Platinum-catalyzed consecutive C-N bond formation-[1,3] shift of carbamoyl and ester groups

Article abstract of DOI:10.1016/j.tetlet.2009.02.108

The reaction of ortho-alkynylphenylureas 1 having a carbamoyl group attached to the nitrogen atom proceeded in the presence of catalytic amounts of PtI₄, affording corresponding indole-3-carbamides 2 in moderate to high yields. In addition, the platinum-catalyzed cyclization of ortho-alkynylphenyl carbamates 3 afforded corresponding indole-3-carboxylates 4 in good yields. The present reaction proceeds through the intramolecular addition of carbon-nitrogen bonds to triple bonds, the so-called carboamination.

Full text of DOI:10.1016/j.tetlet.2009.02.108

Tetrahedron Letters 50 (2009) 2075–2077
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Platinum-catalyzed consecutive C–N bond formation-[1,3] shift of carbamoyl
and ester groups
*
Itaru Nakamura , Yusuke Sato, Sayaka Konta, Masahiro Terada
Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of ortho-alkynylphenylureas 1 having a carbamoyl group attached to the nitrogen atom pro-
ceeded in the presence of catalytic amounts of PtI4, affording corresponding indole-3-carbamides 2 in
moderate to high yields. In addition, the platinum-catalyzed cyclization of ortho-alkynylphenyl carba-
mates 3 afforded corresponding indole-3-carboxylates 4 in good yields. The present reaction proceeds
through the intramolecular addition of carbon–nitrogen bonds to triple bonds, the so-called
carboamination.
Received 13 January 2009
Revised 10 February 2009
Accepted 16 February 2009
Available online 21 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
E
R
Polysubstituted indoles are widely used in the pharmaceutical
field and in organic material science. Because of this, the effi-
cient synthesis of these compounds is still a topic of interest
in organic chemistry.1 The catalytic cyclization of ortho-alkyny-
lanilines is one of the most powerful methods for the synthesis
of 3-nonsubstituted indoles.2 Recently, several groups including
ours have developed efficient protocols for the synthesis of poly-
substituted indoles, which involve the cyclization of ortho-alky-
nylanilines having a migration group attached to the nitrogen
cat. Pt(II), Pd(II), Au(III)
R
N
R'
E
ð1Þ
ð2Þ
N
R'
E: acyl, allyl, MOM, sulfonyl
O
R
YR'
cat. Pt(IV)
O
atom in the presence of
p-acidic transition metal catalysts (Eq.
R
1).3–6 Not only strongly electrophilic functional groups, such as
acyl groups, but also less electrophilic functional groups, such
as allyl, methoxymethyl, and sulfonyl groups, have been em-
ployed as the migrating groups. These results encouraged us to
explore other migrating groups that cannot be directly installed
by Friedel–Crafts-type electrophilic substitution into the 3-posi-
tion of the indole ring for this methodology. Herein, we report
that the reaction of ortho-alkylphenylureas 1 in the presence of
platinum catalysts proceeds via migration of the carbamoyl
N
YR'
N
Me
Me
YR' = NArMe (1)
OR'(3)
YR' = NArMe (2)
OR' (4)
We first optimized the conditions for the reaction of 1a. The
results are summarized in Table 1. The reaction of 1a in the
presence of 10 mol % of PtI4 in ethyl acetate at 100 °C for 6 h
gave 2a in 55% yield along with corresponding 3-protonated
product 5a in 37% yield (entry 1).8 The reaction at 80 °C took
24 h, affording 2a in 52% yield along with 40% of 5a (entry 2).
PtBr4 showed similar catalytic activity, while the use of PtCl4
led to a lower chemical yield (entries 3 and 4). Divalent platinum
salts, such as PtBr2 and PtCl2, were less effective and other metal
salts, such as AuBr3 and InBr3, did not promote the present reac-
tion at all (entries 5–8). The reaction using dimethoxyethane
group, affording the corresponding indole-3-carbamides
2 in
moderate to high yields (Eq. 2).7 Moreover, we found that the
platinum-catalyzed cyclization of ortho-alkynylanilines 3 having
an ester group attached to the nitrogen atom produced the cor-
responding indole-3-carboxylates 4 in good yields. The present
reaction proceeds through the addition of a carbon–nitrogen
bond to
a
carbon–carbon triple bond, the so-called
carboamination.
