Cyclization by catalytic ruthenium carbene insertion into C sp3 -H bonds

Article abstract of DOI:10.1002/anie.201107344

A novel tandem Ru-catalyzed carbene addition to terminal alkynes/insertion into C sp 3-H bonds in alkynyl acetals, ethers, and amines has been accomplished under mild reaction conditions (see scheme; TMS=trimethylsilyl). This cascade provides an efficient

Full text of DOI:10.1002/anie.201107344

Angewandte
Chemie
DOI: 10.1002/anie.201107344
Homogeneous Catalysis
À
Cyclization by Catalytic Ruthenium Carbene Insertion into Csp3
Bonds**
H
Fermꢀn Cambeiro, Susana Lꢁpez, Jesffls A. Varela, and Carlos Saµ*
À
Novel reactions that can selectively functionalize carbon
hydrogen bonds are very important because they offer new
strategic approaches in synthesis.[1] A remarkable method for
À
such C H functionalization involves the insertion of metal
[2]
À
À
carbenes into C H bonds. The regioselectivity of these C H
insertions is governed by electronic, steric, and conforma-
tional factors.[3] Typically, in nonconstrained systems, metal-
À
catalyzed intramolecular C H insertion reactions predom-
inantly afford five-membered rings (1,5-insertions).[2,4] The
formation of smaller and larger rings is achieved only when
À
geometrical constraints or activated C H bonds are
Scheme 1. Ru-catalyzed transformation of alkynyl derivatives in spiro
and fused bicyclic structures. Cbz=benzyloxycarbonyl, cod=1,5-cyclo-
octadiene, TMS=trimethylsilyl.
involved.[5] Usually, Rh-[6] and Cu-catalyzed[7] C H insertions
À
have shown amazing versatility in both intramolecular and
intermolecular reactions, but it is still a challenging goal to
discover other metals and tethers that facilitate the construc-
À
tion of rings by Csp3 H functionalization. Recently, special
attention has been paid to Pt-[8] and Au-catalyzed[9] intra-
molecular coupling between terminal unactivated alkynes
Table 1: Optimization of Ru-catalyzed 1,5-hydride shift/cyclization
sequence in alkynyl dioxolane 1a.[a]
À
and Csp3 H bonds in alkynyl ethers and amines to produce
complex spiro or fused bicyclic systems by a tandem 1,5-
hydride shift/cyclization sequence.[10] The above methods
require temperatures as high as 100–1208C to achieve good
results and under Pt catalysis only 5-exo methylene bicyclic
structures are formed. We report herein a mild procedure
based on a novel tandem Ru-catalyzed carbene addition to
Entry
Solvent
t [min]
2a [%][b]
3a [%][b]
À
terminal alkynes/insertion into Csp3 H bonds in alkynyl
1[c]
2
dioxane
dioxane
Et2O
MeOH
THF
20
20
20
2 h
20
40
30
80
66 (2a’)
36
50
28
–
–
41
–
acetals, ethers, and amines to form complex spiro and fused
bicyclic structures by 1,5- and 1,6-hydride shift/cyclization
sequences (Scheme 1).[11]
3
4[d]
5
The cyclization of dioxolane 1a was the first reaction
examined under a variety of catalytic conditions (Table 1).
After some preliminary experiments,[12] the well-known
conditions, established by Dixneuf and co-workers, for the
preparation of Ru carbenes starting from alkynes were
employed.[13] Thus, a 1,5-hydride shift/cyclization sequence
gave the functionalized spiro[5,5] compound 2a in a moderate
yield of 40% and the linear hydroxyester 3a as the major
6
toluene
Et2O
12 h
12 h
40
34
7[e]
–
[a] Typical reaction conditions: [Cp*Ru(cod)Cl] (10 mol%), N2CHTMS
(1 equiv), RT, [1a]=0.15m. [b] Yields of the isolated products. [c] Reac-
tion performed at 608C. [d] 2a’=desilylated 2a (H instead TMS).
[e] 10 mol% of [CpRu(cod)Cl] was used as catalyst.
isolated product in 50% yield, by stirring a dioxane solution
of 1a (0.15m) with 1 equivalent of N2CHTMS (2m in hexanes)
and 10 mol% of [Cp*Ru(cod)Cl] as catalyst at 608C (Table 1,
entry 1). A lower overall yield and a similar ratio of 2a and 3a
were obtained when the reaction was performed in dioxane at
room temperature (Table 1, entry 2). Gratifyingly, the desired
spiro compound 2a or its desilylated analogue 2a’[13e,g] were
isolated in fairly good yields (66–80%) when the reactions
were carried out in either diethyl ether or MeOH at room
temperature (Table 1, entries 3 and 4).[14] However, other
typical solvents like THF and toluene gave either lower yields
and/or longer reaction times (Table 1, entries 5 and 6).
