Regioselective direct C-H alkylation of NH indoles and pyrroles by a palladium/norbornene-cocatalyzed process

Article abstract of DOI:10.1055/s-0033-1338523

Nitrogen-containing heterocycles, including 1H-indoles and electron-deficient 1H-pyrroles, undergo a palladium/norbornene-cocatalyzed regioselective alkylation at the C-H bond adjacent to the NH group. A primary alkyl halide is used as the electrophile and the reaction proceeds smoothly under mild conditions to give 2-alkyl-1H-indoles and 2-substituted or 2,3-disubstituted 5-alkyl-1H-pyrroles in good yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338523

PRACTICAL SYNTHETIC PROCEDURES
▌35
pRraectigcailosysnethleeticcptriovceedurDesirect C–H Alkylation of NH Indoles and Pyrroles by a
Palladium/Norbornene-Cocatalyzed Process
N-Heterocycle Alkylation
Lei Jiao, Thorsten Bach*
Lehrstuhl für Organische Chemie I and Catalysis Research Center (CRC), Technische Universität München, Lichtenbergstr. 4, 85747 Garching,
Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
PSP
Received: 29.07.2013; Accepted: 03.08.2013
No262
Abstract: Nitrogen-containing heterocycles, including 1H-indoles and electron-deficient 1H-pyrroles, undergo a palladium/norbornene-
cocatalyzed regioselective alkylation at the C–H bond adjacent to the NH group. A primary alkyl halide is used as the electrophile and the
reaction proceeds smoothly under mild conditions to give 2-alkyl-1H-indoles and 2-substituted or 2,3-disubstituted 5-alkyl-1H-pyrroles in
good yields.
Key words: catalysis, alkylations, regioselectivity, heterocycles, palladium, indoles, pyrroles
Procedure 1
variant a (R1 = H):
PdCl2(MeCN)2, norbornene,
K2CO3 or KHCO3, DMA,
H2O (0.5 M), 70 or 90 °C, Ar
variant b (R1 ≠ H):
PdCl2, norbornene, K2CO3,
R1
R1
DMF–DMSO (9:1 v/v),
H2O (0.5 M), 60 °C, air
Y
Y
3
R2
+
R2CH2X
(X = Br, I)
2
2
N
N
23 examples, 46–90%
H
H
1
3
Procedure 2
Y
Y
PdCl2(MeCN)2, norbornene
3
4
5
KHCO3 or K2HPO4, DMA, 90 °C, air
R2
+
R2CH2Br
X
X
2
N
N
22 examples, 45–91%
H
H
2
4 (X or Y = EWG)
5
Scheme 1
tion with alkyl electrophiles usually results in a mixture of
regioisomers;7 other methods for regioselective alkylation
1
Introduction
Indoles and pyrroles are two important classes of N-het- of pyrroles are either circuitous or limited in substrate
erocycles that occur widely in natural products, drugs, and scope.8 Therefore, there remains a considerable need for
biologically active molecules.1 Alkyl-substituted indoles efficient and regioselective methods for alkylation of in-
and pyrroles are of particular interest, because they form doles and pyrroles.
key structural elements of many structurally unique and
biologically active natural products (Figure 1).2 However,
few methods are available for constructing such structures
OH
by direct C–H substitution. Although considerable ad-
vances have been made in the direct C–H functionaliza-
N
H
OMe
N
N
tion of indoles and pyrroles,3 the regioselective
installation of an alkyl group onto these heterocyclic nu-
clei remains a challenge. Indoles undergo Friedel–Crafts
alkylation selectively at the more electron-rich C3 posi-
tion,4 but it is difficult to achieve direct C2 alkylation.5,6
In the case of pyrroles, Friedel–Crafts-type direct alkyla-
N
H
N
HN
Et
HN
H
quebrachamine
goniomitine
streptorubin B
Figure 1 Natural products containing an alkylindole or alkylpyrrole
structure
Inspired by the Catellani reaction,9 we developed a palla-
dium(II)/norbornene-cocatalyzed process that provides
straightforward access to α-alkyl-substituted indole and
SYNTHESIS 2014, 46, 0035–0041
Advanced online publication: 17.09.2013
DOI: 10.1055/s-0033-1338523; Art ID: SS-2013-Z0526-PSP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

36
L. Jiao, T. Bach
PRACTICAL SYNTHETIC PROCEDURES
pyrrole derivatives from NH indoles10 and pyrroles11
(Scheme 1). In this reaction, the N-heterocycle interacts
with palladium(II) and norbornene to give intermediate A,
which then undergoes an intramolecular ortho-palladation
to give palladaheterocycle B in the presence of a base
(Scheme 2).10b,11 Subsequently, intermediate B reacts with
the alkyl halide by oxidative addition, reductive elimina-
tion, norbornene expulsion, and protodepalladation to
give the alkyl-substituted heterocycle. The role of nor-
bornene in this process is to act as a transpositional cocat-
alyst that assists palladium in activating the α-C–H bond
of NH indoles and pyrroles, providing excellent regiose-
lectivities for the alkylation reactions (C2-alkylation on
indole and C5-alkylation on 2-substituted and 2,3-disub-
stituted pyrroles). This reaction adds to the toolbox of syn-
thetic methods for direct C–H functionalization of N-
heterocycles.
