Catching Elusive 2-Furyl Carbenes with Silanes: A Metal-Free Microwave-Assisted Silicon-Hydrogen Bond Functionalization

Article abstract of DOI:10.1002/adsc.201601037

An efficient, metal-free, silicon–hydrogen bond functionalization based on the microwave-assisted reaction of readily available enynones and silanes is reported. This process seemingly proceeds through a 2-furyl carbene species, a particularly elusive intermediate. Preliminary studies on the metal-free oxygen–hydrogen and nitrogen–hydrogen bond functionalization of representative alcohols, azoles and sulfonamides are also provided. (Figure presented.).

Full text of DOI:10.1002/adsc.201601037

UPDATES
DOI: 10.1002/adsc.201601037
Catching Elusive 2-Furyl Carbenes with Silanes: A Metal-Free
Microwave-Assisted Silicon-Hydrogen Bond Functionalization
Silvia Gonzꢀlez-Pelayoa and Luis A. Lꢁpeza,*
a
Departamento de Quꢂmica Orgꢀnica e Inorgꢀnica and Instituto Universitario de Quꢂmica Organometꢀlica “Enrique
Moles”, Universidad de Oviedo, c/ Juliꢀn Claverꢂa, 8, 33006 Oviedo, Spain
E-mail: lalg@uniovi.es
Received: June 13, 2016; Revised: September 19, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601037.
Abstract: An efficient, metal-free, silicon–hydrogen
bond functionalization based on the microwave-as-
sisted reaction of readily available enynones and si-
lanes is reported. This process seemingly proceeds
through a 2-furyl carbene species, a particularly elu-
sive intermediate. Preliminary studies on the metal-
free oxygen–hydrogen and nitrogen–hydrogen bond
functionalization of representative alcohols, azoles
and sulfonamides are also provided.
enynones and the exclusive use of protic solvents
(water and alcohols) as trapping reagents impose sig-
nificant limitations on the synthetic applicability of
this methodology. In particular, silanes and alkenes
were found to be completely unsuccessful trapping re-
agents.
Clearly, the development of readily available pre-
cursors for the generation of 2-furyl carbenes suscep-
tible of being intercepted by suitable trapping re-
agents would be particularly appealing.
Keywords: carbenes; furans; metal-free coinditions;
microwave-assisted reaction; silanes
2-Furyl carbenes are elusive intermediates and, for
this reason, they have traditionally been regarded as
synthetically useless intermediates.[1] As a result, a ple-
thora of transition metal-based alternatives have been
reported in the last years.[2]
Generated from 2-furyl diazo compounds or 2-fur-
yldiazirine derivatives, these intermediates undergo
a rapid ring-opening reaction to give enynones, which
precludes their capture when generated in the pres-
ence of potential trapping reagents (Scheme 1, A).[3]
In a different approach, in 1995, Saito et al. man-
aged the photochemical generation and subsequent
intermolecular trapping by protic solvents of 2-furyl
carbene intermediates arising from enynes featuring
a conjugated a-diketone moiety (Scheme 1, B).[4] The
a-diketone structural motif was found to be crucial
for the success of the cyclization step since substrates
lacking the additional carbonyl group located adja-
cent to that one involved in the cyclization did not
afford any product resulting from the trapping of the
postulated carbene intermediate. Although this con-
tribution represents the first high-yield trapping reac-
tion of 2-furyl carbene intermediates, the need of
Scheme 1. Generation and trapping of 2-furyl carbene inter-
a multistep sequence for the synthesis of the starting mediates.
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Due to our recent interest in the silicon–hydrogen excess of triethylsilane was required (Table 1,
bond functionalization[5] and inspired by a recent entry 7).
work of Bertrand and co-workers on the activation of
Inductively coupled plasma mass spectrometry
Si–H bonds with stable singlet carbenes,[6] we decided (ICP-MS) analyses ruled out the involvement of
to test the thermal behaviour of readily available en- metal species arising from contamination of reactants
ACHTUNGTRENNUNG
hydrogen bond functionalization based on the trap- stration of the feasibility of using enynones as 2-furyl
ping of 2-furyl carbene intermediates.[7] Preliminary carbene precursors for the metal-free silicon–hydro-
studies on the functionalization of other heteroatom– gen bond functionalization.
hydrogen bonds are also disclosed.
