Palladium-catalyzed intermolecular addition of formamides to alkynes

Article abstract of DOI:10.1021/ja910038p

A novel palladium system for an intermolecular addition of formamides to alkynes has been developed. The reaction of formamides with internal alkynes in the presence of a palladium catalyst with acid chloride as an additive afforded (E)-α,β-unsaturated amides regio- and stereoselectively. The same catalyst system realized the first example of the addition of formamides to terminal alkynes giving the corresponding α,β-unsaturated amides bearing a terminal methylene moiety as major products. The present reaction was widely applicable to substrates with various functionalities. This method also could be applied to the reaction of N,N-disubstituted formamides with norbornene. A hydridopalladium species would be formed as a key intermediate with in situ generated HCl under the reaction conditions.

Full text of DOI:10.1021/ja910038p

Published on Web 01/22/2010
Palladium-Catalyzed Intermolecular Addition of Formamides
to Alkynes
Tetsuaki Fujihara, Yuko Katafuchi, Tomohiro Iwai, Jun Terao, and Yasushi Tsuji*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto UniVersity, Nishikyo-ku, Kyoto 615-8510, Japan
Received November 27, 2009; E-mail: ytsuji@scl.kyoto-u.ac.jp
Abstract: A novel palladium system for an intermolecular addition of formamides to alkynes has been
developed. The reaction of formamides with internal alkynes in the presence of a palladium catalyst with
acid chloride as an additive afforded (E)-R,ꢀ-unsaturated amides regio- and stereoselectively. The same
catalyst system realized the first example of the addition of formamides to terminal alkynes giving the
corresponding R,ꢀ-unsaturated amides bearing a terminal methylene moiety as major products. The present
reaction was widely applicable to substrates with various functionalities. This method also could be applied
to the reaction of N,N-disubstituted formamides with norbornene. A hydridopalladium species would be
formed as a key intermediate with in situ generated HCl under the reaction conditions.
Scheme 1
Introduction
Highly atom-efficient1 intermolecular addition of carbonyl
functionalities to unsaturated compounds must be extremely
promising to realize valuable and environmentally benign organic
transformation. Among them, addition of aldehydes (X ) H and
Y ) C in Scheme 1) to unsaturates such as alkenes or alkynes has
been intensively studied (hydroacylation).2 However, the reaction
frequently suffered from decarbonylation3 and appropriate directing
groups were often indispensable for successful reactions.2b,4 We
recently reported an iridium-catalyzed addition of acid chlorides
(X ) Cl, Y ) C) to alkynes.5 The reaction proceeds highly atom-
efficiently without decarbonylation and affords ꢀ-chloro-R,ꢀ-
unsaturated ketones in high yields.
On the other hand, addition of formamides (X ) H, Y ) N)
to unsaturated substrates should provide efficient atom-economic
synthetic methods, while similar addition of formates (X ) H,
Y ) O) was not fully developed.6 Previously, we have found
the first addition of formamides to alkenes in the presence of
Ru3(CO)12 as a catalyst.7a However, in spite of many efforts7b-d
after this finding, the addition of formamides to alkenes was
not so efficient. As for the addition of formamides to alkynes,
there have been only two precedents to date.8,9a The first
example of the addition to alkynes was realized as an intramo-
lecular reaction with a Rh catalyst.8 Very recently, the first
intermolecular addition to alkynes was reported by Nakao and
Hiyama et al. in the presence of a Ni(0) catalyst combined with
AlMe3.9a This publication prompted us to report our independent
studies on Pd-catalyzed intermolecular addition of formamides
to alkynes.9b Distinct features of our finding from the Ni(0)/
AlMe3 catalyst9a are as follows: (1) Terminal alkynes were
successfully utilized and afforded adducts for the first time. (2)
Carbonyl functionalities susceptible to AlMe3 could be tolerated.
