Diastereoselective intramolecular SmI2-H2O-amine mediated couplings

Article abstract of DOI:10.1039/b305428d

The effectiveness of SmI₂-H₂O-amine mixture for intramolecular couplings was discussed. Diastereoselectivities in the coupling of O-cyclohexanyliodophenol derivatives were provided into heterocycles. The amount of coupled product improved significantly as SmI₂, the substrate and amine were premixed followed by a gradual addition of water.

Full text of DOI:10.1039/b305428d

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Diastereoselective intramolecular SmI2–H2O–amine mediated
couplings†
Anders Dahlén, Annika Petersson and Göran Hilmersson*
Organic Chemistry, Department of Chemistry, Göteborg University, SE-412 96 Göteborg,
Sweden. E-mail: hilmers@organic.gu.se; Fax: 46 31 772 3840; Tel: 46 31 772 2904
Received 15th May 2003, Accepted 11th June 2003
First published as an Advance Article on the web 18th June 2003
The SmI2–H2O–amine mixture has been shown to be effect-
ive for intramolecular couplings providing diastereo-
selectivities of up to 100% de in the coupling of O-cyclo-
hexenyliodophenol derivatives into heterocycles.
ling,10 Michael addition,11 photocyclisation12 and electro-
chemical cyclisation.13
Herein we would like to present our recent developments of
intramolecular SmI2–H2O–amine mediated couplings between
aryl iodides and olefins into heterocycles in THF.
There has been an extraordinary development of SmI2 medi-
ated reactions for some 20 years, ever since Kagan’s break-
through in the late 70’s.1 SmI2 in THF has proven useful not
only in the reductions of functional groups,2 pinacol-coupling
reactions3 and as a coupling reagent between alkyl halides and
ketones or olefins,4 but also in sequential reactions.5 Recently
we discovered that a mixture of SmI2 in THF, water and an
amine (e.g. Et3N, TMEDA or PMDTA) resulted in unexpected
rates in the reduction of ketones, imines, α,β-unsaturated esters
and alkyl halides.6 We also found that these powerful mixtures
of SmI2–H2O–amine reduced conjugated double bonds selec-
tively and rapidly in the presence of isolated double bonds at
room temperature.7 It was therefore natural to investigate also
the possibility of intra- and intermolecular couplings to gener-
ate carbon–carbon bonds using this protocol. A wide variety of
alternative synthetic methods for this type of coupling are also
available, e.g. H3PO2–AIBN,8 Bu3SnH–AIBN,9 Heck coup-
First 1-allyloxy-2-iodobenzene (1) was synthesised to estab-
lish whether this type of coupling was achievable at all. Mixing
of SmI2, Et3N, 1 followed by H2O gave an almost instantaneous
reaction and the product was isolated and characterised by
1H-NMR, COSY and GC/MS. We found that the reaction
yielded only one product, the coupled product 3-methyl-2,3-
dihydrobenzofuran (1a). Analogue substrates containing longer
alkyl chains were also investigated for intramolecular coupling
using SmI2–H2O–amine. The formation of five-membered rings
was largely favoured over six- and seven-membered rings in
these substrates (Table 1, entry 2 and 3) and increasing amounts
of reduction occurred as the chain grew longer. Note that the
isolated double bond was not affected even in excess SmI2–
H2O–amine mixtures (entry 3). Interestingly the coupling was
not affected by an additional methyl group at the terminal
position (entry 5), while the isobutenyl isomer (entry 6) gave
a coupling/reduction ratio of 80 : 20, probably due to the
increased steric hindrance.
We established that in order to maximize the amount of
coupled product the water had to be added gradually after the
substrate to suppress the amount of reduced product. This was
† Electronic supplementary information (ESI) available: general syn-
theses and experimental data. See http://www.rsc.org/suppdata/ob/b3/
b305428d/
Table 1 Intramolecular couplings in 1-allyloxy-2-iodobenzene analogues using SmI2–H2O–Et3Na
Entry
1
Substrate
Product(s) Coupled (a)
Reduced (b)
Yield(s)b
>99
(1)
(2)
2
60 : 40c
3
4
(3)
(4)
> 99
> 99
5
6
(5)
(6)
> 99
80/20d
a In a standard procedure SmI2 (2.5–3 equiv.), Et3N (7.5 equiv.), substrate (0.1–0.2 mmol, 1 equiv.) and H2O (12.5 equiv.) were mixed at 20 ЊC. H2O
was added last during 1–5 minutes under vigorous stirring. b Corresponding to the yields and ratios observed on GC. No substrate was observed.
