Diversification of shotgun process

Article abstract of DOI:10.1016/S0040-4020(03)00768-3

Three protocols for shotgun process are put forth in which simultaneous multi-fold reactions occur exclusively to each other. The first one involves simple combination of selective and non-selective reactions. Even if the simple protocol fails to give rise to the high selectivity, satisfactory outcome can be achieved by kinetic control or adjustment of functional groups.

Full text of DOI:10.1016/S0040-4020(03)00768-3

Tetrahedron 59 (2003) 5569–5578
Diversification of shotgun process
*
Yoshifumi Nagano, Akihiro Orita and Junzo Otera
Department of Applied Chemistry, Okayama University of Science, Ridai-cho, Okayama 700-0005, Japan
Received 1 May 2003; revised 14 May 2003; accepted 16 May 2003
Abstract—Three protocols for shotgun process are put forth in which simultaneous multi-fold reactions occur exclusively to each other. The first
one involves simple combination of selective and non-selective reactions. Even if the simple protocol fails to give rise to the high selectivity,
satisfactory outcome can be achieved by kinetic control or adjustment of functional groups. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
necessarily cause deterioration of the selectivity but the
improvement may be attained if appropriate conditions are
fulfilled. We report herein that this is indeed the case and a
variety of shotgun processes are feasible.2
Compaction of multi-step chemical processes is of great
significance from a viewpoint of green chemistry. In this
context, we put forth a new concept, ‘shotgun process’ where
different reactions are feasible on the separate reaction sites
without recourse to protection–deprotection procedures
(Scheme 1).1 The simplest protocol arises from the following
case. Suppose that upon exposure to a mixture of reagents X
and Y, A reacts with X exclusively while B exhibits no
selectivity to react with both X and Y. Even under such
circumstances, the desired one-pot exclusive reactions are
achievable if the reaction between A and X is much faster than
the reaction of B with X and Y. X is consumed totally by the
former reaction before initiation of the reactions of B, which
accordingly has no choice but to react with Y to results in
exclusive formation of A–X and B–Y, respectively. How-
ever, such an ideal situation is often violated since the reagents
are usually employed in excess to attain high conversions and,
moreover, functional groups A and B are liable to experience
interactions with each other or with X and Y at random even
though the interactions are not strong enough to induce the
reactions. As a result, the innate reactivity of the functional
groups is altered. These interactions, however, do not
2. Results and discussion
2.1. Simple shotgun process
An example of a typical shotgun process free from any of
the complicated influences was offered as follows. Treat-
ment of an equimolar mixture of benzylidene aniline (1) and
naphthoquinone (2) with Danishefsky’s diene 3 (1.2 equiv.)
in the presence of Yb(OTf)3 (20 mol%) led to exclusive
reaction with 1 (Table 1, entry 1)3 delivering a candidate for
A–X formation in Scheme 1. On the other hand, a non-
selective reaction took place with cyclopentadiene (5)
(2.0 equiv.) under the same conditions to furnish products
63 and 74 derived from 1 and 2, respectively (entry 2). Then,
these two reactions were integrated into one pot, and only 4
and 7 were obtained quantitatively without contamination of
6 (entry 3). When the reaction of 1 with 3 (1.2 equiv.) was
conducted in the presence of 5 (2.0 equiv.), 4 was obtained
Scheme 1.
Keywords: shotgun process; allylation; Diels–Alder reaction; acetylation; scandium triflate; ytterbium triflate.
*
Corresponding author. Tel.: þ81-86-256-9525; fax: þ81-86-256-4292; e-mail: otera@high.ous.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00768-3

5570
Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
Table 1. Shotgun process consisting of two Diels–Alder reactions
Entry
1
Reagent(s)
Time (h)
6
Product(s)a
2
24
3
3 (1.2 equiv.), 5 (2 equiv.)
24
4 (92%), 7 (96%)
a
Isolated yield after column chromatography.
determined by GLC.
b
quantitatively after 5 min, no sign of formation of 6 being
detected (Eq. (1)). Apparently, 1 reacted with 3 much faster
than with 5 and the substrate had been used up before the
latter reaction was initiated.
while tetraallytin (9) (0.3 mol equiv.) exhibited no selectiv-
ity towards both substrates to furnish 105 and 116 in 25 and
73% yields, respectively (entry 2). Treatment of these
substrates and reagents in one shot again led to quantitative
ð1Þ
A similar simple shotgun process was observed with a
combination between substrates 1/8 and reagents 3/9
(Table 2). Diels–Alder reaction between 1 and 3 took
place quantitatively in the presence of Sc(OTf)3 (entry 1)
formation of 4 and 11 as sole products (entry 3). An
unambiguous evidence for the shotgun process was
provided by quenching the reaction after 1 min (Eq. (2)).
The reaction between 1 and 3 had finished already while
Table 2. Hetero-Diels–Alder reaction/allylation between 1 and 8 in the presence of Sc(OTf)3
Entry
Reagent(s)
3 (1.2 equiv.)
Time (h)
Producet(s)a
1
2
0.5
15
4 (96%)
3
3 (1.2 equiv.), 9 (0.3 mol equiv.)
Isolated yield after column chromatography.
15
4 (96%), 11 (95%)
a

Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
5571
89% of 8 remained unreacted.
