Ruthenium-catalyzed cyclization of 3-en-1-ynyl imines with nucleophiles via tandem 5-exo-dig cyclization and nucleophilic addition

Article abstract of DOI:10.1016/j.tetlet.2004.10.069

Treatment of 3-en-1-ynyl imines with TpRuPPh₃(CH ₃CN)₂PF₆ catalyst (1 mol %) in DCE (50°C, 6 h) effected catalytic cyclization with suitable nucleophiles and gave functionalized pyrroles in good yields. The reac

Full text of DOI:10.1016/j.tetlet.2004.10.069

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9245–9247
Ruthenium-catalyzed cyclization of 3-en-1-ynyl imines
with nucleophiles via tandem 5-exo-dig cyclization
and nucleophilic addition
Hung-Chin Shen, Chia-Wen Li and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua University, Hsinchu 30043, Taiwan, Province of China
Received 10 September 2004; revised 8 October 2004; accepted 13 October 2004
Available online 28 October 2004
Abstract—Treatment of 3-en-1-ynyl imines with TpRuPPh3(CH3CN)2PF6 catalyst (1mol%) in DCE (50°C, 6h) effected catalytic
cyclization with suitable nucleophiles and gave functionalized pyrroles in good yields. The reaction mechanism is proposed to pro-
ceed via (2-pyrrolyl)carbenoid intermediates derived from 5-exo-dig cyclization. This catalytic reaction works well with various
nucleophiles, including water, alcohols and anilines.
Ó 2004 Elsevier Ltd. All rights reserved.
The activation of an alkyne functionality with transi-
tion-metal species is an efficient method for the in situ
generation of metal-carbenoid species, which subse-
quently leads to interesting products via carbene trans-
fer reactions.1–4 This approach avoids the use of
hazardous diazoalkane as a carbenoid precursor.5
Metal-carbenoid species have been postulated to be inter-
mediates in the cycloisomerization of a,x-enynes using
electrophilic metal catalysts.1,2 Recently, Uemura and
Iwasawa reported metal-catalyzed 5-exo-dig cyclization
of 3-en-1-ynyl ketones and imines to generate carbenoid
intermediates (II) as depicted in Scheme 1 (Eq. 1).3 This
active species reacts with olefin to give cyclopropane
derivatives catalytically.3 (2-Furyl)carbenoids (II) of a
special type undergo Doyle–Kirmse reaction6 with inser-
tion into the C–S bond of allylic sulfides by the carb-
enoid carbon.3a One useful application of this catalytic
protocol is to decompose carbenoid intermediates (II)
with nucleophiles7, but such a process has not yet been
achieved. We envision that carbenium species (III)
derived from a cationic metal catalyst will be prone to
nucleophilic addition to give distinct addition products
(Eq. 2). In this study, we report a new cyclization of
3-en-1-ynyl imines with suitable nucleophiles using
cationic ruthenium species. The proposed ruthenium-
carbenoid intermediate (III) readily reacts with water,
alcohol and amines to liberate useful pyrrolyl deriva-
tives. This catalytic reaction is challenging in synthetic
chemistry because terminal alkynes are easily hydro-
lyzed by electrophilic metal catalysts to give correspon-
ding methyl ketones.8
R1
R1
R1
R2
R3
(1)
X
R2
R3
M
X
R2
R3
X
Y = H
M
II
I
H
M
X = O, NR
R1
NR
R1
Table 1 shows the results of these catalytic reactions
over various cationic catalysts and solvents. Treat-
ment of 3-en-1-ynyl imine (1) with 5mol%
TpRuPPh3(CH3CN)2PF6 [A, Tp = tris(1-pyrazolyl)bor-
ate]9,10 and water (1.5equiv) in hot toluene (100°C,
12h) afforded 2-hydroxymethylpyrrole (2) in 47% yield
in addition to an unknown species 3 (26%). The NMR
spectra and mass data suggested species 3 is derived
from an unknown cyclodimerization of starting imine
1, but the structure can not be assigned with certainty.
The yield of byproduct 3 can be effectively reduced with
R1
(2)
R2
R3
R2
R3
+
M
NR
R2
R3
Nu-H
NR
Nu
+
M
+
III
M
H
H
H
Scheme 1.
Keywords: Cyclization; Imines; Nucleophile.