(DME), instead of ethyl acetate, gave
a comparable result,
whereas that using other solvents, such as 1,2-dichloroethane
(DCE), toluene, and 1,4-dioxane, decreased the chemical yield
(entries 9–12). Attempts to suppress the formation of protonated
product 5a by use of such additives as molecular sieves, bases,
and radical scavengers failed (see Supplementary data).
* Corresponding author. Tel.: +81 22795 6754; fax: +81 22 795 6602.
E-mail address: itaru-n@mail.tains.tohoku.ac.jp (I. Nakamura).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.108

2076
I. Nakamura et al. / Tetrahedron Letters 50 (2009) 2075–2077
Table 1
nal alkyne 1i proceeded smoothly, affording 2i in 83% yield (entry
8). The reaction of 1j having a diphenylcarbamoyl group did not
Reaction developmenta
proceed at all.
Ph
n-Pr
O
H
N
[conditions]
100 ºC
Me
O
n-Pr
+
n-Pr
Ph
n-Pr
N
Me
N
N
O
N
Me
2a
Me Me
Ph
N
N
5a
1a
Me Ph
1j
Entry
Catalyst
Solvent
Time (h)
Yield of 2ab (%)
Yield of 5ab (%)
We extended the present methodology to the migration of an
ester group (Eq. 3). The reaction of O-methyl carbamate 3a in the
presence of 10 mol % of PtCl4 afforded corresponding methyl ester
4a in good yield.9 Meanwhile, phenyl ester 4b was obtained in
good yield by using PtCl2 as catalyst. Protonated product 5a was
not obtained at all in these reactions.
1
2c
3
4
5
6
7
8
9
PtI4
PtI4
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DME
6
24
4
24
24
24
24
25
6
55
52
46
28
16
20
0
37
40
46
41
9
18
0
0
31
35
14
39
PtBr4
PtCl4
PtBr2
PtCl2
AuBr3
InBr3
PtI4
PtI4
PtI4
PtI4
0
O
n-Pr
OR
n-Pr
57
35
49
25
10 mol % Pt catalyst
EtOAc, 100 ºC
10
11
12
DCE
Toluene
1,4-Dioxane
6
24
20
O
N
Me
3
OR
N
ð3Þ
a
Me
The reaction of 1a was carried out in the presence of 10 mol % of catalyst at
4
100 °C.
b
The yield was determined by 1H NMR using dibromomethane as an internal
PtCl4, 14 hr
PtCl2, 16 hr
74 % yield
80 % yield
3a (R = Me)
4a (R = Me)
3b (R = Ph)
4b (R = Ph)
standard.
c
At 80 °C.
O
R1
We applied the optimal conditions (Table 1, entry 1) to various
substrates 1 as summarized in Table 2. The reaction of 1b, which
had a weakly electron-withdrawing chloro group at the para posi-
tion of the aromatic ring that is attached to the nitrogen atom of
the migrating amide group, gave 2b in good yield, while that of
1c bearing a strongly electron-withdrawing trifluoromethyl group
proceeded very slowly, affording 2c in low yield (entries 1 and 2).
Substrate 1d having an anisyl group at R2 was quickly converted
into 2d and 5a in 46% and 53% yields, respectively (entry 3). The
dimethylcarbamoyl group showed low migration ability (entry
4). The reaction of 1f that had an alkyl chain at the alkynyl moiety
proceeded smoothly, affording 2f in good yield (entry 5). The reac-
tion of 1g having a cyclopropyl group afforded the desired product
2g, while a phenyl group at the alkynyl terminus totally inter-
rupted the desired reaction (entries 6 and 7). The reaction of termi-
YR2
R1
O
PtX4
N
N
YR2
Me
Me
1 (Y = NMe)
3 (Y = O)
2
4
(Y = NMe)
(Y = O)
X4Pt
R1
PtX4
O
R1
N
Me
6
YR2
N
O
Me
YR2
7
Scheme 1. Plausible mechanism.
