Magnesiation of N-Heterocycles Using i-PrMgCl · LiCl and catalytic diisopropylamine

Article abstract of DOI:10.1080/00397911.2015.1090607

The direct magnesiation of various N-heterocyclic compounds with i-PrMgCl · LiCl and catalytic diisopropylamine allows for preparation of 2-substituted pyrroles, imidazole, indoles, and benzimidazoles, in moderate to good yields. The magnesiated substrates canreadily undergo a Kumada-type coupling with iodo-aryls in the presence of catalytic Pd(PPh3)4.

Full text of DOI:10.1080/00397911.2015.1090607

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Magnesiation of N-Heterocycles Using i-
PrMgCl.LiCl and Catalytic Diisopropylamine
W. Nxumalo & A. Dinsmore
To cite this article: W. Nxumalo & A. Dinsmore (2015): Magnesiation of N-Heterocycles
Using i-PrMgCl.LiCl and Catalytic Diisopropylamine, Synthetic Communications, DOI:
10.1080/00397911.2015.1090607
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1090607
View supplementary material
Accepted online: 12 Sep 2015.
Submit your article to this journal
Article views: 1
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [University of Cambridge]
Date: 16 September 2015, At: 21:41

Magnesiation of N-Heterocycles Using i-PrMgCl.LiCl and Catalytic
Diisopropylamine
W. Nxumalo1, A. Dinsmore2
1Department of Chemistry, University of Limpopo Turfloop campus, Limpopo, Sovenga,
South Africa 2School of Chemistry, University of the Witwatersrand, Johannesburg,
South Africa
Abstract
The direct magnesiation of various N-heterocyclic compounds with i-PrMgCl.LiCl and
catalytic diisopropylamine allows for preparation of 2-substituted pyrroles, imidazole,
indoles and benzimidazoles, in moderate to good yields. The magnesiated substrates can
readily undergo a Kumada-type coupling with iodo-aryls in the presence of catalytic
Pd(PPh3)4.
KEYWORDS: iPrMgCl.LiCl, Catalytic diisopropylamine, Kumada-type coupling,
Sulfonyl migration
INTRODUCTION
The use of magnesium amine bases has recently gained considerable attention, finding
applications in deprotonation of aryl,[1-4] heteroaryl[5-8] substrates, and metal-halogen
exchange.[9-12] Some of the magnesium amine bases e.g. TMPMgCl.LiCl, and
TMP2Zn·2MgCl2·2LiCl, are prepared from stoichiometric amount of the Grignard reagent
1

and the amine, and in some cases require the use of n-BuLi.[13] The presence of LiCl in
the magnesium amine bases has been reported to increase the basicity, solubility and
selectivity of these bases.[1,9] We reported the use i-PrMgCl with catalytic amine to
deprotonate N-phenylsulfonylpyrrole at the 2-position, followed by quenching with
various electrophiles.[6] Herein, we wish to report the use i-PrMgCl.LiCl with catalytic
amine to deprotonate N-sulfonylpyrrole, indole, imidazole and benzimidazole. Our
investigations employed approximately 1.33 M solution of i-PrMgCl.LiCl 1 prepared
according to literature methods.[7,10] We began by finding optimum conditions for
magnesiation using 1 and catalytic amine, in the iodination of N-phenylsulfonylpyrrole 2
at room temperature. Using 1.5 equivalents of 1 and 10 mol% TMP gave the iodopyrrole
3 in 19% yield. The magnesiation occurred exclusively at the most acidic proton at the 2-
position. Similar results were observed in our previous studies[6] and during
deprotonation using n-BuLi.[14] Replacing TMP with diisopropylamine (DA) gave 3 in
65% yield. These results suggest that catalytic DA is superior to TMP, further optimizing
conditions were done using DA. Reducing the equivalence of DA to 5 mol% gave 3 in
48% yield. Reducing the amount of Grignard reagent to 1.2 equivalents and keeping the
amine at 10 mol%, gave 3 in 40% yield. Increasing the Grignard reagent to 1.8
equivalents and keeping the amine at 10 mol% gave 3 in 82% yield, which is an
improvement to our previously reported results[6] (Table 1). As with our previous
findings,[6] no iodopyrrole was detected when no amine was added. Employing 1.5
equivalents of 1 and stoichiometric amount of the amine gave no yield improvement of
iodopyrrole (68% yield), however the magnesiation time was reduced to 12 hours.
2

