3a
:
n = 1
n
)
n
)
(
(
3
4
11b: n = 2
11c: n = 3
12b3a: n = 2
12c3a: n = 3
53
53
O
O
N
N
R
R
N
2. (a) Padwa, A.; Caruso, T.; Nahm, S.; Rodríguez, A. J. Am. Chem. Soc. 1982, 104,
2865; (b) Galons, H.; Bergerat, I.; Combet-Farnoux, C.; Miocque, M.; Decodts, G.;
Bram, G. J. Chem. Soc., Chem. Commun. 1985, 1730; (c) Radl, S.; Kovarova, L.;
Holubek, J. Collect. Czech. Chem. Commun. 1991, 56, 439; (d) Phadtare, S.;
Zemlicka, J. J. Am. Chem. Soc. 1989, 111, 5925; (e) Phadtare, S.; Zemlicka, J. J. Org.
Chem. 1989, 54, 3675; (f) Jones, B. C. N. M.; Silverton, J. V.; Simons, C.; Megati, S.;
Nishimura, H.; Maeda, Y.; Mitsuya, H.; Zemlicka, J. J. Med. Chem. 1995, 38, 1397.
3. For the current benchmark ‘two-step’ procedure, see: (a) Wei, L.-L.; Xiong, H.;
Douglas, C. J.; Hsung, R. P. Tetrahedron Lett. 1999, 40, 6903; (b) Wei, L.-L.;
Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P. Tetrahedron
2001, 57, 459; (c) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron
Lett. 1999, 40, 6903; (d) Xiong, H.; Tracey, M. R.; Grebe, T. P.; Mulder, J. A.;
Hsung, R. P.; Wipf, P.; Smotryski, J. Org. Synth. 2004, 81, 147.
NH
5
6
63
23
13a:
14a3a
:
R = Me
R = Me
O
N
N
13b: R = H
14b16
O
O
O
O
NH
N
7
66
R
R
:
i
i
15a:
16a17
R = Pr
R = Pr
8
9
15b: R = Bn
16b3a: R = Bn
16c: R =
71
72
4. Xuárez, L.; Pellón, R. F.; Fascio, M.; Montesano, V.; D’Accorso, N. Heterocycles
2004, 63, 23.
OMe
OMe
OMe
OMe
15c: R =
5. Fenández, I.; Monterde, M. I.; Plumet, J. Tetrahedron Lett. 2005, 46, 6029.
6. (a) Slater, N. H.; Brown, N. J.; Elsegood, M. R. J.; Kimber, M. C. Org. Lett. 2014, 16,
4606; (b) Singh, S.; Elsegood, M. R. J.; Kimber, M. C. Synlett 2012, 565; (c) Hill, A.
W.; Elsegood, M. R. J.; Kimber, M. C. J. Org. Chem. 2010, 75, 5406; (d) Kimber, M.
C. Org. Lett. 2010, 12, 1128.
Me
Me
NH
N
10
Ts
Ts
68
17
187e
O
O
7. For a review of Au(I)-catalysed [2+2]- and [4+2]-cycloadditions, see: (a) Lopez,
F.; Mascareñas, J. L. Chem. Soc. Rev. 2014, 43, 2904; for selected examples, see:
(b) Lohse, A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430; (c) Li, X.-X.; Zhu, L.-L.;
Zhou, W.; Chen, Z. Org. Lett. 2012, 14, 436; (d) Faustino, H.; Bernal, P.; Castedo,
L.; López, F.; Mascareñas, J. L. Adv. Synth. Catal. 2012, 354, 1658; (e) Suárez-
Pantiga, S.; Hernández-Díaz, C.; Piedrafita, M.; Rubio, E.; Gonzáleza, J. M. Adv.
Synth. Catal. 2012, 354, 1651; (f) Faustino, H.; López, F.; Castedo, L.; Mascareñas,
J. L. Chem. Sci. 2011, 2, 633; (g) Francos, J.; Grande-Carmona, F.; Faustino, H.;
Iglesias-Sigüenza, J.; Díez, E.; Alonso, I.; Fernández, R.; Lassaletta, J. M.; López,
F.; Mascareñas, J. L. J. Am. Chem. Soc. 2012, 134, 14322; (h) Montserrat, S.;
Faustino, H.; Lledos, A.; Mascareñas, J. L.; Lopez, F.; Ujaque, G. Chem. Eur. J.
2013, 19, 15248; (i) Faustino, H.; Alonso, I.; Mascareñas, J. L.; Lopez, F. Angew.
Chem., Int. Ed. 2013, 52, 6526.
11
12
12
54
N
N
H
5
193a
NH
N
20
N
N
2118
a
See Ref. 14 for a general method.
Isolated yields.
b
8. For Au(I) hydroaminations, see: (a) Manzo, A. M.; Perboni, A. D.; Broggini, G.;
Rigamonti, M. Tetrahedron Lett. 2009, 50, 4696; (b) Broggini, G.; Borsini, E.;
Fasana, A.; Poli, G.; Liron, F. Eur. J. Org. Chem. 2012, 3617.
