Structurally-defined direct C-magnesiation and C-zincation of N-heterocyclic aromatic compounds using alkali-metal-mediated metallation

Article abstract of DOI:10.1039/b704362g

Demonstrating direct synergic "low polarity metallation", 1-methylindole is C-magnesiated by (TMEDA)₂·Na ₂MgBu₄ and C-zincated by (TMEDA)·Na( ^tBu)(TMP)Zn(^tBu), and 1-methylpyrrole is C-zincated by the same reagent, with all three metal products successfully crystallographically characterised. The Royal Society of Chemistry.

Full text of DOI:10.1039/b704362g

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Structurally-defined direct C-magnesiation and C-zincation of
N-heterocyclic aromatic compounds using alkali-metal-mediated
metallation{
Ben Conway, Eva Hevia,* Alan R. Kennedy and Robert E. Mulvey*
Received (in Cambridge, UK) 22nd March 2007, Accepted 24th April 2007
First published as an Advance Article on the web 4th May 2007
DOI: 10.1039/b704362g
Demonstrating direct synergic ‘‘low polarity metallation’’,
-methylindole is C-magnesiated by (TMEDA) ?Na MgBu
(TMEDA)?Na( Bu)(TMP)Zn( Bu),
demonstrations of the power of AMMM have come with
6
metallocenes (ferrocene can be fourfold magnesiated ) and of
1
2
2
4
t
t
and
C-zincated
by
AMMZ with anilines (N,N-dimethylaniline undergoes zincation
7
selectively at the meta site ). In this communication we report the
and 1-methylpyrrole is C-zincated by the same reagent,
with all three metal products successfully crystallographically
characterised.
application of AMMM and AMMZ towards N-heterocyclic
aromatic compounds and in doing so reveal the first directly
C-magnesiated indole and C-zincated indole and pyrrole.
As vehicles for effecting C-metallation of aromatic compounds,
magnesium and zinc reagents are definitely in the slow lane due to
their low polarity and low reactivity power. Racing in the fast lane
and undisputed champions of metallation are the high polarity,
highly reactive lithium reagents which depending on the degree of
difficulty of the specific lithium–hydrogen exchange manoeuvre
can be administered in the form of LICKOR (alkyllithium
compounds co-complexed with potassium tert-butoxide) super-
An important structural component in many pharmaceutical
agents, the indole ring system is probably the most widely
8
distributed heterocycle in nature. Since the parent compound,
indole, has an acidic N–H bond which can be readily converted to
N–metal, we selected the N-substituted indole, 1-methylindole, 1,
9
for an attempt at C-magnesiation using AMMM. Significantly,
Sakamoto and co-workers had previously reported that 1 fails to
i
react with the magnesium amide base ‘‘Mg(NPr
)
’’ at elevated
2
2
1
bases, pure alkyllithium compounds, or lithium amides. To access
temperature though success was more forthcoming with the
1
0
C-magnesiated or C-zincated aromatic compounds one would
normally have to prepare C-lithiated intermediates beforehand
then carry out a second reaction (a metathesis) with a metal halide
activated 1-phenylsulfonylindole. In our attempt (Scheme 1), 1
was subjected to the TMEDA-activated ‘‘highly coordinated’’
1
1
2 2 4
sodium tetraalkylmagnesiate ‘‘(TMEDA) ?Na Mg(Bu) ’’ in hex-
(
commonly RMgX or ZnX ) or some other salt. While this
2
ane solution (see ESI{). As this ‘ate has four (potentially) basic
limbs, the indole : base stoichiometry employed was 4 : 1. This
stoichiometry proved to be ideal as the crystalline product of the
reaction in an (isolated) yield of 68% was the disodium tetraindol-
2-ylmagnesiate 2, as determined by solution NMR spectroscopy
and X-ray crystallography. From the NMR data (see ESI{),
metallation at the 2-position of the indole ring was established by
metathetical approach has been successful over a broad range of
aromatic substrates it does nonetheless suffer from certain severe
limitations. Most incapacitating is the intolerance of the method to
many functional groups (esters, ketones, nitriles, etc.) caused by
the strong basicity of lithium reagents and/or the high instability of
