Direct preparation of 7-allyl- and 7-arylindolines

Article abstract of DOI:10.1002/adsc.200900499

Addition of allyl halides to the organolithium species derived from lithiation of N-tert-bu-toxycarbonylindoline with iec-butyllithium (secBuLi) and tetramethylethylenediamine (TMEDA) occurs regioselectively by S_N2 allylation. In contrast, the

Full text of DOI:10.1002/adsc.200900499

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DOI: 10.1002/adsc.200900499
Direct Preparation of 7-Allyl- and 7-Arylindolines
Daniele Leonoria and Iain Coldhama,*
a
Department of Chemsitry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K.
Fax : (+44)-(0)114-222-9346; phone: (+44)-(0)114-222-9428; e-mail: i.coldham@sheffield.ac.uk
Received: July 16, 2009; Published online: October 28, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900499.
Abstract: Addition of allyl halides to the organo-
lithium species derived from lithiation of N-tert-bu-
toxycarbonylindoline with sec-butyllithium (sec-
BuLi) and tetramethylethylenediamine (TMEDA)
occurs regioselectively by SN2 allylation. In contrast,
the organolithium species can be transmetalated to
the mixed zinc cuprate that undergoes regioselec-
tive SN2’ allylations. Transmetalation to the organo-
zinc chloride allows a Negishi-type cross-coupling
reaction with aryl bromides using palladium cataly-
sis with triphenylphosphine (PPh3) as ligand. The
chemistry was applied to a very short synthesis of 7-
prenylindole and of the alkaloid vasconine.
gives 7-substituted N-Boc-indolines in good yields
(Scheme 1).[4] However, the scope of electrophile
used to date is narrow and does not allow direct
Keywords: allylation; arylation; carbanions; in-
doles; lithium; metalation
Scheme 1. 7-Lithiation of N-Boc-indoline.
access to indoles or indolines bearing 7-allyl or 7-aryl
Indoles and indolines are present in many natural substituents, as required for many alkaloids. To
products that have important biological properties.[1,2] expand the reactivity of this organolithium compound
A substituent in the aromatic ring and, in particular, and provide a method to prepare these products, we
at position 7 is a key feature of many Amaryllidaceae decided to investigate the use of allylic and aryl hal-
and other alkaloids (Figure 1).[3] A convenient way to ides as electrophilic coupling partners.
access this position is to protect the indoline nitrogen
Allyl halides represent an interesting class of elec-
atom with a Boc group (Boc=tert-butoxycarbonyl), trophile, particularly due to the presence of 7-allylat-
and perform a regioselective lithiation using sec-BuLi ed indolines and indoles in natural products.[5] How-
and TMEDA.[4]
ever the reaction of this type of electrophile with nu-
This reaction generates an aromatic organolithium cleophiles presents problems of regioselectivity due to
compound that, after quench with an electrophile, competing SN2 and SN2’ pathways. This can lead to
mixtures of regioisomeric products when using un-
symmetrical allyl electrophiles.
A general way to control the regiochemistry is to
choose the nucleophilic partner carefully. Hard nucle-
ophiles, such as organolithiums, tend to react directly
at the sp3 carbon (SN2 attack) whereas softer nucleo-
philes, such as organocopper or organozinc reagents
interact predominantly with the sp2 carbon leading to
SN2’ attack.[6]
We therefore investigated allylations of both the or-
Figure 1. Some 7-substituted indole and indoline alkaloids.
ganolithium and the mixed zinc cuprate species, as il-
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Daniele Leonori and Iain Coldham
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lustrated in Scheme 2. The organolithium compound
With symmetrical allylic bromides (allyl bromide
was generated by treatment of N-Boc-indoline (1) and cyclohex-2-enyl bromide), the desired products
with sec-BuLi/TMEDA (Procedure A),[4] while the 2a and 2b were obtained with good yields by either
procedure (entries 1 and 8, 2 and 9). Prenyl bromide
represents one of the best electrophiles and both re-
gioisomers 2c and 2g were isolated in excellent yields
(entries 3 and 10). Crotyl bromide or 3-chloro-1-
butene could be used as the electrophile to prepare
the products 2d or 2e (entries 4 and 11, 5 and 12).
