Phosphine-catalyzed regioselective heteroaromatization between activated alkynes and isocyanides leading to pyrroles

Article abstract of DOI:10.1016/j.tetlet.2005.02.104

The organophosphine catalyzed reaction of activated alkynes with isocyanides produces the corresponding heteroaromatization products, pyrroles, regioselectively in good yields. The reaction proceeds most probably through the 1,4-addition of the nucleophil

Full text of DOI:10.1016/j.tetlet.2005.02.104

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2563–2566
Phosphine-catalyzed regioselective heteroaromatization
between activated alkynes and isocyanides leading to pyrroles
Shin Kamijo, Chikashi Kanazawa and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 15 January 2005; revised 7 February 2005; accepted 16 February 2005
Abstract—The organophosphine catalyzed reaction of activated alkynes with isocyanides produces the corresponding heteroaroma-
tization products, pyrroles, regioselectively in good yields. The reaction proceeds most probably through the 1,4-addition of the
nucleophilic phosphine catalyst to the alkynes, followed by a [3+2] cycloaddition between the resulting alkenyl phosphine interme-
diates and a carbanion derived from the isocyanides.
ꢀ
2005 Elsevier Ltd. All rights reserved.
One of the rapidly growing research areas in the field of
synthetic organic chemistry is catalytic transformations
using simple organic molecules called organocatalysts.
Various types of organic molecules have already been
found to act as organocatalysts and phosphines are use-
ful for this purpose. It is known that the isomerization,
cyclization, and addition reactions of electron-deficient
we discovered that copper–phosphine complexes
catalyzed the reaction between ethyl 2-butynoate (1a)
and ethyl isocyanoacetate (2a) to form the pyrrole 3a
in variable yields. The effect of phosphine additives on
the yields is summarized in Table 1. Arylphosphines
1
2
alkynes and allenes are catalyzed by organophosphines.
However, to the best of our knowledge, a phosphine-
catalyzed intermolecular heteroaromatization reaction
a
Table 1. Effect of phosphine additives on the yields of 3a
b
NMR yield (%)
Entry
Phosphine
PPh
6 4 3
(p-MeO–C H ) P
3
is not known. We report herein that the reaction
of the alkynes 1, activated with an electron withdrawing
group (EWG ), with isocyanides 2 bearing an EWG is
catalyzed by organophosphines to give the pyrroles 3,
c
1
3
50
38
0
2
3
4
5
6
1
2
(p-CF –C H ) P
3
6
4 3
3
(o-Tolyl) P
0
4
regioselectively, in good yields Eq. 1.
PBu
3
34
13
50
63
50
25
0
(Cyclohexyl)
e
3
P
d
7
dppe
dppp
1
5 mol% dppp
dioxane
R
EWG1
EWG2
d
f
8
d
EWG2
+
R
EWG1
CN
g
9
10
dppb
H
d
h
N
H
dppf
BINAP
1
00 °C
d
1
i
1
1
2
3
a
1
Unless otherwise noted, the reaction of 1a (R = Me, EWG = CO
2
Et,
ð1Þ
2
0
2
.6 mmol) and 2a (EWG = CO Et, 0.5 mmol) was conducted in 1,4-
dioxane (1 mL) in the presence of CuCl (50 lmol, 10 mol%) and
phosphine (150 lmol, 30 mol %) at 100 ꢁC for 6 h.
NMR yield using p-xylene as an internal standard.
During research on the palladium–copper bimetallic cata-
lyzed three-component coupling reaction between alky-
b
c
5
nes (or isocyanides), allyl carbonates, and TMS azide,
3 3
CuCl(PPh ) (50 lmol, 10 mol %) was used as a catalyst instead of
CuCl and PPh
3
.
d
e
f
1
5 mol % of bidentate phosphine was used.
Keywords: Organocatalyst; Phosphine catalyzed reaction; Heteroaro-
matization; Activated alkyne; Isocyanide; Pyrrole; [3+2] Cyclo-
addition.
dppe = 1,2-bis(diphenylphosphino)ethane.
dppp = 1,3-bis(diphenylphosphino)propane.
dppb = 1,4-bis(diphenylphosphino)butane.
g
h
i
0
*
Corresponding author. Tel.: +81 22 217 6581; fax: +81 22 217
784; e-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
dppf = 1,1 -bis(diphenylphosphino)ferrocene.
0 0
BINAP = 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl.
6
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.104