*
Corresponding author. Tel.: +886 3 5721424; fax: +886 3 5711082;
e-mail: rsliu@mx.nthu.edu.tw
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.069

9246
H.-C. Shen et al. / Tetrahedron Letters 45 (2004) 9245–9247
Table 1. Catalytic cyclization of 3-en-l-ynyl imine 1 with water
Table 2. Catalytic cyclizations of 3-en-l-ynyl imines with water
OMe
Ar
1 mol% [Ru]
H2O
N
N
Ar
OMe
N
N
R
catalyst
R
+ H2O
OH
15-25
4-14
OH
2
Iminesa
Pyrrolesb
1
Entries Catalystsa
Solventsb Conditions
A (5.0mol%) Toluene
A (5.0mol%) Benzene
Yieldsc (%)
(1) Ar = C6H5 R = Me (4)
(2) Ar = p-MeC6H4 R = Me (5)
(3) Ar = C6H5 R = nPr (6)
(4) Ar = p-MeC6H4 R = nPr (7)
(5) Ar = p-MeOC6H4 R = nPr (8)
(6) Ar = C6H5 R = nBu (9)
(7) Ar = p-MeC6H4 R = nBu (10)
(8) Ar = p-MeOC6H4 R = nBu (11)
(9) Ar = C6H5 R = nC6H13 (12)
(10) Ar = p-MeC6H4 R = nC6H13 (13)
(11) Ar = p-MeC6H4 R = nC6H13 (14)
15 (78%)
16 (83%)
17 (80%)
18 (83%)
19 (84%)
20 (85%)
21 (86%)
22 (84%)
23 (82%)
24 (84%)
25 (87%)
1
2
100°C (12h) 47 (26)d
80°C (48h)
7
3
A (5.0mol%) DME
A (5.0mol%) CH3CN
A (5.0mol%) DCE
A (1.0mol%) DCE
B (5.0mol%) DCE
C (5.0mol%) DCE
D (5.0mol%) DCE
E (5.0mol%) DCE
80°C (48h) N.R.
80°C (48h) N.R.
4
5
50°C (4h)
50°C (4h)
50°C (4h)
50°C (4h)
50°C (4h)
50°C (4h)
58 (23)d
6
80
41
40
46
32
7
8
9
10
a Water (1.2equiv), [imine] = 1.5M 1mol% catalyst A, DCE, 50°C, 6h.
a Catalysts: TpRuPPh3(CH3CN)2PF6 (A), CpRuPPh3(CH3CN)2PF6
(B), CpRuPnBu3(CH3CN)2PF6 (C), CpRuP0Bu3(CH3CN)2PF6 (D),
CpRuPCy3(CH3CN)2PF6 (E).
b [1] = 1.5M, 1.2equiv H2O.
c Yields were reported after separation from a silica column.
d The values in parentheses represents the yields of unknown 3.
b Yields were reported after elution through a silica column.
tionalized pyrrolyl 26–30 products in reasonable yields
(63–86%). This process was successfully extended to ani-
line and methylaniline to give products 31–32 in 68%–
74% yields (entries 6 and 7). 3-En-1-ynyl imine 12
showed similar catalytic activity towards methanol and
methylaniline, and gave the products 33–34 in 81–89%
yield. Cyclization of imine 1 with phenol, diethyl- or
diisopropyl amines gave a complicated mixture of prod-
ucts. This observation suggests that nucleophiles with
acidic or basic nature are not compatible with this cycli-
zation. Terminal alkynes tended to react with ruthenium
(II) species to give alkynyl metal species in the presence
of basic amines11 (Table 3).
low loading of catalyst (vide ante). Benzene, dimethoxy-
ethane (DME) and acetonitrile were far less active
in this catalytic cyclization (entries 2–4), whereas
1,2-dichloroethane (DCE) gave the desired alcohol 2 in
an improved yield (58%) even at 50°C (entry 5).
Notably, a low loading of catalyst A (1.0mol%) was
more effective, and gave alcohol 2 with in a yield up to
80%. Entries 7–10 show catalytic reactions over vari-
ous cationic ruthenium complexes including CpRu-
PPh3(CH3CN)2PF6 (B), CpRuPnBu3(CH3CN)2PF6 (C),
CpRuPtBu3(CH3CN)2PF6 (D) and CpRuPCy3(CH3-
CN)2PF6 (E), and no catalytic activities were observed
with these catalysts.
