Nucleophilic addition of amines to ruthenium carbenes: Ortho-(alkynyloxy)benzylamine cyclizations towards 1,3-benzoxazines

Article abstract of DOI:10.1002/anie.201410284

A new ruthenium-catalyzed cyclization of ortho-(alkynyloxy)benzylamines to dihydro-1,3-benzoxazines is reported. The cyclization is thought to take place via the vinyl ruthenium carbene intermediates which are easily formed from [CpRuCl(cod)] and N₂CHSiMe₃. The mild reaction conditions and the efficiency of the procedure allow the easy preparation of a broad range of new 2-vinyl-2-substituted 1,3-benzoxazine derivatives. Rearrangement of an internal C(sp) in the starting material into a tetrasubstituted C(sp³) atom in the final 1,3-benzoxazine is highly remarkable.

Full text of DOI:10.1002/anie.201410284

Angewandte
Chemie
DOI: 10.1002/anie.201410284
Synthetic Methods
Nucleophilic Addition of Amines to Ruthenium Carbenes: ortho-
(Alkynyloxy)benzylamine Cyclizations towards 1,3-Benzoxazines**
Carlos Gonzꢀlez-Rodrꢁguez,* Josꢂ Ramꢃn Suꢀrez, Jesffls A. Varela, and Carlos Saꢀ*
Abstract: A new ruthenium-catalyzed cyclization of
ortho-(alkynyloxy)benzylamines to dihydro-1,3-benz-
oxazines is reported. The cyclization is thought to take
place via the vinyl ruthenium carbene intermediates
which are easily formed from [Cp*RuCl(cod)] and
N2CHSiMe3. The mild reaction conditions and the
efficiency of the procedure allow the easy preparation
of a broad range of new 2-vinyl-2-substituted 1,3-
benzoxazine derivatives. Rearrangement of an internal
C(sp) in the starting material into a tetrasubstituted
C(sp3) atom in the final 1,3-benzoxazine is highly
remarkable.
T
he in situ generation of catalytically active metal
carbenes from diazoalkanes (e.g., copper, rhodium,
and ruthenium) has contributed to the recent devel-
opment of synthetically useful transformations cata-
lyzed by these intermediates.[1] Cyclopropa(e)nation
reactions, which involve interaction of the generated
metal carbenes with unsaturated units (alkenes,
À
alkynes, enynes, etc.), and X H bond insertions
(X = C, O, S, N, Si, etc.) are characteristic trans-
formations associated with these metal carbenes.[2]
Recently, efficient syntheses of aza-heterocycles by
direct rhodium-, copper-, and ruthenium-catalyzed
Scheme 1. Azacyclizations catalyzed by metal carbenes. TMS=trimethylsilyl.
intramolecular addition of amines to metal carbenes have
was recently introduced by Dixneuf and co-workers and
employs a combination of a ruthenium precatalyst, a commer-
cial diazo compound, and an alkyne.[4] We recently reported
À
been reported (Scheme 1). Metal carbenoid N H insertion
reactions (Scheme 1a) and [1,2] rearrangements (Scheme 1b)
or [2,3] sigmatropic rearrangements of cyclic ammonium
ylides (Scheme 1c) afforded a broad range of azahetero-
cycles.[3] Nevertheless, the major drawback with these meth-
ods concerns the often troublesome installation of an
activated diazoalkane (e.g., conjugated with a carbonyl
group) within the starting material. A simple and mild
generation of catalytic vinylcarbene ruthenium intermediates
carbocyclizations involving the insertion of vinyl ruthenium
3
carbenes into C(sp ) H bonds[5] and we have now envisioned
À
a new entry into azaheterocycles by intramolecular nucleo-
philic addition of amines to these electrophilic ruthenium
carbenes.[6] To test our hypothesis, we began the study with
the cyclization of the alkynyloxyamine 1a in the presence of
the precatalyst [Cp*RuCl(cod)] and TMSCHN2. To our
surprise, the six-membered 2,2-disubstituted 1,3-benzoxazine
2a was isolated in fairly good yield (Scheme 1d).[7] The crucial
role of the oxygenated tether in this unprecedented rear-
rangement[8] became evident when the alkynylamine 1b
smoothly evolved into the conjugated diene 3b. To our
knowledge, this is the first example of a nucleophilic addition
of an amine to in situ generated vinyl ruthenium carbenes.
