DDQ-promoted functionalization of phenylalkylacetylenes at the propargylic carbon

Full text of DOI:10.1021/jo980966h

J . Org. Chem. 1998, 63, 8035-8037
8035
Sch em e 1
DDQ-P r om oted F u n ction a liza tion of
P h en yla lk yla cetylen es a t th e P r op a r gylic
Ca r bon
Pier Carlo Montevecchi* and Maria Luisa Navacchia
Dipartimento di Chimica Organica “A. Mangini”, Universita`
di Bologna, Viale Risorgimento 4, I-40136 Bologna, Italy
Received May 21, 1998
The oxidation of activated carbon-hydrogen σ bonds
represents a useful protocol for the functionalization of
hydrocarbons linked to activating π systems, particularly
aryl and alkenyl groups.1 In contrast, the oxidation of
alkynes has received much less attention as a method
for functionalizing the propargylic carbon.2 The hitherto
known methods are mainly confined to the oxidative
transformation of the CC triple bond to diketones or
carboxylic acids.1a
of starting alkyne 1a and the exclusive presence of the
enyne 4a as a 95:5 Z/ E mixture. The filtrate and the
solid were dissolved in acetone and chromatographed on
a silica gel column to give the enyne 4a (48%) and
hydroquinone (DDQH2). Elution with methanol gave
unidentifiable black solid material. Performing the reac-
tion at 120 °C in a sealed tube gave identical results,
while the use of boiling acetonitrile (2 h) similarly gave
(Z)-4a in 50% yield (based on reacted 1a ), but alkyne 1a
was recovered in 70% yield. Similar results were ob-
tained with phenylhexyne (1b) and phenyldecyne (1c),
which reacted with 1.5 equiv of DDQ in boiling fluo-
robenzene to give the corresponding (Z)-enynes 4b,c in
a stereoselective mode (45% and 27% yields, respectively;
100% conversion) (Scheme 1). In contrast, neither 1-de-
cyne or 5-decyne reacted under the general conditions
suggesting that terminal acetylenes and dialkylacety-
lenes are unreactive to DDQ in refluxing fluorobenzene.
The effect of the 1-phenyl substituent in promoting the
oxidation of acetylenes 1a -c is likely related to the lower
oxidation potential of the CC triple bond of arylalkyl-
acetylenes as compared with dialkylacetylenes. Cyclic
voltammetry experiments (see the Experimental Section)
showed an oxidation anodic peak at +2.1 V for alkyne
1a , while 5-decyne did not undergo electrochemical
oxidation within 2.5 V.
From a mechanistic standpoint, the first step of the
reaction leading to enynes 4 should be a single-electron-
transfer (SET) process between the alkyne triple bond
and DDQ generating the radical ion pair 2. The latter
should give the ion pair 3 through hydrogen transfer from
the alkyne radical cation to DDQ•-. A proton transfer
from 3 to DDQH- will then generate the enyne 4 and
DDQH2 (Scheme 1). The key step of the entire process
is the SET reaction. The reduction potential for DDQ
was reported to be E° ) +0.51 V in acetonitrile.9 If the
SET process was an equilibrium, the resultant equilib-
rium constant (K ≈ 10-22 at 84 °C) is far too low to take
into account the observed completion of the reaction
within 2 h. Evidently, the driving force for the SET
reaction is the subsequent hydrogen transfer to DDQ•-
that should be fast enough to make the electron transfer
irreversible. We might infer that these two reactions
could occur in a quasiconcerted mechanism; that is, the
radical ion pair 3 is a transition state and not an
intermediate.
Our interest in the chemistry of the CC triple bond3
prompted us to investigate the oxidative functionalization
of alkylacetylenes at the propargylic carbon atom as a
possible route to conjugated enynes. Conjugated enynes
are useful intermediates as building blocks for the
synthesis of natural products4 and are generally obtained
by alkyne/alkene coupling.4,5
Herein, we report results obtained from DDQ-promoted
oxidation of phenylalkylacetylenes. DDQ (2,3-dicyano-
5,6-dichloro-1,4-benzoquinone) is a well-known dehydro-
genating oxidant that has been used for the aromatiza-
tion of dihydrobenzene derivatives,6 dehydrogenation of
steroids and lactones,7 and the oxidation of vinyl sul-
fides.8
Resu lts a n d Discu ssion
In a typical experiment, a fluorobenzene solution (0.1
M) of phenylpentyne 1a was refluxed for 2 h in the
presence of an excess of DDQ (1.5 molar equiv). The
resulting mixture was filtered to separate a black solid,
consisting mainly of hydroquinone (DDQH2). GC-MS
1
and H NMR analysis of the filtrate showed the absence
(1) Oxidations of activated C-H bonds have been extensively
reviewed. See: (a) Hudlicky M. Oxidations in Organic Chemistry; ACS
Monograph 186; American Chemical Society: Washington, DC, 1990.
