Highly regiocontrolled pd-catalyzed cross-coupling reaction of terminal alkynes and allenylphosphine oxides

Article abstract of DOI:10.1021/jo034486o

The cross-coupling of a variety of terminal alkynes 1 with allenylphosphine oxides 2 catalyzed by a Pd(OAc)₂-TDMPP system provided conjugated endo-enynes 3 solely, while the TCPC-catalyzed reaction of the same regents led to the exclusive forma

Full text of DOI:10.1021/jo034486o

High ly Regiocon tr olled P d -Ca ta lyzed Cr oss-Cou p lin g Rea ction of
Ter m in a l Alk yn es a n d Allen ylp h osp h in e Oxid es
Michael Rubin, J elena Markov, Stepan Chuprakov, Donald J . Wink, and
Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago,
Illinois 60607-7061
vlad@uic.edu
Received April 16, 2003
The cross-coupling of a variety of terminal alkynes 1 with allenylphosphine oxides 2 catalyzed by
a Pd(OAc)2-TDMPP system provided conjugated endo-enynes 3 solely, while the TCPC-catalyzed
reaction of the same regents led to the exclusive formation of exo-isomers 4. The mechanistic
rationale for these selective transformations was proposed. Synthetic usefulness of the prepared
exo-enyne 4 was demonstrated in the synthesis of multisubstituted diarylbenzylphosphine oxides
5 via the Pd-catalyzed [4+2]-benzannulation reaction.
The development of straightforward and atom-eco-
nomic approaches toward conjugated enynes, important
synthetic blocks and essential units found in a variety
of biologically active compounds,1 has been a subject of
considerable interest during the past decade. Various
transition2,3 and rear-earth4 metals have been success-
fully employed in addition reactions of terminal alkynes
to alkynes and allenes to provide a multitude of different
enynes. Although a number of efficient protocols were
developed, achieving high degrees of regio- and stereo-
selectivity, especially in reactions involving allenes, often
presents a problem.5 During our investigation of the scope
of the Pd-catalyzed [4+2] benzannulation reaction,6 we
searched for efficient and selective ways of assembling
phosphorus-containing enynes as it will allow for direct
approach to phosphorus-containing aryls and biaryls.
This type of enyne with an exo-methylene moiety (i,
EWG ) Ph2PO, Scheme 1) is available via hydroiodina-
tion of allenylphosphine oxides followed by Sonogashira
coupling, as reported by Ma and co-workers.7 Further-
more, these i and endo-enynes ii are both accessible
via Trost Pd-catalyzed addition of alkynes to allenes
(EWG ) COOR, Scheme 1).3c It was shown that either
exo-enyne i or its endo-isomer ii can be obtained as major
products depending on the type of Pd-catalyst used.
Although this protocol had never provided perfect regio-
control, we chose this method as a potential approach
toward both exo (i, EWG ) R2PO) and endo (ii, EWG )
R2PO) phosphorus-containing enynes. We hoped that
careful optimization of the reaction conditions would
allow for the selective synthesis of these useful synthons
which were planned to be tested in the subsequent Pd-
catalyzed benzannulation reaction with conjugated diynes.
The present paper documents the results on these stud-
ies.
(1) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. (b)
Nicolaou, K. C.; Dai, W.-M.; Tsay, S.-C.; Estevez, V. A.; Wrasidlo, W.
Science 1992, 256, 1172. (c) Trost, B. M. Science 1991, 254, 1471.
(2) For recent reviews on reductive coupling of two alkynes, see: (a)
Bruneau, C.; Dixneuf, P. Acc. Chem. Res. 1999, 32, 311. (b) Trost, B.
M.; Toste, F. D.; Pinkerton, A. B. Chem. Rev. 2001, 101, 2067-2096.
(c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. For
Pd-catalyzed reactions, see: (d) Gevorgyan, V. Alkynyl substitution
via alkynylpalladation-reductive elimination. In Handbook of Orga-
nopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; J ohn
Wiley & Sons: Hoboken, NJ , 2002; Vol. 1, pp 1463-1469. (e) Trost, B.
M.; McIntosh, M. C. J . Am. Chem. Soc. 1995, 117, 7255. (f) Trost, B.
M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ruhter, G. J . Am. Chem.
Soc. 1997, 119, 698. (g) Trost, B. M.; Frontier, A. J . J . Am. Chem. Soc.
2000, 122, 11727. (h) Rubina, M.; Gevorgyan, V. J . Am. Chem. Soc.
2001, 123, 11107. (i) Gevorgyan, V.; Radhakrishnan, U.; Takeda, A.;
Rubina, M.; Rubin, M.; Yamamoto, Y. J . Org. Chem. 2001, 66, 2835.
(3) For Rh-catalyzed reductive coupling of alkyne and allene, see:
(a) Yamaguchi, M.; Omata, K.; Hirama, M. Tetrahedron Lett. 1994,
35, 5689. (b) For Ru-catalyzed reactions, see: Yamaguchi, M.; Kido,
Y.; Omata, K.; Hirama, M. Synlett 1995, 1181. For Pd-catalyzed
reactions, see: (c) Trost, B. M.; Kottirsch, G. J . Am. Chem. Soc. 1990,
112, 2816.