(1) (a) Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233–1246. (b) Trost,
B. M. Acc. Chem. Res. 2002, 35, 695–705.
(6) (a) Ko, S.; Na, Y.; Chang, S. J. Am. Chem. Soc. 2002, 124, 750–751.
(b) Park, E. J.; Min Lee, J. M.; Han, H.; Chang, S. Org. Lett. 2006,
8, 4355–4358. (c) Wang, W.; Floreancig, P. E. Org. Lett. 2004, 6,
4207–4210. (d) Fabre, S.; Kalck, P.; Lavigne, G. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1092–1095. (e) Lin, I. J. B.; Alper, H. J. Chem.
Soc., Chem. Commun. 1989, 248–249. (f) Gre´vin, J.; Kalck, P. J.
Organomet. Chem. 1984, 476, C23–C24. (g) Mlekuz, M.; Joo, F.;
Alper, H. Organometallics 1987, 6, 1591–1593.
(2) (a) Willis, M. C. Chem. ReV. 2009; DOI: 10.1021/cr900096x. (b)
Osborne, J. D.; Randell-Sly, H. E.; Currie, G. S.; Cowley, A. R.; Willis,
M. C. J. Am. Chem. Soc. 2008, 130, 17232–17233. (c) Omura, S.;
Fukuyama, T.; Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem.
Soc. 2008, 130, 14094–14095. (d) Shibahara, F.; Bower, J. F.; Krische,
M. J. J. Am. Chem. Soc. 2008, 130, 14120–14122. (e) Hyatt, I. F. D.;
Anderson, H. K.; Morehead, A. T., Jr.; Sargent, A. L Organometallics
2008, 27, 135–147. (f) Roy, A. H.; Lenges, C. P.; Brookhart, M. J. Am.
Chem. Soc. 2007, 129, 2082–2093. (g) Kundu, K.; McCullagh, J. V.;
Morehead, A. T., Jr. J. Am. Chem. Soc. 2005, 127, 16042–16043.
(3) (a) Iwai, T.; Fujihara, T.; Tsuji, Y. Chem. Commun. 2008, 6215–6217,
a nd references cited therein. (b) Fristrup, P.; Kreis, M.; Palmelund, A.;
Norrby, P.-O.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 5206–5215.
(4) (a) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41,
222–234. (b) Jun, C.-H.; Jo, E.-A.; Park, J.-W. Eur. J. Org. Chem.
2007, 1869–1881.
(7) (a) Tsuji, Y.; Yoshii, S.; Ohsumi, T.; Kondo, T.; Watanabe, Y. J.
Organomet. Chem. 1987, 331, 379–385. (b) Kondo, T.; Okada, T.;
Mitsudo, T. Organometallics 1999, 18, 4123–4127. (c) Ko, S.; Han,
H.; Chang, S. Org. Lett. 2003, 5, 2687–2690. (d) Nath, D. C. D.;
Fellows, C. M.; Kobayashi, T.; Hayashi, T. Aust. J. Chem. 2006, 59,
218–224.
(8) Kobayashi, Y.; Kamisaki, H.; Yanada, K.; Yanada, R.; Takemoto, Y.
Tetrahedron Lett. 2005, 46, 7549–7552.
(9) (a) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem.
Soc. 2009, 131, 5070–5071. (b) Katafuchi, Y.; Fujihara, T.; Terao, J.;
Tsuji, Y. The 89th Annual Meeting of Chemical Society of Japan 2009,
4F1–41, presented on March 30.
(5) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2009,
131, 6668–6669.
9
2094 J. AM. CHEM. SOC. 2010, 132, 2094–2098
10.1021/ja910038p  2010 American Chemical Society

Intermolecular Addition of Formamides to Alkynes
A R T I C L E S
Table 1. Effect of Additives on the Palladium-Catalyzed Addition of
N,N-Dimethylformamide to Diphenylacetylenesa
entry
additive (20 mol %)
yield (%)b
1
2
3
4
5
6
7
8
9
none
0
82
99
HCl (in dioxane, 50 mol %)
n-C5H11COCl
PhCOCl
PhCOBr
Me3SiCl
Ph2POCl
HCl aq.