Close to quantitative yields were obtained on larger scale. c The coupling : reduction ratio was improved to 72 : 28 when n-butylamine was used
instead of Et3N. d The coupling : reduction ratio was improved to 87 : 13 when n-butylamine was used instead of Et3N.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 2 3 – 2 4 2 6
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Scheme 1 Suggested mechanisms for the SmI2 mediated coupling and reduction.
particularly significant for substrates that coupled into six-
membered rings. Adding the substrate last, i.e. with SmI2, Et3N
and H2O premixed, caused the product ratio in entry 2 (Table 1)
to change from 60 : 40 to 30 : 70 in favour of the reduced
product. Replacing the iodide with bromide in the substrates
in Table 1 resulted in longer reaction times and substantially
lower amounts of coupling, i.e. the reduced product was
favoured.
Curran and co-workers have investigated the mechanism of
the samarium Barbier reaction (or samarium Grignard reac-
tion),14 and they concluded that the coupling reaction is most
likely to occur via an organosamarium intermediate. A sug-
gested mechanism in Scheme 1 includes both the coupling and
the reduction reactions. Based on this it is obvious why the
order of and slow addition of water is crucial for the success of
this reaction.
Hexahydrodibenzofuran derivatives include the substructure
of morphine and are interesting in a pharmacological point of
view, since they are known to have narcotic and analgesic prop-
erties.15 A number of racemic 1-(cyclohex-2-enyloxy)-2-iodo-
benzene analogues (12–16), suitable for diastereoselective
coupling into hexahydrodibenzofuran derivatives (12a–16a),
were synthesised to explore further the extent of this coupling
(Table 3). Interestingly the only detected product was the
racemic cis-1,2,3,4,4a,9b-hexahydrodibenzofuran, 12a, after
the coupling of 12 with SmI2–H2O–Et3N. ‡ Similarly only the
cis-products of 13a–16a were formed according to NOESY
analysis (Fig. 1) and separation of the products on chiral
stationary phase GC.
To obtain fast and complete coupling/reduction of these
substrates the proportion between SmI2, H2O and amine have
to be at least 1 : 3 : 3, which is required for full precipitation of
the samarium- and iodide salts, according to titrations.6
We were also interested in the intramolecular coupling of
triple bonds with phenyl iodide. The coupling of 1-iodo-2-(2-
propynyloxy)benzene (7) provided initially the corresponding
five-membered styrene derivative ring (Scheme 2), which within
five minutes was reduced to 3-methyl-2,3-dihydrobenzofuran
(7a) in excess SmI2–H2O–amine. Similar behaviour was
observed for the analogue substrate 8, although in addition
larger amounts of uncoupled reduced products were formed.
Fig. 1 NOE between the two protons on the stereogenic carbons
confirming cis-configuration.
We noticed that different amines produced diverse coupling–
reduction ratios (Table 3). Primary amines (n-butylamine or
isopropylamine) usually increased the amount of coupled
product compared to tertiary amines (triethylamine, TMEDA
or PMDTA), however, the diastereoselectivity decreased
slightly. Encouraged by these results we also investigated
ammonia in water (∼25%) as the “amine”–water source. Once
again 100% de was obtained but compared to primary amines
the yield was slightly lowered and in addition the reaction
required approximately two hours for completion.
Substrates 14 and 15 were synthesised from 5-iodovanillin,
additionally a third substrate (16) was synthesised which was
protected as a 1,3-dithiane (dithioketal). Treating 16 similarly
to the previously mentioned substrates we found that compet-
ing reactions occurred (Scheme 3). When 16 was treated with
SmI2(2.5 equiv.)–H2O(7.5 equiv.)–Et3N(7.5 equiv.), followed by
quenching within 30 seconds, we could isolate the coupled
product still containing the dithioketal (16a). However, excess
SmI2–H2O–Et3N gave a second product within approximately
five minutes in which the dithioketal group had been opened
(16aЈ). This second product was also observed in the SmI2–
NH4OH mediated reaction after two hours of reaction time. A
third product, 16aЉ, was obtained after treating 16 with SmI2–
H2O–n-butylamine for 1–2 hours (or several hours with Et3N).
