ICl-induced intramolecular electrophilic cyclization of 1-[4′-methoxy(1,1′-biphenyl)2-yl]alkynones - A facile approach to spiroconjugated molecules

Article abstract of DOI:10.1002/chem.201301582

Spiro compounds: An iodine monochloride-induced intramolecular cyclization of 1-[4′-methoxy(1,1′-biphenyl)2-yl]alkynones has been developed (see scheme). An electrophilic iodocyclization selectively takes place at the ipso position (versus the ortho elect

Full text of DOI:10.1002/chem.201301582

COMMUNICATION
DOI: 10.1002/chem.201301582
ICl-Induced Intramolecular Electrophilic Cyclization of 1-[4’-Methoxy(1,1’-
biphenyl)2-yl]alkynones—A Facile Approach to Spiroconjugated Molecules
Yu Chen,* Xiaochen Liu, Minwook Lee, Chenlong Huang, Igor Inoyatov, Zhiwei Chen,
Abraham C. Perl, and William H. Hersh[a]
Electrophilic cyclization of functionalized alkynes, in-
duced by halogens and their derivatives, has emerged as an
extremely active field in the past decade. This synthetic
method provides a facile approach for the synthesis of a va-
riety of functionally substituted heterocyclic and carbocyclic
compounds.[1] Among the various halogen-induced electro-
philic cyclization reactions discovered thus far, limited ex-
amples of the intramolecular ipso-cyclization of an alkyne
Scheme 1. Electrophilic cyclization of 1-[4’-methoxy-(1,1’-biphenyl)-2-
yl]alkynone (2)—6-endo-dig versus 7-endo-dig reaction processes.
into spiro compounds have been reported, and even fewer
have yielded spiroconjugated species.[2]
Spiroconjugated molecules are known for their helical
structures,[3] conformational transmission properties,[4] and
potential utility for forming charge-transfer complexes.[5] Be-
cause of their nonconventional optoelectronic properties as
electroactive compounds, spiroconjugated molecules have
the potential application of organic conducting materials for
photochromism.[6] It is these features that have attracted the
attention of chemists in the emerging field of photonics.
To the best of our knowledge, all known examples of hal-
ogen-induced intramolecular ipso-cyclizations of alkynes are
1-(2-bromoaryl)alkynone (1) produced after the first cou-
pling reaction (see the Supporting Information). Our initial
study focused on the reaction of the model substrate 2a
with three equivalents of I2 in acetonitrile (CH3CN) at room
temperature. After 16 h,
a
35% yield of 4’H-
spiro(cyclohexa[2,5]diene-1,1’naphthalene)-4,4’-dione (3a)
AHCTUNGTRENNUNG
was isolated from the reaction mixture, together with un-
reacted starting material 2a (Table 1, entry 1). The structure
of compound 3a was determined by analyzing 1H and
5-endo-dig processes leading to spiroACTHNUTRGNEUNG[4.5]decane core struc-
Table 1. Optimization of reaction conditions for the electrophilic cycliza-
tures or their heterocyclic analogues.[2] Here, we report a
facile ICl-induced intramolecular cyclization of 1-[4’-me-
thoxy(1,1’-biphenyl)-2-yl]alkynones (2), leading to the syn-
thesis of a new class of spiroconjugated compounds—4’H-
tion of 1-[4’-methoxy(1,1’-biphenyl)-2-yl]-3-phenylprop-2-yn-1-one (2a).[a]
spiro(cyclohexaACHTUNGTRENNUNG[2,5]diene-1,1’-naphthalene)-4,4’-diones (3).
We note interesting substituent effects on the distal phenyl
group of substrate 2, leading to 6-endo-dig or 7-endo-dig
cyclization products (Scheme 1).
