Benzannulation of triynes to generate functionalized arenes by spontaneous incorporation of nucleophiles

Article abstract of DOI:10.1002/anie.201412468

The thermal reaction of ester-tethered 1,3,8-triynes provides novel benzannulation products with concomitant incorporation of a nucleophile. Evidence suggests that this reaction proceeds via an allene-enyne intermediate generated by an Alder-ene reaction in the first step. Depending on the substituent of the alkyne moiety on the allene-enyne intermediate, the subsequent transformation can take one of two different paths, each leading to discrete aromatization products. The benzannulation of a silane-substituted 1,3,8-triynes provides arene products with a nucleophile incorporated onto the newly formed benzene core, whereas an aryl substituent leads to nucleophile trapping at the benzylic carbon atom connected to the aryl substituent. The formation of these two different products results from the involvement of two regioisomeric allene-enyne intermediates.

Full text of DOI:10.1002/anie.201412468

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201412468
German Edition: DOI: 10.1002/ange.201412468
Synthetic Methods
Benzannulation of Triynes to Generate Functionalized Arenes by
Spontaneous Incorporation of Nucleophiles**
Rajdip Karmakar, Sang Young Yun, Jiajia Chen, Yuanzhi Xia,* and Daesung Lee*
Abstract: The thermal reaction of ester-tethered 1,3,8-triynes
provides novel benzannulation products with concomitant
incorporation of a nucleophile. Evidence suggests that this
reaction proceeds via an allene-enyne intermediate generated
by an Alder-ene reaction in the first step. Depending on the
substituent of the alkyne moiety on the allene-enyne inter-
mediate, the subsequent transformation can take one of two
different paths, each leading to discrete aromatization prod-
ucts. The benzannulation of a silane-substituted 1,3,8-triynes
provides arene products with a nucleophile incorporated onto
the newly formed benzene core, whereas an aryl substituent
leads to nucleophile trapping at the benzylic carbon atom
connected to the aryl substituent. The formation of these two
Scheme 1. New benzannulation reactions of ester-tethered triynes.
different products results from the involvement of two
regioisomeric allene-enyne intermediates.
B
enzannulation, that is, the construction of benzene rings
by employing various ester- and sulfonimide-tethered 1,3,8-
triynes. Herein, we describe the outcomes of our investigation
on this novel benzannulation reaction focusing on the role of
substituents and nucleophiles for the formation of isomeric
products.
Our investigation commenced with an optimization of the
reaction conditions and the substrate structure in terms of the
silyl substituent on the 1,3-diyne moiety (Table 1). It was
found that the solvent and temperature of the reaction have
a significant impact on the efficiency for the formation of 3a
from 1a. At 908C in CH3CN, the yield was acceptable (54%)
but a substantial amount of by-product was observed by NMR
spectroscopy (entry 1). Lowering the temperature to 608C
under microwave irradiation for 1 hour afforded only 20%
yield of 3a (entry 2). To our delight, however, running the
from acyclic building blocks, is a versatile approach for the
preparation of functionalized arenes, and various synthetic
methods are documented in the literature.[1,2] While study-
ing[3] the scope of the benzannulation reaction of ester-
tethered 1,3,8-triynes, an unprecedented pathway initiated by
an Alder-ene process to form benzannulated products turned
out to be preferred over the expected hexadehydro Diels–
Alder (HDDA) reaction[2] (Scheme 1). Under typical thermal
conditions at 908C, the triyne 1 favorably undergoes an Alder
ene reaction to form the allene-enyne intermediate 2 as long
ꢀ
as there is an available propargylic C H bond, and then leads
to either the benzannulated product 3 or 4 depending on the
substituent (R) on the alkyne moiety of 2. Based on this
initially observed reactivity and selectivity feature of the
transformation, we further explored the scope of the reaction
Table 1: Benzannulation of triynes containing various silyl groups in
different solvents and temperature.
[*] R. Karmakar, Dr. S. Y. Yun, Prof. D. Lee
Department of Chemistry, University of Illinois at Chicago
845 West Taylor Street, Chicago, IL 60607 (USA)
E-mail: dsunglee@uic.edu
J. Chen, Prof. Y. Xia
College of Chemistry and Materials Engineering
Wenzhou University
Wenzhou, Zhejiang Province 325035 (P.R. China)
E-mail: xyz@wzu.edu.cn
Entry
R
T [8C]
Cat.