Table 1 Regioselective Direct Alkylation of 1H-Indole (1a) with
Primary Alkyl Bromides 2a–j (Scheme 1, Procedure 1a)
Entrya Temp Time
Product
Yieldb
(%)
(°C)
(h)
1
70
14
3aa
67c
N
H
12
2
3
4
5
6
90
70
70
70
90
61
14
14
14
20
3ab
3ac
3ad
3ae
3af
59c
58c
82
N
H
N
H
OTBS
OTHP
N
H
73
N
H
cat. Pd(II), base
+
R
X
R
H
N
N
H
OMe
OMe
H
65
N
H
norbornene
Pd(II)
Pd(II)
norbornene
O
7
8
70
70
70
70
14
3ag
3ah
3ai
72
R
N
H
N
N
O
PdIIXL2
PdIIXL2
14
56c
65
CN
Et
A
C
L
N
H
PdII
N
L
base
9
19.5
14
X
R
N
H
B
COOEt
Scheme 2 The mechanism of the newly developed catalytic alkyla-
66c
tion procedure
10
3aj
COOEt
N
H
3
a Reaction conditions: indole 1 (1 mmol), primary alkyl bromide 2 (2
mmol), PdCl2(MeCN)2 (0.1 mmol), norbornene (2 mmol), K2CO3 (2
mmol), DMA + 0.5 M H2O (5 mL), under argon.
b Yield of isolated product.
2
Scope and Limitations
The alkylation of 1H-indole (1a) with alkyl bromides 2a–
j proceeded smoothly with the palladium(II)/norbornene
cocatalytic system to give 2-alkyl-1H-indoles regioselec-
tively (Procedure 1, variant a).10a As shown in Table 1, a
broad range of functionalized primary alkyl bromides are
c A minor amount of the 2,3-dialkyl-1H-indole was isolated as a by-
product.
dopropane) failed to react. The reaction of 1H-indole with
suitable as reaction partners. The reactions were conduct- ethyl 3-bromopropanoate failed to give the desired alkyl-
ed with bis(acetonitrile)dichloropalladium(II) as catalyst,
norbornene as cocatalyst, and potassium carbonate as base
in N,N-dimethylacetamide as solvent containing 0.5 M
water as an additive. In general, the 2-alkylation products
were obtained in moderate to good yields and, in certain
ation product as a result of elimination of hydrobromic
acid under basic conditions to form ethyl acrylate. The use
of an alkyl iodide instead of the corresponding alkyl bro-
mide accelerated the reaction, but resulted in a consider-
able amount of the 2,3-dialkylation byproduct. Alkyl
cases, minor amounts of the 2,3-dialkyl-1H-indole (4– tosylates failed to react. Therefore, both reactivity and sta-
19%) were obtained as overalkylation byproducts. The bility should be taken into account when choosing the al-
steric effect of the alkyl bromide plays an important role
in the alkylation reaction; primary alkyl bromides bearing
a tertiary carbon center in the β-position reacted slowly
(entries 2 and 6), whereas a secondary alkyl halide (2-io-
kyl coupling partners in this reaction.
1H-Indoles bearing electron-donating or electron-with-
drawing substituents were superior substrates in this 2-al-
kylation reaction (Procedure 1, variant a).10a Table 2 lists
Synthesis 2014, 46, 35–41
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
N-Heterocycle Alkylation
37
some results obtained with 5-, 6-, and 7-substituted 1H-in-
doles 1b–k and various primary alkyl bromides. Interest-
ingly, electron-deficient 1H-indoles usually afforded
better yields of the 2-alkylindole products than did elec-
tron-rich 1H-indoles (compare entries 1–4 with entries 5–
11), but a weaker base, such as potassium bicarbonate or
dipotassium hydrogen phosphate had to be used to prevent
generation of undesired N-alkylindole byproducts. Halo-
gen-substituted 1H-indoles were suitable substrates and
successfully gave the corresponding halogen-substituted
2-alkyl-1H-indoles (for example, entries 4–8), allowing
access to more-complex heterocyclic compounds through
cross-coupling reactions.