2564
S. Kamijo et al. / Tetrahedron Letters 46 (2005) 2563–2566
such as PPh and electron rich tris(p-methoxyphenyl)-
3
shortened the reaction time but the yield of 3h remained
moderate (entry 9). The reaction of an electron deficient
alkyne, diethyl acetylenedicarboxylate 1i, gave a com-
plex mixture of unidentified products, probably due to
polymerization (entry 10). It is worthy to mention that
the alkynyl ketone 1j and alkynyl cyanide 1k served as
a starting material to afford the corresponding pyrroles
3j and 3k in 77% and 35% yields, respectively (entries
11 and 12).
phosphine produced the corresponding pyrrole 3a
in moderate yields (entries 1 and 2), whereas electron
deficient tris(p-trifluoromethylphenyl)phosphine and
sterically congested tri(o-tolyl)phosphine did not cata-
lyze the reaction at all (entries 3 and 4). Alkylphosphines
were less effective than PPh (entries 5 and 6). The reac-
3
tivity of the bidentate phosphines, such as dppe, dppp,
and dppb, were comparable to that of PPh (entries 7–
3
6
9
). Among them, dppp gave the highest yield of the de-
Ph
2
CO Et
15 mol% dppp
sired pyrrole 3a. The employment of dppf and BINAP
did not improve the yield of 3a. Very interestingly, fur-
ther studies disclosed that the present heteroaromatiza-
tion could be catalyzed merely by a phosphine such as
dppp, without the aid of CuCl. The reaction of various
alkynes 1 with 2a was carried out under the optimal con-
ditions; dppp (15 mol %) in 1,4-dioxane at 100 ꢁC. The
results are summarized in Table 2.
EWG2
Ph
CO
2
Et + CN
EWG2
H
dioxane
100 °C
N
1f
H
b: EWG2 = CO
tBu
c: EWG2 = CONEt
d: EWG2 = P(O)(OEt)
2
2
2
2
3l: 70% (2 h)
3m: 27% (3.5 h)
3n: 18% (24 h)
2
2
ð2Þ
The reaction between 1a and 2a was completed in 2 h to
give the corresponding pyrrole 3a in 60% yield (entry
We next examined the reactions between ethyl phenyl–
propiolate (1f) and the isocyanides 2b–d (Eq. 2). Instal-
lation of a bulky t-butyl group in the ester moiety, as
shown in 2b, did not affect the reaction progress and
the corresponding pyrrole 3l was produced in 70% yield.
The isocyanides having amide 2c and phosphonate
groups 2d afforded the corresponding pyrroles 3m and
7
1
). The alkyne 1b bearing a hexyl group afforded the
pyrrole 3b in 73% yield (entry 2). Even the unprotected
alkynyl alcohol 1c could be used directly as a starting
material and produced the corresponding product 3c
in 59% yield (entry 3). The reaction of the alkyne 1d hav-
ing a cyclohexyl group proceeded smoothly to produce
the pyrrole 3d in 66% yield after 24 h (entry 4). When
this reaction was carried out in the presence of a cata-
lytic amount of CuCl, the reaction time was reduced
3
n, respectively, however the yields were rather low.
We applied this heteroaromatization reaction to the syn-
9
thesis of the trail pheromone 4 of a leaf-cutting ant,
8
without affecting the yield of 3d (entry 5). In the case
which contains a pyrrole ring as a core structure
(Scheme 1). The alkynoate 1l was prepared by DCC
condensation between 2-butynoic acid and 2-(trimethyl-
silyl)ethanol. The phosphine-catalyzed heteroaromatiza-
tion between 1l and methyl isocyanoacetate proceeded
smoothly to afford the corresponding pyrrole 3o in
64% yield. Protection of the pyrrole nitrogen using
Boc group, followed by treatment with TBAF gave the
pyrrole carboxylic acid. Decarboxylation was carried
of the alkyne 1e bearing a bulky t-butyl group, no reac-
tion took place even after 24 h and significant amounts
of the starting materials were recovered (entry 6). The
reactions of alkynes 1f–h conjugated with an aryl group
gave the corresponding pyrroles 3f–h, respectively (en-
tries 7–9). The introduction of an electron donating
group on the aromatic ring slightly retarded the con-
sumption of the alkyne 1g, though the product 3g was
obtained in a high yield (entry 8). On the contrary,
the introduction of an electron withdrawing group
i
10
out using Cu(OAc)2 in Pr NEt/anisole to produce
2
the final target molecule 4.
a
Table 2. Phosphine-catalyzed pyrrole synthesis using various alkynes 1 and 2a
1
Entry
R
EWG
1
Time (h)
3
Yield (%)
1
2
3
4
Me
CH
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
2
2
2
2
2
2
2
2
2
2
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
1a
1b
1c
1d
1d
1e
1f
2
12
2
3a
3b
3c
3d
3d
3e
3f
60
73
59
66
64
3
2 5
(CH )
2 4
HO(CH )
cyclo-C
cyclo-C
t-Bu
6
H
H
11
24
19
24
1.5
3.5
0.75
0.5
1
b
5
6
11
c
6
7
8
9
—
Ph
79
79
48
p-MeO–C
p-CF –C
Et
6
H
4
1g
1h
1i
3g
3h
3i
3
6 4
H
d
10
11
12
CO
Ph
Ph
2
—
COMe
CN
1j
1k
3j
3k
77
35
0.5
a
2
Unless otherwise noted, the reaction between 1 (0.5 mmol) and 2a (EWG = CO
of dppp (75 lmol, 15 mol%) at 100 ꢁC for the time indicated.
CuCl (25 lmol, 5 mol %) was added.
2
Et, 0.6 mmol) was conducted in 1,4-dioxane (1 mL) in the presence
b
c
A significant amount of the alkyne 1e and the isocyanide 2a were recovered.
Complex mixture.
d