ð2Þ
Scheme 3.
yields (Scheme 3).10 On the other hand, only a trace amount
of product 15 derived from 12 was detected upon decreasing
the amount of this reagent down to 0.2 equiv. It follows
from the above results that under standard conditions, 12
reacted with 1 very rapidly so as to consume this substrate
completely before initiation of the reaction of 9. At this
stage, the molar ratio of 12/9 was 0.2:0.3 and, hence, the
remaining substrate 8 started to react with 9 exclusively. It is
concluded therefore that the substrate selectivity in the
shotgun process could be improved kinetically by adjusting
the ratio of reagents even if the elementary reactions are not
selective.
2.2. Kinetically controlled shotgun process
In striking contrast to 1, ketene silyl acetal 12 responded to
the same substrate mixture in a less selective manner. Thus,
the reaction of 12 (1.2 equiv.) with a mixture of 1 and 8
(each 1 equiv.) furnished two products, 137 and 148 (Eq.
(3)). Nevertheless, integration of this reaction with the
allylation resulted in only two products 13 and 11
quantitatively (Eq. (4)). Apparently, both innately non-
selective reactions were rendered completely selective.
Similar improvement of the substrate selectivity is also
achievable by another one-pot protocol, parallel recognition
where both reactions proceed simultaneously in parallel.9
However, it was suggested by quenching the reaction at an
early stage that the shotgun process operated in the present
case, after 1 min, 1 was totally consumed by reaction with
12 to give a 96% yield of 13 while only a 10% yield of 11
was obtained leaving a large amount of 8 intact (Eq. (5)).
The selectivity is highly sensitive to the amount of the
substrates, and the use of 1.2 equiv. of 12 and 0.3 mol equiv.
of 9 is crucial for attaining the perfect selectivity (standard
conditions). As shown in Scheme 2, employment of
1.1 equiv. of 12 allowed allylation of imine 1 slightly to
give 10 in 2% yield while increase of the amount of 12
(1.5 equiv.) induced reaction of this reagent with hydrazone
8 to give 14 in 15% yield concomitant with a decreased
yield of the allylation of 8. The increase of 9 up to
0.5 mol equiv. triggered allylation of 1 (2% yield). Treat-
ment of the mixture of 12 and 9 in the same ratio as the
standard conditions with 1 afforded 13 exclusively (Eq. (6)).
When the same mixture was exposed to 8, both reagents
reacted to give the corresponding products in comparable
ð3Þ
ð4Þ
ð5Þ
Scheme 2.

5572
Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
tions and reagents occur more frequently to modify the
elementary reactions. We picked substrate 16 to test the
feasibility of the triple-track version (Table 3). Under
catalysis of Sc(OTf)3, the three functions involved in 16 are
known to undergo smoothly the following reactions:
allylation of aldehyde with tetraallytin (9),11 Diels–Alder
reaction of a,b-unsaturated ester with cyclopentadiene (5),4
and acetylation of hydroxy group with acetic anhydride
(18),12 respectively. Notwithstanding, 16 failed to react with
these reagents satisfactorily. Upon treatment with 9 (entry
1), only a 66% yield of allylation product 17 was obtained
while complex mixtures of unidentifiable materials
appeared by exposure to 5 and 18 (entires 2 and 3). It
should be noted that the yields of representative simple
elementary reactions under the same conditions were 85%
for allylation of benzaldehyde, 99% for Diels–Alder
reaction with dimethyl maleate, and 99% for acetylation
of octanol. These results imply that the elementary reactions
are influenced by coexisting functional groups. In sharp
contrast to the reactions given in entries 1–3, addition of the
three reagents in one shot provided a single product 19 in
ð6Þ
2.3. Functionally controlled shotgun process
A triple-track shotgun process where three reactions
proceed on three different reaction sites (Scheme 4) is far
more complicated than the aforementioned double-track
protocol. In addition, interactions between substrate func-
Scheme 4.
Table 3. Sc(OTf)3-catalyzed reactions of multifunctional substrate 16 with various reagents
Entry
Reagent(s)
Time (h)
Product(s)a
1
9 (0.3 mol equiv.)
12
2
3
5 (3 equiv.)
Ac2O 18 (2 equiv.)
12
12
Complex mixture
Complex mixture
5 (3 equiv.)
9 (0.3 mol equiv.)
18 (2 equiv.)
4
24
5 (3 equiv.)
5
24
9 (0.3 mol equiv.)
6
9 (0.3 mol equiv.)
18 (2 equiv.)
24
24
7
5 (3 equiv.)
18 (2 equiv.)
Complex mixture
a
Isolated yield after column chromatography.

Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
5573
81% yield, which corresponds to a 93% yield in average for
each reaction (entry 4).13 When 16 was exposed to a mixture
of reagents 5/9 or 9/18, reasonable yields of the correspond-
ing products as a result of the two reactions were obtained
(entries 5 and 6). On the other hand, no smooth reactions
took place with a combination of reagents 5/18 (entry 7).
Obviously, the shotgun process occurred successfully when
the allylation reaction was involved, and hence, it was
postulated that an aldehyde function retarded the Diels–
Alder and acetylation reactions and rapid consumption of
the aldehyde revived the remaining two reactions in the
shotgun process. This was confirmed by intermolecular
reactions. The yields of Diels–Alder reaction and acety-
lation were decreased in the presence of benzaldehyde
(Eqs. (7) and (8)) while addition of 9 to consume the
aldehyde gave rise to recovery of the yields (Eqs. (9) and
(10)). Figure 1 shows a profile of the time-conversion
relationship in the triple-track shotgun process.14,15
Remarkably, the allylation finished after 15 s and, then,
the Diels–Alder reaction and acetylation followed. As such,
it is now apparent that the smooth shotgun process resulted
from the rapid consumption of the aldehyde function so that
the Diels–Alder and acetylation reactions were freed from
retardation by this function.
