Automated generation and reactions of 3-hydroxymethylindoles in continuous-flow microreactors

Article abstract of DOI:10.1002/chem.200903284

An automated sequential approach for the generation and reactions of 3-hydroxymethylindoles in continuous-flow microreactors is described. Consecutive halogen-magnesium exchanges of four 3-iodoindoles followed by addition to three aldehydes provided twelv

Full text of DOI:10.1002/chem.200903284

DOI: 10.1002/chem.200903284
Automated Generation and Reactions of 3-Hydroxymethylindoles in
Continuous-Flow Microreactors
Thomas Tricotet and Donal F. OꢀShea*[a]
Dedicated to Professor R. N. Butler on the occasion of his retirement
Abstract: An automated sequential ap-
proach for the generation and reactions
of 3-hydroxymethylindoles in continu-
ous-flow microreactors is described.
Consecutive halogen–magnesium ex-
changes of four 3-iodoindoles followed
by addition to three aldehydes provid-
ed twelve 3-hydroxymethylindoles in a
multi-microreactor setup. The synthetic
flow strategy could be coupled with an
in line continuous liquid–liquid extrac-
tion workup protocol for each reaction.
Further elaboration of each of these in-
doles within the fluidic setup was
ACHTUNGTRENUNaNG chieved by acid-catalysed nucleophilic
substitutions with allyltrimethylsilane
and methanol used as nucleophiles.
Overall, a set of four 3-iodoindoles was
converted into thirty-six indole deriva-
tives by a range of transformations in-
cluding iodo–magnesium exchange/
electrophile trapping and acid-cata-
Keywords: automated synthesis
·
continuous flow continuous
·
liquid–liquid extraction · indoles ·
microreactors
lysed nucleophilic substitution in
fully automated sequential fashion.
a
Introduction
ous flow in channels that are 50–500 mm in diameter, rather
than in mixing vessels of conventional process technology.
As a result of the channels size, heat transfer is highly effi-
cient, which results in more precise temperature control.[3]
Side reactions can be minimised and hazardous reactions
can be handled more safely than with traditional batch pro-
cedures, as large quantities of reagents are not mixed. Short-
lived reaction intermediates can be generated for new syn-
thetically useful transformations or mechanism investiga-
tions.[4] Reactions carried out in flow rather than batch pro-
cesses are readily optimised with low consumption of mate-
rials and give rise to a paradigm shift from current need to
“scale up” a chemical reaction to a time “scale out” of a
continuous flow synthesis for process development. This can
be achieved without any further modifications of the reac-
tion conditions being required, thus, offering scalable condi-
tions by design and, therefore, providing a formidable
bridge between fundamental research and the first stages of
process development.[5] Several recent reports have com-
bined flow reactions with heterogeneous supported catalysts
utilising coated microchannels, packed-bed columns and
monolithic reactors.[6] Our current goal is to develop auto-
mated, sequentially performed homogeneous reactions with
in-line continuous liquid–liquid extraction of the products,
thereby providing an operational link between the reaction
and workup apparatus, conceptually comparable to physical-
ly linking the round-bottomed flask and separating funnel.
The tools of the trade for synthetic chemistry have signifi-
cantly diversified from the era of round-bottomed flask and
separating funnel. Nowadays a synthetic chemist can select
from a wide range of reaction conditions and parameters ac-
cessible through the combination of batch/flow, sequential/
parallel, homogenous/solid-supported and external/micro-
wave heating. For example, among the major technology
changes in the past decade, microwave irradiation is now a
routinely used tool in synthetic laboratories.[1] However, the
need for innovative approaches still encourages studies to-
wards refined control and integrated systems for the synthe-
sis–purification–analysis triad. Automated flow synthesis in
microreactors has recently become more accessible and is
now attracting great interest both from academia and indus-
try.[2] In a microreactor, chemical reaction occurs in continu-
[a] Dr. T. Tricotet, Prof. D. F. OꢀShea
Centre for Synthesis and Chemical Biology
School of Chemistry and Chemical Biology
University College Dublin, Dublin 4 (Ireland)
E-mail: donal.f.oshea@ucd.ie
Supporting information for this article (1H and 13C NMR spectra of
all compounds (5a–l, 7a–l and 8a–l, 9a and [D]9a). HPLC analysis
of extractions) is available on the WWW under http://dx.doi.org/
10.1002/chem.200903284.
6678
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6678 – 6686

FULL PAPER
The importance of the indole scaffold in natural products
and active pharmaceutical ingredients maintains a high level
of research interest towards its synthesis and chemical modi-
fication—often with an emphasis on combinatorial strat-
egies.[7] As part of an ongoing medicinal chemistry project
for the biological evaluation of 3-substituted indole deriva-
tives, we raised the challenging task of synthesising a collec-
tion of these compounds through a sequential approach by
using an automated reagent store and a modular combina-
tion of micro-fluidic devices. Herein, we disclose our strat-
egy to achieve the homogeneous and continuous multi-step
generation of compounds that contain the 3-indolylmethyl
motif by using automated micro-fluidic reactors and liquid–
liquid extraction devices as depicted in Scheme 1.[8] It was
envisaged that conversion of the starting 3-iodoindoles 1 to
their corresponding Grignard compounds 2 and subsequent
reaction of these 3-metallated indoles with aldehydes would
provide the 3-hydroxymethylindoles 5. The organometallic
formation, electrophile reaction and aqueous product
workup would be accessible in a three-step continuous-flow
sequence. The versatility of these indoles 5 for further elab-
oration could be exploited by generating indoles 7 and 8
through acid-catalysed elimination–addition sequences via
the intermediate electrophilic indolium cations 6.
Scheme 2. Icons used for the description of the micro-fluidic experi-
ments: A) pump, B) automated injection loops, C) reactor chip (RC)
with residence time (res. time) and temperature and D) liquid–liquid ex-
traction chip (EC).
the cross-membrane pressure (Scheme 2D). The RC tem-
perature is controlled by a heating/cooling plate. The tim-
ings for the sequential injection of the reagents, extraction
and collection of the products and all other reaction param-
eters were controlled by the system Reaction Manager v3.0
software[8] run from a dedicated computer. This software
allows all reaction and workup parameters to be set prior to
initiating a sequence of reactions.
Our first objective was to define optimal metallation con-
ditions for the starting 3-iodoindoles 1 within our continuous
flow micro-fluidic setup. The utility of bromine–lithium ex-
change reactions in conjunction with microreactor technolo-
gy was recently elegantly demonstrated.[10] However, report-
ed examples of synthetic applications that use 3-lithiated in-
doles have shown that isomerisation to the thermodynami-
cally favoured 2-metallated species readily occurs.[11] To
avoid this potential complication, we chose to investigate
magnesiated indole intermediates, which would offer higher
thermal stability and could be generated by an iodine–mag-
nesium exchange procedure from indoles 1a–d. We envis-
aged that the utilisation of iPrMgCl·LiCl, developed by
Knochel and co-workers,[12] would be a flow-compatible re-
agent for the generation of our indole Grignard reagents
that could be subsequently converted in situ. Whereas the
use of preformed Grignard reagents in flow reactions has
been previously described, to the best of our knowledge,
their generation by using iPrMgCl·LiCl and subsequent re-
action has not been reported in the context of continuous
microreactor technology.[13]
Results and Discussion
The microreactor system used for this study has four pumps
that deliver flow rate ranges of 4 to 2500 mLminÀ1 (Sche-
me 2A). The flow streams are connected through poly(tetra-
fluoroethylene) (PTFE) tubing to: 1) an automated injection
system with a liquid handler unit connected by a manifold
to four individual automated injection loops with a pressur-
ising pump to ensure no disruption of the system pressure
during sample insertion (Scheme 2B), 2) a glass reactor chip
(RC), with 0.2 mm inner diameter (ID), with a chip header
that allows the connection of up to three inputs and one
output tubings (Scheme 2C), 3) a continuous micro-fluidic
liquid–liquid extraction chip (EC) module with a PTFE par-
titioning membrane[9] that is software-controlled to maintain
The iodine–magnesium exchange was investigated in our
micro-fluidic setup by using three pumps combined with two
reaction chips (Scheme 3).[14] The indole 1a was chosen to
Scheme 1. Multi-step strategy for the continuous-flow synthesis of 3-hydroxymethylindoles 5 and their conversion to 7 and 8 by acid-catalysed nucleophil-
ic substitution.
Chem. Eur. J. 2010, 16, 6678 – 6686
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6679

D. F. OꢀShea and T. Tricotet
determine the reaction conditions and the chip residence
time to achieve effective halogen–metal exchange. A solu-
tion of 1a in THF was treated with iPrMgCl·LiCl at 08C for
a variable time in microreactor RC1.[15] The output flow was
mixed with a solution of deuterated methanol in a second
reactor RC2.
The optimised magnesiation and subsequent aldehyde
electrophilic quench were then applied to the automated se-
quential generation of library 5 (Table 2). The indoles 1a–d
Table 2. Micro-fluidic setup and results for the generation of 3-hydroxy-
methylindoles 5a–l.
Scheme 3. Micro-fluidic setup for the investigation of halogen–magnesi-
um exchange with 3-iodoindole 1a.
Product
R1
R2
R3
Yield [%]
5a
5b
5c
5d
5e
5 f
5g
5h
5i
MeO
MeO
MeO
H
H
H
MeO
MeO
MeO
H
H
H
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
Ph
48
52
59
53
59
66
46
59
40
58
50
63
nBu
Me
Ph
nBu
Me
Ph
nBu
Me
Ph
nBu
Me
Pleasingly, a satisfying conversion of 72% to deuterated
[D]9a was obtained after 1 min residence time (Table 1,
entry 1) and this could be improved to 85 and >95% by ex-
tending the time to 5 and 10 min, respectively (Table 1, en-
Table 1. Optimisation of the halogen–magnesium exchange conditions
with 3-iodoindole 1a.
5j
5k
5l
Entry
iPrMgCl·LiCl [equiv]
Time [min]
1a/[D]9a[a]
1
2
3
4
5
1.2
1.2
1.2
1.2
1.1
1
5
10
20
10
28:72
15:85
5:95
5:95
12:88
were sequentially treated with a solution of iPrMgCl·LiCl in
THF at 08C for 12 min in microreactor RC1.[16] The output
flow from RC1 was connected to an input port of RC2 to
which a solution of aldehydes 3a–c was also added with a
residence time of 7 min at 08C. The output flow of organic
mixtures from RC2 continued directly into the continuous
extraction module into which an aqueous solution of NH4Cl
was also introduced. The acidic wash and separation of
aqueous and organic phases gave an organic and an aqueous
output flow, whereas collection of the organic output was
achieved by using an automated Gilson liquid handling
system. This could be achieved by using the continuous flow
EC module, in spite of the cross-solubility of THF and
water. Once set up, the twelve sequential magnesiations,
electrophile reactions and aqueous workups and product
collections proceeded without intervention. All reaction
combinations of four iodoindoles and three aldehydes were
successfully achieved to give the products 5a–l with isolated
yields of 40 to 66%. The formation of indoles 9a–d (ca.