Scheme 2 Coupling of 1-iodo-2-(2-propynyloxy)benzene (7) followed
by reduction of the conjugated double bond.
In order to examine the influence of electronic properties in
these couplings a few nitrogen containing analogues to the sub-
strates in Table 1 were also synthesised (Table 2, entry 3–5).
Interestingly the formation of the six-membered ring was
improved to 70 : 30 (coupling–reduction) for the pyridine
analogue (entry 4). However, a 9 : 91 ring vs. reduction ratio
was obtained when the same substrate was added subsequent to
SmI2, Et3N and water. In entry 5 a ratio close to 50 : 50 was
obtained regardless of the addition order of water and
substrate, respectively.
1
This product was isolated in 85% yield. H-NMR and MS
showed that the 1,3-dithiane had been completely removed
leaving a corresponding methyl group at this position. The
complete cleavage of the dithioketal shows large resemblance
to the well-known Raney Ni desulfurization protocol for
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 2 3 – 2 4 2 6
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Table 2 Intramolecular couplings using SmI2–H2O–Et3Na
Entry
1b
Substrate
Product(s) coupled (a)
Reduced (b)
Yield(s)b
90 : 10c
(7)
(8)
2b
38 : 62c
3
4
(9)
>99
(10)
70 : 30
5
(11)
50 : 50
a In a standard procedure SmI2 (2.5 equiv.), Et3N (7.5 equiv.), substrate (0.1–0.2 mmol, 1 equiv.) and H2O (12.5 equiv.) were mixed at 20 ЊC. H2O was
added last during 1–5 minutes under vigorous stirring. b Corresponds to the yields and ratios observed on GC. No substrate was observed.
c For entries 1 and 2 twice the amount of SmI2, amine and water were used for complete formation of the corresponding saturated coupled products.
In entry 2 the triple bond was reduced into the double bond after being left standing over night in excess SmI2.
Table 3 Diastereoselective coupling of 1-(cyclohex-2-enyloxy)-2-iodobenzene analogues with SmI2–H2O–aminea, b
Triethylamine
a : b (% de)
n-Butylamine
a : b (% de)
NH4OHc
a : b (% de)
Entry
Substrate
1
2
3
4
12
13
14
15
72 : 28 (100)
92 : 8 (96)
85 : 15 (100)
77 : 23 (99.7)
84 : 16 (97)
95 : 5 (92)
80 : 20 (98)
85 : 15 (96)
75 : 25 (100)
40 : 60 (100)
60 : 40 (100)
74 : 26 (100)
a In a standard procedure SmI2 (2.5 equiv.), amine (7.5 equiv.), substrate (0.2 mmol, 1 equiv.) and H2O (12.5 equiv.) were mixed at 20 ЊC. H2O was
added last during 1–5 minutes under vigorous stirring. b Corresponding to the yields and ratios observed on GC. c The reactions with ammonia in
water required up to 2 h reaction time for completion.
reduction of a C–S group to a C–H group. This one-pot reac-
tion sequence may therefore also prove useful in other
desulfurizations.
We also investigated the possibility of intermolecular coup-
lings between alkyl halides and alkenes. Unfortunately all
attempts were unsuccessful, and the only species found in the
reaction mixtures, except for the amines, were the corre-
sponding reduced products of the substrates.
The results reported in Tables 1–3 are all performed on 0.1–
0.2 mmol scale. To prove that these coupling reactions are
amenable to scale up we also employed substrate 1 in larger
scale (2 mmol) without any loss in chemical yield (97% isolated
yield of 1a).†
five-membered rings was preferred over six-membered rings,
while formation of seven-membered rings and intermolecular
coupling were unsuccessful, i.e. led exclusively to reduction.