the generated aryllithiums. Another complication is that the use of
ionic salts often restricts the range of solvents available for such
reactions with cheap hydrocarbons and arenes forsaken in favour
of more expensive polar substitutes (commonly THF). Direct one-
step magnesiation and zincation methods avoiding indirect two-
step metathesis reactions would therefore be advantageous. In that
regard Knochel and co-workers have recently pioneered the use of
1
the absence of a 2-CH H resonance (found at 6.46 ppm in the
starting indole) and the large downfield chemical shift of the 2-C
13
C resonance (from 129.05 ppm in the starting indole to
181.11 ppm in 2). The molecular structure of 2{ (Fig. 1) confirmed
2
bases of empirical formula ‘‘R NMgCl?LiCl’’ (these could be
2
labelled ‘‘Turbo’’ Hauser bases ) which can directly magnesiate
various aromatic and heteroaromatic compounds in THF
3,4
solution. We have recently also introduced the concepts of
alkali-metal-mediated magnesiation (AMMM) and zincation
5
AMMZ). Here the alkali metal is a passenger (albeit an essential
(
one), while the magnesium or zinc atoms, under anionic ‘ate
activation, occupies the driver’s seat as these metallations
are strictly Mg–H or Zn–H exchange reactions. Spectacular
WestCHEM, Department of Pure and Applied Chemistry, University of
Strathclyde, Glasgow, UK G1 1XL. E-mail: r.e.mulvey@strath.ac.uk
{ Electronic supplementary information (ESI) available: Full details of
syntheses and spectroscopic characterisation. See DOI: 10.1039/b704362g
Scheme 1 Synthesis of tetraindol-2-ylmagnesiate 2 and its cross-coupling
reaction with iodobenzene.
2
864 | Chem. Commun., 2007, 2864–2866
This journal is ß The Royal Society of Chemistry 2007

View Article Online
Scheme 2 Synthesis of neutral zincoindole 4 and pyrro-2-ylzincate 6.
t
Zn( Bu)
ESI{). The detection of the coproduct ‘‘(TMEDA)Na
(TMP)
2
2
-
Fig. 1 Molecular structure of 2 with hydrogen atoms omitted for clarity,
…
showing Na p-C interactions as dashed lines. In all figures, ellipsoids are
2
’’ in solution from NMR spectra (ESI{), signifies the
drawn at the 50% probability level.
reaction is an auto-dismutation (maximum yield of 4 possible is
thus 50%) of a type seen before in related lithium TMP–zincate
1
6
reactions with ferrocene. NMR spectra of 4 (ESI{) show similar
features to those of 2 with an absent 2-C H resonance and a large
that the metallation was a magnesiation with Mg(1) occupying the
1
2-positions [C(1), C(10), C(25), C(34)] of the four indolyl rings
13
downfield chemical shift of the (zincated) 2- C resonance (at
77.23 ppm: 3.88 ppm less downfield than the corresponding
˚
(mean Mg–C bond length, 2.216 A) and like the outgoing H
1
atoms, lying essentially co-planar with the aryl planes. This is
magnesiated resonance in 2). Lacking Na atoms, the molecular
structure of 4{ (Fig. 2) simplifies in comparison to that of 2, being
mononuclear with a tetrahedrally-(N 6 2; C 6 2)-coordinated
zinc centre. The narrow bite of TMEDA [N(3)–Zn(1)–N(4),
achieved with a modest distortion of the central MgC
4
tetrahedron
[range of CMgC bond angles, 103.58(8)–127.08(8)u; mean,
109.32u]. In contrast to the predominately covalent, s-nature of
these Mg–C bonds, the Na atoms engage in more electrostatic
84.26(7)u] and the requirement to keep the indolyl rings wide apart
cation–p interactions with the indolyl system. Sitting well outside
[C(1)–Zn(1)–C(10), 129.68(8)u] cause this tetrahedron to distort
of the indolyl planes (at distances of 2.570(2), 2.576(2), 2.595(2)
2
and 2.532(2) A) each Na interacts in a g -manner with the
(mean bond angle at Zn, 107.91u). There are no C-zincated indole
structures available for a direct comparison with 4, but comparing
˚
its mean Zn–C bond length (2.003 A) with that of its Mg–C
˚
(deprotonated) 2-C and (proton-bearing) 3-C atoms of two indolyl
˚
ligands [range of lengths: 2.587(2)–2.856(2) A]. Interestingly, some
˚
counterpart in 2 (2.216 A) reveals a significant difference of
Na–3-C contacts are shorter than their 2-C counterparts [e.g.