CF3COOH
CF3SO3H
Figure 1. Crystal structure of 3a with thermal ellipsoids at the 50%
probability level.
99 (96, E/Z ) 99/1)c
the contrary, in the Ni(0)/AlMe3 catalyzed reaction,9a initially
formed (E)-product was readily isomerized to (Z)-isomer (E/Z
) 3:7 even after 30 min). Thus, the present Pd catalyst system
realizes highly stereoselective reaction.
26
18
31
8
1
1
10
Reaction with Internal Alkynes. The scope of the catalytic
reaction was examined by using various internal alkynes 2 and
formamides 1 with benzoyl chloride as an additive (Table 2).
Di(4-acetylphenyl)acetylene (2b) with 1a afforded the corre-
sponding product (3b) stereoselectively in 72% yield (entry 1).
The reaction did not suffer from the E/Z isomerization at all
(vide supra). Furthermore, the acetyl functionality susceptible
to AlMe39a could be tolerated in the reaction. An alkyne bearing
thiophene rings (2c) smoothly afforded the corresponding
product (3c) in 90% yield stereoselectively (entry 2). 5-Decyne
(2d) also provided the corresponding (E)-adduct (3d) in high
stereoselectivity and in high yield (entry 3). Symmetrical
aliphatic alkynes bearing ether (2e) and acetate (2f) function-
alities could be employed in the reaction and gave the addition
products in good yields (entries 4 and 5). As for unsymmetrical
alkynes, even the reaction with a simple hydrocarbon alkyne
such as 2g proceeded with good regioselectivity, and 3g and
3g′ were isolated in pure form in 77 and 6% yields, respectively
(entry 6). Alkynes with ester functionality (2h and 2i) provided
the corresponding adducts (3h and 3i) highly regio- and
stereoselectively (entries 7 and 8). Furthermore, a substrate
having both olefin and ester functionalities (2j) afforded the
corresponding product in good yield (entry 9). In all these
products (entries 7-9), the ester moieties were located away
from the carbamoyl group with (E)-configuration. Gratifyingly,
a boronic acid ester functionality, which will be highly useful
in a further derivatization, was compatible and provided the
corresponding product (3k) in good yield with high selectivity
(entry 10). The reaction of other formamide derivatives (1b-d)
a Diphenylacetylene (1.0 mmol), N,N-dimethylformamide (2.0 mmol),
PdCl2(PhCN)2 (0.025 mmol, 2.5 mol %), Xantphos (0.025 mmol, 2.5 mol
%), additive (20 mol %), mesitylene (1.0 mL) at 140 °C for 20 h. b Yield
based on the GC internal standard technique. c Yield of isolated product. E/
Z ratio (99/1) of the product was determined by the GC analysis.
(3) Adducts with diarylacetylenes did not undergo E/Z
isomerization.
Results and Discussion
Optimization of the Reaction Conditions. First, the reaction
of N,N-dimethylformamide (1a) with diphenylacetylene (2a) was
carried out in the presence of a catalytic amount (2.5 mol %)
of PdCl2(PhCN)2 and Xantphos10 (Table 1). Without an additive,
no adducts were obtained at all (entry 1). In contrast, when
anhydrous HCl (50 mol %) was added to the catalyst system,
an adduct (3a) was obtained in 82% yield. It is well-known
that reaction of HCl with Pd compounds provides Pd-H
species.11 However, the use of anhydrous HCl is not expedient
in a laboratory and yield of 3a decreased to 67% with a smaller
(20 mol %) amount of HCl. Recently, Skrydstrup reported that
in a Pd catalyzed reaction, acid chlorides were useful additives
to generate Pd-H species in situ.12 Actually, hexanoyl chloride
and benzoyl chloride13 as an additive (20 mol %) afforded 3a
in both >99% yields (entries 3 and 4). Thus, Pd-H species
might play an important role in the reaction. Benzoyl bromide
(entry 5) and other chloride sources such as Me3SiCl and
Ph2P(O)Cl (entries 6 and 7) were less effective as the additive.
