Gold-catalyzed synthesis of chroman, dihydrobenzofuran, dihydroindole, and tetrahydroquinoline derivatives

Article abstract of DOI:10.1002/chem.200800210

Different furans containing an ynamide or alkynyl ether moiety in the side chain were prepared. The gold-catalyzed transformation of these compounds delivered dihydroindole, dihydrobenzofuran, chroman, and tetrahydroquinoline derivatives at room temperatu

Full text of DOI:10.1002/chem.200800210

DOI: 10.1002/chem.200800210
Gold-Catalyzed Synthesis of Chroman, Dihydrobenzofuran, Dihydroindole,
and Tetrahydroquinoline Derivatives
A. Stephen K. Hashmi,*[a] Matthias Rudolph,[b] Jan W. Bats,[c] Wolfgang Frey,[b]
Frank Rominger,[a] and Thomas Oeser[a]
Abstract: Different furans containing an ynamide or alkynyl ether moiety in the
side chain were prepared. The gold-catalyzed transformation of these compounds
delivered dihydroindole, dihydrobenzofuran, chroman, and tetrahydroquinoline
derivatives at room temperature through very fast reactions. Furthermore, the sta-
bilizing effect of the heteroatom directly attached to the intermediate arene oxides
led to highly selective reactions, even in the case of only mono-substituted furans,
which is quite different from previous results obtained with non-heteroatom-sub-
stituted alkynes.
Keywords: alkynes · arenes · gold ·
heterocycles
catalysis
·
homogeneous
Introduction
The importance of gold catalysis as a powerful tool for or-
ganic synthesis is continuously increasing;[1] the cyclization
of enynes is playing a major role.[2a,b] In our group, we devel-
oped a gold-catalyzed phenol synthesis (Scheme 1), in which
the first step, like all the other ene–yne cyclizations, proba-
bly involves a cyclopropyl carbenoid (A) or an electronically
related structure, but then due to the additional enol ether
substructure follows a different pathway (via B and the va-
lence tautomers 3/4) to ultimately form the aromatic phe-
nols 2.[3] This methodology has proven to be a powerful tool
for the synthesis of various heterocycles, such as dihydro-
Scheme 1. Gold-catalyzed phenol synthesis.
[a] Prof. Dr. A. S. K. Hashmi, Dr. F. Rominger,+ Dr. T. Oeser+
Organisch-Chemisches Institut, Ruprecht-Karls-Universität
Heidelberg Im Neuenheimer Feld 270
69120 Heidelberg (Germany)
Fax (+49)6221-544205
E-mail: hashmi@hashmi.de
[b] Dipl.-Chem. M. Rudolph, Dr. W. Frey+
Institut für Organische Chemie, Universität Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
[c] Dr. J. W. Bats+
ACHTREUNG
AHCTREUNG
cycle syntheses are based on a propargylic moiety connected
to the heteroatom in the tether of the substrate 1. Herein,
we report on our efforts to use alkynyl moieties directly
connected to the heteroatom as reactive units in the side
chain of the furans, namely alkynyl amides and alkynyl
ethers. This should provide access to other types of hetero-
cycles, such as dihydroindoles, dihydrobenzofurans, chro-
mans, and tetrahydroquinolines.
So far only very few examples of the gold-catalyzed ene–
ynamide[4a] and ene–ynol ether[5] cyclizations have been re-
ported. The gold-catalyzed cyclization of 1,6-ene–ynamides
5 developed by Cossy et al. delivered cyclobutanones 6 as
Institut für Organische Chemie und Chemische Biologie
Johann Wolfgang Goethe-Universität Frankfurt
Marie-Curie-Str. 11, 60439 Frankfurt (Germany)
[+] Crystallographic investigation.