5%) was observed in all cases but it could be easily re-
moved by purification through short plugs of silica to afford
the products with >95% purity.
[a] As determined by integration of the H-2 peaks at d=7.69 and
7.56 ppm, respectively, for compounds 1a and 9a. Deuterium incorpora-
tion was >95% as determined by integration of the H-3 NMR signal of
9a at d=6.49 ppm.
tries 2 and 3). Prolonging the reaction time to 20 min gave
an identical result as that found after a reaction time of
10 min, which shows good stability within the reaction time-
scale of the magnesiated indole 2a at this temperature
(Table 1, entry 4). In addition, no incorporation of deuteri-
um at C-2 was observed, confirming that the migration pro-
cess to the 2-metalated indole observed for halogen–lithium
exchange was suppressed. A lowering of the stoichiometry
of the reagent to 1.1 equiv resulted in a lowering of conver-
sion (Table 1, entry 5). In all cases the deuterium incorpora-
1
tion into 9a was greater than 95% as judged by H NMR
spectroscopy.
A similar optimisation by using benzaldehyde as the elec-
trophile in reactions with magnesiated indole 2a showed
that effective electrophilic quench was achieved when
1.1 equiv of aldehyde was treated for 7 min.
Next, we turned our attention to the further structural
elaboration of 5a–l by using modular micro-fluidic technolo-
6680
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6678 – 6686

3-Hydroxymethylindoles in Continuous Flow Microreactors
FULL PAPER
gy. It was anticipated that diversification of the 3-indolyl-
methyl position could be achieved by extension of our previ-
ously reported acid-catalysed formation and in situ trapping
of the indolium cations of type 6.[17,18] Our first approach
was to introduce an allyl substituent by using allyltrimethyl-
silane as the nucleophile and p-toluene sulfonic acid (p-
TSA) as the catalyst (Table 3).
give compounds 7a–l. In each case the desired product was
isolated; this illustrates the generality of the automated flu-
idic setup to control an acid-catalysed dehydration, in situ
allylation, aqueous basic workup, phase separation and
product isolation for twelve sequential reactions.
As a further illustration of the reactivity of indoles 5a–l in
the context of micro-fluidic devices, we applied the p-TSA-
catalysed nucleophilic displacement to the sequential gener-
ation of methoxy ether derivatives 8a–l by using methanol
as representative nucleophile (Table 4).
Table 3. Results for the generation of indoles 7a–l by using two micro-
reactors and a continuous extraction of the products.
Table 4. Results for the generation of indoles 8a–l.
Product
R1
R2
R3
Yield [%]
8a
8b
8c
8d
8e
8 f
8g
8h
8i
MeO
MeO
MeO
H
H
H
MeO
MeO
MeO
H
H
H
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
Ph
97
98
97
97
90
92
94
93
96
90
98
97
Product
R1
R2
R3
Yield [%]
nBu
Me
Ph
nBu
Me
Ph
nBu
Me
Ph
nBu
Me
7a
7b
7c
7d
7e
7 f
7g
7h
7i
MeO
MeO
MeO
H
H
H
MeO
MeO
MeO
H
H
H
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
Ph
50
45
43
62
49
59
65
46
65
71
54
58
nBu
Me
Ph
nBu
Me
Ph
nBu
Me
Ph
nBu
Me
8j
8k
8l
7j
7k
7l
In spite of the fact that ether-substituted indoles of this
type are known to be relatively unstable and prone to re-
elimination, this reaction was compatible with the micro-flu-
idic approach.[19] Solutions of indoles 5a–l in acetonitrile
were injected sequentially and treated for 20 min at 308C
with methanol in the presence of a catalytic amount of p-
TSA. In this case removal of the acidic catalyst was readily
achieved by using a post-chip Dowex resin extraction with
compounds 8a–l obtained in almost quantitative yields.
Optimisation of the nucleophilic displacement for sub-
strate 5a showed that complete allylation was achieved with
a residence time (RC1) of 8 min when a solution of 5a was
treated in a microreactor with allyltrimethylsilane in the
presence of 20 mol% of p-TSA in acetonitrile at 308C
(Table 3). To achieve an aqueous basic workup of product
7a, the reaction output flow from RC1 was mixed with
aqueous sodium carbonate solution in a second microreactor
(RC2). The product was then continuously extracted with
1,2-dichloroethane (DCE) from the acetonitrile/water mix-
ture by using the EC module. The allylated product 7a was
extracted (>98%) into in the organic output with complete
separation of the acidic catalyst into the aqueous output.
HPLC analysis of the aqueous output showed only the
acidic catalyst together with traces of the starting hydroxyin-
dole 5 (see the Supporting Information). With our reaction
and extraction fluidic setup, the sequential continuous reac-
tion of hydroxyindoles 5a–l and product extractions were at-
tempted (Table 3). After automated collection of the indi-
vidual organic phases, the solutions in DCE were dried,
evaporated and purified by silica gel chromatography to
Conclusion
We have described an efficient automated access to 3-indo-
lylmethyl derivatives by using homogenous continuous-flow
microreactor technology. A primary set of four 3-iodoin-
doles was converted into thirty-six indole derivatives by a
range of transformations, including iodo–magnesium ex-
change/electrophile trapping and acid-catalysed nucleophilic
substitution in an automated sequential fashion. This investi-
gation illustrates the broad future potential for multi-step,
multi-chip reaction sequences in association with continu-
Chem. Eur. J. 2010, 16, 6678 – 6686
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6681

D. F. OꢀShea and T. Tricotet
OCH3), 2.62 (brs, 1H; OH), 1.62 ppm (s, 9H; CACTHNUTRGNEUNG
(CH3)3); 13C NMR
ous-flow extraction technology. Further applications of these
micro-fluidic systems are ongoing and will be reported in
due course.
(125 MHz, CDCl3, 258C): d=155.5 (C), 149.6 (C), 142.3 (C), 129.4 (C),
128.4 (2ꢂCH), 127.7 (CH), 126.8 (C), 126.6 (2ꢂCH), 124.1 (CH), 123.4
(C), 115.8 (CH), 113.0 (CH), 102.8 (CH), 83.5 (C), 70.1 (CH), 55.5
(CH3), 28.1 ppm (3ꢂCH3); IR (KBr disc): n˜ =2984, 1730, 1614, 1597,
1478, 1449 cmÀ1; LRMS (ES): m/z: calcd for C21H23NO4: 353.2; found:
336.1 [MÀOH]+; anal. calcd (%) for C21H23NO4: C 71.37, H 6.56, N 3.96;
found: C 71.53, H 6.76, N 3.82.
Experimental Section
3-(1-Hydroxypentyl)-5-methoxyindole-1-carboxylic acid tert-butyl ester
(5b): The product (74 mg, 52%) was obtained as a light yellow oil.
General methods: All commercially available reagents were used as sup-
plied unless otherwise stated. Dry THF was obtained from a solvent pu-
rification system. The solution of iPrMgCl·LiCl (Acros, 1.10m) was fil-
tered through 0.2 mm pore size Acrodisc PTFE membrane and the con-
centration was determined by titration with menthol in THF by using
1,10-phenanthroline as indicator. Chromatography was performed on
1H NMR (400 MHz, CDCl3, 258C): d=8.10–7.90 (m, 1H; 7-H), 7.49 (s,
4
1H; 2-H), 7.14 (d, 4J4,6 =2.3 Hz, 1H; 4-H), 6.91 (dd, 3J6,7 =9.0, J6,4
=
2.3 Hz, 1H; 6-H), 4.90 (m, 1H; 1’-H), 3.86 (s, 3H; OCH3), 1.98–1.88 (m,
2H; 2’-CH2), 1.81 (brd, 3JOH,1’ =3.5 Hz, 1H; 1’-OH), 1.66 (s, 9H; C-
AHCTUNGTRENNUNG
(CH3)3), 1.64–1.30 (m, 4H; 2ꢂCH2), 0.91 ppm (t, 3J5’,4’ =6.6 Hz, 3H; 5’-
silica gel 60 PF254.
1H and 13C NMR spectra were recorded on a 400 or
H3); 13C NMR (100 MHz, CDCl3, 258C): d=155.6 (C), 149.6 (C), 130.5
(C), 129.4 (C), 123.8 (C), 122.9 (CH), 116.0 (CH), 113.0 (CH), 102.6
(CH), 83.5 (C), 68.1 (CH), 55.7 (CH3), 36.7 (CH2), 28.1 (3ꢂCH3), 28.0
(CH2), 22.5 (CH2), 14.0 ppm (CH3); IR (KBr disc): n˜ =3054, 2983, 2959,
2935, 1728, 1614, 1597, 1478, 1450 cmÀ1; LRMS (ES): m/z: calcd for
C19H27NO4: 333.2; found: 356.4.5 [M+Na]+, 316.4 [MÀOH]+; anal. calcd
(%) for C19H27NO4: C 68.44, H 8.16; N 4.20; found: C 68.58, H 8.23, N
4.02.
500 MHz instrument. The microreactor used in this study was purchased
from Syrris Ltd and was used without modification. The flow reactor con-
sists of four Cavro-type syringe pumps with flow rates ranging from 4 to
2500 mLminÀ1. Reagents were injected by using a Gilson injection robot
connected to an automated injection module with four pressurised
1.0 mL PTFE sample loops. Glass chip reactors of 62.5, 250 or 1000 mL
with inner diameters of 0.2 mm were used and the temperature was con-
trolled by a cooling/heating plate with a working temperature of 0–
1508C. A flow liquid–liquid extraction module with a PTFE membrane
was used and reaction mixtures were collected by using a modified
Gilson FC204 collection robot fitted with a back-pressure regulator.
Modules of the system were connected with 0.5 mm ID/1.6 OD PTFE
tubing. The whole system was pressurised with dry nitrogen and comput-
er controlled by using Reaction Manager v3.0.[8] Starting 3-iodoindoles
1a and 1b were synthesised by using established procedures.[20]
3-(1-Hydroxyethyl)-5-methoxyindole-1-carboxylic acid tert-butyl ester
(5c): The product (73 mg, 59%) was obtained as a light yellow oil.