Addition of Brønsted acids such as conc. HCl aq, trifluoroacetic
acid, and trifluoromethanesulfonic acid only afforded a trace
amount of 3a (entries 8-10). As the ligand, Xantphos was the
most effective. Under the same reaction conditions as in Table
1, other phosphines such as PPh3, P(o-Tol)3. PCy3, dppp, dppf,
and rac-BINAP10 did not afford 3a at all. The reaction proceeds
smoothly at 140 °C, but yields decreased at a lower temperature.
The reaction is perfectly stereoselective to afford only the (E)-
isomer as determined by X-ray crystallography (Figure 1). On
(13) In the case of hexanoyl chloride, HCl may be afforded by a sequence
of oxidative addition, decarbonylation. and ꢀ-hydrogen elimination
as postulated in the literature.12 However, in the case of benzoyl
chloride, ꢀ-hydrogen elimination from the resulting phenyl-palladium
intermediate is not possible. Thus, the material balance after the
reaction (entry 3 in Table 2) was analyzed by GC (eq i). As a result,
0.18 mmol of N,N-dimethylbenzamide was found as well as 3d (0.92
mmol, 92% yield) in the reaction mixture. Therefore, HCl was most
likely generated by the reaction of benzoyl chloride (0.2 mmol) with
1a with concomitant formation of CO (detected by GC). After the
reaction, 0.76 mmol of 1a still remained, indicating further decom-
mission of 1a did not occur substantially.
(10) Abbreviations: Xantphos, 4,5-Bis(diphenylphosphino)-9,9-dimethylx-
anthene; P(o-Tol)3, tri-ortho-tolylphosphine; PCy3, tricyclohexylphos-
phine; dppp, 1,3-bis(diphenylphosphino)propane; dppf, 1,1′-bis(diphe-
nylphosphino)ferrocene; rac-BINAP, 2,2′-bis(diphenylphosphino)-1,1′-
binaphthyl.
(11) (a) Grushin, V. V. Chem. ReV. 1996, 96, 2011–2033. (b) Kudo, K.;
Hidai, M.; Murayama, T.; Uchida, Y. J. Chem. Soc. D: Chem.
Commun. 1970, 1701–1702. (c) Hills, I. D.; Fu, G. C. J. Am. Chem.
Soc. 2004, 126, 13178–13179.
(12) Lindhardt, A. T.; Mantel, M. L. H.; Skrydstrup, T. Angew. Chem.,
Int. Ed. 2008, 47, 2668–2672.
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A R T I C L E S
Fujihara et al.
Table 2. Addition of Formamides 1 to Internal Alkynes 2a
Table 3. Addition of 1a to Terminal Alkynes 4a
a Alkyne (1.0 mmol), 1a (1.0 mL, 13 mmol), PdCl2(PhCN)2 (0.050
mmol, 5.0 mol %), Xantphos (0.050 mmol, 5.0 mol %), PhCOCl (20
mol %), mesitylene (1.5 mL), 140 °C, 20 h. b Isolated yield of a mixture
of 5 and 6. Parentheses shows a ratio of 5/6 determined by GC analysis.
c Isolated yield of pure 5. d 6 contains some olefin isomers.
with 2d also gave the corresponding adducts (3l, 3m, and 3n)
selectively in 78, 95, and 86% yields, respectively (entries
11-13). Thus, these results indicate that the present reaction
can be widely applicable to substrates with various functionali-
ties.