1,3-Benzoxazine derivatives often display a wide range of
biological activities,[9] undergo useful synthetic transforma-
tions,[10] and also polymerize by cationic ring-opening poly-
merization to form polybenzoxazines, which are thermoset-
ting polymers exhibiting versatility in a wide range of
applications.[11] The remarkable and useful properties of
these compounds means that their preparation is always of
great interest,[12] even though procedures based on transition-
[*] Dr. C. Gonzꢀlez-Rodrꢁguez, Dr. J. R. Suꢀrez, Dr. J. A. Varela,
Prof. C. Saꢀ
Departamento de Quꢁmica Orgꢀnica y Centro Singular de Inves-
tigaciꢂn en Quꢁmica Biolꢂgica 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
[**] This work was supported by MICINN [projects CTQ2011-28258 and
Consolider Ingenio 2010 (CSD2007-00006)], Xunta de Galicia, and
the European Regional Development Fund (projects CN2011/054,
GRC2014/032 and EM 2012/051). C.G.-R. thanks the MICINN for
a Juan de la Cierva Contract (JCI-2011-09946).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410284.
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Table 2: Ruthenium-catalyzed cyclization of the ortho-(alkynyloxy)-
benzylamines 1c–l to the 1,3-benzoxazines 2c–l.[a,b]
metal-catalyzed cyclizations remain scarce. Rhodium-cata-
lyzed allylic rearrangement of 2-(allyloxy)benzylamines,[13]
[14]
À
copper-catalyzed C H bond oxidative activation
and
photooxidation of aminoalcohols with photoredox catalysts
of iridium[15] and ruthenium[16] are the most remarkable
contributions. Herein we report a new and efficient ruthe-
nium-catalyzed cyclization of ortho-(alkynyloxy)benzyl-
amines towards 1,3-benzoxazines under very mild reaction
conditions (Scheme 1d).
The reaction was optimized using N-benzyl-1-[2-(prop-2-
yn-1-yloxy)phenyl]methanamine (1a) as the test substrate
(Table 1). The reaction of 1a with TMSCHN2 in the presence
Table 1: Optimization of the ruthenium-catalyzed cyclization of
N-benzyl-1-[2-(prop-2-yn-1-yloxy)phenyl]methanamine 1a.[a]
Entry
[Ru] catalyst
TMSCHN2 (equiv)
Yield [%][b]
[a] Typical reaction conditions: [Ru] (5 mol%), 1 (1 equiv), TMSCHN2
(2.1 equiv), [1]=0.25m, RT. [b] Yields of the isolated products.
[c] [Cp*Ru(cod)Cl], (10 mol%). [d] [Cp*Ru(cod)Cl], (10 mol%), 1,4-
dioxane as solvent, 658C.
1
2
3
4
[Cp*Ru(cod)Cl]
[CpRu(cod)Cl]
[Cp*Ru(CH3CN)3]PF6
[Cp*Ru(CH3CN)3]PF6/
NEt4Cl
[Cp*Ru(cod)Cl]
[Cp*Ru(cod)Cl]
[Cp*Ru(cod)Cl]
2.1
2.1
2.1
2.1
62
–
[c]
–
10
5
6
7
2.1
3.0
46[d]
50
derivatives (Table 2). Electron-withdrawing and electron-
donating aryl substituents are tolerated since the 1,3-benzox-
azines 2c–f were obtained in reasonably good yields. Thus,
para-methoxy-, para-methyl-, para-trifluoromethyl-, and even
para-bromobenzylamine smoothly gave the substituted 1,3-
benzoxazines 2c–f, with slightly better yields obtained for
substrates bearing electron-poor substituents in the position
para to the propargylic ether. Interestingly, the functionalized
4-, 5-, and 6-halo-substituted benzylamines could be effi-
ciently converted into their corresponding halo-substituted
1,3-benzoxazines 2 f–i in fairly good yields. Further manipu-
lation of the above aryl bromides and chlorides using
palladium-catalyzed cross-coupling reactions provide an
easy entry to polysubstituted benzoxazines.[19] Notably, cycli-
zation of the naphthylamine derivative 1j smoothly gave the
naphthoxazine 2j in very good yield. Gratifyingly, the non-
terminal benzylamine derivative 1k also cyclized to give 2k in
very good yield,[20] albeit with a longer reaction time
compared to that of 2 f (60 h versus 6 h) and the need for
a higher catalyst loading (10 mol%). Even a benzylamine
with a long-chain-substituted alkyne, that is, 1l, was able to
cyclize to the corresponding 1,3-benzoxazine 2l, albeit in low
yield. In all cases the benzoxazines 2 were isolated with
complete Z stereoselectivity for the silylated double bond.