1H NMR (500 MHz, CDCl3, 258C): d=8.10–7.90 (m, 1H; 7-H), 7.50 (s,
4
1H; 2-H), 7.15 (d, 4J4,6 =2.4 Hz, 1H; 4-H), 6.93 (dd, 3J6,7 =9.3, J6,4
=
2.4 Hz, 1H; 6-H), 5.12 (m, 1H; 1’-H), 3.86 (s, 3H; OCH3), 1.84 (brs, 1H;
OH), 1.65 (s, 9H; C
(CH3)3), 1.64 ppm (d, 3J2’,1’ =6.3 Hz, 3H; 2’-H3);
AHCTUNGTRENNUNG
13C NMR (125 MHz, CDCl3, 258C): d=155.7 (C), 149.7 (C), 130.4 (C),
129.4 (C), 124.9 (C), 122.4 (CH), 116.0 (CH), 113.1 (CH), 102.6 (CH),
83.5 (C), 63.8 (CH), 55.7 (CH3), 28.1 (3ꢂCH3), 23.2 ppm (CH3); IR (KBr
disc): n˜ =3055, 2982, 2933, 2836, 1728, 1614, 1597, 1478 cmÀ1; LRMS
(ES): m/z: calcd for C16H21NO4: 291.1; found: m/z 314.4 [M+Na]+, 274.4
[MÀOH]+; anal. calcd (%) for C16H21NO4 : C 65.96, H 7.27, N 4.81;
found: C 65.77, H 7.40, N 4.54.
Procedure for investigation of the iodine–magnesium exchange: A repre-
sentative procedure for entry 3, Table 1 is as follows: the solution of
indole 1a (0.50m in THF, 394 mL, 65.0 mLminÀ1
) was treated with
iPrMgCl·LiCl (1.10m in THF, 212 mL, 35.0 mLminÀ1) on microreactor
RC1 (1000 mL, 10.0 min residence time) at 08C. A microreactor RC1
with an internal volume of 250 mL was used for experiments with shorter
residence time (Table 1, entries 1 and 2) and flow rates were adjusted ac-
cordingly. The output flow was treated with a solution of deuterated
methanol (3.0m in THF, 394 mL, 65.0 mLminÀ1) on microreactor RC2
(1000 mL, 6.0 min residence time) at 08C. The resulting solutions
(1000 mL) were filtered through a plug of silica by using ether as eluent
and dried over sodium sulfate. After filtration and evaporation of the sol-
3-(Hydroxyphenylmethyl)indole-1-carboxylic acid tert-butyl ester (5d):
The product (73 mg, 53%) was obtained as a colourless solid. M.p. 74–
758C; 1H NMR (400 MHz, CDCl3, 258C): d=8.15–8.05 (m, 1H; 7-H),
7.51–7.38 (m, 4H; 2-H, 2ꢂHortho, 4-H), 7.36–7.30 (m, 2H; 2ꢂHmeta), 7.30–
7.22 (m, 2H; 5-H, 6-H), 7.15–7.13 (m, 1H; Hpara), 6.07 (m, 1H; 1’-H),
2.24 (brs, 1H; OH), 1.65 ppm (s, 9H; CACTHNUTRGNEUNG
(CH3)3); 13C NMR (100 MHz,
1
vent, samples were analysed by using H NMR spectroscopy.
CDCl3, 258C): d=149.9 (C), 142.4 (C), 135.9 (C), 128.5 (C), 128.4 (2ꢂ
CH), 127.9 (CH), 126.6 (2ꢂCH), 124.5 (CH), 123.6 (C), 123.5 (CH),
122.6 (CH), 120.0 (CH), 115.3 (CH), 83.8 (C), 70.4 (CH), 28.1 ppm (3ꢂ
CH3); IR (KBr disc): n˜ =1730, 1452, 1373, 1254, 1158 cmÀ1; LRMS (ES):
m/z: calcd for C20H21NO3: 323.1; found: 306 [MÀOH]+; anal. calcd (%)
for C20H21NO3: C 74.28, H 6.55, N 4.33; found: C 74.20, H 6.53, N 4.18.
3-Deuterio-5-methoxyindole-1-carboxylic acid tert-butyl ester ([D]9):
3
1H NMR (300 MHz, CDCl3, 258C): d=8.02 (brd, J7,6 =9.0 Hz, 1H; 7-H),
7.57 (s, 1H; 2-H), 7.03 (d, 4J4,6 =2.4 Hz, 1H; 4-H), 6.93 (dd, 3J6,7 =9.0,
4J6,4 =2.4 Hz, 1H; 6-H), 3.85 (s, 3H; OCH3), 1.67 ppm (s, 9H; C
ACTHNUGTRNEUGN(CH3)3).
Procedure for the continuous-flow synthesis of compounds 5a–l: The sol-
utions of indoles 1a–d (0.55m in THF, 776 mL, 52.0 mLminÀ1), iPrMgCl·
LiCl (1.10m in THF, 470 mL, 31.5 mLminÀ1) were injected on microreac-
tor RC1 (1000 mL, 12 min residence time) at 08C by using an automated
liquid handler. The output flow was treated with solutions of aldehyde 2
(0.5m in THF, 932 mL, 62.5 mLminÀ1) on microreactor RC2 (1000 mL,
7 min residence time) at 08C. The resulting flow was connected to the
liquid–liquid extraction module and combined with an aqueous solution
of NH4Cl (50%, 300 mLminÀ1). The back pressure was adjusted to 2.0 bar
and the cross-membrane pressure set at 50 mbar. The minimum volume
of solvent pumped through the system between injections was 450 mL. A
total volume of 2200 mL was collected for each experiment. The solutions
obtained were dried over sodium sulfate. Filtration and parallel evapora-
tion of the solvent by using ActeVap Rack followed by purification on
silica, with cyclohexane/diethyl ether as eluent (9:1 to 7:1 for 5a–f or 9:1
to 1:1 for 5g–l) gave analytically pure products (see Table 2).
3-(1-Hydroxypentyl)indole-1-carboxylic acid tert-butyl ester (5e): The
product (75 mg, 59%) was obtained as a light yellow oil. 1H NMR
(400 MHz, CDCl3, 258C): d=8.13 (brd, 3J7,6 =8.2 Hz, 1H; 7-H), 7.67 (d,
3J4,5 =7.8 Hz, 1H; 4-H), 7.53 (s, 1H; 2-H), 7.32 (m, 1H; 6-H), 7.23 (m,
1H; 5-H), 4.94 (m, 1H; 1’-H), 2.02–1.80 (m, 3H; 2’-H2, OH), 1.67 (s, 9H;
CACTHNUTRGNEUG(N CH3)3), 1.50–1.25 (m, 4H; 3’-H2, 4’-H2), 0.91 ppm (m, 3H; 5’-H3);
13C NMR (100 MHz, CDCl3, 258C): d=149.7 (C), 135.8 (C), 128.6 (C),
124.4 (CH), 124.2 (C), 122.4 (CH), 122.3 (CH), 119.8 (CH), 115.3 (CH),
83.6 (C), 68.1 (CH), 36.9 (CH2), 28.1 (3ꢂCH3), 28.0 (CH2), 22.5 (CH2),
14.0 ppm (CH3); IR (KBr disc): n˜ =3410, 2957, 2932, 2861, 1734, 1453,
1371, 1255, 1159 cmÀ1; LRMS (ES): m/z: calcd for C18H25NO3: 303.2;
found: 326.4 [M+Na]+, 286 [MÀOH]+; anal. calcd (%) for C18H25NO3: C
71.26, H 8.31, N 4.62; found: C 70.98, H 8.35, N 4.58.
3-(1-Hydroxyethyl)indole-1-carboxylic acid tert-butyl ester (5 f): The
product (73 mg, 66%) was obtained as a yellow oil. 1H NMR (500 MHz,
3
CDCl3, 258C): d=8.13 (brd, 3J7,6 =7.8 Hz, 1H; 7-H), 7.67 (d, J4,5
=
3-(Hydroxyphenylmethyl)-5-methoxyindole-1-carboxylic acid tert-butyl
ester (5a): The product (72 mg, 48%) was obtained as a light yellow oil.
1H NMR (500 MHz, CDCl3, 258C): d=7.97 (m, 1H; 7-H), 7.51–7.47 (m,
3H; 2-H, 2ꢂHortho), 7.46–7.40 (m, 2H; 2ꢂHmeta), 7.35–7.29 (m, 1H;
Hpara), 6.89–6.84 (m, 2H; 6-H, 4-H), 5.95 (brs, 1H; CHOH), 3.71 (s, 3H;
7.8 Hz, 1H; 4-H), 7.52 (s, 1H; 2-H), 7.31 (m, 1H; 6-H), 7.23 (m, 1H; 5-
H), 5.14 (dt, 3J1’,OH =6.8, 3J1’,2’ =6.3 Hz, 1H; 1’-H), 1.99 (brs, 1H; OH),
1.66 (s, 9H; C
(125 MHz, CDCl3, 258C): d=149.7 (C), 135.8 (C), 128.5 (C), 125.2 (C),
(CH3)3), 1.63 ppm (d, 3J2’,1’ =6.3 Hz, 3H; 2’-H3); 13C NMR
ACHTUNGTRENNUNG
6682
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6678 – 6686

3-Hydroxymethylindoles in Continuous Flow Microreactors
FULL PAPER
124.4 (CH), 122.5 (CH), 121.7 (CH), 119.7 (CH), 115.3 (CH), 83.6 (C),
63.8 (CH), 28.1 (3ꢂCH3), 23.4 ppm (CH3); IR (KBr disc): n˜ =3390, 2977,
1723, 1372, 1256 cmÀ1; LRMS (ES): m/z: calcd for C15H19NO3: 261.1;
found: 244.2 [MÀOH]+; anal. calcd (%) for C15H19NO3: C 68.94, H 7.33,
N 5.36; found: C 68.64, H 7.22, N 5.13.
2-H), 7.19 (t, 3J6,5 =3J6,7 =7.7 Hz, 1H; 6-H), 4.97 (m, 1H; 1’-H), 3.47 (q,
J=7.3 Hz, 4H; 2ꢂCH2), 1.95 (m, 2H; 2’-H2), 1.86 (d, JOH,1’ =3.4 Hz, 1H;
OH), 1.52–1.30 (m, 4H; 3’-H2, 4’-H2), 1.24 (t, J=7.3 Hz, 6H; 2ꢂCH3),
0.90 ppm (t, 3J5’,4’ =7.3 Hz, 3H; 5’-H3); 13C NMR (125 MHz, CDCl3,
258C): d=154.3 (C), 136.2 (C), 127.3 (C), 123.7 (CH), 122.7 (CH), 122.6
(C), 121.4 (CH), 119.9 (CH), 113.2 (CH), 68.2 (CH), 42.4 (2ꢂCH2), 37.0
(CH2), 28.1 (CH2), 22.5 (CH2), 14.0 (CH3), 13.4 ppm (2ꢂCH3); IR (KBr
3-(Hydroxyphenylmethyl)-5-methoxyindole-1-carboxylic acid diethyl-
ACHTUNGTRENNUNGamide (5g): The product (69 mg, 46%) was obtained as a light yellow oil.
disc): n˜ =3052, 2959, 1657, 1418 cmÀ1
; LRMS (ES): m/z: calcd for
1H NMR (500 MHz, CDCl3, 258C): d=7.51 (d, 3J7,6 =8.8 Hz, 1H; 7-H),
7.46 (brd, J=7.3 Hz, 2H; 2ꢂHortho), 7.37–7.31 (m, 2H; 2ꢂHmeta), 7.31–
7.26 (m, 1H; Hpara), 6.97 (d, 4J4,6 =2.4 Hz, 1H; 4-H), 6.96 (s, 1H; 2-H),
6.88 (dd, 3J6,7 =8.8, 4J6,4 =2.4 Hz, 1H; 6-H), 6.01 (s, 1H; 1’-H), 3.75 (s,
3H; OCH3), 3.39 (q, J=7.4 Hz, 4H; 2ꢂCH2), 2.66 (s, 1H; OH),
1.15 ppm (t, J=7.4 Hz, 6H; 2ꢂCH3); 13C NMR (125 MHz, CDCl3, 258C):
d=155.1 (C), 154.3 (C), 142.7 (C), 131.3 (C), 128.3 (2ꢂCH), 128.1 (C),
127.6 (CH), 126.5 (2ꢂCH), 124.6 (CH), 122.0 (C), 114.0 (CH), 113.1
(CH), 102.2 (CH), 70.0 (CH), 55.6 (CH3), 42.3 (2ꢂCH2), 13.2 ppm (2ꢂ
C18H26N2O2: 302.2; found: 325.4 [M+Na]+, 303.5 [M+H]+, 285.5
[MÀOH]+; HRMS: m/z: calcd for C18H26N2O2Na: 325.1892 [M+Na]+;
found: 325.1908.