Cinnamyl bromide reacted with the organolithium
but only starting material was obtained using proce-
dure B (entries 6 and 13).
No examples are reported in the literature concern-
ing the reactivity of N-Boc-7-lithioindoline toward
alkyl halides, so we tested this reaction using bromo-
Scheme 2. Allylations of N-Boc-indoline (see Table 1).
propane. We were pleased to find that a good yield of
zinc cuprate was prepared from the organolithium by N-Boc-7-propylindoline (3) could be obtained using
direct addition of ZnCl2 and then CuCN·2LiCl (Pro- the direct addition of bromopropane to the organo-
cedure B).[7]
lithium (Scheme 3).
The reaction of these organometallic compounds
has been investigated with a range of different allylic
halides and the results are summarized in Table 1.
These results show a different reactivity between the
organolithium and the mixed zinc cuprate species. In
particular, the organolithium compound was found to
react by an SN2 pathway, while the zinc cuprate reacts
in an SN2’ fashion.
Scheme 3. Alkylation of N-Boc-7-lithioindoline.
Table 1. Formation of 7-allylindolines.
Procedure A
Procedure B
Electrophile
Entry
1
Product
Yield [%]
85
Entry
8
Product
Yield [%]
78
2a
2b
2a
2b
2
53
9
61
3
4
5
2c
2d
2e
81
41
32
10
11
12
2g
2e
2d
83
57
51
6
2f
47
13
–
–
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Direct Preparation of 7-Allyl- and 7-Arylindolines
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We have applied this methodology to a very short
and
efficient
synthesis
of
7-prenylindole
(Scheme 4).[8,9] 7-Prenylindole is a component of
many natural products such as the annonidines[10] and
Scheme 5. Direct metalation-coupling.
arylated compounds 5 in moderate to good yields
(Figure 2).
The reaction was found to be general with different
substituted aryl bromides and both electron-donating
Scheme 4. Synthesis of 7-prenylindole. i) Procedure
A
(81%); ii) a) TFA, CH2Cl2, À108C, 45 min (100%); b)
MnO2, CH2Cl2, heat, 5 h (79%); iii) TFA, CH2Cl2, heat, 1 h
(91%).
asterriquinones[11] and is itself a simple natural prod-
uct.[8] As outlined in Scheme 4, lithiation of N-Boc-in-
doline (1) and addition of prenyl bromide (Procedure
A) gave the desired indoline 2c, in 81% yield. This
was deprotected quantitatively using trifluoroacetic
acid (TFA) at À108C and oxidised to the indole with
manganese oxide.[9f] This completes a three-step syn-
thesis of 7-prenylindole from commercially available
starting material 1 in 64% overall yield. The deprotec-
tion should be carried out below 08C otherwise com-
petitive cyclisation occurs to give the product 4
Figure 2. Structures and yields of 7-arylindolines 5a–f.
(which could be obtained in high yield upon heating). and electron-withdrawing groups were tolerated.
The presence of 7-arylindoles in natural products Thus, bromobenzene and alkoxy-substituted aryl bro-
then inspired us to investigate the use of aryl bro- mides gave the products 5a–c. The electron-poor sub-
mides as electrophiles. We envisaged that the 7-meta- strates 1-bromo-4-chlorobenzene and 3-bromoaceto-
lated indoline could be used in a cross-coupling reac- phenone gave the products 5d and 5e, albeit with
tion with an aryl halide.[12]
lower yields. The chemistry was amenable to the use
Related approaches to 7-arylindoles make use of a of heteroaromatic bromides as shown using 3-bromo-
halogen atom at C-7 and, typically, a boronic acid as pyridine, which gave the indoline 5f. This methodolo-
the other coupling partner.[13] The possibility of in- gy represents an improvement over previous methods
verting this to have a metal atom in the indoline is at- to 7-aryl indolines[13,14] in terms of yields, substrate
tractive as it represents a more efficient and shorter scope and number of steps.