We proceeded to investigate the effect of the N- and
propargylic substitutions on the course of the reaction
(Table 3). Gratifyingly, the presence of primary and secon-
dary alkyl substituents on the nitrogen atom of the benzyl-
amines 1, for example, cyclohexyl or propyl, allowed the
corresponding 1,3-benzoxazines 2m and 2n to be obtained in
very good yields.[21] The chemoselectivity of the reaction was
analyzed in the cyclization of the N-allyl-substituted benzyl-
amine 1q, from which 2q, with an intact allyl group, was
isolated in moderate yield. Interestingly, this result indicates
[e]
[f]
–
–
[a] Typical reaction conditions: [Ru] (5 mol%), 1a (0.3 mmol),
[1a]=0.25m, RT. [b] Yields of isolated products. [c] N-benzyl-N-methyl-1-
[2-(prop-2-yn-1-yloxy)phenyl]methanamine (1a’) was obtained (9%).
[d] Cp*Ru(cod)Cl, (10 mol%). [e] N2CHCOOEt (2.1 equiv) was used.
[f] Ethyl 2-(benzyl(2-(prop-2-yn-1-yloxy)benzyl)amino)acetate 1a’’ was
obtained in 51% yield. cod=1,5-cyclooctadiene, Cp*=C5Me5.
of [Cp*RuCl(cod)] (5% mol) in Et2O at room temperature
gave 2a in 62% yield (entry 1). The reaction was extremely
sensitive to the electronic and steric nature of the ruthenium
catalyst since the starting material was totally recovered upon
using [CpRuCl(cod)] (entry 2). Besides, cationic [Cp*Ru-
(CH3CN)3PF6] or in situ formation of a neutral ruthenium
catalyst, by treatment with Et4NCl,[17] dramatically affected
either the course of the reaction or the catalytic activity, thus
giving very low yields of the methylated starting material 1a’
(9%)[3,18] or 2a (10%), respectively (entries 3 and 4).
Curiously, an increase in the catalyst loading or the amount
of TMSCHN2 was not beneficial for the cyclization reaction,
with 2a isolated in slightly lower yields (entries 5 and 6). The
nature of the solvent was crucial as other cyclic ethers such as
1,4-dioxane or THF were tolerated but gave lower yields, but
bulkier ethers and more polar protic or halogenated solvents
were detrimental to the cyclization.[18] Electronic variation on
the diazoalcane dramatically affected the course of the
reaction since the a-aminoester 1a’’, derived from the
[3]
À
carbenoid N H insertion reaction, was obtained when
N2CHCOOEt was used (entry 7).[18]
Once the optimized reaction conditions were established,
the scope and limitations of the cyclization reaction were
explored by starting with electronically distinct benzylamine
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Table 3: Ruthenium-catalyzed cyclization of N-substituted ortho-(alky-
nyloxy)benzylamines (1m–n, 1q–v) to 1,3-benzoxazines (2m–n, 2q–
v).[a,b]
Scheme 2. Mechanistic proposal for the ruthenium-catalyzed cycliza-
tion of ortho-(alkynyloxy)benzylamines.
esis shown in Scheme 2.[23] The reaction begins with the
starting complex, [Cp*RuCl(cod)], which easily loses its cod
ligand in the presence of TMSCHN2 and 1 to give the
ruthenium carbene species A. Oxidative coupling to the
ruthenacyclobutene followed by ring opening would lead to
the ruthenium vinyl carbene species B, in which the coordi-
nation of the pendant amine could disfavor the coordination
of a second diazoalkane unit.[24] The electrophilic ruthenium
carbene could induce nucleophilic attack by the amine group
to afford the zwitterionic intermediate C.[25] This intermediate
is probably not formed when the nucleophilic character of the
amine is diminished as in the tosylamide 1o. Ring strain of the
cyclic intermediate C, which has a good leaving group
(phenoxide), would facilitate ring opening to afford the
enamine intermediate D, with recovery of A. The reaction
yields obtained for 1,3-benzoxazines (e.g., 2 f versus 2c) seem
to be consistent with the leaving capacity of the phenoxides 1.
In the absence of a phenoxide as a leaving group, the
cyclization did not take place and B would evolve by b-
elimination to afford the observed diene 3. Finally, iminium
formation from D is trapped with the phenoxide to give the
final 1,3-benzoxazine 2 with concomitant release of the
ruthenium complex which re-enters the catalytic cycle.[26]
In conclusion, we report a novel entry to 1,3-benzoxazines
by ruthenium-catalyzed cyclization of ortho-(alkynyloxy)ben-
zylamines. Our method relies on key features such as the use
of readily available ortho-(alkynyloxy)benzylamines, com-
mercially available TMSCHN2, and [Cp*RuCl(cod)], the
ability to introduce functionality at the different positions of
the benzoxazine ring and the mild reaction conditions
employed. This methodology is also the first example of the
addition of an amine nucleophile to in situ generated vinyl
ruthenium carbene intermediates for the direct formation of
heterocyclic compounds. Rearrangement of an internal C(sp)
of the starting material into a tetrasubstituted C(sp3) in the
final 1,3-benzoxazine is highly remarkable.