(4) See, for example: (a) Nishiura, M.; Hou, Z.; Wakatsuki, Y.;
Yamaki, T.; Miyamoto, T. J . Am. Chem. Soc. 2003, 125, 1184. (b)
Haskel, A.; Straub, T.; Dash, A. K.; Eisen, M. S. J . Am. Chem. Soc.
1999, 121, 3014.
(5) Mixtures of regio- and stereoisomers are normally obtained in
transition metal-catalyzed reductive couplings of acetylenes and al-
lenes. See refs 2d and 3.
(6) (a) Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.;
Radhakrishnan, U.; Yamamoto, Y. J . Am. Chem. Soc. 1999, 121, 6391.
(b) Gevorgyan, V.; Yamamoto, Y. J . Organomet. Chem. 1999, 576, 232.
Resu lts a n d Discu ssion
P d -Ca ta lyzed Ad d ition of Ter m in a l Alk yn es to
Allen ylp h osp h in e Oxid es. First, we tested the reaction
of alkynes and allenylphosphine oxides catalyzed by a
Pd(OAc)2-tris-(2,6-dimethoxyphenyl)phosphine (TDMPP)
combination (conditions A), which was reported to pro-
vide the highest endo-selectivity on the allenyl ester
substrates.3c To our delight, the reaction of 1,1-disubsti-
tuted allene 2a with phenylacetylene (1a ) proceeded
smoothly to give endo-product 3a a 8 as a single isomer in
(7) Ma, S.; Xie, H.; Wang, G.; Zhang, J .; Shi, Z. Synthesis 2001, 713.
(8) The structure and configuration of compound 3a a were confirmed
by single-crystal X-ray crystallography. See Supporting Information
for details.
10.1021/jo034486o CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/09/2003
J . Org. Chem. 2003, 68, 6251-6256
6251

Rubin et al.
SCHEME 1
TABLE 1. P d -Ca ta lyzed Red u ctive Cr oss-Cou p lin g of Acetylen es a n d Allen ylp h osp h in e Oxid es
a
b
Reagents and conditions: (A) Pd(OAc)2 (10 mol %), TDMPP (20 mol %), 1 M THF, rt; (B) TCPC (5 mol %), 1 M CH2Cl2, rt. Isolated
yield. c Pd(OAc)2 (5 mol %) and TDMPP (10 mol %) were employed. Isolated yield of a major component. 3m b was detected by GC/MS
d
as a minor component in an 18:82 mixture.
good yield (eq 1, Table 1, entry 1). Monosubstituted allene
2b, under the same conditions, provided the correspond-
ing endo-enyne 3a b in very high yield (Table 1, entry 2).
Variation of the nature of terminal acetylenes employed
showed that the reaction with alkyl- (entries 3 and 4),
alkenyl- (entries 5-7), aryl- (entries 1, 2, and 11),
silylacetylenes (entry 10) and propargyl ether (entry 8)
remained high yielding and perfectly regioselective re-
gardless of the substitution pattern of the allene. The
reaction of allenyl phosphonamide 2c under the same
conditions also proceeded uneventfully, providing the
corresponding product 3bc in good yield (entry 9). In most
6252 J . Org. Chem., Vol. 68, No. 16, 2003

Reaction of Terminal Alkynes and Phosphine Oxides
SCHEME 2
cases 10 mol % of palladium acetate and 20 mol % of
TDMPP (condition A) were necessary to drive the reac-
tion to completion. However, in certain cases we were
able to reduce the amount of palladium and phosphine
ligand twice with neither yield nor selectivity being
affected (entries 3, 4, and 9). Remarkably, all allenyl-
phosphine oxides, in contrast to allenyl esters,3c under
catalytic system A reacted with a variety of alkynes in a
perfectly regioselective manner providing the endo-
enynes 3 as sole products, with no traces of exo-isomers
4 being detected. It deserves noting that the reactions
did not proceed smoothly under strictly anhydrous condi-
tions; the addition of small amounts of water (0.2-2.0
equiv) appeared to be necessary for successful addition
reactions.9
Next, we attempted the synthesis of disubstituted exo-
enynes 4, which are potentially the most attractive
phosphorus-containing substrates for the subsequent
benzannulation reaction.10 Initial experiments were per-
formed by using a TCPC-TTMPP11 combination, which
was reported to provide the best exo-selectivity in the
coupling of acetylenes with allenyl esters.3c In our hands,
this catalytic system provided moderate selectivity (4a b:
3a b 80:20), while a TCPC-TDMPP combination gave
somewhat better results (4a b:3a b 90:10). Optimization
revealed that the phosphine-free conditions (conditions
B, 5 mol % of TCPC in CH2Cl2) allowed for the exclusive
formation of exo-enyne 4. The coupling of alkynes bearing
alkyl (Table 1, entry 13), alkenyl (entry 14), and silyl
(entry 15) substituents was also perfectly regiocontrolled.