9. For Au(I) hydroarylations, see: (a) Watanabe, T.; Oishi, S.; Fuji, N.; Ohno, H. Org.
Lett. 2007, 9, 4821; (b) Pirovano, V.; Decataldo, L.; Rossi, E.; Vicente, R. Chem.
Commun. 2013, 3594; (c) Jia, M.; Cera, G.; Perrotta, D.; Monari, M.; Bandini, M.
Chem. Eur. J. 2014, 20, 9875.
Some technical observations on this procedure deserve com-
ment; (a) we found the use of dry DMSO to be vital to this ‘one-
t
pot’ approach; (b) the quality of the BuOK did effect conversion
t
into the N-allenyl product, and that a fresh bottle of solid BuOK
gave superior yields; and (c) slow dropwise addition of propargyl
bromide is necessary for adequate temperature control of the reac-
tion mixture.
10. For Au(I) hydroalkoxylations, see: (a) Horino, Y.; Takata, Y.; Hashimoto, K.;
Kuroda, S.; Kimurab, M.; Tamaru, Y. Org. Biomol. Chem. 2008, 6, 4105;

352
T. W. Bousfield, M. C. Kimber / Tetrahedron Letters 56 (2015) 350–352
(b) González-Gómez, A.; Domínguez, G.; Pérez-Castells, J. Eur. J. Org. Chem.
2009, 5057.
11. For Au(I) Nazarov type cyclisations, see: Ma, Z.-X.; He, S.; Song, W.; Hsung, R. P.
Org. Lett. 2012, 14, 5736.
12. For Au(I) cyclopropanations, see: Sabbatani, J.; Huang, X.; Veiros, L. F.; Maulide,
N. Chem. Eur. J. 2014, 20, 10636.
13. Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1973, 499.
14. Representative procedure: To a solution of N-methyl p-toluenesulfonamide (17)
(3.70 g, 20.00 mmol) in dry DMSO (40 mL) under an N2 or Ar atmosphere was
added tBuOK (3.36 g, 30.00 mmol) and the resulting solution stirred for 1 h. To
this solution was added propargyl bromide (2) (2.50 ml, 80% soln in toluene,
22.00 mmol) dropwise over 40 min with care! After the addition was
complete, the mixture was stirred at room temperature overnight under N2
or Ar. The mixture was then diluted with H2O (100 mL) and the organic layer
extracted with EtOAc (2 Â 100 mL). The combined organic extracts were dried
over Na2SO4, filtered and the solvent removed under vacuum. The crude
reaction product was then purified by filtration through a pad of silica (EtOAc:/
petroleum ether, 1:1) to yield a pale yellow solid which was recrystallised from
CH2Cl2/petroleum ether giving the desired N-allenyl sulfonamide 187e as
colourless plates (3.01 g, 68%); mp 82.0–82.5 °C; IR (CH2Cl2) mmax 3030, 1598,
1448, 1357, 1157 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.67–7.64 (m, 2H), 7.31–
;
7.28 (m, 2H), 6.87 (t, J = 6.4 Hz, 1H), 5.27 (d, J = 6.4 Hz, 2H), 2.69 (s, 3H), 2.41 (s,
3H) ; 13C NMR (100 MHz, CDCl3) d 201.5, 143.9, 133.7, 129.6, 127.5, 101.8, 87.8,
33.3, 21.7; MS-ESI found, C11H13NO2SNa found 246.0578, [MNa]+ requires
246.0565.
15. The physical data for each known N-allenyl analogue 10, 12a–c, 14a, 16b, 16c,
18, 19 and 21 were in agreement with those previously reported.3a,6c,7e,16
16. Bis-N-allenyl urea 14b; IR (CH2Cl2) m ;
max 3025, 1755, 1520, 1145 cmÀ1 1H NMR
(400 MHz, CDCl3) d 7.00 (t, J = 8.6 Hz, 2H), 5.39 (d, J = 6.8 Hz, 4H), 3.45 (s, 4H);
13C NMR (100 MHz, CDCl3) d 201.7, 153.6, 97.6, 87.6, 40.6; MS-ESI found,
C9H10N2ONa found 185.0685, [MNa]+ requires 185.0691.
17. N-Allenyl carbamate 16a; [
a]
;
25 = 16.0 (c 1.00, CHCl3); IR (CH2Cl2) mmax 3019,
D
1750, 1516, 1408, 1140 cmÀ1
1H NMR (400 MHz, CDCl3) d 6.86 (t, J = 6.4 Hz,
1H), 5.45 (dd, J = 6.4, 10.0 Hz, 1H), 5.39 (dd, J = 6.4, 10.0 Hz, 1H), 4.30 (t,
J = 8.8 Hz, 1H), 4.22 (dd, J = 4.4, 9.2 Hz, 1H), 3.87 (dt, J = 4.0, 8.8 Hz, 1H), 2.38 –
2.31 (m, 1H), 0.90 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 201.4, 155.5, 95.7, 87.6, 63.0, 58.9, 26.9, 17.6, 13.8; MS-ESI found,
C9H13NO2Na found 190.0854, [MNa]+ requires 190.0844.
18. Hubert, A. J.; Reimlinger, H. J. Chem. Soc. C 1968, 606.