Gold(I)-catalysed one-pot synthesis of chromans using allylic alcohols and phenols

Article abstract of DOI:10.3762/bjoc.9.209

A gold(I)-catalysed reaction of allylic alcohols and phenols produces chromans regioselectively via a one-pot Friedel-Crafts allyl-ation/ intramolecular hydroalkoxylation sequence. The reaction is mild, practical and tolerant of a wide variety of substituents on the phenol.

Full text of DOI:10.3762/bjoc.9.209

Gold(I)-catalysed one-pot synthesis of chromans
using allylic alcohols and phenols
Eloi Coutant, Paul C. Young, Graeme Barker and Ai-Lan Lee*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1797–1806.
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh,
EH14 1LP, United Kingdom
doi:10.3762/bjoc.9.209
Received: 26 June 2013
Email:
Accepted: 13 August 2013
Published: 04 September 2013
Ai-Lan Lee* - A.Lee@hw.ac.uk
* Corresponding author
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
Keywords:
allylic alcohols; chromans; Friedel–Crafts; gold catalysis; heterocycles
Guest Editor: F. D. Toste
© 2013 Coutant et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A gold(I)-catalysed reaction of allylic alcohols and phenols produces chromans regioselectively via a one-pot Friedel–Crafts allyl-
ation/intramolecular hydroalkoxylation sequence. The reaction is mild, practical and tolerant of a wide variety of substituents on the
phenol.
Introduction
Chromans (dihydrobenzopyrans) are important and ubiquitous Strong and superacids have also been utilised in the synthesis of
structural motifs found in a variety of important biologically chroman-containing targets [19-21]. Nevertheless, there are still
active natural products such as vitamin E and flavanoids [1-5]. a few drawbacks with these methods, for example, they usually
One approach towards chromans [6-12], which is biosynthetic- require a large excess of substrate (e.g. ~30-fold excess), and in
ally inspired, is the Friedel–Crafts allylation [13] of phenols fol- the case of acid catalysis, also poor yields when the phenol is
lowed by cyclisation of the allylated phenol intermediate (via not para-substituted. Therefore, it would be desirable to have a
hydroalkoxylation). Initially, traditional allylating reagents such milder method which is compatible with a wide range of substi-
as allylic acetates were employed in Friedel–Crafts allylations tuted phenols.
[14], but more recently, there has been a distinct drive towards
utilising more environmentally benign allylic alcohols (via a As part of our continued interest in developing new gold-cata-
direct dehydrative coupling strategy) [15,16]. To this end, the lysed [22-41] reactions [42-51], we have recently shown that
use of molybdenum catalyst CpMoCl(CO)3 together with an gold(I) can catalyse a direct allylic etherification [52-59] of
oxidant, o-chloranil, has been documented to catalyse the reac- unactivated alcohols 2 with unactivated allylic alcohols 1
tion of allylic alcohols with phenols to form chromans [17,18]. (Scheme 1, reaction 1) [60,61]. The reaction is mild, regiose-
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lective, and produces only water as a byproduct. During our Since the reaction is very practical: distilled solvents and inert
studies, a wide range of primary, secondary and tertiary alco- air atmosphere are not required, and the chroman is formed
hols were successfully employed as nucleophiles [61-72], but directly in a mild one-pot procedure with only water as the
our one attempt employing a phenol 5 as a nucleophile surpris- byproduct, we decided to investigate the chroman-forming reac-
ingly produced chroman 6 instead (Scheme 1, reaction 2). tion in more detail, beyond the sole example previously
Although gold(III)-catalysed Friedel–Crafts allylation of reported (Scheme 1, reaction 2). In this paper, we present our
phenols has been reported by Chan and co-workers [73], there further studies on this one-pot chroman synthesis: improving
have been no reports on the direct synthesis of chromans [74] the yield of the desired chroman and exploring the substrate
using gold catalysis [75] with phenols and allylic alcohols prior scope.
to our example shown in Scheme 1.
Results and Discussion
To commence our studies, we first investigated the possibility
of lowering the reaction temperature and used equivalents of
phenol nucleophile. Suspecting that the moderate yield of 6 in
Scheme 1 is due to the slight volatility of 6, an allylic alcohol 7
with a higher molecular weight was chosen as the model sub-
strate in order to avoid any issues of volatility with the chroman
products. As shown in Table 1, the standard conditions (50 °C,
5 equiv phenol 5) pleasingly provide a good 65% yield of the
desired chroman 8 (Table 1, entry 1). Reducing the temperature
is unfortunately detrimental to the formation of chroman:
40 °C gives a lower 59% yield of 8, as well as Friedel–Crafts
allylation products 9 and 10, whereas 30 °C provides
no chroman 8 at all, instead yielding only Friedel–Crafts
products 9 and 10 (Table 1, entries 2 and 3). The ortho-
and para-Friedel–Crafts products 9 and 10 are formed
Scheme 1: Previous work on direct allylic etherification of allylic alco-
hols.
via formal SN2' regioselectivity and 9 is presumably the inter-
mediate towards chroman 8 (vide infra). Thus, the higher
Table 1: Initial temperature and equivalents screens, and control reactions.