The electronic properties of the substituent at the para-
position of arylacetylenes did not affect selectivity in the
reaction; reactions of both electron-rich (entries 17-19)
and electron-poor (entries 16, 20, and 21) substrates
furnished the corresponding exo-enyne 4 as a single
isomer. Acetylene 1m provided the only example without
perfect regiocontrol; small amounts of regioisomeric 3m b
were detected by GC/MS analysis of the crude reaction
mixtures (Table 1, entry 22). In all other cases, employ-
ment of catalytic system B led to exclusive formation of
the exo-enynes 4.
We propose the following mechanistic rationale for the
observed highly regiocontrolled condensation of terminal
alkynes with allenylphoshine oxides. The catalytic cycle
starts from the oxidative addition of Pd-species 6 to
terminal acetylene 1 providing complex 7, which after
carbopalladation of allene 2 produces η3-complex 9
(Scheme 2). η3 T η1 equilibrium with the less bulky
(phosphine free) and more electrophilic Pd(IV) complex
derived from TCPC produces η1-complex 8, in which
electrophilic Pd resides at the most electron-rich carbon
atom. The same equilibrium drives the less electrophilic
and more bulky Pd(II) complex derived from Pd(OAc)2
or Pd2dba312 toward η1-species 10. Reductive elimination
of 8 and 10 produces 4 and 3, respectively. Experiments
with phenylacetylene-d1 revealed selective deuterium
incorporation into the methyl group of 3 under conditions
A and into the methylene group of 4 under conditions
B.13 The equilibrium 10 T 9 T 8 is additionally supported
by the fact that thermodynamically more stable 3 was
obtained as a single reaction product under catalytic
system B at elevated temperatures. When product 4 was
subjected to the latter reaction conditions, no formation
of 3 was observed, thus ruling out a possible equilibrium
between products 3 and 4.
(b) P d -Ca ta lyzed [4+2] Ben za n n u la tion of P h os-
p h in e Oxid e Con ta in in g En yn es. First we attempted
[4+2] benzannulation of enynes 3, which poses a sub-
stantial challenge, since as was shown before the cy-
cloaddition of trisubstituted E-enynes proceeds sluggishly
(12) In early works2f Trost proposed that the catalytic system Pd-
(OAc)2-TDMPP works in Pd(II)-Pd(IV) manifold. We believe that it is
unlikely that Pd(II) species can survive in the presence of several
reducing agents, such as terminal alkynes and phosphines present in
the reaction mixture. The tendency for Pd(II) to be easily reduced into
Pd(0) species under variety of reaction conditions is well-known. See:
Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; J ohn Wiley & Sons: Hoboken, NJ , 2002. In addition,
our test experiments indicated that the Pd2dba3/o-Tol3P combination
works as selective a the s Pd(OAc)2-TDMPP system, albeit a bit slower,
to provide endo-enynes 3. Furthermore, it also was shown by Trost2g
and by us2i that Pd(0) complexes enable head-to-tail homo- and cross-
coupling of acetylenes to be catalyzed.
(9) Although the role of water is not completely understood, strictly
anhydrous conditions render somewhat less selective and less repro-
ducible results. For some examples of use of H2O or ROH additives in
the Pd-catalyzed reactions, see: (a) Quan, L. G.; Gevorgyan, V.;
Yamamoto, Y. J . Am. Chem. Soc. 1999, 121, 3545. (b) Wellace, D. J .;
Goodman, J . M.; Kennedy, D. J .; Davies, A. J .; Cowden, C, J .; Ashwood,
M. S.; Cotrell, I. F.; Dolling, U.-H.; Reider, P. J . Org. Lett. 2001, 3,
671.
(10) It was found that 2,4-disubstituted enynes undergo the Pd-
catalyzed benzannulation reaction much easier than 1,2,4-trisubsti-
tuted enynes. See ref 6a.
(11) TCPC ) [1,2,3,4-tetrakis(methoxycarbonyl)-1,3-butadiene-1,4-
diyl]palladium; TTMPP ) tris(2,4,6-trimethoxyphenyl)phosphine.
(13) Significant deuterium scrambling between deuterated terminal
acetylenes and eventual proton sources in the presence of transition
metals is well documented. See refs 2h and 3a,b.
J . Org. Chem, Vol. 68, No. 16, 2003 6253

Rubin et al.
if at all.6a The fact that electron-withdrawing substituents
facilitate the cycloaddition reaction6a brought some hope
that 3 can potentially be employed in the aforementioned
annulation reaction (eq 2). However, all attempts to
TABLE 2. P a lla d iu m -Ca ta lyzed Cr oss-Ben za n n u la tion
of Exo-En yn es 4 w ith 5,7-Dod eca d iyn e
no.
enyne 4
X
product 5
yield, %
1
2
3
4
5
6
7
8
4a b
4gb
4h b
4ib
4jb
4k b
4lb
H
F
Me
MeO
MeS
NO2
CF3
COOMe
5a
5
5h
5i
5j
5k
5l
75
84
60
76
86
68
75
85
synthesize arylphosphine oxides via benzannulation of
3 under a variety of reaction conditions14 failed; starting
materials were recovered virtually intact (eq 2).
