Copper-catalyzed N-Allenylation of allylic sulfonamides

Article abstract of DOI:10.1021/ol901294j

Figur Presented Allylic allenic amides have been synthesized via a copper-catalyzed cross-coupling between allylic sulfonamides and bromoallenes in moderate to good yields. Copper(I) thiophene-2-carboxylate (CuTC) was used a source of copper with DMEDA as the ligand. The allenylated products obtained are potential substrates for palladium-catalyzed carbocyclizations.

Full text of DOI:10.1021/ol901294j

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3814-3817
Copper-Catalyzed N-Allenylation of
Allylic Sulfonamides
Andreas K. Å. Persson, Eric V. Johnston, and Jan-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received June 10, 2009
ABSTRACT
Allylic allenic amides have been synthesized via a copper-catalyzed cross-coupling between allylic sulfonamides and bromoallenes in moderate
to good yields. Copper(I) thiophene-2-carboxylate (CuTC) was used a source of copper with DMEDA as the ligand. The allenylated products
obtained are potential substrates for palladium-catalyzed carbocyclizations.
In recent years, transition-metal-catalyzed cross-coupling has
become one of the reaction types most frequently used in
organic synthesis.1,2 Early methods were focused on C-C
bond formation,2 but more recently, selective cross-couplings
between carbon and heteroatoms have been developed, e.g.,
formation of C-N and C-O bonds.1 One of the major
achievements in this area was the development of the
Buchwald-Hartwig reaction, which employs Pd(0) as cata-
lyst.3,4 Another important contribution to this area has been
the Ullmann protocol, which instead utilizes Cu(I) as the
catalyst.5,6 Although copper and palladium dominate this area
of research, other metals such as nickel,7 iridium,8 and iron9
can also be used.
we extended our interest in C-allenyls to also include
N-allenyls. So far, the latter compounds have received limited
attention, mainly due to the lack of good procedures for their
preparation.11 In most cases, preparation of allenamides
proceeds via base-catalyzed isomerization of propragylic
amides.12 One major drawback with the isomerization
protocol is that only terminal and monosubstituted allena-
mides can be easily prepared. Recently, the groups of Trost13
(5) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. ReV. 2002, 102, 1359. (c) Ma, D.; Cai, Q. Acc. Chem.
Res. 2008, 41, 1450.
(6) (a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973. (b) Zhang, H.; Ma, D.; Cao, W. Synlett 2007, 243. (c)
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. (d) Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem.
Soc. 2009, 131, 78.
We have for some time been interested in transition-metal-
catalyzed reactions of ene- and diene-allenes.10 Recently,
(1) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. Wolfe, J. P.; Wagaw, S.;
(7) Chen, C.; Yang, L.-M. J. Org. Chem. 2007, 72, 6324.
(8) For the use of Rh, Ru, and Ir, see: (a) Ru: Bertelsen, S.; Nielsen,
M.; Bachmann, S.; Jorgensen, K. A. Synthesis. 2005, 2234. (b) Ir: Pouy,
M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Org. Lett. 2007, 9,
3949. (c) Ru: Goossen, L. J.; Rauhaus, J. E.; Deng, G. Angew. Chem., Int.
Ed. 2005, 44, 4042.
Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805
.
(2) (a) De Meijere, A., Diederich, F., Eds. Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) Hadei, N.;
Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org. Lett. 2005, 7, 3805.
(c) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482
.
(3) Wagaw, S.; Yang, B.; Buchwald, S. J. Am. Chem. Soc. 1999, 121,
10251. Yin, J.; Buchwald, S. J. Am. Chem. Soc. 2002, 124, 6043. Willis,
(9) (a) Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862.
(b) Bistri, O.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 586.
(c) Correa, A.; Bolm, C. AdV. Synth.Catal. 2008, 350, 391.
(10) (a) Piera, J.; Persson, A.; Caldentey, X.; Ba¨ckvall, J. E. J. Am.
Chem. Soc. 2007, 129, 14120. (b) Piera, J.; Na¨rhi, K.; Ba¨ckvall, J. E. Angew.
Chem., Int. Ed. 2006, 45, 6914. (c) Franze´n, J.; Ba¨ckvall, J. E. J. Am. Chem.
Soc. 2003, 125, 6056. (d) Franze´n, J.; Lo¨fstedt, J.; Falk, J.; Ba¨ckvall, J. E.
J. Am. Chem. Soc. 2003, 125, 14140.
M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int. Ed. 2005, 44, 403
.
(4) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969.
Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901. (c)
Urgaonkar, S.; Nagarajan, M.; Verkade, J. G J. Org. Chem. 2003, 68, 452.
(d) Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 4321
.
10.1021/ol901294j CCC: $40.75
Published on Web 08/11/2009
 2009 American Chemical Society

