Regio- and diastereoselective formation of some (η6-2-methylindoline)tricarbonylchromium(0) complex derivatives

Article abstract of DOI:10.1016/S0022-328X(01)00694-5

Complexation of 2-methylindoline 1 and its derivatives 2 and 3 with Cr(CO)₆ gave complexes 4-9. With the TIPS group attached to the nitrogen atom as in compound 3, the complexation was completely diastereoselective producing the endo complex 9.

Full text of DOI:10.1016/S0022-328X(01)00694-5

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Journal of Organometallic Chemistry 626 (2001) 233–242
www.elsevier.nl/locate/jorganchem
Regio- and diastereoselective formation of some
(h6-2-methylindoline)tricarbonylchromium(0) complex derivatives
M. Filomena D. Costa, M. Rute G. da Costa *, M.J. Marcelo Curto
Instituto Nacional de Engenharia e Tecnologia Industrial, Departamento de Tecnologia de Indu´strias Qu´ımicas, Estrada do Pac¸o do Lumiar 22,
1649-038 Lisbon, Portugal
Received 14 February 2000; accepted 22 January 2001
Abstract
Complexation of 2-methylindoline 1 and its derivatives 2 and 3 with Cr(CO)6 gave complexes 4–9. With the TIPS group
attached to the nitrogen atom as in compound 3, the complexation was completely diastereoselective producing the endo complex
9. Treatment of the metallated complexes 8 and 9 with 2-halobenzoyl chlorides as electrophiles allowed for totally regioselective
functionalisation at C(4), while the exo complex 6 was functionalised both at C(4) and C(7); with TMSCl and TIPSCl as
electrophiles, the endo complex 9 also exhibited minor exo benzylic substitution to give 25 and 27. Oxidative decomplexation of
the indoline complexes efficiently releases the free 4-substituted indolines. © 2001 Elsevier Science B.V. All rights reserved.
Keywords: Indolines; Arene complexes; Asymmetric synthesis; Chromium
strong influence upon the regiochemistry of indoline
reactions as is described in the literature [5,6].
1. Introduction
Tricarbonylchromium complexes are well known for
deprotonation of the exo benzylic proton; thus, in
The indoline nucleus is present as an heterocyclic
subunit in a wide range of natural products [1], in a
a-methylbenzylmethylether, 1,3-dihydro-benzo[c]furan,
indane and methylindoline tricarbonylchromium com-
plexes, metallation occurs at the benzylic position
[7a,d,8]. Introduction of substituents possessing a car-
bonyl functional group on the aromatic ring of indoline
having the benzylic positions blocked was carried out
by Oishi et al. using the chemistry of tricar-
bonylchromium complexes, but only poor regioselectiv-
ity was observed [9].
number of medicinally relevant compounds [1,2], photo
active devices, such as phototropic glass, non-linear
optical materials [3], and some chiral indoline deriva-
tives are excellent chiral catalysts for asymmetric syn-
theses [4]. The protecting group on the nitrogen has a
Due to the potential biological activity of indoline
derivatives bearing carbonyl functional groups
[1a,c,2a,e,f] there have been some attempts at their
synthesis [la,6a,l0].
One possible approach, which is the subject of this
paper, was envisaged utilising N-substituted (h6-2-
methylindoline)Cr(CO)3 as building blocks for the syn-
thesis of such indoline derivatives in which the steric
demand of the methyl group at C(2) as well as the
bulky nature of the group attached to the pyrrolidine
nitrogen atom have a profound effect upon the course
of the regio- and diastereoselectivity of those reactions.
Scheme 1. Reagents: Cr(CO)6, dibutyl ether–THF (10:1). Only the
relative stereochemistry indicated. *Complex 8 was obtained from 4.
* Corresponding author. Tel.: +351-217-165141; fax: +351-217-
168100.
E-mail address: rute.costa@mail.ineti.pt (M.R.G. da Costa).