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
dition of furans 14 to enones
19 and subsequent reduction of
the carbonyl group of 20 to the
alcohol 21.[6–8] Alternatively, a
boron
trifluoride
etherate
mediated addition of lithiated
furan to oxetane 17 provided
direct access to the alcohol 18
in good yield (Scheme 5).[9]
The resulting alcohols 16, 18
and 21 were transformed into
the dichlorovinyl ethers 23a–d
(Table 1) by following a proto-
col of Greene et al.[10] The ad-
dition of the alcohols to tri-
chloroethene in THF provided
Scheme 2. Pathways for metal-catalyzed enyne cyclization of ynamides. Ts=tosyl; Cbz=benzylACHTREoUGN xycarbonyl.
major products,[4a] whereas similar substrates in platinum-
catalyzed reactions delivered exclusively formal metathesis
products 7 (Scheme 2).[4b,c] The different chemoselectivity
can be explained by the milder reaction conditions of the
gold-catalyzed reactions. Here a ring expansion of the pri-
mary cyclopropyl carbenoid C, leads to a cyclobutyl cation
D (stabilized by the neighbouring heteroatom). After elimi-
nation of the metal and addition of water to cyclobutene 8,
products 6 are formed. A double cleavage of the primary
carbenoid complex C in the platinum-catalyzed reaction de-
livers carbenoid E, which finally results in products 7 after
elimination of the metal.
23a–d in yields of 66–80%. The addition of decanol (22) to
trichloroethene yielded the alkyl vinyl ether 23e in 70%
yield.
The starting points for the ynamide syntheses were the
toluenesulfonamides 24a–d (Table 2), which were prepared
by literature procedures from the corresponding amines.[3l,n]
Toluenesulfonamides 24e/24g, containing a three-carbon-
atom unit were synthesized from the corresponding alcohols
By the use of substrate 9, which contains a propargylic al-
cohol moiety, the cyclopropyl carbenoid F could be trapped
by a 1,2-hydride shift to deliver the ketone 10 (Scheme 3).[4]
Scheme 3. A third pathway for gold-catalyzed enyne cyclization of yn-
ACHTREUNGamides.
Scheme 4. Reactions of alkynyl ethers in gold-catalyzed reactions. TIPS=
triisopropylsilyl.
The products formed by the gold-catalyzed cyclization of
siloxy enynes 11, reported by Kozmin et al.,[5] are also influ-
enced by a stabilizing effect of the attached heteroatom.
After the initial formation of the cyclopropylcarbenoid G,
ring expansion, leading to cyclobutyl cations H, and a subse-
quent skeletal rearrangement via I to carbenoid J, could ex-
plain the shift of the silyl ether group in the final products
12 or 13 (depending on the substitution pattern, Scheme 4).
Results and Discussion
The introduction of the side chain for the dihydrobenzofur-
an syntheses was achieved by the addition of lithiated furans
14 to oxiranes 15.[3m] The corresponding three-carbon-atom
chain for chroman synthesis was introduced by Michael ad-
Scheme 5. Synthesis of furans with hydroxy groups in the side chain.
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A. S. K. Hashmi et al.
Table 1. Formation of the dichlorovinyl ethers 23.
18a/21a by a Mitsunobu reaction with N-tert-butyloxycar-
bonyl-p-toluenesulfonamide[11] and subsequent deprotection
of 28a/28b with trimethylsilyl iodide (Scheme 6).[12] A de-
protection under acidic conditions led to decomposition of
the starting materials. Alternatively, TiCl4-mediated tosyli-
mine formation and reduction delivered amide 24 f in mod-
erate overall yield (Scheme 6). To introduce the alkyne
Entry
1
16,18,21
R
Product (yield [%])
16a
23a (79)
moiety, we used
a procedure published by Witulskiꢁs
group.[13] Addition of deprotonated amides in toluene to tri-
methylsilylethynylphenyliodonium triflate[14] 25 and depro-
tection with tetrabutylammonium fluoride delivered yn-
2
3
16b
18a
23b (80)
23c (66)
AHCTREaUNG mides 27a–d in moderate overall yields (Table 2). A partial
loss of product might result from problems during purifica-
tion. Unfortunately, amides 24e and 24 f containing a three-
carbon-atom unit did not react—only a slow decomposition
could be detected by TLC.
4
5
21a
22
23d (75)
23e (70)
As a consequence, we switched to a protocol of Brückner
et al. (Table 3).[15] Our inten-
tion was the direct introduc-
tion of the tosylated nitrogen
Table 2. Synthesis of compounds 27 via alkynyliodonium salts.[a]
under Mitsunobu conditions.