The 1-[4’-methoxy(1,1’-biphenyl)-2-yl]alkynone starting
materials (2) were prepared from 2-bromobenzoyl chlorides
through two successive steps, Sonogashira coupling[7] and
Suzuki–Miyaura coupling,[8] with an intermediate compound
Entry
1[c]
2
3
4
Base [mol%]
Solvent
Yield of 3a [%][b]
no base
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CHCl3
35
41
63
85
9
77
35
42
69
99
88
Na2CO3
NaHCO3
Na2HPO4
K3PO4
KH2PO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
no base
5
6
7
8
9[d]
10[e]
11[e]
CH3CN
CH3CN
CH3CN
[a] Prof. Dr. Y. Chen, X. Liu, M. Lee, C. Huang, I. Inoyatov, Z. Chen,
A. C. Perl, Prof. Dr. W. H. Hersh
Department of Chemistry and Biochemistry
Queens College and the Graduate Center of the
City University of New York, 65-30 Kissena Blvd.
Flushing, New York 11367 (USA)
Fax: (+1)718-997-5531
E-mail: yu.chen1@qc.cuny.edu
[a] General procedure: 2a (0.5 mmol, 1 equiv), Na2HPO4 (142.0 mg,
1.0 mmol, 2 equiv), I2 (381.0 mg, 1.5 mmol, 3 equiv), and solvent (4 mL)
were added to a 4 dram vial. The reaction mixture was stirred at room
temperature for 2 h. [b] Isolated yields after column chromatography.
[c] The reaction was carried out at room temperature for 16 h. [d] 2 equiv
of I2 were added. [e] 3 equiv of ICl were substituted for I2 and the reac-
tion was carried out at room temperature for 30 min.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301582.
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Table 2. ICl-induced intramolecular cyclization of 1-[4’-methoxy(1,1’-biphen-
yl)-2-yl]alkynones.[a]
Entry
1
Substrate 2
Product 3+4 (yield)[b]
Figure 1. ORTEP drawing of 3a with complete numbering of atoms.
2
3
13C NMR spectra and mass spectroscopy data. The structure
was further unambiguously determined by an X-ray analysis
of a single crystal of 3a (Figure 1). The reaction rate of this
electrophilic cyclization was enhanced in the presence of
base (Na2CO3, NaHCO3, or KH2PO4; entries 2, 3, and 6).
The reaction was completed in 2 h when two equivalents of
Na2HPO4 were added as the base, and the spiro compound
3a was isolated in high yield (85%, entry 4). Other solvents
including dichloromethane (CH2Cl2) and chloroform
(CHCl3) were also employed in this reaction, but all showed
inferior results to CH3CN, producing low to moderate yields
(entries 7–8). Reducing the loading of I2 to two equivalents
resulted in a lower yield (entry 9). Further investigation re-
vealed that the reaction was completed in 30 min when I2
was replaced with ICl; almost a quantitative yield was ob-
tained (99%, entry 10). The chemical yield decreased to
88% in the absence of Na2HPO4 (entry 11). Taking these re-
sults into account, the conditions listed for entry 10 were
chosen as the optimal reaction conditions.
A variety of substituents, including aryl, heteroaryl, and
alkenyl groups, are well accommodated at the distal position
of the alkynone triple bond (Table 2, entries 1–5). In addi-
tion, excellent yields for the ipso-cyclization products are
obtained in the presence of both electron-rich and -poor
aryl groups (entries 2–3). For the aryl group directly attach-
ed to the carbonyl moiety, both electron-withdrawing and
-donating substituents are well accommodated (entries 6–7).
