Stabilizing N-tosyl-2-lithioindoles with bis(N,N′-dimethylaminoethyl) ether-a non-cryogenic procedure for lithiation of N-tosylindoles and subsequent addition to ketones

Article abstract of DOI:10.1016/j.tetlet.2009.07.120

A practical procedure suitable for large scale lithiation of N-tosylindoles and subsequent addition to ketones is described. Bis(N,N′-dimethylaminoethyl) ether was found to stabilize 2-lithio-N-tosylindole 1A at -25 °C [The temperatures cited are internal

Full text of DOI:10.1016/j.tetlet.2009.07.120

Tetrahedron Letters 50 (2009) 5667–5669
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Tetrahedron Letters
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Stabilizing N-tosyl-2-lithioindoles with bis(N,N0-dimethylaminoethyl)
ether—a non-cryogenic procedure for lithiation of N-tosylindoles and
subsequent addition to ketones
*
Jiang-Ping Wu , Sanjit Sanyal, Zhi-Hui Lu, Chris H. Senanayake
Department of Chemical Development, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical procedure suitable for large scale lithiation of N-tosylindoles and subsequent addition to
ketones is described. Bis(N,N0-dimethylaminoethyl) ether was found to stabilize 2-lithio-N-tosylindole
1A at ꢀ25 °C [The temperatures cited are internal temperatures unless otherwise stated]. Addition of this
reagent allows the lithiation of N-tosyl indoles and subsequent addition to ketones to operate at ꢀ25 °C, a
temperature suitable for large scale reactions.
Received 14 May 2009
Revised 18 July 2009
Accepted 21 July 2009
Available online 25 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The nucleophilic addition of 2-lithiated indoles to electrophiles
provides a straightforward method for the functionalization of in-
dole analogs at the 2-positions (Fig. 1).1 Typically, an indole deriv-
ative equipped with a suitable directing group, such as N-tosyl or
N-Boc group, is treated with a lithiating reagent at ꢀ70 °C,10a and
the resulting 2-lithioindole species is treated with an electrophile
to produce a functionalized indole analog. The requirement of
low temperatures, mostly due to the instability of the lithiated
intermediates, often limits the application of this reaction on large
scale. An ‘in situ trapping’ method specifically addressing this issue
was recently reported.2 In this approach, N-Boc-indoles are lithiat-
ed at 0 °C in the presence of silylchlorides or boronate esters,
which react with the lithiated intermediates immediately after
they are generated, thus preventing the decomposition of the lat-
ter. Another method involves the more stable 2-magnesioindoles,
which can be generated at room temperature.3
Figure 1. Reaction of 2-lithioindoles with electrophiles.
mixture at ꢀ70 °C consisted of 76%10b of the desired product 2a, 6%
of the starting material 1 and other minor peaks (Table 1, entry 1).
In contrast, the HPLC trace of the reaction mixture at ꢀ25 °C
showed multiple peaks,5 with 43% of compound 2a and 11% of
the starting material 1 (Table 1, entry 2). Apparently, a significant
amount of the lithiated intermediate 1A decomposed at ꢀ25 °C.
To stabilize the lithiated intermediate, we considered using che-
lating diamines, such as N,N,N0,N0-tetramethylethylenediamine
(TMEDA), as additives.6 Thus, the reaction at ꢀ25 °C was repeated
in the presence of 1.5 equiv of TMEDA. To our disappointment, the
reaction profile was similar to that without the additive, with 46%
of 2a (Table 1, entry 3).
Recently we required a procedure for the large scale preparations
of an indole analog that contains a 2-dialkylhydroxymethyl moiety
(structure 2, Fig. 2). A procedure developed by our colleagues in
the research division involves treatment of N-tosyl-5-bromoindole
(1) with lithium diisopropylamide (LDA) at ꢀ70 °C followed by addi-
tion of an appropriate ketone. Though convenient on small scales,
the low temperature required presented difficulty for scale up. In
the absence of applicable literature solutions,4 we set out to investi-
gate if the lithiation-addition sequence can be modified to operate at
ꢀ25 °C or higher to suit large scale operations.
The report that bis(N,N0-dimethylaminoethyl) ether effectively
modulates the reactivity of Grignard reagents7 prompted us to test
this reagent as the additive. Thus, bis(N,N0-dimethylaminoethyl)
Br
Br
R1
Br
ketone
We started our studies by treating compound 1 with LDA at
ꢀ70 °C and ꢀ25 °C, respectively. The resulting mixtures were then
treated separately with 2-butanone. The HPLC trace of the reaction
LDA
Li
R2
HO
N
N
N
Ts
Ts
Ts
1
1A
2
2a
, R1 = Me, R2=Et
* Corresponding author.
E-mail address: jiang_ping.wu@boehringer-ingelheim.com (J.-P. Wu).
Figure 2. Lithiation of N-tosyl 5-bromoindole (1) and addition to ketones.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.120