[*] F. Cambeiro, Dr. S. Lꢀpez, Dr. J. A. Varela, Prof. C. Saꢁ
Departamento de Quꢂmica Orgꢁnica y Centro Singular de Inves-
tigaciꢀn en Quꢂmica Biolꢀgica y Materiales Moleculares (CIQUS),
Universidad de Santiago de Compostela
15782 Santiago de Compostela (Spain)
E-mail: carlos.saa@usc.es
Homepage: http://www.usc.es/gi1603/saa
[**] We thank the MICINN [Projects CTQ2008-06557, CTQ2011-28258,
Consolider Ingenio 2010 (CSD2007-00006)] and Xunta de Galicia
(2007/XA084 and CN2011/054) for financial support. F.C. thanks
the Xunta de Galicia and MICINN for a predoctoral grant.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107344.
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Changes in the electronic and steric nature of the neutral RuII
catalyst on using [CpRu(cod)Cl] strongly affected the course
of the reaction resulting in an increase in the reaction time
and an a decrease in the conversion and yield (Table 1,
entry 7).[15]
Table 2: Ru-catalyzed 1,5-hydride Shift/cyclization sequence in alkynyl
acetals 1, ethers 5 and amines 7.[a]
Entry
Substrate
Product
Yield
[%][b]
More challenging substituted dioxolanes 1 were also
examined (Table 2). Thus, spiro compound 2b was obtained
in low yield when the formation of the putative Ru carbene
was hindered by a Csp substituent in dioxolane 1b (Table 2,
entry 1). The nature of Z (see Scheme 1) had a significant
effect on the course of the reaction,[16] with hydroxyester 3c
being the major isolated product in the case of 1c, Z =
(CH2O)2CMe2 (Table 2, entry 2).[17] The course of the reaction
1
25[c]
2
3
61[d]
61[e]
was also influenced by stereoelectronic effects on the
[18]
À
activated C H bond. Thus, rigid cyclic acetal 1a afforded
a higher yield of spiro compound 2a (Table 1, entry 3) in
comparison to the linear acetals 1d and 1e (Table 2, entries 3
4
40[e]
À
and 4). Gratifiyngly, diastereoselective C H activation of
ethers took place to give smoothly the corresponding
functionalized cyclic compounds. Thus, cyclization of acyclic
ether 5a and cyclic tetrahydrofuranyl and tetrahydropyranyl
ethers 5b[19] and 5c gave the corresponding trans-homoallylic
ether 6a and 1-oxaspiro[4,4]nonane and 6-oxaspiro-
[4,5]decane 6b and 6c, respectively, as a single (or major)
diastereoisomer in fairly good yields upon isolation (Table 2,
entries 5, 6 and 8). The presence of an ether to activate the
5
6
7
53[f]
79[g]
55[h]
48[i]
À
Csp3 H for cyclization is mandatory since the hydrocarbon 7a
was totally recovered under all the reaction conditions tried
(Table 2, entry 9). Note also the dramatic effect of the ring
size of the cyclic ether on the reaction time (20 min for a five-
membered ring versus 12 h for a six-membered ring), thus
highlighting the crucial role of steric hindrance in the reaction
(Table 2, entries 6 and 8). When electron-poor N2CHCO2Et
was used instead of N2CHTMS, cyclization of 5b was not
diastereoselective, thus giving the corresponding spiro deriv-
ative 6bꢀ in lower yield (Table 2, entry 7).[13] Interestingly,
pyrrolidine 8a also underwent smooth cyclization to give 1-
azaspiro[4,4]nonane 9a as a single diastereomer in rather
good yield (Table 2, entry 10).
8
[j]
9
–
–
10
85
We next turned our attention to the reactivity of C3-
linked heterocycles such as tetrahydrofurans 10a and piper-
idine 11a (Table 3).[8,9] To our delight, fused bicyclic tetrahy-
drofuran 12a and piperidine 13a were obtained in fairly good
yields (Table 3, entries 1 and 2), thus showing the efficient
[a] Typical reaction conditions: [Cp*Ru(cod)Cl] (10 mol%), N2CHTMS
(1 equiv), RT, 0.5 h–2 h, diethyl ether. [b] Yields of the isolated products.
[c] A small amount of silyl conjugated diene 4b (11%) was also obtained
(see Ref. [13]). [d] Spiro derivative 2c was also obtained in 20% yield as
an E/Z mixture (5:1). [e] Dioxane, 608C, 10 h. [f] Dioxane, 608C, 12 h.