3-(1-Hydroxyethyl)indole-1-carboxylic acid diethylamide (5l): The prod-
1
uct (70 mg, 63%) was obtained as a light yellow oil. H NMR (500 MHz,
CDCl3, 258C): d=7.72 (d, 3J7,6 =7.8 Hz, 1H; 7-H), 7.60 (d, 3J4,5 =8.3 Hz,
1H; 4-H), 7.32–7.27 (m, 1H; 5-H), 7.25 (brs, 1H; 2-H), 7.22–7.18 (m,
1H; 6-H), 5.20 (m, 1H; 1’-H), 3.48 (q, J=7.3 Hz, 4H; 2ꢂCH2), 1.85 (d,
CH3); IR (KBr disc): n˜ =3055, 2980, 2939, 1673, 1477, 1450, 1424 cmÀ1
;
J
OH,1’ =4.4 Hz, 1H; OH), 1.66 (d, 3J2’.1’ =6.3 Hz, 3H; 2’-H3), 1.24 ppm (t,
LRMS (ES): m/z: calcd for C21H24N2O3: 352.1; found: 335.2 [MÀOH]+;
anal. calcd (%) for C21H24N2O3: C 71.57, H 6.86, N 7.95; found: C 71.31,
H, 6.90, N 7.81.
J=7.3 Hz, 6H; 2ꢂCH3); 13C NMR (125 MHz, CDCl3, 258C): d=154.3
(C), 136.2 (C), 127.3 (C), 123.7 (CH), 123.6 (C), 122.2 (CH), 121.5 (CH),
119.9 (CH), 113.1 (CH), 63.9 (CH), 42.4 (2ꢂCH2), 23.5 (CH3), 13.4 ppm
(2ꢂCH3); IR (KBr disc): n˜ =3053, 2975, 2877, 1672, 1475, 1453 cmÀ1
;
3-(1-Hydroxypentyl)-5-methoxyindole-1-carboxylic acid diethylamide
LRMS (ES): m/z: calcd for C15H20N2O2: 260.4; found: 283.4 [M+Na]+,
261.4 [M+H]+, 243.4 [MÀOH]+; HRMS: m/z: calcd for C15H21N2O2:
261.1603 [M+H]+; found: 261.1597.
(5h): The product (83 mg, 59%) was obtained as
a colourless oil.
1H NMR (500 MHz, CDCl3, 258C): d=7.52 (d, 3J7,6 =8.8 Hz, 1H; 7-H),
7.20 (s, 1H; 2-H), 7.16 (d, 4J4,6 =2.4 Hz, 1H; 4-H), 6.91 (dd, 3J6,7 =8.8,
4J6,4 =2.4 Hz, 1H; 6-H), 4.92 (m, 1H; 1’-H), 3.86 (s, 3H; OCH3), 3.46 (q,
J=7.4 Hz, 4H; 2ꢂCH2), 1.94 (m, 2H; 2’-H2), 1.87 (brs, 1H; OH), 1.53–
1.30 (m, 4H; 3’-H2, 4’-H2), 1.23 (t, J=7.4 Hz, 6H; 2ꢂCH3), 0.91 ppm (t,
J=7.4 Hz, 3H; 5’-H3); 13C NMR (125 MHz, CDCl3, 258C): d=155.1 (C),
154.5 (C), 131.2 (C), 128.1 (C), 123.2 (CH), 122.3 (C), 114.0 (CH), 113.1
(CH), 102.2 (CH), 68.1 (CH), 55.8 (CH3), 42.4 (2ꢂCH2), 36.8 (CH2), 28.1
(CH2), 22.5 (CH2), 14.0 (CH3), 13.4 ppm (2ꢂCH3); IR (KBr disc): n˜ =
3055, 2984, 2960, 2937, 1675, 1477, 1450, 1423 cmÀ1; LRMS (ES): m/z:
calcd for C19H28N2O3: 332.2; found: 355.4 [M+Na]+, 315.5 [MÀOH]+;
HRMS: m/z: calcd for C19H28N2O3Na: 355.1998 [M+Na]+, found:
355.2012,.
Procedure for the continuous-flow synthesis of compounds 7a–l: The sol-
utions of indoles 5a–l (0.25m in CH3CN, 800 mL, 80 mLminÀ1) were se-
quentially injected by using the automated liquid handler and treated
with
a solution that contains allyltrimethylsilane (0.1m in CH3CN,
400 mL, 40 mLminÀ1) and p-TSA (1.0m in CH3CN, 400 mL, 40 mLminÀ1
)
on microreactor RC1 (1000 mL, 8.3 min residence time) at 308C. The
output flow was mixed with an aqueous solution of Na2CO3 (2%,
240 mLminÀ1) on microreactor RC2 (1000 mL, 2.8 min residence time).
Products were extracted with a flow of 1,2-dichloroethane (360 mLminÀ1
)
by using the liquid–liquid extraction module with 2.0 bar back-pressure
and 150 mbar cross-membrane pressure. A total volume of 3600 mL was
collected for each experiment. The minimum slug spacing was 450 mL.
The solutions obtained were dried over sodium sulfate. After filtration
and parallel evaporation of the solvent by using an ActeVap rack, prod-
ucts were obtained as described in Table 3. Samples of product 7a–c and
7g–i were purified on silica gel with cyclohexane/diethyl ether as eluent
(9:1 for 7a,b and 1:1 for 7g–i) prior to NMR spectroscopy analysis. Prod-
ucts 7d–f and 7j–l were analysed without purification.
3-(1-Hydroxyethyl)-5-methoxyindole-1-carboxylic acid diethylamide (5i):
The product (49 mg, 40%) was obtained as a light yellow oil. 1H NMR
(500 MHz, CDCl3, 258C): d=7.51 (d, 3J7,6 =8.8 Hz, 1H; 7-H), 7.20 (s,
4
1H; 2-H), 7.16 (d, 4J4,6 =2.4 Hz, 1H; 4-H), 6.91 (dd, 3J6,7 =8.8, J6,4
=
2.4 Hz, 1H; 6-H), 5.14 (m, 1H; 1’-H), 3.85 (s, 3H; OCH3), 3.46 (q, J=
7.4 Hz, 4H; 2ꢂCH2), 2.00 (brs, 1H; OH), 1.64 (d, J2’,1’ =6.8 Hz, 3H; 2’-
H3), 1.22 ppm (t, J=7.4 Hz, 6H; 2ꢂCH3); 13C NMR (125 MHz, CDCl3,
258C): d=155.1 (C), 154.4 (C), 131.2 (C), 128.0 (C), 123.4 (C), 122.7
(CH), 114.0 (CH), 113.2 (CH), 102.1 (CH), 63.8 (CH), 55.8 (CH3), 42.4
(2ꢂCH2), 23.3 (CH3), 13.4 ppm (2ꢂCH3); IR (KBr disc): n˜ =3054, 2977,
2937, 2835, 1668 cmÀ1; LRMS (ES): m/z: calcd for C16H22N2O3: 290.2;
found: 313.4 [M+Na]+, 291.4 [M+H]+, 273.4 [MÀOH]+; HRMS: m/z:
calcd for : C16H22N2O3Na [M+Na]+: 313.1528; found: 313.1543.
5-Methoxy-3-(1-phenylbut-3-enyl)-indole-1-carboxylic acid tert-butyl
ester (7a): The product (38 mg, 50%) was obtained as yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=7.94 (brs, 1H; 7-H), 7.49 (brs,
1H; 2-H), 7.30–7.23 (m, 4H; ArH), 7.21–7.13 (m, 1H; ArH), 6.85 (dd,
4
4
3J6,7 =8.9, J6,4 =2.7 Hz, , 1H; 6-H), 6.72 (d, J4,6 =2.3 Hz, , 1H; 4-H), 5.79
(ddt, 3Jtrans =17.2, 3Jcis =10.2, 3J3’,2’ =7.0 Hz, 1H; 3’-H), 5.10–5.03 (m, 1H;
4’-H), 5.00–4.94 (m, 1H; 4’-Htrans), 4.11 (t, 3J1’,2’ =7.0 Hz, 1H; 1’-H), 3.74
(s, 3H; OCH3), 2.91 (m, 1H; 2’-HA), 2.75 (m, 1H; 2’-HB), 1.69 ppm (s,
3-(Hydroxyphenylmethyl)-indole-1-carboxylic acid diethylamide (5j):
The product (80 mg, 58%) was obtained as a light yellow oil. 1H NMR
(500 MHz, CDCl3, 258C): d=7.61 (d, 3J7,6 =8.3 Hz, 1H; 7-H), 7.53 (d,
3J4,5 =7.8 Hz, 1H; 4-H), 7.48 (d, J=7.4 Hz, 2H; 2ꢂHortho), 7.36 (t, J=
7.4 Hz, 2H; 2ꢂHortho), 7.32–7.22 (m, 2H; Hpara, 6-H), 7.16–7.12 (m, 1H;
5-H), 7.06 (s, 1H; 2-H), 6.10 (d, 3J1’,OH =4.2 Hz, 1H; 1’-H), 3.43 (q, J=
7.3 Hz, 4H; 2ꢂCH2), 2.29 (d, 3JOH,1’ =4.2 Hz, 1H; OH), 1.19 ppm (t, J=
7.4 Hz, 6H; 2ꢂCH3); 13C NMR (125 MHz, CDCl3, 258C): d=142.7 (C),
136.4 (C), 128.4 (2ꢂCH), 127.8 (CH), 127.3 (C), 126.6 (2ꢂCH), 124.1
(CH), 123.8 (CH), 122.2 (C), 121.6 (CH), 120.0 (CH), 113.2 (CH), 70.2
(CH), 42.4 (2ꢂCH2), 13.3 ppm (2ꢂCH3); IR (KBr disc): n˜ =3054, 2978
9H; CACHTNUGRTNEUNG
(CH3)3); 13C NMR (125 MHz, CDCl3, 258C): d=155.5 (C), 149.8
(C), 143.3 (C), 136.6 (CH), 131.0 (C), 128.4 (2ꢂCH), 127.9 (2ꢂCH),
126.4 (CH), 123.5 (C), 123.2 (C), 116.4 (CH2), 115.8 (CH), 112.5 (CH),
102.9 (CH), 83.4 (C), 55.6 (CH3), 42.8 (CH2), 40.0 (CH), 28.2 ppm (3ꢂ
CH3); IR (KBr disc): n˜ =2978, 1725, 1476, 1448, 1381, 1281 cmÀ1; HRMS:
m/z: calcd for C24H28NO3: 378.2069 [M+H]+; found: 378.2060.