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J.-P. Wu et al. / Tetrahedron Letters 50 (2009) 5667–5669
Table 1
Screening of reaction conditions
Entry
Additive
Temperature (°C)
HPLC puritya (%)
2a
1
1
2
3
none
none
TMEDA
(1.5 equiv)
ꢀ70
ꢀ25
ꢀ25
76
43
46
6
11
9
Figure 3. Control experiments using PhCHO and DMF as the electrophiles.
O
N
4
ꢀ25
79
62
11
20
Further experiments focused on the reaction at ꢀ25 °C, using
different ketone electrophiles and with 1.5 equiv of bis(N,N0-
dimethylaminoethyl) ether. The initial set of experiments was con-
ducted in THF. As shown in Table 2, reactions involving aliphatic
ketones gave good yields (Table 2, entries 1–4). However, when
acetophenone (1) was tested, the reaction gave 38% of the desired
product 2 and 60% of the starting material 1. Change of reaction
solvent to 4:1 toluene–THF improved the result. In this system,
the reaction produced 81% of product 2e with 10% of the starting
material 1 (Table 2, entries 5 and 9). Another set of experiments
showed that the 4:1 toluene–THF solvent system was suitable with
other ketones as well (Table 2, entries 6–8).
N
N
(1.5 equiv)
O
N
5
0
(1.5 equiv)
a
HPLC area percentage at 254 nM.
ether (1.5 equiv) was added to a solution of compound 1 in THF.
The solution was then treated with LDA at ꢀ25 °C for 30 minutes
before 2-butanone was added. The reaction mixture was shown
by HPLC to contain 79% of product 2a and 11% of compound 1 (Ta-
ble 1, entry 4), indicating that the decomposition of the lithiated
intermediate was largely suppressed.
Encouraged by this result, we further increased the reaction
temperature to 0 °C. However, the reaction mixture at this temper-
ature contained more starting material 1 (20%), with 62% of the de-
sired compound 2a (Table 1, entry 5).
It was noticed that all the reactions involving ketone electro-
philes contained residual starting material 1 that could not be fur-
ther converted with excess amount of LDA. To determine the
source of the residual starting material, two control experiments
were carried out using the non-enolizable electrophiles phenyl
aldehyde (PhCHO) and dimethylformamide (DMF). Compound 1
was lithiated with LDA in the presence of 1.5 equiv of bis(N,N0-
dimethylaminoethyl) ether at 0 °C, and the lithiated intermediate
was then reacted, separately, with PhCHO and DMF. The reactions
produced 97% and 93% of products 3 and 4, respectively, with <3%
of the starting material 1 observed. These results showed that the
unreacted starting material involving ketone electrophiles is due to
ketone enolizations, and that the lithiated intermediate 1A is stabi-
lized by bis(N,N0-dimethylaminoethyl) ether even at 0 °C (Fig. 3).
A general experimental procedure follows.8 To a solution of
compound 1 (1.0 equiv) in 4:1 toluene–THF (10 mL of solvent mix-
ture per gram of starting material 1) under N2 was added bis(N,N0-
dimethylaminoethyl) ether (1.5 equiv). The solution was cooled to
ꢀ25 °C. LDA (1.2 equiv, 1.8 M in heptane/ethylbenzene/THF, Al-
drich) was added at such a rate that the reaction temperature does
not exceed -20 °C. After 30 min, a ketone (2.0 equiv) was added.
The mixture was stirred at ꢀ25 °C for 15 min and then warmed up
to room temperature over 1 h. The reaction was quenched with 1 N
HCl at 0 °C and the reaction mixture was extracted with EtOAc. The
organic layer was washed with saturated NaCl, dried over Na2SO4,
and concentrated. The crude product was further purified by either
silica gel chromatography or crystallization to give product 2.
To summarize, we found that bis(N,N0-dimethylaminoethyl)
ether can stabilize 2-lithiated N-tosyl lithioindole species. Addition
of this reagent allows the lithiation of N-tosyl indoles and subse-
quent addition to ketones to be carried out at ꢀ25 °C, a tempera-
ture suitable for large scale preparations. Though not fully
explored, the procedure described may find applications when
other electrophiles are involved and when non-cryogenic temper-
atures are desirable.9
Table 2
Lithiation of 1 and subsequent reaction with ketones in the presence of bis(N,N’-
dimethylaminoethyl) ether
Entry
R1, R2
Solvents
THF
HPLC Purity (%) of 2e,f
Yield (%), product
1
2
3
4
5
6
7
8
9
Me, Me
Me, Et
–(CH2)3–
–(CH2)5–
Ph, Me
Me, Me
Me, Et
–(CH2)5–
Ph, Me
74
79
82
62
38d
69
76
73
81
60a, 2b
71b, 2a
65b, 2c
48b, 2d
35a, 2e
68a, 2b
71b, 2a
64b, 2d
61c, 2e
4:1 Tol–THF
a
Purified by silica gel chromatography using hexane–EtOAc as the eluting
solvents.
b
c
d
e
f
Purified by crystallization from MeOH–H2O.
Purified by crystallization from acetone–hexane.
Reaction mixture contains 60A% of the starting material 1.
HPLC area percentage at 254 nM.
Supplementary data
The major by-product in these reactions is the starting material 1, typically 10–
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.120.
15% in the reaction mixtures.