[a] Typical reaction conditions: [Ru] (5 mol%), 1 (1 equiv), TMSCHN2
(2.1 equiv), [1]=0.25m, RT. [b] Yields of the isolated products.
[c] [Cp*RuCl(cod)], (10 mol%).
that polar nucleophile/electrophile interactions dominate the
reactivity of the putative carbene intermediate. Finally, the
diastereoselectivity of the cyclization was explored with the
chiral benzylamine 1r, which gave 2r (5.1 d.r. ratio) in low
yield.
Having established the broad scope of the methodology,
we investigated propargylic-substituted benzylamines (1s–v;
Table 3). Interestingly, the ethyl-substituted 1,3-benzoxazines
2s–u were the exclusive cyclized products in the ruthenium-
catalyzed cyclization of the corresponding benzylamines 1s–
u bearing a methyl substituent in the propargylic position
(R3 = Me, R4 = H). Furthermore, the isopropyl-substituted
1,3-benzoxazine 2v was isolated from the reaction of the
dimethylated substrate 1v (R3, R4 = Me). These results clearly
indicate that the propargylic carbon atom of the starting
ortho-(alkynyloxy)benzylamines 1 becomes the alkyl sub-
stituent of the generated 2-vinyl-2-alkyl 1,3-benzoxazines 2.
This new rearrangement takes place starting from benzyl-
amines bearing ortho-alkynyloxy substituents. However,
when ortho-alkynylthio or ortho-alkynyltosylamide substitu-
ents were present in the starting benzylamine, the reaction did
not give any cyclized products.[22]
In an effort to gain further insights into the mechanism of
the reaction, a deuterium-labeling experiment was conducted.
When the ruthenium-catalyzed cyclization of deuterated
benzylamine [D]-1 f (R2 = D) was carried out under the
optimized reaction conditions, deuterium scrambling was not
observed and the deuterium atom was located at the vinylic
position of the corresponding benzoxazine [D]-2 f.[18]
The results obtained, including those of the labeling study
and the cyclization of the propargylic-substituted benzyl-
amines 2s–v, strongly support the initial mechanistic hypoth-
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Communications
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Angewandte
Chemie
[22] The reaction of thioether 4 under optimized reaction conditions
afforded the corresponding dienyl sulfide 3 in 56% yield and the
reaction of tosylamide 5 gave a complex reaction mixture. See
Supporting Information for details.
of the diene 3b was observed and suggests the formation of
a vinyl ruthenium carbene intermediate.
[24] J. Le Paih, C. Vovard-Le Bray, S. Dꢀrien, P. H. Dixneuf, J. Am.
Chem. Soc. 2010, 132, 7391 – 7397.
[25] The mechanistic alternative based on1,2-propargylic shift to give
an enolether intermediate followed by the amine nucleophilic
attack was discarded since the parent (prop-2-yn-1-yloxy)ben-
zene gave the expected disylilated Z,Z-diene (84%, via a vinyl
Ru carbene, Ref. [24]) instead the rearranged enolether deriv-
ative (Rautenstrauch product). See the Supporting Information
for details.
[23] Alternatively, direct attack of the amine to the triple bond
followed by ring opening without formation of the initial
ruthenium carbene cannot be ruled out (O,N- “extended”
Rautenstrauch rearrangement).[4b] However, when 1b (X =
CH2) was subjected to the reaction conditions, smooth formation
[26] For a Brønsted acid catalyzed cyclization through benzoylimine
intermediates, see Ref. [12h].
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
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.
Angewandte
Communications
Communications
Synthetic Methods
C. Gonzꢁlez-Rodrꢂguez,* J. R. Suꢁrez,
J. A. Varela, C. Saꢁ*
&&& — &&&
Nucleophilic Addition of Amines to
Ruthenium Carbenes: ortho-
(Alkynyloxy)benzylamine Cyclizations
towards 1,3-Benzoxazines
A new addition: A new ruthenium-cata-
lyzed cyclization of ortho-(alkynyloxy)-
benzylamines to 1,3-benzoxazines is
reported. Vinyl ruthenium carbenes are
proposed as the key intermediates, and
the mechanistic hypothesis supposes the
first example of a nucleophilic addition of
amines to vinyl ruthenium carbenes.
Rearrangement of an internal C(sp) into
a tetrasubstituted C(sp3) is highly re-
markable. TMS=trimethylsilyl.
6
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