Reaction with Terminal Alkynes. To date, terminal alkynes
have not been successfully utilized in the addition of formamide,
possibly due to very high catalytic activity of Ni(0)9a for the
trimerization of terminal alkynes.14 In Table 3, various terminal
alkynes 4 afforded the adducts in high yields with an excess 1a
by employing the same Pd catalyst system. In the reaction of
phenylacetylene (4a) with 1a, the adducts were isolated in 96%
yield as a mixture of two regioisomers 5a and 6a in a 89/11
ratio (entry 1). From 2-ethynyltoluene (4b) or 1-ethynylnaph-
thalene (4c), the products (5 and 6) were obtained in 94 or 87%
yields with 92 and 95% regioselectivity for 5, respectively
(entries 2 and 3). Various aromatic (4d-f) and aliphatic (4g-h)
terminal alkynes also afforded the corresponding adducts as
mixtures of two regioisomers in 67-93% yields with 81-87%
regioselectivities. Major regioisomers (5a-h) were easily and
efficiently isolated in analytically pure form by a column chro-
matography in high to moderate yields as shown in Table 3.
Addition of Formamides with Norbornene. Besides alkynes,
the addition reaction of 1a-c with norbornene (7) also pro-
ceeded in the presence of the same palladium catalyst system.
The corresponding adducts (8a-c) were isolated in good yields
with high stereoselectivity (eq 1). In the reaction, without the
addition of benzoyl chloride, no additions occurred. Unfortu-
nately, 1,3-dienes and 1,2-dienes cannot be utilized as substrates
in the present reaction. To date, in all the reported intermolecular
additions of formamides to alkenes, there were severe limitations
with respect to formamides: N,N-disubstituted formamides could
a Alkyne (1.0 mmol), formamide derivative (2.0 mmol), PdCl2(PhCN)2
(0.025 mmol, 2.5 mol %), Xantphos (0.025 mmol, 2.5 mol %), PhCOCl (20
mol %), mesitylene (1.0 mL), 140 °C, 20 h. b Isolated yield. c Determined
by GC analysis. d PdCl2(PhCN)2 (0.050 mmol, 5.0 mol %, Pd/Xantphos/
PhCOCl ) 1/1/4) and 1a (6.0 mmol). e PdCl2(PhCN)2 (0.10 mmol, 10 mol
%, Pd/Xantphos/PhCOCl ) 1/1/1) and 1a (12 mmol). f PdCl2(PhCN)2
(0.050 mmol, 5.0 mol %, Pd/Xantphos/PhCOCl ) 1/1/4) and 1a (10
mmol).
(14) Keim, W.; Behr, A.; Roper, M. In ComprehensiVe Organometallic
Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.;
Pergamon Press: New York, 1982; Vol. 8, pp 410-413.
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2096 J. AM. CHEM. SOC. VOL. 132, NO. 6, 2010

Intermolecular Addition of Formamides to Alkynes
A R T I C L E S
not be employed.7 As for the Ni(0) catalyzed reaction,9a only
intramolecular addition of formamides to alkenes proceeded and
no intermolecular reactions occurred.
Table 4. H/D Exchange between 1a-d7 and 1e under Various
Conditionsa
Reaction Mechanisms. To gain insight into the reaction
mechanisms, some control experiments were carried out. The
reaction might proceed via decomposition of a formamide
derivative into CO and the corresponding amine; that is,
aminocarbonylation15 of alkyne with CO and the amine. When
one equivalent of dibutylamine was added into the reaction
mixture of 1a and 2d, a rapid catalyst decomposition to palla-
dium black occurred, and neither 3d nor 3l were obtained
(eq 2). In addition, under the aminocarbonylation reaction
conditions at 70 and 140 °C employing dibutylamine and
CO (1 or 10 atm), the palladium catalyst was decomposed
even at 70 °C and the corresponding product 3l was not
obtained at all (eq 3). Thus, in the catalytic reaction, the
formamides would directly react with the alkynes, not via
CO and the corresponding amine.
entry
conditions
1a-d7 (mmol)b
1e-d (mmol)b
1
2
3
none
0.98
0.89
0.98
0
0.02
0
PhCOCl (20 mol %)
PdCl2(PhCN)2,
Xantphos (2.5 mol %)
PdCl2(PhCN)2,
Xantphos (2.5 mol %),
PhCOCl (20 mol %)
4
0.86
0.05
a 1a (1.0 mmol), 1e (1.0 mmol), mesitylene (1.0 mL) at 140 °C for 20 h.
b Amounts of 1a-d7 and 1e-d were determined by 1H and 2H NMR
measurements.