ð7Þ
Figure 1. Time-conversion curves of the triple-track shotgun process.

5574
Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
was improved to 94%. Since addition of octyl acetate in
place of octanol gave rise to no influence and addition of
acetic acid lowered the yield, the species responsible for
increasing the yield in the reaction mixture is unambigu-
ously assigned to the octanol. As a whole, the synergistic
relationship between the functional groups and reagents
involved in the present triple-track shotgun process is
summarized in Scheme 5.
ð8Þ
ð9Þ
ð13Þ
ð10Þ
The reactions proceeding in parallel are proved to be
retarded by not only the functional groups of the substrates
but also the coexisting reagents. For instance, when the
Diels–Alder reaction between 5 and dimethyl malonate was
run in the presence of acetic anhydride 18, the color of the
reaction mixture turned black and the yield was decreased to
some extent (Eq. (11)). TLC analysis suggested that
cyclopentadiene had polymerized.16 The yield was further
decreased to 35% upon treatment of Sc(OTf)3 with 18 for
10 min prior to addition of 5 and dimethyl malonate (Eq.
(12)). As we disclosed previously, combining Sc(OTf)3 and
18 gave rise to a new catalytic species,17 which induced
polymerization of 5. Apparently, constant consumption of
18 by concurrent acetylation also served for the smooth
Diels–Alder reaction in the shotgun process. It was revealed
already that this newly created scandium species is
responsible for acceleration of allylation. Thus, acetic
anhydride also served for increasing the rate of the allylation
reaction to accelerate consumption of aldehyde so as to set
the Diels–Alder reaction and acetylation free from
retardation. The enhanced rate of acetylation, then, served
for decreasing the suppressing effect of acetic anhydride on
the Diels–Alder reaction.
Scheme 5.
In conclusion, we have demonstrated three types of the
shotgun processes. In all of these processes, the perfect
recognition between concurrent different reactions on the
separate reaction sites is feasible. Even in the cases where
simple shotgun processes are not applicable, the recognition
can be achieved by adjusting the substrate ratio or by
balancing functional groups. This potentially expands the
scope of the shotgun process and we believe that the concept
disclosed herein will find a wide range of applications for
the simplified processes. Notably, it follows from the
functionally controlled shotgun process that integration of
reactions does not necessarily lead to simple superimposi-
tion of the original reactions. Such effect alters innate
features of respective reactions but would be of great help
for improving selectivity if appropriately used. This is an
important aspect to be taken into account for running
reactions in parallel.
ð11Þ
3. Experimental
3.1. Competition reaction (Table 1, entry 1)
ð12Þ
To a suspension of Yb(OTf)3 (124 mg, 0.20 mmol) in
CH2Cl2 (4.0 mL) was added a CH2Cl2 solution (1.0 mL)
containing 1 (181 mg, 1.0 mmol) and 2 (158 mg, 1.0 mmol)
at 08C. Then, 3 (0.23 mL, 1.20 mmol) was added and the
solution was stirred at 08C for 6 h. Saturated aqueous
NaHCO3 solution was added and the mixture was extracted
with EtOAc. The organic layer was washed with brine
and dried Na2SO4. The crude product obtained after
An additional example of the influence by reagents was
given in Eq. (13). When the reaction 11 was conducted in
the presence of octanol, the yield of the Diels–Alder adduct

Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
5575
filtration and evaporation was purified by column chroma-
tography on silica gel (1:1 hexane/EtOAc) to give 4
(234 mg, 94%).
mixture was stirred for 15 h. After aqueous workup as
described above, the crude product was purified by column
chromatography on silica gel to give 11 (159 mg, 95%)
(17:3 hexane/EtOAc) and 4 (120 mg, 96%) (1:1 hexane/
EtOAc), respectively. When the reaction was quenched
after 1 min, 4 (94%) and 11 (6%) were obtained along with
unreacted 8 (89%).
3.2. Competition reaction (Table 1, entry 2)
The same procedure of Section 3.1 was conducted using 5
(0.17 mL, 2.0 mL) in place of 3. After 24 h, GLC analysis of
the crude product thus obtained indicated formation of 6 in
5% yield. Then, column chromatography of the crude
product on silica gel (17:3 hexane/EtOAc) afforded 7
(222 mg, 99%).
3.8. Competition reaction (Eq. (3))
To a mixed solution of CH3CN (19.0 mL) and THF
(5.0 mL) containing 1 (91 mg, 0.50 mmol), 8 (146 mg,
0.50 mmol) and 12 (0.12 mL, 0.60 mmol) was added a
CH3CN solution (1.0 mL) of Sc(OTf)3 (25 mg, 0.05 mmol)
at room temperature. The mixture was stirred for 30 min.
After aqueous workup as described above, the crude product
was purified by column chromatography on silica gel to give
13 (141 mg, 99%) (19:1 hexane/EtOAc) and 14 (24 mg,
12%) (4:1 hexane/EtOAc), respectively.
3.3. Shotgun process (Table 1, entry 3)
To a suspension of Yb(OTf)3 (124 mg, 0.20 mmol) in
CH2Cl2 (4.0 mL) was added a CH2Cl2 solution (1.0 mL)
containing 1 (181 mg, 1.0 mmol) and 2 (158 mg, 1.0 mmol)
at 08C. Then, a CH2Cl2 solution (1 mL) containing 3
(0.23 mL, 1.20 mmol) and 5 (0.17 mL, 2.0 mL) was added
and the solution was stirred at 08C for 24 h. After aqueous
workup as described above, the crude product was purified
by column chromatography on silica gel to give 7 (215 mg,
96%) (17:3 hexane/EtOAc) and 4 (229 mg, 92%) (1:1
hexane/EtOAc), respectively.
