Synthesis of Functionalized Dihydrobenzofurans by Direct Aryl C?O Bond Formation under Mild Conditions

Article abstract of DOI:10.1002/anie.201605648

A method for the synthesis of dihydrobenzofurans by a direct aryl C?O bond formation is described. A mechanistic pathway for the reaction, distinct from previously described similar transformations, allows for mild reaction conditions that are expected to be compatible with functionalized substrates.

Full text of DOI:10.1002/anie.201605648

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605648
German Edition: DOI: 10.1002/ange.201605648
Oxygen Heterocycles
À
Synthesis of Functionalized Dihydrobenzofurans by Direct Aryl C O
Bond Formation Under Mild Conditions
Joseph Alvarado+, Jeremy Fournier+, and Armen Zakarian*
Abstract: A method for the synthesis of dihydrobenzofurans
À
by a direct aryl C O bond formation is described. A
mechanistic pathway for the reaction, distinct from previously
described similar transformations, allows for mild reaction
conditions that are expected to be compatible with function-
alized substrates.
À
C
H Functionalization has emerged as an increasingly
feasible strategic disconnection for the synthesis of complex
natural products.[1] Among an expanding set of methods, the
À
direct cyclization of tethered heteroatoms onto C H bonds
provides an attractive point of functionalization in synthesis
design. In connection with our interest in developing a concise
approach to Amaryllidaceae alkaloids such as galantamine,
we required a method for the assembly of dihydrobenzofur-
À
ans by direct aryl C O bond formation as illustrated in
Scheme 1a.
Our goals included specific emphasis on mildness of
reaction conditions compatible with functionalized substrates,
À
as many reported methods for C H functionalization require
rather high temperatures and prolonged reaction times.
Recent work from the laboratories of Yu and Davies
described an effective synthesis of dihydrobenzofurans by
cyclization of secondary benzyllic and tertiary alcohols
(Scheme 1b).[2] This method provides an attractive entry to
substituted dihydrobenzofurans. In an attempt to adopt this
reaction in an approach to galantamine, we discovered that
competitive oxidation of a primary or secondary hydroxy
group[3] posed a significant problem. Herein we describe an
alternative method for the synthesis of functionalized benzo-
furans and dihydrobenzofurans by direct intramolecular aryl
Scheme 1.
phenols with hypervalent iodine oxidants in 1,1,1,3,3,3-hexa-
fluoro-2-isopropanol.[8] Notably, this method was found to be
unsuitable for the synthesis of five-membered analogs,
dihydrobenzofurans.
À
C H bond functionalization under mild conditions that
minimize oxidation of alcohols.
The closest precedent for our strategy came from the work
of Onomura and co-workers, who recently described a Cu-
(OTf)2-catalyzed mono-arylation of 1,2- and 1,3-diols with
symmetrical diaryliodonium triflates.[9] According to our
In considering various strategies, we became intrigued by
diaryliodonium derivatives as intermediates for the synthesis
of dihydrobenzofurans, as outlined in Scheme 1c.[4] Previ-
ously, the groups of Olofsson,[5] Gaunt,[6] and Stuart[7]
described catalyst-free diaryl and alkyl aryl ether synthesis
by intermolecular O-arylation of phenols or alkanols under
basic conditions. In a mechanistically distinct process, Kita
and co-workers reported the synthesis of dihydrobenzopyrans
À
reaction design, a mild Cu-catalyzed intramolecular C H
arylation of alcohols[10] affording dihydrobenzofurans will be
accomplished via the intermediacy of non-symmetric diaryl-
iodonium salts, which were to be prepared in situ and
processed further without isolation. The choice of the
prototypical substrate, 2-(3-methoxyphenyl)-2-cyclohexen-1-
ol (1, Table 1) was influenced by its relevance to eventual
synthesis targets (galantamine, morphine). We found that no
established protocol was compatible with our model having
observed only oxidation, decomposition or recovery of 1.
Initial control experiments were carried out with PhI-
(O2CCF3) (PIFA) as the oxidant with no metal additive, and
revealed that only partial cyclization to benzofuran products
took place in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP),
giving a 1:7 mixture of double bond isomers 2 and 3 in
À
(chromans) by oxidative C H cyclization of 3-hydroxypropyl
[*] J. Alvarado,[+] Dr. J. Fournier,[+] Prof. Dr. A. Zakarian
Department of Chemistry and Biochemistry, University of California
Santa Barbara, CA 93106 (USA)
E-mail: zakarian@chem.ucsb.edu
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605648.