The necessary alcohols 28 are
easily available. A Mitsunobu
reaction of N-formyl toluene-
sulfonamide 29 delivered mix-
tures of N- and O-alkylated
products 30/31, which—with-
out purification—were directly
converted to the dichlorovinyl
amides 32a–c in moderate to
good overall yields (depending
on the steric demand of the al-
cohols 28, which led to differ-
ent N/O ratios of the inter-
mediate products 30 and 31
that were formed by substitu-
tion of the ambident forma-
mide nucleophile). Chloride
elimination with nBuLi led to
ynamides 33a–c in excellent
yields.
Entry
1
R
Reaction time
3 d
26 (yield [%])
26a (65)
yield of 27 ([%])
27a (100)
2
16 h
26b (65)
27b (100)
3
4
5
16 h
2 d
26c (43)
27c (99)
27d (99)
–
26d (48)
2 d
slow decomposition
6
2 d
slow decomposition
–
[a] TMS=trimethylsilyl; TBAF=tetrabutylammonium fluoride
For the gold-catalyzed for-
mation of oxygen heterocycles
we used two different proce-
dures (methods A and B as de-
scribed in Scheme 7). Elimina-
tion to 34 with tBuLi at À788C
delivered cleaner crude alkynyl
ethers than elimination with
nBuLi. The isolated alkynyl
ethers 34a–e were used for
gold catalysis without further
purification. Both solvents
CH3CN and CHCl3 were suit-
AHCTREaUNG ble for the gold-catalyzed
transformations. When CH3CN
was used, a competitive addi-
Scheme 6. Different routes to tosylamides 24. DIAD=diisopropyl azodicarboxylate.
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Gold-Catalyzed Heterocycle Synthesis
FULL PAPER
Table 3. Synthesis of ynamides via N-formyl toluenesulfonamides.
chains, which are also stabi-
À
lized by C H–p interactions.
Remarkably, the unsubstituted
furans 34a and 34d reacted se-
lectively as well; the oxygen
atom directly attached to the
intermediate arene oxides 28
led to a selective ring opening;
this is in accord with our
recent studies on the mecha-
nism, which indicated that the
substrate and not the catalyst
determine the selectivity of the
last step, the opening of the in-
À
Entry
1
R OH
R
Reaction time [h]
16
32 (yield [%])
32a (21)
33 (yield [%])
33a (82)
21a
2
3
21b
18
16
48
32b (20)
32c (57)
33b (90)
33c (98)
termediate
arene
oxide
(Scheme 8).[17] The position of
the oxygen atom could be
proven by XRD analysis.
tion of water to substrate 34a finally led to ester 36 as a side
product. All reactions proceeded nicely and very quickly at
room temperature with 3–5 mol% AuCl3. The XRD analysis
of dihydrobenzofuran 35b (Figure 1) shows two independent
molecules with rather similar dimensions.[16] The molecules
are connected by intermolecular hydrogen bonds in zig-zag
Figure 2 shows the four independent conformers of the ele-
mental cell of a single crystal of 35d together with two
water molecules. The corresponding furans with propargylic
heteroatoms in the tether always delivered a mixture of con-
stitutional isomers.[3a] Unfortunately, efforts to achieve an in-
termolecular reaction of substrate 34e, analogous to previ-
ously reported results, with 2,5-dimethylfuran were unsuc-
cessful (Scheme 9).[18]
Scheme 8. The influence of the alkoxy substituent on the ring opening of
the arene oxides.
Figure 1. Solid state structure of 35b.
Scheme 7. Synthesis and gold-catalyzed conversions of the alkynyl ethers. TMEDA=N,N,N’,N’-tetramethylethylenediamine.
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A. S. K. Hashmi et al.
also obtained. The X-ray crys-
tal structure (Figure 4) shows
the typical square-planar sur-
roundings of the gold atom.
Tetrahydroquinolines
42b
and 42c were formed very
quickly and in good to excel-
lent yields from 33b/33c with
AuCl3 in CHCl3. In comparison
to earlier studies for the for-
mation of benzo-anellated six-
membered rings in the phenol
synthesis, the reaction times
here are much shorter. Again,
the unsubstituted furan 33a de-
livered a lower yield of 42a.