Yield [%][a]
1
2
3
4
5
6
1a
1a
1a
1b
1c
1d
SiEt3
SiEt3
SiEt3
SiMe2tBu
SiiPr3
SiPh3
90
60
90
90
90
90
none
none
54
20[b,c]
63
Grubbs II[d]
Grubbs II
Grubbs II
Grubbs II
[**] We thank UIC (LAS-AFS, DL), NSF (CHE-1361620, DL), TACOMA
Technology (DL), the Zhejiang Provincial NSF (LY13B020007, YX),
and the NNSFC (21372178, YX) for financial support. We thank
Prof. Neal Mankad for his help in obtaining X-ray structures. All
computations were carried out on the High Performance Compu-
tation Platform of Wenzhou University. The mass spectrometry
facility at UIUC is greatly acknowledged.
98[e]
68
52
[a] Yield of isolated product. [b] Incomplete reaction. [c] Under micro-
wave irradiation. [d] Other ruthenium complexes such as [CpRu-
(MeCN)3]PF6 and [Cp*RuCl(cod)] mainly provide an unidentified dimeric
product. [e] 46% yield in the absence of Grubbs II. cod=1,5-cyclo-
octadiene, Cp=cyclopentadienyl, Cp*=C5Me5.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412468.
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Table 3: Benzannulation of triynes with different tethers in the presence
of various nucleophiles.
reaction at 908C in CH3CN with a small amount (0.1 mol%)
of the Grubbs second-generation complex (Grubbs II) sup-
pressed the formation of the unknown by-product,[4] thus
improving the yield of 3a to 63% (entry 3). Further improve-
ment was achieved when the triethylsilyl (TES) group of 1a
was replaced with tert-butyldimethylsilyl (TBS) group (1b)
under identical reaction conditions, thus leading to 3b in 98%
(entry 4). In contrast, the triisopropylsilyl (TIPS) group in 1c
or triphenylsilyl (TPS) in 1d had a marginal improvement,
thus providing the corresponding products 3c and 3d[5] in 68
and 52% yield, respectively (entries 5 and 6).
Having defined the optimal silyl functionality in the
substrate and assorted reaction conditions, we explored the
reaction of substrates containing more substituents in the
ester-tethered triyne platform (Table 2). The reaction of 1e,
Table 2: Benzannulation of ester-tethered 1,3,8-triynes.[a]
Numbers within parentheses represent yields of the isolated products.
[a] Grubbs II (0.1 mol%) was used in these reactions. [b] With a bromide
source described in Ref. [2c]. Ts=4-toluenesulfonyl.
1r significantly improved the reaction profile, thus providing
3r in 92% yield within 17 hours. However, only low yield of
3s (39%) was observed when AcOH was used as a trapping
agent. To our surprise, the substrate 1t (R’ = tBu) yielded 3t
which was devoid of the tert-butyl group. The reaction of 1u
with a bromide nucleophile afforded the aryl bromide 3u in
49% yield, and the same substrate in the presence of AcOH
as a nucleophile produced aryl acetate 3v in 53% yield.
Substrates having a ketone linkage can also undergo a benz-
annulation reaction only when a gem-dialkyl moiety is
present. Thus, the benzannulation products 3w and 3x were
obtained in the presence of MeOH and AcOH respectively,
albeit after prolonged heating.
To gain insight into the mechanism of this benzannulation,
we carried out DFT calculations[7] (M06-2X/6-31 + G*
level[8]) with the triyne 1aa as a model system (Scheme 2).
Calculations clearly indicate that the ene reaction leading to
the alkynyl enallene B[9] is kinetically more favorable by
4.6 kcalmolꢀ1 than the HDDA reaction leading to the aryne
A. Under the reaction conditions, B isomerizes to B’, from
which cyclization occurs to form C and D. The Saito–Myers
cyclization[1e,g,h,r] of B’ to form C via TSc (ꢀ6.3 kcalmolꢀ1)[10]
or its ionic version to form C’ via the slightly lower-energy
TSc’ (ꢀ6.6) is energetically reasonable but it does lead to
incorrect connectivity. However, the formation of the dirad-
ical D, bearing the correct connectivity of the observed
product via TSd (37.6 kcalmolꢀ1), does not seem feasible
from either a kinetic or thermodynamic aspect.[7,11] This
energetic consideration suggests an alternative mechanism
involving the Michael addition of AcOH to the allenoate
moiety of B,[12] where the barrier (TS1 = ꢀ9.9 kcalmolꢀ1)
leading to IN1, albeit slightly endergonic, is 3.3 kcalmolꢀ1
lower than even that of the Saito–Myers cyclization (B’!