3-(1-Allylpentyl)-5-methoxy-indole-1-carboxylic acid tert-butyl ester
(7b): The product (32 mg, 45%) was obtained as light yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=7.98 (brs, 1H; 7-H), 7.30 (brs,
2938, 2877, 1673, 1453, 1425 cmÀ1
; LRMS (ES): m/z: calcd for
4
1H; 2-H), 7.00 (d, 4J4,6 =2.3 Hz, 1H; 4-H), 6.90 (dd, 3J6,7 =8.9, J6,4
=
C20H22N2O2: 322.2; found: 345.4 [M+Na]+, 323.4 [M+H]+, 305.4
[MÀOH]+; HRMS: m/z: calcd for C20H22N2O2Na: 345.1579 [M+Na]+;
found: 345.1580; anal. calcd (%) for C20H22N2O2: C 74.51, H 6.88, N 8.69;
found: C 74.19, H 7.05, N 8.78.
3
3
3
2.7 Hz, 1H; 6-H), 5.75 (ddt, Jtrans =17.2, Jcis =10.2, J3’’,2’’ =7.0 Hz, 1H; 3’-
H), 5.01–4.95 (m, 1H; 4’-Hcis), 4.95–4.90 (m, 1H; 4’’-Htrans), 3.86 (s, 3H;
OCH3), 2.82–2.87 (m, 1H; 1’-H), 2.52–2.38 (m, 2H; CH2), 1.75–1.62 (m,
2H; CH2), 1.66 (s, 9H; CACHTUNRGTNE(UNG CH3)3), 1.34–1.20 (m, 4H; 2ꢂCH2), 0.85 ppm
3-(1-Hydroxypentyl)indole-1-carboxylic acid diethylamide (5k): The
(t, J=7.0 Hz, 3H; CH3); 13C NMR (125 MHz, CDCl3, 258C): d=155.4
(C), 137.0 (CH), 124.2 (C), 122.8 (C), 115.9 (CH2), 112.1 (CH), 102.8
(CH), 83.2 (C), 55.7 (CH3), 39.5 (CH), 36.3 (CH2), 34.1 (CH2), 29.5
(CH2), 28.2 (3ꢂCH3), 22.7 (CH2), 14.0 ppm (CH3); IR (KBr disc): n˜ =
product (64 mg, 50%) was obtained as
a
colourless oil. 1H NMR
(500 MHz, CDCl3, 258C): d=7.71 (d, 3J7,6 =7.7 Hz, 1H; 7-H), 7.61 (d,
3
3J4,5 =7.7 Hz, 1H; 4-H), 7.28 (t, J5,6 =3J5,4 =7.7 Hz, 1H; 5-H), 7.23 (s, 1H;
Chem. Eur. J. 2010, 16, 6678 – 6686
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6683

D. F. OꢀShea and T. Tricotet
2930, 1724, 1474, 1450, 1386 cmÀ1
;
LRMS (ES): m/z: calcd for
131.1 (C), 129.5 (C), 128.3 (2ꢂCH), 127.9 (2ꢂCH), 126.3 (CH), 123.6
(CH), 121.8 (C), 116.2 (CH2), 113.9 (CH), 112.5 (CH), 102.3 (CH), 55.6
(CH3), 42.7 (CH), 42.4 (2ꢂCH2), 40.0 (CH2), 13.4 ppm (2ꢂCH3); IR
(KBr disc): n˜ =2976, 1673, 1474, 1422 cmÀ1; HRMS: m/z: calcd for
C24H29N2O2: 377.2229 [M+H]+; found: 377.2233.
C22H31NO3: 357.2; found: 370.5 [M+Na]+; HRMS: m/z: calcd for
C22H32NO3 358.2382 [M+H]+; found: 358.2394.
5-Methoxy-3-(1-methylbut-3-enyl)-indole-1-carboxylic acid tert-butyl
ester (7c): The product (27 mg, 43%) was obtained as a light yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=7.98 (brs, 1H; 7-H), 7.31 (brs,
3-(1-Allylpentyl)-5-methoxyindole-1-carboxylic acid diethylamide (7h):
1H; 2-H), 7.00 (d, 4J4,6 =2.5 Hz, 1H; 4-H), 6.90 (dd, 3J6,7 =8.9, J6,4
=
4
The product (33 mg, 46%) was obtained as a light yellow oil. 1H NMR
3
3
3
(400 MHz, CDCl3, 258C): d=7.58 (d, 3J7,6 =8.9 Hz, 1H; 7-H), 7.01 (d,
2.5 Hz, 1H; 6-H), 5.81 (ddt, Jtrans =17.2, Jcis =10.2, J3’,2’ =7.0 Hz, 1H; 3’-
H), 5.07–5.01 (m, 1H; 4’-Hcis), 5.01–4.97 (m, 1H; 4’-Htrans), 3.86 (s, 3H;
OCH3), 2.97–3.03 (m, 1H; 1’-H), 2.54 (m, 1H; 2’-HA), 2.33 (m, 1H; 2’-
4
4J4,6 =2.7 Hz, 1H; 4-H), 6.99 (brs, 1H; 2-H), 6.91 (dd, 3J6,7 =8.9, J6,4
=
3
3
3
2.7 Hz, 1H; 6-H), 5.75 (ddt, Jtrans =17.2, Jcis =10.2, J3’,2’ =7.0 Hz, 1H; 3’-
H), 5.01–4.97 (m, 1H; 4’-Hcis), 4.96–4.92 (m, 1H; 4’-Htrans), 3.86 (s, 3H;
OCH3), 3.45 (q, J=7.0 Hz, 4H; 2ꢂCH2), 2.89 (p, J=6.8 Hz, 1H; 1’-H),
2.52–2.40 (m, 2H; CH2), 1.77–1.65 (m, 2H; CH2), 1.32–1.20 (m, 4H; 2ꢂ
CH2), 1.23 (t, J=7.0 Hz, 6H; 2ꢂCH3), 0.84 ppm (t, J=7.0 Hz, 3H; CH3);
13C NMR (100 MHz, CDCl3, 258C): d=154.8 (C), 137.1 (C), 131.1 (CH),
129.7 (C), 123.0 (CH), 122.2 (C), 115.8 (CH2), 114.0 (C), 112.2 (CH),
102.2 (CH), 92.2 (CH), 55.8 (CH3), 42.4 (2ꢂCH2), 39.6 (CH), 36.1 (CH2),
34.2 (CH2), 29.5 (CH2), 22.7 (CH2), 14.0 (CH3), 13.4 ppm (2ꢂCH3); IR
(KBr disc): n˜ =2931, 1672, 1472, 1422, 1270 cmÀ1; LRMS (ES): m/z: calcd
HB), 1.66 (s, 9H;
CACHTUNGTRENNUNG(CH3)3), 1.32 ppm (t, J=7.0 Hz, 3H; 1’-CH3);
13C NMR (125 MHz, CDCl3, 258C): d=155.5 (C), 136.9 (CH), 132.0 (C),
125.9 (C), 122.0 (C), 116.1 (CH2), 115.9 (CH), 115.8 (C), 112.3 (CH),
102.5 (CH), 83.1 (C), 55.7 (CH3), 40.9 (CH), 30.3 (CH2), 28.2 (3ꢂCH3),
19.9 ppm (CH3); IR (KBr disc): n˜ =2971, 1724, 1474, 1384 cmÀ1; LRMS
(ES): m/z: calcd for C19H25NO3: 315.2; found: 316.2 [M+H]+; HRMS:
m/z: calcd for C19H26NO3: 316.1913 [M+H]+; found: 316.1993.
3-(1-Phenylbut-3-enyl)-indole-1-carboxylic acid tert-butyl ester (7d):[17]
The product (43 mg, 62%) was obtained as a light yellow oil. 1H NMR
(400 MHz, CDCl3, 258C): d=8.15–7.90 (m, 1H; 7-H), 7.51 (m, 1H; 2-H),
7.35–7.00 (m, 8H; 2ꢂHortho, 2ꢂHmeta, Hpara, 4-H, 5-H, 6-H), 5.79 (ddt,
3Jtrans =17.2, 3Jcis =10.1, 3J3’,2’ =6.6 Hz, 1H; 3’-H), 5.07 (dd, 3Jtrans =17.2,
for C22H32N2O2: 356.2; found: 357.5 [M+H]+, 315.5 [MÀ
(CH2CHCH2)]+;
ACHTUNGTRENNUNG
HRMS: m/z: calcd for C22H33N2O2: 357.2542 [M+H]+; found: 357.2533.
5-Methoxy-3-(1-methylbut-3-enyl)-indole-1-carboxylic acid diethylamide
(7i): The product (41 mg, 65%) was obtained as a light yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=7.56 (d, 3J7,6 =9.0 Hz, 1H; 7-H),
7.02 (d, 4J4,6 =2.3 Hz, 1H; 4-H), 7.01 (brs, 1H; 2-H), 6.91 (dd, 3J6,7 =9.0,
4J6,4 =2.3 Hz, 1H; 6-H), 5.81 (ddt, 3Jtrans =17.2, 3Jcis =10.2, 3J3’,2’ =7.0 Hz,
1H; 3’-H), 5.07–5.03 (m, 1H; 4’-Hcis), 5.02–4.98 (m, 1H; 4’-Htrans), 3.86 (s,
3H; OCH3), 3.46 (q, J=7.2 Hz, 4H; 2ꢂCH2), 3.04–3.08 (m, 1H; 1’-H),
2.55 (m, 1H; 2’-HA), 2.34 (m, 1H; 2’-HB), 1.33 (d, J=7.0 Hz, 3H; 1’-
CH3), 1.23 ppm (t, J=7.2 Hz, 6H; 2ꢂCH3); 13C NMR (100 MHz, CDCl3,
258C): d=154.9 (C), 136.9 (CH), 131.0 (C), 129.4 (C), 124.2 (C), 122.3
(CH), 116.0 (CH), 114.1 (CH), 112.4 (CH), 102.0 (CH), 92.1 (CH), 55.8
(CH3), 42.4 (2ꢂCH2), 41.1 (CH), 30.3 (CH2), 20.1 (CH3), 13.4 ppm (2ꢂ
CH3); IR (KBr disc): n˜ =2973, 1672, 1473, 1422 cmÀ1; LRMS (ES): m/z:
calcd for C19H26N2O2: 314.2; found: 315.5 [M+H]+, 273.4 [MÀ(CH2-
3
4Jcis,2’ =1.5 Hz, 1H; 4’-Hcis), 4.98 (brd, Jcis =10.1 Hz, 1H; 4’-Htrans), 4.17 (t,
3J1’,2’ =7.4 Hz, 1H; 1’-H), 2.97–2.85 (m, 1H; 2’-HA), 2.82–2.70 (m, 1H; 2’-
HA), 1.68 ppm (s, 9H; CACHTUNGTRENNUNG
(CH3)3); 13C NMR (100 MHz, CDCl3, 258C): d=
149.9, 143.4, 136.7, 130.2, 128.4, 128.0, 126.4, 124.2, 123.8, 122.5, 122.3,
119.7, 116.4, 115.2, 83.5, 43.4, 42.8, 40.1, 28.2 ppm; LRMS (ES): m/z:
calcd for C23H25NO2: 347.1; found: 370.5 [M+Na]+.