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Table 1: Evaluation of reaction conditions for C H/OH cyclisation.
virtually identical yields but at the expense of reaction time
(entries 15 and 16).
For the scope studies, we selected the conditions requiring
20 mol% of Cu(hfacac)2 and 1.1 equiv of TIFA for an optimal
balance between the catalyst loading and reaction time
(Table 2). The scope of alcohols was examined first, starting
Entry[a]
Oxidant
Additive (equiv)
Time
2:3
Yield[b]
14%[c,d]
0%[d]
52%[d,e]
62%[d]
69%
67%
73%
75%
54%
40%
48%
55%
38%
58%
75%
73%
Table 2: Scope studies: alcohol variation.[a]
1
2
3
4
5
6
7
8
PIFA
PIFA
PIFA
PIFA
TIFA
TIFA
TIFA
TIFA
TIFA
TIFA
TIFA
TIFA
TIFA
TIFA
TIFA
TIFA
–
–
14 h
14 h
8 h
8 h
5 h
4 h
2 h
10 min
4 h
12 h
4 h
3 h
2 h
30 min
40 min
5 h
1:7
–
Cu(OTf)2 (1.0)
Cu(OTf)2 (1.0)
Cu(OTf)2 (1.0)
Cu(CO2CF3)2 (1.0)
Cu(tfacac)2 (1.0)
Cu(hfacac)2 (1.0)
CuCl2 (1.0)
CuI (1.0)
CuBr·Me2S (1.0)
CuCl (1.0)
0:1
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
9
10
11
12
13
14
15
16
Cu(OTf)·PhMe (1.0)
Cu(CuCN)4BF4 (1.0)
Cu(hfacac)2 (0.2)
Cu(hfacac)2 (0.05)
[a] Unless otherwise noted reaction conditions were as follows:
1 (0.1 mmol), 4-CH3C6H4I(O2CCF3)2 (0.11 mmol), Et3N (0.025 mmol),
CF3CH2OH (0.05m) followed by additive and Et3N (0.4 mmol, 4 equiv),
monitored by TLC analysis until consumption of diaryliodonium salt
intermediate. [b] Isolated yield. [c] HFIP as solvent, no Et3N, isolated as
7:1 mixture of 3/2 product. [d] Consumption of 1 in 1.5 h. [e] No Et3N,
isolated as 3.
a combined 14% yield (Table 1, entry 1). In addition to 2 and
3, by-products from alkene oxidation and allylic rearrange-
ment were formed. To attenuate the acidity and polarity of
the reaction media, the solvent was changed to 2,2,2-
trifluoroethanol (TFE) and 0.25 equiv of Et3N were added
(entry 2). Although no cyclization of 1 was observed with
PIFA under these conditions, an unsymmetrical diaryl-l3-
iodane product was isolated instead in 46% yield (see below).
Isolation of the diaryl-l3-iodane intermediate suggested
the use of copper salt additives for further optimization.[9]
Indeed, addition of 1.0 equiv Cu(OTf)2 to the preformed
diaryl-l3-iodane (PIFA, TFE, 08C, 25 min) afforded 3 exclu-
sively in 52% yield (Table 1, entry 3). To suppress alkene
isomerization in the initially formed benzofuran 2, presum-
ably acid-mediated, another 4 equiv of Et3N were added prior
to the addition of copper catalyst, which delivered 2 in 62%
yield (entry 4). No alkene isomerization to 3 was detected in
this case. Further marginal improvement was observed when
PIFA was replaced with p-tolueneiodonium bis(trifluoroace-
tate) (TIFA), which also reduced the reaction time from 8 to
5 h (entry 5). A further screen of copper compounds identi-
fied more effective reagents. In particular, soluble additives
displayed a substantially increased reactivity as well as the
yield (entries 6–16). Among these, copper bis(hexafluoroace-
tylacetonate) Cu(hfacac)2 was especially reactive, leading to
a complete reaction within 10 min at 238C and affording 2 in
75% isolated yield (entry 8). Subsequent experimentation
revealed that the copper additive was just as effective in
substoichiometric amounts (20 mol% or 5 mol%) with
[a] Unless otherwise noted, reaction conditions include: substrate
(0.5 mmol), 4-CH3C6H4I(O2CCF3)2 (0.55 mmol), Et3N (0.125 mmol),
CF3CH2OH, 08C, followed by Cu(hfacac)2 (0.1 mmol) and Et3N
(2 mmol), 238C; monitored by TLC analysis until consumption of the
substrate, then diaryliodonium salt.