Next, we attempted the synthesis of multisubstituted
benzylphosphine oxides 5 via the Pd-catalyzed benzan-
nulation of exo-enynes 4. As expected, the less substi-
tuted exo-enynes 4 underwent smooth cycloaddition with
5,7-dodecadiyne (eq 3, Table 2). A series of aryl-
substituted enynes were tested under the standard
reaction conditions reported previously for benzannula-
tion of disubstituted enynes.6a The reaction showed
excellent functional group compatibility, neither phos-
phine oxide moiety nor various functional groups at the
aryl ring compromised the benzannulation. All of the
enynes tested, both with electron-releasing (Table 2,
enties 3-5) and electron-withdrawing (entries 2, 6-8)
substituents, smoothly underwent the reaction producing
the corresponding benzylphosphine oxides 5a ,g-m 15 in
good to high yields (Table 2, entiries 1-8).
In conclusion, we described the first examples of
perfectly regiocontrolled transition metal-catalyzed ad-
dition of terminal alkynes to allenes. This method allowed
for the efficient synthesis of endo- (3) and exo-conjugated
enynes (4) as single regioisomers. The plausible mecha-
nism for the formation of endo- (3) or exo-product (4)
based on the different Pd sources was proposed. Efficient
synthesis of diarylbenzylphosphine oxides from exo-
enynes 4 via the Pd-catalyzed benzannulation reaction
was demonstrated. Synthetic studies toward bis(ben-
zylphosphines) via different modes of double benzannu-
lation of phosphorus-containing enynes are currently
underway in our laboratories.
4m b
5m
alkyne 1j, allenylphosphine oxides 2a -c, and selected products
3-5 and their analytical data are provided below. For analyti-
cal and spectral data of other compounds, see the Supporting
Information. All other reagents and solvents used were com-
mercially available.
1j: A solution of t-BuOK (13.49 g, 120 mmol) in anhydrous
THF (130 mL) was added dropwise to a stirred suspension of
[Ph3PCH2Br]Br (25 g, 57 mmol) in anhydrous THF (150 mL)
under argon atmosphere at -78 °C. 4-(Methylthio)benzalde-
hyde (8.68 g, 57 mmol) was added dropwise to the formed
yellow suspension. The mixture was stirred for 10 min at -78
°C, then warmed to room temperature and quenched with
saturated aq NH4Cl (100 mL). The organic phase was sepa-
rated and the aqueous layer was extracted with ether (2 × 50
mL). Combined organic phases were dried (MgSO4), filtered,
and concentrated to a volume of approximately 100 mL. Then,
500 mL of hexane was added and the precipitated phosphine
oxide was filtered off. The clear hexane filtrate was evaporated
and the residue was distilled in a vacuum, bp 74-76 °C (1
mmHg), yield 2.7 g (18.2 mmol, 32%). Spectral properties of
obtained compound 1j were identical with those reported in
the literature.18
2a :19 Diphenylchlorophosphine (1 mL, 5.5 mmol) was added
dropwise to a stirred mixture of 2-butyn-1-ol (375 µL, 5 mmol)
and dry triethylamine (765 µL, 5.5 mmol) in anhydrous DMF
(10 mL) under argon atmosphere. The mixture was stirred for
2 h at -15 °C, then warmed to room temperature, and the
stirring was continued for another 2 h. The mixture was
quenched with 5% aqueous NaCl solution and extracted with
a 1:1 pentane-ether mixture. The organic phase was evapo-
rated and the residue was purified by preparative column
chromatography on silica gel (eluent: EtOAc) to obtain 2a as
a colorless solid. Yield 976 mg (3.61 mmol, 72%). 1H NMR
(500.13 MHz, CDCl3) δ 7.74-7.69 (m, 4H), 7.52-7.48 (m, 2H),
Exp er im en ta l Section
Acetylene 1m was prepared according to the known proce-
dure16 and its spectral properties were identical with ones
reported in the literature.17 Procedures for the preparation of
4
5
7.45-7.41 (m, 4H), 4.62 (dq, J PH ) 11.2 Hz, J HH ) 3.1 Hz,
2H), 1.92 (dt, J PH ) 11.9 Hz, J HH ) 3.1 Hz, 3H); 13C NMR
3
5
(14) All conditions normally used for the benzannulation reaction
(see ref 2i) had been tried: (A) Pd(PPh3)4 (5-10 mol %) in THF or
toluene (1 M) at 100-120 °C; (B) Pd2dba3-CHCl3 (5 mol %), o-Tol3P
(20 mol %) in THF or toluene (1 M) at 60-80 °C; (C) Pd(PPh3)4 (5 mol
%), Pd(OAc)2 (5 mol %), and TDMPP (15 mol %) in toluene (1 M) at
60-100 °C with and without the addition of Lewis acid activator (Et2-
AlCl, 25 mol %). No formation of benzannulation products was detected
under the listed conditions.
(125.76 MHz, CDCl3) δ 212.1 (d, 2J PC ) 7.3 Hz), 132.3 (+), 132.1
3
1
(+, 4C, d, J PC ) 9.4 Hz), 131.3 (2C, d, J PC ) 94.8 Hz), 128.7
2
1
(+, 4C, d, J PC ) 12.2 Hz), 92.7 (d, J PC ) 101.5 Hz), 76.3
(16) Austin, W. B.; Bilow, N.; Kelleghan, W. J .; Lau, K. S. Y. J . Org.