3-(1-Allylpentyl)-indole-1-carboxylic acid tert-butyl ester (7e): The prod-
uct (32 mg, 49%) was obtained as a light yellow oil. H NMR (400 MHz,
CDCl3, 258C): d=8.20–7.90 (m, 1H; 7-H), 7.56 (d, J=7.8 Hz, 1H; ArH),
7.35–7.15 (m, 3H; ArH), 5.74 (ddt, 3Jtrans =17.2, 3Jcis =10.1, 3J3’,2’ =6.8 Hz,
1H; 3’-H), 5.04–4.97 (m, 1H; 4’-Hcis), 4.96–4.91 (m, 1H; 4’-Htrans), 2.87–
2.91 (m, 1H; 1’-H), 2.46 (m, 2H; CH2), 1.77–1.65 (m, 2H; CH2), 1.67 (s,
1
9H; CACHTUNGTRENNUNG(CH3)3), 1.35–1.20 (m, 4H; 2ꢂCH2), 0.84 ppm (t, J=7.0 Hz, 3H;
AHCTUNGTRENNUNG
CHCH2)]+; HRMS: m/z: calcd for C19H27N2O2: 315.2073 [M+H]+;
found: 315.2067.
CH3); 13C NMR (100 MHz, CDCl3, 258C): d=149.9 (C), 137.0 (CH),
135.6 (C), 130.4(C), 124.4 (C), 124.0 (CH), 122.1 (CH), 119.4 (CH), 115.8
(CH2), 115.2 (CH), 83.4 (CH), 39.5 (C), 36.3 (CH2), 34.2 (CH2), 29.6
(CH2), 28.2 (3ꢂCH3), 22.7 (CH2), 14.0 ppm (CH3); IR (KBr disc): n˜ =
2959, 2929, 2865, 1728, 1453, 1375, 1254, 1160 cmÀ1; LRMS (EI): m/z:
3-(1-Phenylbut-3-enyl)-indole-1-carboxylic acid diethylamide (7j): The
product (49 mg, 71%) was obtained as a light yellow oil. 1H NMR
(400 MHz, CDCl3, 258C): d=7.62 (d, 3J7,6 =8.2 Hz, 1H; 7-H), 7.34 (d,
3J4,5 =7.8 Hz, 1H; 4-H), 7.30–7.15 (m, 6H; ArH), 7.14 (brs, 1H; ArH),
7.06 (m, 1H; ArH), 5.80 (ddt, 3Jtrans =17.2, 3Jcis =10.2, 3J3’,2’ =6.8 Hz, 1H;
3’-H), 5.08–5.04 (m, 1H; 4’-Hcis), 4.99–4.95 (m, 1H; 4’-Htrans), 4.23 (t, 1H;
J=7.4 Hz, 1’-H), 3.46 (q, J=7.0 Hz, 4H; 2ꢂCH2), 2.93 (m, 1H; 2’-HA),
2.77 (m, 1H; 2’-HB), 1.22 ppm (t, J=7.0 Hz, 6H; 2ꢂCH3); 13C NMR
(100 MHz, CDCl3, 258C): d=154.6 (C), 143.6 (C), 136.8 (CH), 136.1 (C),
128.7 (C), 128.3 (2ꢂCH), 127.9 (2ꢂCH), 126.3 (CH), 123.5 (CH), 123.0
(CH), 122.1 (C), 121.2 (CH), 119.7 (CH), 116.2 (CH2), 113.1 (CH), 42.6
(CH), 42.4 (2ꢂCH2), 40.1 (CH2), 13.4 ppm (2ꢂCH3); IR (KBr disc): n˜ =
calcd for C21H29NO2: 327.2; found: 230.5 [MÀtBuÀ
[MÀCO2tBuÀ
(CH2CHCH2)]+; HRMS: m/z: calcd for C18H24NO2:
286.1807 [MÀ
(CH2CHCH2)]+; found: 286.1860.
ACHTUNGTREN(NGNU allyl)], 186.5
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
3-(1-Methylbut-3-enyl)-indole-1-carboxylic acid tert-butyl ester (7 f): The
product (34 mg, 59%) was obtained as a light yellow oil. 1H NMR
3
(400 MHz, CDCl3, 258C): d=8.25–8.00 (m, 1H; 7-H), 7.56 (d, J4,5
=
7.4 Hz, 1H; 4-H), 7.34 (brs, 1H; 2-H), 7.30 (dt, J=7.0, 1.2 Hz, 1H;
ArH), 7.22 (dt, J=7.0, 1.0 Hz, 1H; ArH), 5.82 (ddt, 3Jtrans =17.0, Jcis
=
3
10.0, 3J3’,2’ =7.0 Hz, 1H; 3’-H), 5.09–5.02 (m, 1H; 4’-Hcis), 5.02–4.98 (m,
1H; 4’-Htrans), 3.02–3.07 (m, 1H; 1’-H), 2.56 (m, 1H; 2’-HA), 2.34 (m, 1H;
2977, 1676, 1450, 1422, 1343 cmÀ1
; LRMS (GCMS): m/z: calcd for
C23H26N2O: 346.2; found: 305.5 [MÀ
(CH2CHCH2)]+; HRMS: m/z: calcd
ACHTUNGTRENNUNG
2’-HB), 1.67 (s, 9H; CACHTUNGTRENNUNG(CH3)3), 1.33 ppm (d, J=7.0 Hz, 3H; 1’-CH3);
for C23H27N2O : 347.2123; found: 347.2109 [M+H]+.
13C NMR (100 MHz, CDCl3, 258C): d=149.9 (C), 136.9 (CH), 130.0 (C),
126.1 (C), 124.1 (CH), 122.1 (CH), 121.3 (C), 119.3 (CH), 116.1 (CH2),
115.3 (CH), 83.3 (C), 41.0 (CH), 30.4 (CH2), 28.2 (3ꢂCH3), 20.0 ppm
(CH3); IR (KBr disc): n˜ =2977, 1726, 1456, 1375, 1255, 1158 cmÀ1; LRMS
(EI): m/z: calcd for C18H23NO2: 285.4; found: 188.4 [MÀtBuÀ(CH2-
3-(1-Allylpentyl)-indole-1-carboxylic acid diethylamide (7k): The product
(35 mg, 54%) was obtained as a light yellow oil. 1H NMR (400 MHz,
CDCl3, 258C): d=7.66 (d, 3J7,6 =8.2 Hz, 1H; 7-H), 7.59 (d, 3J4,5 =7.8 Hz,
1H; 4-H), 7.26 (m, 1H; ArH), 7.17 (m, 1H; ArH), 7.00 (s, 1H; 2-H),
5.74 (ddt, 3Jtrans =17.2, 3Jcis =10.2, 3J3’,2’ =7.0 Hz, 1H; 3’-H), 5.00–4.96 (m,
1H; 4’-Hcis), 4.94–4.90 (m, 1H; 4’-Htrans), 3.45 (q, J=7.0 Hz, 4H; 2ꢂCH2),
2.94 (p, J=6.8 Hz, 1H; 1’-H), 2.55–2.40 (m, 2H; CH2), 1.85–1.60 (m, 2H;
CH2), 1.35–1.15 (m, 4H; 2ꢂCH2), 1.23 (t, J=7.0 Hz, 6H; 2ꢂCH3),
0.83 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3, 258C):
d=154.7 (C), 137.1 (CH), 136.1 (C), 128.9 (C), 123.3 (CH), 122.5 (C),
122.4 (CH), 121.0 (CH), 119.4 (CH), 115.8 (CH2), 113.2 (CH), 42.4 (2ꢂ
CH2), 39.7 (CH), 36.2 (CH2), 34.3 (CH2), 29.6 (CH2), 22.7 (CH2), 14.0
(CH3), 13.4 ppm (2ꢂCH3); IR (KBr disc): n˜ =2963, 2930, 2870, 1676,
1450, 1423 cmÀ1; LRMS (ES): m/z: calcd for C21H30N2O: 326.2; found:
A
(CH2CHCH2)]+; HRMS: m/z: calcd for
ACHTUNGTRENNUNG
C18H24NO2: 286.1807 [M+H]+; found: 286.1796.
5-Methoxy-3-(1-phenylbut-3-enyl)-indole-1-carboxylic acid diethylamide
(7g): The product (49 mg, 65%) was obtained as a light yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=7.53 (d, 3J7,6 =8.9 Hz, 1H; 7-H),
7.27 (m, 4H; ArH), 7.18 (m, 1H; ArH), 7.12 (brs, 1H; ArH), 6.85 (dd,
3J6,7 =8.9, 4J6,4 =2.7 Hz, 1H; 6-H), 6.75 (d, 4J4,6 =2.7 Hz, 1H; 4-H), 5.80
(ddt, 3Jtrans =17.2, 3Jcis =10.2, 3J3’,2’ =7.0 Hz, 1H; 3’-H), 5.07–5.01 (m, 1H;
3
4’-Hcis), 4.99–4.95 (m, 1H; 4’-Htrans), 4.17 (t, J1’,2’ =7.4 Hz, 1H; 1’-H), 3.72
(s, 3H; OCH3), 3.45 (q, J=7.0 Hz, 4H; 2ꢂCH2), 2.91 (m, 1H; 2’-HA),
2.76 (m, 1H; 2’-HB), 1.22 ppm (t, J=7.0 Hz, 6H; 2ꢂCH3); 13C NMR
(100 MHz, CDCl3, 258C): d=154.9 (C), 154.7 (C), 143.5 (C), 136.7 (CH),
327.5 [M+H]+, 285.5 [MÀ
(CH2CHCH2)]+; HRMS: m/z: calcd for
ACHTUNGTRENNUNG
C21H31N2O: 327.2436; found: 327.2422 [M+H]+.