J.-P. Wu et al. / Tetrahedron Letters 50 (2009) 5667–5669
5669
6. The ‘stabilizing’ effects of TMEDA toward organolithium species are well
documented, though the mechanism of these effects has been the topics of
much discussion, see: (a) Shapiro, R. H. Org. React. 1976, 23, 405; (b) Collum, D.
B. Acc. Chem. Res. 1992, 25, 448–454; (c) Seebach, D. Angew. Chem., Int. Ed. Engl.
1988, 27, 1624–1654.
7. Wang, X.-J.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy, D.; Senanayake, C. H. Org.
Lett. 2005, 7, 5593–5595.
8. (a) All reactions were run under nitrogen atmosphere in oven-dried flasks.
References and notes
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(b) Gharpure, M.; Stoller, A.; Bellamy, F.; Firnau, G.; Snieckus, V. Synthesis 1991,
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(d) Ziegler, F. E.; Spitzner, E. B. J. Am. Chem. Soc. 1973, 95, 7146–7149; (e)
Sundberg, R. J.; Parton, R. L. J. Org. Chem. 1976, 41, 163–165; (f) Katritzky, A. R.;
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applications, see: (g) Zhao, S.; Gan, T.; Yu, P.; Cook, J. M. Tetrahedron Lett.
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4. (a) The ‘in situ trapping’ approach described in Reference 2 cannot be applied
to our situation due to the reactivity of ketones toward LDA. (b) The procedure
described in reference 3 was investigated using 2-butanone as the electrophile.
No desired addition product was observed, likely due to ketone enolization
under the reaction conditions.
(b) The examples in Tables
1 and 2 were run on scales of 2 g to 10 g.
(c) Solvents used were commercial anhydrous solvents. (d) Bis(N,N0-
dimethylaminoethyl) ether was purchased from Aldrich and dried over
4 Å molecular sieves to KF <300 ppm. Other reagents were used as
purchased.
9. N-Boc indoles are not suitable substrates. When N-Boc 5-bromoindole was
treated with LDA at ꢀ25 °C followed by addition of 2-butanone, multiple peaks
were observed on HPLC, with <5A% of the desired addition product.
5. In the absence of bis(N,N0-dimethylaminoethyl) ether, the HPLC trace of the
reaction mixtures at ꢀ25 °C showed several pronounced peaks not fully
identified. LC–MS analysis suggested that some peaks correspond to structures
I and II. These side products were mostly suppressed by the addition of
bis(N,N’-dimethylaminoethyl) ether.
10. (a) The temperatures cited are internal temperatures unless otherwise stated.
(b) All HPLC purities are area percentage measured at 254 nM.