[g] Obtained as a 4:1 diastereomeric mixture of E isomers. [h] Dioxane,
3 equiv of N2CHCO2Et, sealed tube, 1108C, 24 h; obtained as a 1:1
diastereomeric mixture of E isomers. [i] 1 equiv of N2CHTMS, 12 h.
[j] Reaction conditions tried: diethyl ether, RT, dioxane, 608C, and
MeOH, RT.
À
functionalization of secondary C H bonds a to a heteroatom
(O, N). Remarkably, a single diastereoisomer of bicyclic
piperidine 13a, containing three consecutive stereocenters,
was obtained.
Gratifyingly, a new 1,6-hydride shift/cyclization process
took place when dioxolane 14a was smoothly converted into
the 1,4-dioxaspiro[4,5]decane 15a in excellent yield (Table 4,
entry 1). This new tandem process also efficiently occurred in
the case of substituted dioxolane 14b and dioxolanes 14c,d to
afford the corresponding 1,4-dioxaspiro[4,5]decanes 15b–d in
relatively good yields (Table 4, entries 2–4). A comparison of
the cyclizations of dioxolanes 1c (Table 2, entry 2) and 14c
(Table 4, entry 3) shows the easier formation of the 1,4-
dioxaspiro[4,5]decane 15c versus 1,4-dioxaspiro[4,4]nonane
2c; this result clearly indicates that the conformation of the
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Table 3: Ru-catalyzed 1,5-hydride shift/cyclization sequence in alkynyl
C3-linked heterocycles 10 and 11.[a]
Entry
Substrate
Product
Yield
[%][b]
51[c]
87[d]
1
2
61
[a] Typical reaction conditions: [Cp*Ru(cod)Cl] (10 mol%), N2CHTMS
(1 equiv), RT, 0.5 h–2 h, diethyl ether. [b] Yields of the isolated products.
[c] Mixture of diastereomers. [d] Dioxane, 608C.
Scheme 2. Deuterium labeling experiments. THF=tetrahydrofuran.
position. In addition, deuterium was not incorporated into
the cyclized product 6b when the reaction of 5b was
conducted in [D8]THF.[21,22]
Table 4: Ru-catalyzed 1,6-hydride shift/cyclization sequence in alkynyl
acetals 14.[a]
Entry
Substrate
Product
Yield
[%][b]
Although more mechanistic investigations would be
desirable to clarify the role of the solvent in the catalytic
cycle, the labeling studies strongly support the initial mech-
anistic hypothesis shown in Scheme 3. The complex [Cp*Ru-
(cod)Cl] easily loses its cod ligand in the presence of alkyne 1
and N2CHSiMe3, thus leading to ruthenium carbene species
I.[13,23] Oxidative coupling to give a metallacyclobutene,[24]
with a subsequent ring opening of this species would lead to
the Ru vinyl carbene II.[25] The electrophilic Ru carbene could
induce a 1,5-hydride shift that would lead to the formation of
a transient oxonium ion, which would in turn interact with the
nucleophilic ruthenium to afford the metallacycle III. A final
reductive elimination would give rise to the spiro compound 2
with recovery of the catalytic RuII species in the presence of
81
1
90[c]
2
61[d]
3
4
60
51
[a] Typical reaction conditions: [Cp*Ru(cod)Cl] (10 mol%), N2CHTMS
(1 equiv), RT, diethyl ether. [b] Yields of the isolated products. [c] Diox-
ane, 608C. [d] Mixture of diastereomers (3:1) of E isomers.
metallic intermediate plays a definitive role during the course
of the reaction.[20]
In an effort to gain further insights into the mechanism of
these tandem sequences, a series of deuterium labeling
experiments were conducted. We focused on the cyclization
of deuterium labeled tetrahydrofuranyl ethers [D]-5b and
[D]-5b’’ (Scheme 2).
In the reaction of [D]-5b, the deuterium atom in the
position a to the oxygen was completely transferred to the
allylic position of 1-oxaspiro[4,4]nonane [D]-6b, thus sup-
porting a mechanism involving a hydride transfer. On the
other hand, the cyclization of deuterated alkyne [D]-5b’’
afforded the 1-oxaspiro[4,4]nonane [D]-6b’’ in which the
deuterium was incorporated selectively at the b vinylic
Scheme 3. Mechanistic hypothesis for the Ru-catalyzed intramolecular
À
carbene insertion into Csp3 H bonds.
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725

.