Increasing the equivalence of 1 and stoichiometric amounts of DA to 1.8 did not improve
the yields significantly (72% yield).
RESULTS AND DISCUSSION
We selected 1.8eq of 1 and 10% DA to be our optimum conditions and expanded the
scope with other substrates and electrophiles. N-Phenylsulfonylpyrrole 2 was readily
treated with other electrophiles to yield 2-substituted pyrrole in moderate to good yields
(Table 2, entry 1-3). The optimized conditions were readily extended to other N-
heterocyclic compounds and were found to proceed smoothly with imidazole (entry 4),
indole (entry 7) and benzimidazole (entry 8 and 9). Phenylsulfonyloxy was found to be
better protecting/directing group on the pyrrole ring when compared to N,N-
dimethylsulfamoyl protecting group (entries 1&3 vs entries 5&6).
When reacting the magnesiated pyrroles with benzonitrile, unexpected Schiff-base ligand
products were obtained (entries 3 and 6) that resulted from the 1,4 N- to Nsulfonyl
migration. Sulfonyl migration has been reported to occur either via intra- or
intermolecular pathways.[15-17] To investigate which mechanism the N to N- migration
followed, a cross-over experiment was conducted. An equimolar molar mixture of 2-
phenyl-N-toluenesulfonylpyrrole 16 and N-phenylsulfonypyrrole 2 was subjected to our
optimized conditions and quenched with benzonitrile. HREI mass analysis of the crude
gave mass peaks M+ 310 (which correspond to 5), and a peak at M+ 400 (corresponding
to 17). No peaks at m/z 324 and 386, corresponding to the cross-coupled products, were
observed. The results suggest that the 1,4 N- to Nsolfonyl migration occurs via an
3

intramolecular pathway. An intramolecular pathway was also reported on the 1,4 N- to
O- sulfonyl migration during benzo[b]carbazole synthesis.[15] The TMS-Cl and Me-I
electrophiles were also investigated with 2, and afforded the desired 2-substituted pyrrole
in moderate yield as judged by GC and NMR. However, the products could not be
separated from trace amount of unreacted starting material due to identical Rf values.
The magnesiated substrates can readily undergo a Kumada-type coupling with
iodobenzene in the presence of catalytic Pd(PPh3)4 to give 2-aryl substituted pyrrole and
indole (Scheme 2). We were unable to extend our methodology to quinoline 20 and
pyridine 22 substrates. Instead of obtaining the desired 2-iodo products, 2-
isopropylquinoline 21 (Scheme 3a) and 2-isopropylpyridine 23 (Scheme 3b), were
isolated.
The results suggest that i-PrMgCl.LiCl acted as a nucleophile in a similar manner
observed from the Tschitschibabin reaction.[18] Similarly, subjecting ethyl- 3-
chlorobenzoate 24 to our optimised conditions resulted in the formation of 3-(3-
chlorophenyl)-2,4- dimethylpentan-3-ol 25 instead of the desired iodo product (Scheme
3c). These results suggest that the Grignard reagent is reactive toward electrophiles but
not basic enough to deprotonate, and hence should be converted into the less reactive and
more basic magnesium amide base.
We have demonstrated that the magnesiation of various N-heterocyclic compounds with
i-PrMgCl.LiCl and catalytic diisopropylamine allows for preparation of 2-substituted
4