Table 2 Regioselective Direct Alkylation of Substituted 1H-Indoles
1b–k with Primary Alkyl Bromides 2 (Scheme 1, Procedure 1a)
Entrya Base
(equiv)
Time Product
(h)
Yieldb
(%)
1
2
K2CO3 (2)
K2CO3 (2)
18 3bd
68
OTBS
N
H
MeO
14 3cg
62c
O
N
H
O
The same procedure also permits the 2-alkylation of 3-
substituted 1H-indole derivatives (Scheme 3).10b The al-
kylation of 3-methyl-1H-indole (1m) with butyl bromide
proceeded more slowly than the alkylation of 1H-indole
and gave a moderate yield of the 2,3-dialkylated indole
3mk. Therefore, an optimization study was conducted to
improve this type of reaction, especially for more com-
plex substrates. A modified procedure (Procedure 1, vari-
ant b) using alkyl iodide 2n as the electrophile,
palladium(II) chloride as the catalyst, and N,N-dimethyl-
formamide–dimethyl sulfoxide as a solvent mixture in an
atmosphere of air resulted in good conversion and a high
yield in the 2-alkylation of tryptophol derivative 1n
(Scheme 3).
F
3
4
5
K2CO3 (2)
K2CO3 (2)
20 3dk
14 3ee
59d
76
N
H
Cl
OTHP
N
H
Br
Cl
KHCO3 (3) 15 3fk
KHCO3 (3) 14 3gk
74
N
H
6
85
56e
65
87
N
H
Cl
7
KHCO3 (3) 38 3gl
KHCO3 (4) 14 3hk
KHCO3 (3) 14 3ij
BuBr
PdCl2(MeCN)2
norbornene, K2CO3
N
H
I
Bu
DMA, H2O (0.5 M)
N
N
H
H
70 °C, Ar, 14 h, 46%
8f
9
1m
3mk
N
H
Et
COOEt
MeOOC
I
COOEt
OTBS
2m
OTBS
PdCl2
norbornene, K2CO3
N
H
COOEt
N
DMF–DMSO (9:1 v/v)
H2O (0.5 M), 60 °C, air
26 h, 73%
N
H
H
Et
O
O
1n
3nm
10
KHCO3 (3) 14 3jg
K2HPO4 (3) 17 3kk
86
90
MeOOC
O2N
N
Scheme 3 Regioselective direct alkylation of 3-substituted 1H-in-
doles (Scheme 1, Procedure 1b)
H
11
Because of the structural similarity between indole and
pyrrole, our palladium(II)/norbornene-cocatalyzed alkyl-
ation process can also be applied to pyrrole derivatives.11
Interestingly, we found that the reaction worked properly
only with electron-deficient pyrrole derivatives, and that
it failed in the case of 1H-pyrrole itself and other electron-
rich pyrroles. Given that the pyrrole nucleus is more elec-
tron rich and less acidic (pKa = 23) than indole
(pKa = 20.95),12 it is possible that electron-deficient pyr-
roles meet the electronic requirement of this reaction more
closely. Alkyl 1H-pyrrole-2-carboxylates were found to
be ideal substrates, and they underwent smooth 5-alkyla-
tion reactions with various primary alkyl bromides. In a
slight departure from Procedure 1, these reactions were
N
H
a Reaction conditions: indole 1 (1 mmol), primary alkyl bromide 2 (2
mmol), PdCl2(MeCN)2 (0.1 mmol), norbornene (2 mmol), base, DMA
+ 0.5 M H2O (5 mL), 70 °C, under argon.
b Yield of isolated product.
c 23% of the indole substrate was recovered.
d A minor amount of 2,3-dialkyl-1H-indole was isolated as a byprod-
uct.
e 24% of the indole substrate was recovered.
f 4 equiv of BuBr were used.
conducted by using potassium bicarbonate as a mild base
in dry N,N-dimethylacetamide at 90 ºC under air (Proce-
dure 2). Table 3 shows some typical examples of 5-alkyl-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 35–41

38
L. Jiao, T. Bach
PRACTICAL SYNTHETIC PROCEDURES
ation reactions of pyrrole-2-carboxylates 4a–c. The yields
were generally good to excellent, and in all cases a single
regioisomer was obtained. Although higher temperatures
and longer reaction times were required for satisfactory
conversion, this reaction, like the indole alkylation reac-
tion, showed good tolerance to a range of functional
groups. A limitation of this reaction is that is appears to be
restricted to 1H-pyrrole-2-carboxylates as substrates; 2-
cyano-, 2-(dimethylaminocarbonyl)-, 2-formyl-, and 2-
acetyl-substituted 1H-pyrroles failed to give the desired
products. Methyl 1H-pyrrole-3-carboxylate gave a mix-
ture of 5-alkylation and 2,5-dialkylation products in low
yield. Therefore, this procedure is best suited for the al-
kylation of alkyl 1H-pyrrole-2-carboxylates.