Table 2
PtI4-catalyzed cyclization of 1a
R2
R1
O
H
N
10 mol % PtI4
Me
O
R1
+
R1
R2
EtOAc, 100 ºC
N
Me
N
N
N
Me Me
Me
1
2
5
Entry
1
R1
R2
Time (h)
Yield of 2b (%)
Yield of 5b (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
n-Pr
n-Pr
n-Pr
n-Pr
(CH2)3Cl
Cyclopropyl
Ph
p-ClC6H4
p-F3C-C6H4
p-Anisyl
Me
Ph
Ph
4
24
2
2b, 61
2c, 32
2d, 46
2e, 23
5a, 36
5a, 56
5a, 53
5a, 48
5b, 36
5c, 33
5d, 31
trace
4
c
18
48
24
4
2f, 54
2g, 32
d
Ph
Ph
trace
c
H
2i, 83
a
The reaction of 1 (0.25 mmol) was carried out in the presence of 10 mol % of PtI4 in ethyl acetate at 100 °C.
b
c
The yield was determined by 1H NMR using dibromomethane as an internal standard.
Isolated yield.
49% of 1h was recovered.
d

I. Nakamura et al. / Tetrahedron Letters 50 (2009) 2075–2077
2077
PtX4
R
PtX4
H
R
R
O
·
N
N
N
O
N
Me
O
·
N
Me
Me
N
H3C
Ph
H3C
Ph
5
H2C
Ph
A
7'
Scheme 2.
A plausible mechanism of the present reaction is illustrated in
Scheme 1. The Lewis acidic platinum catalyst coordinates to the
alkynyl moiety of substrate 1 or 3. Intramolecular nucleophilic at-
tack of the nitrogen atom on the triple bond yields cyclized inter-
mediate 7. [1,3] Migration of the carbamoyl or alkoxycarbonyl
group followed by elimination of the platinum catalyst, the so-
called carbodemetalation, gives product 2 or 4.
To know if the reaction proceeds via intramolecular or inter-
molecular manner, we carried out a crossover experiment (Eq.
4). The reaction of a 1:1 mixture of 1b and 1f under the stan-
dard conditions afforded a mixture of 2b and 2f; no crossover
products, such as 2a and 2k, were observed in GC–mass. This re-
sult indicates that the present reaction proceeds in an intramo-
lecular manner.
bond to a carbon-carbon triple bond, the so-called carboamination,
this methodology is useful to provide these molecules in an effi-
cient and atom-economic manner.
Acknowledgments
This work was financially supported by a Grant-in-Aid for Sci-
entific Research from Japan Society for Promotion in Science (JSPS)
and The Uehara Memorial Foundation. We also thank reviewers for
valuable suggestions.
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic data of 1, 2, 3, 4, and 5c) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.02.108.
n-Pr
R
O
O
+
10 mol % PtI4
Ar
Ph
References and notes
N
N
N
N
EtOAc, 100 ºC 10 h
Me Me
Me Me
1f [R = (CH2)3Cl]
1. (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045; (b) Cacchi, S.; Fabrizi,
G. Chem. Rev. 2005, 105, 2873; (c) Campo, J.; García-Valverde, M.; Marcaccini, S.;
Rojo, M. J.; Torroba, T. Org. Biomol. Chem. 2006, 4, 757; (d) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
2. For a review (a) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239; (b)
Skouta, R.; Li, C.-J. Tetrahedron 2008, 54, 4917; (c) Fürstner, A.; Davies, P.
W. Angew. Chem., Int. Ed. 2007, 46, 3410; (d) Zhang, L.; Sun, J.; Kozmin, S.
A. Adv. Synth. Catal. 2006, 348, 2271; (e) Widenhoefer, R. A.; Han, X. Eur. J.
Org. Chem. 2006, 4555; (f) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285.