pyrroles, imidazole, indoles and benzimidazoles. The magnesiated substrates can readily
undergo a Kumada-type coupling with iodo-aryls in the presence of catalytic Pd(PPh3)4 to
give 2-aryl substituted substrates.
EXPERIMENTAL
Typical Procedure
To an N-heterocycle was added a solution of i-PrMgCl.LiCl (1.33 M, 1.8 eq. with
respect to N-heterocycle, in THF) and (iPr)2NH (0.1 with respect to N-heterocycle).
The mixture was stirred at room temperature under an argon atmosphere for 18
hours. An electrophile was added and the mixture was stirred at room temperature for
20 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl (20
mL), and a saturated Na2S2O3 solution (20 mL) in the case of I2 as an electrophile.
SUPPLEMENTAL MATERIAL
Full experimental details for this article can be accessed on the publisher’s website.
REFERENCES
1.
2.
Lin, W. W.; Baron, O.; Knochel, P. Org. Lett. 2006, 8, 5673-5676.
Monzon, l.; Tirotta, I.; Nishii Y.; Knochel P. Angew. Chem. Int. Ed. 2012, 51,
10624-10627.
3.
4.
Henderson, K. W.; Kerr, W. J. Chem. Eur. J. 2001, 7, 3430-3437.
Nafe J.; Herbert S.; Auras F.; Karaghiosoff K.; Bein T.; Knochel P. Chem. Eur. J.
2015, 21, 1102-1107.
5

5.
Kondo, Y.; Yoshida A.; Sakamoto T. J. Chem. Soc., Perkin Trans.1996, 2331-
2332.
6.
Dinsmore, A.; Billing, D. G.; Mandy, K.; Michael, J. P.; Mogano, D.; Patil S.
Org. Lett. 2004, 6, 293-296.
7.
8.
Ren, H.; Krasovski, A; Knochel, P. Chem. Commun. 2005, 543-545.
Petersen, T. P.; Becker, M. R.; Knochel, P. Angew. Chem. Int. Ed. 2014, 53,
7933-7937.
9.
Krasovski, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45,
2958-2961.
10.
11.
Ren, H.; Krasovski, A.; Knochel, P. Org. Lett. 2004, 6, 4215-4217.
Manolikakes, S. M.; Ellwart, M.; Stathakis, C. I.; Knochel, P. Chem. Eur. J. 2014,
20, 12289-12297.
12.
13.
14.
15.
Nakamura, K.; Tamba, S.; Sugie, A.; Mori, A. Chem. Lett. 2013, 42, 1200-1202.
Mosrin, M.; Knochel, P. Org. Lett. 2009, 8, 1837-1840.
Chadwick, D. J.; Ngochindo, R. I. J. Chem. Soc., Perkin Trans. I. 1984, 481-486.
Boominathan, S. S. K.; Senadi, G. C.; Vandavasi, J. K.; Chen, J. Y.; Wang, J.
Chem. Eur. J. 2015, 21, 3193-3197.
16.
17.
Yu, X.; Xin, X.; Wan, B.; Li, X. J. Org. Chem. 2013, 4895-4904.
Ji, F.; Peng, H.; Zhang, X.; Lu, W.; Liu, S.; Jiang, H.; Liu, B.; Yin, B. J. Org.
Chem. 2015, 80, 2090-2102.
18.
Tschitschibabin, A. E.; Rjasanzew, M. D. J. Russ. Phys. Chem. Soc. 1915, 47,
1571-1573.
6

Table 1 Iodination of N-Phenylsulfonylpyrrole
iPrMgCl.LiCl eq. Amine (mol %) Time (hrs) Yield (%)a
1.5
1.5
TMP (10)
DA (10)
DA (5)
DA (10)
DA (10)
-
18
18
18
18
18
18
12
10
19
65
48
40
82
0
1.5
1.2
1.8
1.8
1.5
DA (100)
DA (100)
68
72
1.8
a: Isolated yields
7

Table 2 Generation of Magnesiated N-heterocycles and their trapping with electrophiles.a
Entry Substrate
1
Electrophile Product
l2
Yieldb
82
2
3
2
2
DMF
60
60
4
l2
78
5
6
DMF
48
45
8
7
8
l2
85
85
l2
8

9
13
DMF
70
a: conditions: To an N-heterocycle was added a solution of i-PrMgCl.LiCl (1.33 M, 1.8
eq. with respect to N-heterocycle, in THF) and (iPr)2NH (0.1 with respect to N-
heterocycle). The mixture was stirred at room temperature under an argon atmosphere
for 18 hours. An electrophile was added and the mixture was stirred at room temperature
for 20 minutes.
b: isolated yields
9

Scheme 1. Cross-over experiment
10

Scheme 2. Kumada-type coupling reactions
11

Scheme 3.
12