S. Kamijo et al. / Tetrahedron Letters 46 (2005) 2563–2566
2565
SiMe3
O
a
b
Me
O
O
O
O
Me
Me
OH
SiMe3
CO Me
2
CN
CO Me
2
N
HO
SiMe3
H
1l
3o
SiMe3
O
O
c
Me
O
d
Me
OH
CO Me
e
Me
CO Me
CO Me
2
N
2
N
2
N
H
Boc
Boc
4
Scheme 1. Synthesis of the ant trail pheromone 4. Reagents and conditions: (a) 1,3-dicyclohexylcarbodiimide (DCC), pyridine, CH
2
Cl
2
, 0 ꢁC, 1 h,
CN, rt, 13 h, 93%; (d) TBAF, THF,
9
4%; (b) dppp (15 mol %), 1,4-dioxane, 100 ꢁC, 7 h, 64%; (c) (Boc)
0 ꢁC, 8 h; (e) Cu(OAc) (2 equiv), anisole, Pr NEt, 130 ꢁC, 12 h, 42% for two steps.
2
O, 4-dimethylaminopyridine (10 mol %), CH
3
i
6
2
2
EWG1
EWG2
R
EWG1
EWG2
R
C
H
N
H
N
H
R
R
EWG1
D
3
R3P
1
1
1
R
C
EWG
H
EWG
R3P
R P
2
3
N
EWG
A
C
R
EWG1
EWG2
CN
R P
H
3
2
B
CN
EWG2
2′
Scheme 2. A plausible mechanism for the phosphine-catalyzed heteroaromatization.
A plausible mechanism is depicted in Scheme 2. The
present heteroaromatization is most probably initiated
by the 1,4-addition of the nucleophilic phosphine
catalyst to the activated alkynes 1 to form the zwitter-
Further studies on the synthetic application of this new
transformation and on the mechanistic details are
underway in our laboratory.
1
1
ionic intermediate A. The abstraction of an acidic pro-
ton of the isocyanide 2 gives the cationic intermediate B
Acknowledgements
0
and the carbanion 2 . The carbanion would attack the
12
1
carbon bearing the EWG of B and the newly formed
We thank the faculty members in the Research and Anal-
ytical Center for Giant Molecules at the Graduate School
of Science, Tohoku University for the measurement of
NMR spectra, mass spectra, and elemental analysis.
0
anionic center would attack the isocyanide carbon of 2
to form the cyclic intermediate C; this is a [3+2] cycload-
dition process. Intramolecular proton migration and
elimination of the phosphine catalyst produces the inter-
mediate D. Subsequent 1,5-hydrogen shift furnishes the
pyrrole 3 as the final product.
References and notes
We have developed a new phosphine-catalyzed conden-
sation between the alkynes 1 and isocyanides 2, which
produces the pyrroles 3 regioselectively. This new meth-
od was applied to the synthesis of ant trail pheromone 4.
1
. Reviews on the organocatalyzed reactions, see: (a) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726–
3748, and references cited therein; (b) Johnson, J. S.
Angew. Chem., Int. Ed. 2004, 43, 1326–1328.