by evaluation of primary, secondary, and tertiary alcohols
with our reaction conditions, and resulting in formation of the
corresponding dihydrobenzofurans (4a–c) in high yields
(> 90%). Substrates monosubstituted at the benzylic position
with either alkyl (4e), alkenyl (4k) or aryl groups (4g, 4h) are
also suitable substrates for dihydrobenzofurans formation,
with the exception of the pharmaceutical intermediate 4d,
which was obtained in a slightly lower yield (52%). The lower
yield is probably due to the presence of the acetamido group.
Disubstitution at the benzylic position results in no formation
of dihydrobenzofuran 4 f with full recovery of the starting
material. Natural product corsifuran A (4i) was obtained in
a low yield of 27%. This result can be explained by the
presence of two electron rich aromatic rings, which can lead to
competitive oxidation at the undesired site. Indeed, previous
work by Kita and co-workers showed that 4-OMe substituted
arenes react with PIFA through a radical cation pathway,
while 3-OMe-substituted arenes afford iodonium salts.[11]
Antibacterial compound 4j was obtained in a good yield,
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demonstrating selectivity for the dihydrobenzofuran versus
functionalities were well tolerated and provide an excellent
chroman formation. In fact, chroman formation was not
efficient using these reaction conditions as compound 4l was
obtained with only 22% yield, in addition to tolyl group-
transfer by-product.
The scope of arene was then investigated using substrates
with a primary hydroxy group (Table 3). These substrates
handle for subsequent synthetic derivatization. Surprisingly
Me-substituted dihydrobenzofurans 5 f and 5j were obtained
in lower yields of 58% and 34%, respectively, presumably
due to low stability of the products in the air. In our screening
efforts, we placed an emphasis on the use of different
directing groups in order to illustrate the versatility of the
method. Thus -OTBS, -OBn and -OCHF2 functionalities have
been evaluated, providing dihydrobenzofurans 5n–5p in
excellent yields. Interestingly, fluorine was found to be
a suitable directing group, affording dihydrobenzofuran 5q
in 65% yield.
Table 3: Scope studies: arene variation.[a]
To gain initial insight into the mechanism of the process,
we carried out the reaction with substrate 1 in the absence of
a copper additive (Scheme 2a). After 25 min at room temper-
ature, diaryl-l3-iodane 6 could be isolated in 46% yield and
characterized by mass-spectroscopy and 1H, 13C, and 19F NMR
spectroscopy. No cyclization of the intermediate to dihydro-
benzofuran 2 was observed even after 1 week in the absence
of a copper additive. In contrast, a rapid and nearly
quantitative cyclization to dihydrobenzofuran 2 occurred
when diaryl-l3-iodane 6 was treated with 1 equiv of Cu-
[a] Unless otherwise noted, reaction conditions include: substrate
(0.5 mmol), 4-CH3C6H4I(O2CCF3)2 (0.55 mmol), Et3N (0.125 mmol),
CF3CH2OH, 08C, followed by Cu(hfacac)2 (0.1 mmol) and Et3N
(2 mmol), 238C; monitored by TLC analysis until consumption of the
substrate, then diaryliodonium salt. [b] 508C for iodonium salt forma-
tion. [c] 3 Equiv of hydroxyl(tosyloxy)iodobenzene as oxidant. [d] Hexa-
fluoroisopropanol as solvent, 238C for iodonium salt formation.
often required extended reaction times (12–16 h) to reach
completion. Ortho-substitution relative to the newly formed
À
C O bond was well tolerated using both electron donating
(5a, 5b) or electron withdrawing substituents (5c–e). It is
important to note that strongly deactivating groups such as
CF3 require the use of a stronger oxidant, [hydroxy-
(tosyloxy)iodo]benzene, still providing dihydrobenzofuran
5e in good yields (71%). The same pattern of reactivity was
observed when a variety of substituents were introduced at
the ortho position to the directing group. In fact, substrates
with pivalate (5g, 67% yield), cyano (5i, 92% yield), and
dimethyl carbamate (5k, 87% yield) substituents all afforded
good to excellent yields of the products. Notably, chlorine
(5h, 91% yield; 5l, 83% yield) and triflate (5m, 95% yield)
Scheme 2. Preliminary mechanistic studies and mechanistic hypothe-
sis.