6684
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6678 – 6686

3-Hydroxymethylindoles in Continuous Flow Microreactors
FULL PAPER
3-(1-Methylbut-3-enyl)-indole-1-carboxylic acid diethylamide (7l): The
product (33 mg, 58%) was obtained as a light yellow oil. 1H NMR
(400 MHz, CDCl3, 258C): d=7.64 (d, 3J7,6 =8.6 Hz, 1H; 7-H), 7.59 (d,
3J4,5 =7.8 Hz, 1H; 4-H), 7.26 (m, 1H; ArH), 7.18 (m, 1H; ArH), 7.03 (s,
1H; 2-H), 5.81 (ddt, 3Jtrans =17.2, 3Jcis =10.2, 3J3’,2’ =7.0 Hz, 1H; 3’-H),
5.06–5.02 (m, 1H; 4’-Hcis), 5.01–4.97 (m, 1H; 4’-Htrans), 3.46 (q, J=7.4 Hz,
4H; 2ꢂCH2), 3.08–3.12 (m, 1H; 1’-H), 2.56 (m, 1H; 2’-HA), 2.35 (m, 1H;
2’-HB), 1.34 (d, 3J1’,2’ =6.8 Hz, 3H; 1’-CH3), 1.23 ppm (t, J=7.4 Hz, 6H;
2ꢂCH3); 13C NMR (100 MHz, CDCl3, 258C): d=154.7 (C), 137.0 (CH),
136.1 (C), 128.7 (C), 124.4 (C), 123.3 (CH), 121.7 (CH), 121.0 (CH),
119.3 (CH), 116.0 (CH2), 113.2 (CH), 42.4 (2ꢂCH2), 41.2 (CH), 30.4
(CH2), 20.2 (CH3), 13.4 ppm (2ꢂCH3); IR (KBr disc): n˜ =2974, 2933,
1675, 1451, 1422 cmÀ1; LRMS (ES): m/z: calcd for C18H24N2O: 284.2;
C21H23NO3: 337.2; found: 306.5 [MÀOMe]+; HRMS: m/z: calcd for
C20H20NO: 306.1494; found: 306.1492 [MÀOMe]+.
3-(1-Methoxypentyl)indole-1-carboxylic acid tert-butyl ester (8e): The
product (57 mg, 90%) was obtained as a light yellow oil. 1H NMR
(400 MHz, CDCl3, 258C): d=8.14 (brd, J=7.8 Hz, 1H; ArH), 7.70 (d,
J=7.8 Hz, 1H; ArH), 7.49 (s, 1H; 2-H), 7.31 (m, 1H; ArH), 7.22 (m,
1H; ArH), 4.38 (t, J=6.6 Hz, 1H; 1’-H), 3.31 (s, 3H; OCH3), 2.05–1.92
(m, 1H; 2’-HA), 1.90–1.78 (m, 1H; 2’-HB), 1.47–1.20 (m, 4H; 2ꢂCH2),
1.68 (s, 9H; CACTHNUTRGNEUNG
(CH3)3), 0.88 ppm (t, J=7.4 Hz, 3H; CH3); 13C NMR
(100 MHz, CDCl3, 258C): d=149.7, 135.8, 128.9, 124.3, 123.5, 122.4,
121.4, 120.3, 115.2, 83.6, 77.6, 56.3, 35.7, 28.2, 28.1 22.5, 14.0 ppm; IR
(KBr disc): n˜ =2934.5, 2866.4, 1729.2, 1452.7, 1369.5, 1259.3 cmÀ1; LRMS
(ES): m/z: calcd for C19H27NO3: 317.2; found: 286.2 [MÀOMe]+; HRMS:
m/z: calcd for C18H24NO2: 286.1807; found: 286.1873 [MÀOMe]+.
found: 307.4 [M+Na]+, 285.5 [M+H]+, 243.4 [MÀ
(CH2CHCH2)]+;
ACHTUNGTRENNUNG
HRMS: m/z: calcd for C18H25N2O: 285.1967; found: 285.1980 [M+H]+.
Procedure for the continuous flow synthesis of compounds 8a–l: The so-
3-(1-Methoxyethyl)indole-1-carboxylic acid tert-butyl ester (8 f): The
product (50 mg, 92%) was obtained as a light yellow oil. 1H NMR
(400 MHz, CDCl3): d=8.15 (brd, J=7.8 Hz, 1H; ArH), 7.71 (d, J=
7.8 Hz, 1H; ArH), 7.51 (s, 1H; 2-H), 7.32 (m, 1H; ArH), 7.24 (m, 1H;
ArH), 4.63 (q, J=6.2 Hz, 1H; 1’-H), 3.26 (s, 3H; OCH3), 1.68 (s, 9H; C-
ACHTUNGTRENNUNGluACHTUNGTRENNUNG
tions of indoles 5a–l (0.25m in CH3CN, 800 mL, 30 mLminÀ1) were se-
quentially injected by using the automated liquid handler and treated
with a solution of p-TSA (0.05m in MeOH, 800 mL, 30 mLminÀ1) on mi-
croreactor RC1 (1000 mL, 16.6 min residence time) at 308C. The output
flows (1600 mL) were collected, on Dowex 1X8.100 (200 mg) and agitated
for 10 min. Filtration and parallel evaporation of the solvent by using Ac-
teVap Rack gave the products as described in Table 4.
AHCTUNGTRENNUNG
(CH3)3), 1.60 ppm (d, J=6.2 Hz, 3H; 1’-H3); 13C NMR (100 MHz, CDCl3,
258C): d=149.7, 135.9, 128.7, 124.4, 122.9, 122.6, 122.5, 120.1, 115.2, 83.6,
72.8, 56.1, 28.2, 21.7 ppm; IR (KBr disc): n˜ =2980.4, 2932.5, 1730.5,
1452.5, 1371.2 cmÀ1; LRMS (ES): m/z: calcd for C16H21NO3: 275.1; found:
244.1 [MÀOMe]+, 188.0 [MÀOMeÀtBu]+, 144.1 [MÀOMeÀCO2tBu]+;
HRMS: m/z: calcd for C15H18NO2: 244.1338; found: 244.1420
[MÀOMe]+.
5-Methoxy-3-methoxyphenylmethylindole-1-carboxylic acid diethylamide
(8g): The product (69 mg, 94%) was obtained as a light yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=7.53 (d, 3J7,6 =9.0 Hz, 1H; 7-H),
7.47–7.43 (m, 2H; ArH), 7.36 (m, 2H; ArH), 7.29 (m, 1H; ArH), 7.00
(brd, 4J4,6 =2.3 Hz, 1H; 4-H), 6.95 (brs, 1H; 2-H), 6.89 (dd, 3J6,7 =9.0,
4J6,4 =2.3 Hz, 1H;6-H), 5.49 (s, 1H; 1’-H), 3.79 (s, 3H; OCH3), 3.46–3.33
(m, 4H; 2ꢂCH2) overlapped with 3.43 (s, 3H; OCH3), 1.17 ppm (t, J=
7.0 Hz, 6H; 2ꢂCH3); 13C NMR (100 MHz, CDCl3, 258C): d=155.1,
154.3, 140.6, 131.3, 128.4, 128.3, 127.7, 127.2, 125.0, 120.1, 114.0, 112.9,
102.5, 79.3, 56.8, 55.7, 42.4, 13.3 ppmm; IR (KBr disc): n˜ =2974.4, 2938.2,
1673.3, 1474.0, 1450.2 cmÀ1; LRMS (ES): m/z: calcd for C22H26N2O3:
366.2; found: 389.4 [M+Na]+, 367.4 [M+H]+; HRMS: m/z: calcd for
C22H26N2O3Na: 389.1841; found: 389.1855 [M+Na]+.
5-Methoxy-3-(methoxyphenylmethyl)indole-1-carboxylic acid tert-butyl
ester (8a): The product (72 mg, 97%) was obtained as light yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=8.07–7.90 (m, 1H; 7-H), 7.50–7.42
(m, 3H; 2-H, 2ꢂHortho), 7.36 (m, 2H; 2ꢂHmeta), 7.32–7.27 (m, 1H; Hpara),
6.96 (d, 4J4,6 =2.3 Hz, 1H; 4-H), 6.91 (dd, 3J6,7 =8.9, 4J6,4 =2.3 Hz, 1H; 6-
H), 5.46 (s, 1H; 2-H), 3.78 (s, 3H; OCH3), 3.44 (s, 3H; OCH3), 1.66 ppm
(s, 9H; CACHTUNGTRENNUNG
(CH3)3); 13C NMR (100 MHz, CDCl3, 258C): d=155.6, 149.6,
140.5, 130.6, 129.6, 128.3, 127.7, 127.1, 124.6, 121.4, 115.8, 112.9, 103.1,
83.5, 79.3, 56.8, 55.6, 28.1 ppm; IR (KBr disc): n˜ =2981.1, 2936.0, 2828.1,
1727.1, 1599.8 cmÀ1
; LRMS (ES): m/z: calcd for C22H25NO4: 367.2;
found: 390.42 [M+Na]+, 336.5 [MÀOMe]+; HRMS: m/z: calcd for
C21H22NO3: 336.1600; found: 336.1602 [MÀOMe]+.
5-Methoxy-3-(1-methoxypentyl)indole-1-carboxylic acid tert-butyl ester
(8b): The product (70 mg, 98%) was obtained as light yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=8.10–7.90 (m, 1H; 7-H), 7.46 (s,
3
1H; 2-H), 7.17 (d, 3J4,6 =2.7 Hz, 1H; 4-H), 6.93 (dd, 3J6,7 =8.9, J6,4
=
2.7 Hz, 1H; 6-H), 4.34 (t, 3J1’,2’ =6.6 Hz, 1H; 1’-H), 3.86 (s, 3H; OCH3),
3.26 (s, 3H; OCH3), 2.05–1.92 (m, 1H; 2’-HA), 1.89–1.72 (m, 1H; 2’-HA),
5-Methoxy-3-(1-methoxypentyl)indole-1-carboxylic acid diethylamide
(8h): The product (65 mg, 93%) was obtained as a light colourless oil.
1H NMR (400 MHz, CDCl3, 258C): d=7.56 (d, 3J7,6 =9.0 Hz, 1H; 7-H),
1.67 (s, 9H; CACHTUNGTRENNUNG(CH3)3), 1.45–1.20 (m, 4H; 2ꢂCH2), 0.88 ppm (t, J=
7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3, 258C): d=155.6, 149.6,
130.6, 129.6, 124.2, 121.0, 115.9, 113.0, 103.0, 92.1, 83.4, 77.6, 56.2, 55.7,
35.5, 28.2, 22.5, 14.0 ppm; IR (KBr disc): n˜ =2935.3, 2866.8, 1727.3,
1473.8, 1450.7, 1387.5, 1328.8, 1255.5 cmÀ1; LRMS (ES): m/z: calcd for
C20H29NO4: ;347.2 found: 316.5 [MÀOMe]+; HRMS: m/z: calcd for
C19H26NO3: 316.1913; found: 316.1911 [MÀOMe]+.