We have attempted similar catalytic cyclizations on 3-
en-1-ynyl ketones and aldehydes with water, isobutanol
and aniline, but we failed to obtain the expected furan
products. This cyclization is not applicable to those 3-
en-1-ynyl imines bearing an internal alkyne although it
is compatible with p-alkyne reaction intermediates.
The cyclization of 3-en-1-ynyl imine 1 with water is syn-
thetically interesting because many metal complexes cata-
lyze the hydration of terminal alkyne to give methyl
ketone derivatives.8 Surprisingly, such a reaction does
not occur in the present catalytic system. We prepared
various 3-en-1-ynyl imines 4–14 to examine the general-
ity of this cyclization with water; 1.0mol% catalyst A
promoted the reaction in hot DCE (50°C, 6h) without
the formation of other byproducts. The yields of pyrrol-
yl alcohols 15–25 are given after isolation from a silica
column. Entries 1–2 show the application of this process
to 3-en-1-ynyl imines 4–5 bearing a tolyl and p-methoxy-
phenyl groups respectively, to give the desired alcohols
15–16 in 78–83% yields. This method is compatible with
changes in both the R and Ar substituents (R = nPr,
nBu, nC6H13; Ar = C6H5, p-MeC6H4, entries 3–14) of
the starting imines 6–14, and gives the corresponding
alcohols 17–25 in yields exceeding 80%.
Table 3. Cyclization of 3-en-l-ynyl imines with alcohols and amines
OMe
N
[Ru]
OMe
N
+
Nu-H
R
R
Nu
Imines
Nu–H
Pyrrolesa
(1) R = Me (1)
(2) R = Me (1)
(3) R = Me (1)
(4) R = Me (1)
(5) R = Me (1)
(6) R = Me (1)
(7) R = Me (1)
MeOH
iBuOH
26 (86%)
27 (82%)
28 (86%)
29 (78%)
30 (63%)
31 (68%)
32 (74%)
33 (89%)
34 (81%)
CH2@CHCH2OH
iPrOH
tBuOH
PhNH2
PhMeNH
MeOH
PhMeNH
(8) R = nC6H13 (12)
(9) R = nC6H13 (12)
We next examined this catalytic cyclization with other
nucleophiles to enhance its synthetic utility; and the re-
sults are depicted in Table 2. Cyclization of imine 1 with
[Ru] = 1mol% catalyst A, [imine] = 1.50M, NuH (1.2equiv), DCE,
50°C, 6h.
i
various alcohols ROH (R = Me, Bu, CH2 = CHCH2,
iPr, tBu, entries 1–5) proceeded smoothly and gave func-
a Yields were reported after purification from a silica column.

H.-C. Shen et al. / Tetrahedron Letters 45 (2004) 9245–9247
9247
3. (a) Kato, Y.; Miki, K.; Nishino, F.; Ohe, K.; Uemura, S.
Org. Lett. 2003, 5, 2619; (b) Nishino, F.; Miki, K.; Kato,
Y.; Ohe, K.; Uemura, S. Org. Lett. 2003, 5, 2615; (c) Miki,
K.; Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem. Soc.
2002, 124, 5260; (d) Miki, K.; Yokoi, T.; Nishino, F.;
Kato, Y.; Washitake, Y.; Ohe, K.; Uemura, S. J. Org.
Chem. Soc. 2004, 69, 1557; (e) Iwasawa, N.; Shido, M.;
Kusama, H. J. Am. Chem. Soc. 2001, 123, 5814; (f) Casey,
C. P.; Strotman, N. A.; Guzei, I. A. Organometallics 2004,
23, 4121.
4. (a) Yamamoto, Y.; Kitahara, H.; Ogawa, R.; Kawaguchi,
H.; Tatsumi, K.; Itoh, K. J. Am. Chem. Soc. 2000, 122,
4310; (b) Trost, B. M.; Hashmi, A. S. K. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1085; (c) Harrak, Y.; Blaszylowski,
C.; Bernard, M.; Cariou, K.; Mainetti, E.; Mouries, V.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am.
Chem. Soc. 2004, 126, 8656; (d) Mamane, V.; Gress, T.;
Krause, H.; Furstner, A. J. Am. Chem. Soc. 2004, 126,
8654.