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)00694-5

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M.F.D. Costa et al. / Journal of Organometallic Chemistry 626 (2001) 233–242
data are in agreement with Pigge’s data for these com-
plexes obtained by a different route [12a]. The stereo-
chemical assignment of 6 by X-ray analysis was also
carried out by Pigge.
Treatment of the exo complex 6 with n-BuLi fol-
lowed by quenching with an excess of various 2-X-ben-
zoyl chlorides gave red solutions for the separable
regioisomeric pairs: 10/11 (X=F), 12/13 (X=Cl) and
14/15 (X=Br) in 46, 45 and 54% yields (ratio 1:1),
respectively. In all cases some starting material was
recovered (Scheme 2).
1
Scheme 2. Reagents: (i) n-BuLi (1.1 equivalents); (ii) E+=2-X-
C6H4COCl (X=F, Cl, Br).
The H-NMR spectra of complexes 10–15 showed
them to be unequivocally compatible with 4- and 7-sub-
stituted indoline complexes, with no benzylic substitu-
tion being detected. NOE difference spectroscopy of
complex 15 with irradiation of the N-methyl protons at
l 2.80 resulted in enhancement of the methine proton,
the methyl protons at C(2) and the aromatic protons of
the electrophile. These observations are consistent with
7-substitution and therefore complex 14 must be the
4-substituted regioisomer. This conclusion was ex-
tended to all pairs of complexes shown in Scheme 2.
Although complete regioselective functionalisation of
the exo complex 6 was not attained, it should be
stressed that our observation of lack of activation of
the exo benzylic proton is in contrast with literature
results for reactions with this type of complexes
[7b,e,9,14a].
Scheme 3. Reagents: (i) n-BuLi (2.5 equivalents)–TMEDA*; (ii)
E
+=2-XC6H4COCl (X=F, Cl, Br), TMSCl, TIPS.
Decomplexation of some complexes gave the corre-
With these results in hand, a new strategy was under-
taken for the regioselective synthesis of C(4) substituted
2-methylindolines. We turned to TIPS and TMS groups
for N-protection of the indoline nitrogen on the basis
that the steric hindrance caused by these bulky groups
would enhance the regio- and diastereoselectivity of the
corresponding complexes [12e,13b,c,14a]. The endo
complex 9 was obtained from 5, while the same reac-
tion with TMSCl failed, which is quite usual when
TMS is used as the protecting group for amines [15].
Alternatively, complex 9 could be generated as only
one diastereoisomer by thermolysis of Cr(CO)6 with
compound 3 in 69% yield. The high diastereoselectivity
of this reaction could presumably be due to the pres-
ence of the bulky TIPS group attached to the nitrogen
atom of the indoline complex, which causes a hindered
p face to the C(2) methyl group and to the Cr(CO)3
fragment [14a,e]. Taking into account this last result,
complex 8 could only be obtained from the exo com-
plex 4. The same reaction with TMSCl failed com-
pletely as was the case with 5 [15]. The distinction
between the exo and endo complexes 8 and 9 was
carried out by comparison with complexes 4 and 5, and
sponding stable substituted indolines.
2. Results and discussion
Complexation of 1 with Cr(CO)6 gave a 8:1.8 separa-
ble diastereoisomeric mixture of the exo and endo com-
plexes 4 and 5 in 80 and 19% yield, respectively
(Scheme 1). The upfield signal of the C(2) methyl group
in the 1H-NMR spectrum of 4 is consistent with the exo
complex and the downfield signal relative to the same
group is in agreement with the endo complex 5
[9,11,12].