Table 3 Regioselective Direct Alkylation of Electron-Deficient 1H-
Pyrroles 4a–c with Primary Alkyl Bromides 2 (Scheme 1, Procedure
2)
Entrya Time
(h)
Product
Yieldb
(%)
1
22
5aa
86
EtOOC
tBuOOC
EtOOC
EtOOC
BnOOC
EtOOC
EtOOC
EtOOC
tBuOOC
EtOOC
N
12
H
2
22
22
22
22
22
21
23
22
5ba
5ac
5an
5cn
5ao
5ah
5ap
5bp
84
71
77
52
89
87
90
79
N
12
H
3
N
H
Procedure 2 can also be applied to a series of 2,3-disubsti-
tuted electron-deficient 1H-pyrroles 4d–i (Table 4).11
These substrates gave 5-alkylation products regioselec-
tively, albeit in lower yields than pyrrole-2-carboxylates.
Both alkoxycarbonyl and acyl groups can be used as elec-
tron-withdrawing substituents on either the C2- or the C3-
position of pyrrole, although pyrrole carboxylates were
found to be superior. A chlorinated pyrrole substrate 4i
underwent smooth alkylation to give the chloro-substitut-
ed alkylpyrrole 5iq in high yield (entry 9). Because many
methods have been reported for synthesizing 2,3-disubsti-
tuted electron-deficient pyrroles,13 a combination of these
methods and the present 5-alkylation procedure provides
regioselective access to a range of advanced functional-
ized pyrrole derivatives.
OTBS
OTBS
OTBS
CN
4c
5
N
H
N
H
6
9
N
H
7d
8
N
H
COOEt
COOEt
COOEt
N
H
9
N
H
The utility of the alkylation method for constructing α-al-
kylated N-heterocycles was showcased by its successful
application in total syntheses of the Aspidosperma alka-
loids aspidospermidine (6) and goniomitine (7)10b and the
lipophilic pyrrole natural product mycalazal 14 (8).11 In
the syntheses of aspidospermidine and goniomitine, the
indole alkylation protocol permitted an unprecedented
synthetic strategy in which the creation of the indole C2–
alkyl bonds served as key steps in building the core struc-
tures of the two natural products. The syntheses were
completed via the key intermediates 3ai and 3nm, respec-
tively. In the synthesis of mycalazal 14, reduction of the
pyrrole 5-tetradecylation product 5aa was carried out to
afford the target molecule (Scheme 4).
10
22
22
22
5ai
N
84
68
82
H
Et
O
O
O
O
EtOOC
EtOOC
11
12
5ag
5aq
N
H
N
H
O
tBuOOC
N
13
22
5bq
83
H
O
a Reaction conditions: pyrrole 4 (1 mmol), primary alkyl bromide 2 (2
mmol), PdCl2(MeCN)2 (0.1 mmol), norbornene (2 mmol), KHCO3 (3
mmol), DMA (1 mL), 90 ºC, under air.
b Yield of isolated product.
N
c DMA (3 mL) was used as the solvent.
8 steps
OH
Et
d The reaction was conducted under 1 atm O2 in a 9:1 v/v mixture of
DMA and DMSO.
3ai
N
H
N
5 steps
aspidospermidine
H
3nm
(6)
HN
Et
3
Summary
3 steps
goniomitine
OHC
N
nC14H29
5aa
(7)
A straightforward and synthetically useful method for the
regioselective α-alkylation of NH-indoles and pyrroles
has been developed that uses a palladium(II)/norbornene
cocatalytic system. The method provides a one-step trans-
formation of easily available N-heterocycles and alkyl ha-
lides into structurally diverse alkylation products not
H
mycalazal 14
(8)
Scheme 4 Natural products aspidospermidine (6), goniomitine (7),
and mycalazal 14 (8) synthesized through regioselective direct α-al-
kylation of N-heterocycles
Synthesis 2014, 46, 35–41
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
N-Heterocycle Alkylation
39
Procedures
Table 4 Regioselective Direct Alkylation of 2,3-Disubstituted Elec-
tron-Deficient 1H-Pyrroles 4d–i with Primary Alkyl Bromides 2
(Scheme 1, Procedure 2)
Typical procedures for the various substrate classes shown in the
schemes and in the tables are described below. Procedure 1 is sub-
divided into two variants (1a and 1b) that require modification of
the catalyst and the solvent.
Entrya
Time (h) Product
Yieldb (%)
Procedure 1a (Tables 1 and 2)10a
A 50-mL Schlenk flask equipped with a magnetic stirring bar and a
rubber septum was charged with 1H-indole substrate 1 (1.00 mmol),
norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00
mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00
mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A
0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bro-
mide 2 (2.00 mmol) was then added from a syringe, and the result-
ing mixture was degassed by three freeze–pump–thaw cycles with
liquid nitrogen under high vacuum. The flask was then placed in an
oil bath preheated to 70 °C or 90 °C, as indicated, and the mixture
was stirred vigorously under balloon pressure of argon. Upon com-
pletion of the reaction (TLC), the mixture was cooled to r.t., diluted
with Et2O (30 mL), and filtered. The filtrate was concentrated in a
rotary evaporator (60 °C water bath, 8–10 mbar) to remove the Et2O
and most of the DMA. The residue was purified directly by flash
column chromatography [silica gel (dry loading)] to give the alkyl-
ation product 3.