The coupling of 1-(cyclohex-2-enyloxy)-2-iodobenzene deriv-
atives (12–16) yielded high or total diastereoselectivity of the
formed hexahydrodibenzofuran derivatives (12a-16a) in good
to high yields. In addition we also discovered a one-pot reaction
sequence for the dithioketal protected 1-(cyclohex-2-enyloxy)-
2-iodobenzene analogue (16), where the coupling was followed
by complete removal of the dithioketal within two hours using
excess SmI2–H2O–n-butylamine. The use of SmI2–H2O–amine
in C–S bond cleavage is currently under investigation in our
laboratory.
In summary, we have shown that intramolecular coupling of
aryl iodides and alkenes proceeds fast under mild conditions
with the recently developed SmI2–H2O–amine protocol. The
amount of coupled product improved significantly when
SmI2, the substrate and amine were premixed followed by a
gradual addition of water. Furthermore the formation of
Experimental
General synthesis of substrates 1–7, 9–10 and 12–13
2-Iodophenol (3.3 g, 15 mmol) was added to a suspension of
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 2 3 – 2 4 2 6
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also analysed on 1H NMR, and COSY or NOESY when
considered necessary.
1a: 1H NMR (400 MHz, CDCl3) δ 1.35 (d, 3H), 3.55 (m, 1H),
4.08 (t, 1H), 4.70 (t, 1H), 6.80 (d, 1H), 6.88 (t, 1H), 7.13 (t, 1H),
7.17 (d, 1H). MS (EI) m/z 134 (Mϩ), 119, 105, 91, 77.
Acknowledgements
We are grateful for financial support from the Swedish Research
Council and the Carl Trygger Foundation. Knut and Alice
Wallenberg are gratefully acknowledged for financial support
of a glove box. We would also like to thank Fredrik Lehmann
and Marcus Fjällgren for a sample of 3-hydroxy-2-iodo-
pyridine.
Notes and references
‡ The cis–trans diastereomers of the product, 1,2,3,4,4a,9b-hexa-
hydrodibenzofuran, were synthesised as reference in two steps from
dibenzofuran according to literature procedure,16 and the chiral
stationary phase GC confirmed that the two diastereomers (cis–trans)
were well separated. The configuration of the products of the SmI2–
H2O–amine couplings was determined by NOESY experiments.
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Scheme 3 Reactions of 16 after treatment with SmI2–H2O–amine.
K2CO3 (6.2 g, 45 mmol) in DMF (50 ml) stirred under a nitro-
gen atmosphere. Allyl bromide (1.6 ml, 18 mmol) was added
slowly by syringe and the mixture was stirred overnight. Water
(50 ml) was added and the solution was extracted with n-hexane
(4 × 50 ml). The combined organic layer was washed with
water (3 × 50 ml), 10% KOH (2 × 50 ml), Na2S2O3 (50 ml) and
brine (50 ml), dried over MgSO4, filtered and concentrated.
Distillation under vacuum gave 1 as colourless oil (90–100%
yield).
1: 1H NMR (400 MHz, CDCl3) δ 4.60 (d, 2H), 5.30 (d, 1H),
5.50 (d, 2H), 6.06 (m, 1H), 6.68 (t, 1H), 6.79 (d, 1H), 7.24
(t, 1H), 7.76 (d, 1H). MS (EI) m/z 260 (Mϩ), 130, 102.
SmI2–H2O–amine mediated reaction
In a standard procedure, 5 ml SmI2 in THF (0.5 mmol,
2.5 equiv.) was added to a dry Schlenk tube, containing a mag-
netic stirrer bar and fitted with a septum, inside a glove box
under nitrogen atmosphere. The amine (1.5 mmol, 7.5 equiv.
Et3N) and the substrate 1 (0.2 mmol, 1 equiv.) were added
under stirring. To this mixture the proton donor, i.e. H2O (6.25
equiv.), was added slowly at 20.0 ЊC. The reaction was finished
in less than one minute. To 0.2 ml of the quenched solution was
added diethyl ether (1 ml) and HCl (0.1 ml, 0.12 M), or KOH
(10%) for products containing nitrogen, to remove the
inorganic salts and finally saturated Na2S2O3 (5 dr) to remove
excess iodine. The clear organic layer was transferred to a vial
and analysed on GC and GC/MS. Evaporated samples were
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 4 2 3 – 2 4 2 6
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