(b) Bulman Page, P. C.; McCarthy, T. J . Oxidation Adjacent to CdC
Bonds. Comprehensive Organic Synthesis; Pergamon Press: Oxford,
U.K., 1991; Vol. 7, Chapter 2.1. For electrochemical oxidations of
hydrocarbons, see: Lund, H.; Baizer, M. M. Organic Electrochemistry,
3rd ed.; Marcel Dekker: New York, 1991.
(2) Chabaud, B.; Sharpless, K. B. J . Org. Chem. 1979, 44, 4202.
(3) Montevecchi, P. C.; Navacchia, M. L. J . Org. Chem. 1997, 62,
5600. Montevecchi, P. C.; Navacchia, M. L. J . Org. Chem. 1998, 63,
537 and references therein.
(4) A class of insect pheromones belongs to the conjugated enynes
family; see: Mori, K. The Total Synthesis of Natural Products;
ApSimon, J ., Ed.; J ohn Wiley: New York, 1992; Vol. 9.
(5) Normant, J . F. Mod. Synth. Methods 1983, 3, 139. Luh, T.-Y.;
Wong, K.-T. Synthesis 1993, 349. Sonogashira, K. Coupling Reactions
between sp2 and sp Carbon Centers. Comprehensive Organic Synthesis;
Pergamon Press: Oxford, U.K., 1991; Vol. 3, Chapter 2.4.2. Clough,
J . M. The Ramberg-Backlund Rearrangement. Comprehensive Organic
Synthesis; Pergamon Press: Oxford, U.K., 1991; Vol. 3, Chapter 3.8.9.
(6) Walker, D.; Hiebert, J . D. Chem. Rev. 1967, 67, 153. Foster, R.;
Foreman, M. In The Chemistry of the Quinonoid Compounds; Patai,
S., Ed.; J ohn Wiley and Sons: New York, 1974; Part 1, pp 257-423.
(7) Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 78, 317.
Compelling evidence for the role played by the presence
of propargylic hydrogen atoms in the oxidation of the CC
triple bond was obtained by reacting diphenylacetylene
and DDQ in boiling fluorobenzene. We observed the
immediate formation of a deep green color at room
(8) Capella, L.; Montevecchi, P. C.; Nanni, D. J . Org. Chem. 1994,
59, 7379.
10.1021/jo980966h CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/08/1998

8036 J . Org. Chem., Vol. 63, No. 22, 1998
Notes
Sch em e 2
with a 2-fold excess of DDQ. Under these conditions, no
traces of the (E)-enyne (E)-4a were detected by H NMR
1
analysis of the reaction mixture, while the (Z)-enyne (Z)-
4a was still isolated in 50% yield. The oxidation appears
to proceed nonstereoselectively, generating both (E)- and
(Z)-enynes from which the (E)-enyne is selectively re-
moved by further oxidation with DDQ, as shown by
results obtained from reactions of 1a carried out at
different DDQ concentrations (0.25, 0.5, and 1.0 molar
equiv). Under these conditions, we found a ca. 20%, 40%,
and 80% conversion yield, respectively, but in all cases,
the enyne 4a was formed in ca. 45-50% yield (on the
basis of reacted alkyne) as a 93:7 Z/ E mixture. Only
trace amounts of other (unidentified) products could be
1
revealed in the H NMR spectrum of the crude mixture.
The 1-phenyl substituent was also necessary for the
DDQ oxidation of propargylic alcohols. In fact, 1-phe-
nylpropynol (7) gave, under the usual conditions, phe-
nylpropynal 8 in 52% yield as the only identifiable
product, together with DDQH2. In contrast, 1-octyn-3-
ol, hex-5-yn-1-ol, and oct-3-yn-1-ol did not undergo any
DDQ-oxidation to the corresponding carbonyl compounds.
temperature that is likely a charge-transfer complex, but
alkyne and DDQ were recovered unchanged after 2 h.10
However, some evidence (although nonconclusive) that
the radical ion pair 2 might be an actual intermediate
arose from results obtained by reacting 5-phenylpent-4-
1
yn-1-ol (1d ) with DDQ (1.2 molar equiv). In fact, the H
NMR spectrum of the reaction mixture showed the
presence of the (Z)-enyne 4d and the enynaldehyde 5 in
a ca. 1:1 ratio together with comparable amounts of an
unidentified product. The unknown showed multiplets
at δ 2.4 and 4.1 (this signal collapsed to a two-proton AB
system upon irradiation at δ 2.4) and a triplet due to a
vinylic proton at δ 6.50 (this signal collapsed to a singlet
upon irradiation at δ 2.4) in addition to aromatic protons.