3.9. Shotgun process (Eqs. (4) and (5); Scheme 2)
To a mixed solution of CH3CN (19.0 mL) and THF (5.0 mL)
containing 1 (91 mg, 0.50 mmol), 8 (146 mg, 0.50 mmol), 12
(0.12 mL, 0.60 mmol) and 9 (0.04 mL, 0.15 mmol) was added
a CH3CN solution (1.0 mL) of Sc(OTf)3 (25 mg, 0.05 mmol)
at room temperature. The mixture was stirred for 2 h. After
aqueous workup as described above, the crude product was
purified by column chromatography on silica gel to give 13
(138 mg, 97%) (19:1 hexane/EtOAc) and 11 (142 mg, 85%)
(17:3 hexane/EtOAc), respectively. When the reaction was
quenched after 1 min, 13 (96%) and 11 (10%) were obtained
along with unreacted 8 (80%).
3.4. Competition reaction (Eq. (1))
To a suspension of Yb(OTf)3 (124 mg, 0.20 mmol) in
CH2Cl2 (4.0 mL) was added a CH2Cl2 solution (1.0 mL) of
1 (181 mg, 1.0 mmol) at 08C. Then, a CH2Cl2 solution
(1.0 mL) of 3 (0.23 mL, 1.20 mmol) and 5 (0.17 mL,
2.0 mL) was added and the solution was stirred at 08C for
5 min. After aqueous workup as described above, the crude
product was purified by column chromatography on silica
gel (1:1 hexane/EtOAc) to give 4 (239 mg, 96%).
3.10. Competition reaction (Eq. (6))
To a mixed solution of CH3CN (19.0 mL) and THF
(5.0 mL) containing 1 (91 mg, 0.50 mmol), 12 (0.12 mL,
0.60 mmol) and 9 (0.04 mL, 0.15 mmol) was added a
CH3CN solution (1.0 mL) of Sc(OTf)3 (25 mg, 0.05 mmol)
at room temperature. The mixture was stirred for 30 min.
After aqueous workup as described above, the crude product
was purified by column chromatography on silica gel (19:1
hexane/EtOAc) to give 13 (133 mg, 94%).
3.5. Competition reaction (Table 2, entry 1)
To a mixed solution of CH3CN (19.0 mL) and THF
(5.0 mL) containing 1 (91 mg, 0.50 mmol), 8 (146 mg,
0.50 mmol) and 3 (0.12 mL, 0.60 mmol) was added a
CH3CN solution (1.0 mL) of Sc(OTf)3 (25 mg, 0.05 mmol)
at room temperature. The mixture was stirred for 30 min.
After aqueous workup as described above, the crude product
was purified by column chromatography on silica gel (1:1
hexane/EtOAc) to give 4 (120 mg, 96%).
3.11. Competition reaction (Scheme 3)
To a mixed solution of CH3CN (19.0 mL) and THF
(5.0 mL) containing 8 (146 mg, 0.50 mmol), 12 (0.12 mL,
0.60 mmol) and 9 (0.04 mL, 0.15 mmol) was added a
CH3CN solution (1.0 mL) of Sc(OTf)3 (25 mg, 0.05 mmol)
at room temperature. The mixture was stirred for 2 h. After
aqueous workup as described above, the crude product was
purified by column chromatography on silica gel to give 11
(78 mg, 47%) (17:3 hexane/EtOAc) and 15 (56 mg, 31%)
(17:3 hexane/EtOAc). When 0.2 equiv. of 12 was
employed, 11 (87%) and only a trace amount (,1%) of
15 were obtained.
3.6. Competition reaction (Table 2, entry 2)
A similar reaction employing 1 (91 mg, 0.50 mmol), 8
(146 mg, 0.50 mmol) and 9 (0.04 mL, 0.15 mmol) furnished
10 (28 mg, 25%) (column chromatography on silica gel; 19:1
hexane/EtOAc) and 11 (122 mg, 73%) (column chromatog-
raphy on silica gel; 17:3 hexane/EtOAc), respectively.
3.7. Shotgun process (Table 2, entry 3; Eq. (2))
To a mixed solution of CH3CN (19.0 mL) and THF
(5.0 mL) containing 1 (91 mg, 0.50 mmol), 8 (146 mg,
0.50 mmol), 3 (0.12 mL, 0.60 mmol) and 9 (0.04 mL,
0.15 mmol) was added a CH3CN solution (1.0 mL) of
Sc(OTf)3 (25 mg, 0.05 mmol) at room temperature. The
3.12. Reaction of 16 with 9 (Table 3, entry 1)
To a suspension of Sc(OTf)3 (98 mg, 0.20 mmol) in CH2Cl2
(5.0 mL) were added a CH2Cl2 solution (1.0 mL) of 16

5576
Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
(153 mg, 0.50 mmol) and a CH2Cl2 (1.0 mL) solution of 9
(0.04 mL, 0.15 mmol) in succession at 08C. The reaction
mixture was stirred for 12 h at this temperature. After water
had been added, the reaction mixture was extracted with
EtOAc. The combined organic layer was washed with 1N
HCl, sat. aqueous NaHCO3 and brine. The crude product
after drying (Na2SO4), filtration and evaporation was
purified by column chromatography on silica gel (2:3
hexane/EtOAc) to give 17 (115 mg, 66%).