˚
.213 A. This shortened, strengthened metal–C bond in the case of
0
˚
˚
Na(2)–C(35), 2.662(2) A; Na(2)–C(34), 2.854(2) A], a mark of the
Na atoms engaging more with the p-surface than with the 2-C lone
pair. Bidentate TMEDA ligands complete the Na coordination
t
Zn may, in combination with bulky TMP and Bu ligands, be a
key factor in the dismutation of the putative intermediate
t
‘[(TMEDA)?Na(m-indol-2-yl)(m-TMP)Zn( Bu)]’’. Again as in 2,
‘
˚
spheres [range of Na–N bond lengths: 2.416(2)–2.489(2) A]. The
…
Na p interactions must contribute significantly to the non-
the Zn centre in 4 sits in the same plane as the aromatic rings.
t
Interestingly when we mixed together 1-methylindole, Bu Zn, and
…
…
˚
linearity of the Na Mg Na vector [130.85(3) A]. Though new for
2
TMEDA in hexane solution but omitted NaTMP, no reaction
with the indole was observed. This implies that although product 4
is a single metal complex, a mixed-metal synergy is required for its
formation.
…
…
indolyl, the Na Mg Na motif is known for other ligand systems
12
2 2
including enolato in [(TMEDA) ?Na Mg{OC(LCH
2 4
)Mes} ],
where it is much closer to linearity (167.70u). There are no
precedents for C-magnesiated indole structures and only one
To ascertain whether the steric bulk of bicyclic 1-methylindole
contributes to the said dismutation process we repeated the
AMMZ reaction with monocyclic 1-methylpyrrole, 5 (Scheme 2).
1
3
C-lithiated, [3-iodo-2-lithio-1-methylindole?(THF)
2
], which exhi-
bits a dimeric (Li–2-C) ring arrangement markedly different from
2
14
that of 2. Mongin and co-workers recently reported the first
transition metal catalysed cross-coupling reactions of lithium
arylmagnesiates, that provide good access to heteroarylquinolines.
Using a similar approach, we reacted (Scheme 1) the tetraindol-2-
ylmagnesiate 2 with iodobenzene under palladium catalysis using
[PdCl (dppf)] [dppf is 1,19-bis(diphenylphosphino)ferrocene]. This
2
produced 2-phenyl-1-methylindole in a high isolated yield of 84%
(
ESI{).