An interesting substituent effect was observed on both the
methoxy (MeO)-substituted distal phenyl group and the
phenyl group directly attached to the carbonyl moiety. The
spiro compound was exclusively formed when the para-
MeO-group was the sole substituent on the distal phenyl
group. However, whereas the presence of a second substitu-
ent at the ortho position to the 1,1’-diphenyl bond[9] also led
exclusively to the spiro compound (entries 8–9), the intro-
duction of a second substituent at the meta position to the
1,1’-diphenyl bond produced a mixture of spiro compound 3
4
5
6
7
8
and 5H-dibenzoACHTUNGTRENNUNG[a,c][7]annulen-5-one 4 (entries 10–13). With
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A Facile Approach to Spiroconjugated Molecules
Table 2. (Continued)
COMMUNICATION
fluorine atom was the sole substituent at the para position
of the 1,1’-diphenyl bond (entry 6). On the other hand, a
Entry
Substrate 2
Product 3+4 (yield)[b]
mixture of spiro compound 3g and 5H-dibenzoACTHNURTGNEU[GN a,c][7]annu-
len-5-one 4g was obtained when a relatively stronger elec-
tron-donating methoxy group was substituted at the para
position (entry 7). The structures of compounds 4g and 4j–
9
1
m were determined by analysis of H and 13C NMR spectra
and mass spectroscopy data. The structures were further un-
ambiguously determined by an X-ray analysis of a single
crystal of 4j (Figure 2). It should be noted that, for any
10
11
12
Figure 2. ORTEP drawing of 4j with complete numbering of atoms.
product 4, the ortho electrophilic cyclizations take place, re-
giospecifically, at the less hindered site of the two asymmet-
ric ortho positions of the 1,1’-diphenyl bond. This phenom-
enon is evidenced by their H NMR spectra, in which two
isolated proton signals were observed on the tetrasubstitut-
ed phenyl groups.
13
14
15
16
1
This interesting observation prompted us to further study
the substituent effects of the reaction substrates containing
a trisubstituted distal phenyl group. When the second and
third MeO substituents were present at the ortho and meta
positions of the distal phenyl group, the spiro compound
was obtained exclusively (Table 2, entry 14). When the
second and third groups were methyls, and were both pres-
ent at the meta positions of the distal phenyl ring, a mixture
of 3o and 4o was obtained (entry 15). On the other hand,
when more strongly electron-donating groups (MeO) were
present at the meta positions, a 7-endo-dig cyclization took
place, leading exclusively to the dibenzo[7]annulen-5-one
product 4p (entry 16).
A plausible reaction mechanism is proposed to account
for the formation of both the spiro compound 3 and the di-
benzo[7]annulen-5-one 4 (Scheme 2). First, the iodonium in-
termediate 5 forms upon the interaction of the electrophilic
ICl with the alkynone triple bond; thereafter, two reaction
pathways are possible at the distal phenyl site: a) a 6-endo-
dig ipso-cyclization and b) an ortho 7-endo-dig electrophilic
aromatic substitution. When methoxy is the lone substituent,
an intramolecular ipso electrophilic cyclization takes place
to exclusively form an oxonium ion intermediate 6. The
methyl group on 6 is then removed by a chloride anion to
[a] See the Experimental Section for the general procedure. [b] Isolated
yields after column chromatography.
respect to the phenyl group directly attached to the carbonyl
moiety, the spiro compound was exclusively formed when a
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Y. Chen et al.
substituents, as well as on their positions. In the case of sub-
strate 2n, two methoxy groups (at the ortho and para posi-
tions) activate the ipso position for electrophilic attack,
while only one methoxy group (at the meta position) acti-
vates the system for ortho electrophilic cyclization; the com-
bination of the effects from the three substituents results
only in the ipso electrophilic cyclization. In the trisubstituted
substrate 2o, the two methyl groups are present on the
distal phenylꢁs meta positions, while one methoxy group oc-
cupies the para position. For this reaction, two relatively
weakly electron-donating methyl groups activate for an
ortho electrophilic attack, while the lone methoxy activates
for an ipso attack. A mixture of 3o and 4o is obtained. On
the other hand, in the case of substrate 2p, two methoxy
groups are present at the distal phenylꢁs meta position, while
the para methoxy remains present. For this reaction, two
meta methoxy groups activate for an ortho electrophilic
attack, whereas only one methoxy, at the para position, acti-
vates for an ipso attack; therefore, only the ortho electro-
philic aromatic substitution takes place, leading exclusively
to
a dibenzo[7]annulen-5-one, 4p (Table 2, entry 16).