and Hsung14 reported on copper(I)-catalyzed coupling of
amides, carbamates, and ureas with iodo- and bromoallenes,
which afforded N-allenylated products in good yields.15
In connection with a project on the carbocyclization of
N-allyl-N-allenylamides, we required access to these com-
pounds. Copper-catalyzed coupling seemed to be a viable
method for their preparation, and herein we report on the
copper-catalyzed coupling between allylic sulfonamides and
bromoallenes, resulting in N-allenylated allylic amides
(Scheme 1).
Scheme 1
Figure 1. Evaluation of some ligands (L) in the coupling of
sulfonamides and allenes. Reactions run for 16 h at 90 °C.
some further experiments, we found that optimal conversions
were achieved by using the conditions described in Scheme
2, which afforded the desired product (3) in 89% isolated
yield. It is worth noting that the current protocol proceeds
well in both toluene and 1,4-dioxane but performs poorly in
DMF.
In order to investigate the coupling, N-allyl-4-methylben-
zenesulfonamide16 (1) and 1-bromo-3-methylbuta-1,2-diene
(2a) were chosen as model substrates for the initial optimiza-
tion of the reaction conditions. First, the influence of the
copper source was investigated for the model reaction using
toluene as solvent. This showed that copper(I) thiophene-
2-carboxylate (CuTC) was superior to other copper catalysts
such as CuI, CuBr, and CuCN. Replacing CuTC with CuI
consistently resulted in around 15% lower yield, which is in
agreement with previously reported results.13 Next we
focused on the choice of ligand. It was found that N,N′-
dimethylethane-1,2-diamine (DMEDA) was the best ligand
of those investigated and with this ligand a 92% conversion
was obtained after 16 h in toluene at 90 °C (Figure 1).
All of the optimizations were conducted using cesium
carbonate as our base of choice. Other bases such as K3PO4,
K2CO3, and Na2CO3 were briefly tested, but they never gave
as good results as the more soluble cesium carbonate.17 After
Scheme 2
As shown by the optimized reaction conditions, we were
forced to use relatively high catalytic loadings of CuTC (0.15
equiv). All efforts to decrease the amount of catalyst resulted
in poor yields. Decreasing the amount of CuTC to 0.1 equiv
resulted in a 64% yield of 3, and lowering the amount even
further to 0.05 equiv gave only 25% of the desired product.
Despite the high loadings of catalyst, we were intrigued to
see that the coupling worked well under the conditions
employed. During our investigation, 2.5 equiv of bromoallene
was employed; however, we discovered at a late stage that
1.5 equiv is sufficient to promote the coupling without any
substantial loss in yield.18
(11) For some recent reactions involving allenylamides, see: (a) Navarro-
Va´zquez, A.; Rodr´ıguez, D.; Mart´ınez-Espero´n, M. F.; Garc´ıa, A.; Saa´, C.;
Dom´ınguez, D. Tetrahedron Lett. 2007, 48, 2741. (b) Fuwa, H.; Tako, T.;
Ebine, M.; Sasaki, M. Chem. Lett. 2008, 37, 904. (c) Bacci, J. P.; Greenman,
K. L.; Van Vranken, D. L. J. Org. Chem. 2003, 68, 4955. (d) Shen, L.;
Hsung, R. P. Org. Lett. 2009, 7, 775. (e) Fuwa, H.; Sasaki, M. Org. Biomol.
Chem. 2007, 5, 2214. (f) Rameshkumar, C.; Hsung, R. P. Angew. Chem.,
Int. Ed. 2004, 43, 615.
In the coupling protocol reported by Trost13 it was
mentioned that some substrates undergo coupling, followed
by isomerization from allene to 1,3-diene, a phenomenon
we have not observed with our substrates. We noticed,
however, that the products obtained were very sensitive to
acid, giving 1,3-dienes under acidic conditions. As a
consequence, all column chromatograhy purifications were
carried out with basic alumina.19
(12) For preparation of allenamides, see: (a) Armstrong, A.; Emmerson,
D. P. G. Org. Lett. 2009, 11, 1547. (b) Wei, L.; Xiong, H.; Hsung, R. P.
Acc. Chem. Res. 2003, 36, 773. (c) Xiong, H.; Tracey, M. R.; Grebe, T.;
Mulder, J. A.; Hsung, R. P. Org. Synth. 2005, 81, 147. (d) Huang, J.; Xiong,
H.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe, T. P. Org. Lett.
2002, 4, 2417. (e) Wei, L.; Mulder, J. A.; Xiong, H.; Zircsak, C. A.; Douglas,
C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
(13) Stiles, D. T.; Trost, B. M. Org. Lett. 2005, 7, 2117.
(14) Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org.
Lett. 2005, 7, 3081.
(15) For preparation of bromo allenes, see: Black, D. K.; Landor, S. R.;
Patel, A. N.; Whiter, P. F Tetrahedron Lett. 1963, 4, 483.
(18) Using 1.5 equiv of bromoallene gave product 5 in 76% yield.
(19) All attempts to purify the obtained products by column chro-
matography on silica or deactivated silica (SiO2/Et3N) resulted in
isomerized product. Chromatography on basic alumina (pH ) 9.5) was
therefore chosen.
(16) For preparation of N-allylsulfonamides, see the following. Aryl
substituted: Busacca, C. A.; Dong, Y. Tetrahedron Lett. 1996, 37, 3947.
(b) Alkyl substituted: Lei, A.; Lu, X Org. Lett. 2000, 2, 2357.
(17) Cella, A.; Bacon, S. W. J. Org. Chem. 1984, 49, 1122.
Org. Lett., Vol. 11, No. 17, 2009
3815