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H. M. L. Davies, A. Zakarian, J. Am. Chem. Soc. 2014, 136,
17738 – 17749; c) W. R. Gutekunst, P. S. Baran, J. Am. Chem.
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Tran, Acc. Chem. Res. 2015, 48, 1053 – 1064.
(hfacac)2 and triethylamine in TFE at room temperature for
10 min. Based on these results, a tentative mechanism for the
conversion of 1 to dihydrobenzofuran 2 is outlined in
Scheme 2a. In the presence of an activating and directing
group like MeO, the substrate is rapidly converted to the
diaryl-l3-iodane intermediate upon the initial exposure to an
iodine(III) reagent. Subsequent addition of the soluble Cu
À
catalysts results in a rapid oxidative insertion into the C I
bond,[12] affording a putative CuIII intermediate 7.[13] Reduc-
tive elimination affords the dihydrobenzofuran product.[14]
Triethylamine serves as a buffer to minimize acid-mediated
side reactions at various stages of the process.
In summary, we have described an alternative Cu-
[2] a) X. Wang, Y. Lu, H. Dai, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132,
12203 – 12205; b) H. Wang, G. Li, K. Engle, J.-Q. Yu, H. M. L.
Davies, J. Am. Chem. Soc. 2013, 135, 6774 – 6777.
À
catalyzed C H functionalization reaction for the synthesis
of functionalized dihydrobenzofurnans. An important feature
of the reaction is mildness of the reaction conditions that
avoid extremes in temperature and reaction times, strong
bases, and strongly oxidizing reagents. We expect the mildness
of the reaction conditions to be especially relevant in the
synthesis of complex functionalized molecules. In the present
study the utility of the method was illustrated by the synthesis
of several simple bioactive compounds.
[3] Oxidation as a significant reaction pathway during palladium-
À
catalyzed C O bond formation was previously reported:
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Experimental Section
[Bis(trifluoroacetoxy)iodo]p-toluene (0.25 g, 0.55 mmol, 1.1 equiv) or
[hydroxy(tosyloxy)iodo]benzene (0.59 g, 1.5 mmol, 3 equiv) was
added as one portion to a solution of alcohol substrate (0.5 mmol)
and triethylamine (17 mL, 0.13 mmol, 0.25 equiv) in trifluoroethanol
(10 mL, 0.05m) at 08C under argon. The mixture was stirred until the
alcohol was consumed as indicated by TLC analysis (typically
accompanied with a color change to yellow or orange). Triethylamine
(0.28 mL, 2.0 mmol, 4.0 equiv) was then added at 08C followed
immediately by copper(II)hexafluoroacetylacetonate (0.05 g,
0.1 mmol, 20 mol%). The mixture was warmed to 238C and stirred
until iodonium salt intermediate was consumed as indicated by TLC
analysis. To the resulting blue green solution, saturated aqueous
NaHCO3 was added and the mixture was extracted with CH2Cl2 (2 ꢀ
10 mL). The combined organic phases were dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chroma-
tography to give corresponding dihydrobenzofuran.
[9] M. Kuriyama, N. Hamaguchi, O. Onomura, Chem. Eur. J. 2012,
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[10] a) I. Sokolovs, E. Suna, J. Org. Chem. 2016, 81, 371 – 379.
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Acknowledgements
This work was supported by the NSF CHE-1463819, Amgen,
Eli Lilly and the NIH Shared Instrumentation Grant (SIG)
1S10OD012077-01A1.
Keywords: copper · cyclization · fused-ring systems ·
iodonium salts · oxygen heterocycles
Received: June 10, 2016
[1] a) P. Lu, Z. Gu, A. Zakarian, J. Am. Chem. Soc. 2013, 135,
Revised: July 23, 2016
14552 – 14552; b) P. Lu, A. Mailyan, Z. Gu, D. Guptil, H. Wang,
Published online: && &&, &&&&
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Oxygen Heterocycles
J. Alvarado, J. Fournier,
A. Zakarian*
&&&& — &&&&
Synthesis of Functionalized
À
Dihydrobenzofurans by Direct Aryl C O
Bond Formation Under Mild Conditions
Take a walk on the mild side: A method
for the synthesis of dihydrobenzofurans
minimizing competitive alcohol oxidation
is described. The mild reaction condi-
tions are compatible with functional
groups not used previously in such
transformations. A key step in this pro-
cess is the in situ formation of an iodo-
nium salt.
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