With the optimized reaction conditions in hand (mi-
On the outset we studied the reaction of enynone crowave heating at 1408C in toluene, 3 equiv. of
1a with triethylsilane 2a under a variety of reaction silane), the substrate scope of this metal-free silicon–
conditions (Table 1). First, we found that heating hydrogen bond functionalization was assessed using
a mixture of 1a and 2a (6 equiv.) in toluene at 908C a range of enynones and silane derivatives (Table 2).
for 48 hours afforded the furan derivative 3a in 20%
Regarding the enynone component, both electron-
yield after chromatographic purification (Table 1, rich (enynone 1b; R1 =R2 =Me, R3 =p-MeOC6H4)
entry 1). Gratifyingly, when the reaction was per- and electron-poor (enynone 1c; R1 =R2 =Me, R3 =p-
formed under microwave heating at 1408C an im- O2NC6H4) aromatic groups at the acetylenic position
proved yield was achieved (84% isolated yield, (R3) were found to be well tolerated in this transfor-
Table 1, entry 2). Next, we tried to reduce the amount
of the silane component. Although the reaction
worked well with a nearly stoichiometric amount of
Table 2. Microwave-assisted reaction of enynones 1 and si-
lanes 2: scope.[a]
the silane component (Table 1, entry 4), the use of
3 equiv. proved optimal in terms of yield (quantitative
by NMR; 91% isolated yield; Table 1, entry 3). The
reaction could also be performed under standard oil-
bath conditions, although these conditions required
an extended reaction time to afford a comparable
yield (Table 1, entries 5 and 6). The reaction also pro-
ceeded in the absence of solvent but in this case an
R1, R2, R3
R4, R5
3, Yield[b]
Me, Me, Ph
Et, Et
Et, Et
Et, Et
Et, Et
Et, Et
Et, Et
Et, Et
Et, Et
3a, 91% (90)[5a]
3b, 85% (86)[5a]
3c, 82% (69)[5a]
3d, 79% (59)[5a]
3e, 69% (77)[5a]
3f, 71%
Table 1. Optimization of the reaction conditions: summary.[a]
Me, Me, p-MeOC6H4
Me, Me, p-O2NC6H4
Me, Me, 1-cyclohexenyl
Me, Me, n-C5H11
Me, Me, n-C8H17
Me, Me, CH2CH2Ph
Me, Me, (CH2)4OTBS
Et, Et, Ph
3g, 54% (81)[5b]
3h, 55% (70)[5b]
3i, 54%
Et, Et
Et, Et
Me, OEt, Ph
Me, Me, Ph
3j, 53% (65)[5b]
3k, 83% (71)[5b]
3l, 75%
Me, Bn
Me, Bn
Me, Bn
Me, Bn
Me, Ph
Me, Ph
Ph, Me
Ph, Ph
TMS, TMS
Et, H
Entry
n
Solvent
T [8C]
t [h]
Yield [%][b]
Me, Me, p-MeOC6H4
Me, Me, p-O2NC6H4
Me, Me, n-C5H11
Me, Me, Ph
Me, Me, n-C5H11
Me, Me, Ph
Me, Me, Ph
Me, Me, Ph
Me, Me, Ph
1
2
3
4
5
6
7
6
6
3
1.5
3
toluene
toluene
toluene
toluene
toluene
toluene
–
90
48
4
4
4
4
20
3m, 66%
140 (MW)
140 (MW)
140 (MW)
140
140
100
84
3n, 60%
91[c]
71
3o, 77% (67)[5b]
3p, 71% (68)[5a]
3q, 82%[c]
30[d]
80
3
30
12
22
3r, 75%[c]
77
3s, 38%[c]
3t, 91%[c] (54)[5b]
[a]
Unless otherwise stated, these exploratory experiments
were performed on a 0.2 mmol scale.
Isolated yields unless otherwise specified.
99% yield by NMR (dibromomethane as internal stan-
dard).
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol, 3 equiv.),
toluene (0.1M), 1408C (microwave heating).
Yield of isolated product after column chromatography.
The values in parenthesis correspond to the yields report-
ed in the literature for the zinc-catalyzed reaction.[5]
Reaction run with 6 equivalents of silane.
[b]
[c]
[b]
[c]
[d]
Crude yield by NMR (dibromomethane as internal stan-
dard).
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mation providing furan derivatives 3b and 3c in good
isolated yields (85 and 82%, respectively).