A possible catalytic cycle is shown in Scheme 2. A Pd-H
species (A) generated in situ by the reaction with HCl11,12 might
be a key catalytic intermediate. Hydropalladation11a,17 of an
alkyne (2) with A may initiate the catalytic cycle to afford an
alkenyl Pd intermediate (B) (step 1). Then, insertion of CdO
bond of a formamide (1) might take place to form a corre-
sponding alkoxypalladium intermediate (C) (step 2 in cycle I).
Finally, ꢀ-hydride elimination of C could provide the desired
product (3) and the Pd-H species (A) regenerates (step 3).
Alternatively, a cycle involving an oxidative addition of a formyl
C-H bond of 1 to afford a Pd(IV)18 intermediate (D) (step 4)
might be possible. A reductive elimination from D could provide
3, and the Pd-H species (A) would regenerate (cycle II).
Conclusion
Formamides are successfully added to internal alkynes to afford
(E)-R,ꢀ-unsaturated amides regio- and stereoselectively in the
presence of a palladium catalyst with acid chloride as an additive.
Furthermore, the same catalyst system realized the first example
of the addition of formamides to terminal alkynes. Further studies
on the reaction mechanism and the application of the catalysis are
now in progress.
Next deuterium labeling reactions were carried out. In the
reaction of 1a-d7 (99.5 atom % D) with 2d, the adduct 3d-d
was obtained in 89% yield with 88% D incorporation at the
vinyl position (eq 4). Furthermore, the reaction of 1a-d7, 1c,
and 2d afforded the two products 3d-d and 3m-d in 65 and
35% yields, respectively (eq 5). The deuterium of the formyl
moiety of 1a-d7 was scrambled at the olefin positions of 3d-d
and 3m-d (47 and 45% D incorporation, respectively). Here,
H/D exchange between 1a-d7 and 1e16 did not occur (1e-d <
5%, if any) under various reaction conditions as shown in Table
4. Such scrambling shown in eq 5 was not observed in the Ni(0)
catalyzed reaction,9a suggesting that the mechanisms of the Pd
and Ni(0) catalyzed reaction may be distinct.
Experimental Section
General Procedures. All manipulations were performed under an
argon atmosphere using standard Schlenk-type glasswares on a dual-
manifold Schlenk line. Mesitylene was dried and purified by usual
procedures.19 Unless otherwise noted, materials obtained from com-
mercial suppliers were used without further purification. Xantphos was
purchased from Wako. PdCl2(PhCN)2 was prepared according to
literature.20 Substrates 2b,21 2c,21 2d,22 and 4f22 were prepared
according to literatures. IR spectra were recorded on a Shimadzu FTIR-
8300 spectrometer. 1H, 2H and 13C{1H} NMR spectra were measured
with a JEOL ECX-400P spectrometer. The 1H NMR chemical shifts
are reported relative to tetramethylsilane (TMS, 0.00 ppm). The
9
J. AM. CHEM. SOC. VOL. 132, NO. 6, 2010 2097

A R T I C L E S
Fujihara et al.
Scheme 2. Plausible Reaction Mechanisms
General Procedure of Palladium-Catalyzed Addition of
Formamides (1) to Internal Alkynes (2) (Tables 1 and 2). To a
10-mL Schlenk flask with
a reflux condenser were added
PdCl2(PhCN)2 (9.6 mg, 0.025 mmol) and Xantphos (14.5 mg, 0.025
mmol). The flask was evacuated and backfilled with argon three times.