The predominance of 4 is consistent with the incom-
ing chromium unit complexing preferentially to the
less-hindered p face of the arene ring of 1 placing the
methyl group at C(2) anti to the Cr(CO)3 fragment
[12e]. As expected, higher diastereoselectivity was ob-
served on complexation when a bulky group was at-
tached to the nitrogen atom [13a]. Methylation of 1 to
2 followed by complexation of 2 with the Cr(CO)6
afforded the two separable exo and endo complexes 6
and 7 in 67 and 10% yield (ratio 7:1), respectively
(Scheme 1). The 1H-NMR spectra of complexes 6 and 7
showed the chemical shift of the C(2) methyl protons to
be in agreement with those of complexes of 4 and 5.
Complexes 6 and 7 were also synthesised by methyla-
tion of 4 and 5, respectively, and their spectroscopic
6
and 7, respectively, and with literature data
[9,11,12,16].
This was followed by treatment of the lithiated
derivatives of complexes 8 and 9 with 2-halobenzoyl
chlorides, TMSCl and TIPSCl (Schemes 3 and 4). Sub-
stitution at the 4-position was unequivocally observed

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M.F.D. Costa et al. / Journal of Organometallic Chemistry 626 (2001) 233–242
235
of the protons of the TMS group at l 0.34 ppm
resulted in the enhancement of the H(5) signal and
irradiation of H(7) at l 5.43 ppm produced an enhance-
ment of the H(6) and TIPS proton signals. These
observations were consistent with a 4-substituted indo-
line complex derivatives and this conclusion was ex-
tended to the other electrophiles reported in Scheme 4.
As was observed for the functionalisation of com-
plexes 6, 8 and 9 using 2-halobenzoyl chlorides as
electrophiles there were no benzylic substituted byprod-
ucts formed, a result which contrasts the reactions
using (h6-fluorene)Cr(CO)3 [13], the [h6-(1,3-dihy-
drobenzo[c]furan)]Cr(CO)3 [7d] and other complexes
which possess one six-membered heterocyclic ring con-
densed to the aromatic ring [7d,13] where there are no
stereoelectronic constraints. Our results differ with
Oishi’s conclusions [9] and those of Kalinin in which
in all reactions and complexes 16–20 were obtained in
moderate or modest yields (21–45%) besides some
starting materials were also recovered. No traces of
both benzylic and 7-substituted products were detected
1
in the corresponding H-NMR spectra. C-4 functionali-
sation was established by NOE difference spectroscopy
of complex 19. Irradiation of the protons of the TMS
group at l 0.36 ppm resulted in the enhancement of the
H(5) signal and one of the benzylic protons signal at l
2.46 ppm. Irradiation of the H(5) proton at l 4.94 ppm
produced an enhancement of the H(6) and TMS proton
signals. Irradiation of the proton H(7) at l 5.20 ppm
produced an enhancement of the H(6) and TMS proton
signals. This conclusion was extended to the other
electrophiles of Scheme 3.
Using TMSCl and TIPSCl as electrophiles (Scheme
4), traces of C(3)-substituted complexes were also ob-
served (complexes 25 and 27), indicating that the regio-
chemistry related to benzoyl group containing
electrophiles does not transfer completely to elec-
trophiles like TMSCl and TIPSCl. The presence of the
methyl group at C(2) endo to the Cr(CO)3 fragment in
complex 9 would allow, to some extent, C(3) exo
deprotonation and subsequent functionalisation pre-
sumably due to the least steric hindrance in relation to
complex 8. The C(4) functionalisation of 24 was estab-
lished from NOE difference spectroscopy. Irradiation
benzylic
functionalisation
on
(N-methylindo-
line)tricarbonylchromium occurred [7a], presumably
due to the use of a different metallating agent and the
presence (in the present complexes) of the stereogenic
centre at C(2). On the other hand, our results are in
agreement with Simpkins’s studies on the (1,3-dihy-
droisobenzofuran)tricarbonylchromium complex [7b].
Products 12, 19 and 20 were subjected to known
decomplexation procedures [17] in order to produce the
corresponding non-complexed substituted indolines and
to evaluate their stability for further studies in the
enantiomerically pure series (Scheme 5).