In summary, we have reported a new cyclization of 3-en-
1-ynyl imines with suitable nucleophiles, including
water, alcohols and aniline, to afford functionalized
pyrroles in good yields. In the case of water, we did
not observe the hydration of 3-en-1-ynyl imines like
other catalytic systems. A low loading (1mol%) of
TpRuPPh3(CH3CN)2PF6 catalyst (A) promotes the
catalytic cyclization without the formation of byprod-
ucts. This process is thought to involve (2-pyrrolyl)carb-
enoids derived from 5-exo-dig cyclization of the starting
imines.
Acknowledgements
The authors wish to thank the National Science Coun-
cil, Taiwan, for support of this work.
5. (a) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911;
(b) Davies, H. W. L.; Beckwith, R. E. J. Chem. Rev. 2003,
103, 2861.
Supplementary data
6. (a) Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. J. Org.
Chem. 1981, 46, 5094; (b) Kirmse, W.; Kapps, M. Chem.
Ber. 1968, 101, 994.
7. Kirmse, W. In Advances in Carbene Chemistry; Brinker,
U. D., Ed.; JAI: London, England, 1994; Vol. 1, pp
1–57.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.10.069. Synthetic procedures and spectral data
for all reaction products is available.
8. (a) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M.
Angew. Chem., Int. Ed. 2002, 41, 4563; (b) Tokunaga, M.;
Wakatsuki, Y. Angew. Chem., Int. Ed. 1998, 37, 2867; (c)
Damiano, J. P.; Postel, M. J. Organomet. Chem. 1996, 522,
303; (d) Uemura, S.; Miyoshi, H.; Okano, M. J. Chem.
Soc., Perkin Trans. 1 1980, 1098; (e) Baidossi, W.; Lahav,
M.; Blum, J. J. Org. Chem. 1997, 62, 669.
9. For catalytic reactions with catalyst A, see selected papers:
(a) Yeh, K.-L.; Liu, B.; Lo, C.-Y.; Liu, R.-S. J. Am. Chem.
Soc. 2002, 124, 6510; (b) Datta, S.; Chang, C.-L.; Yeh,
K.-L.; Liu, R.-S. J. Am. Chem. Soc. 2003, 125, 9294; (c)
Shen, H.-C.; Pal, S.; Lian, J.-J.; Liu, R.-S. J. Am. Chem.
Soc. 2003, 125, 15762; (d) Madhushaw, R. J.; Lin, M.-Y.;
AbuSohel, S. M.; Liu, R.-S. J. Am. Chem. Soc. 2004, 126,
6895; (e) Chang, C.-L.; Kumar, M. P.; Liu, R.-S. J. Org.
Chem. 2004, 69, 2793.
References and notes
1. For recent reviews of the metal-catalyzed cyclization of
enynes: (a) Aubert, C.; Buisine, O.; Malacria, M. Chem.
Rev. 2002, 102, 813; (b) Diver, S. T.; Giessert, A. J. Chem.
Rev. 2004, 104, 1317; (c) Mendez, M.; Mamane, V.;
Furstner, A. Chemtracts 2003, 16(7), 397.
¨
2. For selected examples: (a) Chatani, N.; Furukawa, N.;
Sakurai, H.; Murai, S. Organometallics 1996, 15, 901; (b)
Mendez, M.; Munoz, M. P.; Nevado, C.; Caedenas, D. J.;
Echavarren, A. M. J. Am. Chem. Soc. 2001, 123, 10511; (c)
Nevado, C.; Cardenas, D. J.; Echavarren, A. M. Chem.
Eur. J. 2003, 9, 2627; (d) Furstner, A.; Szillat, H.; Gabor,
¨
B.; Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305; (e)
Furstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc.
¨
2000, 122, 6785; (f) Furstner, A.; Stelzer, F.; Szillat, H. J.
¨
10. Chan, W.-C.; Lau, C.-P.; Chen, Y.-Z.; Fang, Y.-Q.; Ng,
S.-M.; Jia, G. Organometallics 1997, 16, 34.
Am. Chem. Soc. 2001, 123, 11863; (g) Marion, F.;
Coulomb, J.; Courillion, C.; Fensterbank, L.; Malacria,
M. Org. Lett. 2004, 6, 1509.
11. Bustelo, E.; Carbo, J. J.; Lledos, A.; Mereiter, K.; Puerta,
M. C.; Valerga, P. J. Am. Chem. Soc. 2003, 125,
3311.