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Communications
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À
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In summary, we have shown that a series of readily
available linear alkynyl acetals, ethers, and amines can be
transformed into spirobicycles and fused bicyclic structures by
means of a Ru-catalyzed intramolecular carbene insertion
À
into Csp3 H bonds. These cyclizations, which could be applied
mainly to terminal alkynes, enable the efficient conversion of
À
À
secondary or tertiary Csp3 H bonds into new C C bonds
under practical reaction conditions. Deuterium labeling
experiments support a mechanistic hypothesis involving an
initial 1,5- or 1,6-hydride shift onto a Ru vinyl carbene
followed by cyclization. This investigation opens up oppor-
tunities for the development of new Ru-catalyzed cyclizations
and we are currently studying this area in our laboratories.
Experimental Section
Typical experimental procedure: In a round-bottomed flask contain-
ing 1a (70 mg, 0.273 mmol, 1 equiv), N2CHTMS (0.136 mL,
0.273 mmol, 1 equiv, 2m in hexane) in diethyl ether (2 mL) was
added the catalyst [Cp*RuCl(cod)] (10 mg, 0.027 mmol, 0.1 equiv).
The resulting solution was stirred at room temperature for 20 min
until disappearance of starting material (monitored by TLC and GC/
MS). The reaction was quenched with a saturated aqueous solution of
NH4Cl (2 mL) and extracted with diethyl ether (3 ꢀ 5 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
evaporated to dryness. The crude residue was purified by column
chromatography on silica gel using a mixture of n-hexane/EtOAc
(8:2) as eluent to afford 2a (74 mg, 80%) as a yellowish oil. 1H NMR
(400 MHz, CDCl3): d = 5.95 (dd, J = 18.7, 7.2 Hz, 1H), 5.77 (d, J =
18.7 Hz, 1H), 3.93–3.80 (m, 4H), 3.71 (s, 6H), 2.80–2.72 (m, 1H),
2.56–2.42 (m, 3H), 2.25 (dd, J = 13.4, 12.2 Hz, 1H), 0.02 ppm (s, 9H).
13C NMR (100 MHz, CDCl3): d = 172.4 (CO), 171.8 (CO), 142.8
(CH), 133.7 (CH), 116.4 (C), 65.4 (CH2), 65.0 (CH2), 55.0 (C), 53.0
(CH), 52.9 (CH3), 52.8 (CH3), 43.3 (CH2), 36.8 (CH2), À1.3 ppm (3 ꢀ
CH3). MS (ESI): m/z (%): 365 ([M+Na]+, 100), 298 (13), 214 (14).
HRMS (ESI): m/z calcd for C16H27O6Si: 343.1577 [M+H]+ found:
343.1579.
Received: October 18, 2011
Revised: November 16, 2011
Published online: November 30, 2011
Keywords: alkynyl derivatives · carbenes · cyclization ·
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À
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[10] For
a
Rh-catalyzed tandem 1,5-hydride shift/cyclization
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À
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À
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[14] Neglibible variation in time and yield was observed on using 2m
N2CHTMS in diethyl ether.
[20] Unfortunately, a 1,7-hydride shift/cyclization sequence was not
observed when dioxolane 16 was subjected to the typical and
modified reaction conditions, and starting material was recov-
ered unchanged.
[21] A 4:1 diastereomeric mixture of E isomers is obtained in the
three experiments (see Table 2, entry 6), only the major
diastereomer is shown. See the Supporting Information for
details.
[22] In addition, cyclization of acetal 1a in CD3OD gave rise to
monodeuterated 2a’ as a 1:1 mixture of E and Z isomers (60%
combined yield). See the Supporting Information for details.
[15] Similar effects have been found in other Ru carbene reactions,
see ref. [13g].
[16] No cyclization was observed with 1 f.
=
[23] For the isolation of (C5H5)Cl(PPh3)Ru CHTMS, see: T. Braun,
G. Mꢆnch, B. Windmꢆller, O. Gevert, M. Laubender, H. Werner,
Chem. Eur. J. 2003, 9, 2516 – 2530.
[24] For the isolation and characterization of a cobaltacyclobutene
analogue, see: J. M. OꢅConnor, H. Ji, M. Iranpour, A. L.
Rheingold, J. Am. Chem. Soc. 1993, 115, 1586 – 1588.
[25] For the stereochemical course of ring opening of metallacyclo-
butene intermediates, see Ref. [13g]; for a review on ruthenium
vinyl carbene intermediates in enyne metathesis, see: S. T. Diver,
Coord. Chem. Rev. 2007, 251, 671 – 701.
[17] Cyclization in the presence of molecular sieves (4 ꢄ) gave rise to
a lower overall yield (68%) with a slightly minor proportion of
3c (44%).
[18] E. V. Anslyn, D. A. Dougherty, Modern Physical Organic
Chemistry, University Science Books, 2006.
Angew. Chem. Int. Ed. 2012, 51, 723 –727
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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