3. (a) Migration of allyl groups:, Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998,
63, 1001; (b) Fürstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024; (c)
Istrate, F. M.; Gagosz, F. Org. Lett. 2007, 9, 3181; (d) Propargyl groups, acyl
groups:, Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126,
10546; (e) Sulfonyl groups:, Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 2284.
4. Related papers for indole synthesis via migration from N to C: (a) Cariou, K.;
Ronan, B.; Mignani, S.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2007,
46, 1881; (b) Li, G.; Huang, X.; Zhang, L. Angew. Chem., Int .Ed. 2008, 47, 346; (c)
Takaya, J.; Udagawa, S.; Kusama, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2008, 47,
4906.
1b (R = p-Cl-C6H4)
Ar
Ph
O
O
N
N
Me
Me
5a
5b
+
+
+
11%
28%
n-Pr
R
N
N
ð4Þ
1b
1f
trace
Me
Me
+
+
61%
2b (R = p-Cl-C6H4)
2f [R = (CH2)3Cl]
21%
52%
not observed
Ar
Ph
O
O
N
N
Me
Me
n-Pr
R
N
N
Me
5. For synthesis of benzofurans. Allyl groups: (a) Arcadi, A.; Cacchi, S.; Del Rosario,
M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280; (b) Cacchi, S.; Fabrizi, G.;
Moro, L. Synlett 1998, 741; (c) Monterio, N.; Balme, G. Synlett 1998, 746; (d)
Cacchi, S.; Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998, 39, 5101; (e) Fürstner, A.;
Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785; (f) Fürstner, A.; Stelzer, F.;
Me
2a
2k [R = (CH2)3Cl, Ar = p-Cl-C6H4]
In the reaction of ortho-alkynylphenylureas 1, the formation of
3-protonated by-product 5 was observed (Tables 1 and 2). Because
the formation of the protonated product 5 was not reduced by
addition of drying agents, such as MS 4 Å, protodemetalation by
a trace amount of water in the reaction system is less likely. More-
over, the reaction in deuterated solvents, such as toluene-d8 and
CD2Cl2 did not afford 3-deuterated indoles. Presumably, the forma-
tion of 3-protonated by-products is due to protodemetalation of
the vinylplatinum moiety by a proton derived from the methyl
moiety of the migrating carbamoyl group, which would be elimi-
nated in the [1,3] carbamoyl migration step, as illustrated in
Scheme 2. Further mechanistic investigations are currently ongo-
ing in our laboratory.
Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863; (g)
a-Alkoxyalkyl groups:,
Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022;
(h) Fürstner, A.; Heilmann, E. K.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
4760.
6. For synthesis of benzothiophenes: (a) Nakamura, I.; Sato, T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2006, 45, 4473; (b) Nakamura, I.; Sato, T.; Terada, M.;
Yamamoto, Y. Org. Lett. 2007, 9, 4081; (c) Nakamura, I.; Sato, T.; Terada, M.;
Yamamoto, Y. Org. Lett. 2008, 10, 2649.
7. Zhao, Z.; Jaworski, A.; Piel, I.; Snieckus, V. Org. Lett. 2008, 10, 2617.
8. Representative procedure: To a mixture of 10 mol % of PtI4 and 0.25 mmol of 1
was added 1.0 mL of ethyl acetate in a pressure vial (Wheaton v-vial) at room
temperature, and the mixture was stirred at 100 °C. After complete
consumption of the starting material, which was monitored by TLC, the
reaction mixture was cooled to room temperature. The reaction mixture was
passed through a short pad of silica gel with ethyl acetate. After the solvents
were removed in vacuo, the residue was purified by silica-gel column
chromatography using ethyl acetate/hexane (1:5) as eluent. The obtained
mixture of 2 and 5 was separated by gel permeation chromatography (Japan
Analytical Industry Co. LC-918) to give product 2.
In conclusion, we are now in a position to synthesize indole-3-
carbamides and -carboxylates by the platinum-catalyzed cycliza-
tion of ortho-alkynylphenyl ureas and carbamates. As the present
reaction proceeds through formal addition of a carbon–nitrogen
9. The reaction of 3a with lower catalyst loading (5 mol %) took 20 h, affording 4a
in 60% yield along with 21% of recovered 3a.