Once more, the yield of 42a
could be improved by switch-
Figure 2. Solid state structure of 35d.
Scheme 9. No efficient intermolecular phenol synthesis was observed
with the alkynyl ether 3e. Mes=mesityl; Tf=triflate.
The gold-catalyzed dihydroindole formation with substi-
tuted furan 27a delivered the product 39a in good yield and
with a very short reaction time (short reaction time relative
to other substrates in the phenol synthesis in which a hetero-
ACHTREUNGatom is not directly attached to the alkyne, Table 4) by
using 5 mol% AuCl3 as the catalyst. Single crystals for XRD
analysis could be obtained (Figure 3). An intramolecular hy-
drogen bond between the phenolic hydrogen atom and the
oxygen atom is observed. Problems occurred for unsubstitut-
ed substrate 27b. In this case, the reaction was very unselec-
Figure 3. Solid state structure of 39a.
tive for gold(I) complexes and only the pyridine–goldACHTRE(UNG III)
complexes 40[19] and 41 delivered a small amount of product
39b. During preparation of complex 41, single crystals were
Table 4. Gold-catalyzed conversion of the ynamines 27.
Figure 4. Solid state structure of catalyst 41.
Entry 27
Catalyst
Loading
[mol%]
Reaction
time
39 (yield
[%])
ing to pyridine complexes 40 and 41 (Table 5) in CD3CN.
Fortunately, single crystals for 42a could be obtained. The
X-ray crystal structure (Figure 5) unambiguously shows the
position of the oxygen atom at the 8-position of the tetrahy-
droquinoline structure. Two intermolecular hydrogen bonds
between the phenolic hydroxyl group and the oxygen atom
of the tosyl group are observed. The X-ray crystal structure
of product 42b shows two different conformers, which are
stabilized by two intermolecular hydrogen bonds (Figure 6).
Compound 42c also gave crystals suitable for XRD analysis
1
2
27a AuCl3
5
5 min
39a (62)
27b
27b
3
5 min
39b (13)
3
3
1 h
39b (9)
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Gold-Catalyzed Heterocycle Synthesis
FULL PAPER
Table 5. Gold-catalyzed conversion of the ynamines 33.
Entry 33
Catalyst Loading
[mol%]
T
[8C]
Solvent Reaction 42 (yield
time
[%])
Figure 7. Solid state structure of product 42c.
1
2
3
4
5
33a AuCl3
33a 40
33a 41
33b AuCl3
33c AuCl3
3
0
CDCl3 5 min
42a (17)
42a (26)
42a (37)
42a (88)
42a (67)
5
5
3
3
RT CD3CN 1 h
RT CD3CN 16 h
0
0
(Scheme 10). Compound 27c, with only one carbon atom in
the side chain, also did not produce a selective reaction.
CDCl3 5 min
CDCl3 5 min
Scheme 10. No selective intermolecular phenol synthesis was observed
with 27d.
Conclusion
The routes presented here, allow an efficient access to chro-
mans, dihydrobenzofurans, dihydroindoles, and tetrahydro-
quinolines from furans by two simple steps and a subsequent
gold-catalyzed reaction of the substrates containing an yn-
AHCTREaUNG mide and ynol ether moiety in the side chain. In contrary
to the reported gold-catalyzed reactions, no ring expansion
of the primary cyclopropyl carbenoids could be observed.
This indicates a very fast ring opening of the strained cyclo-
propyl carbenoid A, to form the monocyclic carbenoid B.
Furthermore, due to the stabilizing effect of the heteroatom,
which was directly attached to the intermediate pentadienyl
cation, selectivity problems were not observed for unsubsti-
tuted furans. Relative to other, previously described sub-
strate types for the phenol synthesis, the donor-substituted
alkynes reacted very quickly.
Figure 5. Solid state structure of product 42a.
Acknowledgement
We thank Umicore AG & Co KG, Hanau (Germany) for the donation of
gold salts.
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Figure 6. Solid state structure of product 42b.
(Figure 7). The molecule shows an intramolecular hydrogen
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Published online: June 23, 2008
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