After the initial screening and overcoming some purifica-
tion issues, we moved on to investigating the versatility of
the present method. The results are shown in Table 1. A
selection of bromoallenes is readily available,15 and varia-
tions of the allene moiety in the reaction with allylic
sulfonamides was studied. It was found that 3,3-disubstituted
allenamides generally give good to high yields in the
coupling with allylic sulfonamides (Table 1).
Coupling of a monosubstituted allene gave a lower yield
(Table 1, entry 4). Allylic sulfonamides containing both alkyl
and aryl substituents on the allylic moiety were investigated
in the coupling reaction.16
only small amounts of product could be isolated (not shown).
In addition, when the olefin is replaced by a simple ethyl
group only 10% of the coupled product can be detected with
the present protocol. To our surprise, the introduction of an
aromatic ring on the olefin (Table 1, entry 8) produced no
desired product at 80 °C (decomposition); however, lowering
the temperature to 40 °C gave coupled products in moderate
yields (entries 8-10). As a consequence, the copper-
catalyzed coupling can in these cases proceed at temperatures
close to room temperature. This is a phenomenon we have
not yet fully rationalized.20
Apart from substrates bearing the allylic side chain some
other useful sulfonamides were subjected to the coupling
protocol (Table 2). Protected aryl amines undergo coupling
in moderate yields even with an acyl group introduced in
the ortho-position (Table 2, entries 1 and 2). Surprisingly,
ditoslylated-1,2-diamines (Table 2, entry 3) yielded a cyclic
product in 63% yield. We believe that this product arises
from a monoallenylated intermediate, which undergoes a
cyclization under the conditions employed.
Increased bulk around the olefin of the allylic amide results
in slightly lower yields of coupled product (Table 1, entries
2 and 3). Introduction of a methyl group on the internal
carbon of the olefin results in a very inefficient reaction, and
Table 1. Copper-Catalyzed Cross-Coupling of Allylic Sulfonyl
Amides and Bromoallenesa
Table 2. Cross-Coupling of Sulfonyl Amides and Bromoallenesa
a Conditions: CuTC (0.15 equiv), DMEDA (0.30 equiv), Cs2CO3 (2.0
equiv), Br-allene (2.5 equiv), THF or 1,4-dioxane (65 or 80 °C), 24 h.
b Isolated yields. c Refluxing 1,4-dioxane. d Refluxing THF.
A protected amino acid also furnished coupling product
in moderate yield without any further optimization (Table
2, entry 4).
The present protocol developed has some limitations. All
attempts to replace the sulfonyl group by other protective
groups such as acetyl, Cbz, Boc, or trifluoroacetyl were
unsuccessful and led only to recovered starting material. We
a Conditions: CuTC (0.15 equiv), DMEDA (0.30 equiv), Cs2CO3 (2.0
equiv), Br-allene (2.5 equiv), toluene, 80 °C, 24 h. b Isolated yields.
c Performed at 40 °C.
(20) No product formation was observed when the copper catalyst was
removed from the system.
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Org. Lett., Vol. 11, No. 17, 2009