A degassed mesitylene (1.0 mL) and a formamide (1) (2.0 mmol) were
added to the flask and the resultant solution was stirred at room
temperature for 10 min. Then, additive (0.2 mmol, 20 mol %) was
added to the flask. After stirring for 5 min, an internal alkyne (2) (1.0
mmol) was added to the flask and the mixture was stirred for additional
10 min. The reaction mixture was heated (bath temp. 140 °C) for 20 h
under an argon atmosphere. After cooling to room temperature, the
mixture was evaporated and the product (3) was isolated by silica gel
chromatography using hexane-AcOEt as an eluent.
General Procedure of Palladium-Catalyzed Addition of
N,N-Dimethylformamide (1a) to Terminal Alkynes (4) (Table
3). To a 10-mL Schlenk flask with a reflux condenser were added
PdCl2(PhCN)2 (19.2 mg, 0.05 mmol) and Xantphos (29 mg, 0.05
mmol). The flask was evacuated and backfilled with argon three times.
After a degassed mesitylene (1.5 mL) and 1a (1.0 mL, 13 mmol) were
added to the flask, the resultant solution was stirred at room temperature
for 10 min. Then, benzoyl chloride (24 µL, 0.2 mmol) was added to
the flask. After stirring for 5 min, a terminal alkyne (4) (1.0 mmol)
was added to the flask and the mixture was stirred for additional 10
min. The reaction mixture was heated (bath temp. 140 °C) for 20 h
under an argon atmosphere. After cooling to room temperature, the
mixture was evaporated and the products (5 and 6) were isolated by
silica gel chromatography using hexane-AcOEt as the eluent.
X-ray Crystallographic Analysis of 3a. Single crystal of 3a
was obtained by recrystallization from hot hexane solution. Data
were collected on a Rigaku/Saturn70 CCD diffractometer using
graphite-monochromated Mo KR radiation (λ ) 0.71070 Å) at 153
K, and processed using CrystalClear23 (Rigaku). The structure was
solved by direct methods (SIR97)24 and refined by full-matrix least-
squares refinement on F2. The non-hydrogen atoms were refined
anisotropically. All hydrogen atoms were located on the calculated
positions and not refined. All calculations were performed using
the CrystalStructure25 crystallographic software package. Crystal
data for 3a: C17H17NO, M ) 252.34, monoclinic, space group )
C2/c (#15), a ) 25.137(17) Å, b ) 6.351(4) Å, c ) 19.808(13) Å,
ꢀ ) 116.975(8) °, V ) 2818(3) Å3, Z ) 8, density (calc.) ) 1.189,
total reflections collected ) 10016, unique reflections ) 3150 (Rint
) 0.067), GOF ) 1.003. The final R1 factor was 0.0659 (I > 2σ(I))
(wR2 ) 0.1528 for all data).
13C{1H} NMR chemical shifts are reported relative to CDCl3 (77.0
ppm). HSQC, HMBC, and NOESY were also measured with a JEOL
ECX-400P spectrometer. EI-MS were recorded on a Shimadzu GCMS-
QP5050A with a direct inlet. HR-FAB and HR-EI mass spectra were
measured with a JEOL JMS-HX110A and a JEOL JMS-SX102A,
respectively. Elemental analysis was carried out at Center for Organic
Elemental Microanalysis, Graduate School of Pharmaceutical Science,
Kyoto University. GC analysis was carried out using Shimadzu GC-
17A equipped with an integrator (C-R8A) with a capillary column
(CBP-5, 0.25 mm i.d. × 25 m). Melting points were measured on a
Yanako MP-J3 apparatus. Column chromatography was carried out
on silica gel (Kanto N60, spherical, neutral, 63-210 µm). TLC analyses
were performed on commercial glass plates bearing a 0.25-mm layer
of Merck silica gel 60F254.
Acknowledgment. This work was supported by Grant-in-Aid
for Scientific Research on Priority Areas (“Chemistry of Concerto
Catalysis” and “Synergy of Elements”) from Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental procedures
and characterization of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) (a) Li, Y.; Alper, H.; Yu, Z. Org. Lett. 2006, 8, 5199–5201. (b) Park,
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