Chem. 1981, 46, 2280.
(15) Pd-catalyzed enyne-diyne benzannulation is a regiospecific
process. The regiochemistry of this reaction was established previously
(see ref 6a). Nonetheless, the regiochemistry of the selected benzan-
nulation product 5h was again confirmed by 2D NMR experiments;
see Supporting Information for details.
(17) Negishi, E.; Kotora, M.; Xu, C. J . Org. Chem. 1997, 62, 8957.
(18) Fuerstner, A.; Nikolakis, K. Liebigs Ann. Org. Bioorg. Chem.
1996, 2107.
(19) Berlan, J .; Battioni, J . P.; Koosha, K. Bull. Soc. Chim. Fr. 1977,
183.
6254 J . Org. Chem., Vol. 68, No. 16, 2003

Reaction of Terminal Alkynes and Phosphine Oxides
3
2
(-, d, J PC ) 12.8 Hz), 14.6 (+, d, J PC ) 5.8 Hz); 31P NMR
P r ep a r a tion of Exo-En yn es 4: Typ ica l P r oced u r e. A
5-mL Wheaton microreactor was loaded with TCPC (40.3 mg,
0.1 mmol), allenylphosphine oxide (2b) (480 mg, 2 mmol), and
CH2Cl2 (4 mL). Phenylacetylene (1a ) (219 µL, 2.1 mmol) was
added and the reaction mixture was stirred at room temper-
ature for 12-18 h, until GC/MS analysis showed the reaction
complete. Then, the reaction was directly loaded on a column
of silica gel and elution with CH2Cl2-EtOAc (1:1) gave
compound 4a b as a colorless solid. Yield 520 mg (1.52 mmol,
76%). An analytical sample was obtained by recrystallization
from hexane-CH2Cl2.
(202.46 MHz, CDCl3) δ 28.3.
2b:20 A solution of diphenylchlorophosphine (17.9 mL, 100
mmol) in anhydrous dichloromethane (150 mL) was added
dropwise to a mixture of propargyl alcohol (11.6 mL) and dry
triethylamine (22.2 mL) in anhydrous dichloromethane (200
mL) under argon atmosphere at -78 °C. The mixture was
allowed to warm to 10 °C and was poured into a cold solution
of HCl (concentrated, 5 mL) in water (200 mL). The organic
layer was separated and the aqueous phase was extracted with
dichloromethane. The combined organic phases were washed
(water, brine), dried (MgSO4), filtered, and evaporated. The
4a b:7 mp 126 °C; 1H NMR (500.13 MHz, CDCl3) δ 7.83 (m,
4H), 7.50-7.42 (m, 6H), 7.23 (m, 3H), 7.14 (m, 2H), 5.61 (dd,
solid residue was recrystallized from
a hexane-dichlo-
2
4
4J PH ) 4.1 Hz, J HH ) 0.8 Hz, 1H), 5.56 (dd, J PH ) 4.4 Hz,
romethane mixture to obtain the title compound as colorless
crystals, mp 99-100 °C. Yield 18.636 g (77.57 mmol, 78%).
2c: 2-Butyn-1-ol (1 mmol, 75 µL) was added to a stirred
mixture of bis(diisopropylamino)chlorophosphine (1.1 mmol,
29.9 mg) and triethylamine (153 µL) in dry DMF (2 mL). The
mixture was stirred at 0 °C for 2 h before being warmed up to
room temperature. DMF was evaporated in a vacuum and the
residue was purified by preparative column chromatography
on silica gel (eluent: hexanes-EtOAc, 1:1) to afford 2c as
2J HH ) 0.8 Hz, 1H), 3.35 (d, J PH ) 13.9 Hz, 2H); 13C NMR
2
1
(125.76 MHz, CDCl3) δ 132.8 (d, J PC ) 100.0 Hz, 2C), 132.3
3
(+, 2C), 131.9 (+, 2C), 131.7 (+, d, J PC ) 9.3 Hz, 4C), 128.9
2
(+, d, J PC ) 11.8 Hz, 4C), 128.7 (+), 128.5 (+, 2C), 127.4 (-,
d, 3J PC ) 8.7 Hz), 123.0, 121.3 (d, 2J PC ) 9.1 Hz), 90.4, 90.0 (d,
3J PC ) 4.5 Hz), 39.0 (-, d, J PC ) 66.9 Hz); 31P NMR (161.98
1
MHz, CDCl3) δ 26.8; 1H-13C HMQC (CDCl3, 500.13 MHz,
125.76 MHz) δH/δC 7.83/131.7, 7.52/132.3, 7.45/128.9, 7.23/
128.7, 7.23/128.5, 7.14/131.9 (5.61/127.4 and 5.56/127.4), 3.35/
39.0; GC/MS m/z 342 (M+, 30), 341 (M - H, 40), 201 (Ph2PO+,
100).
1
colorless crystals. Yield 264.4 mg (0.88 mmol, 88%). H NMR
(500.13 MHz, CDCl3) δ 4.65-4.62 (m, 2H), 3.55-3.49 (m, 4H),
1.91-1.87 (m, 3H), 1.25 (dd, J ) 6.8, 1.1 Hz, 12H), 1.18 (dd,
J ) 6.8, 1.1 Hz, 12H); 31P NMR (202.46 MHz, CDCl3) δ 23.1;
GC/MS m/z 300 (M+, 10), 247 ((i-Pr2N)2PO+, 100).