3.18. Shotgun process (Eq. (9))
To a CH2Cl2 suspension (3.0 mL) of Sc(OTf)3 (74 mg,
0.15 mmol) was added a CH2Cl2 solution (1.0 mL)
containig dimethyl maleate (144 mg, 1.00 mmol) and
benzaldehyde (106 mg, 1.00 mmol) followed by a CH2Cl2
solution (1.0 mL) containing 5 (0.12 mL, 1.50 mmol) and 9
(0.07 mL, 0.30 mmol) at 08C. The reaction mixture was
stirred for 12 h at this temperature. After workup as
described in Section 3.12, GLC analysis of the crude
product indicated the formation of 22 and 24 in 93 and 80%
yields, respectively.
3.13. Shotgun process (Table 3, entry 4)
To a suspension of Sc(OTf)3 (98 mg, 0.20 mmol) in CH2Cl2
(5.0 mL) were added a CH2Cl2 solution (1.0 mL) of 16
(153 mg, 0.50 mmol) and a CH2Cl2 solution (1.0 mL)
3.19. Shotgun process (Eq. (10))
containing
5
(0.12 mL, 1.50 mmol),
9
(0.04 mL,
A similar reaction employing octanol (130 mg, 1.00 mmol),
benzaldehyde (106 mg, 1.00 mmol), 18 (0.19 mL,
2.00 mmol) and 9 (0.07 mL, 0.30 mmol) provided 23 and
25 in 89 and 96% yields (on the basis of GLC), respectively.
0.15 mmol) and 18 (0.09 mL, 1.0 mmol) in succession at
08C. The reaction mixture was stirred for 24 h at this
temperatue. After workup as done in Section 3.12, the crude
product was purified by column chromatography on silica
gel (4:1 hexane/EtOAc) to give 19 (202 mg, 81%).
3.20. Diels–Alder reaction in the presence of Ac2O (Eq.
(11))
3.14. Reaction of 16 with 5 and 9 (Table 3, entry 5)
To a CH2Cl2 suspension (3.0 mL) of Sc(OTf)3 (197 mg,
0.40 mmol) was added a CH2Cl2 solution (1.0 mL) of
dimethyl maleate (144 mg, 1.00 mmol) followed by a
To a suspension of Sc(OTf)3 (98 mg, 0.20 mmol) in CH2Cl2
(5.0 mL) were added a CH2Cl2 solution (1.0 mL) of 16
(153 mg, 0.50 mmol) and a CH2Cl2 solution (1.0 mL)
containing 5 (0.12 mL, 1.50 mmol) and 9 (0.04 mL,
0.15 mmol) in succession at 08C. The reaction mixture
was stirred for 24 h at this temperatue. After workup as done
in Section 3.12, the crude product was purified by column
chromatography on silica gel (2:3 hexane/EtOAc) to give 20
(164 mg, 79%).
CH2Cl2 solution (1.0 mL) containing
5 (0.17 mL,
2.00 mmol) and 18(0.09 mL, 1.00 mmol) at 08C. The reaction
mixture was stirred for 12 h at this temperature. After workup
as described in Section 3.1, GLC analysis of the crude product
indicated the formation of 22 in 81% yield.
3.21. Diels–Alder reaction after mixing of Sc(OTf)3 and
Ac2O (Eq. (12))
3.15. Reaction of 16 with 9 and 18 (Table 3, entry 6)
A CH2Cl2 suspension (4.0 mL) containing Sc(OTf)3
(197 mg, 0.40 mmol) and 18 (0.09 mL, 1.00 mmol) was
stirred at 08C for 10 min. A CH2Cl2 solution (1.0 mL) of
dimethyl maleate (144 mg, 1.00 mmol) and 5 (0.17 mL,
2.00 mmol) was added, and the mixture was stirred at 08C
for 12 h. After workup as above, GLC analysis of the crude
product indicated the formation of 22 in 35% yield.
A similar reaction employing 9 (0.04 mL, 0.15 mmol) and
18 (0.09 mL, 1.00 mmol) furnished 21 (173 mg, 80%) after
column chromatography on silica gel (7:3 hexane/EtOAc).
3.16. Diels–Alder reaction in the presence of aldehyde
(Eq. (7))
To a CH2Cl2 (3.0 mL) of suspension of Sc(OTf)3 (74 mg,
0.15 mmol) was added a CH2Cl2 solution (1.0 mL) of
dimethyl maleate (144 mg, 1.00 mmol) and benzaldehyde
(106, mg, 1.00 mmol) followed by a CH2Cl2 solution
(1.0 mL) of 5 (0.12 mL, 1.50 mmol) at 08C. The
reaction mixture was stirred for 12 h at this temperature.
After workup as described in Section 3.1, GLC analysis of
the crude product indicated the formation of 22 in 55%
yield.
3.22. Determination of time-conversion relationship in
triple-track shotgun process (Fig. 1)
The shotgun reaction under the standard conditions was
quenched with Me2NNH2. Column chromatography pro-
vided four fractions consisting of mixtures of 19/21, 26/27,
28/29, and17/20, respectively. Theyieldofeachproductinthe
mixtures was determined on the basis of NMR spectra.