1c
28
23
5dk
5dp
62
EtOOC
Bu
N
H
COOEt
COOEt
2
70
EtOOC
MeO
N
H
3
22
23
5ep
5fk
69
52
EtOOC
EtOOC
N
H
4d
Bu
N
H
Analytical data for representative 2-alkyl-1H-indole products 3aa,
3bd, 3ee, and 3ij are provided below. Data for other products can
be found in the appropriate reference.10a
EtOOC
O
5
23
23
23
22
22
5fq
5gk
5gp
5hk
5iq
71
45
47
59
91
N
H
O
2-Tetradecyl-1H-indole (3aa)
White solid; yield: 213 mg (0.679 mmol, 67%); Rf = 0.64 (pentane–
Et2O, 9:1, UV); mp 58–60 °C.
O
IR (ATR): 3413, 2916, 2847, 1616, 1584, 1551, 1457, 1408, 1290,
1231 cm–1.
6
Bu
N
H
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.23–
1.34 (m, 20 H), 1.35–1.42 (m, 2 H), 1.71 (app quin, J ≈ 7.5 Hz, 2
H), 2.74 (t, J = 7.6 Hz, 2 H), 6.21 (br s, 1 H), 7.06 (app dt, J = 0.9,
J ≈ 7.5 Hz, 1 H), 7.10 (app dt, J = 0.9, J ≈ 7.5 Hz, 1 H), 7.29 (d,
J = 7.9 Hz, 1 H), 7.52 (d, J = 7.2 Hz, 1 H), 7.83 (br s, 1 H).
13C NMR (90.6 MHz, CDCl3): δ = 14.3, 22.8, 28.5, 29.3, 29.49,
29.52, 29.6, 29.7, 29.81, 29.85, 32.1, 99.6, 110.4, 119.7, 119.9,
121.1, 129.0, 136.0, 140.2.
O
COOEt
7
N
H
O
8d,e
MS (EI, 70 eV): m/z (%) = 313 (45) [M+], 144 (45) [M – C12H25]+,
Bu
N
H
130 (100) [M – C13H27]+.
Cl
HRMS (EI, 70 eV): m/z [M+] calcd for C22H35N: 313.2764; found:
313.2759.
9e
O
EtOOC
N
H
7-Methyl-2-{2-[tert-butyl(dimethyl)siloxy]ethyl}-1H-indole
(3bd)
O
Pale-yellow oil; yield: 196 mg (0.677 mmol, 68%); Rf = 0.65
(pentane–Et2O, 9:1, UV).
a Reaction conditions: pyrrole 4 (1 equiv), primary alkyl bromide 2 (2
equiv), PdCl2(MeCN)2 (0.1 equiv), norbornene (2 equiv), KHCO3 (3
equiv), DMA (1 mL per mmol of pyrrole substrate 4, c = 1 M), 90 ºC,
under air.
IR (ATR): 3437, 2954, 2927, 2856, 1614, 1559, 1496, 1461, 1329,
1254 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.10 (s, 6 H), 0.97 (s, 9 H), 2.45
(s, 3 H), 2.98 (t, J = 5.6 Hz, 2 H), 3.94 (t, J = 5.6 Hz, 2 H), 6.22 (s,
1 H), 6.91 (d, J = 7.2 Hz, 1 H), 6.98 (app t, J ≈ 7.5 Hz, 1 H), 7.38 (d,
J = 7.8 Hz, 1 H), 8.70 (br s, 1 H).
b Yield based on recovered starting material.
c BuBr (4 equiv) and KHCO3 (5 equiv) were used.
d c = 0.2 M.
e K2HPO4 (3 equiv) as base.
13C NMR (90.6 MHz, CDCl3): δ = –5.3, 16.9, 18.3, 26.1, 31.2, 63.3,
100.3, 117.7, 119.68, 119.70, 121.7, 127.9, 135.7, 138.3.
readily available by conventional synthetic methods. The
utility of this method was demonstrated by total syntheses
of several indole- and pyrrole-based natural products.
MS (EI, 70 eV): m/z (%) = 289 (21) [M+], 232 (100) [M – C4H9]+,
158 (26) [M – TBSO]+, 109 (36).
HRMS (EI, 70 eV): m/z [M+] calcd for C17H27NOSi: 289.1856;
found: 289.1856.