4jb: mp 107 °C dec; 1H NMR (500.13 MHz, CDCl3) δ 7.83-
7.79 (m, 4H), 7.48-7.40 (m, 6H), 7.07 (d, J ) 8.4 Hz. 2H), 7.03
4
P r ep a r a tion of En d o-En yn es 3: Typ ica l P r oced u r e. A
3-mL Wheaton microreactor was loaded with Pd(OAc)2 (22.4
mg, 0.1 mmol), TDMPP (88.5 mg, 0.2 mmol), allenylphosphine
oxide (2b) (240 mg, 1 mmol), and toluene (2 mL). Phenylacety-
lene (1a ) (1.2 mmol, 125 µL) was added and the reaction
mixture was stirred at room temperature for 1 h. Then the
mixture was filtered through a short column of silica gel
(eluent: EtOAc) and concentrated. Preparative column chro-
matography of the residue on silica gel (eluent: CH2Cl2-
EtOAc, 2:1) gave 3a b as a colorless solid. Yield 308 mg (0.9
mmol, 90%).
(d, J ) 8.4 Hz, 2H), 5.58 (d, J PH ) 3.7 Hz, 1H), 5.52 (d,
2
4J PH ) 3.8 Hz, 1H), 3.33 (d, J PH ) 13.8 Hz, 1H), 2.43 (s, 3H);
1
13C NMR (125.76 MHz, CDCl3) δ 139.9, 132.8 (d, J PC ) 100.0
3
Hz, 2C), 132.3 (+, 2C), 132.2 (+, 2C), 131.6 (+, d, J PC ) 9.3
2
3
Hz, 4C), 128.9 (+, d, J PC ) 11.7 Hz, 4C), 127.2 (-, J PC ) 8.6
3
Hz), 125.9 (+, 2C), 121.3 (d, J PC ) 8.9 Hz), 119.3, 90.3, 90.1
(d, J PC ) 4.2 Hz), 39.1 (-, d, J PC ) 66.9 Hz), 15.7 (+); 31P
NMR (202.46 MHz, CDCl3) δ 26.7; GC/MS m/z 388 (M+, 40),
387 (M - H, 40), 201 (Ph2PO+, 100).
3
1
P d -Ca t a lyzed Ben za n n u la t ion w it h 5,7-Dod eca d i-
yn e: Typ ica l P r oced u r e. An oven-dried 1-mL Wheaton
microreactor was loaded with Pd(PPh3)4 (29 mg, 0.025 mmol),
5,7-dodecadiyne (100 µL, 0.55 mmol), and dry THF (500 µL).
The mixture was stirred for 15 min until homogenized, then
transferred into a 3-mL microreactor preloaded with enyne
4a b (171 mg, 0.5 mmol) and dry THF (500 µL). The mixture
was stirred at 100 °C for 12 h, and the reaction progress was
monitored by GC/MS. When the reaction was complete, the
solvent was removed in a vacuum and the residue was purified
by preparative column chromatography on silica gel (eluent:
hexanes-EtOAc, 2:1) to obtain 5a an as oil. Yield 189 mg (0.38
mmol, 75%). An analytical sample was obtained by recrystal-
lization from hexane-CH2Cl2.
3a b: 1H NMR (400.13 MHz, CDCl3) δ 7.78-7.73 (m, 4H),
2
7.49-7.44 (m, 8H), 7.34-7.31 (m, 3H), 6.48 (d, J PH ) 23.4
Hz, 1H), 2.33 (m, 3H); 13C NMR (100.61 MHz, CDCl3) δ 141.8
2
1
(d, J PC ) 12.5 Hz), 134.6 (d, J PC ) 106.3 Hz), 132.3 (d,
2J PC ) 11.1 Hz), 131.5 (d, J PC ) 9.9 Hz), 129.6, 129.2, 129.1,
3
1
3
129.0, 127.1 (d, J PC ) 101.0 Hz), 122.7, 93.3, 91.5 (d, J PC
)
25.6 Hz), 21.5 (d, 3J PC ) 5.8 Hz); 31P NMR (161.98 MHz, CDCl3)
δ 19.4; IR (KBr) 3028, 2851, 2334, 2185, 1591, 1430, 1192,
1117, 992, 836 cm-1; GC/MS m/z 342 (M+, 100); HRMS calcd
for C23H19OP 342.1174, found 342.1183.