3. Concluding remarks
The presence of the methyl group in the stereogenic
centre at C(2) of the pyrrolidine moiety has a pro-
nounced effect on regio- and diastereoselectivity in the
complexation of some indolines. It was shown that the
exo complex 6, is capable of undergoing exclusively
C(4) and C(7) functionalisation. The choice of the TIPS
bulky group attached to N(1) in compounds 8 and 9
afforded only one regioisomer upon reaction of their
lithiated derivatives and absence of functionalisation at
the benzylic position was observed with 2-halobenzoyl
chlorides. When TMSCl and TIPSCl were used as
electrophiles with the complexes 8 and 9, only exo
benzylic minor products were obtained for the lithiated
derivative of 9, presumably due to the absence of steric
hindrance of the endo methyl group at C(2).
Scheme 4. Reagents: (i) n-BuLi (2.5 equivalents)–TMEDA*; (ii)
E
+=2-XC6H4COCl (X=F, Cl, Br), TMSCl, TIPSCl.
Thus, the high value of (arene) chromium chemistry
for regio- and diastereoselective synthesis of this type of
molecules in relation to free indolines has been demon-
strated, in which the regioselective introduction of sub-
stituents possessing a carbonyl functional group are
relevant.
Scheme 5. (i) hw/O2.

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4. Experimental
4.1.2. 1-Triisopropylsilyl-2-methylindoline (3)
Prepared from 2-methylindoline (1) (1.0 ml, 7.68
mmol), n-BuLi (6.6 ml, 9.24 mmol) and chlorotriiso-
propylsilane (2.0 ml, 9.22 mmol) according to the gen-
eral procedure to afford 3 as a colourless oil (1.48 g,
67%). IR (cm−1) wmax (film): 2946, 2875 (CꢀH), 1605,
Melting points, Reichert Thermovar (uncorrected
values); IR, Perkin–Elmer 1725X FT-IR; 1H-NMR,
General Electric QE (300 MHz) (Me4Si at lH=0.00 as
an internal standard and the spectra were recorded in
CHCl3-d); MS, Kratos MS 25 RF (electron impact or
fast atom bombardment) and Extrell (Waters) FTMS
2001-DT STICR; Elemental analyses, Carlo Erba 1106;
CC, Merck Kieselgel 60 (230–400 mesh); TLC, Merck
silica gel precoated plates (60F-254) 0.5 or 2 mm for
preparative chromatography.
1477 (CꢁC); 1H-NMR:
l
1.03–1.18 (m, 21H,
Si[CH(CH3)2]3 and CH3), 1.32–1.44 (m, 3H,
Si[CH(CH3)2]3), 2.50 (d, 1H, J=14.7 Hz, CH2), 3.20
(dd, 1H, J=8.7 and 14.7 Hz, CH2), 3.99 (m, 1H, CH),
6.64 (t, 1H, J=7.8 Hz, ArH), 6.69 (d, 1H, J=7.8 Hz,
ArH), 6.95 (t, 1H, J=7.8 Hz, ArH), 7.08 (d, 1H,
J=7.8 Hz, ArH); MS (EI), m/z (%): 289 [M+] (21), 246
(100), 160 (6), 132 (6); Anal. Found: C, 74.64; H, 10.79;
N, 4.80. Calc. for C18H31NSi (289.54): C, 74.67; H,
10.79; N, 4.84%.
All reactions involving tricarbonylchromium(0) com-
plexes were carried out in Schlenk flasks under nitrogen
by using septum and syringe techniques. Solvents were
dried and distilled according to standard procedures
[18]. Unless otherwise stated, petrol refers to petroleum
ether b.p. 40–60°C and ether refers to diethyl ether.