We suspected that this product was 1-phenyldihydro-
pyran (6), which might arise through electrophilic attack
of the radical cation 2d at the oxygen atom (Scheme 2).
Unfortunately, the possible pyran 6 was not isolated by
subsequent column chromatography, which only sepa-
rated the (Z)-enyne (Z)-4d (12%) and the enynaldehyde
5 (16%, 6:1 E/ Z mixture) (Scheme 2). The aldehyde 5
was formed by subsequent oxidation of the enyne 4d at
the allylic position, as evidenced by independent experi-
ments.11
This study has been extended to 1-sulfanyl- and 1-silyl-
substituted alkylacetylenes to provide a route to func-
tionalizated enynes that could be useful building blocks
in organic synthesis. 1-(Phenylthio)hex-1-yne (1e) was
reacted with DDQ (1.5 molar equiv) under the usual
reaction conditions and at room temperature for 7 h to
give the corresponding (Z)-enyne (Z)-4e in 32% and 48%
yield, respectively, whereas 1-(trimethylsilyl)dec-1-yne
did not react at all. The marked reactivity of 1e, and
the complete nonreactivity of the 1-silyl derivative, were
not surprising in the light of the postulated requirement
for the R-substituent to stabilize the positively charged
intermediate by delocalization.
Formation of enynes 4a -c from phenylalkylacetylenes
1a -c is of particular interest due to the high Z stereo-
selectivity. Noteworthy is the observation that the Z/ E
ratio changed from 95:5 to 50:50 on standing the enyne
4a at room temperature for 2 days in CDCl3 solution,
indicating that the stereoselectivity is not due to ther-
modynamic factors. The reason for predominant forma-
tion of the (Z)-enyne remains an open question. Possibly,
the (E)-enyne might be selectively removed by DDQ to
give tarry, unidentifiable products. This suggestion
comes from our previous findings that DDQ, probably
owing to steric factors, selectively oxidized vinyl sulfides
only in the E configuration.8 Supporting evidence arose
from results obtained by carrying out the reaction of 1a
In conclusion, we have reported that the DDQ oxida-
tion of phenylalkylacetylenes carried out in boiling fluo-
robenzene provides a potentially useful method to obtain
synthetically interesting conjugated (Z)-enynes in a
highly stereoselective mode. The reaction fails with
1-decyne or 5-decyne, likely as a consequence of the
higher oxidation potential of dialkylacetylenes and ter-
minal alkynes. The importance of an R-substituent
capable of stabilizing the proposed positively charged
intermediate is further seen in the DDQ oxidation of
1-(phenylthio)hex-1-yne that occurs even at room tem-
perature.
(9) Peover, M. E. J . Chem. Soc. 1962, 4540.
(10) It appears that the alkyne radical cation is not willing to be
trapped at alkynic carbon by the DDQ•- counterion. Instead, covalent
complexes between quinones and diarylacetylenes are formed under
photochemical conditions in the solid state; see: Bosch, E.; Hubig, S.
M.; Lindeman, S. V.; Kochi, J . K. J . Org. Chem. 1998, 63, 592.
(11) We also found that, under our conditions, allylic alcohols such
as 1-octen-3-ol can be oxidized by DDQ to the corresponding aldehydes
in good yields. The DDQ oxidation of allylic alcohols has been already
reported in a few cases (see: Braude, E. A.; Linstead, R. P.; Wooldridge,
K. R. J . Chem. Soc. 1956, 3070. Burn, D.; Petrow, V.; Weston, G. O.
Tetrahedron Lett. 1960, 14).
Exp er im en ta l Section
Phenylpentyne (1a ), 1-octyn-3-ol (9), hex-5-yn-1-ol, oct-3-yn-
1-ol, and oct-1-yn-3-ol are commercially available. Phenylalkyl-
acetylenes 1b,12 1c,12 1d [1H NMR δ 1.85 (3H; 2H multiplet
superimposed to a 1H broad singlet), 2.5 (2H, t, J ) 7.0 Hz),
(12) Ward, H. R. J . Am. Chem. Soc. 1967, 89, 5517.