Whereas the para methoxy substituent on the distal phenyl
group directs the electron density to the ipso position of the
1,1’-diphenyl bond in substrate 2g, the para methoxy on the
phenyl group attached to the carbonyl moiety directs the
electron density to the ortho positions of the 1,1’-diphenyl
bond (Scheme 2, structure D). For this reaction, both ipso-
cyclization product 3g and ortho electrophilic aromatic sub-
stitution product 4g are obtained (entry 7).
The ratio between the ipso-cyclization (3g, 3j–m, and 3o)
and the ortho electrophilic aromatic substitution products
(4g, 4j–m, and 4o) are, in general, determined by the rela-
tive electronic effect strength exhibited by substituents at
the distal phenyl position, or by those groups on the phenyl
directly attached to the carbonyl moiety. With respect to the
role of Na2HPO4, while it removes H+ from the carbocation
intermediate 7 in the 7-endo-dig electrophilic aromatic sub-
stitution, its role in the 6-endo-dig cyclization is unclear.
Presumably, the species acts as a proton scavenger, thereby
maintaining a necessary concentration of nucleophilic anion
(such as chloride) in the reaction media. In addition, a
higher concentration of these nucleophilic anions possibly
enhances the demethylation step from intermediate 6 to
final product 3.
Scheme 2. A plausible mechanism for the ICl-induced electrophilic cycli-
zation of 1-[4’-methoxy(1,1’-biphenyl)-2-yl]alkynones.
form the spiro compound 3. With respect to the polysubsti-
tuted distal phenyl group, a similar reaction mechanism
takes place when a second substituent is present at the ortho
position to the 1,1’-diphenyl bond. However, when a second
substituent is present at the meta position, a competing in-
tramolecular electrophilic aromatic substitution takes place,
along with the ipso cyclization. Presumably, when only a
para-methoxy is present on the distal phenyl group, the ipso
position becomes more electron-dense through resonance
(Scheme 2, A) and, therefore, an ipso electrophilic cycliza-
tion takes place. When a second electron-donating substitu-
ent is present at the ortho position of the distal phenyl ring,
an amplification of the para-methoxy groupꢁs electronic
effect reinforces the ipso-cyclization (Scheme 2, B). Howev-
er, when a second substituent, such as methoxy, methyl, or a
halogen is present at the meta position of the distal phenyl
group, the second substituent directs the electron density to
the ortho positions to the 1,1’-diphenyl bond (Scheme 2, C).
Subsequently, both the ipso and the ortho positions of the
distal phenyl group are activated, affording a mixture of
spiro compound (3) and dibenzo[7]annulen-5-one (4). When
three substituents are present on the distal phenyl group,
the outcome of the reaction depends on the identity of the
In summary, an ICl-induced 6-endo-dig electrophilic cycli-
zation of 1-[4’-methoxy(1,1’-biphenyl)-2-yl]alkynones has
been studied, leading to a class of new spiro compounds—
4’H-spiro(cyclohexaACTHNUTRGENUG[N 2,5]diene-1,1’-naphthalene)-4,4’-diones.
An interesting substituent effect was observed during the
course of our experimentation. This substituent effect finds
significance in that, with minor modification to the pattern
of reacting substrate, both ipso and ortho cyclization can be,
regiospecifically, “switched on” or “off”. The outcome of
which cyclization event will occur depends on the identity of
the substituents at the distal phenyl group of the 1-[4’-me-
thoxy(1,1’-biphenyl)-2-yl]alkynones (2), and it is this sensi-
tivity which, we believe, gives this reaction potential synthet-
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A Facile Approach to Spiroconjugated Molecules
COMMUNICATION
ic utility. We have proposed a reaction mechanism that pro-
ceeds by either a 6-endo-dig ipso-cyclization or a 7-endo-dig
electrophilic aromatic substitution. An intramolecular ipso-
iodocyclization predominates when the distal phenyl group
is para-substituted by methoxy, leading exclusively to
spiro(cyclohexaACHTUNGTRENNUNG[2,5]diene-1,1’-naphthalene)-4,4’-diones (3).