3.23. Shotgun process (Eq. (13))
3.17. Acetylation in the presence of aldehyde (Eq. (8))
To a CH2Cl2 (3.0 mL) suspension containing Sc(OTf)3
(197 mg, 0.40 mmol) was added a CH2Cl2 solution
(1.0 mL) of dimethyl maleate (144 mg, 1.00 mmol) and
octanol (130 mg, 1.00 mmol) followed by a CH2Cl2
solution (1.0 mL) of 5 (0.17 mL, 2.00 mmol) and 18
(0.14 mL, 1.50 mmol). The mixture was stirred at 08C for
12 h. After workup as done in Section 3.1, GLC analysis of
the crude product indicated the formation of 22 and 23 in 94
and 100% yields, respectively (based on GLC).
To a CH2Cl2 (3.0 mL) of suspension of Sc(OTf)3 (74 mg,
0.15 mmol) was added a CH2Cl2 solution (1.0 mL) of
octanol (130 mg, 1.00 mmol) and benzaldehyde (106 mg,
1.00 mmol) followed by a CH2Cl2 solution (1.0 mL) of 18
(0.19 mL, 2.0 mmol) at 08C. The reaction mixture was
stirred for 48 h at this temperature. After workup as
described in Section 3.1, GLC analysis of the crude product
indicated the formation of 23 in 75% yield.

Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
5577
3.24. Characterization of new compounds
J¼5.7, 7.3 Hz, 1H), 5.02 (s, 2H), 5.13–5.20 (m, 2H), 5.73–
5.87 (m, 1H), 6.23–6.27 (m, 2H), 7.31 (d, J¼8.4 Hz, 2H),
7.35 (d, J¼8.4 Hz, 2H). 13C NMR (125 MHz, CDCl3) d
24.7, 28.64, 28.65, 43.48, 43.50, 46.10, 46.12, 46.13, 47.96,
48.10, 48.12, 48.5, 61.7, 64.0, 65.88, 65.91, 72.9, 117.9,
125.83, 125.84, 128.18, 128.25, 134.3, 134.7, 134.9, 144.0,
172.2, 172.4. HRMS (EI) for C24H30O6 calcd 414.2042
found 414.2061.
The new compounds were characterized as follows except
the following known compounds (4,3 6,3 7,4 8,8 10,5 13,7
14,8 22,18 2419 and 2520) and commercially available 23.
3.24.1. Compound 11. 1H NMR (300 MHz, CDCl3) d
2.50–2.54 (m, 2H), 4.18 (t, J¼7.1 Hz, 1H), 5.13–5.24 (m,
2H), 5.28 (br, 1H), 5.79–5.93 (m, 1H), 7.28–7.41 (m, 5H),
7.64 (d, J¼8.4 Hz, 2H), 7.69 (d, J¼8.4 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d 40.3, 63.8, 118.1, 123.5 (q, JC–
3.24.7. Compound 21. 1H NMR (500 MHz, CDCl3) d
1.66–1.75 (m, 4H), 2.05 (s, 3H), 2.07 (s, 3H), 2.51–2.67
(m, 2H), 4.08 (t, J¼5.9 Hz, 2H), 4.16 (t, J¼5.9 Hz, 2H),
5.04–5.10 (m, 2H), 5.20 (s, 2H), 5.65–5.73 (m, 1H), 5.79
(dd, J¼6.1, 7.6 Hz, 1H), 6.26 (d, J¼11.9 Hz, 1H), 6.28 (d,
J¼11.9 Hz, 1H), 7.34 (d, J¼8.3 Hz, 2H), 7.36 (d, J¼8.3 Hz,
2H). 13C NMR (125 MHz, CDCl3) d 20.8, 21.0, 24.9, 25.0,
40.5, 63.7, 64.6, 66.6, 74.6, 118.0, 126.6, 128.5, 129.1,
130.3, 133.0, 134.7, 140.3, 164.8, 165.1, 170.0, 170.9.
HRMS (EI) for C23H28O8 calcd 432.1784 found 432.1760.
¼272.9 Hz), 125.5 (q, JC–F¼3.6 Hz), 127.3, 127.6,
F
127.8, 128.5, 133.3 (q, JC–F¼32.7 Hz), 134.3, 136.0,
141.3, 165.9. HRMS (EI) for C18H17F3N2O calcd
334.1293 found 334.1278.
3.24.2. Compound 15. 1H NMR (300 MHz, CDCl3) d 0.97
(s, 3H), 1.27 (s, 3H), 4.47 (d, J¼6.1 Hz, 1H), 6.16 (d,
J¼6.6 Hz, 1H), 7.38–7.46 (m, 5H), 7.70 (d, J¼8.6 Hz, 2H),
7.76 (d, J¼8.4 Hz, 2H). 13C NMR (125 MHz, CDCl3) d
18.8, 21.4, 47.4, 67.8, 123.6 (q, JC–F¼272.6 Hz), 124.9 (q,
JC–F¼3.6 Hz), 127.4, 128.5, 128.6, 129.3, 133.4 (q, JC–
3.24.8. Compound 26. Mixture of diastereomers. 1H NMR
(300 MHz, CDCl3) d 1.33 (d, J¼8.6 Hz, 1H), 1.48 (dt,
J¼1.8, 8.6 Hz, 1H), 1.59–1.63 (m, 4H), 2.03 (s, 3H), 2.28
(br, 1H), 2.42–2.55 (m, 2H), 3.15–3.20 (m, 2H), 3.28 (dd,
J¼2.9, 10.1 Hz, 1H), 3.34 (dd, J¼3.0, 10.2 Hz, 1H), 3.88–
4.07 (m, 4H), 4.72–4.77 (m, 1H), 4.98 (d, J¼12.3 Hz, 1H),
5.07 (d, J¼12.3 Hz, 1H), 5.12–5.20 (m, 2H), 5.74–5.88 (m,
1H), 6.22–6.27 (m, 2H), 7.29–7.36 (m, 4H). 13C NMR
(125 MHz, CDCl3) d 20.9, 25.1, 25.2, 43.8, 46.4, 48.17,
48.20, 48.7, 63.8, 64.0, 66.0, 72.9, 118.4, 125.9, 128.3,
134.3, 134.86, 134.91, 135.2, 144.0, 171.2, 172.2, 172.4.