Notes
J . Org. Chem., Vol. 63, No. 22, 1998 8037
3.80 (2H, t, J ) 6.2 Hz), 7.2-7.5 (5H, m); MS m/z (rel inten) 160
(M+, 40) 159 (20), 141 (80), 128 (60), 115 (100), 104 (80); HRMS
calcd for C11H12O 160.0888; found 160.0885], and 713 were
obtained in ca. 80-90% yield through tetrakis(triphenylphos-
phine)palladium-catalyzed coupling of iodobenzene with the
corresponding terminal alkyne, according to a procedure re-
ported in the literature.14
) 10.5 Hz, J AX ) 7.5 Hz), 7.2-7.6 (5H, m); MS m/z (rel inten)
212 (M+, 80), 155 (700), 141 (80), 128 (90), 115 (100); HRMS
calcd for C16H20 212.1565, found 212.1568.
F r om 1d . Gradual elution with petroleum ether/diethyl ether
mixtures gave (Z)-5-Phenylpent-2-en-4-yn-1-ol ((Z)- 4d ) (12%,
based on reacted 1d ) 1H NMR δ 1.9 (OH, broad signal), 4.50
(2H, dd, J 1 ) 6.5 Hz, J 2 ) 1.5 Hz), 5.8 (1H, dt, J 1 ) 10.5 Hz, J 2
) 1.5 Hz), 6.15 (1H, dt, J 1 ) 10.5 Hz, J 2 ) 6.5), 7.2-7.5 (5H, m)
Hz); MS m/z (rel inten) 158 (M+, 20), 157 (25), 129 (100), 128
(90), 155 (100); HRMS calcd for C11H10O 158.0732, found
158.0734], 5-phenylpent-2-en-4-yn-1-al (5) (6:1 E/ Z mixture)
(16%, based on reacted 1d ) [1H NMR δ (E isomer) 6.45 (1H, B
part of an ABX system, J AB ) 15.5 Hz, J AX ) 7.7 Hz), 6.75 (1H,
A part of an AB system, J AB ) 15.5 Hz), 7.1-7.5 (5H, m), 9.55
(1H, d, J ) 7.7 Hz); δ (Z isomer) 6.25 (1H, dd, J 1 ) 10.5 Hz, J 2
) 8.5 Hz), 6.80 (1H, d, J ) 10.5 Hz), 7.1-7.5 (5H, m), 10.20
(1H, d, J ) 8.5 Hz); MS m/z (rel inten) 156 (M+, 100), 128 (80),
127 (60), 102 (100); HRMS calcd for C11H8O 156.0575, found
156.0578], and starting alkyne 1d (25%). The 1H NMR spectrum
of the reaction mixture showed, in addition to compounds 1d ,
4d , and 5, signals at δ 2.4 (m), 4.1 (2H, m; collapsing to AB
system, J AB ) 10.6 Hz, inner line separation ) 11 Hz, upon
irradiation at δ 2.4), 6.50 (1H, t, J ) 6.0 Hz; collapsing to singlet
upon irradiation at δ 2.4), and 7.1-7.5 (m) ascribable to the
dihydropyran 6. Products 4d , 5, and 6 were found to be in a ca.
1:1:1 ratio.
1-(Phenylthio)pent-1-yne (1e)15 and 1-(trimethylsilyl)dec-1-yne
[1H NMR δ 0.1 (9H, s), 0.85 (3H, t, J ) 7 Hz), 1.2-1.5 (12H, m),
2.2 (2H, t, J ) 7.0 Hz); MS m/z (rel inten.) 210 (M+, 0.1), 195
(60), 73 (100), 59 (80)] were obtained in 70-80% yield as follows.
To a THF solution (80 mL) of the appropriate alkyne (1-hexyne
or 1-decyne) (20 mml) was added a 1.6 M solution of butyllithium
in n-pentane (12.5 mL) at 0-5 °C. The solution was stirred for
15 min, and then diphenyl disulfide (20 mmol) or trimethylsilyl
chloride (20 mmol) in THF (10 mL) was added dropwise at 0
°C. The resulting mixture was refluxed for 2 h and then cooled
and filtered. The filtrate was evaporated and the residue
chromatographed on silica gel column.
1H NMR spectra were recorded at 200 (or 300) MHz with Me4-
Si as an internal standard. Mass spectra (MS and HRMS) were
recorded using electron-impact ionization.