overall process.[14]
Finally, we illustrate the use of this chemistry for a
We decided to investigate the conversion of the or- very short synthesis of vasconine,[15] a natural product
ganolithium to the corresponding organozinc species isolated from Narcissus vasconicus[16] and a member
followed by a Negishi-type cross-coupling reaction. of the Amaryllidaceae alkaloid family.[3] Our synthesis
We were pleased to find that this approach was suc- began with the Negishi cross-coupling between the or-
cessful, as outlined in Scheme 5 (General Procedure ganozinc reagent formed in situ and the commercial
C). Thus, the organolithium (formed from 1 and sec- 6-bromoveratraldehyde. This gave the desired product
BuLi/TMEDA) was converted to the organozinc by 5g in 41% yield (Scheme 6). Deprotection of the Boc
slow addition of ZnCl2. After warming to 608C, the group and concomitant cyclisation with anydrous HCl
aryl bromide, catalytic Pd
ACHTUGNRTEN(NUGN OAc)2 and PPh3 were gave vasconine. This represents an efficient two-step
added and the mixture was heated. This led to the 7- synthesis of this tetracyclic alkaloid (and a formal syn-
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Daniele Leonori and Iain Coldham
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evaporated. The residue was purified by column chromatog-
raphy to give the 7-substituted N-Boc-indoline.
Lithiation-Transmetalation-Cross Coupling of N-Boc-
Indoline – General Procedure C
sec-BuLi (1.2 equiv., 1.40M) was added to a stirred 0.25M
solution of N-Boc-indoline
1 (1 equiv.) and TMEDA
(1.2 equiv.) in THF at À788C. After 2 h, a 0.8M solution of
ZnCl2 (1.3 equiv.) in THF was added over 10 min. After
30 min the mixture was warmed to 258C. After 30 min the
mixture was warmed to 608C and the aryl bromide
Scheme 6. Synthesis of vasconine. i) sec-BuLi, TMEDA then
ZnCl2 then PdACHTUNGTRENNUNG(OAc)2, PPh3, 6-bromoveratraldheyde, 608C,
41%; ii) HCl, CHCl3, room temperature, 89%.
(1.3 equiv.), PdACHTNUGTRNEG(UN OAc)2 (10 mol%) and PPh3 (20 mol%) were
added in one portion. After stirring at 608C overnight, the
mixture was cooled to room temperature and 10% NH4OH
(10 mL) was added. Ether (10 mL) was added, and the mix-
ture was stirred for 20 min. The organic layer was washed
with brine, dried (Na2SO4), filtered and evaporated. The res-
idue was purified by column chromatography to give the 7-
aryl-N-Boc-indoline.
thesis of the alkaloids assoanine and oxoassoani-
ne).[14b]
In conclusion, we have extended the reactivity of
N-Boc-7-lithioindoline particularly using allylic and
aryl bromides. This organolithium can be generated
easily from commercially available N-Boc-indoline 1
and reacts in good yield with allylic bromides in an
SN2 fashion. Conversion of the organolithium to a
mixed organozinc cuprate alters the reactivity to pro-
mote an SN2’ mechanism. Conversion to an organo-
zinc species allows Negishi-type cross-coupling with
For experimental data and NMR spectra, see Supporting
Information.
aryl bromides. These reactions have been applied to Acknowledgements
very short syntheses of the natural products 7-pren-
ACHTUNGTRENNUNGylindole and vasconine.
We thank the EPSRC (grant EP/E012272/1) and the Univer-
sity of Sheffield for support of this work.
Experimental Section
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Direct Preparation of 7-Allyl- and 7-Arylindolines
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