Similarly, a substrate bearing an alkenyl group at
this position (enynone 1d; R3 =cyclohexenyl) posed
no problems giving rise to furan derivative 3d in 79%
isolated yield.
Enynones 1e–g with alkyl chains installed at the
acetylenic position were also suitable substrates for
this transformation affording the corresponding furan
derivatives 3e–g in moderate isolated yields. A pro-
tected alcohol in the alkyl chain [enynone 1h; R3 =
(CH2)4OTBS] was also well tolerated.
Scheme 2. Control experiments performed in the absence of
silane reagent.
tionalization sequence, we decided to extend the
Some modifications on the structure of the enynone study to the generation of the benzofused analogue
component were also realized. Thus, enynones 1i intermediate, namely a benzofuran carbene inter-
(R1 =R2 =Et, R3 =Ph) and 1j (R1 =Me, R2 =OEt, mediate. In this regard, we envisioned alkynyl-substi-
R3 =Ph) behaved similarly and afforded the expected tuted o-hydroxybenzyl alcohol 4 as a suitable starting
furan derivatives 3i and 3j in moderate isolated yields. substrate. We surmised that initial microwave-assisted
Next, the scope of this metal-free silicon–hydrogen thermal dehydration to furnish the corresponding o-
bond functionalization was expanded to other silanes. quinone methide,[9] followed by cyclization and trap-
Indeed, benzyldimethylsilane (2b) and phenyldime- ping of the resulting benzofuryl carbene could repre-
thylsilane (2c) readily reacted with enynones 1 deliver- sent a convenient metal-free approach to silyl-substi-
ing the corresponding furan derivatives 3k–p in good tuted benzofuran derivatives. In fact, the formation of
yields. Diphenylmethylsilane (2d) and triphenylsilane benzofuran derivative 5 in 70% isolated yield after
(2e) also proved to be suitable silane counterparts in heating a mixture of alkynyl-substituted o-hydroxy-
this microwave-mediated transformation providing benzyl alcohol 4 and triethylsilane (2a) in toluene at
the corresponding functionalized furan derivatives 3q 1708C clearly demonstrated the feasibility of this
and 3r in 82 and 75% yields, respectively. Even methodology (Scheme 3).
a highly sterically encumbered trisubstituted silane,
namely tris(trimethylsilyl)silane (2f), was able to par-
ticipate in this transformation although with a signifi-
cant decrease in the yield. Finally, the reaction of eny-
none 1a and diethylsilane (2g) posed no problems de-
livering the corresponding furan derivative 3t in ex-
cellent isolated yield. In contrast, phenylsilane and
triethoxysilane were not suitable reagents under our
reaction conditions.
As shown in Table 2, in most cases the yields of this
metal-free reaction are equivalent or superior to
those reported in our previous zinc-catalyzed reac-
tion.[5]
Next, we conducted some control experiments in
absence of silane aimed at gaining insight into the
structure of the intermediate involved in this transfor-
mation. Thus, when solutions of enynones 1a (R1 =
R2 =Me, R3 =Ph) and 1e (R1 =R2 =Me, R3 =n-C5H11)
Scheme 3. Microwave-mediated, metal-free synthesis of ben-
zofuran derivative 5.
Having established the feasibility of using enynones
in toluene were heated under microwave irradiation 1 as 2-furyl carbene precursors, preliminary studies
at 1408C for 6 h, neither a dimerization product nor were also conducted to assess the potential of this
(in the case of enynone 1e) a vinylfuran derivative re- metal-free methodology for the functionalization of
sulting from a 1,2-H shift were observed, with the ma- oxygen–hydrogen bonds (Scheme 4).[10]
jority of mass balance being unreacted enynone
Initially, we found that the reaction of enynone 1a
(Scheme 2). These observations are in full agreement with methanol (6a) as the trapping reagent under the
with those previously reported by Shechter and co- conditions developed for the silicon–hydrogen bond
workers in the generation of 2-furyl carbenes by functionalization (3 equivalents of methanol, toluene
vacuum pyrolyses of some tosylhydrazone sodium as solvent, microwave heating at 1408C for 6 hours),
salts.[8]
afforded only traces of the corresponding ether 7a.