Particulars of the reagents, substrates, and other chemicals that were
used, together with analytical details, can be found in the appropri-
ate references.10a,b,11
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 35–41

40
L. Jiao, T. Bach
PRACTICAL SYNTHETIC PROCEDURES
6-Chloro-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole
J ≈ 7.5 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 1 H), 7.51 (d, J = 7.7 Hz, 1 H),
8.16 (br s, 1 H).
13C NMR (90.6 MHz, CDCl3): δ = –5.1, 11.9, 14.5, 18.6, 24.1, 25.8,
26.2, 28.4, 32.8, 46.9, 60.6, 64.0, 108.4, 110.6, 118.3, 119.2, 121.2,
128.8, 135.4, 135.5, 176.3.
(3ee)
Pale-yellow oil; yield: 212 mg (0.758 mmol, 76%); Rf = 0.29 (pen-
tane–Et2O, 2:1, UV).
IR (ATR): 3256, 2950, 2878, 1616, 1580, 1541, 1457, 1293, 1201
cm–1.
MS (EI, 70 eV): m/z (%) = 417 (29) [M+], 360 (27) [M – C4H9]+,
1H NMR (500 MHz, CDCl3): δ = 1.53–1.68 (m, 4 H), 1.75–1.81 (m,
1 H), 1.83–1.89 (m, 1 H), 3.02 (app t, J ≈ 5.9 Hz, 2 H), 3.48–3.53
(m, 1 H), 3.71 (app dt, J = 9.6, J ≈ 5.9 Hz, 1 H), 3.81–3.85 (m, 1 H),
4.05 (dt, J = 9.6, J ≈ 5.9 Hz, 1 H), 4.63 (dd, J = 4.8, 2.8 Hz, 1 H),
6.21–6.22 (m, 1 H), 7.02 (dd, J = 8.4, 1.9 Hz, 1 H), 7.26–7.29 (m, 1
H), 7.41 (d, J = 8.4 Hz, 1 H), 8.64 (br s, 1 H).
314 (12), 272 (100) [M – CH2OTBS]+, 240 (30), 198 (30).
HRMS (EI, 70 eV): m/z [M+] calcd for C24H39NO3Si: 417.2694;
found: 417.2691.
Procedure 2 (Tables 3 and 4)11
A reaction tube (30 × 190 mm) equipped with a magnetic stirring
bar and a rubber septum was charged with 1H-pyrrole substrate 4
(1.00 mmol), norbornene (188 mg, 2.00 mmol), KHCO3 (300 mg,
3.00 mmol), PdCl2(MeCN)2 (25.9 mg, 0.100 mmol), and alkyl bro-
mide 2 (2.00 mmol). Anhydrous DMA (1 mL) was added, and the
tube was heated in an aluminum block at 90 °C under a balloon
pressure of air. When the reaction was complete (TLC), the mixture
was cooled to r.t., diluted with Et2O (30 mL), and filtered. The fil-
trate was washed with H2O (20 mL), and the organic phase was sep-
arated. The aqueous layer was extracted with Et2O (2 × 20 mL). The
organic layers were combined, washed with brine (40 mL), dried
(Na2SO4), filtered, and concentrated. The crude product was puri-
fied by flash column chromatography (silica gel) to afford the alkyl-
ation product 5.
13C NMR (90.6 MHz, CDCl3): δ = 20.1, 25.4, 28.7, 31.0, 63.0, 67.3,
99.7, 100.1, 110.6, 120.2, 120.7, 126.9, 127.1, 136.5, 138.8.
MS (EI, 70 eV): m/z (%) = 281 (11) [M+, 37Cl], 279 (25) [M+, 35Cl],
232 (6), 195 (73), 177 (31), 164 (100), 85 (61).
HRMS (EI, 70 eV): m/z [M+] calcd for C15H1835ClNO2: 279.1021;
found: 279.1017.
Methyl 2-(5-Ethoxy-5-oxopentyl)-1H-indole-5-carboxylate (3ij)
White solid; yield: 266 mg (0.877 mmol, 87%); Rf = 0.30 (pentane–
Et2O, 9:1, UV); mp 91–92 °C.
IR (ATR): 3336, 2932, 2861, 1712, 1695, 1614, 1556, 1439, 1325,
1292, 1238 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3 H), 1.69–
1.80 (m, 4 H), 2.35 (t, J = 7.0 Hz, 2 H), 2.77 (t, J = 7.0 Hz, 2 H),
3.92 (s, 3 H), 4.13 (q, J = 7.1 Hz, 2 H), 6.31 (m, 1 H), 7.28 (d,
J = 8.5 Hz, 1 H), 7.83 (dd, J = 8.5, 1.7 Hz, 1 H), 8.28 (m, 1 H), 8.52
(br s, 1 H).