On the other hand, polysubstituted distal phenyl group sys-
tems lead to the formation of varying mixtures of
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spiro(cyclohexa
G
(3)
and dibenzo[7]annulen-5-one (4), ranging from regiospecific
to regioselective product. Further exploration of the synthe-
sis of dibenzo[7]annulen-5-one compounds by using halo-
gen-induced electrophilic cyclization is underway in our lab-
oratory and will be reported in due course. We expect this
group of new spiroconjugated compounds to find applica-
tion in the developing field of chemical photonics, and theo-
retical and material electrochemistry.
Experimental Section
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General experimental details: 1-[4’-Methoxy(1,1’-biphenyl)-2-yl]alkynone
(2, 0.5 mmol, 1 equiv), Na2HPO4 (142.0 mg, 1.0 mmol, 2 equiv), ICl
(243.6 mg, 1.5 mmol, 3 equiv), and acetonitrile (4 mL) were added to a
4 dram vial. The reaction mixture was stirred at room temperature for
30 min. The reaction mixture was then diluted with ethyl acetate (25 mL)
and washed with 0.5m aqueous Na2S2O3 solution (25 mL). The resulting
aqueous phase was extracted with ethyl acetate (2ꢂ15 mL) and the com-
bined organic layers were dried over anhydrous MgSO4 and subsequently
concentrated with rotary evaporation under reduced pressure. The resi-
due was purified by flash column chromatography on silica gel (eluent:
hexanes/ethyl acetate) to afford the corresponding cyclization product.
[4] J. Jamrozik, S. Schab, Monatsh. Chem. 1994, 125, 1145–1151.
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Acknowledgements
[7] K. Sonogashira, in Metal-Catalyzed Cross-Coupling Reactions, Eds:
F. Diederich, P. J. Stang, WILEY-VCH, Weinheim, 1998, pp. 203–
229.
[8] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483.
[9] The terms ortho, para, and meta shall, henceforth, be understood to
mean positions occupied on either the distal phenyl group or the
phenyl directly attached to the carbonyl moiety, relative to the 1–1’-
diphenyl bond.
We thank the Queens College Research Enhancement Award and the
Queens College Undergraduate Research and Mentoring Education
(UR/ME) program for their financial support, and Dr. Cliff Soll at
Hunter College of the City University of New York for recording the
mass spectra for all of the new compounds.
Keywords: cyclization · electrophilic addition/substitution ·
iodine monochloride · spiro compounds · substituent effects
Received: April 25, 2013
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Y. Chen et al.
Synthesis
Y. Chen,* X. Liu, M. Lee, C. Huang,
I. Inoyatov, Z. Chen, A. C. Perl,
W. H. Hersh ................... &&&& — &&&&
Spiro compounds: An iodine mono-
chloride-induced intramolecular cycli-
zation of 1-[4’-methoxy(1,1’-
place at the ipso position (versus the
ortho electrophilic aromatic substitu-
tion) to afford 4’H-spiro(cyclohexa-
ICl-Induced Intramolecular Electro-
philic Cyclization of 1-[4’-
Methoxy(1,1’-biphenyl)2-yl]alky-
nones—A Facile Approach to Spiro-
conjugated Molecules
biphenyl)2-yl]alkynones has been
developed (see scheme). An electro-
philic iodocyclization selectively takes
ACHTUNGTRENN[UNG 2,5]diene-1,1’-naphthalene)-4,4’-
diones, a new group of spiroconjugated
compounds.
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