To further demonstrate the synthetic utility of this Pleasingly, the use of methanol as solvent at 1008C
metal-free cyclization/silicon–hydrogen bond func- provided a significant improvement of the yield. On
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able enynones and silanes to afford functionalized fur-
ylsilanes. This non-diazo silicon–hydrogen bond func-
tionalization is believed to proceed by means of a 2-
furyl carbene intermediate, which in turn would be
trapped by the silane. It is worthy of note that, with
a few notable exceptions, these intermediates have
largely defied trapping. Notable aspects of our proto-
col are: (i) availability of the starting materials, (ii)
easy execution, (iii) complete atom efficiency, and (iv)
synthetically useful yields. Preliminary results demon-
strated that this protocol could be used for the gener-
ation and trapping of other heteroaryl carbenes as
well as for the functionalization of other heteroatom–
hydrogen bonds. In our opinion, these preliminary
findings could open up new pathways for the develop-
ment of new metal-free methodologies, an attractive
field in contemporary organic synthesis. In particular,
our group is actively pursuing the development of
new strategies for the metal-free C–C bond forma-
Scheme 4. Microwave-assisted O–H bond functionalization.
the other hand, reaction of enynone 1a with allylic al- tion, a traditional domain of metal-based methodolo-
cohol (6b, 3 equivalents) in toluene at 1408C proceed- gies.
ed with complete chemoselectivity delivering furyl
ether derivative 7b in excellent isolated yield (91%).
Significantly, under these reaction conditions neither Experimental Section
cyclopropanation of the olefinic moiety nor insertion
into the allylic carbon–hydrogen bonds were ob- Representative Procedure (3a)
served.
A 2–5-mL microwave vial was charged with the enynone 1a
(42.4 mg, 0.2 mmol), triethylsilane 2a (69.8 mg, 0.6 mmol,
3.0 equiv.), toluene (2 mL) and a stirring bar. The vessel was
Finally, we also briefly examined the feasibility of
a hydrogen–nitrogen bond functionalization. After
some optimization, we found that reaction of en-
ACHTUNGTRENNUNGynones 1a (R=Ph) and 1b (R=p-MeOC6H4) with an
excess of pyrazole (8) in toluene at 1408C led to the
formation of furyl- and pyrazolyl-containing triaryl-
methane derivatives 9a and 9b in good isolated yields
(Scheme 5). Extension of this protocol to 4-toluene-
sulfonamide (10) produced the functionalized furan
derivative 11a in 70% isolated yield.
sealed with a septum, placed into the microwave cavity and
irradiated to maintain the reaction at 1408C for 4 hours in
a Biotage Initiator microwave apparatus. The solvent was
removed under reduced pressure. 1H NMR (dibromome-
thane as internal standard) revealed the formation of furan
derivative 3a in quantitative yield. Purification by flash
chromatography (SiO2, hexane:EtOAc=10:1) furnished 3a
as a pale yellow oil; yield: 59.8 mg (91%). 1H NMR:
(400 MHz, CDCl3): d=0.61 (q, J=8.0 Hz, 6H), 0.88 (t, J=
8.0 Hz, 9H), 2.37 (s, 3H), 2.58 (s, 3H), 3.63 (s, 1H), 6.23 (s,
1H), 7.14–7.22 (m, 3H), 7.26–7.30 (m, 2H); 13C-NMR
(100 MHz, CDCl3): d=2.9 (CH2), 7.2 (CH3), 14.5 (CH3),
29.1 (CH3), 35.2 (CH), 105.6 (CH), 122.2 (C), 125.3 (CH),
127.9 (CH), 128.4 (CH), 140.3 (C), 154.8 (C), 156.6 (C),
194.3 (C); HR-MS (EI): m/z=328.1858, calculated for
[C20H28O2Si]+ (M+): 328.1859.
In short, we have described the microwave-mediat-
ed, metal- and additive-free reaction of readily avail-
Acknowledgements
Financial support from Ministerio de Economꢀa y Competiti-
vidad (MINECO) and Principado de Asturias (grants
CTQ2013-41511-P, GRUPIN14-013) is gratefully acknowl-
edged. We are also grateful to Prof. J. M. Gonzꢁlez for inter-
esting discussions.
Scheme 5. Microwave-assisted N–H bond functionalization.
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6 Catching Elusive 2-Furyl Carbenes with Silanes: A Metal-
Free Microwave-Assisted Silicon-Hydrogen Bond
Functionalization
Adv. Synth. Catal. 2016, 358, 1 – 6
Silvia Gonzꢀlez-Pelayo, Luis A. Lꢁpez*
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