3ea : 1H NMR (500.13 MHz, CDCl3) δ 7.70-7.65 (m, 4H),
7.55-7.51 (m, 2H), 7.50-7.46 (m, 4H), 4.31 (s, 2H), 3.41 (s,
3H), 2.19 (m, 3H), 1.88 (d, J PH ) 13.4 Hz, 3H); 13C NMR
3
5a : mp 121-122 °C; 1H NMR (500.13 MHz, CDCl3) δ 7.73-
7.68 (m, 4H), 7.54-7.51 (m, 2H), 7.46-7.43 (m, 4H), 7.36-
2
(125.76 MHz, CDCl3) δ 134.9 (d, J PC ) 13.1 Hz), 133.9 (d,
1J PC ) 96.3 Hz), 133.3 (d, J PC ) 103.5 Hz), 132.2, 131.9 (d,
1
2
7.26 (m, 5H), 6.92 (s, 1H), 6.81 (s, 1H), 3.63 (d, J PH ) 14.1
3J PC ) 9.8 Hz), 129.0 (d, J PC ) 11.9 Hz), 94.0, 87.3 (d, J PC
)
)
2
3
Hz, 2H), 2.71 (t, J ) 7.8 Hz, 2H), 2.28 (t, J ) 6.9 Hz, 2H),
1.25-1.46 (m, 2H), 1.45-1.39 (m, 2H), 1.34-1.26 (m, 4H), 0.91
(t, J ) 7.3 Hz, 3H), 0.85 (t, J ) 7.3 Hz, 3H); 13C NMR (125.76
3
2
22.6 Hz), 60.8, 58.1, 22.5 (d, J PC ) 6.4 Hz), 22.4 (d, J PC
12.9 Hz); 31P NMR (202.46 MHz, CDCl3) δ 29.1; IR (KBr) 2975,
2947, 2818, 2360, 1979, 1578, 1432, 1367, 1259, 1181, 1083,
893, 748, 696, 539 cm-1; GC/MS m/z 324 (M+, 100); HRMS
calcd for C20H21O2P 324.1279, found 324.1290.
1
MHz, CDCl3) δ 146.0, 144.4, 141.4, 132.6 (d, J PC ) 99.1 Hz,
3
2C), 132.2 (+, 2C), 131.7 (+, d, J PC ) 8.9 Hz, 4C), 130.4 (d,
2J PC ) 8.3 Hz), 129.8 (+, 3C), 129.2 (+, d, 3J PC ) 5.5 Hz), 128.9
3fa : 1H NMR (400.13 MHz, CDCl3) δ 7.66-7.63 (m, 4H),
7.49-7.47 (m, 2H), 7.45-7.43 (m, 4H), 2.14 (m, 3H), 1.86 (d,
3J PH ) 13.4 Hz, 3H), 0.18 (s, 9H); 13C NMR (100.61 MHz,
(+, d, 2J PC ) 11.6 Hz, 4C), 127.9 (+, 2C), 127.3 (+), 120.7, 38.7
1
(-, d, J PC ) 66.0 Hz), 35.1 (-), 33.1 (-), 31.0 (-), 23.0 (-),
22.3 (-), 19.7 (-), 14.5 (+), 14.0 (+); 31P NMR (202.46 MHz,
CDCl3) δ 27.8; GC/MS m/z 504 (M+, 30), 303 (M - Ph2PO, 70),
201 (Ph2PO+, 100). Anal. Calcd for C35H37OP: C 83.30, H 7.39,
Found: C 83.30, H 7.50.
2
1
CDCl3) δ 134.8 (d, J PC ) 12.7 Hz), 134.1 (d, J PC ) 96.0 Hz),
133.0 (d, 1J PC ) 103.1 Hz), 131.7, 131.5 (d, 3J PC ) 9.7 Hz), 128.6
2
3
(d, J PC ) 12.0 Hz), 105.1 (d, J PC ) 21.3 Hz), 103.2, 22.0 (d,
2J PC ) 12.9 Hz), 21.9 (d, 3J PC ) 6.5 Hz), -0.1; 31P NMR (161.98
MHz, CDCl3) δ 29.2; IR (KBr) 2096, 1575, 1190 cm-1; GC/MS
m/z 352 (M+, 100); HRMS calcd for C21H25OPSi 352.1412,
found 352.1408.
5g: mp 100-101 °C; 1H NMR (500.13 MHz, CDCl3) δ 7.72-
7.68 (m, 4H), 7.54-7.51 (m, 2H), 7.46-7.44 (m, 4H), 7.32 (dd,
J HH ) 8.4 Hz, J HF ) 5.6 Hz, 2H), 7.00 (ps-t, J HH ≈ J HF ) 8.4
2
Hz, 2H), 6.89 (s, 1H), 6.80 (s, 1H), 3.63 (d, J PH ) 13.9 Hz,
2H), 2.69 (t, J ) 7.7 Hz, 2H), 2.29 (t, J ) 6.9 Hz, 2H), 1.51-
1.46 (m, 2H), 1.46-1.40 (m, 2H), 1.33-1.25 (m, 4H), 0.91 (t,
J ) 7.3 Hz, 3H), 0.86 (t, J ) 7.3 Hz, 3H); 13C NMR (125.76
(20) Brandsma, L.; Verkruijsse, H. D. Synthesis of Acetylenes, Allenes
and Cumulenes; Elsevier: New York, 1981.
J . Org. Chem, Vol. 68, No. 16, 2003 6255

Rubin et al.