Entry
Equiv 5
Temp. (°C)
Catalyst
8 (%)
9 (%)
10 (%)
1
2
5
5
5
2
1
3
4
5
5
5
50
40
30
50
50
60
60
50
50
50
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
No catalyst
HNTf2
65a
59b
–
-
–
20b
27b
22b
19b
–
10b
66b
63b
50b
–
3
4
–
5
–
6
63b
60b
–
7
–
–
8
–
–
9
21a
–
–
–
10
AgNTf2
70b
25b
aIsolated yield. bYield obtained using 1H NMR analysis with 1,2,4,5-tetrachloro-3-nitrobenzene as internal standard.
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temperature is clearly necessary to force the in situ cyclisation carried out (Table 1, entries 8–10). Firstly, no reaction is
of 9 to 8.
observed in the absence of a catalyst (Table 1, entry 8). The
Brønsted acid catalyst HNTf2 does form chroman 8, but in a
Next, lower equivalents of phenol 5 were investigated. Unfortu- poorer isolated yield (21%, Table 1, entry 9) and the silver salt
nately, dropping the equivalents of phenol also appears to be [76] AgNTf2 as a catalyst does not provide any 8, yielding only
detrimental to chroman formation: only Friedel–Crafts products 9 and 10 (Table 1, entry 10). The former is consistent with
9 and 10 are observed with 2 or 1 equivalents of phenol literature reports that Brønsted acid-catalysed reactions give
(Table 1, entries 4 and 5). Pleasingly however, lower equiva- poor yields when the phenol is not para-substituted [19]. There-
lents of phenol are tolerated if the temperature is increased to fore, it seems that the gold(I) catalyst is most efficient in cata-
60 °C (Table 1, entries 6 and 7).
lysing the one-pot formation of chroman 8.
In order to ascertain if the gold(I) catalyst is really necessary for With these results in hand, a phenol screen was carried out next
the formation of chroman 8, several control reactions were (Table 2). Initially, the same conditions that were best for the
Table 2: Phenol nucleophile scope.
Entry Equiv 5 Temp. (°C) Time (h)
Phenol 5
Product
Yield (%)a
64
1
2
5
5
50
50
19
64
5a
8a
N/Db
5b
9b
8b
3
4
5
2
60
60
18
17
57
5b
5c
71
(~1:1
8c:8c')
8c and 8c'
5
6
5
5
60
60
18
17
69
63
5d
5e
8d
8e
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Table 2: Phenol nucleophile scope. (continued)
7
8
2
2
5
2
60
60
60
60
17
18
17
17
71
5f
5g
5h
5i
8f
54
8g
9
58
8h
10
57
8i
11
5
5
70
43
65
83
5j
8j
70, 48 h;
80, 17 h
12c
69
5k
8k
13c,d
5
90
65
83
5l
8l
aIsolated yield. bNot determined. cSolvent: dioxane. dReaction carried out in sealed tube.
formation of 8a were used (50 °C, 5 equiv 5a, Table 2, entry 1) substituent 5f provides 8f in a good 71% yield (Table 2, entry 7)
with p-cresol (5b), but these conditions only produced the and one with an electron-withdrawing substituent 5g pleasingly
Friedel–Crafts intermediate 9b (Table 2, entry 2). Pleasingly, also produces chroman 8g in a reasonable 54% yield (Table 2,
when the temperature was raised to 60 °C, the desired chroman entry 8). p-Bromo-substituted phenol 5h successfully yields
8b is successfully formed in 57% yield (Table 2, entry 3). chroman 8h which provides a handle for further functionalisa-
Therefore, 60 °C was adopted as the new general conditions tion (Table 2, entry 9).