C).[13] From IN1, all the remaining steps, involving proton-
shift-mediated relocation of p bonds to form IN2, its 6p elec-
trocyclization[14] to form IN3, and aromatization by a formal
[1,3]-H shift leading to 3aa, seem to be quite reasonable
energetically.
[a] Numbers within parentheses represent yield of the isolated products.
with an extra propyl substituent (compared to 1a), afforded
the expected product 3e in 66% yield. Although 1 f, with
a benzyloxy substituent at the propargylic carbon atom, did
not yield the product 3 f, its homologue 1g and silyloxy-
substituted substrates 1h and 1i produced the expected
products 3g–i in 66, 56, and 51% yield, respectively. The
slightly lower yields from 1h and 1i are most likely due to its
instability under the reaction conditions. Introducing a sub-
stituent at the propargylic site of the 1,3-diynyl moiety did not
change the reactivity of substrates 1j–m, thus the products
3k–m[5] were obtained in yields in the range of 72–89%, but
only 47% for 3j because of its labile TES group. Replacing
the silyl group with another alkyne in 1n led to the formation
of a mixture of 3n and 3n’ in 48% yield.
To broaden the scope of the reaction, we employed an
assortment of substrates of different tethers and trapping
agents (Table 3). Upon heating 1b at 908C in MeOH, the
benzannulation product 3o was obtained in 26% yield and
accompanied by the methanolysis product 1,3-diynyl prop-
argylic alcohol in 50% yield. The sterically hindered ester 1k
(R’’ = iPr), however, afforded 3p in 63% yield without
methanolysis.[6] Replacing the ester linkage with an amide
improved the yield, although a longer reaction time was
required. For example, the triyne 1q produced 3q in 85%
yield after heating for 72 hours. Replacing the phenyl group in
1q with a more-electron-withdrawing sulfonimide moiety in
2
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Table 4: Benzannulation of triynes with an aryl substituent.[a]
Scheme 2. DFT-based mechanistic rationale.[7]
With this mechanistic rationale in hand, we tried to
diversify the substrate structure, thus surmising that replacing
the silyl group on the 1,3-diyne moiety with other functional
groups should not profoundly alter the reaction profile. To
our surprise, however, the benzannulation of the triynes 1’,
containing an aryl group, provided the compound 4 which
contains an incorporated acetate at the bis-benzylic carbon
atom rather than on the newly formed benzene ring
(Table 4).[15] The reaction was found to be sensitive to the
electronic nature of the aryl group, where an electron-
donating group afforded higher yield of the products. For
example, 4a, with a 4-chloro substituent, was isolated in 61%
yield while 4b, containing a 4-methoxy group, was obtained in
96% yield. Also, a substrate containing a methoxy-substi-
tuted naphthyl group gave 4c in 87% yield. In contrast, the
substrate with a 4-dimethylamino group afforded the alcohol
4d in 39% yield. Probably, the amino group, upon proto-
nation by acetic acid deactivates the substrate yet promotes
the hydrolysis of the acetate during purification by silica gel
column chromatography. An extra alkyl substituent (R’) in 1’
is detrimental to the benzannulation, thus 4e and 4 f were
isolated in lower yield. The beneficial role of the Grubbs
catalyst in these reactions was clearly demonstrated in the
formation of 4 f. Introducing an ortho-substituent on the aryl
moiety produced a mixture of two isomers, 4g and 4g’, in
a combined yield of 59%. A substrate with an electron-
withdrawing substituent on the aryl ring produced a mixture
of isomers, 4h and 4h’, in low yield along with an unexpected
diarylketone product 4h’’ in 19% yield.[5]
[a] Numbers within parentheses represent yields of isolated products.
Scheme 3. Double annulation reactions: [a] Yields are those of isolated
products. [b] Yield of 6a+6a’. [c] Yield after complete conversion.