Turning to AMMZ, on account of its exceptional zincating
properties the heteroleptic alkylamido reagent [(TMEDA)?Na(m-
t
t
15
Bu)(m-TMP)Zn( Bu)], 3, was employed as the base in a reaction
with 1-methylindole (Scheme 2). Direct zincation was easily
achieved under mild conditions in hexane solution, but manifested
not in a mixed-metal ‘ate (akin to magnesiate 2), but in the neutral
bis-indol-2-yl zinc complex 4 (isolated crystalline yield, 34%, see
Fig. 2 Molecular structure of 4 with minor disorder component of
TMEDA ligand and hydrogen atoms omitted for clarity.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 2864–2866 | 2865

View Article Online
2
refinement to convergence on F gave R = 0.0496 (F, 6015 obs. data only)
2
and R
w
= 0.1161 (F , all data), GOF = 1.015. Crystal data for 4:
Zn, M = 441.91, orthorhombic, space group P2 , a =
2.2666(2), b = 13.1709(2), c = 14.3918(2) A, V = 2325.17(6) A , Z = 4, l =
C H
24 32
N
4
r
1 1 1
2 2
3
˚
˚
1
0
R
4
21
˚
.71073 A, m = 1.073 mm , T = 123 K; 54726 reflections, 5323 unique,
2
int = 0.064; final refinement to convergence on F gave R = 0.0309 (F,
616 obs. data only) and R
2
= 0.0601 (F , all data), GOF = 1.024. Flack
w
parameter 20.019(10). The TMEDA group is modeled as disordered over
two sites. Crystal data for 6: C24 NaZn, M = 482.03, orthorhombic,
space group P2 , a = 10.9318(3), b = 14.4362(4), c = 17.5664(5) A, V =
H
49
N
4
r
˚
1 1 1
2 2
3
21
˚ ˚
772.22(13) A , Z = 4, l = 0.71073 A, m = 0.918 mm , T = 123 K; 24509
2
reflections, 6275 unique, Rint = 0.032; final refinement to convergence on F
gave R = 0.0271 (F, 5631 obs. data only) and R = 0.0560 (F , all data),
w
2
2
GOF = 1.057. Flack parameter 0.514(8). CCDC 641398–641400. For
crystallographic data in CIF or other electronic format see DOI: 10.1039/
b704362g
1
M. Schlosser, Organometallics in Synthesis, Wiley, Chichester, 2nd edn,
002, ch. 1. For an authoritative review of hydrogen-metal interconver-
2
sion reactions in aromatic systems, see: M. Schlosser, Angew. Chem., Int.
Ed., 2005, 44, 376.
Fig. 3 Molecular structure of 6 with hydrogen atoms omitted for clarity,
…
2
2 Hauser bases are R NMgX compounds, see: C. R. Hauser and
H. G. Walker, Jr., J. Am. Chem. Soc., 1947, 69, 295. The turbo tag is by
analogy with ‘‘Turbo Grignards’’ used for enhanced metal–halogen
exchange reactivity, see: A. Krasovskiy and P. Knochel, Angew. Chem.,
Int. Ed., 2004, 43, 3333.
showing Na p-C interactions as dashed lines.
Direct regioselective (at the 2-position) C-zincation was again
accomplished, manifested in the sodium heterotrianionic zincate 6
1
3 A. Krasovskiy, V. Krasovskaya and P. Knochel, Angew. Chem., Int.
Ed., 2006, 45, 2958.
(ESI{). NMR spectra of 6 revealed the absence of the 2-C- H
4
5
W. Lin, O. Baron and P. Knochel, Org. Lett., 2006, 8, 5673.
R. E. Mulvey, Organometallics, 2006, 25, 1060.
resonance (at 6.25 ppm in 5) and a large downfield shift of the
13
2
- C-Zn resonance (from 109.04 ppm in 5 to 144.27 ppm in 6)
6 P. C. Andrikopoulos, D. R. Armstrong, W. Clegg, C. J. Gilfillan,
E. Hevia, A. R. Kennedy, R. E. Mulvey, C. T. O’Hara, J. A. Parkinson
and D. M. Tooke, J. Am. Chem. Soc., 2004, 126, 11612.
1
7
(
ESI{). In the molecular structure of 6{ (Fig. 3), whilst collecting
the pyrrol-2-yl ligand (a product of alkyl deprotonation), the Zn
t
centre retains the bridging TMP and terminal Bu ligands of
7
D. R. Armstrong, W. Clegg, S. H. Dale, E. Hevia, L. M. Hogg,
G. W. Honeyman and R. E. Mulvey, Angew. Chem., Int. Ed., 2006, 45,
3775.
reagent 3, leading to a trigonal planar (1 6 N; 2 6 C)
coordination overall. Reflecting the steric constraints within 6
8 G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875.
The pK of N-methylindole in THF solution has been measured with
respect to lithiation, see: R. R. Fraser, T. S. Mansour and S. Savard,
9
a
(which would be magnified in the putative indolyl analogue), the
Zn–C (pyrrolyl) bond is slightly longer than its counterparts in 4
Can. J. Chem., 1985, 63, 3505.