13C NMR (90.6 MHz, CDCl3): δ = 14.3, 24.5, 27.9, 28.5, 34.0, 51.9,
60.5, 100.9, 110.2, 121.7, 122.7, 122.8, 128.5, 138.8, 141.0, 168.6,
173.8.
Analytical data for representative pyrrole alkylation products 5ap,
5fq, and 5iq are provided below. Data for other products can be
found in the corresponding reference.11
Ethyl 5-(4-Ethoxy-4-oxobutyl)-1H-pyrrole-2-carboxylate (5ap)
Pale-yellow solid; yield: 228 mg (0.900 mmol, 90%); Rf = 0.15
(pentane–Et2O, 3:1, UV); mp 54–56 °C.
IR (ATR): 3224, 2978, 1719, 1683, 1201 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 3 H), 1.35 (t,
J = 7.1 Hz, 3 H), 1.97 (app quin, J ≈ 7.4 Hz, 2 H), 2.33 (t, J = 7.3
Hz, 2 H), 2.69 (t, J = 7.5 Hz, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 4.30 (q,
J = 7.1 Hz, 2 H), 5.98 (app t, J ≈ 3.2 Hz, 1 H), 6.83 (dd, J = 3.7, 2.5
Hz, 1 H), 9.44 (br s, 1 H).
MS (EI, 70 eV): m/z (%) = 303 (56) [M+], 257 (34), 201 (100), 188
(68), 170 (26), 129 (21).
HRMS (EI, 70 eV): m/z [M+] calcd for C17H21NO4: 303.1465;
found: 303.1456.
13C NMR (90.6 MHz, CDCl3): δ = 14.3, 14.6, 24.8, 27.1, 33.5, 60.2,
60.5, 108.5, 116.0, 121.7, 137.5, 161.5, 173.3.
MS (EI, 70 eV): m/z (%) = 253 (60) [M+], 207 (35), 165 (70), 152
(100), 106 (75).
HRMS (EI, 70 eV): m/z [M+] calcd for C13H19NO4: 253.1309;
found: 253.1305.
Ethyl (±)-4-[3-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-1H-in-
dol-2-yl]-2-ethylbutanoate (3nm); Procedure 1b (Scheme 3)10b
A 250-mL round-bottom flask equipped with a magnetic stirring bar
and a rubber septum was charged with indole 1n (1.55 g, 5.63
mmol), norbornene (1.06 g, 11.3 mmol), K2CO3 (3.12 g, 22.6
mmol), alkyl iodide 2m (6.11 g, 22.6 mmol), and PdCl2 (100 mg,
0.564 mmol). Anhydrous DMF (25.3 mL), anhydrous DMSO (2.8
mL), and H2O (269 mg, 14.9 mmol) were then added sequentially.
The flask was placed in a preheated oil bath at 60 °C and the mixture
was stirred under a balloon pressure of air for 26 h. The mixture was
then cooled to r.t. and diluted with Et2O (50 mL). H2O was added to
dissolve inorganic salts, and the resulting mixture was extracted
with Et2O (3 × 50 mL). The extracts were combined, washed with
brine, dried (Na2SO4), filtered, and concentrated. The residue was
purified by flash column chromatography [silica gel, pentane–Et2O
(15:1 to 5:1)] to give a pale-brown oil [yield: 1.71 g (73%);
Rf = 0.49 (pentane–Et2O, 2:1, UV)], together with recovered start-
ing material 1n (243 mg, 16% recovery).
Ethyl 5-[2-(1,3-Dioxan-2-yl)ethyl]-2-methyl-1H-pyrrole-3-car-
boxylate (5fq)
Pale-purple oil; yield: 165 mg (0.617 mmol, 61%; 71% based on re-
covered pyrrole substrate 4f); Rf = 0.20 (pentane–Et2O, 1:2, UV).
IR (ATR): 3278, 2926, 1655, 1458, 1232 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H), 1.34–
1.38 (m, 1 H), 1.88 (dt, J = 5.0, 7.4 Hz, 2 H), 2.09 (app tq, J = 5.0
Hz, J ≈ 12.8 Hz, 1 H), 2.47 (s, 3 H), 2.64 (J = 7.4 Hz, 2 H), 3.74–
3.80 (m, 2 H), 4.12 (dd, J = 11.7, 5.0 Hz, 2 H), 4.24 (q, J = 7.1 Hz,
2 H), 4.57 (t, J = 5.0 Hz, 1 H), 6.21 (d, J = 2.9 Hz, 1 H), 8.69 (br s,
1 H).
IR (ATR): 3391, 2930, 2856, 1732, 1715, 1462, 1385, 1254, 1192
cm–1.