Next, we explored double annulation reactions by
employing intramolecular trapping and ring expansion
approaches (Scheme 3). Upon subjecting 5a–d to the stan-
dard reaction conditions (CH3CN at 908C), the compounds
6a’–d’ were isolated along with double annulated products
6a–d in varying ratios. Although the carboxylic acid adduct
6a’ is unstable,[16] the corresponding alcohol adduct 6b’ is
relatively stable, and rearranges into 6b quantitatively over
a 3 day period at room temperature, and 6c’ rearranges into
6c only at high temperature (1208C, 9 days). Monitoring of
the reaction of 5d by 1H NMR spectroscopy indicates that its
conversion into 6d’ is fast at 908C but the conversion of 6d’
into 6d is slow (4 days) at this temperature. The isolation of
6a’–d’ and their conversion into 6a–d suggest that they are
a true intermediate for the benzannulation reaction.[17]
The substrates 1y and 1z were employed to test the
feasibility of a double annulation (Scheme 3). As expected
the initially formed mono-benzannulated vinyl cyclopropane
intermediate 7y undergoes a ring expansion through a 1,3-
alkyl shift to generate the indene derivative 3y.[18] In contrast,
the reaction of 1z afforded only 7z, which is stable and did not
rearrange to the aromatized product 3z under the reaction
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Holden, M. F. Greaney, Angew. Chem. Int. Ed. 2014, 53, 5746 –
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6 – 9.
conditions, even after a prolonged reaction time. These results
also provide strong support for the reaction mechanism
involving the intermediate IN3 in Scheme 2.
In summary, we have discovered the benzannulation of
1,3,8-triynes under thermal conditions to generate highly
functionalized arenes. This reaction proceeds through an
initial Alder-ene reaction to form an allenoate intermediate
with subsequent Michael addition of a nucleophile. Subse-
quent p-bond migrations to form a conjugated diene-allene
system then sets the stage for an electrocyclization and
a formal 1,3-H shift, thus providing nucleophile-incorporated
arene products. Depending on the substituent of the alkyne
moiety on the allenoate intermediate, the subsequent trans-
formation takes one of different pathways. The allenoate
derived from either silane- or alkyne-substituted 1,3,8-triynes
favors the nucleophile addition at an earlier stage, as
supported by DFT calculation, thus leading to benzannula-
tion products with an incorporated nucleophile on the newly
formed benzene core. In contrast, the reaction of the aryl-
substituted 1,3,8-triynes provided benzannulation products
with a trapped nucleophile at the benzylic carbon atom
connected to the aryl substituent. This divergence seems to be
the consequence of the formation of a regioisomeric allene-
enyne intermediate. Investigation on the mechanism of the
latter pathway is underway.
[4] The Grubbs second-generation complex is used as a catalyst
when AcOH is the trapping agent, wherein we believe the
ruthenium complexes catalyzes the isomerization of B to B’ in
Scheme 2. Although the role of these complexes is yet to be
further elucidated, it generally reduces the formation of
unknown by-products. See the Supporting Information for
details.
[5] The structures of 3d (CCDC 1040777), 3l (CCDC 1040778), and
4h’’ (CCDC 1040779) were confirmed by X-ray diffraction
analysis. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
[6] A methanol adduct similar to those described in Scheme 3 was
isolated in 39% yield. See the Supporting Information for
details.
[7] All reported energy values are relative free energies including
solvation corrections. See the Supporting Information for details.
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Keywords: annulation · arenes · rearrangement ·
regioselectivity · ruthenium
[10] A higher barrier (TSc = 15.7 kcalmolꢀ1) is calculated for more
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4
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tentatively propose that with an aryl substituent, B’ favorably
rearranges to a regioisomeric allene-enyne (a consequence of
a formal [1,7]-H shift), which then undergoes an ionic Saito–
Myers cyclization to generate a zwitterionic intermediate, the
trapping of which provides the observed product.
[16] The compound 6a’ does not have a long enough lifetime for
13C NMR spectroscopy, and it readily converts into 6a.
[17] Similarly, the methanol adduct mentioned in Ref. [6] was
converted into the corresponding benzannulated product
under three different conditions. See the Supporting Information
for details.
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Received: December 30, 2014
Revised: February 27, 2015
Published online: && &&, &&&&
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Communications
Synthetic Methods
R. Karmakar, S. Y. Yun, J. Chen, Y. Xia,*
D. Lee*
&&&& — &&&&
Benzannulation of Triynes to Generate
Functionalized Arenes by Spontaneous
Incorporation of Nucleophiles
Small but profound: In the benzannula-
tion reaction of 1,3,8-triynes, a small
structural difference has a profound
impact on the structure of the products.
When R is a silyl group, a nucleophile is
incorporated into the newly formed ben-
zene core, whereas when R is an aryl
group, nucleophile trapping occurs at the
benzylic carbon atom connected to the
aryl group.
6
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