˚
2.0527(18) A vs. 2.003 A] even though this runs counter to the Zn
˚
[
10 Note that magnesioindoles were not isolated in this study but reacted
in situ with electrophiles. See: Y. Kondo, A. Yoshida and T. Sakamoto,
J. Chem. Soc., Perkin Trans. 1, 1996, 2331.
in 6 having a lower coordination number (i.e. 3 vs. 4 in 4). Near in
˚
plane Zn–C (pyrrolyl) (0.244(4) A removed from the plane) and
11 P. C. Andrikopoulos, D. R. Armstrong, E. Hevia, A. R. Kennedy,
2
out of plane Na–g C(pyrrolyl) contacts [2.333(3) A removed from
˚
R. E. Mulvey and C. T. O’Hara, Chem. Commun., 2005, 1131.
12 E. Hevia, K. W. Henderson, A. R. Kennedy and R. E. Mulvey,
Organometallics, 2006, 25, 1778.
˚
˚
the plane: Na(1)–C(14), 2.772(2) A; Na(1)–C(15), 2.831(2) A] are,
as in 2 for the Na/Mg indolyl attachment, also present in 6. The
structure of 6 is completed by TMEDA N,N-attaching to Na.
In conclusion, the first structurally-defined direct
1
3 G. Boche, M. Marsch, J. Harback, K. Harms, B. Ledig,
F. Schubert, J. C. W. Lohrenz and H. Ahlbrecht, Chem. Ber., 1993,
126, 1887.
18
C-magnesiation and C-zincation reactions of N-heterocyclic
aromatic compounds, circumventing the need for an indirect
metathetical approach, have been demonstrated.
14 S. Dumouchel, F. Mongin, F. Tr e´ court and G. Qu e´ guiner, Tetrahedron
Lett., 2003, 44, 3877.
1
5 P. C. Andrikopoulos, D. R. Armstrong, H. R. L. Barley, W. Clegg,
S. H. Dale, E. Hevia, G. W. Honeyman, A. R. Kennedy and
R. E. Mulvey, J. Am. Chem. Soc., 2005, 127, 6184.
We thank the EPSRC (grant award nos. GR/T27228/01 and
GR/R81183/01) and the Royal Society (University Research
Fellowship to E. H.) for their generous sponsorship of this
research.
16 H. R. L. Barley, W. Clegg, S. H. Dale, E. Hevia, G. W. Honeyman,
A. R. Kennedy and R. E. Mulvey, Angew. Chem., Int. Ed., 2005, 44,
6018.
1
7 This is the first crystallographically characterised C-zincated pyrrole.
For a rare example of a C-lithiated pyrrole structure, see: W. Bauer,
G. M u¨ ller, R. Pi and P. v. R. Schleyer, Angew. Chem., Int. Ed. Engl.,
Notes and references
1986, 25, 1103.
{
Crystal data for 2: C48
group P2 /a, a = 15.8300(3), b = 16.8625(3), c = 17.9095(4) A,
b = 91.237(1)u, V = 4779.53(16) A , Z = 4, l = 0.71073 A, m =
H
64MgN
8
Na
2
, M
r
= 823.36, monoclinic, space
18 For related reactions with benzene, see: D. R. Armstrong, W. Clegg,
S. H. Dale, D. V. Graham, E. Hevia, L. M. Hogg, G. W.
Honeyman, A. R. Kennedy and R. E. Mulvey, Chem. Commun.,
2007, 598.
˚
1
3
˚
˚
21
0.096 mm , T = 123 K; 90776 reflections, 9374 unique, Rint = 0.084; final
2
866 | Chem. Commun., 2007, 2864–2866
This journal is ß The Royal Society of Chemistry 2007