temperature. Additionally, it was found that the equivalents of
phenol 5 can be lowered to 2 equivalents in some cases at this Next, the effect of a larger substituent was probed (Table 2,
higher temperature (Table 2, entries 4, 7, 8 and 10). In contrast entries 10 and 11). More hindered 2,4-di-tert-butylphenol (5j,
to the Brønsted acid procedure [19], the substitution position Table 2, entry 11) requires a higher temperature (70 °C) and
has limited effect on the efficiency of the gold-catalysed reac- twice the reaction time (43 h) to go to completion compared to
tion, with p-cresol (5b), m-cresol (5c) and o-cresol (5d) all 4-tert-buylphenol (5i, Table 2, entry 10). Although phenol 5j
forming the desired chromans 8b–d in decent to good yields exhibits the slowest reactivity of the phenols screened, it was
(Table 2, entries 3–5). The regioselectivity of the meta isomer is chosen as the model phenol in the next allylic alcohol substrate
unsurprisingly poor (1:1 of 8c:8c'), and when both meta-posi- screen (Table 3) since the extra molecular weight from the t-Bu
tions are substituted (5e) the reaction proceeds to 8e well substituents should reduce any volatility issues with the
(Table 2, entry 6). A phenol with an electron-donating chroman products [77].
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Beilstein J. Org. Chem. 2013, 9, 1797–1806.
At this point, we observed that the general procedure does not uct 11 (Figure 1, formed by auto-oxidation of the Friedel–Crafts
work if the phenol reactant is insoluble in toluene, such as 5k. intermediate) is observed in 35% yield if the reaction is carried
However, a simple change of solvent from toluene to dioxane out in air (80 °C), resulting in a low 45% yield of 8l. When
provides the desired chroman 8k (Table 2, entry 12), although the reaction vessel is flushed with argon, the yield of 8l
slightly higher temperatures (70–80 °C) and a longer reaction improves to 69%, but ultimately carrying out the reaction at
time (65 h) are required in this polar solvent to push the reac- 90 °C in a sealed tube provides a much better yield of 83%
tion to completion.
(Table 2, entry 13).
Finally, to show the synthetic utility of this procedure, a Next, the allylic alcohol scope was investigated (Table 3).
hydroquinone (trimethylhydroquinone TMHQ (5l)) was also Firstly, going from more hindered Cy substituents (7) to less
evaluated, as TMHQ is commonly used towards the synthesis of hindered n-hexyl substituents (12) allows the reaction to work
vitamin E and its analogues [17,21]. For solubility issues, smoothly at a lower temperature of 60 °C (Table 3. entries 1
dioxane is used as the solvent. Initially, an oxidised side prod- and 2). Hindered 4 works equally well but requires extended
reaction times (67 h) to achieve a good 83% yield (Table 3,
entry 3). Less hindered 13 as well as 14 work smoothly to form
8o and spirocyclic chroman 8p (Table 3, entries 4 and 5). An
aromatic substituent is also well tolerated (Table 3, entry 6).
Next, the effect of substitution along the alkene was investi-
gated (Table 3, entries 7–10). Substitution at the γ-position (16
and 17) seems to be tolerated, forming chromans 8r and 8s re-
spectively albeit in moderate yields (Table 3, entries 7 and 8).
Figure 1: Initial side product with TMHQ.
Substitution at the β-position, however, is not tolerated: the
Table 3: Allylic alcohol scope.
Entry
1
Time (h)
43
Temp. (°C)
Allylic alcohol
Product
Yield (%)a
70
83
7
12
4
8j
8m
8n
8o
2
3
4
43
67
42
60
60
60
69
83
64
13
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Table 3: Allylic alcohol scope. (continued)
5
6
41
41
60
70
61
14
15
8p
66
8q
7
8
43
47
70
70
45
16
17
8r
48b
8s
9
42
42
41
41
60
60
70
60
35
18
19
9t
10
11
12c
78
8o
51
20
21
8u
74
9v
aIsolated yield. bApproximately 2:1 d.r. cHeating at 80 °C for 65 h still only gives 9v and no desired chroman.
reaction stops at the Friedel–Crafts stage (9t), and is reluctant to ciently (Table 3, entry 10), which is the same product as from
undergo further cyclisation to the desired chroman (Table 3, the tertiary allylic alcohol substrate 13 in entry 4. This implies
entry 9). Having investigated a series of tertiary allylic alcohols that 19 undergoes the Friedel–Crafts allylation via opposite
in entries 1–9, we next looked at selected primary and second- regioselectivity (a formal SN2 instead of SN2' observed in all
ary allylic alcohols (Table 3, entries 10–12). The γ,γ-disubsti- other examples so far in Table 2 and Table 3) to form 9, fol-
tuted primary allylic alcohol 19 forms the chroman 8o effi- lowed by cyclisation to form the observed 8o. Using a γ,γ-
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Beilstein J. Org. Chem. 2013, 9, 1797–1806.
disubstituted secondary allylic alcohol 20 also forms chroman
8u via an initial SN2 Friedel–Crafts regioselectivity, thus γ,γ-
disubstitution on the alkene appears to be responsible for the
switch in regioselectivity (Table 3, entry 11). This implies that
the initial Friedel–Crafts allylation goes via Markovnikov
selectivity. The unsubstituted secondary allylic alcohol 21,
however, produces only the Friedel–Crafts allylation product 9v
and is reluctant to undergo cyclisation to the chroman (Table 3,
entry 12) even under more forcing conditions (80 °C, 65 h).