13C NMR (90.6 MHz, CDCl3): δ = 13.3, 14.6, 21.5, 25.8, 34.5, 59.3,
1H NMR (500 MHz, CDCl3): δ = 0.02 (s, 6 H), 0.89 (t, J = 7.4 Hz,
3 H), 0.892 (s, 9 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.46–1.54 (m, 1 H),
1.63–1.70 (m, 1 H), 1.75 (app ddt, J = 12.9, 4.6 Hz, J ≈ 8.2 Hz, 1
H), 1.94–2.01 (m, 1 H), 2.33–2.38 (m, 1 H), 2.66 (app dt, J = 14.9
Hz, J ≈ 8.1 Hz, 1 H), 2.79 (ddd, J = 14.9, 8.6, 5.4 Hz, 1 H), 2.88–
2.97 (m, 2 H), 3.77 (t, J = 7.8 Hz, 2 H), 4.19 (q, J = 7.1 Hz, 2 H),
7.06 (app dt, J = 1.1 Hz, J ≈ 7.4 Hz, 1 H), 7.11 (app dt, J = 1.1 Hz,
66.9, 101.5, 106.8, 111.4, 130.0, 134.4, 166.0.
MS (EI, 70 eV): m/z (%) = 267 (60) [M+], 222 (33), 205 (100), 166
(49), 131 (76).
HRMS (EI, 70 eV): m/z [M+] calcd for C14H21NO4: 267.1465;
found: 267.1463.
Synthesis 2014, 46, 35–41
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
N-Heterocycle Alkylation
41
Ethyl 3-Chloro-5-[2-(1,3-dioxan-2-yl)ethyl]-1H-pyrrole-2-car-
boxylate (5iq)
White solid; yield: 257 mg (0.893 mmol, 91%); Rf = 0.13 (pentane–
EtOAc 4:1, UV); mp 93–94 °C.
see: (a) Shirley, D. A.; Roussel, P. A. J. Am. Chem. Soc.
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(c) Lee, D.-H.; Kwon, K.-H.; Yi, C. S. Science (Washington
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T. J. Am. Chem. Soc. 2012, 134, 17474.
IR (ATR): 3276, 2969, 1673, 1491 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.37 (t, J = 7.2 Hz, 3 H), 1.37–
1.40 (m, 1 H), 1.92 (app q, J ≈ 6.3 Hz, 2 H), 2.06–2.16 (m, 1 H),
2.72 (t, J = 7.0 Hz, 2 H), 3.79 (app t, J ≈ 11.8 Hz, 2 H), 4.16 (dd,
J = 11.6, 4.9 Hz, 2 H), 4.34 (q, J = 7.2 Hz, 2 H), 4.59 (t, J = 4.7 Hz,
1 H), 5.96 (d, J = 2.9 Hz, 1 H), 9.62 (br s, 1 H).
13C NMR (126 MHz, CDCl3): δ = 14.6, 21.9, 25.8, 33.8, 60.5, 67.1,
101.0, 109.8, 117.0, 119.2, 136.6, 160.4.
MS (EI, 70 eV): m/z (%) = 289 (30) [M+, 37Cl], 287 (90) [M+, 35Cl],
212 (85), 140 (100), 114 (70), 101 (89).
HRMS (EI, 70 eV): m/z [M+] calcd for C13H1835ClNO4: 287.0919;
(7) (a) Skell, P. S.; Bean, G. P. J. Am. Chem. Soc. 1962, 84,
4655. (b) Griffin, C. E.; Obrycki, R. J. Org. Chem. 1964, 29,
3090. (c) Castro, A. J.; Deck, J. F.; Ling, N. C.; Marsh, J. P.
Jr.; Means, G. E. J. Org. Chem. 1965, 30, 344. (d) Bean, G.
P. J. Org. Chem. 1967, 32, 228. (e) Papadopoulos, E. P.;
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M. G.; Sebastian, J. F.; Johnson, H. W. Jr.; Pyun, C. J. Org.
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found: 287.0918.
Acknowledgement
This project was supported by the Deutsche Forschungsgemein-
schaft (Ba 1372/19-1). L.J. acknowledges the Alexander von Hum-
boldt Foundation for a postdoctoral fellowship.
(8) For selected recent examples of direct alkylation of pyrroles,
see: (a) Guerrero, M. A.; Miranda, L. D. Tetrahedron Lett.
2006, 47, 2517. (b) Guadarrama-Morales, O.; Méndez, F.;
Miranda, L. D. Tetrahedron Lett. 2007, 48, 4515. (c) Trost,
B. M.; Müller, C. J. Am. Chem. Soc. 2008, 130, 2438.
(d) Sheng, Y.-F.; Gu, Q.; Zhang, A.-J.; You, S.-L. J. Org.
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Bull. Korean Chem. Soc. 2011, 32, 3130.
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(c) Catellani, M.; Motti, E.; Della Ca’, N. Acc. Chem. Res.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 35–41