The titration of n-BuLi was carried out using diphenyl-
acetic acid as standard [19]. Organic extracts were dried
over anhydrous magnesium sulphate. 1,2-Dimethylin-
doline (2) was not stable and consequently, good micro-
analytical data could not be obtained. In contrast,
microanalytical data from its complexes exo- and endo-
4.2. General methods for preparation of
(p6-N-substituted-2-methylindoline)-
tricarbonylchromium(0) complexes
Procedure A: A mixture of a slight excess of indoline
(2-methylindoline (1), 1,2-dimethylindoline (2) and 1-
triisopropylsilyl-2-methylindoline (3)) and hexacar-
bonylchromium(0) in deoxygenated dibutyl ether (80
ml)–THF (8 ml) were heated under reflux for 48 h. The
resulting solution was cooled, filtered through silica
with ether and concentrated under reduced pressure to
afford a crude product which was purified by column
chromatography to yield complexes 4–7 and 9.
(h6-1,2-dimethylindoline)tricarbonylchromium(0)
and 7), respectively, are correct.
(6
4.1. General method for the preparation of
N-substituted indolines
Procedure B:
A
solution of (h6-2-methylindo-
n-BuLi (1.2 equivalents) was added to a solution of
2-methylindoline (1) in THF at −78°C and stirred for
2 h. The chosen electrophile (methyl iodide or chlorotri-
isopropylsilane) was added, the mixture stirred for 1 h
at −78°C and the solution allowed to react for 24 h at
room temperature. Water–ether was added, the ether
portion separated, dried and the solvent removed to
afford a crude product, which was purified by flash
chromatography (n-hexane) to yield compounds 2 and
3.
line)tricarbonylchromium(0) complex [4 (exo) or 5
(endo)] in THF was added to a suspension of NaH (five
equivalents) previously washed in n-hexane (50 ml).
When no further gas was evolved, the mixture was
cooled (0°C) and methyl iodide or chlorotriisopropylsi-
lane was added. The reaction was stirred for 2 h at 0°C
and 24 h at room temperature. Diethyl ether was added
and the resulting solution filtered under vacuum
through a silica column. When necessary the crude
product was purified by column chromatography to
yield complexes 6–9.
4.1.1. 1,2-Dimethylindoline (2)
Prepared from 2-methylindoline (1) (1.0 ml, 7.68
mmol), n-BuLi (6.6 ml, 9.24 mmol) and methyl iodide
(0.6 ml, 9.60 mmol) according to the general procedure
4.2.1. exo-(p6-2-Methylindoline)tricarbonylchromium(0)
(4) and
endo-(p6-2-methylindoline)tricarbonylchromium(0) (5)
By procedure A: from 2-methylindoline (1) (2.0 ml,
15.37 mmol) and hexacarbonylchromium(0) (3.08 g,
14.02 mmol) to give after column chromatography (n-
hexane–ether: 60:40) complexes 4 and 5. Recrystallisa-
tion from ether–n-hexane gave yellow crystals in both
cases. Following the order of elution: Complex 4 (2.95
g, 80%); m.p. 95–96°C; IR (cm−1) wmax (KBr): 3426
(NꢀH), 3092 (CꢀH)Ar, 2970, 2932 (CꢀH), 1942, 1861,
to afford 2 as a yellow oil (890 mg, 79%). IR (cm−1
)
wmax (film): 3050 (CꢀH)Ar, 2959, 2931, 2871 (CꢀH),
1608, 1486, 1461 (CꢁC); 1H-NMR: l 1.31 (d, 3H,
J=6.3 Hz, CH3), 2.58 (dd, 1H, J=10.2 and 15.0 Hz,
CH2), 2.69 (s, 3H, NCH3), 3.06 (dd, 1H, J=8.1 and
15.0 Hz, CH2), 3.38 (m, 1H, CH), 6.44 (d, 1H, J=7.5
Hz, ArH), 6.65 (t, 1H, J=7.5 Hz, ArH), 7.05 (m, 2H,
ArH); MS (EI), m/z (%): 147 [M+] (44), 132 (100), 117
(33).
1
1833 (CꢂO), 1562, 1471 (CꢁC); H-NMR: l 1.33 (d,