2566
S. Kamijo et al. / Tetrahedron Letters 46 (2005) 2563–2566
2
3
4
. Review on the phosphine-catalyzed reactions: Lu, X.; MHz, CDCl ): d 1.32 (3H, t, J = 7.2 Hz), 1.35 (3H, t, J =
3
Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535–544, and
references cited therein.
. Phosphine-mediated furan synthesis, see: Jung, C.-K.;
Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc. 2004, 126,
7.2 Hz), 2.14 (3H, d, J = 0.6 Hz), 4.30 (2H, q, J = 7.2 Hz),
4.33 (2H, q, J = 7.2 Hz), 6.65 (1H, dd, J = 2.8, 0.8 Hz),
9.29 (1H, br s, NH); C NMR (75.5 MHz, CDCl ): d
3
1
3
10.87, 14.24 (· 2), 60.66, 60.79, 120.09, 120.55, 121.79,
122.11, 160.19, 165.56; IR (neat) 3308, 1705, 1699, 1279,
4118–4119.
ꢀ
1
1259, 1194, 1126, 1078, 1036 cm ; HRMS (EI) Calcd for
. Reviews on the chemistry of pyrroles, see (a) Comprehen-
sive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, 1979; Vol. 4, pp 275–320; (b)
Black, D. S. In Science of Synthesis; Maas, G., Ed.; Georg
Thieme: Stuttgart, 2001; Vol. 9, pp 441–552; (c) Gossauer,
A. In Methoden der Organischen Chemie (Houben-Weyl);
Kreher, R. P., Ed.; Gerog Thieme: Stuttgart, 1994; Vol.
E6a, pp 556–798.
+
11 4
C H15NO (M ) 225.099. Found: 225.099.
8. The CuCl catalyst probably coordinates both dppp and
the isocyanide in this case. The coordination to the
isocyanide makes it easy to generate the anionic interme-
0
diate 2 in Scheme 2 and stabilizes the derived species.
Moreover, the ligation to the phosphine holds intermedi-
0
ates B and 2 close together and accelerates the formation
of the cyclized intermediate C.
5
6
. Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 7786–7787.
. The reactions using dppp as an organocatalyst: (a) Trost,
B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819–
9. (a) Tumlinson, J. H.; Silverstein, R. M.; Moser, J. C.;
Brownlee, R. G.; Ruth, J. Nature 1971, 234, 348–349; (b)
Tehrani, K. A.; Borremans, D.; De Kimpe, N. Tetrahe-
dron 1999, 55, 4133–4152; (c) Sonnet, P. E. J. Med. Chem.
1972, 15, 97–98; (d) Xiao, D.; Schreier, J. A.; Cook, J. H.;
Seybold, P. G.; Ketcha, D. M. Tetrahedron Lett. 1996, 37,
1523–1526.
1
0820; (b) Trost, B. M.; Dake, G. R. J. Org. Chem. 1997,
62, 5670–5671.
7
. Representative experimental procedure for the phosphine-
catalyzed heteroaromatization leading to the pyrrole 3: To
a 1,4-dioxane solution (1 mL) of 1,3-bis(diphenylphosphino)-
propane (dppp) (30.9 mg, 75 lmol) were added ethyl
butynoate (1a) (58 lL, 0.5 mmol) and ethyl isocyanoace-
tate (2a) (66 lL, 0.6 mmol) under an Ar atmosphere. The
solution was stirred at 100 ꢁC for 2 h. After the consump-
tion of 1a, the reaction mixture was cooled to room
temperature and filtered through a short Florisil pad and
concentrated. The residue was purified by column chro-
matography (silica gel, n-hexane/AcOEt 50:1–3:1) to
10. Carter, P.; Fitzjohn, S.; Halazy, S.; Magnus, P. J. Am.
Chem. Soc. 1987, 109, 2711–2717.
11. (a) See Ref. 2; (b) Grossman, R. B.; Comesse, S.; Rasne,
R. M.; Hattori, K.; Delong, M. J. Org. Chem. 2003, 68,
871–874; (c) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem.
Lett. 1993, 241–244; (d) Wang, J.-C.; Ng, S.-S.; Krische,
M. J. J. Am. Chem. Soc. 2003, 125, 3682–3683.
12. Similar types of addition reactions have reported: (a)
Han e´ danian, M.; Loreau, O.; Taran, F.; Mioskowski, C.
Tetrahedron Lett. 2004, 45, 7035–7038; (b) Lu, C.; Lu, X.
Org. Lett. 2002, 4, 4677–4679.
afford 2,3-di(ethoxycarbonyl)-4-methylpyrrole (3a) in
6
1
0% yield as a colorless oil (67.1 mg). H NMR (600