HRMS (EI) for C26H32O7 calcd 456.2148 found 456.2159.
¼32.6 Hz), 134.5, 136.4, 164.1, 174.5. HRMS (EI) for
F
C19H17F3N2O2 calcd 362.1242 found 362.1223.
3.24.3. Compound 16. 1H NMR (300 MHz, CDCl3) d
1.56–1.79 (m, 4H), 1.88 (br, 1H), 3.65 (t, J¼6.2 Hz, 2H),
4.18 (t, J¼6.4 Hz, 2H), 5.30 (s, 2H), 6.29 (d, J¼12.0 Hz,
1H), 6.34 (d, J¼12.0 Hz, 1H), 7.55 (d, J¼8.2 Hz, 2H), 7.90
(d, J¼8.2 Hz, 2H), 10.02 (s, 1H). 13C NMR (125 MHz,
CDCl3) d 24.8, 28.9, 62.1, 65.2, 66.1, 128.4, 128.8, 129.9,
130.8, 136.1, 141.8, 164.8, 165.1, 191.8. HRMS (EI) for
C16H18O6 calcd 306.1103 found 306.1093.
3.24.9. Compound 27. 1H NMR (500 MHz, CDCl3) d
1.65–1.72 (m, 4H), 2.04 (s, 3H), 2.23 (br, 1H), 2.45–2.55
(m, 2H), 4.03 (t, J¼5.9 Hz, 2H), 4.15 (t, J¼5.9 Hz, 2H),
4.75 (dd, J¼5.2, 7.6 Hz, 1H), 5.14–5.19 (m, 2H), 5.21 (s,
2H), 5.76–5.85 (m, 1H), 6.26 (d, J¼11.9 Hz, 1H), 6.28 (d,
J¼11.9 Hz, 1H), 7.37 (s, 4H). 13C NMR (125 MHz, CDCl3)
d 20.9, 24.96, 25.03, 43.7, 63.8, 64.7, 66.8, 72.8, 118.4,
126.0, 128.5, 129.1, 130.3, 134.2, 144.4, 164.8, 165.2,
171.1. HRMS (EI) for C21H26O7 calcd 390.1679 found
390.1666.
3.24.4. Compound 17. 1H NMR (300 MHz, CDCl3) d
1.48–1.70 (m, 4H), 2.37 (br, 1H), 2.42–2.56 (m, 2H), 3.60
(t, J¼6.2 Hz, 2H), 4.11 (dt, J¼2.1, 6.5 Hz, 2H), 4.75 (dd,
J¼5.3, 7.5 Hz, 1H), 5.13–5.20 (m, 4H), 5.74–5.87 (m, 1H),
6.24 (d, J¼12.0 Hz, 1H), 6.29 (d, J¼12.0 Hz, 1H), 7.37 (s,
4H). 13C NMR (75 MHz, CDCl3) d 24.6, 28.5, 43.4, 61.6,
65.0, 66.7, 72.8, 117.9, 125.9, 128.4, 128.7, 130.4, 134.0,
134.2, 144.3, 164.8, 165.2. HRMS (EI) for C19H24O6 calcd
348.1573 found 348.1598.
3.24.5. Compound 19. Mixture of diastereomers. 1H NMR
(300 MHz, CDCl3) d 1.33 (d, J¼8.4 Hz, 1H), 1.48 (dt,
J¼1.8, 8.7 Hz, 1H), 1.63–1.66 (m, 4H), 2.04 (s, 3H), 2.07
(s, 3H), 2.49–2.69 (m, 2H), 3.17–3.18 (m, 2H), 3.29 (dd,
J¼3.1, 10.3 Hz, 1H), 3.34 (dd, J¼2.7, 10.2 Hz, 1H), 3.88–
4.08 (m, 4H), 4.95 (d, J¼12.5 Hz, 1H), 5.03–5.11 (m, 3H),
5.62–5.76 (m, 1H), 5.79 (dd, J¼6.1, 7.5 Hz, 1H), 6.23 (d,
J¼6.4 Hz, 1H), 6.26 (d, J¼7.0 Hz, 1H), 7.31 (s, 4H). 13C
NMR (125 MHz, CDCl3) d 20.8, 21.0, 25.0, 25.2, 40.5,
46.2, 46.3, 48.00, 48.04, 48.6, 63.7, 63.8, 65.77, 65.78, 74.7,
118.0, 126.5, 128.21, 128.25, 133.0, 134.71, 134.72, 134.8,
135.6, 139.93, 139.94, 170.0, 170.9, 172.1, 172.3. HRMS
(EI) for C28H34O8 calcd 498.2254 found 498.2277.