3
4
7.18–7.15 (m, 2H; ArH), 6.92 (dd, J6,7 =9.0, J6,4 =2.3 Hz, 1H; 6-H), 4.38
(t, J=6.6 Hz, 1H; 1’-H), 3.85 (s, 3H; OCH3), 3.52–3.41 (m, 4H; 2ꢂCH2),
3.27 (s, 3H; OCH3), 2.03–1.92 (m, 1H; 2’-HA), 1.91–1.80 (m, 1H; 2’-HB),
1.45–1.20 (m, 4H; 2ꢂCH2) overlapped with 1.23 (t, J=7.0 Hz, 6H; 2ꢂ
CH3), 0.87 ppm (t, J=7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3,
258C): d=155.0, 154.5, 131.2, 128.2, 124.3, 119.2, 114.0, 113.0, 102.4, 77.6,
56.1, 55.8, 42.4, 35.6, 28.2, 22.5, 14.0, 13.4 ppm; IR (KBr disc): n˜ =2935.6,
1675.3, 1615.4, 1470.0, 1423.4, 1273.9 cmÀ1; LRMS (ES): m/z: calcd for
C20H30N2O3: 346.2; found: 369.5 [M+Na]+, 315.5 [MÀMeO]+; HRMS:
m/z: calcd for C20H30N2O3Na: 369.2154; found: 369.2162 [M+Na]+.
5-Methoxy-3-(1-methoxyethyl)-indole-1-carboxylic acid tert-butyl ester
(8c): The product (59 mg, 97%) was obtained as a light yellow oil.
1H NMR (400 MHz, CDCl3, 258C): d=8.10–7.90 (m, 1H; 7-H), 7.48 (s,
3
1H; 2-H), 7.17 (d, 3J4,6 =2.3 Hz, 1H; 4-H), 6.93 (dd, 3J6,7 =8.9, J6,4
=
2.7 Hz, 1H; 6-H), 4.59 (q, 3J1’,2’ =6.2 Hz, 1H; 1’-H), 3.86 (s, 3H; OCH3),
3.30 (s, 3H; OCH3), 1.66 (s, 9H; C(CH3)3), 1.59 ppm (d, J=6.2 Hz, 3H;
5-Methoxy-3-(1-methoxyethyl)indole-1-carboxylic acid diethylamide (8i):
The product (58 mg, 96%) was obtained as a light yellow oil. 1H NMR
(400 MHz, CDCl3, 258C): d=7.53 (d, 3J7,6 =9.0 Hz, 1H; 7-H), 7.19 (s,
1H; 2-H), 7.17 (d, J=2.3 Hz, 1H; 4-H), 6.92 (dd, 3J6,7 =9.0, 4J6,4 =2.3 Hz,
1H; 6-H), 4.62 (q, J=6.6 Hz, 1H; 1’-H), 3.86 (s, 3H; OCH3), 3.52–3.41
(m, 4H; 2ꢂCH2), 3.31 (s, 3H; OCH3), 1.60 (d, J=6.6 Hz, 3H; CH3),
1.23 ppm (t, J=7.0 Hz, 6H; 2ꢂCH3); 13C NMR (100 MHz, CDCl3, 258C):
d=155.1, 154.5, 131.2, 128.2, 123.8, 120.6, 114.0, 113.0, 102.3, 72.8, 55.9,
55.8, 42.4, 21.6, 13.4 ppm; IR (KBr disc): n˜ =2977.5, 2936.4, 1674.5,
AHCTUNGTRENNUNG
1’-H3); 13C NMR (100 MHz, CDCl3, 258C): d=155.6, 149.6, 130.6, 129.5,
123.6, 122.2, 115.9, 113.0, 102.9, 83.4, 72.8, 56.0, 55.7, 28.1, 21.6 ppm; IR
(KBr disc): n˜ =2979.7, 2934.2, 1727.7, 1609.5, 1473.7 cmÀ1; LRMS (ES):
m/z: calcd for C17H23NO4: 305.4; found: 274.0 [MÀOMe]+; HRMS: m/z:
calcd for C16H20NO3: 274.1443; found: 274.1451 [MÀOMe]+.
3-Methoxyphenylmethylindole-1-carboxylic acid tert-butyl ester (8d):
The product (66 mg, 97%) was obtained as a colourless oil. 1H NMR
(400 MHz, CDCl3, 258C): d=8.13 (m, 1H; ArH), 7.52 (d, J=7.8 Hz, 1H;
ArH), 7.50–7.46 (m, 3H; ArH), 7.36 (m, 2H; ArH), 7.30 (m, 2H; ArH),
7.18 (m, 1H; ArH), 5.50 (s, 1H; 1’-H), 3.44 (s, 3H; OCH3), 1.67 ppm (s,
1472.2, 1422.4 cmÀ1
; LRMS (ES): m/z: calcd for C17H24N2O3: 304.2;
found: 327.4 [M+Na]+, 273.4 [MÀMeO]+; HRMS: m/z: calcd for
C17H24N2O3Na: 327.1685; found: 327.1669 [M+Na]+.
9H;
CN
3-Methoxyphenylmethylindole-1-carboxylic acid diethylamide (8j): The
product (60 mg, 90%) was obtained as a light yellow oil. 1H NMR
(400 MHz, CDCl3, 258C): d=7.61 (d, 3J7,6 =8.6 Hz, 1H; 7-H), 7.57 (d,
3J4,5 =7.4 Hz, 1H; 4-H), 7.46 (m, 2H; ArH), 7.38–7.32 (m, 2H; ArH),
135.8, 128.8, 128.3, 127.7, 127.1, 124.4, 123.9, 122.5, 121.8, 120.2, 115.2,
83.7, 79.3, 56.8, 28.1 ppm; IR (KBr disc): n˜ =2981.2, 2934.4, 1731.5,
1451.9, 1373.9, 1256.4, 1158.0 cmÀ1
; LRMS (ES): m/z: calcd for
Chem. Eur. J. 2010, 16, 6678 – 6686
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www.chemeurj.org
6685

D. F. OꢀShea and T. Tricotet
7.32–7.22 (m, 2H; ArH), 7.14 (m, 1H; ArH), 6.98 (brs, 1H; ArH), 5.52
(brs, 1H; 1’-H), 3.47–3.35 (m, 4H; 2ꢂCH2) overlapped with 3.43 (s, 3H;
OCH3), 1.18 ppm (t, J=7.0 Hz, 6H; 2ꢂCH3); 13C NMR (100 MHz,
CDCl3, 258C): 1 C missing d=154.3, 140.7, 136.3, 128.3, 127.8, 127.7,
127.2, 124.4, 123.7, 121.6, 120.4, 120.1, 113.1, 79.3, 56.8, 42.4, 13.3 ppm;
IR (KBr disc): n˜ =2979.0, 1678.7, 1449.8, 1422.9, 1273.5 cmÀ1; LRMS
(ES): m/z: calcd for C21H24N2O2: 336.2; found: 359.5 [M+Na]+, 337.5
[M+H]+, 305.5 [MÀOMe]+; HRMS: m/z: calcd for C20H21N2O2:
305.1654; found: 305.1666 [MÀOMe]+.
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3-(1-Methoxypentyl)indole-1-carboxylic acid diethylamide (8k): The
product (62 mg, 98%) was obtained as a light colourless oil. 1H NMR
(400 MHz, CDCl3, 258C): d=7.72 (d, 3J7,6 =7.8 Hz, 1H; 7-H), 7.64 (d,
3J4,5 =8.2 Hz, 1H; 4-H), 7.28 (m, 1H; ArH), 7.21–7.15 (m, 2H; ArH),
3
4.42 (t, J1’,2’ =6.6 Hz, 1H; 1’-H), 3.52–3.42 (m, 4H; 2ꢂCH2), 3.27 (s, 3H;
OCH3), 2.05–1.94 (m, 1H; 2’-HA), 1.93–1.82 (m, 1H; 2’-HB), 1.45–1.22
(m, 4H; 2ꢂCH2), 1.24 (t, J=7.0 Hz, 6H; 2ꢂCH3), 0.87 ppm (t, J=
6.6 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3, 258C): d=154.4, 136.3,
127.6, 123.7, 123.6, 121.4, 120.2, 119.6, 113.1, 77.6, 56.3, 42.4, 35.8, 28.2,
22.5, 14.0, 13.4 ppm; IR (KBr disc): n˜ =2935.0, 1677.2, 1450.8,
1425.2 cmÀ1; LRMS (ES): m/z: calcd for C19H28N2O2: 316.2; found: 339.5
[M+Na]+, 285.5 [MÀOMe]+; HRMS: m/z: calcd for C19H28N2O2Na:
339.2048; found: 339.2055 [M+Na]+.
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3-(1-Methoxyethyl)indole-1-carboxylic acid diethylamide (8l): The prod-
uct (54 mg, 97%) was obtained as
a
light colourless oil. 1H NMR
(400 MHz, CDCl3, 258C): d=7.72 (d, 3J7,6 =7.8 Hz, 1H; 7-H), 7.62 (d,
3J4,5 =8.2 Hz, 1H; 4-H), 7.28 (m, 1H; ArH), 7.23–7.15 (m, 2H; ArH),
4.42 (q, J=6.6 Hz, 1H; 1’-H), 3.55–3.40 (m, 4H; 2ꢂCH2), 3.31 (s, 3H;
OCH3), 1.61 (d, J=6.6 Hz, 3H; CH3), 1.24 ppm (t, J=7.0 Hz, 6H; 2ꢂ
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123.2, 121.4, 120.9, 120.1, 113.1, 72.8, 56.1, 42.4, 21.8, 13.4 ppm; IR (KBr
disc): n˜ =2979.0, 2934.2, 1676.8, 1449.9, 1422.3 cmÀ1; LRMS (ES): m/z:
calcd for C16H22N2O2: 274.2; found: 297.4 [M+Na]+, 243.4 [MÀOMe]+;
HRMS: m/z: calcd for C16H22N2O2Na: 297.1579; found: 297.1581
[M+Na]+.
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Acknowledgements
The Irish Research Council for Science, Engineering and Technology,
and Schering-Plough (Avondale) are acknowledged for financial support
to T.T. under the Enterprise Partnership Scheme.
[14] Three pumps were connected to a single THF reservoir that deliv-
ered controlled solvent flow into the injection loops.
[15] Commercial iPrMgCl·LiCl solution was filtered by using a 0.2 mm
pore size PTFE membrane to avoid potential reactor chip blockag-
es.
[16] The microreactors were washed with 1000 mL of solvent prior to the
automated injection of another set of reagents (see the Supporting
Information for details of parameters used). The minimum volume
of solvent being pumped through the system between two experi-
ments equalled the time between two injections ꢂ the lowest flow
rate used in the system.
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Received: November 30, 2009
Published online: April 22, 2010
6686
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Chem. Eur. J. 2010, 16, 6678 – 6686