Rea ction of Alk yn es 1a -e, 7, a n d 9 w ith DDQ. Gen er a l
P r oced u r e. A solution of the appropriate alkyne 1a -e, or 7 (3
mmol) and DDQ (1.0 g, 4.5 mmol; 0.8 g in the case of 1d ) in
fluorobenzene (30 mL) was refluxed for 2 h. The reaction
mixture was cooled and the black solid filtered off. The filtrate
was evaporated and the residue analyzed by GC-MS and then
chromatographed on a silica gel column by elution with petro-
leum ether (bp 40-60 °C), unless otherwise stated. The follow-
ing reaction products were obtained as oily products:
F r om 7. Phenylpropynal 8 exhibited spectral properties
identical to those reported16 (52%).
F r om 1e. (Z)-1-(Phenylthio)hex-3-en-1-yne ((Z)-4e) (32%): 1H
NMR δ 1.05 (3H, t, J ) 7.5 Hz), 2.35 (2H, d quintuplet, J q ) 7.5
Hz, J d ) 1.5 Hz), 5.60 (1H, dt, J d ) 11 Hz, J t ) 1.5 Hz), 5.95
(1H, dt, J d ) 11 Hz, J t ) 7.5 Hz), 7.15-7.5 (5H, m); MS m/z (rel
F r om 1a . 1-Phenylpent-3-en-1-yne (4a ) (48%; 95:5 Z/ E
inten) 188 (M+, 80), 173 (70), 77 (100); HRMS calcd for C12H12
S
mixture): 1H NMR δ [Z isomer] 1.95 (3H, dd, J 1 ) 7.0 Hz, J 2
)
188.0660, found 188.0663. This reaction, repeated by stirring
1e and DDQ at room temperature for 6-7 h, gave the (Z)-enyne
(Z)-4e in 48% yield.
Electr och em ica l Exp er im en ts. Cyclic voltammetry ex-
periments were carried out at 25 °C in acetonitrile/0.1 M LiClO4.
CV curves, recorded on Pt electrode vs saturated calomel
electrode (SCE), showed an irreversible oxidation for 1-phenyl-
pentyne 1a , with an anodic peak at 2.1 V. No anodic peak was
observed within 2.5 V for dec-5-yne.
1.7 Hz), 5.70 (1H, dq, J d ) 10 Hz, J q ) 1.7 Hz), 6.0 (1H, dq, J d
) 10 Hz, J q ) 7.0 Hz), 7.1-7.4 (5H, m); δ [E isomer] 1.85 (3H,
dd, J 1 ) 7.0 Hz, J 2 ) 2.0 Hz), 5.72 (1H, dq, J d ) 15 Hz, J q ) 2.0
Hz), 6.25 (1H, dq, J d ) 15 Hz, J q ) 7.0 Hz), 7.1-7.4 (5H, m);
MS m/z (rel inten) 142 (M+, 50), 141 (100), 115 (100); HRMS
calcd for C11H10 142.0782, found 142.0784. In
a repeated
experiment, the filtrate and the black solid were collected and
chromatographed to give enyne 4a . Elution with diethyl ether
gave hydroquinone (DDQH2; yield not determined). Further
elution with methanol gave black tarry material.
Ack n ow led gm en t . This investigation was sup-
ported by the University of Bologna (funds for selected
research topics A.A. 1997-99). We also acknowledge
financial support from the Ministero dell’Universita` e
della Ricerca Scientifica e Tecnologica (MURST) and
CNR (Rome).
F r om 1b. (Z)-6-Phenylhex-3-en-1-yne ((Z)-4b) (45%): 1H
NMR δ 1.05 (3H, t, J ) 7 Hz), 2.40 (2H, d quintuplet, J q ) 7.0
Hz, J d ) 2 Hz), 5.65 (1H, dt, J d ) 10 Hz, J q ) 2 Hz), 5.97 (1H,
dt, J d ) 10 Hz, J t ) 7.0 Hz), 7.1-7.4 (5H, m); MS m/z (rel inten)
156 (M+, 80), 155 (40), 141 (80), 115 (100); HRMS calcd for C12H12
156.0939, found 156.0936.
F r om 1c. (Z)-1-Phenyldec-3-en-1-yne ((Z)-4c) (27%): 1H NMR
δ 0.85 (3H, t, 7.5 Hz); 1.2-1.6 (10H, m), 2.35 (2H, dq, J q ) 7.5
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
all new compounds (8 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
Hz, J d ) 1.4 Hz), 5.65 (1H, B part of an ABX2 system, J AB
)
10.5 Hz, J AX ) 1.4 Hz), 5.95 (1H, A part of an ABX2 system, J AB
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