3.24.10. Compound 28. Mixture of diastereomers. 1H NMR
(300 MHz, CDCl3) d 1.32 (d, J¼8.6 Hz, 1H), 1.46–1.65 (m,
5H), 2.07 (s, 3H), 2.48–2.69 (m, 2H), 3.15–3.19 (m, 2H),
3.26–3.36 (m, 2H), 3.61 (t, J¼5.5 Hz, 2H), 3.86–4.05 (m,
2H), 4.97 (d, J¼12.5 Hz, 1H), 5.03–5.11 (m, 3H), 5.62–
5.80 (m, 2H), 6.25 (t, J¼1.7 Hz, 2H), 7.31 (s, 4H). 13C NMR
(125 MHz, CDCl3) d 21.1, 24.9, 29.1, 40.6, 46.28, 46.36,
46.38, 48.18, 48.20, 48.6, 62.2, 64.16, 64.18, 65.8, 65.9,
74.88, 74.90, 118.1, 126.6, 128.2, 128.4, 133.1, 134.78,
134.81, 134.88, 134.91, 135.68, 135.70, 139.97, 140.01,
170.2, 170.3, 172.3, 172.4. HRMS (EI) for C26H32O7 calcd
456.2148 found 456.2170.
1
3.24.11. Compound 29. H NMR (300 MHz, CDCl3) d
3.24.6. Compound 20. Mixture of diastereomers. 1H NMR
(300 MHz, CDCl3) d 1.32 (d, J¼8.6 Hz, 1H), 1.43–1.60 (m,
5H), 2.42–2.57 (m, 2H), 3.14–3.19 (m, 2H), 3.27 (ddd,
J¼0.8, 3.1, 10.2 Hz, 1H), 3.34 (ddd, J¼2.2, 3.1, 10.1 Hz,
1H), 3.56 (t, J¼6.1 Hz, 2H), 3.80–3.99 (m, 2H), 4.73 (dd,
1.53–1.76 (m, 4H), 2.07 (s, 3H), 2.49–2.69 (m, 2H), 3.63 (t,
J¼6.2 Hz, 2H), 4.15 (t, J¼6.4 Hz, 2H), 5.04–5.11 (m, 2H),
5.20 (s, 2H), 5.62–5.76 (m, 1H), 5.78 (dd, J¼6.1, 7.6 Hz,
1H), 6.24 (d, J¼12.0 Hz, 1H), 6.29 (d, J¼12.0 Hz, 1H), 7.33
(d, J¼8.7 Hz, 2H), 7.36 (d, J¼8.7 Hz, 2H). 13C NMR

5578
Y. Nagano et al. / Tetrahedron 59 (2003) 5569–5578
(c) Chen, J.; Sakamoto, K.; Orita, A.; Otera, J. Tetrahedron
1998, 54, 8411.
(75 MHz, CDCl3) d 21.1, 24.8, 28.9, 40.6, 62.1, 65.1, 66.7,
74.9, 118.1, 126.7, 128.6, 128.9, 130.6, 133.0, 134.8, 140.4,
164.9, 165.2, 170.3. HRMS (EI) for C21H26O7 calcd
390.1679 found 390.1679.
10. The reaction of 8 with 12 provided cyclized product 15 under
these conditions.
11. (a) Kobayashi, S.; Wakabayashi, T.; Oyamada, H. Chem. Lett.
1997, 831. (b) Hachiya, I.; Kobayashi, S. J. Org. Chem. 1993,
58, 6958.
References
12. (a) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H.
J. Org. Chem. 1996, 61, 4560. (b) Ishihara, K.; Kubota, M.;
Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc. 1995, 117,
4413.
1. Nagano, Y.; Orita, A.; Otera, J. Tetrahedron 2002, 58, 8211.
2. A part of this study appeared in a preliminary form: Orita, A.;
Nagano, Y.; Nakazawa, K.; Otera, J. Synlett 2000, 599.
3. Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis 1995,
1195.
13. With catalyst concentration lower than 40%, the Diels–Alder
reaction did not complete.
4. (a) Kobayashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994,
59, 3758. (b) Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani, H.
Tetrahedron Lett. 1993, 34, 3755. (c) Kobayashi, S.; Hachiya,
I.; Takahori, T.; Araki, M.; Ishitani, H. Tetrahedron Lett.
1992, 33, 6815.
14. The reaction was quenched with Me2NNH2 because allylation
with 9 takes place in the presence of water.11
15. For analysis of the products, see Section 3.
16. Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, 1990.
5. For reaction of imine with allyltributyltin: Bellucci, C.; Cozzi,
P. G.; Umani-Ronchi, A. Tetrahedron Lett. 1995, 36, 7289.
6. Kobayashi, S.; Sugita, K.; Oyamada, H. Synlett 1999, 138.
7. Kobayashi, S.; Araki, M.; Ishitani, H.; Nagayama, S.; Hachiya,
I. Synlett 1995, 233.
17. Nagano, Y.; Orita, A.; Otera, J. Adv. Synth. Catal. 2003, 345,
643.
18. Pagni, R. M.; Kabalka, G. W.; Hondrogiannis, G.; Bains, S.;
Anosike, P.; Kurt, R. Tetrahedron 1993, 49, 6743.
19. Davis, A. P.; Jaspars, M. J. Chem. Soc., Perkin Trans. 1 1992,
2111.
8. (a) Kobayashi, S.; Furuta, T.; Sugita, K.; Oyamada, H. Synlett
1998, 1019. (b) Oyamada, H.; Kobayashi, S. Synlett 1998, 249.
9. (a) Chen, J.; Otera, J. Angew. Chem. Int. Ed. Engl. 1998, 37,
91. (b) Chen, J.; Otera, J. Tetrahedron Lett. 1998, 39, 1767.
20. Falck, J. R.; Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995, 117,
5973.