bromoallene to the copper(I) diamine (A) complex would
produce a copper(III) intermediate (B).22 Exchange of the
bromide with the tosyl amide (C, C′) followed by reductive
elimination would lead to coupling product. Our experimental
data suggest that the presence of an allylic double bond on
the amide might act as a ligand in the catalytic cycle. This
would explain why increased bulk around the olefin or
removal of this moiety results in lower yields and longer
reaction times.
Scheme 3
.
Proposed Mechanism for the Copper-Catalyzed
Cross-Coupling
In conclusion, we have developed a method for copper-
catalyzed coupling of bromoallenes and N-allylsulfonamides
to give N-allyl-N-alleneylsulfonamides. These structures can
serve as excellent substrates for further transition-metal-
catalyzed transformations.23
Acknowledgment. Financial support from the Swedish
Foundation for Strategic Research, the Swedish Research
Council, and The Berzelii Center EXSELENT is gratefully
acknowledged.
Supporting Information Available: Complete experi-
mental procedures, characterization data, and copies of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
speculate that this has to do with the pKa of the amides, where
the p-toluenesulfonamide has a pKa of around 16, whereas
the other amides have a pKa above 20.21 In addition,
introducing a substituent in the R-position of the sulfonamide
shuts down the reaction yielding only traces of coupled
product.
OL901294J
(22) For copper(III) intermediate in oxidative addition of organohalides
to copper(I), see: (a) Karlstro¨m, A. S. E.; Ba¨ckvall, J. E Chem.sEur. J.
2001, 7, 1981. (b) Ga¨rtner, T.; Henze, W.; Gschwind, R. M. J. Am. Chem.
Soc. 2007, 129, 11362. For copper(III) intermediates in cuprate additions
to enones, see: (c) Bertz, S. H.; Cope, S.; Murphy, M.; Ogle, C. A.; Taylor,
B. J. J. Am. Chem. Soc. 2007, 129, 7208. (d) Hu, H.; Snyder, J. P. J. Am.
Chem. Soc. 2007, 129, 7210.
A mechanism of the copper-catalyzed cross-coupling
reaction is proposed in Scheme 3. Oxidative addition of the
(21) (a) Bordwell, F. G.; Fried, H. E.; Hughes, D. L.; Lynch, T.; Satish,
A. V.; Whang, Y. E. J. Org. Chem. 1990, 55, 3330. (b) Bordwell, F. G.;
Fried, H. E. J. Org. Chem. 1991, 56, 4218. (c) Bordwell, F. G. Acc. Chem.
Res. 1988, 21, 456.
(23) Carbocyclization of the aza-enallene product in table 1 (entry 3)
in the presence of 5 mol % of Pd(OAc)2 and 2 equiv of p-benzoquinone in
THF at 55 °C afforded the the pyrroline product (1-tosyl-3-(2-isopropenyl-
4-vinyl-2-pyrroline) in 89% yield: Persson, A. K. Å; Ba¨ckvall, J. E.
Unpublished results.
Org. Lett., Vol. 11, No. 17, 2009
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