Scheme 3: Control reactions.
(Table 3, entry 12). Indeed, the reaction of 21 with 5j success-
fully produces the desired chroman 8v in 52% yield when
HNTf2 is added as a co-catalyst (Scheme 4), further suggesting
that the hydroalkoxylation step is most likely Brønsted acid
catalysed or co-catalysed.
Since 9 is always observed as a precursor towards 8 (i.e. at
lower temperatures, shorter reactions times or when the reac-
tion is analysed before completion), the most likely mechanism
is the expected gold(I)-catalysed Friedel–Crafts allylation of the
phenol (via Markovnikov regioselectivity), with allylic alcohol
[15,73], followed by cyclisation of the intermediate 9 via
hydroalkoxylation to form chroman 8 (Scheme 2) [13,15,16].
Chan and co-workers have previously proposed that the
Friedel–Crafts mechanism could involve the activation of the
allylic alcohol by the gold catalyst to turn the hydroxy group
into a better leaving group [73]. The observed regioselectivities
is then due to the subsequent attack at the less hindered pos-
ition of this presumed activated intermediate [73,78].
Scheme 4: Reaction of 21 with added Brønsted acid co-catalyst.
Our subsequent investigations with the Friedel–Crafts inter-
mediate 9a suggests that the second hydroalkoxylation step is
not (or not solely) gold catalysed (Scheme 3). When isolated 9a The suggested mechanism is presented in Scheme 5. Gold(I)
is resubjected to the reaction conditions with or without add- catalysts are known to coordinate to alcohols [80], in this case
itional phenol (5a), no cyclisation to the chroman 8a occurs turning the hydroxy group into a better leaving group (I), as
(Scheme 3). Thus, the second cyclisation step is most likely previously suggested by Chan [73]. Attack at the less hindered
Brønsted acid catalysed (or acid and gold(I) co-catalysed) [79], position could occur either directly on I [SN2' shown, but in the
where the H+ required is being released in situ during the first case of γ,γ-disubstituted substrates (e.g. 19 and 20), this will
Friedel–Crafts step to form 9. This would explain why 9 readily occur via SN2] or via an allylic cation intermediate II. The
cyclises to chroman 8 in situ, but is reluctant to do so when it is intermediate 9 subsequently undergoes an acid-catalysed
isolated before being resubjected to more gold(I) catalyst, as in hydroalkoxylation to produce the desired chroman 8. Active
Scheme 3. Nevertheless, simply using the equivalent Brønsted catalyst LAu+ is presumably regenerated by protonolysis of
acid HNTf2 is not as efficient as using gold(I), as shown in LAuOH [81].
Table 1, entry 9.
Conclusion
If the hydroalkoxylation step is indeed H+ catalysed, addition of In conclusion, a simple one-pot procedure towards chromans is
a Brønsted acid co-catalyst could force the chroman formation described via gold(I)-catalysed reaction of readily accessible
from substrates such as 21, which do not undergo the second phenols with allylic alcohols. This one-pot procedure involves a
hydroalkoxylation step under just gold(I)-catalysed conditions regioselective Friedel–Crafts allylation followed by cyclisation
Scheme 2: Proposed pathway.
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Beilstein J. Org. Chem. 2013, 9, 1797–1806.
Scheme 5: Suggested mechanism.
via hydroalkoxylation to form the chromans in good yields. At Acknowledgements
lower temperatures or shorter reaction times, the Friedel–Crafts We thank EPSRC (EP/K00736X/1), EPSRC DTA studentship
allylation intermediates are usually observed. The reaction (PCY), Erasmus Programme and Ministère français de
works with ortho-, meta- and para-substituents as well as elec- l'Éducation Nationale (EC) for funding. Mass spectrometry data
tron donating and withdrawing substituents on the phenol, and was acquired at the EPSRC UK National Mass Spectrometry
hydroquinones (Table 2). A variety of allylic alcohol substrates Facility at Swansea University.
work well, although substitution on the alkene is only tolerated
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