1
MHz, CDCl3) δ 161.5 (d, 1J FC ) 245.1 Hz), 146.1, 143.4, 137.4,
5j: mp 118 °C; H NMR (500.13 MHz, CDCl3) δ 7.72-7.68
(m, 4H), 7.53-7.51 (m, 2H), 7.46-7.43 (m, 4H), 7.29 (d, J )
8.3 Hz, 2H), 7.20 (d, J ) 8.3 Hz, 1H), 6.90 (s, 1H), 6.79 (s,
1
3
132.6 (d, J PC ) 94.6 Hz, 2C), 132.2 (2C), 131.7 (+, d, J PC
)
)
3
2
9.3 Hz, 4C), 131.4 (+, d, J FC ) 7.4 Hz, 2C), 130.4 (d, J PC
3
3
2
9.3 Hz), 129.9 (+, d, J PC ) 4.6 Hz), 129.1 (+, d, J PC ) 4.6
Hz), 128.9 (+, d, J PC ) 12.0 Hz, 4C), 120.8, 114.7 (d, J FC
1H), 3.62 (d, J PH ) 14.0 Hz, 2H), 2.69 (t, J ) 7.7 Hz, 2H),
2
2
)
2.50 (s, 3H), 2.30 (t, J ) 6.9 Hz, 2H), 1.51-1.46 (m, 2H), 1.46-
1.41 (m, 2H), 0.91 (t, J ) 7.3 Hz, 3H), 0.87 (t, J ) 7.3 Hz, 3H);
13C NMR (125.76 MHz, CDCl3) δ 146.1, 143.7, 138.3, 137.4,
1
21.3 Hz, 2C), 98.1, 78.4, 38.6 (-, d, J PC ) 65.7 Hz), 35.1 (-),
33.1 (-), 31.0 (-), 23.0 (-), 22.3 (-), 19.7 (-), 14.4 (+), 14.0
(+); 19F NMR (470.59 MHz, CDCl3) δ -117.5; 31P NMR (202.46
MHz, CDCl3) δ 27.7.
1
132.6 (d, J PC ) 98.0 Hz, 2C), 132.2 (+, 2C), 131.7 (+, d,
3J PC ) 9.3 Hz, 4C), 130.4 (d, J PC ) 8.3 Hz), 130.2 (+, 2C),
2
1
3
3
5h : mp 96-98 °C; H NMR (500.13 MHz, CDCl3) δ 7.72-
129.8 (+, d, J PC ) 4.6 Hz), 129.1 (+, d, J PC ) 4.6 Hz), 128.9
2 1
7.68 (m, 4H), 7.54-7.51 (m, 2H), 7.47-7.43 (m, 4H), 7.25 (d,
J ) 8.2 Hz, 2H), 7.12 (d, J ) 8.2 Hz, 2H), 6.90 (s, 1H), 6.79 (s,
(+, d, J PC ) 12.0 Hz, 4C), 120.6, 98.1, 78.5, 38.7 (-, J PC )
65.7 Hz), 35.1 (-), 33.1 (-), 31.0 (-), 23.0 (-), 22.3 (-), 19.7
(-), 16.3 (+), 14.5 (+), 14.0 (+); 31P NMR (202.46 MHz, CDCl3)
δ 27.7.
2
1H), 3.63 (d, J PH ) 14.1 Hz, 2H), 2.70 (t, J ) 7.8 Hz, 2H),
2.36 (s, 3H), 2.29 (t, J ) 6.9 Hz, 2H), 1.52-1.47 (m, 2H), 1.47-
1.41 (m, 2H), 1.34-1.27 (m, 4H), 0.91 (t, J ) 7.3 Hz, 3H), 0.86
(t, J ) 7.3 Hz, 3H); 13C NMR (125.76 MHz, CDCl3) δ 146.0,
Ack n ow led gm en t. The support of the National
Science Foundation (CHE 0096889) is gratefully ac-
knowledged.
1
144.3, 138.5, 137.0, 132.6 (d, J PC ) 97.1 Hz, 2C), 132.2 (+,
3
2
2C), 131.7 (+, d, J PC ) 8.9 Hz, 4C), 130.3 (d, J PC ) 7.9 Hz),
3
3
129.7 (+, 2C), 129.6 (+, d, J PC ) 4.6 Hz), 129.2 (+, d, J PC
)
2
4.6 Hz), 128.9 (+, d, J PC ) 11.7 Hz, 4C), 128.6 (+, 2C), 120.7,
Su p p or tin g In for m a tion Ava ila ble: Analytical and spec-
tral data for compounds 3-5, 2D NMR data for compound 5h ,
1
97.8, 78.7, 38.7 (-, d, J PC ) 66.1 Hz), 35.1 (-), 33.1 (-), 31.0
(-), 23.0 (-), 22.3 (-), 21.6 (+), 19.8 (-), 14.5 (+), 14.0 (+);
31P NMR (202.46 MHz, CDCl3) δ 27.9; GC/MS m/z 518 (M+,
15), 461 (M - Bu, 7), 317 (M - Ph2PO, 70), 201 (Ph2PO+, 100).
Anal. Calcd for C36H39OP: C 83.36, H 7.58. Found: C 83.26,
H 7.50.
and H and 13C NMR charts for all unknown compounds; X-ray
1
data for compound 3a a . This material is available free of
charge via the Internet at http://pubs.acs.org..
J O034486O
6256 J . Org. Chem., Vol. 68, No. 16, 2003